Peptide drug conjugates for targeted therapy of kidney diseases

Abstract

The present invention provides therapeutic compounds of formula I, which are therapeutic or anti-cancer agents: [Case 1] TIFF2026502619000119.tif54160 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, pharmaceutical compositions containing them, methods of using them, and methods for preparing these compounds are provided.

Description

[Technical Field]

[0001] Provided herein are novel bioactive compounds, pharmaceutical compositions thereof, methods of their use, and methods for their preparation. These novel agents and compositions thereof have therapeutic activity useful in the treatment of inflammatory kidney disorders, particularly chronic kidney disease (CKD), systemic lupus erythematosus (SLE), diabetic nephropathy, chronic glomerulonephritis, and acute kidney injury (AKI). [Background technology]

[0002] Kidney disease encompasses various classes of serious kidney disorders that significantly impact human lives worldwide. Renal inflammation can result from a variety of exogenous and endogenous factors, including exposure to nephrotoxic substances, surgical procedures (e.g., kidney transplants), chemotherapy (e.g., in the treatment of cancer, diabetes, or infections), infections (e.g., urinary tract infections and pyelonephritis), and certain chronic conditions. Among these, acute and chronic kidney disease (e.g., CKD) has been reported to be a global epidemic (e.g., as reviewed in, e.g., Levey et al., Kidney Int., 2005, pp. 2089-2100 and Stenvinkel, J. Intern. Med., 2010, 268, pp. 456-467). Unfortunately, the long-term treatment of CKD required to manage this medical condition typically involves severe side effects that generally result in unsatisfactory outcomes and poor patient compliance.

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

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

[0005] Importantly, many side effects that limit the use of current drugs and the development of new drugs are related to excessively wide systemic exposure to such bioactive molecules. In other words, bioactive agents that target kidney disease and are administered orally or intravenously will inevitably circulate in the bloodstream of mammals or patients requiring such treatment before reaching the kidney. This undesirable but unavoidable distribution of bioactive molecules throughout various body compartments and to organs other than the kidney results in off-target effects, which typically manifest as adverse events.

[0006] Therefore, targeted renal drug delivery, which involves selective transport of bioactive molecules to the kidney, is preferable to conventional treatments that necessarily involve exposure of other organs to the drug, which may induce side effects in non-renal compartments. This allows the bioactive effects of the drug to be applied directly to the site of kidney disease, thereby widening the therapeutic window of the drug, reducing systemic side effects, and improving the efficiency of such treatments.

[0007] Several renal drug delivery systems (also called renal vectors or molecular delivery systems) have been described, which target structures into renal tissue. For example, peptide carrier structures have been described in the publications Molecular Therapy, 2007, pp.1647-1654, Bioconjugate Chem. 2012, pp.1200-1210, Bioconjugate Chemistry, 2016, pp.1050-1057, and U.S. Patent No. 10,413,614. Other molecular delivery systems that act as renal vectors include polymers such as polyvinylpyrrolidone (Nat. Biotechnol. 2003, pp. 399-404), chitosan (J. Drug Target, 2007, pp. 269-278), glucosamine (J. Controlled Release, 2013, pp. 148-156), and proteins (e.g., as described in J. Med. Chem., 1992, pp. 1246-1259; and Int. J. Nanomedicine, 2017, pp. 5673-5686).

[0008] Another category of drugs for targeted therapy of kidney disorders includes prodrugs that selectively release bioactive drug structures by kidney-associated enzymes (see, e.g., J. Controlled Release, 2013, pp. 148-156; and RSC Adv. 4, 2014, pp. 50828-50831).

[0009] Among serious kidney disorders, CKD is recognized as a global public health problem. Over time, this chronic condition can progress to debilitating end-stage renal disease. Ultimately, life-sustaining options are limited to time-consuming and expensive kidney dialysis and / or kidney transplantation. The serious situation is exacerbated by the absence or shortage of dialysis stations in many parts of the world. Therefore, there is an unmet medical need for CKD treatments that can prevent end-stage renal disease through improved treatment and disease management (e.g., as reviewed in Perico et al., Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24).

[0010] CKD is a complex disease associated with multiple contributing factors. Among the major contributing factors is inflammation, which often results from the overexpression of proinflammatory mediators such as endothelin-1, monocyte chemoattractant protein-1, normal T cells, and osteopontin (Perico et al., Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24). Acute kidney injury (AKI) is another risk factor associated with CKD (see, for example, Campbell et al., J. Clin. Hypertension, 2015, 17, pp. 514-527). Furthermore, AKI can also manifest independently of CKD, for example, as a result of exposure to nephrotoxins, such as nephrotoxic proinflammatory substances. In kidney transplantation, renal ischemia-reperfusion injury is the primary etiology of AKI. Similar to the pathogenesis of CKD, renal inflammation plays a major role in the pathophysiology of ischemic AKI (reviewed, for example, in Bonventre and Zuk, Kidney Int. 2004, 66, pp. 480-485).

[0011] Subsequently, certain anti-inflammatory drugs are used to treat CKD and AKI. For example, anti-inflammatory therapy with the corticosteroid dexamethasone was reported by Moonen et al., BMC Nephrology. 2018, 19:343.

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

[0013] However, long-term exposure to most anti-inflammatory drugs, such as steroids and NSAIDs (nonsteroidal anti-inflammatory drugs), is associated with serious side effects, including bone mineral density loss, cataracts, or muscle weakness. Therefore, safer and more effective drugs are needed for the treatment of CKD, SLE, LN, AKI, and various other inflammatory kidney diseases or kidney damage. Such treatments must have improved selectivity, directing the drug's bioactive effects to the site of disease and thus minimizing or eliminating side effects due to off-target toxicity caused by exposure of healthy tissues and organs.

[0014] One recent approach to achieving improved drug selectivity is targeted delivery of highly active agents directly to the kidney (e.g., as reviewed in Wischnjow et al., Bioconjugate Chemistry, 2016, pp. 1050-1057). In this approach, an active agent (such as an antibacterial agent) is connected (or conjugated) to an organ-targeting structure that has high affinity for kidney cells. As a result, the active agent or drug is selectively delivered to the organ requiring treatment.

[0015] The present invention provides unique conjugates of specific anti-inflammatory agents with acyclic and cyclic peptides (cyclopeptides) suitable for targeted therapy of various renal diseases. Conjugation (covalent bonding) of bioactive agents to peptides is achieved through the careful design of appropriate linking groups (linkers) and additional structural elements (such as connectivity-altering spacers) that help maximize targeted delivery and therapeutic bioactivity. The agents provided herein are particularly suitable for the treatment of CKD, AKI, and other non-cancer renal disorders.

[0016] Various cyclopeptides are disclosed, for example, in WO 2019136298, WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, U.S. Patent Application Publication No. 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, Chinese Patent No. 103923190, U.S. Patent Application Publication No. 2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, Chinese Patent No. 103130876, WO 2014 / 0031602 ...0031602, WO 2014 / 0031602, WO 2014 / 0031602, WO 2014 / 0031602, WO 2014 / 0031602, WO 2014 / 0031602, WO 2014 / 0031602, WO 2014 / 003160 No. 2013 / 072695, WO 2012 / 168820, WO 2012051663, U.S. Patent Application Publication No. 2012 / 0316105, U.S. Patent Application Publication No. 2012 / 0283176, U.S. Patent Application Publication No. 2010 / 0160215, U.S. Patent Application Publication No. 2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, U.S. Patent Application Publication No. 2006 / 0004185, U.S. Patent No. 6,380,356, and U.S. Patent No. 3,450,687. Specific conjugates of acyclic peptide structures for kidney-targeted delivery of protective agents against nephrotoxic substances are described, for example, in U.S. Patent No. 10,413,614. None of these references specifically describe or generally contemplate the compositions provided herein. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] International Publication No. 2021 / 150792 [Patent Document 2] U.S. Patent Application Publication No. 2018 / 155389 [Patent Document 3] U.S. Patent Application Publication No. 2019 / 167804 [Patent Document 4] International Publication No. 2023 / 280227 [Patent Document 5] International Publication No. 2022 / 150637 Summary of the Invention [Problem to be solved by the invention]

[0018] Provided herein are novel compounds and compositions useful for targeted therapy of inflammatory renal disorders. [Means for solving the problem]

[0019] These novel compounds demonstrate a surprising ability to target renal tissues, particularly renal cells, affected by inflammation, including inflammation resulting from the overexpression of endogenous proinflammatory mediators, or inflammation induced by exogenous nephrotoxic substances, or inflammation caused by another therapeutic agent (such as a cytotoxic anticancer agent or a nephrotoxic antibacterial agent). This unique affinity of the compositions herein for renal tissues affected by renal damage makes it possible to achieve selective delivery and accumulation of the molecules at the diseased site while minimizing or eliminating accumulation of these therapeutic agents in other tissues not affected by the medical condition.

[0020] As a result, selective and generally safer renal therapy is achieved while significantly minimizing side effects on other normal organs of the mammal being treated compared to current standard therapeutic agents used to treat inflammatory kidney diseases, such as steroids and NSAIDs.

[0021] In one aspect of the present invention, the therapeutic effect of the compounds herein is achieved by the release of one or more anti-inflammatory elements (bioactive payloads and / or drugs) incorporated into these designer molecules. The active payloads (drugs) may include steroid structures, NSAID structures, or immunomodulatory structures. These are selected from bioactive structures with the ability to suppress or counteract inflammation (such as inflammation due to AKI or in transplant surgery, or inflammation induced by cytokines), or similarly activate immunomodulation of a therapeutic anti-inflammatory response.

[0022] In general, the compounds provided herein contain, within a single conjugate molecule, a peptide, cyclopeptide, or other "target seeker" (ligand) structure with high affinity (ability to bind) to kidney cells, along with an active drug moiety. The active drug (payload) is connected to the kidney-affinity structure via a specially designed linker and spacer framework. This unique design allows for efficient release of the active drug (payload) directly into kidney tissue, resulting in a therapeutic anti-inflammatory effect.

[0023] In another embodiment, the composition possesses anti-inflammatory properties in the molecular form of the intact conjugate without release of the active drug (payload) (contained within the structure) at the site of nephritis. Upon accumulation at the site of nephritis, the compound exerts its anti-inflammatory effect directly. In a related embodiment, the conjugate is degraded to generally non-toxic metabolites after exerting the desired bioactive effect. In yet another aspect, the anti-inflammatory effect is achieved by the combined effect of (i) the direct anti-inflammatory effect of the compound (upon accumulation at the cancer site) and (ii) the release of the active payload (drug) contained within the structure.

[0024] In additional embodiments, either the intact conjugate and / or the drug released from the conjugate in the kidney exhibits a protective effect against nephrotoxic agents, such as cytotoxic anti-cancer drugs.

[0025] Surprisingly, certain compounds and compositions provided herein lack significant antibiotic and / or other biological activity and exert the desired anti-inflammatory effect only on kidneys affected by renal disease.

[0026] Furthermore, while certain compositions provided herein incorporate cyclopeptide moieties (structures) from a chemical class (such as polymyxins) that are generally known to cause nephrotoxicity, the therapeutic compounds of the present invention exhibit little or no nephrotoxicity at the therapeutic dosage levels required to treat inflammatory renal disorders.

[0027] Those skilled in the art will understand that not all molecular constructs incorporating an anti-inflammatory element (payload) with a "heatseeker" affinity structure (a ligand that targets kidney cells) with an appropriate linker and a purposefully positioned spacer (strategically placed between the ligand and the biologically active payload) are suitable for use as a therapeutic. Surprisingly, the compounds and compositions provided herein have a favorable pharmacological profile, with adequate stability in plasma that prevents premature biological activity, coupled with their preferential accumulation in kidney cells and / or kidneys affected by inflammatory kidney damage.

[0028] Even more surprisingly, certain compounds provided herein exert their bioactive effects by self-targeting delivery directly to inflamed kidney cells or only in the vicinity of inflamed tissues. In part, the compositions comprise a class of molecules that can specifically release an anti-inflammatory payload (incorporated within their structure) as a result of metabolic cleavage by enzyme classes (cathepsins, glutaminases, glutathione transferases, and peptide deformylases or PDFs, peptidases, reductases, and similar known enzymes) that are specific to or overexpressed (enriched) in inflamed kidney cells.

[0029] In addition to metabolic degradation by overexpressed enzyme classes (e.g., cathepsins, glutaminases, PDFs) in inflamed kidney cells, certain compounds provided herein are degraded in vivo through chemical cleavage, such as the pH-dependent autocleavage known for molecules bearing both a cleavable group (e.g., an ester, amide, or carbamate group) and a free nucleophilic group (e.g., an amine, alcohol, or thiol group). When these two types of cleavable group and the nucleophilic group are in certain spatial proximity to each other and the nucleophilic group is essentially free (e.g., an amine group under neutral, basic, or physiological pH conditions), the nucleophilic group may be acylated by an ester group, resulting in the transfer of the acyl group to the nucleophilic atom (e.g., the nitrogen atom in the amine group). Alternatively or additionally to the above process(es), the free amine may activate an amide functional group adjacent to the carbamate group, inducing reaction of the carbamate with that functional group, resulting in the conversion of the original amide to a bis-acylated imide group. In some compositions herein, cleavage of the chemical designer linker occurs after initial enzymatic metabolism of an auxiliary enzyme-cleavable linker (e.g., a peptide moiety, etc.), resulting entirely in the release of the anti-inflammatory payload within renal tissue.

[0030] In one aspect, provided herein are compounds of formula I:

[0031] [ka]

[0032] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R 1 is X 1 and at any one of the H-containing groups independently selected from NH, NH, OH, and SH, 1 formed by subtracting a single H atom from H, R 1 H is selected from compounds that have or can induce glucocorticoid receptor (GR) activity modulating activity; Array-X 1-X 2 -X 3 -X integrally connected to 1 , X 2 , and X 3 each group comprises a cleavable linker, X 1 is absent or is -CHNH-, -C(=O)NHC(=O)C 1~6 alkylene NH-,

[0033] [ka]

[0034] and

[0035] [ka]

[0036] and wherein X is selected from the group consisting of 1 The left side of the group is R 1 is bound to X 2 is either absent or comprises an amino acid or a peptide residue of 1 to 6 amino acids selected from alpha-, beta- or gamma-amino acids, 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, unsubstituted or substituted at any N atom, and 2 The carbonyl end of the group is X 1 or R 1 (X 1 is not present), X 3 -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-, and X 3 The left side of the group is X 1 Group(X 2(if no group is present) or X 2 is bonded to the group, R 2 is a 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 Alkyleneheteroarylene, C 1~3 Alkyleneheteroarylene 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 -, and R 2 is unsubstituted C 1~6 When it is alkylene, X 1 or X 2 exists, or R 2 is substituted C 1~6 When R is alkylene, 2 is 1 to 4 R 14 is replaced by R 3 is absent or is NH, N(C 1~6 alkylene) and C 1~6 alkylene; R 4 is absent or is an arylene, heteroarylene, C(C 3~10 Cycloalkylene)2, C 3~10 Cycloalkylene, heterocycloalkylene, and (OCH2CH2O) q and R 5 does not exist or C1~6 alkylene, R 6 does not exist or is OC 1~6 Alkylene and

[0037] [ka]

[0038] and R 13 does not exist or C 1~12 Alkylene, C 3~10 Cycloalkylene, C 3~10 Cycloalkylene C 1~6 is any one selected from the group consisting of alkylene, heterocycloalkylene, heteroarylene, and arylene; R 13 is 1 to 4 R 15 and optionally substituted with R 14 independently, -C 0~3 Alkylene-Polyethylene Glycol, Halo, OH, NH2, SH, CN, C 3~10 Cycloalkyl, C 1~8 selected from the group consisting of alkoxy, aryl, and heteroaryl; R 15 are independently halo, OH, NH2, SH, C 3~10 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; A 8 ~A 11are alpha-, beta- or gamma-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-Glu, 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, azetidine-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-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid any amino acid residue independently selected from residues of bicyclo[3.2.1]octane-2-carboxylic acid, 6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 3-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, and 4-amino-6-azabicyclo[3.1.1]heptane-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 t-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.

[0039] In another embodiment, a compound of formula Ia

[0040] [ka]

[0041] 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. In another embodiment, a compound of formula Ib

[0042] [ka]

[0043] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R a is CH2CH(CH3)2 or CH2Ph.

[0044] In another embodiment, the compound of formula R 1 -X 1 -X 2 -X 3 Drug-linker intermediate compounds are provided, represented by —OH, wherein: R 1 is X 1 and at any one of the H-containing groups independently selected from NH, NH, OH, and SH, 1 formed by subtracting a single H atom from H, R 1 H is selected from compounds that have or can induce glucocorticoid receptor (GR) activity modulating activity; Array-X 1 -X 2 -X 3 -X integrally connected to 1 , X 2 , and X 3 each group comprises a cleavable linker, X 1 is absent or is -CHNH-, -C(=O)NHC(=O)C 1~6 alkylene NH-,

[0045] [ka]

[0046] and

[0047] [ka]

[0048] and wherein X is selected from the group consisting of 1 The left side of the group is R 1 is bound to X 2 is either absent or comprises an amino acid or a peptide residue of 1 to 6 amino acids selected from alpha-, beta- or gamma-amino acids, 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, unsubstituted or substituted at any N atom, and 2 The carbonyl end of the group is X 1 or R 1 (X 1 is not present), X 3 -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-, and X 3 The left side of the group is X1 Group(X 2 (if no group is present) or X 2 is bonded to the group, R 2 is a 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 Alkyleneheteroarylene, C 1~3 Alkyleneheteroarylene 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 -, and R 2 is unsubstituted C 1~6 When it is alkylene, X 1 or X 2 exists, or R 2 is substituted C 1~6 When R is alkylene, 2 is 1 to 4 R 14 is replaced by R 3 is absent or is NH, N(C 1~6 alkylene) and C 1~6 alkylene; R 4 is absent or is an arylene, heteroarylene, C(C 3~10 Cycloalkylene)2, C 3~10 Cycloalkylene, heterocycloalkylene, and (OCH2CH2O) q and R5 does not exist or C 1~6 alkylene, R 6 does not exist or is OC 1~6 Alkylene and

[0049] [ka]

[0050] and R 13 does not exist or C 1~12 Alkylene, C 3~10 Cycloalkylene, C 3~10 Cycloalkylene C 1~6 alkylene, heterocycloalkylene, heteroarylene, or arylene; R 13 is 1 to 4 R 15 and optionally substituted with R 14 independently, -C 0~3 Alkylene-Polyethylene Glycol, Halo, OH, NH2, SH, CN, C 3~10 Cycloalkyl, C 1~8 selected from the group consisting of alkoxy, aryl, and heteroaryl; R 15 are independently halo, OH, NH2, SH, C 3~10 selected from 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.

[0051] In another embodiment, the compound of the formula: -X 1 -X 2 -X 3 - A linker for obtaining a peptide-drug conjugate is provided, in which a drug (preferably, the drug is dexamethasone or a variant thereof) is conjugated to a peptide (preferably, the peptide is PMBN, PMBH, or a variant thereof) via the linker, the linker being represented by the formula: X 1 is absent or is -CHNH-, -C(=O)NHC(=O)C 1~6 alkylene NH-,

[0052] [ka]

[0053] and

[0054] [ka]

[0055] and wherein X is selected from the group consisting of 1 The left side of the group is R 1 is bound to X 2 is either absent or comprises an amino acid or a peptide residue of 1 to 6 amino acids selected from alpha-, beta- or gamma-amino acids, 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, unsubstituted or substituted at any N atom, and 2 The carbonyl end of the group is X 1 is bound to X 3 -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-, and X 3 The left side of the group is X 1 Group(X 2(if no group is present) or X 2 is bonded to the group, R 2 is a 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 Alkyleneheteroarylene, C 1~3 Alkyleneheteroarylene 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 -, and R 2 is unsubstituted C 1~6 When it is alkylene, X 1 or X 2 exists, or R 2 is substituted C 1~6 When R is alkylene, 2 is 1 to 4 R 14 is replaced by R 3 is absent or is NH, N(C 1~6 alkylene) and C 1~6 alkylene; R 4 is absent or is an arylene, heteroarylene, C(C 3~10 Cycloalkylene)2, C 3~10 Cycloalkylene, heterocycloalkylene, and (OCH2CH2O) q and R 5 does not exist or C1~6 alkylene, R 6 does not exist or is OC 1~6 Alkylene and

[0056] [ka]

[0057] and R 13 does not exist or C 1~12 Alkylene, C 3~10 Cycloalkylene, C 3~10 Cycloalkylene C 1~6 alkylene, heterocycloalkylene, heteroarylene, or arylene; R 13 is 1 to 4 R 15 and optionally substituted with R 14 independently, -C 0~3 Alkylene-Polyethylene Glycol, Halo, OH, SH, CN, C 3~10 Cycloalkyl, C 1~8 selected from the group consisting of alkoxy, aryl, and heteroaryl; R 15 are independently halo, OH, NH2, SH, C 3~10 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; The integer q is selected from 1 to 10; The integer p is independently selected from 1 and 2.

[0058] In another embodiment, X 2 is either absent or comprises amino acid or peptide residues selected from Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Glu-Gly, Asp-Val-Glu-Asp, Ala-Ala-Gly, and Ala-Ala.

[0059] In another embodiment, X 2 is either absent or comprises amino acid or peptide residues selected from Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Ala-Ala-Gly, and Ala-Ala.

[0060] In another embodiment, R 2 is a 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 1~6Alkylene)-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- is selected from the group consisting of:

[0061] In another embodiment, R 14 independently, -C 0~3 Alkylene-polyethylene glycol, C 0~3 Alkylene NHC(=O)CH(NH2)C 1~6 Alkylene C(=O)OH, Halo, OH, SH, CN, C 3~10 Cycloalkyl, C 1~8 It is selected from the group consisting of alkoxy, aryl, and heteroaryl.

[0062] In another embodiment, X 3are -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)C H2-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-CH2 CH2C(=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)-,

[0063] [ka]

[0064] and

[0065] [ka]

[0066] is selected from the group consisting of:

[0067] In another embodiment, -X 1 -X 2 -X 3 is independently selected from the following structures:

[0068] [ka]

[0069] [ka]

[0070] In another embodiment, -X 1 -X 2 -X 3 is independently selected from the following structures:

[0071] [ka]

[0072] [ka]

[0073] In another embodiment, -X 1 -X 2 -X 3 To the left of - is R 1 is connected to.

[0074] In another embodiment, R 1 H is represented by formula II:

[0075] [ka]

[0076] [In formula: R 8 and R 9 are independently H, C 1~12 Alkyl, C 1~12 selected from the group consisting of alkylC(=O)O-, -OH, and halo; or R 8 and R 9 Let's get together and

[0077] [ka]

[0078] wherein E is independently selected from CH and O; When E is CH2, G is N, or when E is O, G is CH or C(C 1~6 alkyl), R 11 -WYZR 12 or -WYZC 1~6 Alkylene-R 12 and R 7 -C 1~6 Alkylene-NR i R j , -C 1~6 Alkylene -OH, -C 1~6 Alkylene-Halo, -SC 1~6 Alkylene-halo, -C 1~6 Alkylene-TWYZR 12 , and -C 1~6 Alkylene-TWYZC 1~6 Alkylene-R 12 is selected from the group consisting of R 12 is, in each occurrence independently, H, NR i R j , OH, and SH; T is S(=O), S(=O)2, S(=O)2NR i, O, S, C(=O)NR i , C(=O), and NR i is selected from the group consisting of W and Z, in each occurrence, are independently absent or independently each represent 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 is selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, optionally substituted with Y, in each occurrence, is independently absent or -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)NR 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-, R 10is, at each occurrence, independently selected from the group consisting of OH, halo, alkyl, ═O, and arylalkyl; R i and R j is, at each occurrence, independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Dotted line

[0079] [ka]

[0080] represents either a single or double bond, and n is an integer from 0 to 19.

[0081] In another embodiment, R 1 H is represented by formula IIa, IIb, IIc or IId according to Formula II.

[0082] [ka]

[0083] In another embodiment, R 1 is the structure R 1 It is derived by subtracting H from a primary alcohol CH2OH group, a phenylene -OH group, or an NH2 group in H.

[0084] In another embodiment, the bioactive agent R 1 Compounds of any of Formula I, Ia, or Ib are provided that exert a therapeutic effect after administration to a mammal by releasing H.

[0085] In another aspect, provided are compounds of any of Formula I, Ia, or Ib that have anti-inflammatory activity or a therapeutic effect against renal disease as determined by (i) a reduction or delay in renal cytokine release, such as TNF-α, IL-6, or IL-12; (ii) a reduction in one or more biomarkers (optionally, the one or more biomarkers are selected from protein levels, blood urea nitrogen, and serum creatinine); or (iii) an improvement in the condition of a mammal in a patient or animal model in need of treatment.

[0086] In another aspect, compounds of any of Formula I, Ia, or Ib are provided that have anti-inflammatory activity, wherein the anti-inflammatory activity is the treatment of renal inflammation, inflammatory conditions in renal injury or dysfunction, or inflammation induced by a nephrotoxic agent (including a pharmaceutical nephrotoxic agent such as an anti-cancer, anti-diabetic, anti-infective, or another chemotherapeutic agent).

[0087] In another embodiment, a similar dose of free agent or drug R incorporated into the compound is used as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory, or nephroprotective activity. 1 Compounds of any of Formula I, Ia, or Ib are provided that have enhanced anti-inflammatory, immunomodulatory, or nephroprotective effects when compared to H.

[0088] In yet another aspect, there is provided a compound of any of Formula I, Ia, or Ib, wherein when administered to a mammal, the compound exhibits preferential accumulation in the kidney, and the ratio of its molar concentration in the kidney to its molar concentration in the blood is between about 5 and 500.

[0089] In yet another aspect, there is provided a compound of any of Formula I, Ia, or Ib, wherein when administered to a mammal, the compound exhibits preferential accumulation in the kidney, and the ratio of its molar concentration in the kidney to its molar concentration in the blood is at least about 20.

[0090] In a further embodiment, the drug R 1When administered to a mammal in a dose (expressed in molar amounts) equal to a standard therapeutic dose (molar amount) of H, the compound reacts with the free drug R 1 Approximately 1.5 to 15 times higher tissue concentration and / or renal drug R compared to standard doses of H 1 Compounds of any of Formula I, Ia, or Ib are provided that exhibit a drug exposure (area under the curve, AUC) of H.

[0091] In an additional aspect, Drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to the standard therapeutic dose (molar amount) of H, the drug R 1 Compounds of any of Formula I, Ia, or Ib are provided that exhibit approximately 1.5-15 times greater potency than standard doses of H, with the therapeutic effect being determined as slowing, halting, or reversing the progression of inflammation (as determined by changes in cytokine release and / or biochemical biomarkers or similar methods for monitoring disease).

[0092] In another embodiment, the drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to the standard therapeutic dose (molar amount) of H, the drug R 1 Compounds of any of Formula I, Ia, or Ib are provided that exhibit at least two-fold greater efficacy compared to standard doses of H, where the therapeutic effect is determined as slowing, halting, or reversing the progression of inflammation or kidney damage (as determined by levels of cytokine release and / or by using biochemical biomarkers to monitor inflammation, or by radiography, or magnetic resonance imaging, etc.).

[0093] In another embodiment, the drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to a standard therapeutic dose (molar amount) of H, R 1Compounds of any of Formula I, Ia, or Ib are provided that exhibit at least a two-fold reduced rate of side effects and / or off-target toxicity compared to a standard dose of H, as determined by medical observation of the mammal during treatment, blood counts, tissue biopsies, and / or by analysis of biochemical biomarkers, or similar methods.

[0094] In one aspect, a compound of any of Formula I, Ia, or Ib is provided for treating renal inflammation, wherein the inflammation is in chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), or inflammation in kidney transplant surgery.

[0095] In another aspect, there is provided a method of treating inflammatory kidney disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any of Formulas I, Ia, or Ib.

[0096] In additional aspects, compounds of any of Formula I, Ia, or Ib are provided that have enhanced in vivo efficacy against inflammatory kidney disease compared to the related (parent) anti-inflammatory, immunomodulatory, or nephron-protective structure (compound) incorporated in the compound, as determined by in vivo testing in animal models of such kidney disorders, where the compound and the related free drug (conjugated in the compounds provided herein) are administered at the same molar dose.

[0097] In an additional aspect, there is provided a pharmaceutical composition comprising a compound of Formula I, Ia, or Ib, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.

[0098] In another aspect, there is provided a method of 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 a pharmaceutical composition.

[0099] In another aspect, there is provided a method of treating inflammatory kidney disease in a human or other warm-blooded animal by 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 a pharmaceutical composition.

[0100] The compounds of Formula I, Ia, or Ib, or pharmaceutically acceptable salts, solvates, or hydrates thereof, or pharmaceutical compositions thereof, are administered to a mammal parenterally, transdermally, orally, intranasally, topically, rectally, or via intratumoral administration in a pharmaceutical composition.

[0101] In another aspect, the renal inflammation is inflammation in chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), diabetic nephropathy, chronic glomerulonephritis, or renal transplant surgery.

[0102] In yet another aspect, novel intermediates and processes for preparing compounds of Formula I, Ia, or Ib are provided.

[0103] In another embodiment, a compound of formula II:

[0104] [ka]

[0105] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R 8 and R 9 are independently H, C 1~12 Alkyl, C 1~12 selected from the group consisting of alkylC(=O)O-, -OH, and halo; or R 8 and R 9 Let's get together and

[0106] [ka]

[0107] wherein E is independently selected from CH and O; When E is CH2, G is N, or when E is O, G is CH or C(C 1~6 alkyl), R 11 -WYZR 12 or -WYZC 1~6 Alkylene-R 12 and R 7 -C 1~6 Alkylene-NR i R j , -C 1~6 Alkylene -OH, -C 1~6 Alkylene-Halo, -SC 1~6 Alkylene-halo, -C 1~6 Alkylene-TWYZR 12 , and -C 1~6 Alkylene-TWYZC 1~6 Alkylene-R 12 is selected from the group consisting of R 12 is, in each occurrence independently, H, NR i R j , OH, and SH; T is S(=O), S(=O)2, S(=O)2NR i , O, S, C(=O)NR i , C(=O), and NR i is selected from the group consisting of W and Z, in each occurrence, are independently absent or independently each represent 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 is selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, optionally substituted with Y, in each occurrence, is independently absent or -C 0~6Alkylene-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)NR 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-, R 10 is, at each occurrence, independently selected from the group consisting of OH, halo, alkyl, ═O, and arylalkyl; R i and R j is, at each occurrence, independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Dotted line

[0108] [ka]

[0109] represents either a single or double bond, and n is an integer from 0 to 19.

[0110] In another embodiment, R 8 and R 9 Let's get together and

[0111] [ka]

[0112] wherein E is independently selected from CH and O; When E is CH2, G is N, and R 11 -Z-NR i R j , -Z-OH, and -WYZR 12 Selected from R 7 -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 alkylene-TZ-OH; or when E is O, G is CH and R 11 is selected from the group consisting of alkyl, R 7 -C 1~6 Alkylene-T-heteroarylene-NR i R j Or or when E is O, G is CH and R 11 is -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, G is CH, and R 11 -Z-NR i R j , -Z-OH, and -WYZR 12 and R 7 -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 alkylene-NH2; R 12 is, in each occurrence independently, H, -NR i R j , —OH, and —SH; T is S(=O), S(=O)2, S(=O)2NR i , O, C(=O)NR i , C(=O), and NR i is selected from the group consisting of W is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; Z, in 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 is, at each occurrence, independently selected from the group consisting of -OH, halo, alkyl, and arylalkyl; R i and R j is, at each occurrence, independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Dotted line

[0113] [ka]

[0114] represents either a single or double bond, and n is an integer from 0 to 19. In another embodiment, the compound has formula IIa, IIb, IIc, or IId according to Formula II.

[0115] [ka]

[0116] In another embodiment, W is

[0117] [ka]

[0118] [ka]

[0119] and

[0120] [ka]

[0121] is selected from the group consisting of:

[0122] In another embodiment, Z, at each occurrence, is independently selected from the group consisting of:

[0123] [ka]

[0124] In another embodiment, the compound of formula II is selected from the following structures:

[0125] [ka] DETAILED DESCRIPTION OF THE INVENTION

[0126] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0127] The carbon atom content of various hydrocarbon-containing moieties is indicated by prefixes that designate the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C i~j denotes a moiety of integer "i" to integer "j" carbon atoms (inclusive). Thus, for example, C 1~14 Alkyl refers to alkyl of 1 to 14 carbon atoms (inclusive).

[0128] The term alkyl refers to both straight-chain and branched saturated hydrocarbon groups. Reference to an individual group, such as "propyl," encompasses only the straight-chain group; branched-chain isomers, such as "isopropyl," are specifically mentioned. Unless otherwise specified, "alkyl" contains 1 to 12 carbon atoms. In addition to any groups specifically recited in any of the embodiments or claims, alkyl groups also include halo, hydroxy, cyano, C 1~12 Alkyl, C 3~7 and optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of cycloalkyl, aryl, biaryl, heterocyclic, or heteroaryl (Het) groups. In some embodiments, alkyl is selected from the group consisting of difluoromethyl, 2-fluoroethyl, trifluoroethyl, (adamantan-1-yl)methyl, 3-(cyclohexyl)propyl, 4-propylcyclohexyl, -CH=CH-aryl, -CH=CH-Het 1 In some embodiments, the alkyl is unsubstituted. 1 " or "Alkyl 2" refers to independently selected alkyl groups that may be different from each other or independently equal to each other. When the term "alkyl" is used multiple times in the same group, each "alkyl" is independent of another "alkyl" at each occurrence.

[0129] The term "Alk" refers to alkyl as defined herein.

[0130] The term "alkylene" refers to a divalent alkyl group. Unless otherwise specified, straight chain "alkylene" contains 1 to 12 carbon atoms. Alkylene groups are optionally substituted as described for alkyl. In some embodiments, alkylene is unsubstituted. "Alkylene" and "alkylene 1 " or "Alkylene 2 " refers to independently selected alkylene groups that may be different from each other or independently equal to each other, where C0 alkylene represents absence.

[0131] The term alkenyl refers to both straight-chain and branched hydrocarbon groups containing at least one double bond, and in some embodiments, one, two, or three double bonds. Unless otherwise specified, "alkenyl" contains 2 to 12 carbon atoms. In addition to any groups specifically recited in any of the embodiments or claims, alkenyl also includes halo, C 1~12 Alkyl, C 3~7 Cycloalkyl, aryl, biaryl, Het 1 In some embodiments, alkenyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of 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 alkenyl is unsubstituted.

[0132] The term "alkenylene" refers to a divalent alkenyl group. Unless otherwise specified, "alkenylene" contains 2 to 12 carbon atoms. Alkenylene groups are optionally substituted as described for alkenyl. In some embodiments, alkenylene groups are unsubstituted.

[0133] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, bridged polycyclic, or spirocyclic ring assembly containing 3 to 12, 3 to 10, or 3 to 7 ring atoms, or the indicated number of atoms. Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic rings include, for example, norbornane, decahydronaphthalene, and adamantane. For example, C3-C8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane. These encompass fused structures. As used herein, the term "fused" refers to two or more rings having at least two atoms and one bond in common, such as two cyclohexane rings sharing one carbon-carbon bond. As used herein, the term "bridged polycyclic" refers to a compound in which a cycloalkyl contains one or more atomic bonds connecting non-adjacent atoms. As used herein, "spirocyclic" (or "spiro") refers to two rings that share one atom in common and are not connected by a bridge. Examples of fused cycloalkyl groups include decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups include bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0134] In addition to any groups specifically recited in any of the embodiments or claims, cycloalkyl groups can also be selected from halo, C 1~12 Alkyl, C3~7 Optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, aryl, and Het or heteroaryl. In some embodiments, the cycloalkyl is unsubstituted.

[0135] The term "cycloalkylene" refers to a cycloalkyl group, as defined above, that links at least two other groups, i.e., a divalent hydrocarbon group. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene. In addition to any groups specifically recited in any of the embodiments or claims, cycloalkylene groups are optionally substituted as described for cycloalkyl. In some embodiments, cycloalkylene is unsubstituted. In some or any embodiments, R 4 ~R 10 C formed by any two of 3~6 The cycloalkylene group is C 1~6 It is optionally substituted with one or two groups independently selected from alkyl and aryl.

[0136] The term "heterocycloalkyl" refers to a cycloalkyl, as defined above, containing 1 to 5 heteroatoms, such as N, O, and S. The heteroatoms may also be oxidized, including, but not limited to, -S(O)- and -S(O)-. For example, heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl, and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl. The term "heterocycloalkylene" refers to a heterocycloalkyl group, as defined above, that links at least two other groups. The two moieties linked to the heterocycloalkylene can be linked to the same atom or different atoms of the heterocycloalkylene.

[0137] The term "heteroalkyl" refers to N, O, and S(O). n wherein n is an integer from 0 to 2, and in some embodiments, the substituents include hydroxy (OH), C 1~4 It refers to alkyl or cycloalkyl groups as defined above, which have a substituent, such as alkoxy, amino, thio (—SH), etc. The heteroatom may be incorporated at any position in the heteroalkyl group [e.g., heteroalkyl is a C 1~4 AlkylC(=O)OC 3~6 In some embodiments, the substituents include -NR a R b , -OR a , and -S(O) n R c wherein each R a are independently hydrogen, C 1~4 Alkyl, C 3~6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, or —C(O)R, where R is C 1~4 alkyl), and each R b are independently hydrogen, C 1~4 alkyl, -SO2R (wherein R is C 1~4 Alkyl or C 1~4 hydroxyalkyl), -SONR R' (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 of 0 to 2, and each R c are independently hydrogen, C1~4 Alkyl, C 3~6 cycloalkyl, optionally substituted aryl, or NR a R b (In the formula, R a and R b is as defined above. In some embodiments, heteroalkyl includes, but is not limited to, 2-methoxyethyl (-CHCHOCH), 2-hydroxyethyl (-CHCHOH), hydroxymethyl (-CHOH), 2-aminoethyl (-CHCHNH), 2-dimethylaminoethyl (-CHCHNHCH), benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.

[0138] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0139] The term "aryl" refers to a monocyclic or fused bicyclic, tricyclic or higher aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, benzyl, or naphthyl, preferably phenyl. Aryl groups can include fused polycyclic ring assemblies in which only one ring in the polycyclic ring assembly is aromatic. Aryl groups may be mono-, di-, or tri-substituted with one, two, or three groups. Preferred aryl groups are naphthyl, phenyl, or phenyl mono- or di-substituted with alkoxy, phenyl, halogen, alkyl, or trifluoromethyl, especially phenyl, or phenyl mono- or di-substituted with alkoxy, halogen, or trifluoromethyl, especially phenyl. In addition to any groups specifically recited in any of the embodiments or claims, aryl can independently be selected from halo, -C 1~12 Alkyl (unsubstituted or, in one embodiment, substituted with 1, 2, or 3 halo), aryl, -OH, -OC 1~12 Alkyl, -S(O) n C 1~4 alkyl (wherein n is 0, 1 or 2), -C 1~4 AlkylNH2, -NHC 1~4Alkyl, -C(=O)H, C(=O)OR a , OC(=O)R a , OC(=O)NR a R c , OC(=O)heteroaryl, OC(=O)(heterocyclic ring) and -C=N-OR d (In the formula, R d is hydrogen or -C 1~4 The aryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, aryl, aryl- ... 4~7 It can form a cycloalkyl or a 4- to 7-membered heterocyclic group. 1 " or "aryl 2 " refers to independently selected aryl groups that may be different from each other or independently equal to each other. When the term "aryl" is used multiple times in the same group, each "aryl" is independent of another "aryl" at each occurrence.

[0140] The term "arylene" refers to an aryl group, as defined above, that links at least two other groups. The two moieties linked to the arylene are linked to different atoms of the arylene. Arylene groups include, but are not limited to, phenylene. The term "arylalkyl" refers to an alkyl group substituted with an aryl group, each as defined herein, including where the aryl and alkyl are optionally substituted as described in their respective definitions.

[0141] The term "arylheteroaryl" refers to an aryl group substituted with a heteroaryl group, each as defined herein, including where the aryl and heteroaryl are optionally substituted as described in their respective definitions.

[0142] The term "heteroarylaryl" refers to a heteroaryl group substituted with an aryl group, each as defined herein, including where aryl and heteroaryl are optionally substituted as described in their respective definitions.

[0143] The term "biaryl" refers to an aryl group, as defined herein, substituted with another aryl group, as defined herein, including where the aryl groups are independently optionally substituted as described in the definition.

[0144] The term "biarylalkyl" refers to an alkyl group substituted with an aryl group that is substituted with another aryl group, each as defined herein, including where each aryl (independently) and alkyl is optionally substituted as described in their respective definitions.

[0145] The terms heterocyclic, heterocyclic ring and heterocycle refer to a ring containing 3 to 12 carbon atoms and oxygen, nitrogen, P(=O) and S(O) in the ring. m where m is an integer from 0 to 2. In addition to any groups specifically recited in any of the embodiments or claims, a heterocyclic ring may also include one, two, or three halo, C(═O)OR a , OC(=O)R a , OC(=O)NR a R b , -C 1~20 Alkyl, -OH, -NH2, -OC 1~20 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 d (In the formula, each R a , R b and R d are independently hydrogen or -C1~20 In some embodiments, the heterocyclic ring is unsubstituted. In some or any embodiments, R 4 ~R 10 and / or R 11 and R 12 and / or R 4 and R 11 and / or R 6 and R 12 The 4-7 or 5-7 membered ring formed by is optionally substituted as described herein for heterocycles. In some or any embodiments, R 11 and R 12 and / or R 4 and R 11 and / or R 6 and R 12 The 5- to 7-membered ring formed by 1~6 It is optionally substituted with one or two groups independently selected from alkyl and aryl.

[0146] Het in each occurrence 1 The term is a C-linked 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.

[0147] The term "unsaturated" in the context of the terms cycloalkyl, cycloalkylene, and heterocycle refers to a partially unsaturated, but non-aromatic ring.

[0148] In some embodiments, heterocyclic rings include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxazolinone, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydro-isoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole ... Examples of heterocyclic rings include, but are not limited to, azole, thiadiazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, 1,3-benzoxazine, 1,4-oxazin-3-one, 1,3-benzoxazin-4-one, pyrrolidine, pyrrolidin-2-one, oxazolidin-2-one, azepine, perhydroazepine, perhydroazepin-2-one, perhydro-1,4-oxazepine, perhydro-1,4-oxazepin-2-one, perhydro-1,4-oxazepin-3-one, perhydro-1,3-oxazepin-2-one, azabicyclo[3.1.0]hexane, and the like, and N-oxides of such nitrogen heterocycles. In addition to any groups specifically recited in any of the embodiments or claims, heterocyclic rings may be C(═O)OR a , OC(=O)R a , OC(=O)NR a R b (In the formula, each R a and R b are independently hydrogen or C 1~6 The term "substituted" includes substituted and unsubstituted rings, including those substituted with a group selected from the group consisting of alkyl, aryl, arylsulfonyl ...

[0149] The term heteroaryl refers to a 5- or 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 called a benzo-heterocyclic group.In some embodiments, heteroaryl includes pyridine, thiophene, furan, pyrazole, indole, benzimidazole, quinoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyridaz ...pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 4-pyridazinyl, 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-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl aryl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3-oxathiazol-1-oxide, 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 Examples of heteroaryl groups include, but are not limited to, 1,2,4-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-thiazolinyl, 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 recited in any of the embodiments or claims, heteroaryl groups include C(═O)OR. a , OC(=O)R a , and OC(=O)NRa R b (In the formula, each R a and R b are independently hydrogen or C 1~6 The terms "heteroaryl" and "heteroaryl" refer to substituted and unsubstituted rings, including those substituted with a group selected from the group consisting of aryl, aryl, aryl, aryl- ... 1 " or "heteroaryl 2 " refers to independently selected heteroaryl groups that may be different from each other or independently equal to each other. When the term "heteroaryl" is used multiple times in the same group, each "heteroaryl" is independent of another "heteroaryl" at each occurrence. The term "heteroarylene" refers to a divalent group based on the heteroaryl described above.

[0150] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, each as defined herein.

[0151] The term "monosubstituted" refers to a group having at least one substituent in the group, not counting 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 functional groups in the group, not counting the point of attachment of the group to the main structure or general formula.

[0152] Unless otherwise specified, a "carbon atom" is defined as H, halo, NR a R b , C 1~12 Alkyl, C 3~7 means an atom of the element carbon optionally substituted with a cycloalkyl, aryl, heteroaryl, or heterocyclic ring. Carbon atoms include atoms with sp3, sp2, and sp electron hybridization.

[0153] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "an aryl group optionally mono- or di-substituted with an alkyl group" means that alkyl may, but need not, be present, and that the description includes situations where the aryl group is mono- or di-substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0154] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0155] Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when 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 the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0156] The compounds provided herein may have one or more asymmetric centers, and therefore, such compounds may be produced as individual (R) or (S) stereoisomers or as 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 separating stereoisomers are well known in the art (see Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).

[0157] Hydrogen (H), carbon (C), or nitrogen (N) substitutions in the compounds of Formulas I-IV include substitutions with any isotope of the respective atom. Thus, hydrogen (H) substitutions may be desirable, for example, for certain therapeutic or diagnostic therapies, or metabolic research applications, or for improved stability. 1 H, 2 H (deuterium), or 3 Optionally, the compounds of the present invention may be substituted with radioactive isotopes or radioisotopes known in the art, such as any number of 3 H, 15 O. 12 C, or 13 An N isotope can be incorporated to provide radiolabeled compounds of each of Formulas I-IV.

[0158] "Pharmaceutically acceptable carrier" means a carrier that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier" includes one or more such carriers.

[0159] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the compound. Such salts include: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with 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-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chloroisothiazolinone ... acid addition salts formed with organic acids such as chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic 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, and muconic acid; (2) Salts formed when an acidic proton is present in the parent compound, either replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0160] "Treating," "treatment," or "therapy" of a disease includes: (1) To prevent disease, i.e., not develop clinical symptoms of disease, in mammals that may have been exposed to or may be predisposed to disease but have not yet experienced or exhibited symptoms of disease; (2) inhibiting the disease, i.e., preventing or reducing the onset of the disease or its clinical symptoms; or (3) To alleviate the disease, i.e., to cause regression of the disease or its clinical symptoms.

[0161] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0162] "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group capable of being displaced by a nucleophile, such as halogen, C 1~4 Includes alkylsulfonyloxy, ester, or amino, such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxyl-amino, and the like.

[0163] A "prodrug" refers to any compound that releases an active parent drug, such as a compound provided herein, in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds provided herein are prepared by modifying functional groups present in the compounds provided herein such that the modified moiety can be cleaved in vivo to release the parent compound. Prodrugs include compounds provided herein in which a hydroxyl, sulfhydryl, amide, or amino group in the compound can be cleaved in vivo to regenerate a free hydroxyl, amide, amino, or sulfhydryl group. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, benzoate, phosphate, or phosphonate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds provided herein, and the like. Prodrugs of the compounds provided herein can be used for certain therapeutic applications, such as for pulmonary delivery of aerosols containing the prodrug of the compound or to improve tolerance to the drug. For example, a methanesulfonate prodrug form of the polymyxin drug colistin (e.g., as described in Bergen et al., Antimicrob. Agents Chemother. 2006, vol. 50, p. 1953) has been used to reduce the neurotoxic effects of colistin and for aerosol administration of the drug. This and other known forms of prodrugs can likewise be used to further improve the pharmaceutical properties of the compounds provided herein.

[0164] The term "mammal" refers to all mammalian species, including humans, livestock, and companion animals.

[0165] The compounds described herein are generally named according to IUPAC or CAS nomenclature. Abbreviations known to those skilled in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour(s), and "rt" for room temperature).

[0166] Illustrative Embodiments Within the broadest definition of the invention, certain compounds of formula I may be preferred. The specific and preferred values ​​listed below for groups, substituents, and ranges are for illustrative purposes only and do not exclude other specified values ​​or other values ​​within defined ranges for groups and substituents.

[0167] In some preferred compounds described herein, C 1~14 Alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, octyl, nonyl, decyl, and isomers thereof.

[0168] In some preferred compounds described herein, C 2~12 Alkenyl can be vinyl, propenyl, allyl, butenyl, and the isomers thereof (including cis and trans isomers).

[0169] In some preferred compounds described herein, C 3~7 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their isomers.

[0170] In some preferred compounds described herein, C 1~14 Heteroalkyl can be hydroxymethyl, hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(4-morpholino)ethyl, and 2-methoxyethyl.

[0171] In some preferred compounds described herein, halo may be fluoro (F) or chloro (Cl).

[0172] Those skilled in the art will also recognize that the compounds described herein contain additional chiral centers and may be isolated in optically active and racemic forms. The present invention encompasses any racemic, optically active, tautomeric, geometric, or stereoisomeric form of the compounds of the present invention, or mixtures thereof.

[0173] Any embodiment described herein can be combined with any other embodiment described herein.

[0174] In one preferred embodiment, R in the compound of formula II 1 The parent (precursor) structure of is selected from the following structures:

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka]

[0179] [ka]

[0180] In one preferred embodiment, R in the compound of formula II 1 The parent (precursor) structure of is selected from the following structures:

[0181] [ka]

[0182] [ka]

[0183] [ka]

[0184] [ka]

[0185] [ka]

[0186] Some preferred compounds of formula I (including any salts thereof), such as the hydrochloride salt, sulfate salt, or another pharmaceutically acceptable salt, are exemplified below.

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193]

change

[0194]

change

[0195]

change

[0196]

change

[0197]

change

[0198]

change

[0199]

change

[0200]

change

[0201] In one preferred embodiment, there is provided a compound of any one of Formula I, Ia, or Ib, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, having anti-inflammatory activity or therapeutic effect against renal disease as determined by attenuating or delaying renal cytokine release, such as TNF-α, IL-6, IL-12, or a reduction in biomarkers, such as protein levels, blood urea nitrogen, serum creatinine, or an improvement in the condition of a mammal in a patient or animal model in need of treatment.

[0202] In some or any embodiments, a compound of any one of Formula I, Ia, or Ib, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is useful for treating inflammation, wherein the inflammation is renal inflammation, or an inflammatory disease in renal injury or dysfunction, or inflammation induced by a nephrotoxic agent (including a pharmaceutical nephrotoxic agent such as an anti-cancer, anti-diabetic, anti-infective, or another chemotherapeutic agent).

[0203] In some or any embodiments, a compound of any one of Formula I, Ia, or Ib, or any embodiment thereof, is administered in a manner that inhibits or reduces the activity of a compound of Formula I, Ia, or Ib at a similar dose of a free agent or drug R incorporated therein, as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory, or nephroprotective activity. 1 have enhanced anti-inflammatory, immunomodulatory, or renal protective effects when compared to

[0204] In some or any embodiments, there is provided a compound comprising any one of Formula I, Ia, or Ib, or any of its embodiments, which, when administered to a mammal, selectively accumulates in the kidney, with a ratio of the molar concentration of the compound in the kidney to the molar concentration in the blood ranging from about 5 to 50.

[0205] In some or any embodiments, there is provided a compound comprising any one of Formula I, Ia, or Ib, or any of its embodiments, which, when administered to a mammal, selectively accumulates in the kidney such that the ratio of the molar concentration of the compound in the kidney to the molar concentration in the blood is at least about 20 or greater.

[0206] In some or any embodiments, compounds comprising any one of Formulas I, Ia, or Ib, or any of the embodiments thereof, are provided. 1 When administered to a mammal in a dose (expressed in molar amounts) equivalent to a standard molar dose of the free drug R 1 Approximately 1.5 to 15 times higher tissue concentration and / or renal drug R compared to standard drug doses. 1 The drug exposure (area under the curve, AUC) is shown.

[0207] In some or any embodiments, a compound is provided comprising any one of Formulas I, Ia, or Ib, or any of its embodiments. The compound is a compound comprising the drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to the standard dose (molar amount) of 1 and the therapeutic effect is determined as a slowing, halting, or reversal of the progression of inflammation (as determined by changes in cytokine release and / or biochemical biomarkers or similar methods for monitoring the disease).

[0208] In some or any embodiments, a compound is provided comprising any one of Formulas I, Ia, or Ib, or any of its embodiments. The compound is a compound comprising the drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to the standard dose (molar amount) of 1and the therapeutic effect is determined as a slowing, halting, or reversal of the progression of inflammation or kidney damage (as determined by the level of cytokine release and / or by using biochemical biomarkers to monitor inflammation, or by radiography, or magnetic resonance imaging, etc.).

[0209] In some or any embodiments, a compound is provided comprising any one of Formulas I, Ia, or Ib, or any of its embodiments. The compound is a compound comprising the drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equal to a standard dose (molar amount) of R 1 and / or a reduced rate of side effects and / or off-target toxicity compared to a standard therapeutic dose of at least 2-fold, as determined by medical observation of the mammal during treatment, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers, or similar methods.

[0210] In some embodiments and aspects, the compounds provided herein may be used in combination with adjuncts, including other anti-cancer or immunomodulatory agents, such as monoclonal antibodies, or other anti-inflammatory agents, or other anti-cancer or antibacterial agents, or humanized antibodies such as pembrolizumab, to synergize and / or enhance the therapeutic effects of the compounds themselves, or the adjuncts, or both.

[0211] In one such aspect, the compounds provided herein have little or no anti-inflammatory activity in vitro, but exhibit high anti-inflammatory efficacy when administered to a mammal in need of such treatment.

[0212] 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 a compound defined in any of the embodiments described herein, and a pharmaceutically acceptable carrier.

[0213] General synthesis method The compounds of the present invention can be prepared, for example, according to one or more of the methods described in the following references: The general synthesis of certain relevant starting materials is described in the literature. For example, the preparation of Boc-protected polymyxin nonapeptides is described in O'Dowd et al., Tetrahedron Lett. 2007, vol. 48, p. 2003. Additional protected polymyxin B nonapeptide and colistin nonapeptide derivatives can be prepared as described in Okimura et al., Chem. Pharm. Bull. 2007, vol. 55, pp. 1724-1730. Similarly, general peptide acylation chemistry is described in the reference Tetrahedron Lett. 2007, vol. 48, pp. 2003-2005.

[0214] Additional general methods suitable for preparing compounds of Formulas I-III are described in WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, U.S. Patent Application Publication No. 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, Chinese Patent No. 103923190, U.S. Patent Application Publication No. 2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, Chinese Patent No. 103130876, WO ...162937, WO 2014 / 028087, WO 2013 / 112548, WO 2014 and U.S. Patent Application Publication Nos. 13 / 072695, WO 2012 / 168820, WO 2012051663, U.S. Patent Application Publication Nos. 2012 / 0316105, 2012 / 0283176, 2010 / 0160215, U.S. Patent Application Publication No. 2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, U.S. Patent No. 2006 / 0004185, U.S. Patent Application Publication No. 6,380,356, and U.S. Patent No. 3,450,687.

[0215] Suitable methods for incorporating suitable enzymatically and / or chemically cleavable groups X, Y, and Z (and additional spacers / linkers therein) in compounds of Formulas I-III are described, for example, in U.S. Pat. No. 20170355769; J. Am. Chem. Soc. 2018, 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. Pharmaceutics 2015, 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 therein.

[0216] 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 that will be apparent to one skilled in the art of synthetic organic chemistry.

[0217] Additional syntheses of certain compounds described herein are exemplified by various synthetic schemes in the following examples, which are similarly applicable to the preparation of additional compounds provided herein.

[0218] [Example] Embodiments of the present invention are described in the following examples, which are intended to be illustrative and not limiting of the scope of the invention. Common abbreviations well known to those skilled in the synthetic arts are used throughout.

[0219] Abbreviation: NMR: 400 MHz recorded in D2O unless otherwise stated 1 H NMR spectrum (δ, ppm). LCMS: liquid chromatography-mass spectrometry. MS: Mass spectrometry data (m / z) by positive ionization. Chromatography: Silica gel chromatography using common organic solvents unless otherwise stated. TLC: thin layer chromatography. HPLC: Reversed-phase high performance chromatography using a commercially available C18 phase column. TES: Et3SiH. TFA:CF3COOH. TCFH: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate. EA: EtOAc. ACN:MeCN. DMF: N,N-dimethylformamide. DCC: N,N'-dicyclohexylcarbodiimide. DCE: 1,2-dichloroethane. NMP: N-methylpyrrolidinone. NsCl: 4-nitrophenylsulfonyl chloride. PE: Hexane or light petroleum ether. C18 Chromatography: Reverse phase chromatography using a gradient of 0.1% TFA in water and acetonitrile (ACN). PMBN(Boc)4 (same as PMBNBoc4): H-Thr-Dab(Boc)-cyclo[Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]. PMBH(Boc)3 (same as PMBNBoc3): Cyclo[Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr].

[0220] Abbreviations for other reagents are those used in the general synthesis literature, including the American Chemical Society abbreviation lists, for example, as found in the Journal of Organic Chemistry or the Journal of Peptide Chemistry. Unless otherwise noted, all reagents were either from commercial sources or made by conventional methods described in the available literature.

[0221] Example 1 Synthesis of the compound of Example 1:

[0222] [ka]

[0223] Intermediate 1. To a solution of Fmoc-Glu(OtBu)-OH (542 mg, 1.27 mmol) in DMF (5.00 mL), DIEA (247 mg, 1.91 mmol) and TBTU (404 mg, 1.26 mmol) were added at 25° C. and stirred at 25° C. for 10 minutes. A mixture 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 then stirred at 25° C. for 12 hours. The crude product was diluted with MeOH (1 mL). The crude product was purified by HPLC (Phenomenex Luna C18 75×30 mm×3 μm, water-FA / ACN) to give 600 mg of Intermediate 1 as a white solid. MS: 800.6 [M+H] + .

[0224] Intermediate 2. To a solution of Intermediate 1 (100 mg, 0.125 mmol) in DCM (1.00 mL) was added TFA (0.200 mL, 2.61 mmol) at 25° C., followed by stirring 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] + .

[0225] Intermediate 3. To a solution of intermediate 2 (50.5 mg, 0.041 mmol) in DMF (1.00 mL), 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 at 0° C., followed by stirring at 25° C. for 12 hours. The crude product was diluted with DMF (1 mL). The mixture was purified by HPLC (Phenomenex Luna C18 75×30 mm×3 μm, water-FA / ACN gradient) to give 30.0 mg of intermediate 3 as a pale yellow solid.

[0226] Compound of Example 1. To a solution of Intermediate 3 (20 mg, 0.010 mmol) in DCM (0.50 mL) was added diethylamine (0.001 mL, 0.005 mmol) at 25° C., followed by stirring at 25° C. for 2 hours. The mixture was adjusted to pH=1 using TFA at 0° C., and then TFA (0.300 mL) was added to the mixture at 25° C., followed by stirring 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 (TFA)-ACN) to give 18.16 mg of compound of Example 1 as a white solid. MS: 1467.05 [M+H] + . 1 H NMR(400 MHz,CD3OD):7.41(d,J=10.1 Hz,1H),7.33-7.20(m,5H),6.29(dd,J=1.9,10.1 Hz,1H),6.09(s,1H),5.16(d,J=4.6 Hz,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),1.56-1.4 7(m,2H),1.46-1.34(m,2H),1.27-1.16(m,6H),1.02(s,3H),0.87(d,J=7.4 Hz,3H),0.80-0.72(m,3H),0.71-0.64(m,3H).

[0227] Example 2 Synthesis of the compound of Example 2:

[0228] [ka]

[0229] Intermediate 5. A mixture of dexamethasone (1 g, 2.5 mmol), 4-nitrophenylsulfonyl chloride (1.13 g, 5.1 mmol), and TEA (1.06 mL, 7.6 mmol) in DCM (10 mL) was stirred at room temperature under Ar for 16 h. The mixture was extracted with DCM (80 mL), washed with saturated NaHCO3 (2 x 10 mL) and brine (10 mL), dried, and evaporated to give 1.1 g of crude Intermediate 5. MS: 411.19 [M+H] + .

[0230] Intermediate 6. A mixture of intermediate 5 (1.1 g crude, 2.5 mmol) and NaN3 (1.6 g, 25 mmol) in acetone (15 mL) was stirred at 50 °C under Ar for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc (80 mL) and washed with brine (10 mL x 2). After drying, evaporation, and purification by silica column (EtOAc / PE = 0-100%), 0.9 g of intermediate 6 was obtained. MS: 418.22 [M+H] + .

[0231] Intermediate 7. A mixture of intermediate 6 (417 mg, 1 mmol), 1 M HCl (2 mL), and PPh3 (394 mg, 1.5 mmol) in THF (10 mL) was stirred at room temperature under Ar for 16 h. The mixture was purified using a C18 column (ACN / HO = 0-80%) to give 265 mg of intermediate 7. MS: 392.32 [M+H] + .

[0232] Intermediate 9. A mixture of Boc-L-Ala-L-Ala-OMe (823 mg, 3 mmol) and TFA (2 mL) in DCM (6 mL) was stirred at room temperature under Ar for 3 hours. The solvent was removed to give 1.1 g of crude Intermediate 9. MS: 175.19 [M+H] + .

[0233] Intermediate 10. A mixture of intermediate 9 (1.1 g crude, 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 Ar for 5 h. The mixture was extracted with EtOAc (50 mL) and washed with 1 M HCl (2 × 15 mL), 0.5 M NaOH (2 × 5 mL) and brine (5 mL). Drying and evaporation gave 0.8 g of intermediate 10. MS: 332.05 [M+H] + .

[0234] Intermediate 11. A mixture of intermediate 10 (0.8 g) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature under Ar for 3 hours. The solvent was removed to give 0.9 g of crude intermediate 11. MS: 232.12 [M+H] + .

[0235] Intermediate 12. A mixture of PMBN-Boc4 (500 mg, 0.37 mmol) and succinic anhydride (48 mg, 0.48 mmol) in ACN / HO (5 mL / 1 mL) was stirred at room temperature under Ar for 16 h. The mixture was extracted with EtOAc (50 mL) and washed with 1 M HCl (2 × 5 mL) and brine (2 × 5 mL). Drying and evaporation gave 560 mg of Intermediate 12. MS: 1463.55 [M+H] + .

[0236] 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 Ar for 3 h. The mixture was extracted with EA (60 mL) and washed with 1 M HCl (2 × 10 mL) and brine (10 mL). The mixture was dried, evaporated, and purified using a C18 column (gradient ACN / HO = 0 to 90%) to give 450 mg of Intermediate 13. MS: 1676.56 [M+H] + .

[0237] Intermediate 14. A mixture of intermediate 13 (430 mg, 0.256 mmol), LiOH·HO (22 mg, 0.513 mmol), and HO (1 mL) in THF (4 mL) was stirred at room temperature under Ar for 4 h. The mixture was extracted with EA (60 mL) and washed with 1 M HCl (10 mL) and brine (10 mL). The mixture was dried, evaporated, and purified using a C18 column (ACN / HO = 0-90%) to give 305 mg of intermediate 14. MS: 1662.59 [M+H] + .

[0238] 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 Ar for 0.5 h. Intermediate 17 (105 mg, 0.21 mmol) was then added to the reaction and stirred at room temperature under Ar for 1 h. The mixture was extracted with EA (60 mL) and washed with 1 M HCl (2 × 8 mL) and brine (8 mL). The mixture was dried, evaporated, and purified using a C18 column (ACN / HO = 0-90%) to give 178 mg of Intermediate 15. MS: 1018.72 [M+H] + .

[0239] Compound of Example 2. A mixture of Intermediate 15 (150 mg, 0.07 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred at room temperature under Ar for 1 h. The solvent was removed and purified using a C18 column (ACN / HO = 0-60%) to give 62.4 mg of compound of Example 2. MS: 1635.93 [M+H] + . 1H NMR:7.46(d,J=10.0 Hz,1H),7.33(t,J=7.4 Hz,2H),7.28(t,J=7.3 Hz,1H),7.20(d,J=7.5 Hz,2H),6.35(d,J=10.1 Hz,1H),6.16(s,1H),4.54(t,J=8.2 Hz,1H),4.40(dt,J=15.7,8.9 Hz,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=24.0,14.8,8.0 Hz,5H),2.12-2.02(m,3H),1.85(d,J=53.6 Hz,5H),1.74(q,J=12.2 Hz,1H),1.64(d,J=14.0 Hz,1H),1.48(s,3H),1.37(dd,J=7.3,2.2 Hz,4H),1.33(t,J=7.3 Hz,3H),1.20(s,1H),1.16(dd,J=6.4,2.1 Hz,3H),1.13(d,J=6.2 Hz,3H),0.89(d,J=4.6 Hz,3H),0.80(dd,J=7.4,2.3 Hz,3H),0.72(d,J=6.6 Hz,3H),0.65(d,J=6.5 Hz,3H).

[0240] Example 3. Synthesis of the compound in Example 3:

[0241]

change

[0242] A 6.25 mL flask was charged with PMBHBoc3 (127.2 mg, 0.12 mmol), succinic anhydride (18.01 mg, 0.18 mmol), DMAP (43.96 mg, 0.36 mmol), and water / ACN (5 mL / 5 mL). The reaction mixture was then stirred at room temperature for 12 hours. The mixture was concentrated and purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 182.2 mg of Intermediate 16 as a white solid. MS: 1162.26 [M+H] + .

[0243] Intermediate 17. Triamcinolone (800 mg, 2.0 mmol), tert-butyl(4-formylphenyl)carbamate (496 mg, 2.2 mmol), MgSO (1.2 g, 10 mmol) in ACN (15 mL) was stirred at room temperature for 15 minutes, then HClO (0.856 mL) was added to the reaction and stirred at room temperature overnight. Extracted with EtOAc and washed with aqueous NaHCO and brine. Drying and evaporation gave 840 mg of crude Intermediate 17 as a white solid. MS: 498.16 [M+H] + .

[0244] Intermediate 18. A mixture of intermediate 17 (780 mg crude, 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 Ar for 5 h. The mixture was extracted with EtOAc (50 mL) and washed with 1 M HCl (2 × 15 mL), 0.5 M NaOH (2 × 5 mL), and brine (5 mL). Drying (MgSO), evaporation, and purification using a C18 column gave 0.3 g of intermediate 18.

[0245] Intermediate 19. A mixture of intermediate 18 (0.15 g) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature under Ar for 3 h. The solvent was removed to give 0.17 g of crude intermediate 19.

[0246] Intermediate 20. A mixture of Intermediate 19 (114 mg crude, 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 Ar for 5 h. The mixture was extracted with EtOAc (50 mL) and washed with 1 M HCl (2 × 15 mL), 0.5 M NaOH (2 × 5 mL), and brine (5 mL). After drying and evaporation, the residue was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0 to 100%) to give 60.8 mg of Intermediate 20 as a white solid. MS: 1897.61 [M+H] + .

[0247] Compound of Example 3. A 25 mL flask was charged with Intermediate 29 (60.8 mg, 0.032 mmol), TFA (0.5 mL), and DCM (2.5 mL) under air. The reaction mixture was then stirred at room temperature for 3 hours. Volatiles were removed in vacuo, and the residue was purified by passage through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 33.6 mg of compound of Example 3 as a white solid. MS: 1597.8 [M+H] + . 1H NMR(600 MHz, DMSO-d6):8.79(d,J=6.4 Hz,1H),8.44(d,J=8.4 Hz,1H),8.34-8.22(m,2H),7.94-7.89(m,3H),7.87(dq,J=10.1,5.0 Hz,3H),7.83-7.79(m,4H),7.76(s,1H),7.62(dd,J=12.2,8.4 Hz,2H),7.36(dd,J=8.7,3.2 Hz,1H),7.34-7.29(m,2H),7.29-7.25(m,3H),7.24(d,J=17.8 Hz,1H),7.22-7.16(m,1H),6.24(dt,J=10.2,2.1 Hz,1H),6.12-6.05(m,1H),6.04(d,J=3.5 Hz,1H),5.50(s,2H),5.43(s,1H),4.94(d,J=4.9 Hz,1H),4.55-4.49(m,2H),4.38(q,J=7.5 Hz,2H),4.22(dt,J=19.2,9.4 Hz,6H),4.01(s,1H),3.94(t,J=5.9 Hz,1H),3.01(s,1H),2.95(dq,J=13.3,6.5,5.8 Hz,3H),2.87(q,J=8.7,7.6 Hz,4H),2.80(s,1H),2.76(d,J=15.3 Hz,1H),2.66(d,J=15.4 Hz,2H),2.58(s,1H),2.46-2.41(m,2H),2.39-2.31(m,3H),2.16(td,J=11.9,6.4 Hz,2H),2.06-1.92(m,5H),1.87-1.82(m,2H),1.69(q,J=8.4,7.1 Hz,4H),1.59(d,J=16.0 Hz,2H),1.50(s,3H),1.44(s,1H),1.34(d,J=12.3 Hz,2H),1.11(s,1H),1.05(d,J=6.2 Hz,3H),0.90-0.81(m,9H),0.81-0.73(m,5H),0.72(s,2H).

[0248] Example 4. Synthesis of the compound in Example 4:

[0249]

change

[0250] Intermediate 21. A 100 mL flask was charged with fluocinolone acetonide (1.22 g, 2.7 mmol) and HBF (40% aqueous solution, 25 mL). The reaction mixture was then 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] + .

[0251] Intermediate 22. A 100 mL flask was charged with Intermediate 21 (965.9 mg, 2.342 mmol), butyraldehyde (0.227 mL, 2.6 mmol), HClO (70%, 980 μL, 11.7 mmol), MgSO (1.41 g, 11.7 mmol), and ACN (25 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product, which was dissolved in EtOAc, washed with saturated NaHCO, brine, dried over NaSO, concentrated under reduced pressure, and dried under vacuum to give 1.18 g of Intermediate 22 as a white solid. MS: 467.22 [M+H] + .

[0252] Intermediate 23. A 100 mL flask was charged with Intermediate 22 (932.4 mg, 2 mmol), 4-nitrophenylsulfonyl chloride (664.8 mg, 1.5 mmol), TEA (0.834 mL, 6 mmol), and DCM (30 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated NH4Cl, and the DCM layer was separated. The aqueous layer was extracted twice with DCM. The combined DCM layers were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 943.5 mg of Intermediate 23 as an off-white solid. MS: 652.20 [M+H] + .

[0253] A 25 mL flask was charged with Intermediate 23 (629 mg, 0.963 mmol), tert-butyl N-(4-hydroxyphenyl)carbamate (222.3 mg, 1.063 mmol), KCO (400.5 mg, 2.898 mmol), and DMF (12 mL) under N. The reaction mixture was then stirred at room temperature for 12 h and purified by passage through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 103.8 mg of Intermediate 24 as an off-white solid. MS: 658.32 [M+H] + .

[0254] A 5.25 mL flask was charged with Intermediate 24 (103.8 mg, 0.158 mmol), TFA (0.5 mL), and DCM (2.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure to give 116.2 mg of crude Intermediate 25 as an off-white solid. MS: 558.32 [M+H] + .

[0255] A 25 mL flask was charged with Intermediate 25 (116.2 mg, crude, 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 h. It was diluted with EtOAc, washed with saturated NH4Cl, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 23.1 mg of Intermediate 26 as a white solid. MS: 1036.27 [M+H] + .

[0256] Intermediate 27. A 10 mL flask was charged with Intermediate 26 (23.1 mg, 0.0223 mmol), DEA (0.2 mL), and MeOH (1 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles 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]+ .

[0257] A 25 mL flask containing Intermediate 28 was charged with Intermediate 27 (32.4 mg, 0.0233 mmol), Intermediate 16 (40.6 mg, 0.035 mmol), TCFH (17.5 mg, 0.0699 mmol), NMI (1.91 mg, 0.0233 mmol), and dry ACN (2.5 mL) under N. The reaction mixture was then stirred overnight at room temperature. It was diluted with EtOAc, washed with saturated NH.sub.4Cl, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 20.6 mg of Intermediate 28 as a white solid. MS: 1958.18 [M+H] + .

[0258] Compound of Example 4. A 25 mL flask was charged with Intermediate 37 (20.6 mg, 0.01 mmol), TFA (0.5 mL), and DCM (2.5 mL) under Ar. The reaction mixture was then stirred at room temperature for 12 h. Volatiles were removed under reduced pressure, and the residue was purified by passage through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 14.2 mg of compound of Example 4 as a white solid. MS: 1529.72 [M+H] + . 1H NMR:7.42(d,J=10.1 Hz,1H),7.29(t,J=7.4 Hz,2H),7.24(t,J=7.3 Hz,1H),7.18-7.14(m,2H),6.32(dd,J=10.1,1.9 Hz,1H),6.13(s,1H),4.94(d,J=15.3 Hz,2H),4.48-4.40(m,2H),4.30(d,J=10.5 Hz,1H),4.21(dt,J=13.5,6.3 Hz,2H),4.13-4.04(m,4H),3.33(dt,J=14.4,7.3 Hz,1H),3.05-2.99(m,4H),2.99-2.88(m,3H),2.83-2.74(m,1H),2.70(dt,J=12.5,7.6 Hz,1H),2.66-2.59(m,1H),2.42(dt,J=11.5,6.1 Hz,2H),2.37(d,J=12.7 Hz,1H),2.25(s,1H),2.19(s,1H),2.13(d,J=14.3 Hz,3H),2.02(q,J=12.9,12.3 Hz,4H),1.90-1.81(m,5H),1.72(q,J=12.0 Hz,2H),1.61(d,J=14.3 Hz,1H),1.45(s,3H),1.39(d,J=12.5 Hz,2H),1.36(s,3H),1.31(q,J=11.7,9.7 Hz,2H),1.18(d,J=12.6 Hz,1H),1.10(d,J=6.3 Hz,3H),0.87(s,3H),0.77(d,J=7.3 Hz,3H),0.66(s,3H),0.62-0.56(m,3H).

[0259] Example 5. Synthesis of the compound in Example 5:

[0260]

change

[0261] Intermediate 29. A 100 mL flask was charged with Intermediate 21 (1102.8 mg, 2.67 mmol), tert-butyl(4-formylphenyl)carbamate (650.8 mg, 2.94 mmol), HClO (70%, 1.123 mL, 13.35 mmol), MgSO (1.607 g, 13.35 mmol), and ACN (25 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 528.1 mg of Intermediate 29 as a yellow solid. MS: 616.22 [M+H] + .

[0262] A 0.25 mL flask was charged with Intermediate 29 (528.1 mg, 0.86 mmol), TFA (1 mL), and DCM (5 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure to give 306.1 mg of Intermediate 30 as a yellow solid. MS: 516.21 [M+H] + .

[0263] Intermediate 31. A 50 mL flask was charged with Intermediate 30 (306.1 mg crude, 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 h. It was diluted with EtOAc, washed with saturated NH4Cl, brine, and dried over Na2SO4. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 267.8 mg of Intermediate 31 as a yellow solid. MS: 758.27 [M+H] + .

[0264] Intermediate 32: A 25 mL flask was charged with Intermediate 31 (267.8 mg, 0.353 mmol), TFA (0.5 mL), and DCM (2.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure to give 413.6 mg of Intermediate 32 as a yellow solid. MS: 658.21 [M+H] + .

[0265] Intermediate 33. A 100 mL flask was charged with Intermediate 32 (413.6 mg crude, 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 h. It was diluted with EtOAc, washed with saturated NH4Cl, brine, and dried over Na2SO4. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 119.9 mg of Intermediate 33 as a yellow solid. MS: 815.23 [M+H] + .

[0266] Intermediate 34: A 25 mL flask was charged with Intermediate 33 (119.9 mg, 0.147 mmol), TFA (0.5 mL), and DCM (2.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure to give 192.3 mg of Intermediate 34 as a yellow solid. MS: 715.21 [M+H] + .

[0267] A 5.25 mL flask was charged with 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 h. It was diluted with EtOAc, washed with saturated NH4Cl, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by passing through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 124.1 mg of Intermediate 35 as a white solid. MS: 1858.29 [M+H] + .

[0268] Example 5 Compound. A 25 mL flask was charged with Intermediate 35 (124.1 mg, 0.0668 mmol), TFA (0.5 mL), and DCM (2.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure, and the residue was purified by passage through a C-18 column with ACN / water (0.05% TFA, gradient 0-100%) to give 32.6 mg of Example 5 compound as a white solid. MS: 1557.77 [M+H] + . 1H NMR:7.41(d,J=4.2 Hz,1H),7.36(d,J=10.1 Hz,1H),7.27(d,J=6.4 Hz,1H),7.21(s,4H),7.15(s,0H),7.08(s,1H),6.73(d,J=8.3 Hz,1H),6.35(d,J=20.8 Hz,2H),5.59(s,0H),5.55(s,0H),5.50(s,1H),5.04(s,0H),4.46(t,J=13.2 Hz,1H),4.38-4.22(m,4H),4.20(d,J=19.7 Hz,2H),4.11(s,3H),3.81(d,J=17.9 Hz,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=30.8 Hz,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=7.2 Hz,3H),1.09(d,J=6.6 Hz,2H),0.85(d,J=5.0 Hz,2H),0.66(d,J=17.9 Hz,3H),0.60-0.53(m,2H).

[0269] Example 6. Synthesis of the compound in Example 6:

[0270]

change

[0271] Intermediate 36. A round-bottom flask was charged with 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 h. 9 mL of HO was added and stirred for an additional 18 h. The mixture was cooled, diluted with water (200 mL), added to a separatory funnel, and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column eluting with a gradient of 0-80% EA-PE to give 3.2 g of the title compound as a clear oil that crystallized overnight. 1 H NMR(400 MHz,CDCl3):9.97(s,1H),7.80(d,J=5.2 Hz,2H),7.35(d,J=5.2 Hz,2H),7.28(brs,1H),7.18-7.23(m,2H),6.85(d,J=4.8 Hz,1H),6.47(brs,1H),4.02(s,2H),1.50(s,9H).

[0272] Compound of Example 6. A round-bottom flask was charged with 16-α-hydroxyprednisolone (2.02 g, 5.38 mmol), Intermediate 36 (3.02 g, 9.68 mmol), and MgSO (1.98 g, 16.4 mmol). The mixture was suspended in acetonitrile (80 mL), and the mixture was cooled to 0 °C. Trifluoromethanesulfonic acid (2.35 mL, 26.8 mmol) was then added dropwise and stirred for an additional 1 h. The mixture was poured into 100 mL of aqueous NaHCO and extracted with EtOAc (100 mL × 1, 50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography eluting with 0 to 100% EtOAc in petroleum ether 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 (0-65% CH3CN in water, 0.1% TFA) to give 340 mg of the title compound as a white powder. MS: 570.25 [M+H] + .

[0273] The following compounds were prepared using the method described for Example 6.

[0274] [Table 1]

[0275] Example 14. Synthesis of the compound of Example 14:

[0276] [ka]

[0277] Compound of Example 14 Intermediate 37. To a solution of dexamethasone (200 mg, 0.510 mmol) in ethyl acetate was added (4-chlorosulfonyl)-carbamic acid tert-butyl ester (223 mg, 0.765 mmol) and triphenylphosphine (601 mg, 62.5 mmol). The mixture was warmed to 50° C. and stirred for 1 h. DIPEA (10.0 g, 2.295 mmol) was added and stirring was continued at 50° C. for 1 h. 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 brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography to give 283.2 mg of the title compound as a yellow solid. MS: 600.35 [M+H] + .

[0278] Compound of Example 14. TFA (0.3 mL) was added to a solution of Intermediate 37 (52 mg, 0.087 mmol) in 1 mL of DCM. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 41.2 mg of the title compound as a white powder. MS: 500.02 [M+H] + .

[0279] The following compounds were prepared using the method described for Example 3.

[0280] [Table 2A]

[0281] [Table 2B]

[0282] The following compounds were prepared using the methods described for Example 4.

[0283] [Table 3]

[0284] Example 21. Synthesis of the compound of Example 21:

[0285] [ka]

[0286] Intermediate 38. To a mixture of PMBH(Boc)3 (100 mg, 0.094 mmol) in THF (2.00 mL) was added 3-mercaptopropionic acid (13.0 mg, 0.120 mmol), DIEA (51.1 mg, 0.360 mmol), and HOBt (19.0 mg, 0.140 mmol), EDCI (27.0 mg, 0.140 mmol) was added under N2 at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was purified by preparative TLC (EA) to give 50 mg of Intermediate 38 as a white solid.

[0287] Intermediate 39. To a mixture 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 h. 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] + .

[0288] Intermediate 40. To a mixture of Fmoc-Gly-Gly-OH (50.0 g, 141 mmol) in dioxane (500 mL), HOSu (20.0 g, 169 mmol) and DCC (35.0 g, 169 mmol) were added at 25 °C and stirred for 12 h. HO (300 mL) was added, followed by L-phenylalanine (23.0 g, 141 mmol) and NaHCO (15.0 g, 183 mmol) at 25 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was washed with ethyl acetate (100 mL × 3), and then the aqueous phase was acidified with 2 M HCl to pH = 4 and extracted with DCM (200 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give 53 g of crude Intermediate 40 as a pale yellow oil. MS:502.2[M+H] + .

[0289] Intermediate 41. To a mixture of intermediate 40 (52.0 g, 104 mmol) in THF (500 mL), HOSu (12.0 g, 104 mmol) and DCC (21 g, 104 mmol) were added at 25° C. and stirred for 12 h. HO (300 mL) was added, followed by 2-[(2-aminoacetyl)amino]acetic acid (14.0 g, 104 mmol) and NaHCO (10.0 g, 114 mmol) at 25° C. and stirred for 12 h. 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); eluent gradient 0.2% FA in HO (eluent A) to 0.2% FA in ACN (eluent B) 30% to 60%] to give 20 g of intermediate 41 as a white solid. MS: 616.3 [M+H] + .

[0290] Intermediate 42. To a mixture 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 N. The mixture was 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 in vacuo to give 5.7 g of intermediate 42 as a white solid.

[0291] Intermediate 43. To a mixture 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. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove DCM and TFA. The crude product was purified by flash column (gradient DCM / MeOH from 50 / 1 to 10 / 1) to give 4.4 g of intermediate 43 as a white solid.

[0292] Intermediate 44. To a mixture 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 stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC (column Welch Xtimate C18 250 × 100 mm # 10 μm; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 25% to 55%, 18.00 min) to give 400 mg of intermediate 44 as a white solid. MS: 740.4 [M+H] + .

[0293] Intermediate 45. To a mixture of Intermediate 44 (250 mg, 0.270 mmol) in DMF (3.00 mL), 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) were added at 25 °C and stirred for 12 h. The residual mixture was purified by HPLC (column: Phenomenex Luna C18 100 x 40 mm x 3 μm; mobile phase: [A: HO (0.2% FA); B: ACN]; B%: 30.00% to 60.00%, 8.00 min) to give 120 mg of Intermediate 45 as a white solid. MS: 891.3 [M+H] + .

[0294] Compound of Example 21. To a mixture of Intermediate 39 (70.0 mg, 0.073 mmol) in HO (1.50 mL) and ACN (1.50 mL) at 0 °C, Intermediate 45 (26.0 mg, 0.029 mmol) and NaHCO (18.0 mg, 0.22 mmol) were added and stirred for 2 h. The residue was purified by HPLC (Phenomenex Luna C18 column 75 × 30 mm × 3 μm; eluent gradient 0.2% FA in HO (eluent A) to 0.2% FA in ACN (eluent B) 30% to 60%) to give 32 mg of Compound of Example 21 as a white solid. MS: 871.3 [M+2H] + / 2.1H NMR(400 MHz,MeOD):8.63-8.43(m,2H),7.41-7.18(m,11H),6.24(dd,J=10.1,1.8 Hz,1H),6.08(s,1H),4.77(d,J=10.6 Hz,2H),4.73-4.66(m,2H),4.63(d,J=1.4 Hz,1H),4.60-4.51(m,2H),4.40-4.32(m,3H),4.31-4.24(m,2H),4.23-4.18(m,1 H),4.15-4.05(m,2H),4.02-3.98(m,1H),3.95-3.74(m,8H),3.70(dd,J=14.1,6.8 Hz,1H),3.26-3.21(m,1H),3.20-2.87(m,14H),2.78-2.35(m,9H),2.31-2.19(m,2H),2.16-2.07(m,3H),2.00-1.84(m,4H) ,1.80-1.64(m,1H),1.62-1.55(m,4H),1.54-1.44(m,2H),1.34-1.25(m,1H),1.24-1.12(m,4H),1.01(s,3H),0.86(d,J=7.3 Hz,3H),0.71(brs,3H),0.65(brs,3H).

[0295] Example 22. Synthesis of the compound of Example 22:

[0296] [ka]

[0297] Intermediate 46. To a solution of intermediate 17 (1 g, 2 mmol), imidazole (683.8 mg, 10.05 mmol) in DCM (25 mL) was added TBDMSCl (904 mg, 6.03 mmol) at 0° C., and the mixture was then stirred at room temperature for 2 hours. The mixture was washed with water (15 mL) and brine (15 mL), dried over NaSO, filtered, and concentrated to give intermediate 46.

[0298] Intermediate 47. Intermediate 46 (140 mg, 0.229 mmol) was added to a mixture 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). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, 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] + .

[0299] Intermediate 48. TFA (0.45 mL) was added to a solution of intermediate 47 (120 mg, 0.117 mmol) in 1 mL of DCM. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 110 mg of crude intermediate 48 as a white powder.

[0300] Intermediate 49. Intermediate 48 (80 mg, 0.098 mmol) was added to a mixture of intermediate 16 (114 mg, 0.098 mmol), HATU (41 mg, 0.108 mmol) and DIPEA (38 mg, 0.294 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered and evaporated. The residue was purified by reverse phase HPLC to give 80 mg of intermediate 49 as a white solid. MS: 1960.24 [M+H] + .

[0301] 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. The mixture was concentrated. The crude product was dissolved in HO and then lyophilized to give 75.7 mg of compound of Example 22 as a white powder. MS: 1660.85 [M+H] + . 1H NMR(400 MHz,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=10.0 Hz,2.0 Hz,1H),6.03(s,1H),5.42-5.47(m,2H),4.93(d,J=4.4 Hz,1H),3.58-4.54(m,31H),2.66-3.18(m,13H),1.67-2.38(m,23H),0.74-1.50(m,28H).

[0302] Example 23. Synthesis of the compound of Example 23:

[0303] [ka]

[0304] Intermediate 50. The compound of Example 7 (100 mg, 0.165 mmol) was added to a mixture of Boc-Ala-Ala-OH (43 mg, 0.165 mmol), HATU (69 mg, 0.182 mmol), and DIPEA (64 mg, 0.496 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase C18 column (0.05% TFA in ACN-water, gradient 0-100%) to give 76 mg of Intermediate 50 as a white powder. MS: 848.12 [M+H] + .

[0305] Intermediate 51. TFA (0.3 mL) was added to a solution of intermediate 50 (76 mg, 0.079 mmol) in 1.0 mL of DCM. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give 65 mg of intermediate 51 as a white powder. MS: 748.28 [M+H] + .

[0306] Intermediate 52. Intermediate 51 (65 mg, 0.087 mmol) was added to a mixture of Intermediate 16 (100 mg, 0.087 mmol), HATU (34 mg, 0.096 mmol), and DIPEA (33 mg, 0.261 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase C18 column (0.05% TFA in ACN-water, gradient 0-100%) to give 66 mg of Intermediate 52 as a white powder. MS: 1891.12 [M+H] + .

[0307] 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. The mixture was concentrated. The residue was dissolved in HO and then lyophilized to give 53 mg of compound of Example 23 as a white powder. MS: 1591.97 [M+H] + . 1 H NMR(400 MHz,DMSO-d6):9.81(d,J=1.6 Hz,1H),8.77-8.81(m,1H),8.07-8.34(m,7H),7.71-7.94(m,14 H),7.19-7.50(m,15H),6.90-6.98(m,1H),6.29(dd,J=6.4 Hz,1.2 Hz,1H),6.13(s,1H),5.32-5.70(m,4H),4.94(d,J=3.6 Hz,1H),3.88-4.52(m,35H),2..80-3.16(m,10H),1.57-2.38(m,24H),1.50(s,3H),1.18-1.27(m,13H),1.04(d,J=3.6 Hz,3H),0.71-0.91(m,12H).

[0308] Example 24. Synthesis of the compound of Example 24:

[0309] [ka]

[0310] [ka]

[0311] 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. The mixture was diluted with EA (30 mL), washed with water (3 × 15 mL) and brine (15 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (ACN-0.1% TFA in water, gradient 0-100%) to give 236 mg of Intermediate 53 as a white solid. MS: 963.42 [M+H] + .

[0312] 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. The mixture was concentrated in vacuo. The residue was purified by reverse-phase C18 column (CHCN in water (0.1% TFA), 0% to 100%) to give 53 mg of intermediate 54 as a white solid. MS: 741.41 [M+H] + .

[0313] Intermediate 55. To a solution of L-valine benzyl ester hydrochloride (200 mg, 0.821 mmol) and Fmoc-Glu(OtBu)-OH (384 mg, 0.903 mmol) in DMF (6.0 mL) was added 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. The mixture was diluted with EA (20 mL), washed with water (2 × 15 mL) and brine (15 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (ACN-water with 0.1% TFA, gradient 0-100%) to give 470 mg of Intermediate 55 as a white solid. MS: 615.20 [M+H] + .

[0314] 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. The mixture was concentrated in vacuo. The residue was purified by reverse-phase C18 column (ACN-water with 0.1% TFA, gradient 0-100%) to give 265 mg of Intermediate 56 as a pale yellow solid. MS: 393.36 [M+H] + .

[0315] 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 h. The mixture was diluted with EA (30 mL), washed with water (2 × 15 mL) and brine (15 mL), dried over NaSO, filtered, and concentrated. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 350 mg of Intermediate 57 as a white solid. MS: 786.33 [M+H] + .

[0316] 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. The mixture was concentrated in vacuo. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 222 mg of intermediate 58 as a pale yellow solid. MS: 564.80 [M+H] + .

[0317] 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. The mixture was diluted with EA (30 mL), washed with water (2 × 15 mL) and brine (15 mL), dried over NaSO, filtered, and concentrated. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 217 mg of intermediate 59 as a white solid. MS: 843.22 [M+H] + .

[0318] 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 in vacuo. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 92 mg of Intermediate 60 as a white solid. MS: 621.38 [M+H] + .

[0319] Intermediate 61. To a solution of Intermediate 16 (48 mg, 0.0413 mmol) in DMF (2.0 mL) were 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. The mixture was diluted with EA (15 mL), washed with water (2 × 10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 38 mg of Intermediate 61 as a white solid. MS: 1765.71 [M+H] + .

[0320] Intermediate 62. To a solution of Intermediate 61 (38 mg, 0.0215 mmol) in MeOH (4 mL) was added Pd / C (6 mg) at room temperature. The mixture was stirred under an H atmosphere for 4 hours. The mixture was filtered and concentrated. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 35 mg of crude Intermediate 62 as a white solid. MS: 1675.54 [M+H] + .

[0321] Intermediate 63. To a solution of Intermediate 62 (35 mg, 0.022 mmol) in DMF (2.0 mL) were 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. The mixture was diluted with EA (15 mL), washed with water (2 × 8 mL) and brine (8 mL), dried over NaSO, filtered, and concentrated. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 25 mg of Intermediate 63 as a white solid. MS: 1199.31 [M+2H] + / 2.

[0322] 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. The mixture was concentrated in vacuo. The residue was purified using a C18 column (0.1% TFA in ACN-water, gradient 0-100%) to give 6.7 mg of compound of Example 24 as a white solid. MS:1929.70.1H NMR(600 MHz,DMSO):12.22(s,3H),9.84(s,1H),8.78(s,1H),8.32-8.23(m,5H),8.11(m,2H),8.02(d,J=7.6 Hz,2H),7.79-7.62(m,11H),7.44-7.41(m,2H),7.38(d,J=7.9 Hz,2H),7.32-7.19(m,12H),6.89(d,J=7.6 Hz,1H),6.16(d,J=10.2 Hz,1H),5.93(s,1H),5.39(s,1H),5.09(s,1H),4.92(d,J=5.4 Hz,1H),4.86(s,1H),4.78(d,J=3.5 Hz,1H),4.67-4.58(m,2H),4.51-4.48(m,2H),4.40(d,J=7.2 Hz,1H),4.28-4.13(m,9H),3.97(d,J=7.5 Hz,2H),3.88(s,2H),3.71(s,2H),3.16(s,1H),2.98-2.95(m,2H),2.85-2.80(m,4 H),2.77-2.71(m,2H),2.67(s,1H)2.57-2.54(m,2H),2.39(s,4H),2.31(d,J=11.3 Hz,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=9.4 Hz,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=14.8 Hz,3H),0.84-0.78(m,10H),0.74(dd,J=6.6 Hz,4H). Example 25. Synthesis of the compound of Example 25:

[0323] [ka]

[0324] Intermediate 64. A mixture of 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) in DMF (4.5 mL) was stirred at room temperature for 16 hours. The mixture was extracted with EA (3×), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (gradient EA-PE 0-90%) to give 372 mg of Intermediate 64 as a white powder. MS: 977.47 [M+H] + .

[0325] Intermediate 65. To a mixture of Intermediate 64 (315 mg, 0.32 mmol) in ACN (4 mL) was added DEA (400 μL) and stirred at room temperature for 2 h. The mixture was then concentrated, and the residue was purified by flash chromatography (gradient 0-10% MeOH in DCM) to give 89 mg of Intermediate 65 as a white powder. MS: 755.61 [M+H] + .

[0326] Intermediate 66. A mixture of 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) in DMF (9 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic layer was washed three times with brine and concentrated. The residue was purified by reverse-phase HPLC (ACN-water with 0.1% TFA, gradient 0-100%) to give 843 mg of Intermediate 66 as a white powder. MS: 1469.38 [M+H] + .

[0327] Intermediate 67. To a mixture of Intermediate 66 (843 mg, 0.57 mmol) in MeOH (9 mL), DEA (900 μL) was added and stirred at room temperature for 6 hours. The mixture was then concentrated. The residue was purified by chromatography (gradient 0-15% MeOH in DCM) to give 521 mg of Intermediate 67 as a white powder. MS: 1248.99 [M+H] + .

[0328] Intermediate 68. To a solution of Intermediate 67 (521 mg, 0.42 mmol) in ACN (6 mL) and HO (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-0.1% TFA in water, gradient 30-100%) to give 461 mg of Intermediate 68 as a white powder. MS: 1346.11 [M+H] + .

[0329] Intermediate 69. A mixture of intermediate 68 (461 mg, 0.34 mmol), benzyl glycinate hydrochloride (55 mg, 0.33 mmol), HATU (168 mg, 0.44 mmol), and 2,6-lutidine (81 μL, 0.69 mmol) in DMF (5.5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with brine (3×), dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (ACN-water, gradient 30-100%) to give 295.8 mg of intermediate 69 as a white powder. MS: 1495.16 [M+H] + .

[0330] 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 under H at room temperature for 2 h. The mixture was filtered over Celite, and the resulting solution was evaporated in vacuo to give 272 mg of crude Intermediate 70 as a white solid, which was used directly in the next step. MS: 1403.22 [M+H] + .

[0331] Intermediate 71. A mixture of 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) in DMF (3 mL) was stirred at room temperature for 6 h. The mixture was diluted with EA, washed three times with brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (0-10% MeOH in DCM) to give 58 mg of Intermediate 71 as a white powder. MS: 1071.06 [M+H] + .

[0332] Compound of Example 25. A mixture of Intermediate 71 (58 mg, 0.027 mmol) in DCM (2.5 mL) was treated with TFA (625 μL) and stirred at room temperature for 1 hour. The mixture was then concentrated. The residue was purified by flash chromatography (0-50% ACN in water, 0.1% TFA) to give 14 mg of compound of Example 25 as a white powder. MS: 1729.88 [M+H] + .

[0333] Example 26. Synthesis of the compound of Example 26:

[0334] [ka]

[0335] Compound of Example 26. Compound of Example 26 was made in a similar manner to the method for synthesizing compound of Example 21 according to the scheme above. MS: 1690.57 [M+H] + .

[0336] Example 27. Synthesis of the compound of Example 27:

[0337] [ka]

[0338] Compound of Example 27. Compound of Example 27 was made in a similar manner to the method for synthesizing compound of Example 21 according to the scheme above. MS: 1630.64 [M+H] + .

[0339] Example 28. Synthesis of the compound of Example 28:

[0340] [ka]

[0341] Compound of Example 28. Compound of Example 28 was made in a similar manner to the method for synthesizing compound of Example 21 according to the scheme above. MS: 1557.78 [M+H] + .

[0342] Usability and Testing The compounds provided herein exhibit potent activity against various inflammatory renal disorders, including CKD, AKI, postoperative inflammation (such as kidney transplant surgery), or inflammation induced by anti-cancer or antibacterial treatment, or in the treatment of diabetes, or due to exposure to nephrotoxic substances.Therefore, these agents are useful for treating such renal diseases.

[0343] The in vitro activity of the compounds provided herein can be evaluated by standard bioassay testing procedures used to evaluate the active entities (payloads) incorporated (conjugated) into the compositions provided herein. The selection of a particular assay is determined by the known or predicted mode of action of the payload structure. For example, a conjugate incorporating an anti-inflammatory vanin-1 inhibitor can be tested in a human vanin-1 enzyme assay, as described in WO 2020 / 114943.

[0344] Preferential renal targeting of the compounds provided herein to verify delivery to the kidney (or site of renal damage) can be evaluated by pharmacokinetic (PK) studies, such as standard rodent PK studies. PK data is generally used to establish important parameters predicting therapeutic outcomes. Thus, the drug concentration at a given time point (C), the drug concentration in the target tissue (C-target), the area under the curve (AUC) of a plot monitoring the change in systemic drug concentration over time, and other parameters generally predict therapeutic efficacy. For example, drug concentration in cancer-affected organs is important for the effective action of anticancer drugs (see, for example, Zhang et al., Drug Metabolism and Disposition. 2019, vol. 47, p. 1122).

[0345] Representative compounds provided herein were tested in an intravenous rodent PK model conducted similarly to the method described in the monograph Current Protocols in Pharmacology, 2005, 7.1.1-7.1.26, John Wiley & Sons, Inc. Exemplary mouse PK data for the compounds of Examples 3, 5, and 15 are summarized below in Table 1. As is evident from the data, the compounds of the present invention exhibit a surprising ability to target the kidney, as evidenced by high levels of preferential drug concentration in renal tissue, the organ for targeted therapy of the present invention.

[0346] [Table 4]

[0347] a The administration was by injection into the tail vein of the mice. b A dose of 1 mg / kg expressed in μmol / kg per molecular weight (MW) of 392 daltons. c A dose of 4 mg / kg expressed in μmol / kg per MW of the compound of Example 3, 1,939 Daltons (3TFA). dA dose of 4 mg / kg expressed in μmol / kg per MW of the compound of Example 5 of 1,900 daltons (3TFA). e Dose of 2.5 mg / kg expressed in μmol / kg per MW of the compound of Example 15, 2,012 Daltons (3TFA).

[0348] In vivo efficacy was evaluated in a lipopolysaccharide (LPS) mouse model described by Chen et al., PLoS One 2015, 10(7), e0134653. Briefly, male ICR mice weighing 23-25 ​​g were randomly divided into groups of 10 mice each. Prior to testing, they were fasted for 12 hours with free access to water. Each group received intravenous administration of the test drug and vehicle, followed 1 hour later by intraperitoneal injection of 15 mg / kg LPS. After 18 hours, blood was collected from each group, allowed to stand for 3 hours, and serum was separated by centrifugation at 10,000 rpm for 3 minutes. Serum creatinine (CREA) was determined by standard procedures using a biochemical analyzer. As shown in Table 2, the compounds of the present invention were able to significantly reduce LPS-induced serum creatinine levels. This indicates a beneficial reduction in the level of nephritis (damage) induced by the LPS toxin used in the model.

[0349] [Table 5]

[0350] a When administered, the 2.5 mg / kg (6.4 μmol / kg) dexamethasone dose was approximately 5-fold the active glucocorticoid in the compound of Example 15 (administered at 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). b In a separate study of the compound of Example 26, the CREA data for dexamethasone (2.5 mg / kg) was 45.6±19.3, respectively.

[0351] Notably, administration of the active glucocorticoid receptor agonists in the novel conjugated forms of the compounds of Examples 3, 5, and 15 enhanced renal drug levels (measured as renal tissue concentrations) by approximately 5-6 fold compared to the renal levels of dexamethasone achieved by injection of dexamethasone in its (unconjugated) drug form. Because drug levels at disease sites directly affect the therapeutic efficacy (in vivo activity) of a pharmaceutical product, the data illustrated in Table 1 demonstrate the significantly enhanced in vivo therapeutic potential of the novel compositions provided herein.

[0352] The data illustrated in Table 1 further demonstrate that less frequent administration of such drugs is possible compared to the standard administration of dexamethasone. Based on these data, the compounds of Examples 3 and 5 can be administered much less frequently, for example, once a day or once a week. This advantage greatly benefits patients who require such treatment. In addition, this useful feature provides a significant economic benefit to the drug, as it minimizes the need for hospital medical procedures to administer the treatment.

[0353] The data illustrated in Table 2 demonstrate that dexamethasone exerts a dose-dependent renal protective effect, exactly as would be expected for a drug. Surprisingly, at much lower molar doses than dexamethasone, the compounds of Examples 3, 15, and 26 significantly reduce LPS-induced renal injury, as determined experimentally using the serum creatinine (CREA) biomarker (reported in the literature as an important parameter in the development of acute kidney injury (AKI)). At equivalent doses of active glucocorticoid, the compounds of Examples 3, 15, and 26 surprisingly outperform the dexamethasone control. This is consistent with the enhanced renal exposure of the free drug in pharmacokinetic studies of exemplary compounds of the present invention, including AUC and active residence time in the kidney.

[0354] The in vivo activity of the compounds provided herein can also be evaluated by, for example, the test procedures for evaluating the anti-inflammatory and immunomodulatory effects of corticosteroids described by Chen et al., Inflammopharmacology, 2018 26, pp. 1331-1338, or the tests in rodent models of non-diabetic and diabetic chronic nephropathy described by 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, and for additional test methods in the references cited therein.

[0355] Surprisingly, certain compounds provided herein, when tested in rodent models of nephritis and kidney disease by intravenous administration at a molar dose equivalent to the standard dose of dexamethasone or another corticosteroid, or a nonsteroidal anti-inflammatory agent (such as naproxen, or a vanin-1 inhibitor), are more than twice as effective as the standard dose of the agent, the therapeutic effect being determined as slowing, halting, or reversing the progression of kidney inflammation or kidney disease (including, for example, nephropathy or acute kidney injury induced by cytotoxic agents such as chemical agents or chemotherapeutic anti-cancer agents, or in transplant surgery).

[0356] Surprisingly, while possessing high efficacy in mammals, the compounds provided herein exhibit little or no toxicity to normal kidney cells both in vitro (such as in the human kidney cell HK-2 assay) and in living mammalian models, such as rodent models.

[0357] The safety profile of the compounds of the present invention can be further established in biomarker assays that predict nephrotoxicity. Some such assays (including the NGAL assay) are described, for example, in Keirstead et al., Toxicol. Sci. 2014, vol. 137, pp. 278-291.

[0358] Surprisingly, certain compounds provided herein, when administered to a mammal at a dose (expressed in molar amounts) equivalent to a standard dose (molar amount) of dexamethasone or another corticosteroid, or a nonsteroidal anti-inflammatory agent (such as naproxen or a vanin-1 inhibitor), exhibit at least a two-fold reduced rate (frequency or incidence) of side effects and / or off-target toxicity manifestations (such as myelosuppression or myelotoxicity) (e.g., as determined by platelet and / or other blood cell counts associated with myelosuppression or myelotoxicity) compared to a standard dose of axitinib, brivanib, pazopanib, or sunitinib.

[0359] As such, certain compounds of the present invention exhibit high efficacy in treating inflammatory renal disorders, but do not suffer from excessive off-target toxicity that limits standard treatments for such diseases.

[0360] Thus, the novel compounds and compositions provided herein potentially offer much-needed, safer, and more effective targeted therapies for kidney disease and injury, including CKD, AKI, and other kidney injuries encountered in kidney transplantation.

[0361] Administration and Pharmaceutical Formulations Generally, the compounds provided herein can be administered in a therapeutically effective amount by any of the accepted modes of administration for drugs that provide similar utility.For example, the compounds provided herein can be administered orally, parenterally, transdermally, topically, rectally, or intranasally, or can be administered by direct intratumoral administration into cancerous tumors.The actual amount of the compounds provided herein, i.e., the active ingredient, depends on many factors, such as the disease to be treated, i.e., the severity of the infection, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors, all of which are within the scope of the attending physician.

[0362] Data obtained from cell culture assays and animal experiments can be used to formulate a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include therapeutic efficacy with little or no toxicity. Dosages may vary within this range depending on the dosage form used and the route of administration utilized. The therapeutically effective dose of any compound used in the methods provided herein can be initially estimated from animal models. Dosages are determined based on IC20 determined in cell culture. 50 Animal models can be prepared to achieve a circulating plasma concentration range that includes 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.

[0363] When used as pharmaceuticals, the compounds provided herein are typically 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.

[0364] The compounds provided herein are effective as injectable, oral, inhalable, topical, or intratumoral compositions. Such compositions are prepared by methods well known in the pharmaceutical arts and contain at least one active compound.

[0365] The present invention also includes pharmaceutical compositions containing one or more of the compounds provided herein above as an active ingredient in association with a pharmaceutically acceptable carrier. In preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid vehicles), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0366] The compositions are preferably formulated in unit dosage form, each dosage containing about 0.1 to about 2000 mg, more usually about 1 to about 900 mg, of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical excipient. Preferably, the compounds provided herein above are used in an amount of about 20% by weight or less, more preferably about 15% by weight or less, of the pharmaceutical composition, with the remainder being a pharmaceutically inert carrier.

[0367] The active compounds are effective over a wide dosage range and are generally administered in a pharmaceutically or therapeutically effective amount. However, it will be understood that the amount of compound actually administered will be determined by the physician in light of the relevant circumstances, including the condition being treated, the severity of the bacterial infection being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0368] In therapeutic use for treating or inhibiting bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof can be administered orally, topically, transdermally, and / or parenterally at a dosage to achieve and maintain an antibacterialally effective concentration, i.e., amount or blood level, of the active ingredient in the animal undergoing treatment. Generally, such an antibacterial or therapeutically effective amount of the active ingredient (i.e., an effective dosage) will range from about 0.1 mg / kg to about 250 mg / kg, more preferably from about 1.0 mg / kg to about 50 mg / kg of body weight per day.

[0369] To prepare solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly distributed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

[0370] The tablets or pills described herein can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released later. A variety of materials can be used for the enteric layer or coating, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0371] Liquid forms into which the novel compositions described herein may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0372] In addition, liposomal formulations of the compounds of the present invention may be used to enhance the treatment of certain infectious diseases, such as, for example, pneumonia or lung infections.

[0373] Intratumoral administration of the compounds provided herein utilizes solutions or gels thereof prepared in suitable aqueous solutions containing suitable excipient additives such as dextrose, polyethylene glycol, cremophor, cyclodextrins, and the like.

[0374] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0375] Other formulations suitable for use in the present invention may be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

[0376] Optionally, the compounds of the present invention may be co-administered with additional agents, including antioxidants such as ascorbic acid, or megalin receptor inhibitors, which are generally known to attenuate the side effects of polymyxin drugs.

[0377] As described above, the compounds described herein are suitable for use in the various drug delivery systems described above. Additionally, to enhance the in vivo serum half-life of the administered compounds, the compounds may be encapsulated, incorporated into the lumen of liposomes, prepared as colloids, or other conventional techniques that provide extended serum half-life for the compounds may be used. Various methods for preparing liposomes are available, for example, as described in U.S. Patent Nos. 4,235,871, 4,501,728, and 4,837,028 to Szoka et al., each of which is incorporated herein by reference. Optionally, the compounds described herein can be administered as nanomicelles or nanomaterial-encapsulated compositions, for example, as described in Taki et al., Pharmaceut., 2012, Vol. 3, p. 1092.

[0378] As described above, the compounds administered to patients are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The resulting aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0379] The disclosures of any and all patents, patent applications, and publications (e.g., journals, articles, and / or textbooks) cited herein are hereby incorporated by reference in their entirety. Additionally, as used in this specification and the appended claims, singular forms such as "a," "an," and "one" are intended to refer to either the singular or the plural. While the present invention has been described herein in conjunction with preferred embodiments, those skilled in the art, after reading the foregoing specification, may make modifications, equivalent substitutions, and other types of changes to the invention described herein. Each of the above embodiments may also include or incorporate variations or embodiments as disclosed with respect to any or all of the other embodiments. The present invention also should not be limited in terms of the particular embodiments described herein, which are intended as single illustrations of each embodiment provided herein. As will be apparent to those skilled in the art, many modifications and variations of the present invention can be made without departing from the spirit and scope of the invention. In addition to the methods enumerated herein, functionally equivalent methods within the scope of the invention will be apparent to those skilled in the art from the foregoing description. It is to be understood that this invention is not limited to particular methodologies, reagents, process conditions, materials, etc., which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Accordingly, it is intended that this specification be considered as illustrative.

Claims

1. A compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R 1 is X 1 is a residue bound to NH 2 , NH, OH, and SH, in any one of the H-containing groups independently selected from the parent (precursor) structure R 1 formed by subtracting a single H atom from H, R 1 H is selected from compounds that have or can induce glucocorticoid receptor (GR) activity modulating activity; Array-X 1 -X 2 -X 3 X connected to - 1 , X 2 , and X 3 each group comprises a cleavable linker, X 1 is absent or -CH 2 NH-, -C(=O)NHC(=O)C 1～6 alkylene NH-, 【Chemistry 2】 and 【Transformation 3】 and wherein X is selected from the group consisting of: 1 The left side of the group is R 1 is bound to X 2 is either absent or comprises an amino acid or a peptide residue of 1 to 6 amino acids selected from alpha-, beta- or gamma-amino acids 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, unsubstituted or substituted at any N atom, and 2 The carbonyl end of the group is X 1 or R 1 (X 1 is not present), X 3 is -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 X 1 Group (X 2 (if no group is present) or X 2 is bonded to the group, R 2 is a 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 Alkyleneheteroarylene, C 1～3 Alkyleneheteroarylene 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 -, and R 2 is unsubstituted C 1～6 When it is alkylene, X 1 or X 2 exists, or R 2 is substituted C 1～6 When R is alkylene, 2 is 1 to 4 R 14 is replaced by R 3 is absent or NH,N(C 1～6 alkylene) and C 1～6 alkylene; R 4 is absent or is an arylene, heteroarylene, C(C 3～10 Cycloalkylene) 2 , C 3～10 Cycloalkylene, heterocycloalkylene, and (OCH 2 CH 2 O) q and R 5 does not exist or C 1～6 alkylene, R 6 does not exist or is OC 1～6 Alkylene and 【Chemistry 4】 and R 13 does not exist or C 1～12 Alkylene, C 3～10 Cycloalkylene, C 3～10 Cycloalkylene C 1～6 is any one selected from the group consisting of alkylene, heterocycloalkylene, heteroarylene, and arylene; R 13 is 1 to 4 R 15 and optionally substituted with R 14 are independently -C 0～3 Alkylene-Polyethylene Glycol, Halo, OH, NH 2 , SH, CN, C 3～10 Cycloalkyl, C 1～8 selected from the group consisting of alkoxy, aryl, and heteroaryl; R 15 are independently halo, OH, NH 2 , S.H., C. 3～10 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; A 8 ~A 11 is an alpha-, beta- or gamma-amino acid unsubstituted or substituted at any N atom, Ala, Arg, Asn, 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-Glu, 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, azetidine-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, 2-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-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid any amino acid residue independently selected from residues of cyclo[3.2.1]octane-2-carboxylic acid, 6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 3-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, and 4-amino-6-azabicyclo[3.1.1]heptane-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 t-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 of claim 1 of formula Ia: 【Transformation 5】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R a is CH 2 CH (CH 3 ) 2 or CH 2 Ph, The integer f is 1 or 2.

3. The compound of claim 1 of formula Ib: 【Transformation 6】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R a is CH 2 CH (CH 3 ) 2 or CH 2 Ph].

4. X 2 is either absent or comprises an amino acid or peptide residue selected from Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Glu-Gly, Asp-Val-Glu-Asp, Ala-Ala-Gly, and Ala-Ala, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5. R 2 is 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)-S-C 1～3 Alkylene -CH(NH 2 ) -, -C 1～6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-S-C 1～12 Alkylene-, -C 1～6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-S-C 3～6 Cycloalkylene-, -C 1～6 Alkylene-(OCH 2 CH 2 O) q -C 1～6 Alkylene-R 6 -S-R 13 -, -C 1～6 Alkylene-arylene-S-S-R 13 -, -arylene-C 1～6 Alkylene-S-S-R 13 -, -N (C 1～6 alkylene)-arylene-C 1～6 Alkylene-S-S-C 2～6 Alkylene-, -N(C 1～6 alkylene)-arylene-C 1～6 Alkylene-S-S-C 3～10 Cycloalkylene C 1～6 Alkylene-, -N(C 1～6 alkylene)-arylene-S-S-C(CH 3 ) 2 -C 1～3 Alkylene-, -N(C 1～6 Alkylene)-arylene-S-S-C 3～10 Cycloalkylene C 1～6 Alkylene-, -N(C 1～6 Alkylene)-C 1～6 Alkylene-S-S-C 1～3 Alkylene-C(NH 2 ) -, -N (C 1～6 Alkylene)-C 1～6 Alkylene-S-S-C 2～6 Alkylene-, -N(C 1～6 Alkylene)-OC 1～6 Alkylene-S-S-R 13 -, -C 2～6 Alkylene-S-S-C 3～10 Cycloalkylene C 1～6 Alkylene-, -C 3～6 Alkylene-S-S-C 1～6 Alkylene-, -C 3～6 Cycloalkylene-S-S-C 1～6 Alkylene-, -C 1～6 Alkylene-S-S-C 3～6 Cycloalkylene- and -C 3～6 Cycloalkylene-S-S-C 3～6 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from the group consisting of: cycloalkylene-;

6. X 3 -C(=O), -C(=O)CH 2 C(=O)-,-C(=O)CH 2 CH 2 C(=O)-,-C(=O)OCH 2 CH (CH 3 )-S-S-CH 2 C(=O)-,-C(=O)CH 2 CH 2 NHC(=O)CH 2 CH 2 C(=O)-, -C(=O)CH(NH 2 ) CH 2 CH 2 C(=O)-, -C(=O)cyclobutylC(=O)-, -(C=O)S-S(C=O)-, -(C=O)CH 2 -S-S-C (CH 3 ) 2 (C=O)-,-(C=O)CH 2 -S-S-C (cyclopropyl) 2 (C=O) -, -(C=O)C(CH 3 ) 2 -S-S-CH 2 (C=O)-, -(C=O)C(cyclopropyl) 2 -S-S-CH 2 (C=O)-, -(C=O)NHCH 2 CH 2 -S-S-C (CH 3 ) 2 CH 2 C(=O)-,-(C=O)NHCH 2 C(CH 3 ) 2 -S-S-C (CH 3 ) 2 CH 2 C(=O)-, -C(=O)NHCH 2 CH 2 -S-S-C (cyclopropyl) 2 -, -(C=O)OCH 2 CH 2 -S-S-C (CH 3 ) 2 CH 2 C(=O)-,-(C=O)OCH 2 C(CH 3 ) 2 -S-S-C (CH 3 ) 2 CH 2 C(=O)-,-C(=O)OCH 2 CH 2 -S-S-C (cyclopropyl) 2 -, -(C=O)CH 2 CH 2 -(2,5-dioxopyrrolidine-1,3-diyl)-S-CH 2 CH 2 C(=O)-,-(C=O)CH 2 CH 2 -(2,5-dioxopyrrolidine-1,3-diyl)-S-CH 2 CH(NH 2 )C(=O)-,-(C=O)CH 2 -(2,5-dioxopyrrolidine-1,3-diyl)-S-CH 2 CH 2 C(=O)-,-(C=O)CH 2 -(2,5-dioxopyrrolidine-1,3-diyl)-S-CH 2 CH(NH 2 )C(=O)-,-(C=O)C 1－6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-S-C(CH 3 ) 2 CH 2 -C(=O)-,-(C=O)C 1－6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-S-C(CH 3 ) 2 C(CH 3 ) 2 -C(=O)-, 【Transformation 7】 and 【Transformation 8】 6. The compound of any one of claims 1 to 5, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

7. -X 1 -X 2 -X 3 - is independently selected from the following structures, -X 1 -X 2 -X 3 The left side of the - is R 1 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, connected to: 【Chemistry 9】 【Chemistry 10】

8. R 1 8. The compound of any one of claims 1 to 7, wherein H is represented by formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 【Chemistry 11】 [In the formula: R 8 and R 9 are independently H, C 1～12 Alkyl, C 1～12 selected from the group consisting of alkylC(═O)O—, —OH, and halo; or R 8 and R 9 Let's get together and 【Chemistry 12】 wherein E is CH 2 and O, E is CH 2 When E is O, G is N, or when E is O, G is CH or C(C 1～6 alkyl), R 11 is -W-Y-Z-R 12 Or -W-Y-Z-C 1～6 Alkylene-R 12 and R 7 is -C 1～6 Alkylene-NR i R j , -C 1～6 Alkylene -OH, -C 1～6 Alkylene-halo, -S-C 1～6 Alkylene-halo, -C 1～6 Alkylene-T-W-Y-Z-R 12 , and -C 1～6 Alkylene-T-W-Y-Z-C 1～6 Alkylene-R 12 is selected from the group consisting of R 12 is, in each occurrence independently, H, NR i R j , OH, and SH; T is S(=O), S(=O) 2 , S(=O) 2 NR i , O, S, C(=O)NR i , C(═O), and NR i is selected from the group consisting of W and Z, in each occurrence, are independently absent or independently each represent 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 is selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, optionally substituted with Y, in each occurrence, is independently absent or -C 0～6 Alkylene-CR i R j -C 0～6 Alkylene-, -C 0～6 Alkylene-O-C 0～6 Alkylene-, -C 0～6 Alkylene-S-C 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) 2 NR 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≡C-C 0～6 alkylene-, R 10 is, at each occurrence, independently selected from the group consisting of OH, halo, alkyl, ═O, and arylalkyl; R i and R j is independently selected at each occurrence from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The dotted lines represent either single or double bonds; n is an integer from 0 to 19.

9. R 1 9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein H is represented by formula IIa, IIb, IIc, or IId according to Formula II. 【Chemistry 13】

10. R 1 10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein H is selected from the following structures: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】

11. R 1 However, structure R 1 Primary alcohol CH in H 2 OH group, phenylene-OH group, or NH 2 11. The compound of claim 10, derived by subtracting H from a group.

12. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from the following structures: [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】

13. 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, having anti-inflammatory activity or therapeutic effect against renal disease, wherein the therapeutic effect is determined by (i) attenuating or delaying renal cytokine release, such as TNF-α, IL-6, IL-12, or the like; (ii) a decrease in one or more biomarkers, optionally wherein the one or more biomarkers are selected from protein levels, blood urea nitrogen, and serum creatinine; or (iii) an improvement in the condition of a mammal in a patient or animal model in need of such treatment.

14. 14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the anti-inflammatory activity is the treatment of renal inflammation, inflammatory diseases in renal injury or dysfunction, or inflammation induced by a nephrotoxic agent, including pharmaceutical nephrotoxic agents such as anti-cancer, anti-diabetic, anti-infective, or another chemotherapeutic agent.

15. Similar doses of free agent or drug R incorporated into the compound as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory, or nephroprotective activity. 1 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, having enhanced anti-inflammatory, immunomodulatory, or nephroprotective effects when compared to H.

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

17. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein, when administered to a mammal, the compound exhibits preferential accumulation in the kidney, and the ratio of its molar concentration in the kidney to its molar concentration in the blood is at least about 20.

18. Drug R 1 When administered to a mammal in a dose (expressed in molar amounts) equivalent to a standard molar dose of H, the compound reacts with the free drug R 1 Approximately 1.5 to 15 times higher loading dose (tissue concentration) and / or intrarenal drug R compared to the standard dose of H 1 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which exhibits a drug exposure (area under the curve, AUC) of H

19. Drug R 1 When administered to a mammal in a dose (expressed in molar quantities) equal to the standard therapeutic dose (molar quantity) of H, the drug R 1 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which exhibits about 1.5 to 15 times greater efficacy compared to the standard dose of H, wherein the therapeutic effect is determined as a slowing, halting, or reversal of the progression of inflammation (as determined by changes in cytokine release and / or by using biochemical biomarkers or similar methods to monitor the disease).

20. Drug R 1 When administered to a mammal in a dose (expressed in molar quantities) equal to the standard therapeutic dose (molar quantity) of H, the drug R 1 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which exhibits at least two-fold greater efficacy compared to the standard dose of H, wherein the therapeutic effect is determined as a slowing, halting, or reversal of the progression of inflammation or kidney damage (as determined by levels of cytokine release and / or by using biochemical biomarkers to monitor inflammation, or by radiography, or by magnetic resonance imaging, etc.).

21. Drug R 1 When administered to a mammal in a dose (expressed in molar quantities) equal to a standard therapeutic dose (molar quantities) of H, R 1 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which exhibits at least a two-fold reduced rate of side effects and / or off-target toxicity compared to the standard dose of H, as determined by medical observation of the mammal during treatment, blood counts, tissue biopsies, and / or by analysis of biochemical biomarkers, or similar methods.

22. 22. A pharmaceutical composition comprising a therapeutically effective amount of a 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. 23. A method of treating kidney inflammation in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition of claim 22.

24. The compound or its pharmaceutical 24. The method of claim 23, wherein an acceptable salt, solvate, or hydrate, or the pharmaceutical composition is administered to the mammal parenterally, transdermally, orally, intranasally, topically, rectally, or via intratumoral administration in a pharmaceutical composition.

25. The method of claim 23 or 24, wherein the renal 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: 【Chemistry 31】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: R 8 and R 9 Let's get together and 【Chemistry 32】 wherein E is CH 2 and O, E is CH 2 If G is N and R is 11 is -Z-NR i R j , -Z-OH, and -W-Y-Z-R 12 Selected from R 7 is -C 1～6 Alkylene -OH, -C 1～6 Alkylene-NH 2 , -C 1～6 Alkylene-T-W-Y-Z-R 12 , -C 1～6 Alkylene-T-Z-NR i R j , and -C 1～6 alkylene-T-Z-OH; or when E is O, G is CH and R 11 is selected from the group consisting of alkyl, R 7 is -C 1～6 Alkylene-T-Heteroarylene-NR i R j Or or when E is O, G is CH and R 11 is -heteroarylene-NR i R j , -arylene-heteroarylene-NR i R j , -Z-OH, -W-Y-Z-SH, and -W-Y-Z-OH; R 7 is -C 1～6 alkylene-OH or When E is O, G is CH, and R 11 is -Z-NR i R j , -Z-OH, and W-Y-Z-R 12 and R 7 is -C 1～6 Alkylene-T-W-Y-Z-R 12 , -C 1～6 Alkylene-T-Z-OH, -C 1～6 Alkylene-T-Z-NR i R j , and -C 1～6 Alkylene-NH 2 or selected from the group consisting of R 12 is, in each occurrence, independently, H, −NR i R j , —OH, and —SH; T is S(=O), S(=O) 2 , S(=O) 2 NR i , O, C(=O)NR i , C(═O), and NR i is selected from the group consisting of W is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; Z, in 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 is, at each occurrence, independently selected from the group consisting of —OH, halo, alkyl, and arylalkyl; R i and R j is independently selected at each occurrence from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The dotted lines represent either single or double bonds; n is an integer from 0 to 19.

27. 27. The compound of claim 26, having formula IIa, IIb, IIc or Iid. 【Transformation 33】

28. W is, 【Transformation 34】 【Chemistry 35】 and 【Transformation 36】 28. The compound of claim 26 or 27, selected from the group consisting of:

29. 29. The compound of any one of claims 26-28, wherein Z, at each occurrence, is independently selected from the group consisting of: 【Chemistry 37】

30. 30. The compound of any one of claims 26 to 29, selected from the following structures: 【Transformation 38】

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