Compounds and compositions for targeted therapy of kidney disease

Abstract

This application provides therapeutic compounds, e.g., compounds of formula I, or pharma- ceutically acceptable salts, hydrates or solvates thereof that are therapeutic or anti-cancer agents, pharmaceutical compositions thereof, methods of use thereof, and methods of preparing these compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 224,402, filed July 21, 2021, the entire contents of which are incorporated herein by reference for all purposes.

[0002] This application provides novel biologically active compounds, pharmaceutical compositions thereof, methods of use thereof, and methods for their preparation. These novel reagents and compositions have therapeutic activity useful in the treatment of inflammation-related kidney diseases, particularly chronic kidney disease (CKD), systemic lupus erythematosus (SLE), diabetic nephropathy, chronic glomerulonephritis, and acute kidney injury (AKI). [Background technology]

[0003] Kidney disease encompasses a wide variety of serious kidney disorders and has a profound impact on the lives of people worldwide. Renal inflammation can be caused by a variety of exogenous and endogenous factors, including exposure to nephrotoxic substances, surgery (e.g., kidney transplantation), chemotherapy (e.g., treatment for cancer, diabetes, or infection), infections (e.g., urinary tract infection, pyelonephritis), and several chronic diseases. Among these, acute and chronic kidney diseases, such as CKD, have been reported to have reached epidemic proportions worldwide (see, e.g., Levey et al., Kidney Int., 2005, pp. 2089-2100; Stenvinkel, J. Intern. Med., 2010, 268, pp. 456-467). However, the long-term treatments required to manage these disease states typically involve serious side effects, produce unsatisfactory results, and often result in poor patient compliance.

[0004] Systemic lupus erythematosus (SLE) is another common chronic inflammatory disease that often affects the kidneys (see, for example, Almani et al., Clin. J. Am. Soc. Nephrol. 2017, 12, pp. 825-835). SLE can lead to the debilitating disease lupus nephritis (LN), which must be treated with high-dose corticosteroids, toxic cyclophosphamide, or strong immunosuppressants (e.g., cyclosporine). This chemotherapy is usually limited by a series of adverse reactions.

[0005] Furthermore, developing new and improved therapies for these kidney diseases is difficult. For example, as described by Wischnjow et al. in Bioconjugate Chemistry, 2016, pp. 1050-1057, some drug candidates, including those used to treat CKD, autosomal dominant polycystic kidney disease (ADPKD), and diabetic nephropathy, have failed in clinical trials due to safety and / or efficacy issues.

[0006] Importantly, many of the side effects that limit the use of current pharmaceuticals and the development of new agents are related to excessive and widespread systemic exposure to such biologically active molecules. In other words, biologically active agents targeted at renal disorders, administered orally or intravenously, must circulate in the bloodstream of the mammal or patient requiring such treatment before reaching the kidney. This undesirable but unavoidable distribution of biologically active molecules to various body compartments and organs other than the kidney results in off-target effects that typically manifest as adverse events.

[0007] Therefore, targeted renal drug delivery, which involves selectively transporting biologically active molecules to the kidney, is preferable to conventional therapies that require exposing other organs to drugs that may cause side effects in non-renal areas. This allows the bioactive effects of drugs to be applied directly to the site of kidney disease, thereby expanding the therapeutic range of drugs, reducing systemic side effects, and improving the efficacy of such treatments.

[0008] Several kidney disease drug delivery systems (also called kidney vectors or molecular delivery systems) that target structures in kidney tissue have been described. For example, peptide vector structures are described in 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 used as kidney 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 (see, e.g., J. Med. Chem., 1992, pp. 1246-1259 ; and Int. J. Nanomedicine, 2017, pp. 5673-5686 ).

[0009] Another class of reagents for the targeted treatment of kidney diseases includes prodrugs that selectively release biologically active drug structures via kidney-associated enzymes (see, e.g., J. Controlled Release, 2013, pp. 148-156; and RSC Adv. 4, 2014, pp. 50828-50831).

[0010] Among severe kidney diseases, CKD (chronic kidney disease) is recognized as a global public health problem. Over time, this chronic disease progresses to debilitating end-stage renal disease. Ultimately, life-sustaining options are limited to time-consuming and expensive renal dialysis and / or kidney transplantation. This dire situation is further exacerbated by the lack or absence of dialysis stations in many parts of the world. Therefore, end-stage renal disease can be prevented by improving treatment and disease management (see, for example, Perico et al., Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24). CKD treatment represents an unmet medical need.

[0011] CKD is a complex disease involving multiple contributing parameters. One of the major contributing factors is inflammation, which is usually caused by the overexpression of pro-inflammatory mediators, such as endothelin-1, monocyte chemoattractant protein-1, normal T cells, and osteopontin, as described by Perico et al. in 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. in J. Clin. Hypertension, 2015, 17, pp. 514–527). Furthermore, AKI can develop independently of CKD, for example, due to exposure to nephrotoxins, such as nephrotoxic pro-inflammatory substances. In kidney transplantation, renal ischemia-reperfusion injury is the primary etiology of AKI. Similar to the pathogenesis of CKD, renal inflammation plays an important role in the pathophysiology of ischemic AKI (see, for example, Bonventre and Zuk, Kidney Int. 2004, 66, pp. 480-485).

[0012] Subsequently, specific anti-inflammatory drugs have been used to treat CKD and AKI. For example, Moonen et al. described anti-inflammatory treatment with the corticosteroid dexamethasone in BMC Nephrology. 2018, 19:34 3.

[0013] Additionally, supportive anti-inflammatory therapy is commonly used during cancer treatment, for example, to counteract the toxic effects of anticancer drugs (see, e.g., Shih et al., J. Pain Palliative Care Pharmacother. 2007, 21, pp. 69-76; 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).

[0014] However, long-term exposure to most anti-inflammatory drugs, such as steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), can result in serious side effects, including bone loss, cataracts, and muscle weakness. Therefore, safer and more effective drugs are needed to treat CKD, SLE, LN, AKI, and various other inflammation-related kidney diseases or disorders. Such therapies must have improved selectivity, whereby the drug's biological activity is directed to the diseased site, thereby minimizing or eliminating off-target toxic side effects caused by exposure to healthy tissues and organs.

[0015] A recent approach to improving drug selectivity is to target highly active agents directly to the kidney (see, for example, Wischnjow et al., Bioconjugate Chemistry, 2016, pp. 1050-1057). In this approach, the active agent (e.g., an antibacterial agent) is linked (or bound) to an organ-targeting structure that has a high affinity for kidney cells. As a result, the active agent or drug can be selectively delivered to the organ in need of treatment.

[0016] This application describes unique conjugates of certain anti-inflammatory agents with acyclic and cyclic peptides (cyclic peptides) suitable for the targeted treatment of various kidney diseases. Covalent attachment of the bioactive agent to the peptide is achieved by carefully designing appropriate linkers and additional structural elements (e.g., attachment-modifying spacers) to maximize targeted delivery and therapeutic bioactivity. The reagents provided herein are particularly suitable for the treatment of CKD, AKI, and other non-cancerous kidney diseases.

[0017] For example, WO 2021 / 150792, WO 2019136298, WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, US 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, CN 103923190, US 2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, CN 103130876, WO 2013 / 072695, WO 2012 / 168820, WO 2012051663, US Various cyclic peptides are described in WO 2012 / 0316105, US 2012 / 0283176, US 2010 / 0160215, US 2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, US 2006 / 0004185, US 6380356, and US 3450687. Several conjugates of acyclic peptide structures for renal-targeted delivery of protective agents against nephrotoxic substances have already been described, for example, in U.S. Pat. No. 10,413,614. None of these references specifically describe or generally consider the compositions provided by the present application. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] International Publication No. 2016 / 100578 [Patent Document 2] International Publication No. 2014 / 014890 [Patent Document 3] US Patent Application Publication No. 2018 / 099022 Summary of the Invention [Problem to be solved by the invention]

[0019] The present application provides novel compounds and compositions useful for the targeted treatment of inflammation-related kidney diseases.

[0020] These novel compounds are unexpectedly capable of targeting renal tissues, particularly renal cells affected by inflammation, including inflammation caused by overexpression of innate pro-inflammatory mediators, inflammation induced by exogenous nephrotoxic substances, or inflammation caused by other therapeutic agents (e.g., cytotoxic anticancer drugs or nephrotoxic antibacterial agents). The unique affinity of the compositions described herein for renal tissues affected by kidney disease can enable the selective delivery and accumulation of such molecules at the diseased site, with minimal or no accumulation in other tissues not affected by such pathological conditions.

[0021] This provides a more selective and generally safer renal therapy than the standard therapeutic agents currently used to treat inflammation-related kidney diseases (e.g., steroids and NSAID agents), with significantly reduced side effects on other normal organs of the mammal being treated. [Means for solving the problem]

[0022] In one aspect, the therapeutic effect of the compounds of the present application is achieved by releasing one or more anti-inflammatory elements (biologically active payloads and / or drugs) incorporated into such engineered molecules. The active payloads (drugs) may include steroid structures, NSAID structures, or immunomodulatory structures. For example, they may be selected from biologically active structures capable of suppressing or combating inflammation (e.g., inflammation caused by AKI or transplantation, or inflammation induced by cytokines), or activating immunomodulation of a therapeutic anti-inflammatory response.

[0023] In general, the compounds provided herein consist of a peptide, cyclic peptide, or other "target seeker" (ligand) structure with high affinity (binding capacity) for kidney cells, and an active drug substructure, present within a single conjugated molecule. The active drug (payload) is attached to the kidney-affinity structure via a uniquely designed linker and spacer framework. This unique design effectively releases the active drug (payload) directly into kidney tissue, resulting in a therapeutic anti-inflammatory effect.

[0024] In another aspect, the composition possesses anti-inflammatory properties in the intact molecular form of the conjugate without releasing the active drug payload (contained within the structure) at the site of renal inflammation. Upon accumulation at the site of renal inflammation, the compound exerts a direct anti-inflammatory effect. In a related respect, the conjugate is degraded, usually to non-toxic metabolites, after exerting the desired biological activity.

[0025] In another aspect, the anti-inflammatory effect is achieved by a combination of (i) the direct anti-inflammatory effect of the compound (when accumulated at the cancer site) and (ii) the release of an active payload drug contained within the structure.

[0026] In another aspect, in the kidney, the intact conjugate and / or the drug released from said conjugate exhibits protection against nephrotoxic agents, such as cytotoxic anticancer drugs.

[0027] Surprisingly, some of the 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 kidney disease.

[0028] Furthermore, while the compositions provided herein include cyclic peptide molecules (structures) from a chemical class generally known to cause nephrotoxicity (e.g., polymyxins), the therapeutic compounds described herein exhibit little or no nephrotoxicity at the therapeutic dose levels required to treat inflammation-associated kidney disease.

[0029] As can be readily appreciated by those skilled in the art, not all molecular structures incorporating an anti-inflammatory element (payload) and a heat-seeker affinity structure (a ligand that targets renal cells) with appropriate linkers and strategically placed spacers (strategically placed between the ligand and the biologically active payload) are suitable for use as therapeutics. Surprisingly, the compounds and compositions provided herein have favorable pharmacological characteristics, adequate stability in plasma, prevent premature biological activity, and preferentially accumulate in renal cells and / or kidneys affected by inflammatory renal damage.

[0030] Even more surprisingly, some compounds provided herein are self-targeted and either directly delivered to renal cells affected by inflammation or exert their biological activity only in the vicinity of tissue affected by inflammation. In part, the compositions comprise molecules that can specifically release an anti-inflammatory payload (incorporated into their structure) as a result of metabolic degradation by classes of enzymes (e.g., cathepsins, glutaminases, glutathione transferases, and peptide decarboxanases, or PDFs, peptidases, reductases, and similar known enzymes) that are specific to or overexpressed (enriched) in renal cells affected by inflammation.

[0031] In addition to metabolic degradation by enzymes overexpressed in renal cells affected by inflammation (e.g., cathepsins, glutaminases, PDFs, etc.), some compounds provided herein are degraded in vivo by chemical cleavage, such as the pH-dependent autocleavage of molecules known to possess a cleavable group (e.g., an ester, amide, or urethane group) and a free nucleophilic group (e.g., an amine, alcohol, or thiol group). When these two types of degradable and nucleophilic groups are in close spatial proximity and the nucleophilic group is essentially free (e.g., an amine group under neutral, basic, or physiological pH conditions), the nucleophilic group is acylated with the 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 in combination with the above process, a free amine can activate an amide functional group adjacent to the carbamate group and induce a carbamate reaction with the latter, converting the native amide into a bis-acylated imide group. In some compositions described herein, cleavage of the chemically designed linker occurs after initial enzymatic metabolism of an auxiliary enzyme-cleavable linker (e.g., a peptide substructure or analog) to release the anti-inflammatory payload in renal tissue.

[0032] In one aspect, the present application provides a compound of formula IP-1

[0033] [ka]

[0034] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 1 and R 2 is any group, and R 1 and R 2 is present in formula IP-1, and R 1 and R 2 are independently selected from alkyl groups, aryl groups, biaryl groups, heteroaryl groups, heteroarylaryl groups, and arylheteroaryl groups; or (H) n R 1 and (H)o R 2 If present in R 1 and R 2 is a hydrogen-containing group independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH, and S(=O)NH, at any one position of the corresponding parent (precursor) structure (H)nR 1 and (H) o R 2 are residues bonded independently to X and Z by removing one or more H atoms from a)(H) n R 1 and (H) o R 2 are independently anti-inflammatory compounds, immunomodulatory compounds, nephroprotective compounds, and compounds that modulate glucocorticoid receptor (GR) activity, modulate cytokine release, or otherwise exhibit, have activity, or are capable of inducing biological activity against inflammation-related kidney disease or kidney injury; or b)(H) n R 1 and (H) o R 2 are selected from the group consisting of aldosterone, AN3485 (6-(4-(aminomethyl)-2-chlorobenzeneoxy)benzo[c][1,2]oxaboron-1(3H)-ol), beclomethasone, betamethasone, budesonide, budesonide metabolites, celecoxib, 11-deoxycortisone, dexamethasone, hydrocortisone, fluticasone mometasone, ibuprofen, naproxen, prednisolone, triantherone, valdecoxib, heteroaromatic vanillin inhibitor compounds (selected from compounds described in PCT WO2020 / 114943 and US2020 / 0354338), heterocyclic TYK2 inhibitor compounds (selected from compounds described in PCT WO2020 / 86616 and US2020 / 0354338), and independently selected from an INFα inhibitory compound selected from the compounds described in WO2020 / 159904 and EP3917912, or a variant thereof; c)(H) n R 1 and (H)o R 2 are compounds that are independently active against inflammation-related kidney disease, or d)(H) n R 1 is a glucocorticoid structure that is bound to X at any one of the O or N atoms, and at least one of these atoms is the structure (H) n R 1 exists in, and Any group R 1 If R is not present, the fragment R is 11a is replaced by R 11a is H, alkyl group, C 3-7 Cycloalkyl groups, 5- to 6-membered heterocyclic groups, aryl groups, biaryl groups, heteroaryl groups, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C 1-12 Alkyl group)C(=O), AlkSO2, AlkNHSO2, C 3-7 Cycloalkyl group C(=O), C 3-7 Cycloalkyl group NHC(=O), C 3-7 Cycloalkyl group N(C 1-12 Alkyl group C(=O), aryl group C(=O), aryl group OC(=O), aryl group OC(=O), aryl group NHC(=O), aryl group NHC)C(=O), aryl SO2, aryl NHSO2, heteroaryl C(=O), heteroaryl OC(=O), heteroaryl NHC(=O), heteroaryl N(C 1-12 alkyl)C(=O), heteroarylSO2, heteroarylNHSO2, or Any group R 2 does not exist, fragment R 2 Z is R 12a is replaced by R 12a is H, alkyl group, C 3-7 Cycloalkyl groups, 5- to 6-membered heterocyclic groups, aryl groups, biaryl groups, heteroaryl groups, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C 1-12 Alkyl group (yl)C(=O), AlkSO2, AlkNHSO2, C 3-7 Cycloalkyl group ylC(=O), C3-7 Cycloalkyl group OC(=O), C 3-7 Cycloalkyl group NHC(=O), C 3-7 Cycloalkyl group N(C 1-12 Alkyl group)C(=O), aryl group C(=O), aryl group OC(=O), aryl group OC((C 1-12 Alkyl)C(=O), ArylSO2, ArylNHSO2, HeteroarylC(=O), HeteroarylOC(=O), HeteroarylNHC(=O), HeteroarylN(C 1-12 alkyl)C(=O), heteroarylSO2, heteroarylNHSO2, or integers n and o are independently selected from 0, 1, 2, 3, 4, 5, 6, and 7, such that [n+o]>1; A 1 ~A 11is any amino acid residue, unsubstituted or substituted at any of the N atoms, including α-, β-, or γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine from 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, 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-arylbutyric acid, 4-amino-3-(3-chlorophenyl)butyric acid, and 5-amino-4-arylvaleric acid; and The integers a to k, m, and zz are independently selected from 0, 1, and 2, and [m+zz]≧1, where If any one of the integers a to k is 0, then any two groups adjacent to the corresponding non-existent group (by the integer 0 of the non-existent group) are directly connected to each other, and If the integers a to g are all 0, then the group A 1 ~A 7 does not exist and A 8 is COOH, CH2OH or C(=O)NR 3 R 4 terminated by R 3 and R 4 are independently selected from H, alkyl groups, aryl groups, heteroaryl groups, or heterocyclic groups, or a group A 8 is directly attached to the group Y, and Any divalent group X is independently selected from the following: O, NH, N(C 1-6 Alkyl group), S, SS, SN, S(=O), SO2, C(=O), OC(=O), C(=O)O, NHC(=O)NH, N(C 1-6 Alkyl group C(=O)NC 1-6 alkyl group), NHC(=O)NC 1-6 alkyl group), C 1-12 an alkylene group, an arylene group, a biaryl group, a (heteroaryl)arylene group, an (aryl)heteroaryl group, a heterocycloalkyl group, (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 5 )C(=O), C(=O)N(R 5 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2、P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 )s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) rS-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), and C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), or variants of the above groups formed by rearranging, adding or deleting the fragments C(=O), OC(=O), N(R5)C(=O), P(=O)(OCR5R6)CF2, P(=O)(OH)CF2, or C(=O)N(R5)SO2 therein, and R 6 , R 7 , R 9 , R9 and R 10 are independently H, NH2, halogen, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; R 5 are H, NH2, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl or heteroarylalkyl; or R 5 ~R 10 any two of these together with the atoms to which they are attached form a 4-7 membered saturated or unsaturated heterocycle, said heterocycle containing at least one O atom, or one O atom and another heteroatom independently selected from N and S, and the remaining atoms being carbon atoms; or R 5 ~R 10Any two of these, together with the carbon atoms to which they are attached, may form a 4- to 7-membered saturated or unsaturated C 3-6 forming a cycloalkylene group, or i) R 6 and R 7 ii) any one of R9 and R10 together with the atom to which they are attached is a saturated or unsaturated C 3-6 forming a cycloalkylene group, or R 5 ~R 10 any two of these together with the atoms to which they are attached form a 5- to 7-membered saturated or unsaturated heterocyclic ring, wherein said ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one, or R 6 and R 8 together with the atoms to which they are attached form a 4-6 membered saturated heterocyclic ring containing at least one O atom, wherein said heterocyclic ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one; and Integers p, r, and s are independently selected from 0, 1, and 2, Fragment (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 7 R 8 ) r (CR 9 R 10 ) s exists, then [r+s]≧1, or Alternatively, each of any divalent groups X independently has the structure: 12 or A 13 arbitrarily connected to (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 5 )C(=O), C(=O)N(R 5 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m , P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 )CF2、P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2、P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) sN(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O), C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), or C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2 or C(=O)N(R 5 ) any variant of said X group formed by rearranging, adding or deleting SO2 therein, among which amino acid residue A 12 and A 13 and both are incorporated to the right of said group to contain group X, then residue A 12 or A 13 Peptide bond A 12 -A 13 and interconnect with If any group X is absent, then the group R 1 is group A 8 , A 9 , A 10 or A 11 directly connected to either Additionally, each of any divalent groups X may independently be C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylene, (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s OC(=O), (CH2) p O(CH2) r O(CH2) s NHC(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), O(CH2) p O(CH2) r O(CH2) s C(=O), O(CH2) p O(CH2) r O(CH2) s OC(=O), O(CH2)pO(CH2)rO(CH2)sNHC(O), O(CH2)pO(CH2)rO(CH2)sN(C 1-14 alkyl group)C(=O), NH(CH2)pO(CH2)rO(CH2)sC(=O), NH(CH2)pO(CH2)rO(CH2)sOC(=O), NH(CH2) p O(CH2) r O(CH2) s NHC(=O), NH(CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) rO(CH2) s OC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s NHC(=O), N(C 1-14 alkyl)(CH2) p O(CH2)rO(CH2) s N(C 1-14 incorporating another divalent group selected from alkyl)C(=O) and similar linear groups; Any divalent group Y and Z is independently selected from the group consisting of O, NH, N(C 1-6 Alkyl group), S, SS, SN, S(=O), SO2, C(=O), OC(=O), C(=O)O, NHC(=O)NH, N(C 1-6 alkyl group)C(=O)NC 1-6 Alkyl group, NHC(=O)NC 1-6 Alkyl group, C 1-12 an alkylene group, an alkylene group, a biarylidene group, a (heteroaryl)arylene group, an (aryl)heteroaryl group, a heterocycloalkyl group, (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 5 )C(=O), C(=O)N(R 5 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 )s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5=CR 7 -(CR 9 R 10 ) s OC(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 )s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O -C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), and C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), Or C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2 or C(=O)N(R 5 ) any variant of said group formed by rearranging, adding, or deleting SO2 therein, among which R 5 ~R 10 is as defined above, or Alternatively, any divalent group Z may have the structure: 12 or A 13 Optionally connect to (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 5 )C(=O), C(=O)N(R 5 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 )s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), or C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O),

[0035] or fragments C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2 or C(=O)N(R 5 ) any variant of said Z group formed by rearranging, adding or deleting SO2 therein, among which amino acid residue A 12 and A 13 When both of the groups are incorporated to the left of said group and contain a group Z, the residue A 12 or A 13 Peptide bond A 12 -A 13 and interconnect.

[0036] In an alternative embodiment of formula IP-1, R 5 and R 6 along with the atoms to which they are attached, saturated or unsaturated C 3-6 Forms a cycloalkylene group.

[0037] In an alternative embodiment of formula IP-1, the fragment (CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 5 R 6 ) p (CR 7 R 8 )r (CR 9 R 10 ) s exists and [p+r+s]≧1.

[0038] In an alternative embodiment of formula IP-1, the fragment (CR 5 R 6 ) p (CR 7 R 8 ) r or (OCR 5 R 6 ) p (CR 7 R 8 ) r exists and [p+r]≧1.

[0039] In an alternative embodiment of formula IP-1, each of the optional divalent groups X is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4)C(=O), C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said X group formed by rearranging, adding or deleting SO2; or X is C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 [[ID=eleven]]) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR. 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) . s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、及び C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR[[ID=eleven]] 9 R 10 ) s N(R 5 )C(=O)から独立して選択され、 It should be noted that the original text seems to be some chemical formula or technical notation, and the translation is done as accurately as possible while maintaining the original format. If there are specific requirements or corrections needed for the translation in the context of a particular field, further adjustments might be necessary.where R 8 is H, NH2, halogen, NH(C 1-6 alkyl group), NH(OC 1-6 alkyl group), C 1-14 Alkyl group, C 3-6 independently selected from a cycloalkyl group, an aryl group, an arylalkyl group, a biaryl group, a biarylalkyl group, a heteroarylalkyl group, or R 6 and R 8 together with the atoms to which they are attached form a 4-6 membered saturated heterocycle containing at least one O atom, wherein said heterocycle optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises a 1,3-dioxol-2-one heterocycle.

[0040] In an alternative embodiment of formula IP-1, each optional divalent group X is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 )s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)(CR 5 R6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variation of said X group formed by rearranging, adding or deleting SO2; Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 or X is C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 )s OC(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s independently selected from OC(=O), Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 to be connected arbitrarily.

[0041] In an alternative embodiment of formula IP-1, each of the optional divalent groups X is S(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s is OC(=O) or is selected from the following groups:

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] and fragment N(R 4 any variant of said X group formed by rearranging, adding, or deleting a C(=O); or Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 Optionally connect to where xx is 1, 2, or 3, R 100 and R 101 is independently selected from H and an alkyl group; X 1 and X 2 are O, NH and CR 5 R 6 are independently selected from All other variables are defined in Formula IP-1 herein.

[0046] In an alternative embodiment of formula IP-1, each of the optional divalent groups Y and Z is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 )s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) independently selected from any variant of said group formed by rearranging, adding, or deleting SO2; or Each of the optional divalent groups Y and Z is C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m , P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2、P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 )r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p SS(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r SS(CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r SS(CR 9 R 10 ) s C(=O), and C(=O)(CR 5 R 6 ) p SS(CR 7 R 8 ) r SS(CR 9 R 10 ) s are independently selected from O—C(═O).

[0047] In an alternative embodiment of formula IP-1, each of the optional divalent groups Z is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) independently selected from any variant of said group formed by rearranging, adding, or deleting SO2; Among them, the Z group is 1 to 2 amino acid residues A 12 or A 13 or Each of the optional divalent groups Z is C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m , P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) rC(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 ) p (CR 7 R<于 8 ) r S-S(CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O), and C(=O)(CR 5 R 6 ) p (CR 7 R 8 [[ID=|119]]) r (CR 9 R 10 )s N(R 5 )C(=O), Among them, the Z group is 1 to 2 amino acid residues A 12 or A 13 to be connected arbitrarily.

[0048] In another embodiment, a compound of formula IP-2

[0049] [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 1 and R 2 is any group, and R 1 and R 2 is present in formula IP-2, and R 1 and R 2 are independently selected from alkyl groups, aryl groups, biaryl groups, heteroaryl groups, heteroarylaryl groups, steroid groups, and arylheteroaryl groups; or (H) n R 1 and (H) o R 2 If present in R 1 and R 2 is a hydrogen-containing group independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH, and S(=O)NH, at any one position of the corresponding parent (precursor) structure (H)nR 1 and (H) o R 2 are residues that connect independently to X and Z, respectively, by removing one or more H atoms from a)(H) n R 1 and (H) o R 2are independently an anti-inflammatory compound, an immunomodulatory compound, or a nephroprotective compound, or a compound that modulates glucocorticoid receptor (GR) activity, modulates cytokine release, or otherwise exhibits, has activity, or is capable of inducing biological activity against inflammation-related kidney disease or kidney injury; or b)(H) n R 1 and (H) o R 2 are independently selected from aldosterone, AN3485, beclomethasone, betamethasone, budesonide, budesonide metabolites, celecoxib, 11-deoxycortisone, dexamethasone, hydrocortisone, fluticasone mometasone, ibuprofen, naproxen, prednisolone, triantherone, valdecoxib, a heteroaromatic vanin inhibitor compound (selected from compounds described in PCT WO2020 / 114943 and US2020 / 0354338), a heterocyclic TYK2 inhibitor compound (selected from compounds described in PCT WO2020 / 86616 and US2020 / 0354338), and an INF-α inhibitor compound (selected from compounds described in PCT WO2020 / 159904 and EP3917912), or variants thereof; c)(H) n R 1 and (H) o R 2 are compounds that are independently active against inflammation-related kidney disease, or d)(H) n R 1 has at least one structure (H) n R 1 a glucocorticoid structure or variant thereof, which is bound to X at any one of the O or N atoms present in Any group R 1 does not exist, fragment R 1 X is R 11a is replaced by R 11a H, Alk, C 3-7Cycloalkyl groups, 5-6 membered heterocyclic groups, aryl groups, biaryl groups, heteroaryl groups, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C1-12 alkyl group)C(=O), AlkSO2, AlkNHSO2, C 3-7 Cycloalkyl group C(=O), C 3-7 Cycloalkyl group NHC(=O), C 3-7 Cycloalkyl group N(C 1-12 Alkyl group C(=O), aryl group C(=O), aryl group OC(=O), aryl group OC(=O), aryl group NHC(=O), aryl group NHC)C(=O), aryl SO2, aryl NHSO2, heteroaryl C(=O), heteroaryl OC(=O), heteroaryl NHC(=O), heteroaryl N(C 1-12 alkyl)C(=O), heteroarylSO2, heteroarylNHSO2, or Any group R 2 does not exist, fragment R 2 Z is R 12a is replaced by R 12a H, Alk, C 3-7 Cycloalkyl groups, 5-6 membered heterocyclic groups, aryl groups, biaryl groups, heteroaryl groups, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C1-12 alkyl group)C(=O), AlkSO2, AlkNHSO2, C 3-7 Cycloalkyl group C(=O), C 3-7 Cycloalkyl group NHC(=O), C 3-7 Cycloalkyl group N(C 1-12 Alkyl group C(=O), aryl group C(=O), aryl group OC(=O), aryl group OC(=O), aryl group NHC(=O), aryl group NHC)C(=O), aryl SO2, aryl NHSO2, heteroaryl C(=O), heteroaryl OC(=O), heteroaryl NHC(=O), heteroaryl N(C 1-12 alkyl)C(=O), heteroarylSO2, heteroarylNHSO2, or integers n and o are independently selected from 0, 1, 2, 3, 4, 5, 6, and 7, such that [n+o]>1; and A 1 ~A 11 is any amino acid residue, α-, β-, or γ-amino acid, unsubstituted or substituted at any of the N atoms, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine from 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, 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-arylbutyric acid, 4-amino-3-(3-chlorophenyl)butyric acid, and 5-amino-4-arylvaleric acid; and The integers a to k, m, and zz are independently selected from 0, 1, and 2, and [m+zz]≧1; and If any one of the integers a to k is 0, then any two groups adjacent to the corresponding non-existent group (by the integer 0 of the non-existent group) are directly connected to each other, and If integers a to g are all 0, then A 1 ~A 7 does not exist, and A 8 is COOH, CH2OH or C(=O)NR 3 R 4 terminated by R 3 and R 4 are independently selected from H, alkyl groups, aryl groups, heteroaryl groups, or heterocyclic groups, or a group A 8 is directly connected to the group Y, and Any divalent group X, Y, and Z is independently selected from the group consisting of: O, NH, N(C 1-6 alkyl), S, SS, SN, S(=O), SO2, C(=O), OC(=O), C(=O)O, NHC(=O)NH, N(C 1-6 alkyl)C(=O)NC 1-6 alkyl), NHC(=O)NC 1-6 alkyl), C 1-12 alkylene, arylene, biaryl, (heteroaryl)arylene, (aryl)heteroaryl, heterocycloalkyl, (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R5)C(=O), C(=O)N(R5)(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 )r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2、P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) sC(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 )r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), or C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 5 ) any variant of the above group formed by rearranging, adding, or deleting SO2 therein, and R 6 , R 7 , R 9 , and R 10 are independently H, NH2, halogen, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; R 5 are H, NH2, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl or heteroarylalkyl; or R 5 ~R 10 any two of these together with the atoms to which they are attached form a 4-7 membered saturated or unsaturated heterocycle, said heterocycle containing at least one O atom, or one O atom and another heteroatom independently selected from N and S, and the remaining atoms being carbon atoms; or R5 ~R 10 Any two of these, together with the carbon atoms to which they are attached, may form a 4- to 7-membered saturated or unsaturated C 3-6 forming a cycloalkylene group, or i) R 6 and R 7 , ii) R 9 and R 10 Any one of the C, along with the atom to which they are attached, 3-6 forming a cycloalkylene group, or R 5 ~R 10 any two of these together with the atoms to which they are attached form a 5- to 7-membered saturated or unsaturated heterocyclic ring, wherein said ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one, or R 6 and R 8 together with the atoms to which they are attached form a 4-6 membered saturated heterocyclic ring containing at least one O atom, wherein said heterocyclic ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one; and Integers p, r, and s are independently selected from 0, 1, and 2, Fragment (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 7 R 8 ) r (CR 9 R 10 ) s exists, then [r+s]≧1, or X, Y, and Z are 1 to 4 amino acid residues A connected via peptide bonds. 12 , A 13 , A 14 and A 15 are independently selected from A 12 , A 13 , A14 or A 15 are independently unsubstituted or substituted at any of the N atoms, α-, β- or γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Glu, D-His, 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-diaminovaleric 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, piperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, alkyl-2-carboxylic acids, 4-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid and 4-amino-6-azabicyclo[3.1.1]heptane-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-(3-chlorobenzene)butanoic acid, 4-amino-3-(3-chlorobenzene)butanoic acid, 5-amino-4-arylvaleric acid, or similar natural or unnatural amino acid residues, or X is a group containing the following structure, and on the right side of the following structure, 1 to 2 amino acid residues A 12 or A 13 and further connect with (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C1-12 アルキレン)、 (C 1-12 アルキレン)C(=O)、N(R5)C(=O)(C 1-12 アルキレン)、 (C 1-12 アルキレン)N(R5)C(=O)、C(=O)N(R5)(C 1-12 アルキレン)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6)CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O), C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), or C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 5 ) any variant of said group formed by rearranging, adding, or deleting SO2 therein, among which amino acid residue A 12 and A 13 and both are incorporated to the right of said group to contain group X, then residue A 12 or A 13 Peptide bond A 12 -A 13 and interconnect with If any group X is absent, then the group R 1 is group A 8 , A 9 , A 10 or A 11 directly connected to either Z is a group containing the following structure, and on the left side of the following structure, 1 to 2 amino acid residues A 12 or A 13 and further connect with (C 1-12 alkylene)OC(=O), OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R 5 )C(=O)(C 1-12 alkylene), (C 1-12 a alkylene)N(R 5 )C(=O), C(=O)N(R 5 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR9 R 10 ) s N(R 5 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) rS-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )CR 5 =CR 7 -(CR 9 R10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)- C 3-6 cycloalkylene-C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O), C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 alkyl]CH2CH2COOH]CH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O), or C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 alkyl]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 5 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 5 ) any variant of said group formed by rearranging, adding, or deleting SO2 therein, among which amino acid residue A 12 and A 13 When both of the groups are incorporated to the left of said group and contain a group Z, the residue A 12 or A13 Peptide bond A 12 -A 13 and interconnect with If any group Z is absent, then group R 2 is the group Y, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 or A 8 directly connected to either Any group X may independently be selected from the group C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylene, (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s OC(=O), (CH2) p O(CH2) r O(CH2) s NHC(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), O(CH2) p O(CH2) r O(CH2) s C(=O), O(CH2) p O(CH2) r O(CH2) s OC(=O), O(CH2)pO(CH2)rO(CH2)sNHC(=O), O(CH2)pO(CH2)rO(CH2)sN(C 1-14 alkyl group)C(=O), NH(CH2)pO(CH2)rO(CH2)sC(=O), NH(CH2)pO(CH2)rO(CH2)sOC(=O), NH(CH2) p O(CH2) r O(CH2)s NHC(=O), NH(CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s OC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sNHC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s N(C 1-14 Incorporating another divalent group selected from alkylC(=O) or similar linear groups.

[0050] In an alternative embodiment of formula IP-2, R 5 and R 6 along with the atoms to which they are attached, C 3-6 Forms a cycloalkylene group.

[0051] In an alternative embodiment of formula IP-2, the fragment (CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s exists and [p+r+s]≧1.

[0052] In an alternative embodiment of formula IP-2, the fragment (CR 5 R 6 ) p (CR 7 R 8 ) r or (OCR 5 R 6 ) p (CR 7 R 8 ) r exists and [p+r]≧1.

[0053] In an alternative embodiment of formula IP-2, any of the divalent groups X, Y, and Z is (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 4 )CR 5=CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 )r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), and C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), Fragment N(R 4 )C(=O) or C(=O)N(R 4 ) independently selected from any variant of said group formed by direct rearrangement, addition, or deletion of SO2; or Any divalent group X, Y, and Z is independently selected from the group consisting of: C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R8 ) r SS(CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sC(=O)、 C(=O)N[(CR5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sOC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 THE15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)-(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 )s C(=O), and C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), Among them, R 8 is H, NH2, halogen, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl group, C 3-6 independently selected from a cycloalkyl group, an aryl group, an arylalkyl group, a biaryl group, a biarylalkyl group, a heteroarylalkyl group, or R 6 and R 8 together with the atoms to which they are attached form a 4-6 membered saturated heterocyclic ring containing at least one O atom, wherein said heterocyclic ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one.

[0054] In an alternative embodiment of formula IP-2, any divalent group X is (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10) s C(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), and Fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group formed by direct rearrangement, addition, or deletion of SO2; Among them, X is 1 to 2 amino acid residues A 12 or A 13 further connected to, or Each of any divalent groups X is independently selected from: C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m , P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O), P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 )p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sOC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 THE 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)- (CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 )p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), where X is 1-2 amino acid residues A 12 or A 13 Connect further to.

[0055] In an alternative embodiment of formula IP-2, each of the optional divalent groups X is S(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s is OC(=O) or is selected from the following groups:

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] Fragment N(R 4 ) any variation of the above X group formed by rearrangement, addition or deletion of a C(=O) therein; or Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 arbitrarily connected to where xx is 1, 2, or 3, R 100 and R 101 is independently selected from H and an alkyl group; X 1 and X2 are O, NH and CR 5 R 6 are independently selected from All other variables are defined herein in formula IP-2.

[0060] In an alternative embodiment of formula IP-2, any divalent group Z is (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) sN(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r(CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), and Fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group formed by direct rearrangement, addition, or deletion of SO2; Among them, X is 1 to 2 amino acid residues A 12 or A 13 further connected to, or Each of the optional divalent groups Z is C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)N(R 5 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 5 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sOC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) sO(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)- (CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), and C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR5R6)p and Z is independently selected from OC(=O)(CR7R8)r(CR9R10)sC(=O), wherein Z is selected from 1 to 2 amino acid residues A 12 or A 13 is further connected to

[0061] In an alternative embodiment of formula IP-2, R 5 and R 6 along with the atoms to which they are attached, saturated or unsaturated C 3-6 Forms a cycloalkylene group.

[0062] In one aspect, the compound of formula IP-1 or formula IP-2 is a compound of formula I-1

[0063] [ka]

[0064] or a pharmaceutically acceptable salt, solvate or hydrate thereof; Among them, the integer zz is 1 or 2.

[0065] In one embodiment, the compound of formula I-1 is a compound of formula I-2

[0066] [ka]

[0067] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 1 is the corresponding parent (precursor) structure HR 1 is a residue formed by removing an H atom from a HR 1 is selected from the following: a) anti-inflammatory compounds, immunomodulatory compounds, nephroprotective compounds, and compounds that modulate glucocorticoid receptor (GR) activity, reduce proteinuria / creatinine levels, modulate cytokine release, or otherwise exhibit, have activity, or are capable of inducing biological activity against inflammation-related kidney disease or kidney injury; b) aldosterone, AN3485, beclomethasone, betamethasone, budesonide, budesonide metabolites, celecoxib, 11-deoxycortisone, dexamethasone, hydrocortisone, phenerizone, fluhydrocortisone, flunitrisone, flunitrisone, fluticasone mometasone, ibuprofen, naproxen, prednisolone, triantherone, valdecoxib, heteroaromatic vanillin inhibitor compounds (selected from compounds described in PCT WO2020 / 114943 and US2020 / 0354338), heterocyclic TYK2 inhibitor compounds (selected from compounds described in PCT WO2020 / 86616 and US2020 / 0354338), and a structure independently selected from an INF-α inhibitor compound or a variant thereof selected from the compounds described in WO2020 / 159904 and EP3917912; and c) Structure HR 1 Glucocorticoid structure, which connects to X through an OH group residue present in integers a through k are independently selected from 0, 1, and 2; A 1 ~A 11is any amino acid residue, unsubstituted or substituted at any of the N atoms, and is selected from the group consisting of α-, β-, and γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine to 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, 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-arylbutyric acid, 4-amino-3-(3-chlorophenyl)butyric acid, and 5-amino-4-arylvaleric acid; If any one of the integers a to k is 0, then any two groups adjacent to the corresponding non-existent group (by the integer 0 of the non-existent group) are directly connected to each other, and a) any divalent group X is independently selected from: -C(=O)(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)(Aryl) p (CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)(CR 2 R 3 )p(アリール)r(CR 6 R 7 )sC(=O)-、 -C(=O)O(CR 2 R 3 )O(CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)O(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、-C(=O)N(R 5 )(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 )s OC(=O)-、-C(=O)(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s N(R 4 )C(=O)-、 -C(=O)CR 2 =CR 4 -(CR 6 R 7 ) s C(=O)-、 -C(=O)OCR 2 =CR 4 -(CR 6 R 7 ) s C(=O)-、-C(=O)N(R 5 )CR 2 =CR 4 -(CR 6 R 7 ) s C(=O)-、 -C(=O)CR 2 =CR 4 -(CR 6 R 7 ) s OC(=O)-、-C(=O)CR 2 =CR 4 -(CR 6 R 7 ) s N(R 4 )C(=O)-、 -C(=O)(CR 2 R 3 ) p S-S(CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)O(CR 2 R 3 ) p S-S(CR 4 R 5 ) r (CR 6 R 7) s C(=O)-、 -C(=O)(CR 2 R 3 ) p S-S(CR 4 R 5 ) r (CR 6 R 7 ) s OC(=O)-、 -C(=O)(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s N(R 5 )C(=O)-、 -C(=O)(CR 2 R 3 ) p (CR 4 R 5 ) r S-S(CR 6 R 7 ) s C(=O)-、 -C(=O)O(CR 2 R 3 ) p (CR 4 R 5 ) r S-S(CR 6 R 7 ) s C(=O)-、 -C(=O)(CR 2 R 3 ) p S-S(CR 4 R 5 ) r S-S(CR 6 R 7 ) s OC(=O)-、 -C(=O)N[(CR 2 R 3 ) p (CR 4 R 5 ) r NHC(=O)(CR 6 R 7 )s NCH(NH2)COOH]CH2CH2C(=O)-、 -C(=O)N[(CR 2 R 3 ) p (CR4R5) r N(C 1-6 アルキル)C(=O) - (CR 6 R 7 ) s NCH(NH2)COOH]CH2CH2C(=O) -、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)-、 -(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 アルキル]CH2CH2C(=O)-、 -C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 2 R 3 ) p (CR 4 R 5 ) r C(=O)O(CR 6 R 7 ) s C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 2 R 3 ) p( CR 4 R 5 ) r OC(=O) (CR 6 R 7 ) s C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 2 R 3 ) p C(=O)O(CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-、 -C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 2 R 3 )p OC(=O)(CR 4 R 5 ) r (CR 6 R 7 ) s C(=O)-, C(=O)N[CH2CH2N(C 1-6 alkyl)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2) COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 4 )COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 4 )COOH]CH2CH2C(=O), -C(=O)CH2CH2C(=O)-, and -C(=O)CHMeCHMeC(=O)-, or b) Any divalent group X is S(CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s is OC(=O) or is selected from the following groups:

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] x is 1, 2, or 3; R 100 and R 101 is independently selected from H and an alkyl group; X 1 and X 2 are O, NH and CR 5 R 6 are independently selected from R 41 are independently selected from H, alkyl groups, aryl groups, heteroaryl groups, and heterocyclic groups; R 2 , R 4 , R 5 , R 6 and R 7 is H, NH2, halogen, NH(C 1-6 alkyl group), NH(OC 1-6 alkyl group), C 1-14 Alkyl group, C 3-6 independently selected from cycloalkyl groups, aryl groups, arylalkyl groups, biaryl groups, biarylalkyl groups, and heteroarylalkyl groups; R 3 are H, NH2, NH(C 1-6 alkyl group), NH(OC 1-6 alkyl group), C 1-14 Alkyl group, C 3-6 independently selected from cycloalkyl groups, aryl groups, arylalkyl groups, biaryl groups, biarylalkyl groups, and heteroarylalkyl groups; or R 2 ~R 7 any two of these together with the atom to which they are attached form a 4-7 membered saturated or unsaturated heterocycle containing at least one O atom, or one O atom and another heteroatom independently selected from N and S, and the remaining atoms are carbon atoms; or R 2 ~R 7Any two of these, together with the carbon atoms to which they are attached, form a 4- to 7-membered saturated or unsaturated C 3-6 forming a cycloalkylene, or i) R 2 and R 3 , ii) R 4 and R 5 , iii)R 6 and R 7 Any one of the C, along with the atom to which they are attached, can be saturated or unsaturated. 3-6 forming a cycloalkylene, or R 5 ~R 7 any two of these together with the atoms to which they are attached form a 5- to 7-membered saturated or unsaturated heterocyclic ring, wherein said ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms; R 3 and R 5 together with the atoms to which they are attached form a 4-6 membered saturated heterocyclic ring, said saturated heterocyclic ring containing at least one O atom and optionally other heteroatoms selected from N, O and S, and the remaining atoms being carbon, or the resulting ring comprises 1,3-dioxol-2-one; and Integers p, r, and s are independently selected from 0, 1, and 2, Fragment (CR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s or (OCR 2 R 3 ) p (CR 4 R 5 ) r (CR 6 R 7 ) s If there exists, then [p+r+s]≧1 and Fragment (CR 2 R 3 ) p (CR 4 R 5 )r Or(OCR 2 R 3 ) p (CR 4 R 5 ) r If there exists, then [p+r]≧1 and Fragment CR 4 R 5 ) r (CR 6 R 7 ) s Or(OCR 4 R 5 ) r (CR 6 R 7 ) s If there exists, then [r+s]≧1 and A 1 ~A 11is any amino acid residue, unsubstituted or substituted at any of the N atoms, and, if present, is selected from α-, β-, or γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine to 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, 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-arylbutyric acid, 4-amino-3-(3-chlorophenyl)butyric acid, and 5-amino-4-arylvaleric acid; Integers a through k are independently selected from 0, 1, and 2, and If any one of the integers a to k is 0, then any two groups adjacent to the corresponding non-existent group (by the integer 0 of the non-existent group) are directly connected to each other, and If the optional group X is absent, then the group R 1 is the group A 8 , A 9 , A 10 or A 11 Connect directly to one of the

[0072] In one embodiment, there is provided a compound of Formula IP-1, Formula IP-2, Formula I, Formula I-1, Formula I-2, or Formula II-P-1, wherein integers a through g are each 1; and A 1 is Thr or Ser, and A 2 , A 3 , A 6 and A 7 are each independently selected from Dab, Dap, Ser, or Thr; A 4 is Leu or Ile, and A 5 are Phe, D-Phe, Bip, D-Bip, Val, D-Val.

[0073] In other embodiments, the cyclic peptide structure in the compound of Formula I-P1, Formula I-P2, Formula I, Formula I-1, Formula I-2, or Formula II-P-1 includes any of amino acid residues A1-A7 and is the same cyclic peptide structure as that present in polymucosin A, polymucosin B, polymucosin B nine peptide (H-Thr-Dab-cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]), polymucosin B heptapeptide (H-ring cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]), polymucosin E, an octapeptide (octapeptin), or a similar structure.

[0074] In other embodiments, the integers a through g of the compound of Formula I-P1, Formula I-P2, Formula I, Formula I-1, Formula I-2, or Formula II-P-1 are each 1.

[0075] In other embodiments, A 1is Thr or Ser, and A 2 , A 3 , A 6 and A 7 are independently selected from Dab, Dap, Ser and Thr, and A 4 is Leu or Ile, and A 5 are Phe, D-Phe, Bip, D-Bip, Val, D-Val.

[0076] In another embodiment, the bioactive agent HR after administration to a mammal 1 The present invention provides a compound of any of formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P that exerts a therapeutic effect by releasing

[0077] In another aspect, there is provided a compound of any of Formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P that has anti-inflammatory activity as determined by slowing or retarding the release of renal cytokines such as TNF-α, IL-6, IL-12, or one or more biomarkers such as blood urea nitrogen and serum creatinine, or by measuring said compound in an animal model.

[0078] In another aspect, there is provided a compound of any of Formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P having anti-inflammatory activity, wherein the inflammation is renal inflammation, inflammation in renal injury, or inflammation induced by a nephrotoxic agent, including a drug nephrotoxic agent such as an anti-cancer, anti-infective, or other chemotherapeutic agent.

[0079] In another aspect, a compound of any of Formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P is provided, which comprises a compound of Formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, and a compound of Formula ...2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I- n R 1In another aspect, a compound of formula IP-1, IP-2, or II-P-1 is provided that has enhanced anti-inflammatory, immunomodulatory, or nephroprotective activity as compared to a similar dose of free (unbound) reagent or drug (H) incorporated into the compound, as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory, or nephroprotective activity. n R 1 and / or (H) o R 2 have enhanced anti-inflammatory, immunomodulatory or renal protective effects as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory or renal protective activity compared to

[0080] In another aspect, there is provided a compound of any of formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, wherein the compound exhibits preferential accumulation in the kidney when administered to a mammal, and has a molar concentration in the kidney to a molar concentration in the blood ratio of about 5-500.

[0081] In another aspect, there is provided a compound of any of formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, wherein HR 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (molar amount) of 1 The compound reduces HR in the kidney compared to a standard therapeutic dose of 1 In another aspect, compounds of formula IP-1, IP-2, or II-P-1 are provided, wherein the HR 1 and / or (H) o R 2 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (molar amount) of 1 and / or (H) o R 2 The compound reduces HR in the kidney compared to a standard therapeutic dose of 1and / or (H) o R 2 This indicates that the burden (tissue concentration) and / or drug exposure (area under the curve, AUC) of

[0082] In another aspect, there is provided a compound of any of formula I-1, I-2, Ia, Ib, Ic, II-P-2, III-P, III, or IV-P, wherein HR 1 When administered to a mammal in a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (molar amount) of the agent, HR 1 and (H)oR2, wherein the therapeutic effect is determined by a delay, halt, or reversal of inflammation or kidney damage (e.g., as determined by cytokine release levels and / or the use of biochemical biomarkers to monitor inflammation, or by radiography, magnetic resonance imaging, etc.). In another aspect of the invention, compounds of formula IP-1, IP-2, or II-P-1 are provided, which, when administered to a mammal at a dose (expressed in molar amounts) equal to the standard therapeutic dose (molar amount) of the HR1 reagent and / or (H)oR2, exhibit at least a two-fold increase in efficacy compared to the standard therapeutic dose of the HR1 reagent and / or (H)oR2, wherein the therapeutic effect is determined by a delay, halt, or reversal of inflammation or kidney damage (e.g., as determined by cytokine release levels and / or the use of biochemical biomarkers to monitor inflammation, or by radiography, magnetic resonance imaging, etc.).

[0083] In another aspect, there is provided a compound of any of Formulas Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, wherein the agent HR 1 When administered to mammals at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1and / or II-P-1, wherein the compound exhibits at least a two-fold reduction in adverse reactions and / or occurrence of off-target toxicity compared to a standard therapeutic dose of 100 mg / kg / day, as determined by medical observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods. In another aspect, a compound of formula IP-1, IP-2, or II-P-1 is provided, wherein the compound is selected from the group consisting of: 1 and / or (H) o R 2 When administered to mammals at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1 and / or (H) o R 2 demonstrate at least a two-fold reduction in the incidence of adverse reactions and / or off-target toxicities compared to a standard therapeutic dose of the compound, as determined by medical observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods.

[0084] In one aspect, there is provided a compound of any of Formulas IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P for treating inflammation of the kidney, wherein the inflammation is inflammation in chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), or kidney transplant surgery.

[0085] In another aspect, there is provided a method of treating inflammation-associated kidney disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, or IV-P.

[0086] In another aspect, there is provided a compound of any of Formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, which has enhanced in vivo efficacy against inflammation-associated kidney disease compared to a related (parent) anti-inflammatory, immunomodulatory, or nephroprotective structure (compound) incorporated into the compound, as measured by in vivo testing in an animal model of the kidney disease, where the compound and the related free agent (incorporated into the compound provided herein) are administered in the same molar amount.

[0087] In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, or a pharmaceutically acceptable salt, prodrug, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0088] In another aspect, there is provided a method of treating inflammation-associated 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 IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III or IV-P or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof.

[0089] Compounds of formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III or IV-P can be administered, for example, orally, parenterally, transdermally, topically, rectally, intranasally, or intratumorally.

[0090] In another aspect, novel intermediates and methods for preparing compounds of formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III-P, III or IV-P are provided. [Brief explanation of the drawings]

[0091] [Figure 1] Figure 1 shows the anti-inflammatory activity (per reduction in CREA and BUN levels) of the compounds of Examples 1 and 2 compared to the dexamethasone control in a cisplatin-induced acute kidney injury mouse model. All exemplary compounds were administered at 4 mg / kg, and all doses were not corrected for solvation water content. In Figure 1, Cis is cisplatin and Dex is dexamethasone. DETAILED DESCRIPTION OF THE INVENTION

[0092] Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0093] The carbon atom content of various molecules, including hydrocarbons, is expressed by prefixes that indicate the minimum and maximum number of carbon atoms in the molecule. i-j represents a carbon atom molecule from integer "i" to integer "j", inclusive. For example, C 1-14 By alkyl group is meant an alkyl group having 1 to 14 (inclusive) carbon atoms.

[0094] The term alkyl refers to straight-chain and branched-chain saturated hydrocarbon groups. When referring to individual groups (e.g., "propyl"), only the straight-chain group is included; the branched-chain isomer (e.g., "isopropyl") is specifically mentioned. An "alkyl group" contains 1 to 12 carbon atoms, unless otherwise specified. In addition to the groups specifically recited in any embodiment or claim, alkyl groups may also contain halogens, hydroxyl groups, cyano groups, C 1-12 Alkyl group, C 3-7

[0033] The alkyl group may be substituted with one, two, three, or four substituents selected from a cycloalkyl group, an aryl group, a biaryl group, a heterocyclic group, and a heteroaryl group (Het). In some embodiments, the alkyl group is selected from a difluoromethyl group, a 2-fluoroethyl group, a trifluoroethyl group, an (adamantan-1-yl)methyl group, a 3-(cyclohexyl)propyl group, a 4-propylcyclohexyl group, a -CH=CHaryl group, a -CH=CH-Het 1In some embodiments, the alkyl group is unsubstituted. The term "alkyl group" can be used interchangeably with "alkyl" or "alkyl." 2 " are independently selected alkyls that may be different from each other or may be independently the same. When an "alkyl group" is used multiple times in the same group, each occurrence of "alkyl" is independent of every other "alkyl group".

[0095] The term "Alk" means an alkyl group as defined herein.

[0096] The term "alkylene" refers to a divalent alkyl group. An "alkylene" contains 1 to 12 carbon atoms, unless otherwise specified. In some embodiments, an "alkylene" is a linear group. An alkylene group can be substituted like an alkyl group. In some embodiments, an alkylene group is unsubstituted. The terms "alkylene" and "alkylene" are interchangeable. 1 " or "Alkylene 2 " are independently selected alkylenes that may be different from each other or independently the same.

[0097] The term "alkenyl" refers to straight-chain and branched hydrocarbon groups containing at least one double bond, and in some embodiments, one, two, or three double bonds. "Alkenyl groups" contain 2 to 12 carbon atoms, unless otherwise specified. In addition to the groups specifically recited in any embodiment or claim, alkenyl groups also include halogens, C 1-12 Alkyl group, C 3-7 Cycloalkyl groups, aryl groups, biaryl groups, Het 1 and Het 2In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is selected from the group consisting of difluoromethyl, 2-fluoroethyl, trifluoroethyl, (adamantan-1-yl)methyl, 3-(cyclohexyl)propyl, 4-propylcyclohexyl, -CH=CHaryl, -CH=CH-Het 1 , -CH2-phenyl group, biphenylmethyl group, and the like.

[0098] The term "alkylene" refers to a divalent alkenyl group. Unless otherwise specified, an "alkylene" contains 2 to 12 carbon atoms. Alkylene groups can be substituted as described for alkenyl groups. In some embodiments, alkylene groups are unsubstituted.

[0099] The term "cycloalkyl" refers to a cyclic saturated, monovalent, monocyclic or bicyclic, saturated or unsaturated hydrocarbon group having 3 to 18 (in some embodiments, 3 to 6) carbon atoms. In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclohexyl, cyclododecanoyl, and the like. In addition to the groups specifically mentioned in any embodiment or claim, cycloalkyl groups can also include halogen, C 1-12 Alkyl group, C 3-7 Cycloalkyl groups, aryl groups, Het 1 , Het 2 and heteroaryl groups. In some embodiments, the cycloalkyl group is unsubstituted.

[0100] The term "cycloalkylene group" refers to a divalent cycloalkyl group. In addition to the groups specifically recited in any embodiment or claim, cycloalkylene groups may be substituted, like cycloalkyl groups. In some embodiments, cycloalkylene groups are unsubstituted. In some or any embodiments, R 5~R 10 C formed from any two of 3-6 The cycloalkylene group is C 1-6 It may be substituted with one or two groups independently selected from alkyl groups and aryl groups.

[0101] 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 substituent is a hydroxyl group (OH), C 1-4 Heteroatoms may be incorporated into any part of the heteroalkyl group (e.g., heteroalkyl groups may be C 1-4 AlkylC(=O)O or C 3-6 In some embodiments, the substituents include NR a1 R b1 , OR a1 and S(O) n R c1 , of which each R a1 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or —C(O)R, where R is C 1-4 alkyl), and each R b1 are independently H, C 1-4 Alkyl, -SO2R (where R is C1-4 Alkyl or C 1-4 hydroxyalkyl), -SO2NR R' (wherein R and R' are independently H or C 1-4 alkyl), or -CONR'R" (wherein R' and R" are independently H or C 1-4 alkyl), n is an integer from 0 to 2, and each R c1 are independently H, C 1-4 Alkyl, C3-6 cycloalkyl, optionally substituted aryl or NR a1 R b1 and R a1 and R b1 is as defined above. In some embodiments, heteroalkyl groups include, but are not limited to, 2-methoxyethyl (-CH2CHOCH3), 2-hydroxyethyl (-CH2CH2OH), hydroxymethyl (-CH2OH), 2-aminoethyl (-CH2CH2NH2), 2-dimethylaminoethyl (-CH2CH2NHCH3), benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.

[0102] The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0103] "Aryl group" means a substituted or unsubstituted phenyl, biphenyl, triphenyl, or naphthyl group. In addition to the groups specifically mentioned in any embodiment or claim, an aryl group can also include halogen, -C 1-12 Alkyl (unsubstituted or substituted, in one embodiment 1, 2 or 3 halogens), aryl, -OH, -OC 1-12 Alkyl, S(O) n C 1-4 alkyl (n is 0, 1, or 2), -C 14 AlkylNH2, -NH 1-4 Alkyl, -C(=O)H, C(=O)OR a1 , OC(=O)R a1 , OC(=O)NR a1 R c1 , OC(=O) heteroaryl, OC(=O) (heterocycle), and C=N-OR d (Rd is H or -C 1-4 The aryl group is optionally substituted with 1 to 3 substituents independently selected from C alkyl. Two adjacent substituents in the aryl group are C fused to the aryl group. 4-7 They may be connected to form a cycloalkyl group or a 4- to 7-membered heterocyclic group. 1 " or "aryl2 " are independently selected aryls that may be different from each other or may be independently the same. When the term "aryl" is used multiple times in the same group, each "aryl" is independent of every other "aryl" at each occurrence.

[0104] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, where aryl and alkyl are each optionally substituted as defined herein.

[0105] The term "arylheteroaryl" means an aryl group substituted with a heteroaryl group, each of which is optionally substituted as defined herein.

[0106] The term "heteroarylaryl" means a heteroaryl group substituted by an aryl group, wherein aryl and heteroaryl are each as defined herein and are optionally substituted as defined herein.

[0107] The term "biaryl" means an aryl group, as defined herein, substituted with another aryl group, as defined herein, where each aryl group is optionally substituted as defined herein.

[0108] 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 group and alkyl group is independently optionally substituted as defined herein.

[0109] The term heterocycle ("heterocyclic ring", "heterocyclic ring" or "heterocycle") refers to a monocyclic or bicyclic aromatic ring or rings containing 3 to 12 carbon atoms and oxygen, nitrogen, P(=O) and S(O) atoms.m and 1 to 4 heteroatoms independently selected from the group consisting of: a1 , OC(=O)R a1 , OC(=O)NR a1 R b1 , -C 1-20 Alkyl, -OH, -NH2, -OC 1-20 Alkyl, S(O) m C 1-20 alkyl (m is 0, 1, or 2), C 120 Alkyl-NH2, -NHC 1-4 Alkyl, -C(=O)H, or C=N-OR d1 and optionally substituted by, among which R a1 , R b1 and R d1 are independently H or C 1-20 In some embodiments, the heterocycle is unsubstituted. In some or any embodiments, R 5 ~R 10 and / or R 6 and R 8 The 4-7 or 5-7 membered ring formed by may be substituted with a heterocycle as described herein. 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 may be substituted with one or two groups independently selected from an alkyl group and an aryl group.

[0110] In some embodiments, the heterocycle is selected from the group consisting of azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indole, indoline, indazole, purine, quinoline, isoquinoline, quinoline, ophthalmethazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pterin, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxalinone, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-hydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b] ]thiophene, thiazole, thiadiazoletetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholin (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, azapine, perhydrodiazepam, perhydrodiazepam-2-one, perhydro-1,4-oxirane, perhydro-1,4-oxan-2-one, perhydro-1,4-oxan-3-one, perhydro-1,3-oxan-2-one, nitrogen heterobicyclo[3.1.0]hexane, and the like, and N-oxides of said nitrogen heterocycles. In addition to the groups specifically recited in any embodiment or claim, heterocycles can also be C(═O)OR a1 , OC(=O)R a1 , OC(=O)NR a1 R b1 and further includes substituted and unsubstituted rings containing a group selected from, a1 and R b1 are independently H or C 1-6 It is an alkyl group.

[0111] The term "heteroaryl" means a five (5) or six (6) membered C- or N-linked heterocyclic ring, optionally fused to benzene or another heterocyclic ring, at least one of which is aromatic. A heterocyclic ring fused to a benzene ring is also called a benzoheterocyclic group.In some embodiments, heteroaryl is selected from 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-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, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3-oxathiazole-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 In addition to the groups specifically recited in any embodiment or claim, heteroaryl includes, but is not limited to, thiadiazol-5-yl, 1,2,4 triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazole, 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. a1 , OC(=O)R a1 and OC(=O)NR a1 Rb1 and unsubstituted rings, including rings substituted with groups selected from a1 and R b1 are each independently H or C 1-6 In some embodiments, the heteroaryl is unsubstituted. 1 " or "heteroaryl 2 " are independently selected heteroaryl groups that may be different or the same. When the term "heteroaryl" is used multiple times in the same group, each "heteroaryl" may be independent of other "heteroaryls" at each occurrence.

[0112] The term "heteroarylalkyl" means an alkyl group substituted with a heteroaryl, each as defined herein.

[0113] Het 1 is independently at each occurrence a 5- or 6-membered C-linked heterocycle having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring.

[0114] Het 2 Each occurrence of is independently a 5- or 6-membered N-linked heterocycle having 1 to 4 nitrogen atoms and optionally one oxygen or sulfur atom in the ring.

[0115] The term "monosubstituted" refers to a group having at least one substituent in the group, not including the point of attachment of the group to the main structure or general formula. The term "multiple substituted" refers to a group having at least two substituents in the group, not including the point of attachment of the group to the main structure or general formula.

[0116] The term "unsaturated" in the context of the terms cycloalkyl group, cycloalkylene group and heterocycle means not partially saturated but not aromatic.

[0117] Unless otherwise specified, a "carbon atom" is any atom including H, halogen, NR a1 R b1 , C 1-12 Alkyl group, C 3-7 It refers to an atom of the element carbon, optionally substituted with a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocycle. Carbon atoms include atoms with sp3, sp2, and sp electron hybridization.

[0118] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "an aryl group optionally mono- or di-substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the aryl group is mono- or di-substituted with an alkyl group and cases where the aryl group is not substituted with an alkyl group.

[0119] Compounds that have the same molecular formula but differ in the nature or sequence of atomic bonding or in the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers."

[0120] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center, it is bonded to four different groups, and a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center, described by the Cahn and Prelog R- and S-ordering rules, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0121] The compounds provided herein may contain one or more asymmetric centers; therefore, such compounds can be produced as single (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all single enantiomers and any mixtures thereof, racemic, partially racemic, or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0122] Hydrogen (H), carbon (C), or nitrogen (N) substitutions in the compounds described herein include substitutions with any isotope of the corresponding atom. Thus, hydrogen (H) substitutions may be desirable, for example, for certain therapeutic or diagnostic treatments, metabolic research applications, or for improved stability. 1 H, 2 H (deuterium) or 3 The compounds described herein may contain any number of isotope substitutions to provide the corresponding radiolabel of the compounds described herein. 3 H, 15 O. 12 C or 13 Any radioactive isotope (or radioisotope) known in the art, such as the N isotope, may be incorporated.

[0123] "Pharmaceutically acceptable carrier" means a carrier that is generally safe, non-toxic, and biologically or otherwise undesirable and is useful for preparing pharmaceutical compositions, and includes carriers useful in veterinary and human medicine. As used in the specification and claims, "pharmaceutically acceptable carrier" includes one or more such carriers.

[0124] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically usable and that possesses the required pharmacological activity of the parent compound. (1) Acids formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or from 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-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, and tertiary Acid addition salts formed from organic acids such as butyl acetate, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) Salts formed by substituting the acidic protons present in the parent compound with metal ions such as alkali metal ions, alkaline earth ions, and aluminum ions, or by combining the parent compound with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine.

[0125] "Treating," "treatment," or "therapy" of a disease (1) To prevent the disease, i.e., to prevent the development of clinical symptoms of the disease in mammals that have been exposed to or are susceptible to the disease but that have not experienced or manifested symptoms of the disease; (2) Disease inhibition, i.e., arresting or reducing the progression of the disease or its clinical symptoms, or (3) Disease palliation, including the regression of a disease or its clinical symptoms.

[0126] "Therapeutically effective amount" means the amount of a compound sufficient to affect treatment of a disease in a mammal. The therapeutically effective amount varies depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0127] "Leaving group" has the meaning commonly associated with it in synthetic organic chemistry, i.e., halogen, C 1-4 An atom or group that can be substituted with a nucleophile, including an alkylsulfonyloxy group, an ester group, or an amino group, such as chlorine, bromine, iodine, a formyloxy group, a toluyloxy group, a trifluorosulfonyloxy group, a methoxy group, or an N,O-dimethylhydroxyamino group.

[0128] "Prodrug" refers to a compound that releases the active parent drug in vivo in response to a compound provided herein when a mammalian subject ingests the prodrug. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds provided herein, which can be cleaved in vivo to release the parent compound. Prodrugs include compounds provided herein in which a hydroxy, sulfhydryl, amide, or amino group in the compound is coupled with any group that can be cleaved in vivo to regenerate the free hydroxyl, amide, amide, or sulfhydryl group, respectively. Prodrug embodiments include, but are not limited to, esters (e.g., acetate, formate, benzoate, phosphate, or phosphonate derivatives) of the hydroxy functional group in the compounds provided herein, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like. Prodrugs of the compounds provided herein are useful for certain therapeutic applications, such as pulmonary delivery of aerosols containing prodrugs of such compounds, or for improving tolerance to the same. For example, the methanesulfonic acid prodrug form of the polymyxin drug colistin (see, e.g., Bergen et al., Antimicrob. Agents Chemother. 2006, vol. 50, p. 1953) has been used to reduce colistin's neurotoxic effects and is used for aerosol administration of the drug. Such prodrugs and other known forms can also be used to further improve the pharmaceutical properties of the compounds provided herein.

[0129] The term "mammal" refers to all mammalian animals, including humans, livestock, and companion animals (pets).

[0130] The compounds described herein are generally named according to the IUPAC or CAS nomenclature system. Abbreviations familiar to those skilled in the art (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hours, "rt" for room temperature) may be used.

[0131] Illustrative Examples In the broadest definition, some compounds of formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III-P, or IV-P may be preferred. Specific and preferred values ​​of groups, substituents, and ranges listed herein are used for illustration only, and they do not exclude other defined values ​​of groups and substituents, or other values ​​within defined ranges.

[0132] In some preferred compounds described herein, C 1-14 The alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, octyl, nonyl, decyl, and the isomeric forms thereof.

[0133] In some preferred compounds described herein, C 2-12 Alkenyl can be vinyl, propenyl, allyl, butenyl, and the isomeric forms thereof (including cis and trans isomers).

[0134] In some preferred compounds described herein, C 3-7 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the isomeric forms thereof.

[0135] In some preferred compounds described herein, C 1-14 The heteroalkyl group can be a hydroxymethyl group, a hydroxyethyl group, a 2-(N,N-dimethylamino)ethyl group, a 2-(4-morpholino)ethyl group, and a 2-methoxyethyl group.

[0136] In some preferred compounds described herein, the halogen may be fluorine (F) or chlorine (Cl).

[0137] As will be understood by those skilled in the art, the compounds described herein may contain additional chiral centers and may be isolated in optically active and racemic forms. The present application includes any racemic, optically active, tautomeric, geometric or stereoisomeric form of the compounds described herein, or mixtures thereof.

[0138] Any embodiment described herein may be combined with any other embodiment described herein.

[0139] In one embodiment, the compound of formula IP-1 is a compound of formula II-P-1:

[0140] [ka]

[0141] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 1 and R 2 is any group, among which R 1 and R 2 is present in formula II-P-1, and R 1 and R 2 are independently selected from alkyl groups, aryl groups, biaryl groups, heteroaryl groups, heteroarylaryl groups, and arylheteroaryl groups; or (H)nR1 and (H) o R 2 If present in R 1 and R 2 each represents a corresponding parent (precursor) structure (H)R and (H) at any one position of any hydrogen-containing group independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH, and S(=O)NH. o R 2 by subtracting one or more H atoms from a)(H) n R 1 and (H) o R 2are independently an anti-inflammatory compound, an immunomodulatory compound, a renal protective compound, or a compound that modulates glucocorticoid receptor (GR) activity, reduces proteinuria / creatinine levels, modulates cytokine release, or otherwise exhibits, has activity, or is capable of inducing biological activity against inflammation-related kidney disease or kidney injury; and b)(H) n R 1 and (H) o R 2 are independently selected from aldosterone, AN3485, beclomethasone, betamethasone, budesonide, budesonide metabolites, celecoxib, 11-deoxycortisone, dexamethasone, hydrocortisone, fluticasone mometasone, ibuprofen, naproxen, prednisolone, triantherone, or valdecoxib, or a heteroaromatic vanillin inhibitor compound (selected from compounds described in PCT WO2020 / 114943 and US2020 / 0354338), or a heterocyclic TYK2 inhibitor compound (selected from compounds described in PCT WO2020 / 86616 and US2020 / 0354338), and an INF-α inhibitor compound (selected from compounds described in PCT WO2020 / 159904 and EP3917912), or a variant thereof; and c)(H) n R 1 and (H) o R 2 are independently effective compounds for treating kidney disease, and d)(H) n R 1 is a glucocorticoid structure bound to X at an O atom or an N atom, and at least one of these atoms is the structure (H) n R 1 exists in, and Any group R 1 does not exist, fragment R 1 X is R 11a Selected from R 11a H, Alk, C 3-7Cycloalkyl, 5-6 membered heterocyclyl, aryl, biaryl, heteroaryl, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C 1-12 )Alkyl)C(=O), AlkSO2, AlkNHSO2, C 3-7 CycloalkylC(=O), C 3-7 CycloalkylOC(=O), C 3-7 CycloalkylNHC(=O), C 3-7 CycloalkylN(C 1- 12 Alkyl)C(=O), ArylC(=O), ArylOC(=O), ArylNHC(=O), ArylN(C 1-12 Alkyl)C(=O), ArylSO2, ArylNHSO2, HeteroarylC(=O), HeteroarylOC(=O), HeteroarylNHC(=O), HeteroarylN(C 1-12 alkyl)C(=O), heteroarylSO2, and heteroarylNHSO2; or Any group R 2 does not exist, fragment R 2 Z is R 12a Selected from R 12a H, Alk, C 3-7 Cycloalkyl, 5-6 membered heterocyclyl, aryl, biaryl, heteroaryl, AlkC(=O), AlkOC(=O), AlkNHC(=O), AlkN(C 1-12 )Alkyl)C(=O), AlkSO2, AlkNHSO2, C 3-7 CycloalkylC(=O), C 3-7 CycloalkylOC(=O), C 3-7 CycloalkylNHC(=O), C 3-7 CycloalkylN(C 1- 12 Alkyl)C(=O), ArylC(=O), ArylOC(=O), ArylNHC(=O), ArylN(C 1-12 Alkyl)C(=O), ArylSO2, ArylNHSO2, HeteroarylC(=O), HeteroarylOC(=O), HeteroarylNHC(=O), HeteroarylN(C 1-12 alkyl)C(=O), heteroarylSO2, and heteroarylNHSO2; or integers n and o are independently selected from 0, 1, 2, 3, 4, 5, 6, and 7, such that [n+o]>1; and A 1 ~A 11 is any amino acid residue, unsubstituted or substituted at any of the N atoms, α-, β-, or γ-amino acid, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine from 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, 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-arylbutyric acid, 4-amino-3-(3-chlorophenyl)butyric acid, and 5-amino-4-arylvaleric acid; and The integer zz is 1 or 2, Integers a through k and m are independently selected from 0, 1, and 2, [m+zz]≧1, and If any one of the integers a to k is 0, any two groups adjacent to the corresponding non-existent group (by the integer 0 of the non-existent group) are directly connected to each other, and If integers a to g are all 0, then A 1 ~A 7 does not exist and A 8 is COOH, CH2OH or C(=O)NR 3 R 4 terminated by R 3 and R 4 are independently selected from H, alkyl groups, aryl groups, heteroaryl groups, or heterocyclic groups, or a group A 8 is directly attached to the group Y, and Any divalent group X is independently selected from the following: O, NH, N(C 1-6 Alkyl group), S, SS, SN, S(=O), SO2, C(=O), OC(=O), C(=O)O, NHC(=O)NH, N(C 1-6 Alkyl group C(=O)NC 1-6 alkyl), NHC(=O)NC 1-6 alkyl), C 1-12 an alkylene group, an arylene group, a biaryl group, a (heteroaryl)arylene group, an (aryl)heteroaryl group, a heterocycloalkyl group, (C 1-12 alkylene)C(=O)O, OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4) (C1-12 アルキレン)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O) 、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R8 ) r C(=O) 、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O) 、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O) 、 C(=O)OCR 5 =CR 7 -(CR9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O) 、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) 、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O) 、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O) 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O) 、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R10 ) s C(=O) 、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O) 、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O) 、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O) 、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O) 、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O) 、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O) 、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) rNHC(=O)A 14 ](CR 9 R 10 ) s C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 alkyl)C(=O)A 14 ](CR 9 R 10 ) s NHC(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 alkyl)C(=O)A 14 ](CR 9 R 10 ) s C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 alkyl)C(=O)A 14 ](CR9 R 10 ) s NHC(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 alkyl)C(=O)A 14 ](CR 9 R 10 ) s OC(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O) 、 C(=O)N[(CR 5 R6 ) p (CR 7 R 8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O) 、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 alkyl)C(=O)-(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CMe2C(=O)OCH2CH2C(=O) 、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH(Me)-CH2C(=O) 、 C(=O)N[CH2CH2N(C 1-6 アルキル)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O) 、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2) COOH]CH2CH2C(=O) 、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 4 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 4 ) any variant of said group formed by rearranging, adding, or deleting SO2 therein, among which: R 6 , R 7 , R 9 , and R 10 are independently H, NH2, halogen, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; R 5 are H, NH2, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl or heteroarylalkyl; or R 5 ~R 10 any two of these together with the atom to which they are attached form a 4-7 membered saturated or unsaturated heterocycle containing at least one O atom, or one O atom and another heteroatom independently selected from N and S, and the remaining atoms are carbon atoms; or R 5 ~R 10 Any two of these, together with the carbon atoms to which they are attached, form a 4- to 7-membered saturated or unsaturated C 3-6 forming a cycloalkylene, or i) R 4 and R5 , ii) R 6 and R 7 , iii)R 4 and R 6 , iv) R 9 and R 10 Any one of the C, along with the atom to which they are attached, can be saturated or unsaturated. 3-6 forming a cycloalkylene, or R 5 ~R 10 any two of these together with the atoms to which they are attached form a 5- to 7-membered saturated or unsaturated heterocyclic ring, wherein said ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one; and R 6 and R 8 together with the atoms to which they are attached form a 4-6 membered saturated heterocyclic ring containing at least one O atom, wherein said heterocyclic ring optionally contains another heteroatom selected from N, O and S, and the remaining atoms are carbon atoms, or the resulting ring comprises 1,3-dioxol-2-one; and Integers p, r, and s are independently selected from 0, 1, and 2, Fragment (CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s If there exists, then [p+r+s]≧1 and Fragment (CR 5 R 6 ) p (CR 7 R 8 ) r or (OCR5 R 6 ) p (CR 7 R 8 ) r If there exists, then [p+r]≧1 and Fragment (CR 7 R 8 ) r (CR 9 R 10 ) s or (OCR 7 R 8 ) r (CR 9 R 10 ) s exists, then [r+s]≧1, or Alternatively, each of any divalent groups X independently has the structure: 12 or A 13 Optionally connect to (C 1-12 alkylene)C(=O)O, OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O)N(R4), N(R4)C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R4)C(=O), C(=O)N(R4)(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 )s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR9 R 10 ) s C(=O)、C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 )s N(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 )s N(R 4 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )r OC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)-(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 )r OC(=O) (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CMe2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH(Me)- CH2C(=O)、 C(=O)N[CH2CH2N(C 1-6 アルキル)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2) COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 4) C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 4 ) any variant of said X group formed by rearranging, adding or deleting SO2 therein, among which amino acid residue A 12 and A 13 and both are incorporated to the right of said group to contain group X, then residue A 12 or A 13 Peptide bond A 12 -A 13 and interconnect with If any group X is absent, then the group R 1 is group A 8 , A9 , A 10 or A 11 directly connected to either Additionally, each of any divalent groups X may independently be C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylene, (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s OC(=O), (CH2) p O(CH2) r O(CH2) s NHC(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), O(CH2) p O(CH2) r O(CH2) s C(=O), O(CH2) p O(CH2) r O(CH2) s OC(=O), O(CH2) p O(CH2) r O(CH2)sNHC(O), O(CH2) p O(CH2) r O(CH2)sN(C 1-14 alkyl)C(=O), NH(CH2) p O(CH2) r O(CH2)sC(=O), NH(CH2) p O(CH2) r O(CH2)sOC(=O), (CH2) p O(CH2) r O(CH2) s NHC(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14alkyl)C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s OC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2)sNHC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2)sN(C 1-14 alkyl)C(=O), and similar linear groups; The optional divalent groups Y and Z are independently selected from the following: O, NH, N(C alkyl), S, SS, SN, S(=O), SO, C(=O), OC(=O), C(=O)O, NHC(=O)NH, N(C 1-6 Alkyl group C(=O)NC 1-6 alkyl group), NHC(=O)NC 1-6 alkyl group), C 1-12 an alkylene group, an arylene group, a biaryl group, a (heteroaryl)arylene group, an (aryl)heteroaryl group, a heterocycloalkyl group, (C 1-12 alkylene)C(=O)O, OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4)(C 1-12 アルキレン)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2, P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2, P(=O)(OH)CF2(CR 7 R8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 )s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 )s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)CR 5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 THE 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 )p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)- (CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)O- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH] CH2CH2OC(=O)- C 3-6 シクロアルキレン-C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CMe2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH(Me)-CH2C(=O)、 C(=O)N[CH2CH2N(C 1-6 alkyl)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2) COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), and (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O)、 Or C(=O), OC(=O), N(R 4 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2 or C(=O)N(R 4 ) any variant of said group formed by rearranging, adding, or deleting SO2 therein, among which R 5 ~R 10 is as defined above, or Alternatively, any divalent group Z may have the structure: 12 or A 13 Optionally connect to (C 1-12 alkylene)C(=O)O, OC(=O)(C 1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O)N(R 4 ), N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)O(CR 5 R 6 )O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), P(=O)(OCR 5 R6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 7 R 8 ) p (CR 9 R 10 ) r P(=O)(OCR 5 R 6 ) m 、 P(=O)(NHCR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 P(=O)(OCR 5 R 6 )CF2、P(=O)(OCR 5 R 6 )CF2(CR 7 R 8 ) r C(=O)、 P(=O)(OH)CF2、P(=O)(OH)CF2(CR 7 R 8 ) r C(=O)、 C(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s P(=O)(NHCR 5 R 6 ) p 、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、C(=O)N(R 4)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4)SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r (CR 9 R 10 ) s OC(=O)、 C(=O)(CR5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)O(CR 5 R 6 ) p (CR 7 R 8 ) r S-S(CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p S-S(CR 7 R 8 ) r S-S(CR 9 R 10 ) s OC(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)CR5 =CR 7 -S-S-(CR 9 R 10 ) s C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R10 ) s OC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキルC(=O)A 14 ](CR 9 R 10 ) s NHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) sC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 )p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 THE 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)- (CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(OH)CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(R)-CH(NH2)]CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)H]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)-[(S)-CH[NHC(=O)Me]]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OCH(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC 3-6 シクロアルキレン- C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH(Me)OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2C(Me)2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O)OC 3-6 シクロアルキレン- C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)CH(Me)C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOH]CH2CH2OC(=O)C(Me)2C(Me)2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)H]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)Me]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NHC(=O)C 1-6 アルキル]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH[NH(A 1 )]CH2CH2COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH(NH2)CH2CH2COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 アルキル]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p (CR 7 R 8 ) r C(=O)O(CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p( CR 7 R 8 ) r OC(=O) (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH](CR 5 R 6 ) p C(=O)O(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR 5 R 6 ) p OC(=O)(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CMe2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH(Me)- CH2C(=O)、 C(=O)N[CH2CH2N(C 1-6 アルキル)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2) COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or fragments C(=O), OC(=O), N(R 4 )C(=O), P(=O)(OCR 5 R 6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 4 ) any variant of said group Z formed by rearranging, adding or deleting SO2 therein, and Among them, amino acid residue A 12 and A 13 When both of the groups are incorporated to the left of said group and contain a group Z, the residue A 12 or A 13 Peptide bond A 12 -A 13 and interconnect with If any group Z is absent, then group R 2 is the group Y, A1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 Connect directly to one of the

[0142] In an alternative embodiment of Formula II-P-1, each of the optional divalent groups X is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), C(=O)(CR 5 R 6 ) p (CR 7R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s OC(=O),C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group X formed by rearranging, adding or deleting SO2.

[0143] In an alternative embodiment of Formula II-P-1, each of the optional divalent groups X is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R4)(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7-(CR 9 R 10 ) s N(R 4 )C(=O)、C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group X formed by rearranging, adding or deleting SO2; Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 to be connected arbitrarily.

[0144] In an alternative embodiment of formula IP-2, each of the optional divalent groups X is S(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s is OC(=O) or is selected from the following groups:

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] and fragment N(R 4 ) any variation of the above X group formed by rearrangement, addition or deletion of a C(=O) therein; or Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 arbitrarily connected to where xx is 1, 2, or 3, R 100 and R 101 is independently selected from H and an alkyl group; X 1 and X 2 are O, NH and CR 5 R 6 are independently selected from All other variables are defined in Formula II-P-1 herein.

[0149] In an alternative embodiment of formula II-P-1, each of the optional divalent groups Y and Z is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R4 )C(=O)、 C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、 C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10) s N(R 4 )C(=O), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group formed by rearranging, adding or deleting SO2.

[0150] In an alternative embodiment of Formula II-P-1, each optional divalent group Z is N(R 4 )C(=O)(C 1-12 alkylene), (C 1-12 alkylene)N(R 4 )C(=O), C(=O)N(R 4 )(C 1-12 alkylene), C(=O)N(R 4 )(CR 5 R 6 ) p(CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O),C(=O)OCR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O)、C(=O)N(R 4 )SO2(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O)、 C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )SO2C(=O)、 C(=O)N(R 4 )(CR 5 R 6 )p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s C(=O), C(=O)(CR 5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s N(R 4 )C(=O), C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O) and fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of said group formed by rearranging, adding or deleting SO2; Among them, the Z group is 1 to 2 amino acid residues A 12 or A13 to be connected arbitrarily.

[0151] In one embodiment, the compound of formula IP-1 of formula II-P-2

[0152] [ka]

[0153] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 11 is CH2CH(CH3)2 or CH2Ph, and R 12 is CH2NH2 or CH2CH2NH2, and the other groups and integers in the compound of formula II-P-2 are selected as defined above for the compound of formula IP-1.

[0154] In one embodiment of Formula II-P-2, R 11 is CH2Ph, R 12 is CH2NH2 or CH2CH2NH2, and z is 1. In one embodiment, R 12 is H.

[0155] In one embodiment, the compound of formula I-2 of formula III

[0156] [ka]

[0157] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which integers x, y, z are independently selected from 1, 2, and 3; The integer zz is 1 or 2, and R 11 is CH2CH(CH3)2 or CH2Ph.

[0158] In one embodiment, the compound of formula I-2 is a compound of formula Ia

[0159] [ka]

[0160] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: integers x, y, and z are independently selected from 1, 2, and 3; R a represents the side chain of an amino acid selected from D-leucine, D-isoleucine, D-phenylalanine, D-deleucine, D-valine, D-devaline, and D-tert-butylglycine, and 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.

[0161] In another embodiment, the compound of formula I-2 is a compound of formula Ib

[0162] [ka]

[0163] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: A 8 is 2,3-diaminopropionic acid (Dap) or 2,4-diaminobutyric acid (Dab), A 9 is Thr, Glu or Lys, and R a is CH2CH(CH3)2 or CH2Ph.

[0164] In another embodiment, the compound of formula I-2 is a compound of formula Ic

[0165] [ka]

[0166] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 11 is CH2CH(CH3)2 or CH2Ph.

[0167] A preferred group of compounds of formula IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III or IV-P are shown below, wherein each X is independently selected from the structures below, and the left or right side of X shown below is R 1 is connected to.

[0168] [ka]

[0169] Alternative preferred groups of compounds of formula IP-1, IP-2, I-1, I-2, I, Ia, Ib, Ic, II-P-1, II-P-2, III or IV-P are those shown below, wherein each X is independently selected from the structures below, and the left or right side of X shown below is R 1 is connected to.

[0170] [ka]

[0171] Another preferred embodiment of formula IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III, or IV-P is shown below, wherein each X is independently selected from the following structures: 1 is connected to.

[0172] [ka]

[0173] Alternative preferred embodiments of formula IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III, or IV-P are those shown below, wherein each X is independently selected from the following structures: 1 is connected to.

[0174] [ka]

[0175] In any preferred embodiment, the group X is, on its left or right side, C 1-12 Alkylene, C2-12 alkylene, C2-12 alkylene, (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s OC(=O), (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), (CH2) p O(CH2) r O(CH2) s C(=O), O(CH2) p O(CH2) r O(CH2) s OC(=O), O(CH2) p O(CH2) r O(CH2) s NHC(=O), O(CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), NH(CH2) p O(CH2)r O(CH2) s C(=O), NH(CH2) p O(CH2) r O(CH2) s OC(=O), NH(CH2) p O(CH2) r O(CH2) s NHC(=O), NH(CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s OC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s NHC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2)sN(C 1-14 Incorporates another divalent group selected from alkyl)C(=O), and similar linear groups.

[0176] In another embodiment, the compound of formula IP-1 is a compound of formula III-P

[0177] [ka]

[0178] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which R 13 and R 14 H, halogen, NH2-, CN, OH, OC1-14 Alkyl, O-aryl, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 Cycloalkyl, aryl, aralkyl, biaryl, biaralkyl, heteroarylalkyl, C(=O)OH, C 1-14 Alkyl C(=O)OH and C 1-14 AlkylC(=O)-OC 1-14 alkyl, and the other groups and integers in the compound of formula III-P are selected as defined above for the compound of formula IP-1.

[0179] Another preferred group of compounds of formula IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2 or III-P is one in which the Z group is selected from the following structures, and the right hand side of the Z group as depicted below is R 2 is connected to.

[0180] [ka]

[0181] In another alternative preferred embodiment, the Z group has on its left side C 1-12 Alkylene, C 2-12 Alkenyl, C 2-12 Alkynyl, (CH2) p O(CH2) r O(CH2) s C(=O), (CH2) p O(CH2) r O(CH2) s OC(=O), (CH2) p O(CH2) r O(CH2) s NHC(=O), (CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), O(CH2) p O(CH2)r O(CH2) s C(=O), O(CH2) p O(CH2) r O(CH2) s OC(=O), O(CH2) p O(CH2) r O(CH2) s NHC(=O), O(CH2) p O(CHg2) r O(CH2) s N(C 1-14 alkyl)C(=O), NH(CH2) p O(CH2) r O(CH2) s C(=O), NH(CH2) p O(CH2) r O(CH2) s OC(=O), NH(CH2) p O(CH2) r O(CH2) s NHC(=O), NH(CH2) p O(CH2) r O(CH2) s N(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s O C(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s NHC(=O), N(C 1-14 alkyl)(CH2) p O(CH2) r O(CH2) s N(C 1-14 Incorporates a divalent radical selected from alkyl)C(=O), and similar linear groups.

[0182] In another embodiment, the compound of formula IP-1 is a compound of formula IV-P

[0183] [ka]

[0184] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: X is selected from the following structures, and the left side of X is connected to R1; C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s C(=O), C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s NHC(=O), C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 ](CR 9 R 10 ) s OC(=O), C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 alkyl)C(=O)A 14 ](CR 9 R 10 )sNHC(=O), C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sNHC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 )rN(C 1-6 アルキル)C(=O)A 14 ](CR 9 R 10 )sOC(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R10 ) s N(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r OC(=O)A 14 A 15 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r NHC(=O) (CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R 8 ) r N(C 1-6 アルキル)C(=O)(CR 9 R 10 ) s NCH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOC 1-6 alkyl]CH2CH2C(=O)、 C(=O)N[CH2CH2OC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O)OCH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH2CH2C(=O)、 C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CMe2C(=O)OCH2CH2C(=O), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2OC(=O)CH(Me)CH2C(=O), C(=O)N[CH2CH2N(C 1-6 alkyl)C(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH(C=O)R 7 )COOH]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(Me)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(=O), (S)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), and (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), R 11 is C 1-12 alkyl, CH(CH3)2, CH2aryl, or CH2Ph, R 12 is CH2NH2, CH2CH2NH2, or CH2CH2CH2CH2NH2, R 15 , R 17 and R 17 are each independently H, Me or C 1-12 is alkyl, and The other groups and integers in the compound of formula IV-P are selected as defined above for the compound of formula IP-1. In one embodiment of formula IV-P, R 12 is H.

[0185] R 1 Non-limiting examples include:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] In one preferred embodiment, the group R in the compound of formula IV-P 1 is the structure R 1 It is derived from the removal of H from the OH group in (H), and among them, R 1 (H) is selected from the following structures:

[0190] [ka]

[0191] In another preferred embodiment, the group R in the compounds of formula I-P1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III-P, III or IV-P1 is the structure HR 1 It is derived from the removal of H from the OH group of , among which HR 1 is selected from the following structures:

[0192] [ka]

[0193] [ka]

[0194] In another preferred embodiment, the group R in any compound of formula IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III-P, III or IV-P 1 is the structure HR 1 It is derived from the removal of H from the OH group of , among which HR 1 is selected from the following structures:

[0195] [ka]

[0196] Below are illustrated some preferred compounds of formula IP-1 or IP-2, including their salts, such as hydrochloride, sulfate, or other pharmaceutically acceptable salts.

[0197] [ka]

[0198] [ka]

[0199] [ka]

[0200] Below are exemplified some preferred compounds of the present invention, including their salts such as hydrochloride, sulfate or other pharmaceutically acceptable salts.

[0201] [ka]

[0202] The following are examples of additional preferred compounds of Formula I, Ia, Ib, or Ic, including salts thereof, such as hydrochloride, sulfate, or other pharmaceutically acceptable salts.

[0203] [ka]

[0204] [ka]

[0205] The following are examples of additional preferred compounds of Formula I, Ia, Ib, or Ic, including salts thereof, such as hydrochloride, sulfate, or other pharmaceutically acceptable salts.

[0206] [ka]

[0207] In a preferred embodiment, there is provided a compound of any of Formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which has anti-inflammatory activity or therapeutic efficacy against kidney disease as determined by (i) reducing or delaying the release of renal cytokines such as TNF-α, IL-6, IL-12, (ii) lowering one or more biomarkers such as protein levels, serum urea nitrogen, serum creatinine, or (iii) improving the condition of a patient or mammal in animal studies in need of treatment.

[0208] In some or any embodiments, a compound of any of Formulas IP-1, IP-2, I-1, I-2, Ia, Ib, Ic, II-P-1, II-P-2, III-P, III, or IV-P, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is useful for treating inflammation, said inflammation being renal inflammation, or inflammatory diseases in renal damage or renal insufficiency, or inflammation induced by nephrotoxicants, including drug nephrotoxicants such as anti-cancer agents, anti-diabetic agents, anti-infective agents, or other chemotherapeutic agents.

[0209] In some or any embodiments, a compound of any of Formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, or any embodiment thereof, may be administered in combination with a similar dose of free agent or drug HR incorporated into said compound. 1 In some or any embodiments, the compound of formula IP-1, IP-2 or II-P-1, or any embodiment thereof, has enhanced anti-inflammatory, immunomodulatory or nephroprotective activity as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory or nephroprotective activity compared to a similar dose of the free agent or drug HR incorporated into said compound. 1 and / or (H) o R 2have enhanced anti-inflammatory, immunomodulatory or renal protective effects as determined by in vitro or in vivo testing for anti-inflammatory, immunomodulatory or renal protective activity compared to

[0210] In some or any embodiments, for a compound of any of Formula IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, or any embodiment thereof, the compound exhibits preferential accumulation in the kidney when administered to a mammal, and has a ratio of its molar concentration in the kidney to its molar concentration in the blood of about 5-500.

[0211] In some or any embodiments, for a compound of any of Formulas IP-1, IP-2, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P, or any embodiment thereof, the compound exhibits preferential accumulation in the kidney when administered to a mammal, and has a ratio of its molar concentration in the kidney to its molar concentration in the blood of about 20.

[0212] In some or any embodiments, for any of compounds Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, or any embodiment thereof, HR 1 When administered to a mammal in a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1 The compound significantly reduced HR in the kidney compared to the standard therapeutic dose of 1 In some or any of the embodiments, the loading (tissue concentration) and / or drug exposure (area under the curve, AUC) of the compound of formula IP-1, IP-2, or I-1, I-2, II-P-1, or any of the embodiments thereof, is about 1.5 to 15 times higher. 1 and / or (H) o R 2 When administered to a mammal in a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1and / or (H) o R 2 The compound significantly reduced HR in the kidney compared to the standard therapeutic dose of 1 and / or (H) o R 2 This indicates that the burden (tissue concentration) and / or drug exposure (area under the curve, AUC) of

[0213] In some or any embodiments, a compound of any of formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, or any embodiment thereof, is selected from the group consisting of HR 1 When administered to a mammal in a dose (expressed in molar amounts) equal to the standard therapeutic dose (in molar amounts) of the agent, HR 1 When compared to standard therapeutic doses of the reagent, the therapeutic effect is determined as a delay, halt, or reversal of inflammation (as determined by changes in cytokine release and / or the use of biochemical biomarkers or similar methods for disease monitoring). In some or any embodiments, the compound of any of formulas IP-1, IP-2, or II-P-1, or any embodiment thereof, is administered in combination with the reagent HR. 1 and / or (H) o R 2 When administered to a mammal at a dose (expressed in molar amounts) equal to the standard therapeutic dose (in molar amounts) of 1 Compared to standard therapeutic doses of the reagents, they exhibit approximately 1.5-15 times greater efficacy, with the therapeutic effect being determined as a delay, cessation, or reversal of inflammation (as determined by changes in cytokine release and / or the use of biochemical biomarkers or similar methods for disease monitoring).

[0214] In some or any embodiments, a compound of any of formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III, or IV-P, or any embodiment thereof, is selected from the group consisting of HR 1 When administered to a mammal in a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (molar amount) of the agent, HR 1In some or any embodiments, the compound of formula IP-1, IP-2, or II-P-1, or any embodiment thereof, exhibits at least two-fold increased efficacy when compared to standard therapeutic doses of the agent, the therapeutic effect being determined as a delay, halt, or reversal of inflammation or kidney damage (e.g., as determined by cytokine release levels and / or the use of biochemical biomarkers to monitor inflammation, or by radiography, or magnetic resonance imaging, etc.). In some or any embodiments, the compound of formula IP-1, IP-2, or II-P-1, or any embodiment thereof, exhibits HR 1 and / or (H) o R 2 When administered to a mammal in a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (molar amount) of the agent, HR 1 The therapeutic effect is at least two-fold greater than the standard therapeutic dose of the agent, and the therapeutic effect is determined as a delay, halt, or reversal of inflammation or kidney damage (e.g., as determined by cytokine release levels and / or the use of biochemical biomarkers to monitor inflammation, or by radiography, or magnetic resonance imaging, etc.).

[0215] In some or any embodiments, a compound of any of formula Ia, Ib, Ic, I-1, I-2, II-P-2, III-P, III or IV-P, or any embodiment thereof, is selected from the group consisting of the drug HR 1 When administered to mammals at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1 In some or any embodiments, a compound of formula IP-1, IP-2, or II-P-, or any embodiment thereof, is administered as a drug HR. 1 and / or (H) o R 2 When administered to mammals at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of 1 and / or (H) o R 2demonstrates at least a two-fold reduction in the incidence of adverse reactions and / or off-target toxicities when compared to a standard therapeutic dose of the compound, as determined by medical observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods.

[0216] In some embodiments and aspects, the compounds described herein can be used in combination with adjunct agents to act synergistically and / or enhance the therapeutic effect of the compound itself, the adjunct, or both. Such adjunct agents include monoclonal antibody reagents, or other anti-inflammatory reagents, or other anti-cancer or antibacterial reagents, or other anti-cancer or immunomodulatory agents, such as humanized antibodies.

[0217] In some embodiments and aspects, there is provided a method of treating inflammation-associated kidney disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formulas IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P.

[0218] In one such aspect, the compounds provided herein have moderate or no anti-inflammatory activity in vitro, but exhibit a high anti-inflammatory effect when administered to a mammal in need of such treatment.

[0219] In some or any embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III or IV-P, or a compound defined in any embodiment described herein, and a pharmaceutically acceptable carrier.

[0220] General synthesis method The compounds described herein can be prepared by one or more methods, for example, in the following references: The general synthesis of some relevant starting materials is described in the literature. For example, O'Dowd et al., Tetrahedron Lett. 2007, vol. 48, p. 2003, describes the preparation of Boc-protected polymucosin naphthopeptides. Further protected polymucosin B naphthopeptide and mucosin naphthopeptide derivatives can be prepared as described by Okimura et al., Chem. Pharm. Bull. 2007, vol. 55, pp. 1724-1730. Similarly, Tetrahedron Lett. 2007, vol. 48, pp. 2003-2005, describes general peptide acylation chemistry.

[0221] Other general methods suitable for the preparation of compounds of formula IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III or IV-P are described in the following publications: WO 2021 / 150792, WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, US 2015 / 0031602, WO 2014 / 188469, WO 2014 / 028087, WO 2013 / 112548, WO 103130876, WO 2013 / 072695, WO 2012 / 168820, WO 2012051663, US 2012 / 0316105, US 2012 / 0283176, US 2010 / 0160215, US 2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, US 2006 / 0004185, US 6380356, and US 3450687.

[0222] Suitable methods for incorporating appropriate enzymatically and / or chemically cleavable groups X, Y, and Z (and other such spacers / linkers) into compounds of formula IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P are described in general relevant synthetic techniques for preparing ADCs and other reagents, and are described, for example, in the following publication: US 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 in the said publications.

[0223] It will be apparent to one skilled in the art of synthetic organic chemistry that certain methods, amino acid reagents, and linker / spacer structures described in the above references can be directly adapted to prepare compounds of formula IP-1, IP-2, I, Ia, Ib, Ic, I-1, I-2, II-P-1, II-P-2, III-P, III, or IV-P by simple variation of specific reagents and protection / deprotection schemes.

[0224] Alternative syntheses of certain compounds described herein are illustrated by various synthetic schemes in the Examples below, and are equally applicable to the preparation of other compounds described herein.

[0225] Example The embodiments described herein are illustrated in the following examples, which are intended to illustrate, but not limit, the scope of the disclosure. Common abbreviations familiar to those skilled in the synthetic arts are used throughout. Abbreviation: NMR: 400 MHz in DO unless otherwise specified 1 H spectrum (δ, ppm). LCMS: liquid chromatography-mass spectrometry. MS: Mass spectrometry data (m / z) using positive ionization. Chromatography: Silica gel chromatography with organic solvents unless otherwise specified. TLC: thin layer chromatography. HPLC: High performance reversed phase liquid chromatography using a commercially available C18 column. TES:Et3SiH. TFA:CF3COOH. EA: EtOAc or ethyl acetate. CDI: carbonyldiimidazole. EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. DMAP: 4-dimethylaminopyridine. DIPEA: N,N-diisopropylethylamine. HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, azabenzotriazolium tetramethyluranium hexafluorophosphate. Cs2CO3: Cesium carbonate. MeOH: methanol. ACN:MeCN. DMF: N,N-dimethylformamide. DCC: N,N'-dicyclohexylcarbodiimide. DCE: 1,2-dichloroethane. DCM: 1,2-dichloromethane. NMP: N-methylpyrrolidone. PE: Hexane or light petroleum ether. T3P: Tripropylphosphinic anhydride. C18 chromatography: Reversed phase chromatography using a gradient of water and acetonenitrile (ACN) with 0.1% TFA. PMBN(Boc)4:H-Thr-Dab(Boc)-cyclo[Dab(Boc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]. PMBH(Boc)3: H-cyclo[Dab(Boc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]. Dab(Boc)PMBN(Boc)4:Dab(Boc)-Thr-Dab(Boc)-Cyclo[Dab(Boc)-Dab(Boc)-D-Phe-Leu- Dab(Boc)-Dab(Boc)-Thr] [Same as H-Dab(Boc)-Thr-Dab(Boc)-cyclo[Dab(Boc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]]. Dex-Pnp: 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl(4-nitrophenyl)carbonate. Ar: Argon rt or RT: room temperature. Other reagent abbreviations are similar to those used in the general synthesis literature, including the American Chemical Society abbreviation lists found in journals such as the Journal of Organic Chemistry or the Journal of Peptide Chemistry. Unless otherwise specified, all reagents are commercially available or prepared by conventional methods described in the existing literature.

[0226] Example 1 Synthesis of the compound of Example 1:

[0227] [ka]

[0228] Intermediate 1 Dexamethasone (101.1 mg, 0.26 mmol), 2,3-dimethylsuccinic acid (49.7 mg, 0.34 mmol), EDC (58.2 mg, 0.30 mmol), and DMAP (48.2 mg, 0.39 mmol) were added to DCM (2.5 mL) with stirring at room temperature. After 1 h, the mixture became clear and was stirred at room temperature overnight. The mixture was evaporated in vacuo. The residue was dissolved in ACN (2 mL), and the product was purified by HPLC (0-100% ACN-water with a gradient of 0.05% TFA) to give Intermediate 1 (102 mg) as a white solid in 76% yield. LCMS: 521.26 [M+H] + .

[0229] Intermediate 2 DIPEA (0.1 mL, 0.57 mmol) was added to a mixture of Intermediate 1 (102 mg, 0.196 mmol), PMBN(Boc)4 (253.5 mg, 0.186 mmol), and HATU (89.4 mg, 0.235 mmol) in DMF (2.5 mL). The resulting mixture was stirred at room temperature overnight. The desired product was detected by LCMS. The mixture was then purified by HPLC (0-100% ACN-water with 0.05% TFA gradient) to give Intermediate 2 (146 mg) as a white powder in 42% yield. LCMS: 1866.34 [M+H] + .

[0230] Compound of Example 1 TFA (1 mL) was added to a solution of Intermediate 2 (146 mg, 0.078 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 3 hours. Volatiles were evaporated in vacuo, and the crude product was dissolved in HO / ACN (1 mL / 1 mL) and purified by HPLC (0.05% TFA gradient 0-60% water-ACN) to give the TFA salt of Example 1 (116.9 mg). NMR:7.45 (d, J = 10.4 Hz, 1H), 7.34-7.18 (m, 5H), 6.35 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 6.16 (s, 1H), 5.08-4.87 (m, 2H), 4.52 (t, J = 8.4 Hz, 1H), 4.45-4.39 (m, 2H), 4.34-4.31 (m, 1H), 4.26-4.13 (m, 7H), 3.30-3.24 (m, 1H), 2.74-2.38 (m, 11H), 2.16-1.63 (m, 15H), 1.48 (s, 3H), 1.42-1.32 (m, 2H), 1.17-1.11 (m, 12H), 0.91 (s, 3H), 0.80 (d, J = 7.2 Hz, 3H), 0.70 (d, J = 6.4 Hz, 3H), 0.63 (d, J = 6.0 Hz, 3H). MS: 1466.80 [M+H] + .

[0231] Example 2 Synthesis of the compound of Example 2:

[0232] [ka]

[0233] Intermediate 3 To a solution of dexamethasone (105.0 mg, 0.268 mmol) in anhydrous pyridine (2 mL), DMAP (71.8 mg, 0.588 mmol) was added, and succinic anhydride (117.4 mg, 1.173 mmol) was added at room temperature. The mixture was stirred under Ar for 2 hours, then poured into 20 mL of 1 M HCl and filtered. The resulting white solid was washed with water (5 mL) and dried under vacuum overnight to give intermediate 3 (120.5 mg, 91% yield). LCMS: 493.07 [M+H] + .

[0234] Intermediate 4 A mixture of intermediate 3 (120.5 mg, 0.24 mmol), PMBN(Boc)4 (339.2 mg, 0.25 mmol), and HATU (111.0 mg, 0.29 mmol) in DMF (25 mL) and DIPEA (0.1 mL, 0.57 mmol) was stirred at room temperature overnight. The mixture was then purified by HPLC (gradient 0-100% water-MeOH) to give crude intermediate 4 (181 mg) as a white powder. LCMS: 1837.91 [M+H] + .

[0235] Compound of Example 2 TFA (0.2 mL) was added to a solution of Intermediate 4 (140 mg, approximately 50% purity, 0.076 mmol) in DCM (2.5 mL). The resulting mixture was stirred at room temperature for 3 hours. After stirring for 1 hour, the mixture was evaporated under reduced pressure, and the crude product was purified by HPLC (0.05% TFA gradient 0-100% ACN-water) to give the compound of Example 2. NMR: 7.39 (d, J = 10.4 Hz, 1H), 7.30-7.21 (m, 5H), 6.28 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 6.07 (s, 1H), 5.11-5.06 (m, 1H), 4.50-4.07 (m, 12H), 3.60-3.54 (m, 2H), 3.08-1.18 (m, 57H), 1.00 (s, 3H), 0.91-0.68 (m, 10H). MS: 1437.75 [M+H] + .

[0236] Example 3 Synthesis of the compound of Example 3:

[0237] [ka]

[0238] Intermediate 5 Dexamethasone (239.8 mg, 0.61 mmol), CsCO (234.0 mg, 0.723 mmol), and tert-butyl 4-(bromomethyl)benzoate (171.8 mg, 0.63 mmol) were added to ACN (10 mL) at room temperature under Ar, and the resulting mixture was stirred at 65 °C for 4 h. The mixture was filtered, evaporated under vacuum, and purified by high-performance chromatography column (silica gel, gradient PE-EtOAc 0-45%) to give intermediate 5 (116 mg) as a white solid in 76% yield. LC / MS: 583.01 [M+H] + .

[0239] Intermediate 6 TFA (1 mL) was added to a solution of intermediate 5 (110 mg, 0.188 mmol) in DCM (4 mL). The mixture was stirred for 2 hours. The mixture was evaporated in vacuo and the crude product was used directly in the next reaction. LCMS: 527.16 [M+H] + .

[0240] Intermediate 7 DIPEA (0.08 mL, 0.46 mmol) was added to a mixture of intermediate 6 (approximately 0.188 mmol), PMBN(Boc)4 (260 mg, 0.19 mmol), and HATU (89 mg, 0.23 mmol) in DMF (2.5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with 10 mL of EtOAc, and the organic layer was washed with water (5 mL), brine (10 mL), and dried over Na2SO4. The volatiles were removed in vacuo, and the crude product was purified by high-performance chromatography (silica gel, gradient 0-12% DCM-MeOH) to give intermediate 7 (293.8 mg) as a colorless solid in 83% yield over two steps. LCMS: 1871.52 [M+H] + .

[0241] Compound of Example 3 To a solution of Intermediate 7 (293.8 mg, 0.157 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The volatiles were evaporated in vacuo, and the crude product was purified by HPLC (0-45% ACN-water with 0.05% TFA) to give Example 3. NMR:7.80 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 10.0 Hz, 1H), 7.34-7.25 (m, 3H), 7.19-7.17 (m, 2H), 6.33-6.30 (m, 1H), 6.13 (s, 1H), 4.69-4.08 (m, 15H), 3.25-1.18 (m, 1H), 3.06-2.94 (m, 7H), 2.80-2.59 (m, 3H), 2.50-2.36 (m, 2H), 2.18-1.66 (m, 13H), 1.46 (s, 3H), 1.42-1.31 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H), 1.19-1.13 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H), 0.84-0.76 (m, 6H), 0.70 (d, J = 6.4 Hz, 3H), 0.63 (d, J = 7.0 Hz, 3H). MS: 1471.74 [M+H] + .

[0242] Example 4 Synthesis of the compound of Example 4:

[0243] [ka]

[0244] Compound of Example 4. The compound of Example 4 was prepared by a similar process to that of the compound of Example 2, except that intermediate 3 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4 used in Example 2. NMR:7.44 (d, J = 10.4 Hz, 1H), 7.25-7.34 (m, 3H), 7.19 (d, J = 6.8 Hz, 2H), 6.334 (dd, J = 10 Hz, 1.6 Hz, 1H), 6.15 (s, 1H), 4.98 (d and d, J = 18 Hz, 2H), 4.42-4.51 (m, 2H), 4.10-4.32 (m, 7H), 3.29-3.36 (m, 1H), 2.37-3.11 (m, 18H), 1.76-2.22 (m, 12H), 1.60 (d, J = 14 Hz, 1H), 1.47 (s, 3H), 1.28-1.42 (m, 3H), 1.17-1.23 (m, 1H), 1.12 (d, J = 6 Hz, 3H), 0.90 (s, 3H), 0.80 (d, J = 7.2 Hz, 3H), 0.68-0.69 (m, 3H), 0.61 (d, J = 5.6 Hz, 3H). MS: 1236.76 [M+H] + .

[0245] Example 5 Synthesis of the compound of Example 5:

[0246] [ka]

[0247] Compound of Example 5 The compound of Example 5 was prepared by the same procedure as the compound of Example 2, except that 4-(tert-butoxycarbonyl)benzoic acid was used instead of succinic anhydride. NMR:8.12 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 10 Hz, 1H), 7.25-7.34 (m, 3H), 7.19 (d, J = 6.8 Hz, 2H), 6.34 (dd, J = 1.6Hz, 10 Hz, 1H), 6.15 (s, 1H), 5.17-5.31 (m, 2H), 4.09-5.52 (m, 12H), 3.17-3.30 (m, 1H), 2.99-3.04 (m, 10H), 2.37-2.82 (m, 5H), 1.71-2.22 (m, 15H), 1.48 (s, 3H), 1.31-1.44 (m, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.17-1.22 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H), 0.96 (s, 3H), 0.83 (d, J = 7.2 Hz, 3H), 0.70 (d, J = 6.0 Hz, 3H), 0.63 (d, J = 6.0 Hz, 3H). MS: 1486.02 [M+H] + .

[0248] Example 6A Synthesis of the compound of Example 6:

[0249] [ka]

[0250] Compound of Example 6 The compound of Example 6 was prepared from dexamethasone according to the synthetic steps described above.

[0251] Example 6B Alternative synthesis of the compound of Example 6:

[0252] [ka]

[0253] [ka]

[0254] Intermediate 12 A mixture of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (505 mg, 1.67 mmol) and CDI (324 mg, 2 mmol) in DMF (4 mL) was stirred at room temperature for 1.5 h, and then ethylene-1,2-diamine (1.1 mL, 16.7 mmol) was added. The mixture was stirred at room temperature for 1.5 h and partitioned between DCM (10 mL) and brine (10 mL). After extraction with DCM (60 mL), the organic layer was washed with water (2 × 10 mL), brine (10 mL), and dried (NaSO). The solvent was evaporated in vacuo to give crude Intermediate 12 (0.62 g). MS: 346.16 [M+H] + .

[0255] Intermediate 13 A mixture of intermediate 12 (0.62 g, 1.67 mmol) and acrylic acid benzyl ester (0.24 g, 1.5 mmol) in ACN (4 mL) was stirred at 45 °C under Ar for 36 h. The volatiles were removed in vacuo and the residue was purified by HPLC (gradient ACN-water 0-80%) to give intermediate 13 (0.5 g). MS: 508.31 [M+H] + .

[0256] Intermediate 14 A suspension of intermediate 13 (0.5 g, 0.99 mmol) and Pd / C (0.15 g) in t-BuOH (5 mmol) was stirred at room temperature with H for 4.5 hours. The mixture was filtered and dried under vacuum to give intermediate 14 (0.42 g). MS: 418.25 [M+H] + .

[0257] Intermediate 15 Intermediate 14 (190 mg, crude) and Dex-Pnp (254 mg, 0.46 mmol) were dissolved in THF (5 mL), and DIEA (117.5 mg, 0.91 mmol) was added. The mixture was stirred at room temperature for 2 days. The mixture was concentrated and purified by HPLC (5-60% ACN-water with 0.05% TFA) to give Intermediate 15 (180 mg) as a white solid. MS: 836.14 [M+H] + .

[0258] Intermediate 16 To a solution of intermediate 15 (100 mg, 0.12 mmol) in DMF (3 mL) was charged DIEA (77 mg, 0.60 mmol) followed by T3P (150 mg, 0.24 mmol, 50% w / w in EA). The resulting mixture was stirred at room temperature for 30 minutes. PMBN-Boc4 (160 mg, 0.12 mmol) was charged. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (10 mL), washed with water (10 mL), and the organic phase was dried (Na2SO4) and evaporated in vacuo to give intermediate 16 (200 mg). MS: 1091.17 [M+2H] 2+ .

[0259] Compound of Example 6 The compound of Example 6 was prepared by a similar procedure to that of Example 1. 1H NMR:7.45 (d, J = 10.1 Hz, 1H), 7.30 (dq, J = 14.6, 7.3 Hz, 3H), 7.19 (d, J = 7.1 Hz, 2H), 6.34 (dd, J = 10.1, 1.6 Hz, 1H), 6.15 (s, 1H), 4.91 (d, J = 12.5 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.32 (d, J = 9.0 Hz, 1H), 4.19 (ddd, J = 21.2, 14.3, 4.2 Hz, 8H), 3.96 (dt, J = 23.4, 6.5 Hz, 1H), 3.67 - 3.20 (m, 8H), 3.11 - 2.91 (m, 10H), 2.87 - 2.35 (m, 10H), 2.22 - 2.00 (m, 10H), 1.95 - 1.72 (m, 6H), 1.62 (d, J = 13.2 Hz, 1H), 1.48 (s, 3H), 1.43 - 1.32 (m, 3H), 1.25 - 1.07 (m, 7H), 0.91 (d, J = 4.0 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 5.7 Hz, 3H), 0.62 (d, J = 5.9Hz, 3H). MS: 1624.87 [M+H] + .

[0260] Example 7A Synthesis of the compound of Example 7:

[0261] [ka]

[0262] Compound of Example 7 The compound of Example 7 was prepared from dexamethasone according to the synthetic steps described above.

[0263] Example 7B Synthesis of the compound of Example 7:

[0264] [ka]

[0265] Compound of Example 7 The compound of Example 7 was prepared in a similar manner to the compound of Example 6, except that intermediate 15 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4. 1 H NMR:7.43 (dd, J = 10.1, 4.6 Hz, 1H), 7.33 - 7.22 (m, 3H), 7.17 (d, J = 7.5 Hz, 2H), 6.32 (d, J = 10.1 Hz, 1H), 6.13 (s, 1H), 5.03 (d, J = 18.2 Hz, 1H), 4.90 (s, 1H), 4.51 - 4.40 (m, 1H), 4.29 (d, J = 10.1 Hz, 1H), 4.24 - 4.03 (m, 6H), 3.92 (dd, J = 24.1, 17.9 Hz, 1H), 3.67 - 3.51 (m, 2H), 3.51 - 3.14 (m, 6H), 3.12 - 2.86 (m, 9H), 2.80 (ddd, J = 15.5, 9.7, 6.2 Hz, 1H), 2.76 - 2.32 (m, 8H), 2.25 - 1.93 (m, 9H), 1.93 - 1.53 (m, 7H), 1.46 (s, 3H), 1.42 - 1.24 (m, 3H), 1.17 (s, 1H), 1.09 (s, 3H), 0.88 (d, J = 12.0 Hz, 3H), 0.77 (d, J = 7.1 Hz, 3H), 0.71 - 0.65 (m, 3H), 0.60 (t, J = 6.0Hz, 3H). MS: 1423.77 [M+H] + .

[0266] Example 8 Synthesis of the compound of Example 8:

[0267] [ka]

[0268] [ka]

[0269] Intermediate 18 N 1 3.35 g (32 mmol) of 2-aminoethylethylene-1,2-diamine was dissolved in 30 mL of DCM and cooled to 0° C. A solution of ethyl trifluoroacetate (9.69 g, 68 mmol) in 10 mL of DCM was slowly added. After 1 h, TEA (3.87 g, 38.4 mmol) was added, followed by a solution of CbzCl (6.0 g, 35.2 mmol) in 10 mL of DCM at 0° C. The mixture was stirred at room temperature for 16 h and then diluted with water and DCM. The organic layer was separated and evaporated under vacuum, and the crude product was purified by silica gel chromatography to give intermediate 18 (2.9 g) as a white solid in 21% yield. MS: 430.0 [M+H] + .

[0270] Intermediate 19 To a solution of intermediate 18 (2.0 g, 4.7 mmol) in MeOH (152 mL) was added KCO (256 mg, 1.9 mmol). The mixture was stirred at 65 °C overnight. The solvent was removed in vacuo and the product was purified by HPLC to give intermediate 19 (490 mg) as a colorless oil. MS: 334.2 [M+H] + .

[0271] Intermediate 20 At 0°C, DIPEA (561 mg, 4.35 mmol) and HATU (771 mg, 2.03 mmol) were added to a mixture of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (527 mg, 1.74 mmol) in DMF (5 mL), followed by intermediate 19 (483 mg, 1.45 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water (20 mL), and evaporated in vacuo. The residue was purified by HPLC (0.1% TFA gradient ACN-water 0-80%) to give intermediate 20 (355 mg) as a colorless oil. MS: 619.1 [M+H] + .

[0272] Intermediate 21 To a solution of intermediate 20 (355 g, 0.57 mmol) in MeOH (5 mL) / HO (0.5 mL) was added KCO (79 mg, 0.57 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (10 mL), washed with water (10 mL), and evaporated in vacuo. The residue was purified by HPLC (0.1% TFA gradient ACN-water 0-60%) to give intermediate 21 (188 mg) as a colorless oil. MS: 523.31 [M+H] + .

[0273] Intermediate 22 To a solution of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (146 mg, 0.43 mmol) in DMF (4 mL) at 0° C., HATU (178 mg, 0.4 mmol) and DIEA (139 mg, 1.08 mmol) were added, and the mixture was stirred at 0° C. for 20 minutes. Next, Intermediate 21 (188 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with 20 mL of EtOAc, washed with 20 mL of water, and evaporated in vacuo. The residue was purified by HPLC (ACN-water with 0.1% TFA 0-90%) to give Intermediate 22 (210 mg) as a colorless oil. MS: 842.3 [M+H] + .

[0274] Intermediate 23 To a solution of intermediate 22 (85 mg, 0.10 mmol) in EA (3 mL) was added Pd / C (10 mg, 10%), and the mixture was stirred overnight under an H atmosphere. It was then filtered through Celite and evaporated in vacuo to give intermediate 23 (59.5 mg) as a colorless oil. MS: 618.4 [M+H] + .

[0275] Intermediate 24 DIEA (31 mg, 0.24 mmol) was added to a solution of Intermediate 23 (49.5 mg, 0.08 mmol) and 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentane[a]phenanthren-17-yl)-2-oxyethyl(4-nitrophenyl)carbonate (53.6 mg, 0.096 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 3 days, then diluted with EtOAc (10 mL), washed with water (10 mL), and evaporated in vacuo. The residue was purified by HPLC (0.1% TFA gradient ACN-water 0-80%) to give Intermediate 24 (30 mg) as a colorless oil. MS: 1036.2 [M+H] + .

[0276] Intermediate 25 To a solution of intermediate 24 (20 mg, 0.019 mmol) in DMF (2 mL) was added T3P (50% in EtOAc, 24 mg, 0.038 mmol), followed by DIEA (12 mg, 0.096 mmol) and PMBN-Boc4 (26 mg, 0.019 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (10 mL), washed with water (10 mL), and evaporated in vacuo. The residue was purified by HPLC (0.1% TFA gradient ACN-water 0-80%) to give intermediate 24 (30 mg) as a colorless oil. MS: 1191.1 [M+2H] 2+ .

[0277] Compound of Example 8 To a solution of Intermediate 24 (30 mg, 0.0126 mmol) in DCM (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by HPLC (0.05% TFA gradient ACN-water 5-30%) to give Example 8 (7.07 mg) as a white solid. 1 H NMR:7.45 (d, J = 10.3 Hz, 1H), 7.31 (d, J = 6.8 Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 7.4 Hz, 2H), 6.35 (d, J = 10.1 Hz, 1H), 6.15 (s, 1H), 5.01 (d, J = 18.4 Hz, 1H), 4.90 (d, J = 18.1 Hz, 1H), 4.50 (dd, J = 13.9, 8.3 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.32 (d, J = 9.4 Hz, 1H), 4.26 (d, J = 4.5 Hz, 1H), 4.23 - 4.11 (m, 8H), 4.01 - 3.88 (m, 2H), 3.52 - 3.33 (m, 8H), 3.25 (dt, J = 15.3, 7.6 Hz, 1H), 3.10 - 2.98 (m, 10H), 2.95 - 2.89 (m, 1H), 2.85 - 2.77 (m, 1H), 2.72 (s, 1H), 2.68 - 2.60 (m, 1H), 2.50 - 2.33 (m, 6H), 2.09 (ddd, J = 23.8, 20.8, 10.5 Hz, 13H), 1.87 (s, 3H), 1.81 - 1.71 (m, 2H), 1.61 (d, J = 13.6 Hz, 1H), 1.48 (s, 3H), 1.45 - 1.32 (m, 3H), 1.13 (dd, J = 16.8, 6.3 Hz, 6H), 0.91 (s, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 5.7 Hz, 3H), 0.62 (d, J = 5.0 Hz, 3H). MS: 1724.9 [M+H] + .

[0278] Example 9 Synthesis of the compound of Example 9:

[0279] [ka]

[0280] Compound of Example 9 The compound of Example 9 was prepared in a similar manner to the compound of Example 1 from octanoic acid, except that intermediate 26 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4. 1 H NMR (CD3OD): 7.30 (d, J = 10.1 Hz, 1H), 7.24 - 7.10 (m, 5H), 6.19 (dd, J = 10.1, 1.8 Hz, 1H), 5.98 (s, 1H), 4.92 - 4.80 (m, 2H), 4.45 (dd, J = 9.4, 4.4 Hz, 1H), 4.31 (dd, J = 10.1, 6.3 Hz, 1H), 4.26 - 4.14 (m, 3H), 4.10 - 3.92 (m, 4H), 3.54 (br d, J = 7.6 Hz, 1H), 3.02 - 2.93 (m, 5H), 2.92 - 2.84 (m, 3H), 2.62 (d, J = 6.4 Hz, 1H), 2.44 - 2.26 (m, 5H), 2.26 - 2.10 (m, 4H), 2.09 (br s, 4H), 1.89 - 1.73 (m, 4H), 1.64 (d, J = 12.0 Hz, 1H), 1.61 - 1.52 (m, 5H), 1.49 (s, 3H), 1.47 - 1.37 (m, 2H), 1.37 - 1.24 (m, 5H), 1.24 - 1.17 (m, 2H), 1.15 - 1.08 (m, 4H), 0.91 (s, 3H), 0.76 (d, J = 7.3 Hz, 4H), 0.68 - 0.54 (m, 6H). MS: 647.4 [M+2H] 2+ .

[0281] Example 10 Synthesis of the compound of Example 10:

[0282] [ka]

[0283] Compound of Example 10 The compound of Example 10 was prepared in a similar manner to the compound of Example 1, except that intermediate 29 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4. 1 H NMR (CD3OD): 7.32 (d, J = 10.1 Hz, 1H), 7.11 - 7.26 (m, 5H), 6.20 (dd, J = 10.1, 1.8 Hz, 1H), 6.00 (s, 1H), 4.83 - 4.99 (m, 2H), 4.42 - 4.49 (m, 1H), 4.28 - 4.36 (m, 1H), 4.15 - 4.27 (m, 3H), 3.93-4.14 (m, 4H), 3.51 - 3.62 (m, 1H), 2.86-3.06 (m, 9H), 2.76 - 2.86 (m, 1H), 2.55 - 2.69 (m, 1H), 2.36 - 2.45 (m, 3H), 2.31 (dd, J = 11.1, 5.5 Hz, 2H), 2.19 - 2.27 (m, 3H), 2.09 - 2.19 (m, 2H), 1.98-2.08 (m, 3H), 1.75 - 1.90 (m, 4H), 1.52 - 1.71 (m, 6H), 1.48 - 1.52 (m, 3H), 1.35 - 1.47 (m, 2H), 1.17 - 1.31 (m, 2H), 1.08 - 1.17 (m, 4H), 0.92 (s, 3H), 0.72 - 0.81 (m, 3H), 0.55 - 0.69 (m, 5H). MS: 633.4 [M+2H] 2+ .

[0284] Utility and Measurement The compounds provided herein demonstrate potent in vivo efficacy against various inflammation-related kidney diseases, including CKD and AKI, postoperative inflammation (e.g., inflammation in kidney transplant surgery), inflammation induced by anticancer or antibacterial treatment or diabetes treatment, or inflammation caused by exposure to environmental nephrotoxicants, making these agents useful for treating such kidney diseases.

[0285] The in vitro activity of the compounds provided herein may be determined by the active entity (payload, e.g., HR) incorporated (conjugated) into the compositions provided herein. 1 The activity of the conjugates can be assessed using standard bioassay procedures to evaluate the activity of the payload. The choice of a particular assay will depend on the known or anticipated mode of action of the payload structure. For example, conjugates that bind to anti-inflammatory vanin-1 inhibitors can be measured in a human vanin-1 enzyme assay, as described in the disclosure of PCT WO 2020 / 114943.

[0286] The preferential renal targeting of the compounds provided herein for delivery to the kidney (or site of renal damage) is assessed by pharmacokinetic (PK) measurements, such as standard rodent PK measurements. PK data are typically used to establish important parameters for predicting therapeutic outcome. Thus, the drug concentration at a given time point (C), the drug concentration in the target tissue (C), and the drug concentration in the target tissue (C) are used to determine the renal targeting potential. Target The area under the curve (AUC) and other parameters of the graph monitoring the time course of systemic drug concentrations can usually predict the efficacy of treatment. For example, drug concentrations in organs affected by cancer are important for the effective action of anticancer drugs (e.g., Zhang et al., Drug Metabolism and Disposition. 2019, vol. 47, p. 1122).

[0287] Representative compounds provided herein are measured in an intravenous rodent PK model performed in a manner similar to that described in the monograph Current Protocols in Pharmacology, 2005, 7.1.1-7.1.26, John Wiley & Sons, Inc. Illustrative mouse PK data for the compounds of Examples 1 and 2 are summarized in Table 1 below. As can be seen from the data, these compounds demonstrate a surprising ability to target the kidney, confirmed by high levels of preferential concentration in kidney tissue, the organ of interest for targeted therapy.

[0288] [Table 1]

[0289] For the compound of Example 1, c A dose of 4 mg / kg is expressed in μmol / kg per MW of 1921.79 Daltons (not corrected for measured solvated water content).

[0290] For the compound of Example 2, d A dose of 4 mg / kg is expressed in μmol / kg per MW of 1893.73 Daltons (not corrected for measured solvated water content).

[0291] It is noteworthy that administration of the compounds of Examples 1 and 2 (including the conjugated form of dexamethasone) results in approximately 9-fold and 7-fold higher renal dexamethasone levels (measured as drug concentration in renal tissue), respectively, compared to the renal levels of dexamethasone obtained by injecting the (unconjugated) drug form of dexamethasone.

[0292] Even more surprisingly, this beneficial enhancement was observed even though the total amount (dose) of dexamethasone administered via the exemplary compounds herein was much lower than that administered as free (unbound) drug. Because drug levels at disease-affected sites directly determine the therapeutic efficacy of a formulation, the data presented in Table 1 suggest a significant improvement in the therapeutic potential (in vivo activity) of the novel compositions herein.

[0293] Furthermore, based on the PK data, the release of dexamethasone administered in the form of the compounds of Examples 1 and 2 was sustained for at least 24 hours (T = 24 hours, the final time point evaluated), with renal drug concentrations of 21.5 and 18.5 ng / g for Examples 1 and 2, respectively. This contrasts sharply with the barely detectable drug levels obtained by standard injection of unbound dexamethasone after only 6 hours. The surprising beneficial effects of the compounds described herein further demonstrate the potential for improved treatment of inflammation-related diseases with the compounds provided herein.

[0294] The data presented in Table 1 demonstrate that such agents can be administered less frequently than standard dexamethasone administration. Based on this data, the compounds of Examples 1 and 2 can be administered less frequently, for example, once daily, once more daily, or once weekly. This advantage represents a significant benefit to patients requiring this treatment. Furthermore, this useful feature minimizes the need for hospitals to provide treatments such as intravenous administration, resulting in significant pharmaceutical economic benefits.

[0295] The in vivo activity of the compounds provided herein can be assessed, for example, by the assay procedures described below, i.e., those used to assess the anti-inflammatory and immunomodulatory effects of corticosteroid drugs as described by Chen et al. in Inflammopharmacology, 2018, 26, pp. 1331-1338, or in rodent models of non-diabetic and diabetic chronic nephropathy as described by Perico et al. in Kidney International, 2005, Vol. 68, Supplement 98, pp. S21-S24; Yang et al. in Process Biochemistry, 2019, Vol. 83, pp. 198-205; and Remuzzi et al. in Kidney International, 2002, Vol. 62, pp. 885-894, and other assays in the references cited therein.

[0296] Specifically, in one study, cisplatin (20 mg / kg) was administered intraperitoneally to C57BL / 6 mice (male, weight range 20-25 g) to induce acute kidney injury. One hour later, the test article (saline, dexamethasone, or the compound of Example 1 or 2) was administered intravenously. Blood creatinine (CREA) and blood urea nitrogen (BUN) were measured on day 3. Exemplary in vivo efficacy data for the compounds of Examples 1 and 2 are summarized in Figure 1 below.

[0297] As shown in Figure 1 , in this animal model, a single dose of 20 mg / kg cisplatin induced acute kidney injury (AKI), confirmed by elevated blood urea nitrogen (BUN) and creatinine (CREA), standard biomarkers of AKI.

[0298] The BUN and CREA values ​​in Figure 1 reveal that the compounds of Examples 1 and 2 have significantly increased anti-inflammatory effects in the AKI model compared to dexamethasone. Surprisingly, the compounds of Examples 1 and 2 achieved enhanced efficacy at only approximately 20% of the dexamethasone equivalent dose compared to the free (unbound) drug dose. In other words, the compounds described herein exhibit approximately 4-5-fold increased in vivo efficacy compared to dexamethasone. As noted in the pharmacokinetic studies above, this surprising effect is consistent with the significantly enhanced exposure of dexamethasone levels in the kidneys of the compounds described herein (Table 1).

[0299] Although effective in mammals, some of the compounds provided herein exhibit little or no toxicity to normal kidney cells in vitro (e.g., human kidney cell HK-2 assay) and in live mammalian (rodent) models.

[0300] The safety profile of the compounds described herein can be further established in biomarker assays to predict nephrotoxicity. For example, Keirstead et al., HYPERLINK "http: / / www.ncbi.nlm.nih.gov / pubmed / 24189134" Toxicol. Sci. 2014, vol. 137, pp. 278-291 describes several such measurements (including NGAL measurements).

[0301] Thus, several compounds described herein are highly effective in treating inflammation-associated kidney diseases, but do not suffer from the excessive detargeted toxicity that limits standard treatments for such diseases.

[0302] Thus, the novel compounds and compositions described herein may provide a long-term, safer, and more effective targeted treatment for kidney disease and injury, including CKD, AKI, and kidney injury in kidney transplantation.

[0303] Administered drugs and drug formulations In general, the compounds described herein can be administered in a therapeutically effective amount by any acceptable administration pattern for similarly used agents. For example, the compounds provided herein can be administered orally, parenterally, transdermally, topically, rectally, intranasally, or intratumorally. The actual amount of the compounds provided herein (i.e., active ingredient) will depend on many factors, including the severity of the disease (i.e., infection) being treated, 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 purview of the attending physician.

[0304] Data obtained from cell culture assays and animal studies can be used to determine a range of dosages to be administered to humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the therapeutic effect with little or no toxicity. The dosage can vary within this range depending on the dosage form and route of administration used. For any compound used in the methods provided herein, the therapeutically effective dose can be estimated in advance from animal models. Dosages can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the measured compound that achieves a half-maximal inhibition of symptoms) determined in cell culture. Such information can be used to more accurately determine useful dosages in humans.

[0305] 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 nasal administration.

[0306] The compounds provided herein are useful as compositions for injection, oral, inhalation, topical, or intratumoral administration. Such compositions are prepared by methods well known in the pharmaceutical arts and contain at least one active compound.

[0307] The present disclosure also includes pharmaceutical compositions containing one or more of the compounds described above as an active ingredient along with a pharmaceutically acceptable carrier. When preparing the compositions of the present disclosure, the active ingredient is generally mixed with an excipient, diluted with an excipient, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material that functions as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, tablets, sachets, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid media), such as ointments containing up to 10% of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0308] The compositions are preferably formulated in unit dosage form, each dosage containing from about 0.1 to about 2000 mg, more usually from about 1 to about 900 mg, of the active ingredient. The term "unit dosage form" refers to 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 the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Preferably, the compound is used in an amount of no more than about 20% by weight, more preferably no more than about 15% by weight, of the pharmaceutical composition, with the remainder being a pharmaceutically inert carrier.

[0309] The active compounds are effective over a wide dosage range and are generally administered in a pharmaceutically or therapeutically effective amount. However, it should be understood that the amount of compound actually administered can be determined by the physician depending on circumstances including the condition to be treated, the severity of the bacterial infection being treated, the selected route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0310] In therapeutic use for treating or combating bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions may be administered orally, topically, transdermally, and / or parenterally at a constant dose to achieve and maintain a constant concentration, i.e., a constant amount, or blood level of the active ingredient in the treated animal that will be antimicrobially effective. Generally, such an antimicrobially or therapeutically effective amount (i.e., effective amount) of the active ingredient will be in the range of about 0.1 mg / kg to about 250 mg / kg body weight / day, more preferably in the range of about 1.0 mg / kg to about 50 mg / kg body weight / day.

[0311] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein. These preformulation compositions are referred to as homogeneous, meaning that the active ingredient is dispersed evenly throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, or capsules. This solid preformulation is then subdivided into unit dosage forms of the types described above containing, for example, 0.1 to about 500 mg of the active ingredient described herein.

[0312] The tablets or pills described herein can be coated or otherwise compounded to provide a dosage form with the advantage of extended action. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. These two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to enter the duodenum completely or be released in a delayed manner. Such enteric layers or coatings can be made of a variety of materials, including polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0313] Liquid forms into which the novel compositions described herein can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical carriers.

[0314] Additionally, liposomal formulations of the compounds described herein can be used to enhance the therapeutic effect of certain infections, such as pneumonia or pulmonary infections.

[0315] Intratumoral administration of the compounds provided herein utilizes solutions or gels prepared in suitable aqueous solutions containing suitable excipients (e.g., glucose, polyethylene glycol, polyoxyethylene castor oil, cyclodextrin, etc.).

[0316] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions of the present invention are administered via the oral or nasal respiratory route to achieve a local or systemic effect. Compositions in pharmaceutically acceptable solvents, preferably, can be nebulized using an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, which can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered in a manner appropriate to the device delivering the formulation, preferably orally or nasally.

[0317] Other formulations suitable for use are described in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

[0318] Optionally, the compounds described herein can be administered in combination with other agents, including antioxidants such as ascorbic acid, or megalin receptor inhibitors, which are commonly known to reduce adverse reactions to polymyxin drugs.

[0319] As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems. Furthermore, to improve the in vivo serum half-life of administered compounds, the compounds can be encapsulated, incorporated into the lumen of liposomes, formulated as colloids, or other conventional techniques for extending the serum half-life of compounds can be employed. Various methods can be used to prepare liposomes, such as those described in U.S. Patents 4,235,871, 4,501,728, and 4,837,028 to Szoka et al., each of which is incorporated herein by reference. Optionally, the compounds described herein can be administered as nanomicelles or nanomaterial-encapsulated compositions, as described by Taki et al. in Pharmaceut., 2012, Vol. 3, p. 1092.

[0320] As noted above, the compounds administered to patients are in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or sterile filtered. The resulting aqueous solutions can be packaged and used as is or lyophilized, and lyophilized formulations can be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulations is typically 3-11, more preferably 5-9, and most preferably 7-8. It should be understood that the use of some of the above-mentioned excipients, carriers, or stabilizers results in the formation of pharmaceutical salts.

[0321] The disclosures of each patent, patent application, and publication (e.g., journal, article, and / or textbook) cited herein are hereby incorporated by reference in their entirety. Furthermore, as used in this application and the appended claims, singular articles such as "a," "an," and "one" are intended to mean singular or plural. While this application describes the present disclosure in connection with preferred embodiments, those skilled in the art may, after reading the foregoing specification, affect modifications, equivalent substitutions, and other types of variations of the disclosure described herein. Each of the above embodiments may also include or incorporate such variations or embodiments disclosed with respect to any or all other embodiments. This disclosure is not limited to the particular embodiments described herein, but is intended as a single description of the various embodiments described herein. Numerous modifications and variations can be made to the present disclosure without departing from the spirit and scope of the present disclosure, and will be readily apparent to those skilled in the art. In addition to the methods enumerated herein, functionally equivalent methods within the scope of the present disclosure will be readily apparent to those skilled in the art from the foregoing description. It should be understood that the present disclosure is not limited to particular methods, reagents, process conditions, materials, etc., and it is to be understood that these methods, reagents, and materials can vary. It should also be understood that the terminology used in this application is used only to describe particular embodiments and is not intended to be limiting. Accordingly, the present specification should be considered as illustrative.

Claims

1. Compounds of formula II-P-2, 【Chemical 1】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, R 1 is the residue that binds to X and corresponds to the parent (precursor) structure (H)nR 1 is formed by removing an H atom from the OH group of (H)nR 1 is selected from the following structures: 【Chemistry 2】 Integers h to k are 0, Each X is independently selected from the following structures, and either the left or right side of X below is connected to R 1 : 【Chemistry 3】 R11 is CH 2 CH(CH 3 ) 2 or CH 2 Ph, R 12 is CH 2 NH 2 or CH 2 CH 2 NH 2 or H, The integer zz is 1 or 2, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

2. A compound of formula III, 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, R 1 is the residue that binds to X and corresponds to the parent (precursor) structure (H)nR 1 is formed by removing an H atom from the OH group of (H)nR 1 is selected from the following structures: 【Chemistry 5】 the integers j and k are 0, integers h and i are independently selected from 0 and 1; wherein A8 and A9 are any amino acid residues, unsubstituted or substituted at any N atom, and when present, are selected from α-, β-, or γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine from 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), and 2,4-diaminobutyric acid (Dab); Among them, Each X is independently selected from the following, and the left or right side of the following X is connected to R1: 【Chemistry 6】 integers x, y, z are independently selected from 1, 2, and 3; The integer zz is 1 or 2, and R 11 is CH 2 CH(CH 3 ) 2 or CH 2 Ph, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

3. Compounds of formula II-P-2, 【Chemistry 7】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, R 11 is CH 2 Ph and R 12 is CH 2 NH 2 or CH 2 CH 2 NH 2 or H, and 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the integer zz is 1.

4. A compound of formula Ic, 【Chemistry 8】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, R 11 is CH 2 CH(CH 3 ) 2 or CH 2 3. The compound according to claim 2, wherein the compound is Ph, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

5. R 1 is the structure R 1 Primary alcohol CH in (H) 2 2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that it is derived from the removal of H from an OH group.

6. A compound characterized in that it is selected from the following structure: or a pharmaceutically acceptable salt, solvate or hydrate thereof. 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】

7. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, having anti-inflammatory activity or therapeutic effect against kidney disease as determined by (i) reducing or attenuating the release of kidney cytokines such as TNF-α, IL-6, IL-12, (ii) reducing one or more biomarkers, where the one or more biomarkers are optionally selected from protein levels, blood urea nitrogen and serum creatinine, or (iii) improving the condition of a patient or mammal in need of such treatment in an animal study.

8. A similar dose of free agent or drug incorporated into the compound (H) n R 1 and / or (H) o R 2 7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, having enhanced anti-inflammatory, immunomodulatory, or nephroprotective activity as determined by in vitro or in vivo measurements of anti-inflammatory, immunomodulatory, or nephroprotective activity compared to

9. 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which, when administered to a mammal, exhibits preferential accumulation in the kidney, and the ratio of the molar concentration in the kidney to the molar concentration in the blood is 5 to 500.

10. Mammalian Reagent (H) n R 1 and / or (H) o R 2 When administered at a dose (expressed in molar amounts) equal to the standard therapeutic dose (molar amounts) of n R 1 and / or (H) o R 2 in the kidney compared to the standard therapeutic dose of n R 1 and / or (H) o R 2 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that the loading (tissue concentration) and / or reagent exposure (area under the curve, AUC) of the compound is 1.5 to 15 times that of the compound according to claim 1.

11. Mammalian Reagent (H) n R 1 and / or (H) o R 2 When administered at a dose (expressed in molar amounts) equal to the standard therapeutic dose (in molar amounts) of n R 1 and / or (H) o R 2 7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that it exhibits at least a two-fold reduction in the occurrence of adverse reactions and / or off-target toxicities compared to a standard therapeutic dose of 100 mg / kg / day, as determined by medical observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in treating inflammation in a mammal, The compound is administered to a mammal via parenteral, transdermal, oral, intranasal, topical, rectal, or intratumoral administration.

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