Novel compounds and compositions for targeted treatment of renal cancer

Abstract

The present invention provides therapeutic compounds, such as compounds of formula I, or pharma- ceutically acceptable salts, hydrates or solvates thereof, pharmaceutical compositions thereof, methods of use thereof, and methods for making these compounds, as therapeutic or anti-cancer agents.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 224,406, filed July 21, 2021, the entire contents of which are incorporated herein by reference for all purposes.

[0002] This application provides novel active compounds, pharmaceutical compositions thereof, methods of their use, and methods of their manufacture. These novel agents and compositions have therapeutic activity useful in the treatment of kidney-related cancers. [Background technology]

[0003] Cancer encompasses a wide range of devastating diseases and has a profound impact on the lives of people worldwide. Renal cell carcinoma (RCC) is the most common form of kidney cancer. Globally, more than 200,000 patients are diagnosed with RCC each year (see, for example, Escudier and Gore, Drugs R&D. 2011, vol. 11, p. 113). This devastating disease is responsible for approximately 100,000 deaths annually. Worryingly, the incidence of RCC is increasing. Since 1950, the incidence rate has increased by 126% and the mortality rate by 36.5% in the United States alone. In particular, metastatic RCC (mRCC) is known to be highly resistant to conventional treatments, with a low 5-year survival rate of 0–10% for patients with typically diagnosed stage IV disease (see, for example, Motzer et al., N. Engl. J. Med. 1996, vol. 335, pp. 865–75).

[0004] A small number of drugs, including standard therapies such as axitinib and sunitinib, have been developed for the treatment of several forms of kidney cancer, including renal cell carcinoma (RCC) and metastatic RCC (mRCC). However, anticancer drugs typically exhibit high levels of side effects, significantly limiting their therapeutic efficacy. These side effects are typically due to the cytotoxicity of the anticancer drug. A cytotoxic model of chemotherapeutic drug activity is necessary to determine its anticancer therapeutic efficacy. Therefore, most anticancer drugs are inherently cytotoxic. This toxicity can manifest as adverse side effects, including severe side effects, and chemotherapy-related mortality is typically associated with chemotherapy. Thus, sunitinib, one of the current standard therapies for kidney cancer, is known to exhibit a high incidence of hematologic toxicity (see, for example, Kato et al., BMC Cancer. 2017, Vol. 17, p. 214). This unwanted toxicity (also called bone marrow suppression or bone marrow toxicity) significantly limits the use of sunitinib in some patient populations and potentially limits the prescribed dosing regimen needed for optimal anti-cancer efficacy (see Kato et al., BMC Cancer. 2017, vol. 17, p. 214). Deaths from such drug toxicity have also been reported. For example, axitinib (Inlyta), a drug used to treat kidney cancer, R The prescribing information for INLYTA-Axitinib includes a warning of severe hypertension (including hypertensive crisis) and that heart failure has been observed with this drug and can be fatal (see Prescribing Information. INLYTA-Axitinib Tablet. June 2020, Pfizer). These side effects are typically attributable to the untargeted action of cytotoxic chemotherapy compounds, with unique patterns of toxic effects affecting unexpected biological compartments, such as the bone marrow or heart. Regarding this toxicity, treatment-induced "bystander killing" of healthy human cells in the vicinity of cancer cells has also been reported (see, for example, Staudacher and Brown, British Journal of Cancer. 2017, vol. 117, p. 1736).

[0005] Therefore, safer anticancer drugs are urgently needed. More specifically, novel anticancer therapies must target only cancer cells in the affected biological compartment (organ) while minimizing the impact on healthy tissues and organs, while simultaneously improving the selectivity of their cytotoxic effects.

[0006] An emerging approach to improving the selectivity of anticancer drugs is to target delivery of active but toxic drugs only to disease-affected organs, or more specifically, to cancer cells therein (see, for example, Tekewe et al., Int. J. Pharm Sci. Res. 2013; Vol. 4, p. 1). In recent years, this urgent need has prompted the emergence of monoclonal antibody-drug conjugates (ADCs), which exploit the innate affinity of antibodies for cancer cells and then release an anticancer drug "payload" directly at the target site (see, for example, Cazzamalli et al., J. Am. Chem. Soc. 2018, Vol. 140, p. 1617). However, the development of ADCs as viable therapeutics poses several significant challenges, including high manufacturing costs, variability in active payload / antibody ratios requiring specialized bioanalytical characterization, relatively poor chemical stability, long in vivo circulation times, release of toxic payloads in unexpected biological compartments, and limited ability of ADCs to penetrate solid tumors (e.g., kidney-associated cancers).

[0007] Other approaches include efforts to achieve targeted drug delivery using non-antibody constructs, such as organic molecular ligands (targeted complexes), also known as small molecule drug conjugates (SMDCs). These typically utilize molecules that recognize specific targets present in cancer cells, such as the folate receptor, prostate-specific membrane antigen, somatostatin receptor, or carbonic anhydrase IX (as cited by Cazzamalli et al. in J. Am. Chem. Soc. 2018, vol. 140, p. 1617). However, this approach is limited by the significant difficulty of identifying unique small molecules that can selectively identify cancer-affected organs. Furthermore, most such ligands contain linear peptides that are generally unstable in vivo due to rapid metabolism by peptidase enzymes widely present throughout the body (see, for example, Page and Cera in Cell. Mol. Life Sci. 2008, vol. 65, p. 1220).

[0008] The present application provides unique derivatives of acyclic and cyclic peptides (cyclopeptides) that are particularly useful for the targeted treatment of various cancers, including renal cancer. Various cyclic peptides are described, for example, in the publications WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, WO 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, CN103923190, US2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, CN103130876, WO 2013 / 072695, WO 2012 / 0316105, WO 2012 / 0283176, US2010 / 0160215, WO 2008 / 0215677, WO 2006 / 017156, WO 2006 / 045156, US2006 / 0004188 5, US 6380356, US 3450687. Several acyclic peptide structures with the potential for targeted delivery of active agents are described, for example, in publications WO 2019136298, US 20180015173, WO 2021 / 150792, and the references cited therein. None of these references specifically describe or generally consider the compositions provided herein. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2014 / 014890 [Patent Document 2] International Publication No. 2018 / 073449 [Patent Document 3] US Patent Application Publication No. 2018099022 [Patent Document 4] US Patent Application Publication No. 2009215677 [Patent Document 5] International Publication No. 2016 / 100578 [Non-patent literature]

[0010] [Non-Patent Document 1] HAMILL, KM et al., "Polymyxins Facilitatic entry into mammalian cells", Chemical Science, Vol. 7, 25 April 2016 (2016-04-25), Pages 5059-5068 [Non-patent document 2] WANG, Jiayi et al., "Rapid one-step enzyme immunoassay and lateral flow immunochromatographic assay for colistin in animal feed and food", Journal of Animal Science and Biotechnology, 17 October 2019 (2019-10-17), pages 1-10 Summary of the Invention

[0011] The present invention provides novel compounds and compositions useful for the targeted treatment of cancer, particularly kidney-related cancers.

[0012] These novel compounds are unexpectedly able to target kidney tissue, particularly the cancer cells therein. The specific affinity of the compositions described herein for tissue affected by kidney cancer allows these molecules to be selectively delivered to and accumulated at the cancer site, with minimal or no accumulation of these therapeutic agents in other healthy tissues.

[0013] This results in a selective and generally safer anti-cancer treatment that significantly minimizes adverse effects on other normal organs of the mammal being treated compared to standard therapeutic agents currently used to treat, for example, renal cancer (e.g., axitinib, bliniib, pazopanib, and sulnitinib).

[0014] In one embodiment, the therapeutic effect of the compounds described herein is achieved by the release of one or more anti-cancer elements (e.g., biologically active payloads and / or drugs) attached to the compounds. The active payloads (drugs) can include cytotoxic, antibody, and / or immunomodulatory structures selected from biologically active structures capable of killing cancer cells, inhibiting cancer cell growth, or activating an immunomodulatory response, thereby producing similar anti-cancer effects.

[0015] In general, the compounds described herein comprise a peptide, cyclic peptide, or other "target seeker" (ligand) structure with high affinity (binding capacity) for kidney cancer and / or kidney cells, and an active drug substructure within a single molecule. The active drug (payload) is connected to the kidney-affinity structure via a uniquely designed linker and spacer framework. This unique design allows for the effective drug (payload) to be released directly into or near kidney cancer cells, resulting in a targeted anti-cancer effect.

[0016] In one embodiment, the composition has cytotoxic properties against cancer cells without releasing an active drug payload (contained within the administration structure) at the site of kidney cancer, which may then accumulate at the site of kidney cancer and either directly kill the cancer cells or inhibit their proliferation, after which it is generally degraded to non-toxic metabolites.

[0017] In another embodiment, the composition exhibits little or no inherent toxicity to cancer cells as an intact molecule, but instead accumulates in the kidney and is metabolized in organs affected by kidney cancer, thereby releasing an anti-cancer drug (or cytotoxic agent) at the cancer site, resulting in an anti-cancer therapeutic effect.

[0018] In another embodiment, the anti-cancer effect (when accumulated at the cancer site) is achieved by the combined action of (i) the direct cytotoxic effect of the compound and (ii) the release of the active payload drug contained within the structure.

[0019] In another aspect, cyclic peptide conjugates of tyrosine kinase inhibitors are provided. In some or any embodiments, the cyclic peptide is a polymyxin cyclic peptide provided herein.

[0020] Surprisingly, some of the compounds and compositions provided herein lack significant antibiotic and / or other biological activity (e.g., antibacterial activity) and exert their desired cytotoxic effects only on kidneys affected by cancerous disease.

[0021] Furthermore, while some of the compositions provided herein contain 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 renal cancer.

[0022] Those skilled in the art can readily appreciate that not every molecular structure linking a cytotoxic element (payload) with a "heat-seeker" affinity structure (a ligand that targets kidneys and / or kidney cancer cells) with an appropriate linker and a carefully positioned spacer (strategically placed between the ligand and the cytotoxic payload) is suitable for use as a therapeutic agent. Surprisingly, the compounds and compositions provided herein have favorable pharmacological characteristics, adequate stability in plasma, prevent premature cytotoxic effects, and preferentially accumulate in kidney cancer cells and / or kidneys affected by kidney cancer.

[0023] Even more surprisingly, some compounds provided herein exert their cytotoxic anticancer effects either directly to renal cancer cells via self-targeted delivery or only in the vicinity of cancer-affected tissues. In part, the compositions comprise a class of molecules that can specifically release their cytotoxic payload (bound within their structure) as a result of metabolic degradation of enzymes specific to or overexpressed (enriched) in cancer cells (e.g., cathepsins, glutaminases, and peptide decarboxanases (PDFs), peptidases, reductases, and similar known enzymes).

[0024] In addition to metabolic degradation by enzymes overexpressed in cancer cells (e.g., cathepsins, glutaminases, PDFs, or similar enzymes), 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 can be 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). In another scenario, a free amine can activate an amide functionality 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 of the present application, cleavage of the chemically designed linker occurs after initial enzymatic metabolism of an auxiliary enzyme-cleavable linker (e.g., a peptide substructure or similar linker), overall affecting the release of the cytotoxic payload at the cancer target.

[0025] In one aspect, the present application provides a compound of formula IP-1

[0026] [ka]

[0027] 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) nR 1 and (H) o R 2 If present in R 1 and R 2 are each independently a residue connected to X and Z, and are any one of hydrogen-containing groups independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH and S(=O)NH, which are the corresponding parent (precursor) structure (H) n R 1 and (H) o R 2 is formed by removing a single H atom from a)(H) n R 1 and (H) o R 2 is a compound that has independent biological or therapeutic activity, or b)(H) n R 1 and (H) o R 2 are each independently a cytotoxic compound, an antibody, or an immunomodulatory compound that has activity against or can induce activity against one or more cancer cells, including a compound that has activity against one or more renal cancer cells; or c)(H) n R 1 and (H) o R 2 are monovalent or polyvalent antibodies, each independently active against one or more cancer cells; or d)(H) n R 1 and (H) o R 2independently, afatinib ((E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-tetrahydrofuryl-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide), ARS-1630 ((R)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-2-en-1-one), axitinib (N-methyl-2-[[3-[(E)1H-indazole 1-(6,7-dihydro-5H-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-yl)-3-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]rotenyl-3-yl]-1,2,4-triazole-3,5-diamine), BLU-554 (N-[(3S,4S)-3-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]oxan-4-yl]propan-2-enamide), Brivanib ((S)-(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl-2-aminopropionic acid ester), (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)propan-2-ol, cabozantinib, cediranib, ceritinib, cifradanone denant), derazantinib, dovitinib (same as 4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one), E-7046, (4-[(1S)-1-[[3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]carbonyl]amino]ethyl]benzoic acid), emtansine, englin ((1R,3aR,4S,5R,7R,8S,8aR)-5-(acetoxy)-7-isopropyl-1,4-dimethyldecahydro-4,7-epoxyazulen-8-yl(2E)-3-phenylacrylate, foretinib, lenvatinib (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide), monomethyl auristatin E E) ((S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-(S)-3-methyl-2-(methylamino)butanamide) butanamide), irinotecan, maytansinoid, lenatinib, nilotinib, nintedanib, ozogamicin, paclitaxel, pazopanib (5-[[4-[(2,3-dimethylindane [Zol-6-yl]-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide), regophenyl, sartizumab, selpercatinib, semaxanib ((Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indol-2-one), soraphenyl (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide), sulunitinib b) ((Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindole-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide), SN-38 (7-ethyl-10-hydroxycamptothecin), soraphenyl (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide), trastuzumab (trastuzumab), tesirin (tesirin) (4-[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxy Pyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino]-3-methylbutanyl]amino]propionyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxy-6a,7-dihydropyrrole[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxy-6a,7-dihydro- 6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate), temsirolimus ([(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexadecane-16,24,26,28-tetraen12-yl]propionate [propyl]-2-methoxycyclohexyl]-3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid ester), tivantinib, tivozanib (1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methylisoxazol-3-yl)urea), vatalanib, veliparib, vinblastine, or a variant thereof; e)(H) n R 1 and (H) o R 2 are compounds that are independently active against renal cancer disease, or f)(H) n R 1 is the structure (H) n R 1 one or more heterocyclic ring structures connected to X at one of the one or more heterocyclic single atoms present in the heterocyclic ring, wherein the nitrogen atom is changed to a nitrogen atom having a single positive charge, such as an imidazolium group, a pyrazolium group, a pyridinium group or an indazolium group; and Any group R 1 does not exist, fragment R 1 X is R 11a is replaced by R 11a H, Alk, 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 H, Alk, 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; and A 1 ~A 11are independently optional and, when present, are selected from any amino acid residue unsubstituted or substituted at any of the N atoms, each amino acid residue, when present, being 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, 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 (depending on 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 and heterocyclic groups, or a group A 8 is directly attached to the group Y, and and any divalent group X is independently selected from the following: 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 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)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(R5)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 R10 ) 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 ) 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 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 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 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 X formed by rearranging, adding or deleting SO2 therein, among which: R 6 , R 7 , R 9 , 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, 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, can be saturated or unsaturated. 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, which 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 the 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 are arbitrarily connected to (C 1-12 alkylene)OC(=O), OC(=O)(C1-12 alkylene), (C 1-12 alkylene)OC(=O), C(=O)O(C 1-12 alkylene), (C 1-12 alkylene)C(=O), N(R5)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 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)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 (CR9 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(CR7 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(CR9 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 -(CR9 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(A1 )]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(=OCH(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 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 Furthermore, each of the optional divalent groups X may 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) 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)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 1-14alkyl)(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 alkyl)C(═O), and similar linear groups; 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 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(R5 )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 )(CR5 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(CR7 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 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 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 following structure: 12 or A 13 arbitrarily connected 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(R5)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 ) s C(=O)、 C(=O)CR 5 =CR 7 -(CR 9R 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)(CR5 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(=OCH(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), 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 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 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 Connect directly to one of the

[0028] 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.

[0029] 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 (OCR5 R 6 ) p (CR 7 R 8 ) r (CR 9 R 10 ) s exists and [p+r+s]≧1.

[0030] 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.

[0031] 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(R4 )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), and 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 or 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)(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)(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(CR7 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)、[[ID=9​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​(CR 9 R 10 ) s N(R 5 )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 the 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.

[0032] 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(R4 )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), or 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 independently selected from the following: 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 ) sC(=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 R6 ) p SS(CR 7 R 8 ) r SS(CR 9 R 10 ) s OC(=O), Among them, the group X is 1 to 2 amino acid residues A 12 or A 13 and connect arbitrarily.

[0033] 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:

[0034] [ka]

[0035] [ka]

[0036] [ka]

[0037] and fragment N(R 4 any variant of the above X group formed by rearranging, adding or deleting a C(=O) therein; 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; X1 and X 2 are O, NH and CR 5 R 6 are independently selected from All other variables are defined in formula IP-1 of the present application.

[0038] 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 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(R4 )C(=O), and 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), or fragment N(R 4 )C(=O) or C(=O)N(R 4 ) independently selected from any variant of the above group formed by rearrangement, addition, or deletion of 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 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 SS(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).

[0039] 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(R4 )C(=O)、C(=O)N(R 4 )(C 1-12 アルキレン)、 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 9R 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<着 7 R 8 ) r (CR着 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), and C(=O)N(R 4 )CR 5 =CR 7 -(CR 9 R 10 ) s C(=O), C(=O)CR 5 =CR 7 [[ID=1​​​​​​​​​​) independently selected from any variant of the above group formed by rearrangement, addition, or deletion of SO2; Among them, the group Z 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 R6 )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 (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<00024​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​r (CR 9 R 10 ) s N(R 5 )C(=O), Among them, the group Z is 1 to 2 amino acid residues A 12 or A 13 and connect arbitrarily.

[0040] In one embodiment, the compound of formula IP-1 is a compound of formula I

[0041] [ka]

[0042] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: (H) n R 1 If present in R 1 is any hydrogen-containing group independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH, and S(=O)NH, and is a group that is independently selected from the parent (precursor) structure (H)nR 1 is a residue formed by removing a single H atom from 1 teeth, a) a cytotoxic compound and an immunomodulatory compound that has activity against or can induce activity against one or more cancer cells; b) Afatinib, ARS-1630, axitinib, BGB-324, BLU-554, brivanib, (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol, cabozant, auristatinib, cediranib, ceritinib, siforadanone, delazantinib, dovitinib, emtansine, engelin, monomethyl auristatin E, irinotecan, methane Quirinolux, neratinib, nilotinib, nintedanib, oxazomycin, paclitaxel, pazopanib, regorafenib, satelizumab, serpatinib, semanib, sorafenib, sunitinib, SN-38, temsirolimus, tifantinib, tivozanib, vatalanib base, veliparib, vinblastine, and variants thereof, and c)(H) n R 1 a nitrogen-containing heterocyclic structure connected to X at one of the heterocyclic nitrogen atoms present in said heterocyclic ring, said nitrogen atom being changed to a nitrogen atom having a single positive charge, said nitrogen-containing heterocyclic structure being independently selected from nitrogen-containing heterocyclic structures such as an imidazolium, pyrazolium, pyridinium, or indazolium group; the integer n is independently selected from 1, 2, and 3; 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 (depending on 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 and heterocyclic groups, or a group A 8 is directly attached to the group Y, and The integers zz are independently selected from 1, 2, and 3, and each of the optional divalent groups X is independently selected from 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)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 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 4 )(CR 5 R 6 ) p (CR7 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 (CR7 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 (CR9 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 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)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[(CR5 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(=OCH(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 R10 ) 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), and (R)-C(=O)N[CHCHNHC(=O)CHNH(CHCHNH)]CHCHC(=O), or each of any divalent groups X is independently selected from:

[0043] [ka]

[0044] [ka]

[0045] [ka]

[0046] 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 8 , R 9 and R 10 is H, NH2, halogen, NH(C 1-6 alkyl group), NH(OC 1-6 alkyl group), C1-14 Alkyl group, C 3-6 independently selected from a cycloalkyl group, an aryl group, an arylalkyl group, a biaryl group, a biarylalkyl group, or a heteroarylalkyl group; 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 R 5 ~R 10 Any two of these, together with the carbon atoms to which they are attached, are 4- to 7-membered saturated or unsaturated C 3-6 form a cycloalkylene, or i) R 5 and R 6 , ii) R 6 and R 7 , iii)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 8together 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 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 Integers p, r, and s are independently selected from 0, 1, and 2; and Among them, fragments (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 Among them, fragments (CR 5 R 6 ) p (CR 7 R 8 ) r or (OCR 5 R 6 ) p (CR 7 R 8 ) r If there exists, then [p+r]≧1 and Among them, fragments (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 the divalent groups X may be selected from 1 to 2 amino acid residues A 12 or A 13 and are arbitrarily connected, 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) rO(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), 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)rO(CH2) s N(C 1-14to one or more other divalent groups selected from alkyl)C(=O) and similar linear groups; A 1 ~A 15 are independently optional and, when present, are independently selected from any amino acid residue unsubstituted or substituted at any of the N atoms, and each amino acid residue, when 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, 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.

[0047] In one embodiment of Formula I, (H) n R 1 (H) of (a) and (b) n R 1 The nitrogen-containing heterocyclic structure is independently selected from the nitrogen-containing heterocyclic structures included in (H) n R 1 One of one or more heterocyclic nitrogen atoms present in the heterocycle is connected to X, and the nitrogen atom is changed to a nitrogen atom having a single positive charge, such as an imidazolium group, a pyrazolium group, a pyridinium group, an indazolium group, etc.

[0048] In one embodiment, a compound of Formula I, Formula IP-1, or Formula IP-2 is provided, 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 independently selected from 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Ser, or Thr, and A 4 is Leu or Ile, and A 5 are Phe, D-Phe, Bip, D-Bip, Val, and D-Val.

[0049] In another aspect, there is provided a compound of formula I, formula IP-1, formula IP-2, formula II-P, formula III or formula IV-P, wherein the group X is, on its left or right 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)pO(CH2)rO(CH2)sC(=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)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) s OC(=O), NH(CH2) p O(CH2) r O(CH2) s NHC(=O), NH(CH2)pO(CH2)rO(CH2)sN(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sOC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sNHC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sN(C 1-14 It is bonded to one or more other divalent groups selected from alkyl)C(=O) and similar linear groups. In one embodiment, it is bonded to 1, 2, 3, 4, or 5 other divalent groups, independently selected.

[0050] In another aspect, compounds of Formula I, Formula IP-1 or Formula IP-2 are provided, wherein any amino acid residue A 1 ~A 7 is the same cyclic peptide structure present in polymyxin B, polymyxin E, or octapeptin or similar cyclic peptide structures. In another embodiment, a compound of Formula I, Formula IP-1, or Formula IP-2 is provided, wherein any amino acid residue A 1 ~A 7 is the same cyclic peptide structure as that present in polymyxin B, polymyxin E, or octapeptin or analogous structures containing cyclic peptide structures. In other embodiments, compounds of Formula I, Formula IP-1, or Formula II-P-2 are provided, wherein any amino acid residue A 1 ~A 7 is a cyclic peptide structure identical to a cyclic peptide structure present in polymyxin A, polymyxin B, polymyxin B nonapeptide (H-Thr-Dab-cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]), polymyxin B heptapeptide (H-cyclo[Dab-Dab-D- Phe-Leu-Dab-Dab-Thr]), polymyxin E, or octapeptin, or an analogous structure containing a cyclic peptide structure.

[0051] In another embodiment, the molecule (H) n R 1 In another aspect, the present invention provides a compound of any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, which exhibits a therapeutic effect by releasing molecule (H) after administration to a mammal. n R 1 and / or (H) o R 2 The present invention provides compounds of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, that exhibit a therapeutic effect by releasing

[0052] In another aspect, there is provided a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula V, and Formula V, or any embodiment provided herein, that has anticancer activity against cancer cells, as determined by inhibiting or slowing the growth of cancer cells using an in vitro cytotoxicity assay or assessment, or by assaying the compound in an animal model of cancer.

[0053] In another embodiment, the cancer is renal or kidney cancer.

[0054] In another aspect, there is provided a method of treating kidney cancer disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein.

[0055] In another aspect, there is provided a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, comprising a related cytotoxic structure (compound, e.g., (H) n R 1 In another aspect, a compound of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, is provided, which compound has a related cytotoxic structure (compound, e.g., (H)) attached thereto, as determined by in vitro cytotoxicity assay or evaluation. n R 1 and / or (H) o R 2 ), its cytotoxicity against non-cancerous mammalian cells is reduced as determined by in vitro cytotoxicity assays or evaluations.

[0056] In another aspect, there is provided a compound of any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP and Formula V, or any embodiment provided herein, comprising a related (parent) cytotoxic structure (compound, e.g., (H) n R 1 ), which exhibit increased in vivo efficacy against cancer as determined by in vivo testing in cancer animal models, including the use of compounds and related cytotoxic structures (compounds such as (H) n R 1 ) is administered to an animal in the same molar amount as the same cytotoxic structure in the test and control compounds. In another aspect, a compound of formula IP-1, formula IP-2 or formula III-P, or any embodiment provided herein, is provided, which has attached thereto a related (parent) cytotoxic structure (compound, e.g., (H) n R 1 and / or (H) o R 2 ), which exhibit increased in vivo efficacy against cancer as determined by in vivo testing in cancer animal models, including the use of compounds and related cytotoxic structures (compounds such as (H) n R 1 and / or (H) o R 2 ) are administered to animals in molar amounts that are identical to the cytotoxic structures in the test and control compounds.

[0057] In another aspect, there is provided a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, that exhibits at least a two-fold increase in anti-cancer potency in vivo compared to a related cytotoxic moiety (compound) attached to said compound.

[0058] In another aspect, there is provided a pharmaceutical composition comprising a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, or a pharmaceutically acceptable salt, prodrug, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0059] In another aspect, there is provided a method of treating kidney cancer in a human or other warm-blooded animal by administering to a subject in need thereof a therapeutically effective amount of a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, or a pharmaceutically acceptable salt, prodrug, solvate, or hydrate thereof.

[0060] Compounds of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, can be administered, for example, orally, parenterally, transdermally, topically, rectally, intranasally, or intratumorally.

[0061] In yet another aspect, there are provided novel intermediates and methods for preparing compounds of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment thereof provided herein. [Brief explanation of the drawings]

[0062] [Figure 1] 1 shows the therapeutic effect of the compound of Example 1 vs. axitinib in an orthotopic model. The compound of Example 1 was administered at doses of 12 and 4 mg / kg (equivalent to 2.0 and 0.67 mg / kg axitinib free drug form, based on the molecular weights of the compound of Example 1 and axitinib: 2303.0 Daltons (6-TFA salt) and 386.47, respectively). The compound of Example 1 was measured without correction for solvates or water content. BLI stands for bioluminescence. [Figure 2] Figure 1 shows the change in body weight during a therapeutic efficacy study of the compound of Example 1 vs. axitinib. The compound of Example 1 is administered at 12 mg / kg and 4 mg / kg, and axitinib is administered at 30 mg / kg. The compound of Example 1 was measured without correction for solvates or water content. DETAILED DESCRIPTION OF THE INVENTION

[0063] Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0064] 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.

[0065] 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 include 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. 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. 1 " or "Alkyl 2 " and " 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 occurrence of "alkyl."

[0066] The term "Alk" means an alkyl group as defined herein.

[0067] The term "alkylene" refers to a divalent alkyl group. An "alkylene group" contains 1 to 12 carbon atoms, unless otherwise specified. In some embodiments, an "alkylene group" 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.

[0068] 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" contains 2 to 12 carbon atoms, unless otherwise specified. In addition to the groups specifically recited in any embodiment or claim, alkenyl also includes halogen, 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 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.

[0069] The term "alkylene" refers to a divalent alkenyl group. Unless otherwise specified, an "alkylene" contains 2 to 12 carbon atoms. An alkenylene may be substituted as described for alkenyl. In some embodiments, an alkylene group is unsubstituted.

[0070] 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.

[0071] The term "cycloalkylene group" refers to a divalent cycloalkyl group. In addition to the groups specifically recited in any embodiment or claim, the cycloalkylene group may be substituted as described for cycloalkyl groups. In some embodiments, the cycloalkylene group is unsubstituted. In some or any embodiments, R5 ~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.

[0072] 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 The heteroatom may be incorporated into any part of the heteroalkyl group (e.g., the heteroalkyl group may be C 1-4 AlkylC(=O)O or C 3-6 In some embodiments, the substituents include NR a R b , OR a and S(O) n R c , 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 b 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 of 0 to 2, and each R c are independently H, C 1-4Alkyl, C 3-6 cycloalkyl, optionally substituted aryl or NR a R b and R a and R b 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.

[0073] The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0074] "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 with 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 a , OC(=O)R a , OC(=O)NR a R c , OC(=O)heteroaryl, OC(=O)(heterocycle), and C=N-OR d (R d 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 "aryl 2 " 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.

[0075] The term "arylene" refers to a divalent aryl group, as defined herein.

[0076] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, where aryl and alkyl are each optionally substituted as defined herein.

[0077] The term "arylheteroaryl" means an aryl group substituted with a heteroaryl group, each of which is optionally substituted as defined herein.

[0078] The term "(heteroaryl)arylene" means a divalent aryl group substituted with a heteroaryl group, as defined herein.

[0079] The term "heteroarylaryl" means a heteroaryl group substituted by an aryl group, each as defined herein, including when aryl and heteroaryl are optionally substituted as defined herein.

[0080] The term "(aryl)heteroaryl" means a divalent heteroaryl group substituted with an aryl group, as defined herein.

[0081] 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.

[0082] The term "biaryl" means a divalent biaryl group, as defined herein.

[0083] 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.

[0084] 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: a , OC(=O)R a , OC(=O)NR a R b , -C 1-20 Alkyl, -OH, -NH2, -OC 1-20 Alkyl, S(O) m C 1-20 alkyl (m is 0, 1, or 2), C 120 Alkyl-NH2, -NHC 1-4 Alkyl, -C(=O)H, or C=N-OR d and optionally substituted by, among which R a , R b and R d 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 8The 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.

[0085] 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, thiomorpholine (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 a , OC(=O)NR a R b and further includes substituted and unsubstituted rings containing a group selected from, a and R b are independently H or C 1-6 It is an alkyl group.

[0086] 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 groups within the ring.

[0087] Het 2 is independently at each occurrence a 5- or 6-membered N-linked heterocycle having 1 to 4 nitrogen atoms in the ring and optionally one oxygen or sulfur atom in the ring.

[0088] The term "heterocyclylene" means a divalent heterocyclyl group, as defined herein.

[0089] The term "unsaturated" in the context of the terms cycloalkyl group, cycloalkylene group and heterocycle means not partially saturated but not aromatic.

[0090] 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. a , OC(=O)R a and OC(=O)NR a Rb and unsubstituted rings, including rings substituted with groups selected from a and R b are each independently H or C 1-6 In some embodiments, the heteroaryl is unsubstituted. 1 " or "heteroaryl 2 " are independently selected heteroaryls that may be different from each other 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.

[0091] The term "heteroarylalkyl" means an alkyl group substituted with a heteroaryl, each as defined herein.

[0092] 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.

[0093] Unless otherwise specified, a "carbon atom" is any atom including H, halogen, NR 1 R b , 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.

[0094] "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.

[0095] 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."

[0096] 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-sequencing 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."

[0097] 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").

[0098] Hydrogen (H), carbon (C), or nitrogen (N) substitutions in compounds of formula IVP 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 H (tritium) isotope substitutions. The compounds described herein may be substituted with any number of isotopes to provide a corresponding radiolabeled compound of formula IVP. 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.

[0099] "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.

[0100] 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, 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 Acid addition salts formed from organic acids such as methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like, or (2) Salts formed by replacing 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.

[0101] "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.

[0102] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect treatment for that disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0103] "Leaving group" has the meaning commonly associated with it in synthetic organic chemistry, i.e., halogen, C 1-4 Alkyl sulfonyloxy (C 1-4 alkylsulfonyloxy, ester groups, or atoms or groups that can be substituted with nucleophiles, including chloro, bromo, iodo, formyloxy, toluoyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxyl-amino, and the like.

[0104] "Prodrug" refers to a compound that releases the active parent drug in vivo in response to a compound provided herein when the prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds provided herein, which modifications 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 to any group that can be cleaved in vivo to regenerate the free hydroxyl, amide, amide, or sulfhydryl group, respectively. Examples of prodrugs 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.

[0105] The term "mammal" refers to all mammalian animals, including humans, livestock, and companion animals.

[0106] 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.

[0107] Illustrative Examples In another aspect, the present application provides a compound of formula IP-2

[0108] [ka]

[0109] 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, and arylheteroaryl groups; or (H) n R 1 and (H) o R 2 If present in R 1 and R 2 are independently a residue and are any one of the hydrogen-containing groups independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH and S(=O)NH, which are the same or different from the corresponding parent (precursor) structure (H) n R 1 and (H) o R 2 is formed by removing a single H atom from a)(H) n R 1 and (H) o R 2 is a compound that has independent biological or therapeutic activity, or b)(H) n R 1 and (H) o R 2 is a cytotoxic compound, an antibody, or an immunomodulatory compound that has or can induce activity against cancer cells (including compounds that have activity against renal cancer cells); or c) (H)nR1 and (H)oR2 are monovalent or polyvalent antibody structures active against cancer cells, or d) Structure (H) n R 1 and (H) o R 2are independently listed as afatinib ((E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide), ARS-1630, axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide), BGB-324, BLU-554, brivanib ((S)-(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-Aminopropanoic acid), (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol, cabozantinib, cediranib, ceritinib, siforadenant, delazantinib, dovitinib (4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one), same as E-7046, emtansine, englerin ((1R,3aR,4S,5R,7R,8S,8aR)-5-(glycoloyloxy)-7-isopropyl-1,4-dimethyldecahydro-4,7-epoxyazulen-8-yl (2E)- 3-phenylacrylate), foretinib, lenvatinib (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide), monomethyl auristatin E ((S)-N-((3R,4S,5S) )-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl -3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamide)butanamide), irinotecan, maytansinoids, neratinib, nilotinib, nintedanib, ozogamicin, paclitaxel, pazopanib (5-[[4-[(2,Same as (3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide), regorafenib, sacituzumab, selpercatinib, semaxanib ((Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one), sorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide), sunitinib ((Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide), SN-38 (7-ethyl-10-hydroxy-camptothecin), sorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino],phenoxy]-N-methyl-pyridine-2-carboxamide), trastuzumab, tesirin ([4-[[(2S)-same as] 2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl))propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS) )-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepine-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy- 8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate), temsirolimus ([(1R,2R,4S)-4-[ (2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy -15,17,21,23,29,35-Hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid), tivantinib, tivozanib (1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea), vatalanib, veliparib, vinblastine, or variants thereof, or (H) n R 1 and (H) o R 2 are compound structures that independently have activity against renal cancer disease, or Any group R 1 does not exist, fragment R 1 X is R 11a is replaced by R 11a H, Alk, 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 H, Alk, C 3-7Cycloalkyl 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), C 3-7 Cycloalkyl groups 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 e)(H) n R 1 (H) of (a) and (b) n R 1 (H) is one or more heterocyclic structures included in n R 1 one of one or more heterocyclic nitrogen atoms present in the heterocyclic ring is connected to X, and the nitrogen atom is changed to a nitrogen atom having a single positive charge, such as an imidazolium group, a pyrazolium group, a pyridinium group, or an indazolium group; 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 11are independently optional and, when present, are selected from any amino acid residue unsubstituted or substituted at any of the N atoms, each amino acid residue, when present, being 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, 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 (depending on the integer 0 of the non-existent group) are directly connected to each other, and Adjacent group A 1 -A 2 , A 3 -A 4 , A 5 -A 6 or A 1 -A 7 In the formula, when two integers among a to k are 0, the corresponding adjacent group A 1 -A 2 , A 3 -A 4 , A 5 -A 6 or A 1 -A 7 does not exist, generating an acyclic structure of formula IP, of which A 1 ~A 7 One of the remaining groups selected from A 8 or Y, and the final amino acid residue of the resulting peptide sequence (group A 8 or not connected to group Y) is COOH, CHOH or C(=O)NR 3 R 4 terminated by, among which, R 3 and R 4 are independently selected from H, alkyl groups, aryl groups, heteroaryl groups, and heterocyclic groups; If integers a to g are all 0, then A 1 ~A 7 is not present and the group A 8 is COOH, CH2OH or C(=O)NR 3 R 4 or terminated with a group A 8 is directly attached to the group Y, and and any divalent groups X, Y, and Z are independently selected from 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 1-6alkyl 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 5 ), 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 R10 ) 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 ) 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 7R 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 -(CR9 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[(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[(CR5 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)A 14 ](CR9 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 TO 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(=OCH (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), and (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]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: 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 is 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 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) 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; 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 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 , A 14 or A 15are unsubstituted or substituted at any of the N atoms and independently represent 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 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 acid, 4-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid or selected from the group consisting of 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; 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)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 アルキレン)C(=O)N(R 5 )、N(R 5 )C(=O)(C 1-12 アルキレン)、 (C 1-12 アルキレン)N(R 5 )C(=O)、C(=O)N(R 5 )(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)(OCR5 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 ) 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 )(CR5 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[(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)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[(CR5 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 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 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 OC(=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), or, (R)-C(=O)N[CH2CH2NHC(=O)CHNH(CH2CH2NH2)]CH2CH2C(=O), or, fragment C(=O), OC(=O), N(R 5) C(=O), P(=O)(OCR 5 R6 )CF2, P(=O)(OH)CF2, or C(=O)N(R 5 ) any variant of said group formed by direct rearrangement, addition, or deletion of 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)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 5 ), 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 R6 ) 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 ) sOC(=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[(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 R6 ) 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)A 14 ](CR 9 R10 ) 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[(CR5 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 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 R6 ) 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 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 direct rearrangement, addition, or deletion of 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 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 Connect directly to one of the

[0110] In an alternative embodiment of formula IP-2, R 5 and R 6 C, along with the atoms to which they are attached. 3-6 Forms a cycloalkylene group.

[0111] 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.

[0112] 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.

[0113] In an alternative embodiment of formula IP-2, any divalent group X, Y, and Z is independently selected from: (C 1-12 alkylene)C(=O)N(R 4 ), N(R4 )C(=O)(C 1-12 アルキレン)、 (C 1-12 アルキレン)N(R 4 )C(=O)、C(=O)N(R 4 )(C 1-12 アルキレン)、 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)(CR5 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 =CR7 -(CR 9 R 10 ) s N(R 4 )C(=O), Or, fragment N(R 4 )C(=O) or C(=O)N(R 4 ) any variant of the above group formed by direct rearrangement, addition or deletion of SO2; or Any divalent group X, Y, and Z 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 ) sC(=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 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 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 R10 ) 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 R8 ) 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 ](CR9 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 ) sNCH(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), 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.

[0114] In an alternative embodiment of formula IP-2, each of the optional divalent groups 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)CR5 =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), and C(=O)CR 5 =CR 7 -(CR 9 R 10 ) s N(R 4 )C(=O), or 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, wherein X is selected from 1 to 2 amino acid residues A 12 or A 13 further connected to, or Each of the optional divalent groups 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)N(R 5 )(CR 5 R 6 ) p (CR 7 R 8 ) r (CR9 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 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 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 ](CR9 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), 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), wherein X is 1 to 2 amino acid residues A 12 or A 13 is further connected to

[0115] 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:

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] 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 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-2 of the present application.

[0120] In an alternative embodiment of formula IP-2, each of the optional divalent groups 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 (CR9 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), Or, 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, Z is 1 to 2 amino acid residues A 12 or A 13 further connected to, or Each of any divalent group 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<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​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)(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 R6 ) p SS(CR 7 R 8 ) 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 R10 )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)A 14 ](CR 9 R 10 ) s O(C=O)、 C(=O)N[(CR 5 R 6 ) p (CR 7 R8 ) 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 ) rOC(=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 OC(=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), wherein X is 1 to 2 amino acid residues A 12 or A 13 is further connected to

[0121] In the broadest scope, certain compounds of formula IP-1, formula IP-2, or formula I are preferred. The specific and preferred values ​​of groups, substituents, and ranges listed below are used for illustration only, and they do not exclude other limits or other values ​​within the defined ranges of groups and substituents.

[0122] 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 their isomeric forms.

[0123] In some preferred compounds described herein, C2 12 Alkenyl can be vinyl, propenyl, allyl, butenyl, and the isomeric forms thereof (including cis and trans isomers).

[0124] In some preferred compounds described herein, C 3-7 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the isomeric forms thereof.

[0125] In some preferred compounds described herein, C 1-14The 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.

[0126] In some preferred compounds described herein, the halogen may be fluorine (F) or chlorine (Cl).

[0127] Those skilled in the art will also recognize that the compounds described herein may contain additional chiral centers and may be isolated in optically active and racemic forms. The compounds described herein may be racemic, optically active, tautomeric, geometric or isomeric, or mixtures thereof.

[0128] Any embodiment described herein may be combined with any other embodiment described herein.

[0129] Embodiment 1: A compound of Formula I, Formula IP-1 or Formula IP-2 above, wherein The integers a to g are each 1, and A 1 is 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 is Phe, D-Phe, Bip, D-Bip, Val, or D-Val.

[0130] Embodiment 2: Provided is a compound of Formula I, Formula IP-2, or Formula IP-2 or a compound of embodiment 1, wherein the cyclic peptide structure of Formula I, Formula IP-1, or Formula IP-2 is at any amino acid residue A 1 ~A 7and has a cyclic peptide structure identical to that of polymyxin A, polymyxin B, polymyxin B nonapeptide (H-Thr-Dab-cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]), polymyxin B heptapeptide (H-cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]), polymyxin E, or octapeptin, or similar structures.

[0131] Embodiment 3: A compound of formula IP-1 or a compound of embodiment 1 or 2 according to formula II-P

[0132] [ka]

[0133] 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.

[0134] Embodiment 4: A compound of Formula I or a compound of embodiment 1 or 2 according to Formula III

[0135] [ka]

[0136] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: The integer zz is 1 or 2, R 1are independently selected from residues formed by removing a single H atom in any of the hydrogen-containing groups, said hydrogen-containing groups being selected from the group consisting of afatinib, ARS-1630, axitinib, BGB-324, BLU-554, brivanib, cabozantinib, cediranib, ceritinib, siforadenant, delazantinib, dovitinib, foretinib, lenvatinib, monomethyl auristatin E, irinotecan, maytansinoids, neratinib, nilotinib, nintedanib, ozogami, paclitaxel, pazopanib, regorafenib, sacituzumab, selpercatinib, semacianib, sorafenib, sunitinib, SN-38, trastuzumab, tesirin, temsirolimus, tivantinib, or variants derived from said structures by chemical modification of said structures, independently selected from NH, OH, SH, C(=O)OH, CONH, SO2NH, and S(=O)NH; X is 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), and The structure contains C(=O)N[CH2CH2OC(=O)CH(NH2)CH2CH2COOH]CH2CH2C(=O).

[0137] Embodiment 5: A compound of Formula I, Formula IP-1, Formula IP-2, Formula II-P or Formula III, wherein: The group X is selected from the following structures, and the left or right side of the group X is R 1 Connect to

[0138] [ka]

[0139] Embodiment 6: A compound of Formula I, Formula IP-1, Formula IP-2, Formula II-P, or Formula III of embodiment 4, wherein the group X is, on its left or right 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)pO(CH2)rO(CH2)sC(=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)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) s OC(=O), NH(CH2) p O(CH2) r O(CH2) s NHC(=O), NH(CH2)pO(CH2)rO(CH2)sN(C 1-14 alkyl)C(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sOC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sNHC(=O), N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sN(C 1-14 and (c) (C(═O)), and similar linear groups. In one embodiment, 1, 2, 3, 4, or 5 additional divalent groups are introduced and independently selected.

[0140] Embodiment 7: A compound of formula IP-2 or a compound of embodiment 1 or 2 according to formula III-P,

[0141] [ka]

[0142] Among them, R 13 and R 14 are independently H, halogen, NH2, CN, OH, OC 1-14 Alkyl, O-aryl, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 Cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, heteroarylalkyl, C(=O)OH, C 1-14 AlkylC(=O)-OC 1-14 alkyl.

[0143] Embodiment 8: The group Z is selected from the following structures, and the right side of the group Z is R 2 and the compound of formula III-P of embodiment 7 is connected to

[0144] [ka]

[0145] In one embodiment, the compound of formula IP-1 is a compound of formula II-P

[0146] [ka]

[0147] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 11 is CH2CH(CH3)2 or CH2Ph, R 12 is CH2NH2 or CH2CH2NH2, and Other groups and integers in the compound of formula II-P are as defined above for the compound of formula IP-1 or any embodiment thereof.

[0148] A preferred group of compounds of Formula I, Formula IP-1, Formula IP-2, Formula II, Formula II-P, Formula III, or Formula III-P are shown below, in which each X is independently selected from the following structures, in which the left or right side of X is R 1 is connected to.

[0149] [ka]

[0150] A preferred group of compounds of Formula I, Formula IP-1, Formula IP-2, Formula II, Formula II-P, Formula III, or Formula III-P are shown below, in which each X is independently selected from the following structures, in which the left or right side of X is R 1 is connected to.

[0151] [ka]

[0152] In another embodiment, a compound of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula II, Formula III-P, or Formula III is provided, wherein each X is independently selected from the following structures: 1 is connected to.

[0153] [ka]

[0154] In another embodiment, a compound of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula II, Formula III-P, or Formula III is provided, wherein each X is independently selected from the following structures: 1 is connected to.

[0155] [ka]

[0156] In another preferred embodiment, each of the Xs shown in the above two paragraphs is, on its left or right side, 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) pO(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 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 1-14In one embodiment, the compound of formula IP-1 is a compound of formula III-P, wherein ...

[0157] [ka]

[0158] Among them, R 13 and R 14 are independently H, halogen, NH2, CN, OH, OC 1-14 Alkyl, O-aryl, NH(C 1-6 alkyl), NH(OC 1-6 alkyl), C 1-14 Alkyl, C 3-6 Cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, heteroarylalkyl, C(=O)OH, C 1-14 AlkylC(=O)-OC 1-14 alkyl, and Wherein, the other groups and integers in the compound of formula III-P are selected as defined above for the compound of formula IP-1 or any embodiment thereof.

[0159] A preferred group of compounds of formula III-P is where Z is selected from the following structures and the right side of Z is R 2 is connected to.

[0160] [ka]

[0161] In another preferred embodiment, each Z is, on its left side, C 1-12 alkylene, C 2-12 Alkenylene, C 2-12 Alkynylene, (CH2) p O(CH2) r O(CH2) sC(=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)pO(CH2)rO(CH2)sC(=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)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) s OC(=O)、NH(CH2) p O(CH2) r O(CH2) s NHC(=O)、 NH(CH2)pO(CH2)rO(CH2)sN(C 1-14 alkyl)C(=O)、 N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sC(=O)、 N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sOC(=O)、 N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sNHC(=O)、 N(C 1-14 alkyl)(CH2)pO(CH2)rO(CH2)sN(C1-14 It is bonded to one or more other divalent groups selected from alkyl)C(=O) and similar linear groups. In one embodiment, it is bonded to 1, 2, 3, 4, or 5 other divalent groups, independently selected.

[0162] In another preferred embodiment, the compound of formula IP-1 is a compound of formula IV-P

[0163] [ka]

[0164] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: X is selected from the following structures, and to the left of X is R 1 connected to 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 (CR7 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)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 R6 ) 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]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]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), 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 Other groups and integers are as defined for compounds of formula IP-1.

[0165] In another preferred embodiment, the compound of formula IP-1 is a compound of formula VP

[0166] [ka]

[0167] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 18 is H or C 1-12 is an alkyl group, R 19 is H, C 1-12 Alkyl, C(=O)H, C(=O)C 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)NHC 1-12 Alkyl, SO2C 1-12 -Alkyl, SO2Aryl, C(=O)C 3-7 Cycloalkyl, C(=O)OC 3-7 Cycloalkyl, C(=O)NHC 3-7 Cycloalkyl, C(=O)NHC 1 -12Alkyl, SO2C 3-7 cycloalkyl, or A 1 and Each of the optional groups L is an aryl group, CR 20 R 21 OC(=O)CR 22 R 23 and CR 20 R 21 C(=O)OCR 22 R 23 is selected from R 20 ~R 23 are independently H, C 1-12 Alkyl and C 3-7 cycloalkyl, or two adjacent groups R 20 and R 21 , or R 22 and R 23 Either independently or together C 3-7 forming a cycloalkyl group, the integer t is 0, 1, or 2, Integers u and w are independently 0 or 1, and Other groups and integers are as defined for compounds of formula IP-1.

[0168] In another preferred embodiment, the compound of formula IP-1 is a compound of formula V

[0169] [ka]

[0170] or a pharmaceutically acceptable salt, solvate or hydrate thereof, among which: R 18 is H or C 1-12 is alkyl, R 19 is H, C 1-12 Alkyl, C(=O)H, C(=O)C 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)NHC 1-12 Alkyl, SO2C1-12 -Alkyl, SO2Aryl, C(=O)C 3-7 Cycloalkyl, C(=O)OC 3-7 Cycloalkyl, C(=O)NHC 3-7 Cycloalkyl, C(=O)NHC 1 -12 Alkyl, SO2C 3-7 cycloalkyl, or A 1 and Each optional group L can be an aryl group, CR 20 R 21 OC(=O)CR 22 R 23 and CR 20 R 21 C(=O)OCR 22 R 23 is selected from R 20 ~R 23 are independently H, C 1-12 Alkyl and C 3-7 cycloalkyl, or two adjacent groups R 20 and R 21 , or R 22 and R 23 Either of these can be independently C 3-7 forming a cycloalkyl group, the integer t is 0, 1, or 2, Integers u and w are independently 0 or 1, and Other groups and integers are as defined for compounds of formula IP-1.

[0171] In one embodiment of Formula VP or Formula V, R 18 is H or C 1-12 alkyl, and R 19 is H, C 1-12 Alkyl, C(=O)H, C(=O)C 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)OC 1-12 Alkyl, C(=O)NHC 1-12 Alkyl, C(=O)C 3-7 Cycloalkyl, C(=O)OC 3-7 Cycloalkyl, C(=O)NHC 3-7Cycloalkyl, or C(=O)NHC 1-12 -alkyl, and each optional group L is an alkyl group, CR 20 R 21 OC(=O)CR 22 R 23 and CR 20 R 21 C(=O)OCR 22 R 23 Selected from R 20 ~R 23 is H and C 1-12 Alkyl groups and C 3-7 cycloalkyl; integer t is 0, 1, or 2; integer n is 0 or 1; and integers u and w are 1.

[0172] In a preferred embodiment, compounds according to formula VP or formula V are provided, wherein: R 1 is R 1 (H) is obtained by removing H from any NH group in R 1 (H) is axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide) or tivozanib (1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea); R 5 ~R 8 is H, and Any group A 8 and L is absent and the group A is absent 8 and integers h and t are both 0 so that atoms adjacent to L are directly connected to each other.

[0173] R 1 Non-limiting examples include:

[0174] [ka]

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka] [ka]

[0179] [ka]

[0180] [ka]

[0181] In a preferred embodiment, a compound of any of formula I, formula IP-1, formula IP-2, formula II-P, formula III, formula III-P, formula IV-P, formula VP, and formula V is provided, wherein R 1 is selected from the following structures:

[0182] [ka]

[0183] In one preferred embodiment, the compound is selected from the following structure: or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0184] [ka]

[0185] [ka]

[0186] In one preferred embodiment, the compound is selected from the following structure: or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] In one preferred embodiment, the compound is selected from the following structure: or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] In one preferred embodiment, the compound is selected from the following structure: or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0195] [ka]

[0196] [ka]

[0197] [ka]

[0198] In one preferred embodiment, the compound is selected from the following structure: or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0199] [ka]

[0200] In some or any embodiments, the compound is any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and after administration to a mammal, produces a biologically active or cytotoxic agent (H)nR 1 In some or any embodiments, the compound is of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, and after administration to a mammal, releases a biologically active or cytotoxic agent H). n R 1 and / or ((H) o R 2 It exerts its therapeutic effect by releasing

[0201] In some or any embodiments, the compound is according to any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and the reagent or agent (H) incorporated into the compound is n R 1In some or any embodiments, the compound has reduced cytotoxicity against non-cancer mammalian cells as determined by an in vitro cytotoxicity assay, such as a cell growth inhibition assay, compared to a compound of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, and the reagent or agent (H) incorporated into the compound n R 1 and / or (H) o R 2 In comparison, its cytotoxicity against non-cancer mammalian cells is reduced as determined by in vitro cytotoxicity assays such as cell growth inhibition assays.

[0202] In some or any embodiments, the compound is of any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and has Formula (H): n R 1 In some or any embodiments, the compound is of formula IP-1, formula IP-2, and formula III-P, or any embodiment provided herein, and has at least about 50% reduced cytotoxicity to non-cancerous mammalian cells as determined by an in vitro cytotoxicity assay, such as a cell growth inhibition assay, compared to a corresponding reagent or agent of formula (H). n R 1 and / or (H) o R 2 Compared to corresponding reagents or drugs, their cytotoxicity to non-cancerous mammalian cells is reduced by at least about 50% as determined by in vitro cytotoxicity assays such as cell growth inhibition assays.

[0203] In some or any embodiments, the compound is of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and when administered to a mammal, exhibits preferential accumulation in the kidney, with a ratio of kidney concentration to blood concentration of about 10-500.

[0204] In some or any embodiments, the compound is of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and when administered to a mammal, exhibits preferential accumulation in the kidney, with a ratio of kidney concentration to blood concentration of at least 20.

[0205] In some or any embodiments, the compound is of any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and (H) n R 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 Compared with the standard therapeutic dose of n R 1 In some or any embodiments, the compound is of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, and (H) n R 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 (in molar amounts) of (H) n R 1 and / or (H) o R 2 Compared with the standard therapeutic dose of n R 1 and / or (H) o R 2 This indicates that the burden (tissue concentration) of

[0206] In some or any embodiments, the compound is of any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and (H)n R 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 Compared with the standard therapeutic dose of n R 1 In some or any embodiments, the compound is of formula IP-1, formula IP-2, and formula III-P, or any embodiment provided herein, and (H) n R 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 (in molar amounts) of (H) n R 1 and / or (H) o R 2 Compared with the standard therapeutic dose of n R 1 and / or (H) o R 2 This indicates that the burden (tissue concentration) of

[0207] In some or any embodiments, the compound is according to any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and (H) n R 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 In some or any embodiments, the compound is of formula IP-1, formula IP-2, and formula III-P, or any embodiment provided herein, and is about 1.5 to 15 times more potent than the standard therapeutic dose of (H), with therapeutic efficacy being determined as delay, halt, or reversal of cancer progression (as determined by changes in cancer tumor size and / or the use of biochemical biomarkers or similar methods for cancer monitoring). In some or any embodiments, the compound is of formula IP-1, formula IP-2, and formula III-P, or any embodiment provided herein, and is n R 1and / or (H) o R 2 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 and / or (H) o R 2 Compared to the standard therapeutic dose, it exhibits approximately 1.5 to 15 times higher efficacy, with therapeutic efficacy being determined as delay, halt, or reverse progression of cancer (as determined by changes in cancer tumor size and / or the use of biochemical biomarkers or similar methods for cancer monitoring).

[0208] In some or any embodiments, the compound is according to any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and (H) n R 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 and (H) is at least two-fold more effective than the standard therapeutic dose of (H), with the therapeutic effect being determined as a delay, halt, or reversal of cancer progression (as determined by changes in cancer tumor size and / or the use of biochemical biomarkers or similar methods for cancer monitoring). In some or any embodiments, the compound is of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, and is n R 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 (in molar amounts) of (H) n R 1 and / or (H) o R 2 The therapeutic effect is determined as a delay, halt, or reversal of cancer progression (as determined by changes in cancer tumor size and / or the use of biochemical biomarkers or similar methods for cancer monitoring).

[0209] In some or any embodiments, the compound is according to any of Formula I, Formula II-P, Formula III, Formula IV-P, Formula VP, and Formula V, or any embodiment provided herein, and (H) n R 1 When administered to a mammal at a dose (expressed in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of (H) n R 1 and (H) the compound exhibits at least a two-fold reduction in the occurrence of side effects and / or off-target toxicity when compared to a standard therapeutic dose of 100 mg / kg / day, as determined by general observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods. In some or any embodiments, the compound is of any of Formula IP-1, Formula IP-2, and Formula III-P, or any embodiment provided herein, and is n R 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 (in molar amounts) of (H) n R 1 and / or (H) o R 2 demonstrates at least a two-fold reduction in the occurrence of side effects and / or off-target toxicities when compared to a standard therapeutic dose of the compound, as determined by general observation of the treated mammal, blood counts, tissue biopsies, and / or analysis of biochemical biomarkers or similar methods.

[0210] In some or any embodiments, there is provided a method for treating a cancer disease (e.g., kidney or cancer kidney disease) in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or as defined in any of the Examples described herein.

[0211] In some or any embodiments, there is provided a method for treating a cancer disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or a compound as defined in any of the Examples described herein, wherein the compound is administered to the mammal in a pharmaceutical composition via oral, parenteral, transdermal, topical, rectal, intranasal, or intratumoral administration (e.g., injection), including in aerosol form. In some or any embodiments, the method is a method wherein the cancer is renal cell carcinoma (RCC) or metastatic renal cell carcinoma (mRCC).

[0212] In some embodiments and aspects, the compounds provided herein may be used in combination with adjuncts to act synergistically and / or enhance the therapeutic effect of the compound itself, the adjunct, or both, including other anti-cancer or immunomodulatory agents, such as monoclonal antibodies, or other cytotoxic agents, or other oncology (cancer) agents, or humanized antibodies, such as pembrolizimab.

[0213] These compound combinations provided by the present invention are useful in the prevention, treatment and alleviation of symptoms of cancer diseases, particularly kidney cancer.

[0214] In one such embodiment, the compounds provided herein have moderate or no anti-cancer activity in vitro, but exhibit high anti-cancer efficacy when administered to a mammal in need of cancer treatment.

[0215] In some or any embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of any compound of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or any compound defined in any embodiment herein, and a pharmaceutically acceptable carrier.

[0216] In another aspect, there is provided a method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, and Formula V, or a compound as defined in any embodiment described herein, or a pharmaceutical composition thereof (i.e., the compound and a pharmaceutically acceptable carrier). In some or any embodiments, the compound may be administered to the mammal as a pharmaceutical composition via parenteral, transdermal, oral, intranasal, topical, rectal, or intratumoral administration. In some or any embodiments, the cancer is renal cancer, including renal cell carcinoma (RCC) and metastatic RCC (mRCC).

[0217] 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 polymyxin nappeptides. Protected polymyxin B nappeptide and colistin nappeptide derivatives can further 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.

[0218] Other general methods suitable for preparing compounds of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP or Formula V are described in the following publications: WO 2021 / 150792, WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, US 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, CN 103923190, US 2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, CN 103130876, WO 2013 / 072695, WO 2012 / 168820, WO 2012051663, US 2012 / 0316105, US 2012 / 0283176, US 2010 / 0160215, US 2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, US 2006 / 0004185, US 6380356, and US 3450687.

[0219] Suitable methods for incorporating appropriate enzymatically and / or chemically cleavable groups X, Y, and Z (and other equivalent spacers / linkers) into compounds of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, or Formula V are described in generally relevant synthetic techniques for preparing ADCs and other reagents, and are reported, for example, in the following publications: 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 above publications.

[0220] It will be readily apparent to those skilled in the art of synthetic organic chemistry that by straightforward modification of the specific methods, specific reagents, and protection / deprotection schemes described in the above references, the amino acid reagents, and linker / spacer structures can be directly adapted to prepare compounds of Formula I, Formula IP-1, Formula IP-2, Formula II-P, Formula III, Formula III-P, Formula IV-P, Formula VP, or Formula V.

[0221] 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.

[0222] Example The following examples are provided to illustrate, but not to limit, the scope of the present disclosure. Common abbreviations familiar to those of ordinary skill in the art of synthesis are used throughout. NMR refers to 400 MHz NMR recorded in DO unless otherwise specified. 1H NMR spectrum (delta, ppm). LCMS means liquid chromatography-mass spectrometry. MS means mass spectrometry data (m / z) using positive ionization. Chromatography means silica gel chromatography using an organic solvent unless otherwise specified. TLC means thin-layer chromatography. HPLC means high-performance reversed-phase liquid chromatography using a commercially available C18 column. CDI means carbonyldiimidazole. DCM means dichloromethane. TES means Et3SiHTFA, CF3COOH, EA means EtOAc or ethyl acetate, ACN means MeCN, DMF means N,N-dimethylformamide, DCC means N,N'-dicyclohexylcarbodiimide, DCE means 1,2-dichloroethane, NMP means N-methylpyrrolidone, and PE means hexane or light petroleum ether. MeOH means methanol, and t-BuOH means tert-butyl alcohol. THF means tetrahydrofuran. Cs2CO3 means cesium carbonate, NaHCO3 means sodium bicarbonate, and Na2SO4 means sodium sulfate. HCl means hydrochloric acid. T3P means propanephosphinic anhydride. DIEA means N,N-diisopropylethylamine, and DMAP means 4-dimethylaminopyridine. HATU means (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, azabenzotriazole tetramethyluronium hexafluorophosphate. Boc means t-butoxycarbonyl, and Cbz means benzyloxycarbonyl. Pd means palladium. r·t or RT means room temperature. Ar means argon. C18 chromatography refers to reverse-phase chromatography using a gradient of water and acetonitrile (ACN) or the same gradient containing 0.05% to 1% TFA. The reagent PMBN(Boc)4 is H-Thr-Dab(Boc)-cyclo[Dab(Boc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr].The reagent Dab(Boc)PMBN(Boc)4 [same as Dab(Boc)-PMBN(Boc)4] is H-Dab(Boc)-Thr-Dab(Boc)-cyclo [Dab(Boc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr] [Dab(Boc)-Thr-Dab(Boc)-cyclo [Dab(Bofc)-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]]. Axitinib-Pnp (Axitinib-Pnp) is (E)-4-nitrophenyl 6-((2-(methylcarbamoyl)phenyl)thio)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-1-carboxylate. 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.

[0223] Example 1 Synthesis of the compound of Example 1:

[0224] [ka]

[0225] [ka]

[0226] Intermediate 1 (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) were stirred at room temperature for 1.5 h, and then ethane-1,2-diamine (1.1 mL, 16.7 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (20 mL), extracted with DCM (15 mL × 4), and washed with HO (10 mL × 2) and brine (10 mL). The mixture was dried and evaporated to give crude intermediate 1 (0.62 g). MS: 346.16 [M+H] + .

[0227] Intermediate 2 Intermediate 1 (0.62 g, 1.67 mmol) and acrylic acid benzyl ester (0.24 g, 1.5 mmol) were stirred in ACN (4 mL) at 45 °C under Ar for 36 h. The volatiles were removed, and the residue was purified on a C18 column (ACN / HO = 0-80%) to give Intermediate 2 (0.5 g). MS: 508.31 [M+H] + .

[0228] Intermediate 3 Intermediate 2 (0.5 g, 0.99 mmol) and 10% Pd / C (0.15 g) in t-BuOH (5 mL) were degassed with H 5 times and then stirred at room temperature for 4.5 hours. Filtration and drying gave crude intermediate 3 (0.42 g). MS: 418.25 [M+H] + .

[0229] Intermediate 4 Intermediate 3 (0.313 mg, 0.75 mmol), axitinib-Pnp (0.413 g, 0.75 mol), and DIEA (0.2 mL, 1.13 mmol) were stirred in NMP (5 mL) at room temperature under Ar overnight, then diluted and extracted with EA (50 mL x 3), washed with HO (5 mL x 2) and brine (5 mL), dried, and evaporated. Purification on a C18 column (ACN / HO = 0-90%) gave intermediate 4 (0.35 g). MS: 830.16 [M+H] + .

[0230] Intermediate 5 Intermediate 4 (0.34 g, 0.41 mmol), PMBN(Boc)4 (0.56 g, 0.41 mmol), HATU (0.187 g, 0.49 mmol), and DIEA (0.145 mL, 0.82 mmol) were stirred in DMF (3 mL) at room temperature for 4 h. The mixture was extracted with EA (60 mL) and washed with HO (10 mL × 2) and brine (10 mL). The mixture was dried and evaporated. Purification on a C18 column (ACN / HO = 0-80%) gave intermediate 5 (0.45 g). MS: 1087.95 [M+2H] 2+ .

[0231] Compound of Example 1 Intermediate 5 (110 mg, 0.05 mmol) was added to TFA / DCM (0.5 mL / 1.5 mL) and stirred at room temperature for 3 minutes. The crude product was separated by distillation and purified by HPLC (ACN / H_2O=0~50%) and the compound of Example 1 (43 mg) was obtained. NMR:8.45 (t, J = 7.9 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.82 (t, J = 6.6 Hz, 1H), 7.65 (s, 2H), 7.50 - 7.38 (m, 4H), 7.25 (dq, J= 14.9, 7.3 Hz, 4H), 7.14 (d, J = 7.4 Hz, 2H), 4.47 (dt, J = 11.4, 5.9 Hz, 1H), 4.42 - 4.31 (m, 2H), 4.22 - 4.00 (m, 8H), 3.88 (s, 2H), 3.74 (s, 3H), 3.38 (s, 1H), 3.21 (s, 1H), 3.09 - 2.87 (m, 9H), 2.83 - 2.55 (m, 7H), 2.26 (d, J = 6.1 Hz, 2H), 2.20 - 2.03 (m, 5H), 1.92 (s, 4H), 1.87 - 1.66 (m, 3H), 1.39 (ddd, J = 14.0, 9.6, 4.3 Hz, 1H), 1.30 (ddd, J = 14.4, 10.6, 4.1 Hz, 1H), 1.07 (t, J = 5.2 Hz, 3H), 0.98 (s, 3H), 0.78 - 0.64 (m, 4H), 0.59 (t, J = 5.0 Hz, 3H). MS: 1619.68 [M+H] + .

[0232] Example 2 Synthesis of the compound in Example 2:

[0233]

change

[0234] Intermediate 6 Intermediate 6 was prepared by a similar procedure to intermediate 5, except that intermediate 4 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4. MS: 887.7 [M-99] 2+ .

[0235] Compound of Example 2 The compound of Example 2 was prepared by a similar procedure to that of Example 1, except that intermediate 4 was coupled with PMBH(Boc)3 instead of PMBN(Boc)4. NMR (600 MHz, deuterium oxide) δ 8.55 (dt, J = 6.1, 2.7 Hz, 1H), 8.46 - 8.37 m, 1H), 8.18 (s, 1H), 7.90 - 7.84 (m, 1H), 7.78 (ddd, J = 7.3, 5.9, 1.2 Hz, 1H), 7.65 (s, 1H), 7.42 - 7.32 (m, 4H), 7.22 - 7.14 (m, 3H), 7.09 - 7.03 (m, 2H), 4.33 (s, 1H), 4.18 - 3.56 (m, 13H), 3.30 (s, 1H), 3.07 (dt, J = 13.9, 7.3 Hz, 1H), 2.93 (dddd, J = 37.3, 15.9, 10.9, 6.4 Hz, 5H), 2.83 - 2.68 (m, 3H), 2.58 (d, J = 6.9 Hz, 6H), 2.18 (t, J = 7.5 Hz, 2H), 2.14 - 1.72 (m, 9H), 1.64 (d, J = 44.5 Hz, 2H), 1.31 (d, J = 9.8 Hz, 2H), 0.96 (s, 3H), 0.62 (d, J = 6.5 Hz, 3H), 0.58 - 0.51 (m, 3H). MS: 1417.62 [M+H] + .

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

[0237] [ka]

[0238] [ka]

[0239] Compound of Example 3 The compound of Example 3 was prepared by a similar process to that of Example 1, except starting with (S)-2-acetamido-5-(tert-butoxy)-5-oxopentanoic acid instead of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxypentanoic acid.

[0240] Example 3B Alternative synthesis of the compound of Example 3:

[0241] [ka]

[0242] [ka]

[0243] Intermediate 7B To tert-butyl (2-aminoethyl)carbamate (25 g, 156 mmol) in MeOH (250 mL) was added methyl propan-2-enoate (10.8 g, 125 mmol) dropwise at 0 °C under a N atmosphere, followed by stirring at room temperature for 12 h. Evaporation and purification by silica gel chromatography gave Intermediate 7B (25.0 g, 65.1% yield). NMR (400 MHz, CDCl) δ 4.98 (br s, 1H), 3.68 (s, 3H), 3.20 (q, J = 5.7 Hz, 2H), 2.88 (t, J = 6.5 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H), 2.50 (t, J = 6.5 Hz, 2H), 1.43 (s, 9H).

[0244] Intermediate 8B To a mixture of intermediate 7B (25.0 g, 102 mmol) and NaHCO3 (17.1 g, 203 mmol) in dioxane (125 mL) and HO (125 mL) was added CbzCl (22.5 g, 132 mmol) dropwise at 0 °C. The reaction mixture was slowly heated to 25 °C and stirred for 4 h. The mixture was diluted with HO (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give intermediate 8B (40 g crude) as a yellow oil. NMR (400 MHz, CDCl3) δ 7.39 - 7.35 (m, 3H), 7.34 - 7.27 (m, 2H), 5.12 (s, 2H), 3.64 (d, J = 10.7 Hz, 3H), 3.56 (t, J = 7.1 Hz, 2H), 3.40 (br s, 2H), 3.26 (d, J = 11.6 Hz, 2H), 2.70 - 2.47 (m, 2H), 1.42 (s, 9H).

[0245] Intermediate 9B To a solution of intermediate 8B (10.0 g, 26.3 mmol) in THF (90.0 mL) was added LiOH (1.43 g, 34.2 mmol) dissolved in HO (30.0 mL) at 0 °C. The reaction mixture was heated to 25 °C and stirred for 2.5 h. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous phase was acidified to pH = 4 with 2 M HCl and extracted with 150 mL of DCM (50 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated to give intermediate 9B (13.0 g crude) as a yellow oil. MS: 267.1 [M-99] + .

[0246] Intermediate 10B To a solution of intermediate 9B (11.0 g, 30 mmol) in DMF (100 mL) was added CsCO (29.3 g, 90.1 mmol), and (bromomethyl)benzene (7.70 g, 45.0 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 12 h. The mixture was poured into H0 (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography to give intermediate 10 (9.00 g, 65.7% yield) as a brown oil. MS: 357.2 [M-99] + .

[0247] Intermediate 11B To a solution of Intermediate 10B (9.00 g, 19.7 mmol) in DCM (90 mL) was added HCl (4 M in dioxane, 29.6 mL, 118 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated to give Intermediate 11B (crude, 7.00 g) as a white solid.

[0248] Intermediate 12 To a mixture of (S)-2-acetylamino-5-(tert-butoxy)-5-oxovaleric acid (2.00 g, 8.15 mmol) and Intermediate 11B (3.84 g, 9.79 mmol) in DCM (10 mL) was added TEA (3.40 mL, 24.5 mmol) and T3P (7.78 g, 12.2 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The mixture was washed with brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give Intermediate 12B (1.80 g, 37.8% yield) as a pale yellow solid. MS: 528.2 [M-55] + .

[0249] Intermediate 13B To a solution of Intermediate 12B (1.75 g, 3.00 mmol) in 2,2,2-trifluoroethan-1-ol (20.0 mL), 10% Pd / C (0.350 g, 3.29 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The suspension was filtered through a pad of silica gel, and the filter cake was washed with 2,2,2-trifluoroethan-1-ol (20.0 mL x 3). The combined filtrate was concentrated under reduced pressure to give Intermediate 13B (1.00 g, 92.6% yield) as a yellow oil. MS: 360.2 [M+H] + .

[0250] Intermediate 14B Intermediate 14B was prepared in 58.2% yield by a similar procedure to intermediate 4. MS: 772.3 [M+H] + .

[0251] Intermediate 15B Intermediate 15B was prepared in 55% yield by a similar procedure to intermediate 5. MS: 1059.7 [M+2H] 2+ .

[0252] Compound of Example 3 The compound of Example 3 was prepared by the same procedure as that for the compound of Example 1. NMR (400 MHz, deuterium oxide) δ 8.67 (d, J = 5.9 Hz, 1H), 8.57 - 8.50 (m, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.07 - 7.98 (m, 2H), 7.90 (t, J = 6.6 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.58 - 7.45 (m, 4H), 7.36 - 7.26 (m, 4H), 7.23 - 7.15 (m, 2H), 4.28 - 4.05 (m, 10H), 3.98 - 3.72 (m, 5H), 3.61 - 3.41 (m, 3H), 3.33 - 3.20 (m, 2H), 3.17 - 2.94 (m, 10H), 2.89 - 2.61 (m, 8H), 2.30 - 2.11 (m, 7H), 2.02 (s, 1H), 1.94 - 1.78 (m, 7H), 1.53 - 1.29 (m, 3H), 1.21 - 0.99 (m, 6H), 0.78 - 0.62 (m, 6H). MS: 831.4 [M+2H] 2+ .

[0253] Example 4A Synthesis of the compound of Example 4:

[0254] [ka]

[0255] [ka]

[0256] Compound of Example 4 The compound of Example 4 is prepared by a similar process to that of Example 1, except starting with (S)-2-carboxamido-5-(tert-butoxy)-5-oxopentanoic acid instead of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxypentanoic acid.

[0257] Example 4B Alternative synthesis of the compound of Example 4:

[0258] [ka]

[0259] [ka]

[0260] Intermediate 16B To a solution of (S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid (5.00 g, 24.6 mmol) in formic acid (3.17 mL, 246 mmol) was slowly added AcO (1.01 mL, 10.8 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched at room temperature by adding HO (20.0 mL), filtered, and concentrated under reduced pressure to give Intermediate 16B (2.60 g, 45.7% yield) as a white solid. MS: 230.0 [MH] - .

[0261] Intermediate 17B Intermediate 17B was prepared in the same manner as Intermediate 12B. The yield was 19.5%, and the product was a yellow oil. MS: 514.3 [M-55] + .

[0262] Intermediate 18B Intermediate 18 is a white solid prepared by a similar procedure to Intermediate 13B. MS: 346.2 [M+H] + .

[0263] Intermediate 19B Intermediate 19 is a white solid prepared by a similar procedure to Intermediate 4. MS: 758.4 [M+H] + .

[0264] Intermediate 20B Intermediate 20B was a white solid prepared in a similar manner to that of Intermediate 5, with a yield of 28.8%. MS: 1002.6 [M+2H] 2+ .

[0265] Compound of Example 4 The compound of Example 4 was prepared by the same procedure as that for the compound of Example 1. NMR (400 MHz, deuterium oxide) δ 8.67 (d, J = 5.6 Hz, 1H), 8.58 - 8.51 (m, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.05 - 7.95 (m, 3H), 7.94 - 7.87 (m, 1H), 7.76 - 7.68 (m, 2H), 7.57 - 7.44 (m, 5H), 7.37 - 7.24 (m, 5H), 7.19 (d, J = 7.3 Hz, 2H), 4.53 (t, J = 8.0 Hz, 1H), 4.41 (td, J = 9.1, 4.7Hz, 2H), 4.30 - 4.10 (m, 11H), 3.98 - 3.69 (m, 5H), 3.49 (br s, 2H), 3.32 - 3.23 (m, 1H), 3.13 - 2.97 (m, 11H), 2.89 - 2.69 (m, 5H), 2.67 (s, 3H), 2.32 - 2.13 (m, 8H), 2.10 - 1.95 (m, 3H), 1.93 - 1.83 (m, 3H), 1.77 (br s, 3H), 1.50 - 1.31 (m, 2H), 1.17 - 1.02 (m, 7H), 0.86 - 0.75 (m, 2H), 0.75 - 0.71 (m, 3H), 0.65 (d, J = 5.9 Hz, 3H). MS: 824.2 [M+2H] 2+ .

[0266] Example 5A Synthesis of the compound of Example 5:

[0267] [ka]

[0268] [ka]

[0269] Compound of Example 5 According to the above steps, the compound of Example 5 was produced from Intermediate 1.

[0270] Example 5B Alternative synthesis of the compound of Example 5:

[0271] [ka]

[0272] Intermediate 21B 2-Methylethylene oxide (0.164 mL, 2.34 mmol) was added to a solution of Intermediate 1 (810 mg, 2.34 mol) and TEA (0.418 mL, 3 mmol) in 10 mL of EtOH. The mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel chromatography to give Intermediate 21B (220 mg) as a colorless oil. MS: 404.3 [M+H] + .

[0273] Intermediate 22B A solution of intermediate 21B (112 mg, 0.28 mmol), Axi-PNP.HCl (127 mg, 0.22 mmol), and TEA (0.2 mL, 1.4 mmol) in DMF (2 mL) was stirred at room temperature for 3 h. 113 mg of succinic anhydride and 38.6 mg of DMAP were added. The mixture was stirred at room temperature overnight. The mixture was partitioned between HO (10 mL), 0.5 M HCl (5 mL), and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase C18 PRE-HPLC to give intermediate 22B (43 mg). MS: 916.2 [M+H] + .

[0274] Intermediate 23B Intermediate 23B was a white solid prepared in a similar manner to that of Intermediate 5, with a yield of 28.8%. MS: 1131.4 [M+2H] 2+ .

[0275] Compound of Example 5 The compound of Example 5 was prepared by the same procedure as that for the compound of Example 1. NMR (600 MHz, deuterium oxide) δ 8.63 (d, J = 6.0 Hz, 1H), 8.58 - 8.51 (m, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.45 (t, J = 8.4 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.30 - 7.21 (m, 4H), 7.16 (d, J = 7.8 Hz, 2H), 4.51 (t, J = 7.8 Hz, 1H), 4.38 (m, 2H), 4.20 - 4.11 (m, 11H), 3.91 - 3.69 (m, 5H), 3.37 - 3.22 (m, 3H), 3.03 - 2.94 (m, 11H), 2.80 (m, 2H), 2.72 - 2.61 (m, 5H), 2.46 - 2.42 (m, 2H), 2.29 - 2.25 (m, 2H), 2.21 - 1.76 (m, 13H), 1.44 - 1.32 (m, 2H), 1.10 - 1.09 (m, 9H), 0.80 - 0.75 (m, 2H), 0.70 - 0.68 (m, 3H), 0.63 - 0.61 (m, 3H). MS: 1705.3 [M+H] + .

[0276] Example 6 Synthesis of the compound of Example 6:

[0277] [ka]

[0278] [ka]

[0279] Intermediate 24 A mixture of intermediate 3 (1.2 g, 2.87 mmol) and TEA (0.8 mL, 5.75 mmol) in DCM (15 mL) was stirred at 0 °C, and CbzCl (0.45 mL, 3.16 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. The mixture was extracted with DCM (80 mL) and washed with HO (30 mL) and brine (30 mL). The extract was dried and evaporated. Purification on a C18 column (ACN / HO = 0-80%) gave intermediate 24 (635 mg). MS: 552.15 [M+H] + .

[0280] Intermediate 25 A mixture of intermediate 24 (600 mg, 1.09 mmol), benzyl 2-hydroxyacetate (451 mg, 2.72 mmol), DCC (671 mg, 3.26 mmol), and DMAP (27 mg, 0.22 mmol) in DCM (20 mL) was stirred at room temperature under Ar for 18 hours. The mixture was extracted with DCM (80 mL) and washed with HO (30 mL) and brine (30 mL). The mixture was dried and evaporated. Purification on a C18 column (ACN / HO = 0-90%) gave intermediate 25 (407 mg). MS: 700.16 [M+H] + .

[0281] Intermediate 26 A suspension of intermediate 25 (400 mg, 0.57 mmol) and Pd / C (56% HO, 200 mg) in t-BuOH (10 mL) was degassed five times with H and then stirred at room temperature with H for 6 h. Filtration and evaporation gave intermediate 26 (250 mg). MS: 476.26 [M+H] + .

[0282] Intermediate 27 A mixture of intermediate 26 (250 mg, 0.53 mmol), Axi-Pnp (319 mg, 0.57 mmol), and DIEA (0.23 mL, 1.31 mmol) in NMP (5 mL) was stirred at room temperature for 6 hours. The mixture was extracted with EA (20 mL × 3), washed with HO (10 mL × 2) and brine (10 mL), dried, and evaporated. Purification on a C18 column (ACN / HO = 0-80%) gave intermediate 27 (280 mg). MS: 888.89 [M+H] + .

[0283] Intermediate 28 A reaction mixture of intermediate 27 (240 mg, 0.27 mmol), PMBN(Boc)4 (368 mg, 0.27 mmol), HATU (113 mg, 0.30 mmol), and DIEA (0.096 mL, 0.54 mmol) in DMF (6 mL) was stirred at 25 °C under Ar atmosphere for 5 h. The mixture was extracted with EA (50 mL) and washed with HO (5 mL × 2) and brine (5 mL). The extract was dried and evaporated. Purification using a C18 column (ACN / HO = 0-90%) gave intermediate 28 (85 mg). MS: 1117.00 [M+2H] 2+ .

[0284] Compound of Example 6 A solution of intermediate 28 (83 mg, 0.037 mmol) in TFA / DCM (1 mL / 3 mL) was stirred at room temperature for 1 hour. The volatile matter was removed, and the residue was refined with C18 carbon dioxide (ACN / H2O=0~70%), and the compound of Example 6 (23 mg) was obtained. NMR: δ 8.56 - 8.51 (m, 1H), 8.34 (t, J= 8.1 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 16.7, 1.9 Hz, 1H), 7.73 (t, J = 6.7 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.46 - 7.42 (m, 1H), 7.40 - 7.35 (m, 3H), 7.20 (dt, J = 6.9, 4.7 Hz, 3H), 7.18 - 7.14 (m, 1H), 7.09 - 7.05 (m, 2H), 4.42 (t, J = 8.2 Hz, 1H), 4.31 (ddd, J = 9.6, 5.2, 2.3 Hz, 2H), 4.18 - 4.11 (m, 3H), 4.09 - 4.00 (m, 6H), 3.90 (s, 1H), 3.67 (s, 2H), 3.33 (s, 1H), 3.16 (dq, J = 14.6, 7.4 Hz, 1H), 3.00 - 2.86 (m, 10H), 2.76 (s, 2H), 2.73 - 2.68 (m, 1H), 2.62 (q, J = 11.8, 10.2 Hz, 1H), 2.55 (s, 3H), 2.18 (t, J = 7.3 Hz, 2H), 2.13 - 1.59 (m, 15H), 1.33 (ddd, J = 14.0, 9.9, 4.2 Hz, 1H), 1.29 - 1.20 (m, 1H), 1.00 (dd, J = 15.3, 6.4 Hz, 6H), 0.61 (d, J = 6.5 Hz, 3H), 0.54 (d, J = 6.4 Hz, 3H). MS: 1677.92 [M+H] + .

[0285] Example 7 Synthesis of the compound in Example 7:

[0286] [ka]

[0287] [ka]

[0288] Intermediate 29 A mixture of 2-aminoethan-1-ol (47.8 g, 295 mmol) and TEA (41.0 mL, 295 mmol) in ACN (500 mL) was stirred at 50 °C under a N atmosphere for 4 h. The reaction mixture was concentrated under reduced pressure to give intermediate 29 (71.3 g crude), a yellow solid.

[0289] Intermediate 30 To a solution of intermediate 29 (73.1 g, 327 mmol) in ACN / MeOH = 2 / 1 (600 mL), benzyl chloroformate (92.2 mL, 655 mmol) and TEA (50.1 mL, 360 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give intermediate 30 (103 g, 88.0% yield) as a yellow oil.

[0290] Intermediate 31 To a solution of intermediate 30 (10.0 g, 27.9 mmol) in DCM (100 mL) was added (S)-5-(tert-butoxycarbonyl)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (8.49 g, 27.9 mmol), DMAP (4.10 g, 33.5 mmol), and DCC (6.93 g, 33.5 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding HO (100 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give intermediate 31 (13.0 g, 72.2% yield) as a yellow oil. MS: 543.2 [M-99] + .

[0291] Intermediate 32 Under a N2 atmosphere, Pd / C 10% (0.83 g, 7.77 mol) was added to a solution of Intermediate 31 (5.00 g, 7.77 mmol) in 2,2,2-trifluoroethanol (100 mL). The suspension was degassed and purged twice with H2. The mixture was stirred at room temperature under a H2 (15 psi) atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give Intermediate 32 (3.00 g, 92% yield) as a white solid. MS: 419.2 [M+H] + .

[0292] Intermediate 33 Axi PNP (590 mg, 1.00 mmol) and DIEA (648 mg, 5.01 mmol) were added to a solution of intermediate 32 (700 mg, 1.67 mmol) in NMP (7 mL). The mixture was stirred at room temperature for 12 hours. The crude product was purified by prep-HPLC (TFA) to give intermediate 33 (600 mg, 43% yield). MS: 831.5 [M+H] + .

[0293] Intermediate 34 A reaction mixture of intermediate 33 (900 mg, 1.08 mmol), PMBH(Boc)3 (1.15 g, 1.08 mmol), DIEA (419 mg, 3.24 mmol), and HATU (617 mg, 1.625 mmol) in THF (8 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA conditions) to give intermediate 33 (1.30 g, 64% yield). MS: 888.5 [M+2H] 2+ .

[0294] Compound of Example 7 A solution of Intermediate 34 (1.30 g, 0.693 mmol) in TFA / DCM (3 mL / 15 mL) was stirred at room temperature for 12 hours. The volatiles were removed and the residue was purified on a reverse-phase C18 column to give Example 7 (1126 mg, 0.601 mmol, 86.7% purity). NMR (400 MHz, deuterium oxide): δ 8.60 - 8.40 (m, 2H), 8.22 (d, J = 7.6 Hz, 1H), 7.92 - 7.78 (m, 3H), 7.66 (br s, 1H), 7.57 (d, J = 16.3 Hz, 1H), 7.46 - 7.34 (m, 4H), 7.20 (d, J = 7.3 Hz, 3H), 7.13 (br s, 1H), 7.08 (d, J = 7.1 Hz, 2H), 4.45 - 4.21 (m, 6H), 4.13 (d, J = 5.1 Hz, 3H), 4.05 (br s, 2H), 3.92 (br s, 6H), 3.08 (dd, J = 13.8, 7.3 Hz, 2H), 3.03 - 2.88 (m, 5H), 2.87 - 2.69 (m, 5H), 2.60 (s, 6H), 2.23 - 1.96 (m, 7H), 1.94 - 1.59 (m, 7H), 1.32 (br s, 2H), 0.95 (br s, 3H), 0.76 (br s, 1H), 0.63 (d, J = 5.9 Hz, 3H), 0.55 (d, J = 5.5 Hz, 3H). MS: 710.2 [M+2H] 2+ .

[0295] Example 8 Synthesis of the compound of Example 8:

[0296] [ka]

[0297] [ka]

[0298] Intermediate 35 N1-(2-aminoethyl)ethane-1,2-diamine (3.35 g, 32 mmol) was dissolved in DCM (30 mL) and cooled to 0 °C. Ethyl trifluoroacetate (9.69 g, 68 mmol) was slowly added to DCM (10 mL). 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 DCM (10 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. The DCM solution was diluted with water, separated, and concentrated. The residue was purified by silica gel chromatography to give intermediate 35 (2.9 g) as a white solid in 21% yield. MS: 430.0 [M+H] + .

[0299] Intermediate 36 To a solution of intermediate 35 (200 mg, 0.47 mmol) in MeOH (5 mL) / HO (1 mL) was added KCO (129 mg, 0.93 mmol). The mixture was stirred at room temperature overnight. The solvent was removed and the mixture was purified by prep-HPLC (TFA) to give intermediate 36 (90 mg, 81% yield) as a colorless oil. MS: 238.2 [M+H] + .

[0300] Intermediate 37 To a solution of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (115 mg, 0.38 mmol) in DMF (1 mL) at 0°C, CDI (58 mg, 0.36 mmol) was added, followed by intermediate 36 (90 mg, 0.38 mmol). The resulting mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10 mL of EtOAc and washed with 10 mL of water. The organic layer was separated and concentrated. The residue was purified by pre-HPLC (CHCN (0.1% TFA) / HO, 0-60%) to give intermediate 37 (93 mg, 47% yield) as a colorless oil. MS: 523.3 [M+H] + .

[0301] Intermediate 38 To a solution of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (72 mg, 0.21 mmol) in DMF (2 mL) cooled at 0 °C, HATU (88 mg, 0.23 mmol) and DIEA (68.9 mg, 0.53 mmol) were added, and the mixture was stirred at 0 °C for 20 min. Intermediate 37 (93 mg, 0.18 mmol) was then added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with 10 mL of EtOAc and washed with 10 mL of water. The organic layer was separated and concentrated. The residue was purified by pre-HPLC (CHCN (0.1% TFA) / HO, 0-90%) to give Intermediate 38 (110 mg, 73% yield) as a colorless oil. MS: 842.2 [M+H] + .

[0302] Intermediate 39 To a solution of intermediate 38 (110 mg, 0.13 mmol) in 20 mL of EtOAc was added 10% Pd / C (50% content, 10 mg), and the mixture was stirred overnight at room temperature under an H atmosphere. The mixture was filtered through diatomaceous earth and concentrated to give intermediate 39 (crude, 94 mg) as a colorless oil. MS: 618.4 [M+H] + .

[0303] Intermediate 40 DIEA (53 mg, 0.41 mmol) was added to a solution of Intermediate 39 (84 mg, 0.13 mmol) and 4-nitrophenyl(E)-6-((2-(methylcarbamoyl)phenyl)thio)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-1-carboxylate (75 mg, 0.136 mmol) in DMF (2 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with 10 mL of EtOAc and washed with 10 mL of water. The organic layer was separated and concentrated. The residue was purified by pre-HPLC (CHCN (0.1% TFA) / HO, 0-80%) to give Intermediate 40 (24 mg, 17% yield) as a white solid. MS: 1030.3 [M+H] + .

[0304] Intermediate 41 To a solution of intermediate 40 (21 mg, 0.02 mmol) in DMF (2 mL), HATU (9.8 mg, 0.024 mmol) was added, followed by DIEA (19.2 mg, 0.14 mmol) and PMBH-Boc3 (25 mg, 0.022 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with 10 mL of EtOAc and washed with 10 mL of water. The organic layer was separated and concentrated. The residue was purified by pre-HPLC (CHCN (0.1% TFA) / HO, 0-80%) to give intermediate 41 (17 mg, 41% yield) as a white solid. MS: 1037.6 [M+2H] 2+ .

[0305] Compound of Example 8 To a solution of Intermediate 41 (17 mg, 0.008 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified using a reverse-phase C18 column (TFA 0.05% CHCN:HO = 5-30%) to give Example 8 (6.2 mg, 32% yield) as a white solid. NMR (400 MHz, deuterium oxide): δ 8.66 - 8.55 (m, 1H), 8.38 - 8.36 (m, 1H), 8.19 - 8.14 (m, 1H), 8.05 - 7.88 (m, 3H), 7.80 - 7.68 (m, 3H), 7.56 - 7.47 (m, 4H), 7.32 - 7.29 (m, 3H), 7.21 - 7.16 (m, 2H), 4.48 - 4.41 (m, 6H), 4.20 - 4.11 (m, 4H), 3.85 - 3.77 (m, 8H), 3.08 - 2.97 (m, 10H), 2.77 - 2.60 (m, 6H), 2.25 - 2.12 (m, 14H), 1.98 - 1.36 (m, 16H), 1.09 - 1.08 (m, 3H), 0.72 - 0.70 (m, 3H), 0.65 - 0.63 (m, 3H). MS: 1517.7 [M+H] + .

[0306] Example 9 Synthesis of the compound of Example 9:

[0307] [ka]

[0308] [ka]

[0309] Intermediate 42 A mixture of N-Bc-ethylenediamine (2.4 g, 15 mmol) and methyl acrylate (0.86 g, 10 mmol) in MeOH (4 mL) was stirred at 0-4 °C under Ar atmosphere for 4 h. The volatiles were evaporated in vacuo, and the residue was purified by silica gel chromatography (gradient 0.1% TEA-EA / 0.1% TEA-PE 0-100%) to give Intermediate 42 (1.3 g). MS: 247.2 [M+H] + .

[0310] Intermediate 43 A mixture of intermediate 42 (1.3 g, 5.3 mmol), CbzCl (1 g, 5.8 mmol), and TEA (1.5 mL, 10.6 mmol) in DCM (10 mL) was stirred at 5 °C under Ar atmosphere for 4 h. The volatiles were removed, extracted with EA (50 mL), and washed with HO (5 mL x 2) and brine (5 mL). The EA layer was dried (NaSO), filtered, and evaporated. The crude product was purified by silica gel chromatography (EA / PE 0-60%) to give intermediate 43 (2.0 g). MS: 381.2 [M+H] + .

[0311] Intermediate 44 A solution of intermediate 43 (2.0 g, 5.26 mmol) in TFA / DCM (2 mL / 15 mL) was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo to give intermediate 44 (2.1 g), which was used directly in the next step. MS: 281.2 [M+H] + .

[0312] Intermediate 45 A mixture of intermediate 44 (2.1 g, 5.26 mmol), (S)-5-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)-5-oxovaleric acid (1.33 g, 4.38 mmol), HATU (2.33 g, 6.14 mmol), and DIEA (1.55 mL, 8.77 mmol) in DMF (12 mL) was stirred at 40 °C for 4 h. The mixture was cooled to room temperature, extracted with EA (100 mL), and washed with HO (15 mL x 2) and brine (15 mL). The EA layer was dried (NaSO), and the solvent was evaporated in vacuo. The product was purified by silica gel chromatography (EA / PE 0-80%) to give intermediate 45 (2.6 g). MS: 566.1 [M+H] + .

[0313] Intermediate 46 Intermediate 45 (0.4 g, 0.7 mmol) was added to a solution of LiOH·HO (45 mg, 1.1 mmol) in MeOH / HO (2 mL / 1 mL). The reaction mixture was stirred at room temperature for 6.5 h. After oxidation, the mixture was extracted with EA (50 mL) and washed with HO (5 mL x 2) and brine (5 mL). The EA layer was dried and evaporated. The product was purified by silica gel chromatography (EA / PE 0-90%) to give Intermediate 46 (0.22 g). MS: 552.0 [M+H] + .

[0314] Intermediate 47 A mixture of intermediate 46 (0.22 g, 0.4 mmol), PMBN(Boc)4 (0.544 g, 0.4 mmol), HATU (0.182 g, 0.48 mmol), and DIEA (0.172 mL, 0.8 mmol) in DMF (6 mL) was stirred at 40 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EA (100 mL). The organic layer was washed with HO (15 mL x 2), brine (15 mL), dried (NaSO), and evaporated in vacuo. The product was purified by C18 column chromatography (ACN / HO 0-100%) to give intermediate 47 (0.49 g). MS: 1896.5 [M+H] + .

[0315] Intermediate 48 A mixture of intermediate 47 (0.49 g, 0.28 mmol) and 10% Pd / C (0.1 g) in MeOH (10 mL) was stirred at room temperature under H2 for 4.5 h, filtered, evaporated, and dried to give intermediate 48 (0.385 g). MS: 1762.8 [M+H] + .

[0316] Intermediate 49 A mixture of intermediate 48 (0.35 g, 0.2 mmol), Axitinib Pnp (0.175 g, 0.35 mmol), and DMAP (0.049 g, 0.4 mmol) in NMP (5 mL) was stirred at 50 °C under Ar atmosphere for 5 h. The mixture was cooled to room temperature, extracted with EA (50 mL), and washed with HO (5 mL x 2) and brine (5 mL). The EA layer was dried (NaSO) and evaporated. The product was purified by C18 column chromatography (ACN / HO 0-90%) to give intermediate 49 (0.208 g).

[0317] Compound of Example 9 A solution of Intermediate 49 (0.27 g, 0.124 mmol) in a mixture of TFA (1 mL) and DCM (6 mL) was stirred at room temperature for approximately 1 hour. The volatiles were removed in vacuo, and the residue was purified by C18 column chromatography (ACN / HO 0-40%) to give Example 9 (125 mg) as a TFA salt. MS: 1618.9 [M+H] +. NMR:8.44 (d, J 8.2 Hz, 1H), 8.25 (d, J 8.0 Hz, 1H), 7.95 (s, 2H), 7.82 (t, J 6.7 Hz, 1H), 7.66 (s, 2H), 7.49 (s, 1H), 7.47 - 7.40 (m, 3H), 7.31 - 7.20 (m, 5H), 7.14 (d, J 7.6 Hz, 2H), 4.48 (t, J8.1 Hz, 1H), 4.36 (d, J 7.0 Hz, 2H), 4.23 - 4.16 (m, 3H), 4.14 - 4.00 (m, 7H), 3.87 (s, 2H), 3.75 (s, 3H), 3.37 (s, 1H), 3.20 (d, J 13.0 Hz, 1H), 3.00 (d, J 43.2 Hz, 12H), 2.72 (d, J 53.7 Hz, 4H), 2.62 (s, 4H), 2.24 (t, J 7.6 Hz, 2H), 2.13 (s, 7H), 2.02 - 1.65 (m, 10H), 1.08 - 1.04 (m, 3H), 0.97 (s, 3H), 0.73 (s, 1H), 0.67 (d, J 6.5 Hz, 3H), 0.60 (d, J 6.4 Hz, 3H).

[0318] Alternatively, the TFA salt of the compound of Example 9 can be converted to an HCl salt, H2SO4 salt, citrate salt, lactate salt, mandelate salt, or another pharmaceutically acceptable salt. Generally, this can be accomplished by standard ion exchange procedures using the HCl (or other acid) form of an anion exchange resin (see, for example, Elder, J. Chem. Education. 2005, vol. 82, p. 575). Alternatively, the TFA salt can be dissolved in an aqueous medium, an excess of HCl solution added, and then lyophilized under vacuum or the solution directly evaporated. The resulting solid product can optionally be recrystallized from an alcohol-containing medium, such as EtOH-EtOAc, isopropyl alcohol-water, or a similar solvent system.

[0319] Utility and Measurement The compounds of the present invention exhibit significant therapeutic efficacy against various kidney cancers, including RCCs and mRCCs, and therefore, these agents are useful for the targeted treatment of kidney-related cancers.

[0320] The novel compounds provided herein typically comprise anti-cancer bioactive molecules conjugated to carrier peptide fragments (e.g., polymyxin cyclic peptide derivatives), which are used as vectors for delivering such compounds to the kidney due to the unique ability of said peptide fragments to bind to kidney tissue.

[0321] First, some of the compounds provided herein, as complete molecular structures, exhibit intrinsic activity (or anti-cancer cytotoxicity) against cancer cells, such intrinsic activity being inherent to the molecule and not dependent on metabolic release of the anti-cancer drug bound within the structure (i.e., the peptide moiety is covalently attached to a peptide fragment used as a carrier for delivering the compound to the kidney because it has a propensity to bind to kidney tissue).

[0322] Second, some of the compounds provided herein exhibit moderate or no inherent anticancer cytotoxicity as intact molecules. After administration, these substances accumulate in the kidney and are metabolized in organs affected by renal cancer. This metabolism releases the anticancer drug (or cytotoxic agent) incorporated into the administered compound, resulting in an anticancer therapeutic effect at the cancer site (e.g., manifested as a reduction in cancer tumor size or cessation of tumor growth). Importantly, this metabolic degradation occurs selectively, releasing the active ingredient in the desired pharmaceutical form (without metabolic changes that may reduce the desired anticancer activity).

[0323] Third, some compounds provided herein combine the inherent anticancer activity of the intact molecule with the anticancer effect of metabolic release of an active anticancer drug (cytotoxic agent) conjugated within the administered molecule. This combined effect may be additive or synergistic in nature. This mode includes a dual mode of action that advantageously combines the intrinsic activity of the intact conjugate compound with the activity of the metabolically released drug (bioactivity) incorporated into such an administered conjugate.

[0324] Importantly, all of the above therapeutic modes manifest upon selective or targeted delivery of the compounds provided herein to the kidney, i.e., the compound administered to a mammal in need of treatment rapidly accumulates in the cancer-affected kidney.

[0325] The preferential accumulation of the compounds provided herein in the kidney (or near the site of kidney cancer) can be assessed by pharmacokinetic (PK) studies, such as standard rat PK studies. PK data typically include drug concentrations at a given time point (C), drug concentrations in target tissues (C), and the like. Target ) are used to establish important parameters for predicting treatment outcome, such as the area under the curve (AUC) and other parameters of graphs monitoring the time course of systemic drug concentrations. Therefore, drug concentrations in organs (or body compartments) affected by cancer are important for the effective action of anticancer drugs (see, for example, Zhang et al., Drug Metabolism and Disposition. 2019, vol. 47, p. 1122).

[0326] 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.

[0327] In PK studies, the level (concentration) of a therapeutic drug is determined by a defined time process in a critical body compartment, such as blood or a specific organ tissue. Because the active compound is intended to target the disease, the level of the active compound in the organ affected by the disease is particularly important. In the treatment of kidney cancer, the target organ is the kidney.

[0328] Anticancer efficacy (in vivo activity) is dependent on and directly tracks the required levels of the anticancer drug in the mammal in need of treatment (see, e.g., Fogli et al., Cancer Treatment Reviews. 2020, Vol. 84, 101966; Hu-Low et al., Clin. Cancer Research. 2008, Vol. 14, p. 7272; Zhang et al., Drug Metabolism and Disposition. 2019, Vol. 47, p. 1122). This concentration-treatment relationship is rooted in the mode of action of the anticancer drug, which is typically based on concentration-dependent inhibition of cancer cell proliferation (e.g., cancer cells manifesting as tumors).

[0329] Therefore, if the drug concentration is too low to achieve inhibition of cancer cells (or tumor growth), inhibition may be incomplete or absent. This usually results in ineffective treatment and usually increases with the risk of cancer progressing to drug resistance (see, for example, Komarova et al., PNAS. 2005, vol. 102, p. 9714). Conversely, if the drug concentration in the target organ is higher, enhanced anticancer effects are observed, minimizing the risk of cancer drug resistance.

[0330] For example, the efficacy of the kidney cancer drug axitinib can be reliably predicted from its blood concentration in the blood circulation surrounding the affected kidney (see Hu-Lowe et al., Clin. Cancer Research, 2008, vol. 14, p. 7272). Specifically, a total axitinib blood concentration of approximately 40 ng / mL has been reported as a strong marker (predictor) of therapeutic efficacy for kidney cancer. Therefore, drug concentrations below 40 ng / mL are expected to result in decreased therapeutic efficacy (see Hu-Lowe et al., Clin. Cancer Research, 2008, vol. 14, p. 7272). After axitinib administration, kidney drug concentrations typically do not exceed those in the blood (and are typically lower than those in the blood; see, for example, Table 2 below).

[0331] Thus, axitinib kidney concentrations of 40 ng / mL or approximately 39 ng / mL (per kidney tissue density of 1.03 g / mL) can generally predict effective inhibition of renal cancers required for successful treatment in mammals.

[0332] Exemplary mouse PK data for the compound of Example 1 are summarized in Table 1 below. As can be seen from the mouse PK model data, this compound exhibits effective kidney targeting capabilities by preferentially accumulating at high levels in the target organ, kidney tissue.

[0333] [Table 1]

[0334] Further PK data in rodents for the compounds of Examples 1, 2, and 7 of the present application and the reference compound of Example 9 are shown in Table 2 below, which demonstrates targeted delivery of the anti-cancer drug axitinib, which is preferentially released from these compounds to the kidney.

[0335] [Table 2]

[0336] As can be seen from the PK data in mice, the compounds of Examples 1, 2, and 7 and Reference Compound 9 administered at 3 mg / kg showed effective kidney targeting ability (>40 ng / g). In fact, the level of active drug in the kidney was much higher than that of axitinib administered at 30 mg / kg. This indicates that the compounds described in this application are at least as effective as the active agent axitinib in anti-cancer treatment.

[0337] Surprisingly, as can be seen from Table 2, high levels of axitinib released from the compound of Example 1 were detected in kidney tissue. For example, the axitinib detected from the compound of Example 1 at 3 hours was more than 6-fold higher than that of axitinib itself (1955.3 / 301.0 = 6.50), and approximately 15-fold higher at 6 hours. Furthermore, although axitinib was detected at much higher levels from the reference compound of Example 9 than that of axitinib itself, the amount was much lower compared to the compound of Example 1. Even more surprisingly, the levels of axitinib detected in the kidney for the compounds of Examples 2 and 7 were significantly higher than those for the compound of Example 1. These data suggest targeted delivery of the anticancer drug axitinib, preferably to the kidney, from the compounds described herein. Specifically, administration of the compounds provided herein allows for beneficially high levels of the therapeutic agent in the kidney compared to administration of axitinib in the standard free drug form.

[0338] Conversely, administration of axitinib itself results in high blood concentrations, which is a major cause of off-target side effects with axitinib and other drugs in the treatment of renal cancer (see, for example, Fogli et al., Cancer Treatment Reviews. 2020, vol. 84, 101966).

[0339] As previously mentioned, a therapeutic effect of axitinib is predicted by a plasma total drug concentration of at least 40 ng / mL (see Hu-Lowe et al., Clin. Cancer Research. 2008, vol. 14, p. 7272). According to the experimental data in Table 2, the compound of Example 1 efficiently and selectively delivers axitinib to the kidney, with the drug being released from the compound at levels significantly higher than 40 ng / mL. These data demonstrate the efficacy of compounds described herein, such as the compound of Example 1, in treating renal cancer.

[0340] As can be seen from the above data, the exemplary compounds provided herein selectively deliver renal cancer drugs to the kidney (site of disease), at levels significantly higher than those achieved by the use of axitinib itself. For example, 24 hours after administration, only trace amounts (below the BLQ, level of quantification) of axitinib were detected in the kidneys of rodents (Table 2). In contrast, administration of the compound of Example 1 delivered therapeutic levels of >40 ng / mL to the kidneys throughout representative PK time points, demonstrating surprisingly high drug levels of approximately 708 ng / mL at T=24 hours.

[0341] It is noteworthy and surprising that the administration of the compound of Example 1 at a modest dose of only 3 mg / kg resulted in axitinib kidney levels of 707.8 mg / mL at 24 hours. In contrast, the kidney levels of axitinib administered orally at a very high dose of 30 mg / kg (exceeding the standard therapeutic dose of approximately 0.17 mg / kg used in humans) were too low to be quantified (BLQ) after 24 hours of administration in the standard free (unconjugated) form. These data conclusively demonstrate that the efficacy of the compounds provided herein is significantly increased compared to standard axitinib treatment for renal cancer.

[0342] The significantly increased drug levels at the renal cancer site (obtained with exemplary compounds) compared to standard administration of axitinib demonstrates improved therapeutic efficacy (in vivo activity) of the compounds. Importantly, this allows for a reduction in the amount of axitinib administered in the form of compounds provided herein (e.g., the compound of Example 1).

[0343] Furthermore, these favorable and surprising PK data suggest that the compounds provided herein may be administered less frequently and / or at reduced dosages compared to axitinib. For example, the standard twice-daily administration of axitinib may be replaced by once-daily or once-weekly administration of the compounds provided herein, significantly improving convenience for patients undergoing cancer treatment.

[0344] Furthermore, the selective (or targeted) renal delivery of the compounds provided herein offers significant safety benefits. Standard treatments with cytotoxic cancer therapeutics typically involve significant side effects. For example, axitinib treatment has multiple side effects, as described in the warnings in the prescribing information for the drug (marketed as Inlyta). Hypertensive side effects, in particular, have been reported (see, for example, Fogli et al., Cancer Treatment Reviews. 2020, vol. 84, 101966), with an incidence of 40–64%, including hypertensive crisis. These side effects are primarily caused by high levels of axitinib circulating in the blood, which distributes to vital organs unaffected by renal cancer.

[0345] Indeed, the PK data in Table 1 show that blood drug levels after standard dosing of free axitinib in mice are similar to kidney drug levels. Thus, as observed with axitinib use in humans, this drug may exert deleterious cytotoxic effects, commonly referred to as "off-target activity," in healthy organs not targeted by such cancer therapy (see, e.g., Fogli et al., Cancer Treatment Reviews. 2020, Vol. 84, 101966).

[0346] In contrast, administration of the exemplary compounds provided herein significantly reduces the amount of active drug in the blood (released), advantageously delivering the drug to the kidney via selective (targeted) delivery. Therefore, treatment with the compounds of the present invention is expected to significantly reduce off-target activity (toxicity) compared to standard anti-cancer drugs (e.g., axitinib).

[0347] The in vitro activity of the compounds provided herein can be assessed using standard assay procedures in various cancer cell lines (along with normal cell controls), such as those described in ACS Pharmacol. Transl. Sci. 2019, vol. 2, p. 18 and J. Med. Chem. 2018, vol. 61, p. 5304, and the references cited therein.

[0348] It is important to distinguish between in vitro activity (potency) and in vivo activity (efficacy). In vitro measurements allow direct interaction of the test compound with cancer cells, typically by introducing the test compound to cancer cells suspended in a nutrient solution that allows cell growth.

[0349] In contrast to in vitro measurements, in vivo assessments require the administration of a compound, such as intravenous injection, to a mammal (e.g., rodent). The compound then circulates in the blood and distributes to organs and tissues. Such distribution can occur with different efficiency in different organs, resulting in drug accumulation in some organs while the same drug is present at low levels in others. Importantly, this process exposes the compound to many proteins and enzymes (e.g., esterases and peptidases) that can metabolize (break down) the compound during its in vivo measurement.

[0350] For example, some compounds provided herein are metabolized in vivo to release active drug molecules attached to the compound using metabolically degradable linkers. Thus, compounds that have no or only moderate in vivo activity (potency) when measured in vitro may exhibit high in vivo activity (potency) when measured in vivo.

[0351] The in vitro anticancer activity of certain compounds provided herein is surprising because they conjugate anticancer drug structures to novel chemical compositions that significantly alter the anticancer molecules conjugated to them compared to the unconjugated (highly optimized) original anticancer drug structures, such as axitinib.

[0352] The inherent anticancer activity of the novel axitinib peptide conjugates provided herein is particularly surprising given the highly restrictive structure-activity relationship (SAR) of their analogs. For example, Molecules. 2018, 23, 747 reported that multiple isosteric designs that closely mimic the structure of axitinib failed to reproduce the drug's activity, resulting in several-fold reduced inhibition of target cancer enzymes (e.g., VEGFR-2 kinase) compared to axitinib itself. Specifically, we found that substituting these groups with NMe to disrupt the NH hydrogen bond was detrimental to the inhibition of cancer enzymes such as VEGFR-2. Therefore, the in vitro anticancer activity of the present compounds, which indicates that they inhibit the intrinsic ability of cancer cells, was completely unexpected.

[0353] As previously mentioned, certain compounds described herein exhibit reduced in vitro cytotoxicity against cancer cells and beneficially reduced off-target activity against healthy organs (these off-target effects are responsible for most side effects of standard cancer treatments). While the cytotoxicity of the intact conjugate molecules is reduced in vitro, these compounds exert therapeutic anticancer effects in vivo after being metabolized in the cancer target organ, resulting in the release of the active drug (conjugated within the administered molecule). Thus, administration of these compounds (which may be inactive in vitro) to mammals in need of cancer treatment results in selective targeted delivery therapy with significant observed anticancer activity in vivo.

[0354] Surprisingly, although the compound of Example 1 contains a polymyxin structure, it exhibits minimal antibacterial activity (in vitro MIC measurements, minimum inhibitory concentration) against polymyxin antibiotics such as polymyxin B and colistin.

[0355] The in vivo activity of the compounds provided herein can be assessed by assay procedures such as those described in J. Vis. Exp. 2014, (86), e51485 Experimental & Molecular Medicine. 2018, vol. 50, p. 30 and the references cited therein.

[0356] Surprisingly, in rodent kidney cancer models, when administered intravenously (IV) at doses (expressed in molar amounts) equivalent to the standard therapeutic doses (molar amounts) of axitinib, blinib, pazopanib, sunitinib, and tivozanib, the efficacy is more than two-fold greater than the standard therapeutic doses of axitinib, blinib, pazopanib, sunitinib, and tivozanib, where the therapeutic effect is determined as a delay, halt, or reversal of cancer progression (as determined by changes in cancer tumor size and / or the use of biochemical biomarkers or similar methods for cancer monitoring, e.g., as described in J. Vis. Exp. 2014, (86), e51485; Experimental & 50, p. 30).

[0357] Exemplary therapeutic efficacy studies of the compounds described herein were conducted in an orthotopic mouse model. This model uses the luciferase-expressing A498 cancer cell line (A498-luc). Cancer cells were implanted into renal cysts, and tumor growth and efficacy were monitored by image size on an IVIS Lumina III (Perkin Elmer) and changes in mouse weight. Specifically, after fasting for 24 hours, mice were placed in a Zoleti TM The mice were anesthetized by SC injection of 50 (Virbac SA). The skin of the anesthetized mice was disinfected with iodine and then with alcohol. 6 Luciferase-expressing A498-luc cells were implanted into the left kidney using an insulin syringe. The skin incision was closed with autosuturing clips. Tumor growth was monitored by imaging analysis. Mice were randomly divided into four groups (10 mice per group) and treated with two doses of Example 1 (4 and 12 mg / kg) administered intraperitoneally (ip) once daily (QD), a control group of saline, and a control group of axitinib administered orally (PO) twice daily (BID). Mice were administered 15 mg / mL (5 mL / g body weight) of D-fluorescein (Pharmaron) and anesthetized with 1-2% isoflurane by inhalation. Images of the mice were taken 10 minutes after luciferin injection (once a week). In vivo imaging software (Perkin Elmer) was used to calculate regions of interest (ROIs) and integrate the total bioluminescence signal within each ROI. Bioluminescence signals (photos / s) from the ROIs are quantified and used as indicators of tumor growth and antitumor activity. Throughout the study process, the body weights of all mice are measured twice a week. Exemplary therapeutic efficacy results of the compound of Example 1 are summarized in Figures 1 and 2.

[0358] As shown in Figure 1, the compound of Example 1 achieved tumor growth inhibition (TGI) efficacy (82.5% and 52%) QD at doses of 12 and 4 mg / kg (2.0 and 0.67 mg / kg axitinib), whereas axitinib achieved 89.7% BID at a dose of 30 mg / kg / day. These data demonstrate that axitinib released from the compound of Example 1 can achieve a TGI of greater than 80% at approximately one-fifteenth the dose of axitinib. Importantly, the compound of Example 1 also requires less frequent administration (QD) than axitinib (BID).

[0359] The compound of Example 1 demonstrated high efficacy at 12 mg / kg / day (equivalent to 2.0 mg / kg free axitinib) when injected intraperitoneally, while also demonstrating superior safety and minimizing weight loss compared to free axitinib at 30 mg / kg / day, as shown in the data in Figure 2. Weight loss is an established marker of toxicity for many cancer drugs and is typically associated with other side effects. The data herein demonstrate that the compounds described herein effectively inhibit tumor growth while significantly improving the safety index (therapeutic index) in cancer treatment.

[0360] Surprisingly, despite their potent anticancer effects in mammals, the compounds of the present invention exhibit limited toxicity to noncancerous renal cells. This is demonstrated by the following assay. The cytotoxicity of the compound of Example 1 was evaluated in an in vitro assay using the HK-2 cell line, an immortalized proximal tubule cell line derived from a healthy human kidney. The assay is similar to that described, for example, by Keirstead et al. in Toxicol. Sci. 2014, vol. 137, pp. 278-291. The results are summarized in Table 3.

[0361] [Table 3]

[0362] As shown in Table 3, the activity of the compound of Example 1 (axitinib in conjugated form) was at least 2-3 times lower, indicating that it is safer than axitinib (free drug form).

[0363] The exemplary compound of Example 1 is also well tolerated in a 14-day repeat dose mouse tolerance study when administered to test animals at doses of at least 18 mg / kg / day.

[0364] Biomarker assays for predicting nephrotoxicity further establish improved safety profiles for the compounds described herein. For example, Keirstead et al., Toxicol. Sci. 2014, vol. 137, pp. 278-291, describe several such assays, including NGAL assays.

[0365] Surprisingly, certain compounds provided herein, when administered to a mammal at a dose (in molar amounts) equivalent to the standard therapeutic dose (in molar amounts) of axitinib, brivanib, pazopanib, or sunitinib, result in at least a two-fold reduction in the incidence (frequency or incidence) of undesirable reactions and / or off-target toxicity (e.g., myelosuppression or myelotoxicity) compared to the standard therapeutic dose of axitinib, brivanib, pazopanib, or sunitinib (e.g., as determined by platelet and / or other blood counts of myelosuppression or myelotoxicity).

[0366] Thus, some compounds provided herein exhibit high anti-cancer efficacy, but do not exhibit excessive off-target toxicity to organs not affected by renal cancer, and exhibit little or no nephrotoxicity to normal kidney cells.

[0367] Thus, the novel compounds and compositions provided herein may offer long-term, safer, and more effective targeted treatment of renal cancer, including metastatic renal cancer. Administered drugs and drug formulations

[0368] 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, or intranasally, or directly to cancer tumors via intratumoral administration. The actual amount of the compounds provided herein (i.e., active ingredients) 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.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] The present application also includes pharmaceutical compositions containing one or more of the above-described compounds as an active ingredient together with a pharmaceutically acceptable carrier. In preparing the compositions of the present application, the active ingredient is typically 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 acts 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.

[0373] 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.

[0374] 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.

[0375] 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., an 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.

[0376] 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.

[0377] 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.

[0378] 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.

[0379] Additionally, liposomal formulations of the compounds described herein can be used to enhance the therapeutic effect of certain infections, such as, for example, pneumonia or pulmonary infections.

[0380] 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.).

[0381] 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.

[0382] Other formulations suitable for use are described in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

[0383] 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 the side effects of polymyxin drugs.

[0384] 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.

[0385] 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.

[0386] 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. A compound selected from the following structures: or a pharmaceutically acceptable salt, solvate or hydrate thereof. 【Chemical 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】

2. have in vitro and / or in vivo anticancer activity against cancer cells as determined by inhibiting or slowing the growth of cancer cells using an in vitro cytotoxicity test or assay or by measuring the compound in an animal model of cancer; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the cancer is renal cancer or kidney cancer.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, characterized in that, when administered to a mammal, the compound exhibits preferential accumulation in the kidney, and the ratio of the molar concentration in the kidney to the molar concentration in the blood is about 10 to 500.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

5. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in treating cancer in a mammal in need thereof.

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