Iron supplement therapy

Abstract

The present application provides compounds and methods for iron supplement therapy.

Description

[0001] Claim priority

[0002] This application claims the benefit of U.S. patent application serial numbers 63 / 416,889, filed October 17, 2022, and 63 / 449,748, filed March 3, 2023. The entire contents of the foregoing applications are incorporated herein by reference.

[0003] Federally funded research or development

[0004] This invention was made with government support under Grant Nos. DK120663 and DK130004 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0005] The present disclosure relates to compounds and methods for iron replacement therapy. In particular, the present disclosure relates to iron coordination complexes that are capable of transporting iron directly to the iron carrier protein, transferrin, when administered to patients suffering from any form of anemia or iron deficiency. Background Art

[0006] Anemia is a common condition that affects approximately 40% of children and 30% of women of childbearing age worldwide and can have serious health consequences. Anemia is often multifactorial. For example, malnutrition, infection, chronic immune activation, kidney disease and genetic mutations may all cause or contribute to anemia, and chronic diseases are often the most common causes of anemia. The consequences of anemia may include immune system dysfunction, gastrointestinal disorders, impaired temperature regulation and neurocognitive function. In addition, untreated anemia may be a risk or prognostic factor for other diseases such as tuberculosis and heart failure. In the United States alone, the socioeconomic burden attributable to anemia varies depending on the type and severity of pre-existing comorbidities and is very large, exceeding $30,000 / year for each affected individual. Summary of the Invention

[0007] The present disclosure is based, at least in part, on the recognition that iron coordination compounds, such as those claimed herein, are capable of converting Fe 3+ Directly transported to the iron carrier protein transferrin. Thus, in one embodiment, administration of Fe 3+The coordination compound causes an increase in the percentage of transferrin saturation while also avoiding the release of toxic free iron ions (also referred to as "labile iron") that are not bound to transferrin or any other plasma protein in the patient's bloodstream, which is typically the result of direct iron supplementation (e.g., intravenous infusion of ferrous salts). Therefore, the compound is advantageously used in effective, efficient and safe "transferrin-directed" iron supplementation therapy. The compounds and methods in the present claims allow parenteral iron supplementation in patients with iron deficiency anemia (including anemia associated with inflammatory disease states where endogenous pathways of iron mobilization are severely inhibited, making iron supplementation therapy challenging). The supplementation advantageously results in alleviation and complete recovery of symptoms associated with anemia (e.g., fatigue, pale skin, shortness of breath, dizziness, vertigo, or rapid heartbeat) without any significant adverse events or any significant risks or iron poisoning.

[0008] In one general aspect, the present disclosure provides a compound which is Fe of formula (AI) 3+ Complexes:

[0009]

[0010] or a pharmaceutically acceptable salt thereof.

[0011] In another general aspect, the present disclosure provides a compound which is Fe of formula (BI) 3+ Complexes:

[0012]

[0013] or a pharmaceutically acceptable salt thereof.

[0014] In yet another general aspect, the present disclosure provides a compound which is Fe of formula (CI) 3+ Complexes:

[0015]

[0016] or a pharmaceutically acceptable salt thereof.

[0017] In yet another general aspect, the present disclosure provides a compound which is Fe of formula (DI) 3+ Complexes:

[0018]

[0019] or a pharmaceutically acceptable salt thereof.

[0020] In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising an iron coordination compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] In yet another general aspect, the present disclosure provides a method of treating iron deficiency anemia, comprising administering to a subject in need thereof a therapeutically effective amount of an iron coordination compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0022] In yet another general aspect, the present disclosure provides compounds of formula (A):

[0023]

[0024] or a salt thereof.

[0025] In yet another general aspect, the present disclosure provides compounds of formula (B):

[0026]

[0027] or a salt thereof.

[0028] In yet another general aspect, the present disclosure provides compounds of formula (C):

[0029]

[0030] or a salt thereof.

[0031] In yet another general aspect, the present disclosure provides compounds of formula (D):

[0032]

[0033] or a salt thereof.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials for use in this application are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification, including definitions, will control.

[0035] Other features and advantages of the application will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1A A synthetic scheme illustrating the preparation of compound BBG is shown (see Example 1).

[0037] Figure 1B A synthetic scheme illustrating the preparation of the compound Fe-BBG is shown (see Example 2).

[0038] Figure 2A HPLC traces of Fe-BBG detected at 220 nm (top) and 454 nm (bottom) are shown. The HPLC method used a Waters X-Bridge C18 column (3.5 μm; 4.6×150 mm) and the following method: The method used on these systems was as follows: (A1) Eluent A: 10 mM ammonium acetate in water, eluent B: 90:10 acetonitrile:MeCN: 10 mM ammonium acetate in water, gradient: 5% B 2 min, 5% B to 95% B over 10 min, 95% B 1 min, 95% B to 5% B 1 min, then 5% B 1 min; flow rate 0.7 mL / min.

[0039] Figure 2B The UV-visible spectrum of Fe-BBG is shown. A photograph of a 0.1 mM Fe-BBG solution is shown in the inset.

[0040] Figure 3A- Figure 3F Shown are solutions of 0.1 mM Fe-BBG incubated with between 0 and 100 molar equivalents of bicarbonate (panel A), acetate (panel B), lactate (panel C), phosphate (panel E), and 0 to 10 molar equivalents of citrate (panel F). The data indicate that BBG binds Fe with a significantly higher affinity than endogenous chelators generally thought to be associated with labile Fe and non-transferrin-bound iron. 3+ .

[0041] Figure 4A Shown are the fluorescence spectra of 20 μM apo-transferrin after 2 h incubation with 0, 0.5, 1 or 2 molar equivalents of Fe-BBG (conditions: 50 mM HEPES buffer supplemented with 25 mM bicarbonate, pH 7.4, 37° C.).

[0042] Figure 4B Urea gel electrophoresis separation of apotransferrin, monoferric transferrin, and diferric (holo) transferrin from a mixture containing 10 μM apotransferrin incubated with 0, 1, 2, 5, and 10 equivalents of Fe-BBG is shown, and it is demonstrated that 2 molar equivalents of Fe are present in a stoichiometric amount of Fe. 3+ Transport to apotransferrin. Incubation with FPC was a positive control, and the stable compound Fe-PyC3A was a negative control (conditions: 50 mM HEPES buffer supplemented with 25 mM bicarbonate, pH 7.4, 37°C).

[0043] Figure 5 The fluorescence emission intensity at 330 nm was recorded for Fe 3+Time course of transchelation reaction (λ ex = 280 nm, instrument time resolution = 6 s), and showed Fe 3+ Transport was completed within 6 s of mixing (conditions: 50 mM HEPES buffer supplemented with 25 mM bicarbonate, pH 7.4, room temperature).

[0044] Figure 6 Shown are UV-visible spectra of 0.1 mM Fe-BBG incubated without or with 1 molar equivalent of ascorbate, pH 7.4 (pH 7.4, 50 mM HEPES buffer).

[0045] Figure 7 Shown is a comparison of thiobarbituric acid-reactive species generated by incubation of Fe-BBG and other iron complexes (ferric citrate pyrophosphate, Fe-NTA, Fe-EDTA) under the following conditions: 5 mM Fe 3+ Complex, 2.8 mM H2O2, 2.8 mM deoxyribose, 0.1 mM ascorbic acid, 100 mM pH 7.4 phosphate buffer, 37°C. The data indicate that Fe-BBG does not participate in redox cycling and does not generate Fenton radicals. The assay was performed as described in Methods in Enzymology 1994, 233, 57-66.

[0046] Figure 8A- Figure 8C Shown are coronal T1-weighted magnetic resonance images obtained after 0.14 mmol / kg Fe-BBG was injected into mice. Panel A shows liver enhancement and gallbladder enhancement (yellow arrows), which is consistent with partial hepatobiliary excretion. Panel B shows early and rapidly diminishing kidney enhancement, which is consistent with rapid elimination through the kidneys. Panel C depicts the time course of signal intensity recorded in the vena cava, and a blood elimination half-life of 5.5 ± 2.8 min was estimated from a single exponential fit to the data.

[0047] Figure 9A- Figure 9D Serum Fe parameters recorded ex vivo from serum collected from mice 5, 60, and 100 min after injection of 0.56 μg Fe / g animal or 5.6 μg Fe / g animal with Fe-BBG are shown. The data demonstrate that Fe-BBG injection rapidly increases serum Fe (panel A) and total iron binding capacity (panel B) compared to placebo-treated mice, does not significantly reduce UIBC (most likely due to the presence of BBG ligand) (panel C), and significantly increases % TSAT (panel D).

[0048] Figure 10Quantification of labile iron in serum collected from mice 5, 60, and 100 min after injection of Fe-BBG at 0.56 μg Fe / g animal or 5.6 μg Fe / g animal is shown. These are the same serum samples as in FIG9 . The assay was performed as described in Blood 2003, 102(7), 2670-2677. The data indicate that Fe-BBG does not generate detectable amounts of labile Fe even 5 min after injection of the 5.6 μg Fe / g animal dose when total serum Fe is significantly greater than TBIC.

[0049] Figure 11A Shown is a solution of 20 μM holo-transferrin and a solution of BBG at a concentration between 0 and 100 μM (0-5 molar equivalents) at 37° C. in 50 mM HEPES buffer supplemented with 25 mM carbonate at pH 7.4 for 24 h, and the removal of Fe from transferrin was monitored using fluorescence spectroscopy (excitation wavelength: 280 nm). No evidence of Fe removal from transferrin was observed.

[0050] Figure 11B Shown is a 10 μM holotransferrin incubated with 100 μM BBG (10 molar equivalents) for 24 h at 37° C. in 50 mM HEPES buffer, pH 7.4, supplemented with 25 mM carbonate, and Fe removal monitored by urea gel electrophoresis assay. No evidence of Fe removal from transferrin was observed.

[0051] Figure 12 Cyclic voltammograms of 50 mM HEPES buffer solution at pH 7.4 in the absence of 10 mM Fe-BBG (upper trace) and in the presence of 10 mM Fe-BBG (lower trace) are shown. Glassy carbon working electrode, Pt counter electrode, electrolyte: 0.5 M KNO3, scan rate = 300 mV / s, RT.

[0052] Figure 13A Shown are the absence and presence of 1 molar equivalent of Fe 3+ 、Cu 2+ or Zn 2+ The BBG and its corresponding Fe were determined by pH potentiometric titration of BBG(L) 3+ 、Cu 2+ and Zn 2+ Thermodynamics of aqueous solutions of complexes.

[0053] Figure 13B All thermodynamic parameters are tabulated. Fe-BBG(logK FeL pH7.4 ) at pH 7.4, the stability constant is 19.51, while for Cu-BBG and Zn-BBG, logK CuL pH 7.4 Value and logK ZnL pH 7.4 The values ​​are 10.49 and 4.49 respectively. 2+ The stability is 9 orders of magnitude greater than that of Fe 3+ Combined, and with a ratio of Zn 2+ 15 orders of magnitude greater stability than Fe 3+ combination.

[0054] Figure 14 Shown are human plasma samples containing between 0-5 mM BBG incubated for 1 h at 37°C before ultrafiltration through a 10 kDa molecular weight cutoff filter to separate low molecular weight solution components. The concentrations of Cu and Zn, as well as Mn, Mg, and Ca, of the plasma concentrate and ultrafiltrate were determined by ICP-MS.

[0055] Figure 15 Includes a table showing the results of bone marrow and liver tissue analysis by qPCR for gene expression related to erythropoietic activity, Fe exposure, oxidative stress, and inflammation. Fe-BBG did not induce upregulation of hepatic heme oxygenase 1 (Hmox1), glutamate-cysteine ​​ligase catalytic subunit (Gclc), or NAD(P)H quinone dehydrogenase 1 (Nqo1), suggesting that Fe-BBG does not cause oxidative stress. Expression of serum amyloid A1 (Saa1), a sensitive marker of inflammation, was also unchanged after repeated administration of Fe-BBG.

[0056] Figure 16 It was shown that repeated administration of Fe-BBG to Tmprss6 knockout mice did not cause significant differences in any clinical chemistry parameters, including serum markers routinely used in drug toxicity screening.

[0057] Figure 17 A synthetic scheme illustrating the preparation of compound SBBG is shown (see Example 17).

[0058] Figure 18The HPLC trace of SBBG detected at 280 nm is shown (top). The MS chromatogram of the detected m / z-=366 (corresponding to the SBBG anion) is shown in the bottom. The HPLC method used a Waters X-Bridge C18 column (3.5 μm; 4.6×150 mm) and the following method: eluent A: 10 mM ammonium acetate in water, eluent B: 90:10 acetonitrile:MeCN: 10 mM ammonium acetate in water, gradient: 5% B 2 min, 5% B to 95% B over 10 min, 95% B 1 min, 95% B to 5% B 1 min, then 5% B 1 min; flow rate 0.7 mL / min.

[0059] Figure 19 A synthetic scheme illustrating the preparation of the compound Fe-SBBG is shown (see Example 18).

[0060] Figure 20 HPLC traces of Fe-SBBG detected at 254 nm (top) and 465 nm (center) are shown. Detected m / z - =455 (corresponding to [Fe(SBBG)(H2O)2] - ions) is shown in the lower portion. The HPLC method used a Phenomenex Luna C18 column (3.5 μm; 4.6×100 mm) and the following method: Eluent A: 0.1% formic acid in water, Eluent B: 90:10 acetonitrile:0.1% formic acid in water, Gradient: 5% B to 40% B over 4 min, 40% B to 95% B over 1 min, 95% B to 5% B for 1 min, then 5% B for 2 min; flow rate 1.0 mL / min (see Example 18).

[0061] Figure 21 A synthetic scheme illustrating the preparation of compound BBG-COOH is shown (see Example 19).

[0062] Figure 22 HPLC trace of BBG-COOH detected at 80 nm is shown (top). Detected m / z -= 330 (corresponding to the anionic form of BBG-COOH) is shown in the lower part. The HPLC method used a Waters X-Bridge C18 column (3.5 μm; 4.6×150 mm) and the following method: eluent A: 10 mM ammonium acetate in water, eluent B: 90:10 acetonitrile:MeCN: 10 mM ammonium acetate in water, gradient: 5% B 2 min, 5% B to 95% B over 10 min, 95% B 1 min, 95% B to 5% B 1 min, then 5% B 1 min; flow rate 0.7 mL / min (see Example 19).

[0063] Figure 23 A synthetic scheme illustrating the preparation of the compound Fe-BBG-COOH is shown (see Example 20).

[0064] Figure 24 HPLC traces of Fe-BBG-COOH detected at 254 nm (top) and 465 nm (center) are shown. Detected m / z - =419 (corresponding to the anion [Fe(BBG-COOH)(H2O)2] - ) is shown in the lower portion. The HPLC method used a Phenomenex Luna C18 column (3.5 μm; 4.6×100 mm) and the following method: Eluent A: 0.1% formic acid in water, Eluent B: 90:10 acetonitrile:0.1% formic acid in water, Gradient: 5% B to 40% B over 4 min, 40% B to 95% B over 1 min, 95% B to 5% B for 1 min, then 5% B for 2 min; flow rate 1.0 mL / min (see Example 20). DETAILED DESCRIPTION

[0065] Several forms of anemia, including anemia of inflammation (AI) and iron-refractory iron deficiency anemia (IRIDA), are caused in part by pathological iron (Fe) restriction. In these conditions, chronic immune activation or genetic mutations upregulate the Fe regulatory hormone hepcidin, which in turn inhibits the activity of ferroportin, the only known Fe exporter. Therefore, an excess of hepcidin causes severe hypoferremia because the Fe released by hemoglobin recycling in macrophages, the nutritional iron absorbed by intestinal epithelial cells, and other stored Fe cannot be exported to the plasma iron carrier protein, transferrin, for distribution.

[0066] Fe supplementation in patients with hepcidin overdose can be challenging. Most intravenous Fe supplementation drugs are Fe-carbohydrate nanoparticles that accumulate and metabolize in macrophages and require ferroportin for Fe mobilization. Therefore, intravenous iron supplementation may have limited efficacy in correcting anemia and may also cause iron overload in macrophages. Hepcidin-driven restrictions also limit the efficacy of nutritional Fe supplements because Fe export from enterocytes is also ferroportin-mediated. In the case of hepcidin inhibition, administered Fe reaches toxic levels in enterocytes, and anemia remains largely untreated.

[0067] There are no commercially available hepcidin-modulating drugs.

[0068] Another approach is to deliver Fe to transferrin via a mechanism that does not rely on ferroportin. A method of directly delivering Fe to transferrin is to infuse unstable iron salts via intravenous administration, but it must be noted that the serum total iron binding capacity cannot be exceeded, otherwise exposure to toxic unstable iron may occur. Typically, unstable iron preparations are infused into the patient over a period of several hours, thereby delivering a therapeutic amount of iron without exceeding the serum total iron binding capacity.

[0069] The present disclosure advantageously provides compounds that are iron complexes useful as iron supplemental drugs. These iron complexes are designed to allow iron in a trivalent oxidation state (Fe 3+ ) is stable, Fe is delivered directly and stoichiometrically to transferrin and is stable to the transchelation of the part that forms (specification) with the in vivo material that participates in unstable iron and non-transferrin binding iron. The experimental data in this disclosure provide the credible evidence that these complexes can be safely and effectively applied to dialysis patients or non-dialysis patients via quick and simple IV injection. What is important here is that the iron complexes in this claim can be safely applied with a very high initial dose so that the concentration of the iron complexes in the serum far exceeds the serum transferrin concentration. Without being bound by any particular theory or speculation, it is believed that the iron complexes in this claim selectively transport iron to the protein transferrin when entering the bloodstream, but retain the chelated iron ions to significantly avoid "unstable iron" in the bloodstream, keeping the free iron ion concentration far below the threshold value required for toxicity. If the iron complexes are given so that the serum concentration is high enough, the complexes should continue to supplement transferrin-iron within the time of several transferrin-Fe half-lives. Some embodiments of iron complexes and the parts that form these complexes are described herein. Described herein are pharmaceutical formulations comprising iron complexes and methods of using the iron complexes to treat, for example, iron deficiency anemia.

[0070] Compounds of formula (A)

[0071] In some embodiments, the present application provides compounds of formula (A), which can be used as chelates of iron ions (e.g., Fe 3+ ) to form an iron complex as described herein. In some embodiments, the compound of formula (A) has the following formula:

[0072]

[0073] or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:

[0074] L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0075] Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0076] R 1 Selected from OH, CO2R A 、P(O)(OR A )(OR B ), and (C=O)NRA R 10 ;

[0077] Each q is independently 0 or 1;

[0078] Each R A and R B are independently H or C 1-3 alkyl;

[0079] X 2 selected from N and C;

[0080] X 3 Selected from N and CR 3 ;

[0081] X 4 Selected from N and CR 4 ;

[0082] X 5 Selected from N and CR 5 ;

[0083] X 6 Selected from N and CR 6 ;

[0084] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0085] X 2a selected from N and C;

[0086] X 3a Selected from N and CR 3a ;

[0087] X 4a Selected from N and CR 4a ;

[0088] X 5a Selected from N and CR 5a ;

[0089] X 6a Selected from N and CR 6a ;

[0090] The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N;

[0091] R 3 、R 3a 、R4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ;

[0092] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0093] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0094] In some embodiments, if L 1 R 1 is CH2C(=O)OR A or CH(CH3)C(=O)OR A ,but:

[0095] X 2 With X 2a Different; or X 3 With X 3a Different; or X 4 With X 4a Different; or X 5 With X 5a Different; or X 6 With X 6a Different; or X 2N; or X 2a is N. In some of the foregoing embodiments, L 1 R 1 is CH2CH2C(=O)OR A .

[0096] In some embodiments, X 2 With X 2a In some embodiments, X 3 With X 3a In some embodiments, X 4 With X 4a In some embodiments, X 5 With X 5a In some embodiments, X 6 With X 6a different.

[0097] In some embodiments, the compound of Formula (A) is not any of the following compounds:

[0098]

[0099] In some embodiments, X 2 is N. In some embodiments, X 2 is C. In some embodiments, X 3 is N. In some embodiments, X 3 CR 3 In some embodiments, X 4 is N. In some embodiments, X 4 CR 4 In some embodiments, X 5 is N. In some embodiments, X 5 CR 5 In some embodiments, X 6 is N. In some embodiments, X 6 CR 6 .

[0100] In some embodiments, X 2a is N. In some embodiments, X 2a is C. In some embodiments, X 3a is N. In some embodiments, X 3a CR 3a In some embodiments, X 4a is N. In some embodiments, X 4a CR 4a In some embodiments, X 5ais N. In some embodiments, X 5a CR 5a In some embodiments, X 6a is N. In some embodiments, X 6a CR 6a .

[0101] In some embodiments, the compound of formula (A) has the formula:

[0102]

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula (A) has the formula:

[0105]

[0106] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound of formula (A) has the formula:

[0108]

[0109] or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 It is propylene.

[0111] In some embodiments, the compound has the formula:

[0112]

[0113] or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound has the formula:

[0115]

[0116] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound has the formula:

[0118]

[0119] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, R 1 Selected from CO2R A 、P(O)(OR A )(OR B ), and (C=O)NR A R 10 In some embodiments, R 1 In some embodiments, R 1 P(O)(OR A )(OR B ). In some embodiments, R 1 is P(O)(OH)2. In some embodiments, R 1 CO2R A In some embodiments, R 1 is C(O)OH. In some embodiments, R 1 (C=O)NR A R 10 In some embodiments, R 1 (C=O)NR A R 10 .

[0121] In some embodiments, R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 In some embodiments, R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl)q OH, and -(C 1-3 alkyl) q CN. In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, and -(C 1-3 alkyl) q CN. In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of them is R 10 .

[0122] In some embodiments, R 3a 、R 4a 、R 5a and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 In some embodiments, R 3a 、R 4a 、R 5a and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, and -(C 1-3 alkyl) q CN. In some embodiments, R 3a 、R 4a 、R 5a and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, and -(C 1-3 alkyl) q CN. In some embodiments, R 3a 、R 4a 、R 5a and R 6a At least one of them is R 10 .

[0123] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the following are independently selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the 1-3 Alkyl-OPO(OR A )(OR B ),-C 1-3 Alkyl-CO2R A 、-C 1-3 Alkyl-SO3R A , and -C 1-3 Alkyl-(C=O)NR A R B In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R5a 、R 6 and R 6a At least one, at least two or at least three of the 1-3 Alkyl-OPO(OH)(OH), -C 1-3 Alkyl-C(O)(OH), -C 1-3 Alkyl-SO2(OR A ), and -C 1-3 Alkyl-(C=O)NH2.

[0124] In some embodiments, R 5 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy, halogen; and R 5a Selected from -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

[0125] In some embodiments, R 3 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy, halogen; and R 3a Selected from -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

[0126] In some embodiments, R 4 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy, halogen; and R 4a Selected from -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

[0127] In some embodiments, R 6 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C1-3 haloalkoxy, halogen; and R 6a Selected from -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

[0128] In some embodiments, R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 .

[0129] In some embodiments, R 10 For-(C 1-3 alkyl) q CO2R A In some embodiments, R 10 For-(C 1-3 alkyl) q CO2H. In some embodiments, R 10 For-(C 1-3 alkyl) q OP(R 8 )O2R B In some embodiments, R 10 For-(C 1-3 alkyl) q (C=O)NHSO2R 8 In some embodiments, R 10 For-(C 1-3 alkyl) q PO3R A R 8 .

[0130] In some embodiments, R 10 For-(C 1-3 alkyl) q 3R A In some embodiments, R 10 For-(C 1-3 alkyl) q SO2R8 In some embodiments, R 10 For-(C 1-3 alkyl) q NHSO2R 8 In some embodiments, R 10 For-(C 1-3 alkyl) q NR A R B In some embodiments, R 10 For-(C 1-3 alkyl) q (C=O)NR A R B In some embodiments, R 10 For-(C 1-3 alkyl) q OPO3R A R B .

[0131] In some embodiments, q is 0. In some embodiments, q is 1.

[0132] In some embodiments, R 8 C 3-9 In some embodiments, R 8 For-(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 In some embodiments, R 11 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 In some embodiments, R 11 C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0133] In some embodiments, R 8 Selected from:

[0134]

[0135] In some embodiments, the compound of formula (A) is selected from any one of the following compounds:

[0136]

[0137]

[0138] or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound of formula (A) is selected from any one of the following compounds:

[0140]

[0141]

[0142] or a pharmaceutically acceptable salt thereof.

[0143] Compounds of formula (I)

[0144] In some embodiments, compounds of formula (A) as described herein encompass compounds of formula (I). Thus, in some embodiments, the present disclosure provides compounds of formula (I):

[0145]

[0146] or a pharmaceutically acceptable salt thereof. In some embodiments, Formula (I) includes L as described for any formula herein (including but not limited to Formula A and Formula I). 1 , L 2 , L 3 、X 1 、X 2 、X 3 ,n,R 3 、R 4 and R 5 Any combination of .

[0147] In some embodiments:

[0148] L 1 C 1-3 alkylene;

[0149] L 2 C 1-3 alkylene;

[0150] X 1 Selected from N and CR 1 ;

[0151] R 1 Selected from OH, SH, NH2, C 1-3 Alkylamino and di(C 1-3alkyl)amino;

[0152] n is 0, 1, 2, 3 or 4;

[0153] Each R 3 independently selected from OH, NO2, CN, halogen, S(=O)2OH, S(=O)2NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carboxyl, and C 1-3 Alkoxycarbonyl;

[0154] X 2 Selected from N and CR 2 ;

[0155] R 2 Selected from OH, SH, NH2, C 1-3 Alkylamino and di(C 1-3 alkyl)amino;

[0156] m is 0, 1, 2, 3 or 4;

[0157] Each R 4 independently selected from OH, NO2, CN, halogen, S(=O)2OH, S(=O)2NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carboxyl, and C 1-3 Alkoxycarbonyl;

[0158] X 3 Selected from OH, SH, NH2, C 1-3 Alkylamino and di(C 1-3 alkyl)amino;

[0159] L 3 C 1-6 an alkylene group; and

[0160] R 5 Selected from C(=O)OH, S(=O)2OH, and P(=O)(OH)2.

[0161] In some embodiments, the compound of Formula (I) is not any of the following compounds:

[0162]

[0163] In some embodiments, L 1 C 1-3 In some embodiments, L 1 is selected from methylene, ethylene and propylene. 1 is CH2. In some embodiments, L 1 is CH2CH2. In some embodiments, L 1 is CH(CH3).

[0164] In some embodiments, L 2 C 1-3 In some embodiments, L 2 is selected from methylene, ethylene and propylene. 2 is CH2. In some embodiments, L 2 is CH2CH2. In some embodiments, L 2 is CH(CH3).

[0165] In some embodiments, L 3 C 1-6 In some embodiments, L 3 is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, 2-methyl-1-butylene, n-pentylene, 3-pentylene, n-hexylene, and 1,2,2-trimethylpropylene. In some embodiments, L 3 is CH2CH2.

[0166] In some embodiments:

[0167] L 1 is a methylene group;

[0168] L 2 is a methylene group; and

[0169] L 3 Absent or selected from methylene, ethylene and propylene.

[0170] In some embodiments:

[0171] L 1 is a methylene group;

[0172] L 2 is a methylene group; and

[0173] L 3 Selected from propylene and butylene.

[0174] In some embodiments, each alkylene group herein is optionally replaced by 1, 2, 3, 4, or 5 independently selected R a In some embodiments, each R a Independently selected from OH, NO2, CN, halogen, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3 Alkylsulfonyl, carbamoyl, C 1-3 Alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxyl, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonylamino, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino, and di(C 1-3 In some embodiments, each alkylene group herein is optionally replaced by 1, 2, or 3 independently selected R a In some embodiments, each alkylene group herein is optionally substituted with 1 or 2 independently selected R a replace.

[0175] In some embodiments, R 5 is C(=O)OH. In some embodiments, R 5 is S(=O)2OH. In some embodiments, R 5 It is P(=O)(OH)2.

[0176] In some embodiments, X 1 is N. In some embodiments, X 1 CR 1 .

[0177] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is NH2.

[0178] In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0179] In some embodiments, each R 3 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3 Alkylsulfonyl, carbamoyl, C 1-3 Alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxyl, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonylamino, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino.

[0180] In some embodiments, each R 3 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carboxyl, and C 1-3 Alkoxycarbonyl.

[0181] In some embodiments, each R 3 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, and carboxyl.

[0182] In some embodiments, X 2 is N. In some embodiments, X 1 CR 2 .

[0183] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is NH2.

[0184] In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0185] In some embodiments, each R 4 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3Alkylsulfonyl, carbamoyl, C 1-3 Alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxyl, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonylamino, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino.

[0186] In some embodiments, each R 4 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carboxyl, and C 1-3 Alkoxycarbonyl.

[0187] In some embodiments, each R 4 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, and carboxyl.

[0188] In some embodiments, n is 0 and m is 0.

[0189] In some embodiments, n is 1 or 2 and m is 1 or 2.

[0190] In some embodiments:

[0191] n is 1 or 2;

[0192] m is 1 or 2;

[0193] Each R 3Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, and carboxyl; and

[0194] Each R 4 Independently selected from OH, NO2, CN, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, and carboxyl.

[0195] In some embodiments, X 3 In some embodiments, X 3 In some embodiments, X 3 In some embodiments, X 3 In some embodiments, X 3 is NH2. In some embodiments, X 3 C 1-3 In some embodiments, X 3 For two (C 1-3 alkyl)amino.

[0196] In some embodiments, the compound of formula (I) has the formula:

[0197]

[0198] or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the compound of formula (I) has the formula:

[0200]

[0201] or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the compound of formula (I) has the formula:

[0203]

[0204] or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the compound of formula (I) has the formula:

[0206]

[0207] or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound of formula (I) has the formula:

[0209]

[0210] or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the compound of formula (I) has the formula:

[0212]

[0213] or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the compound of formula (I) has the formula:

[0215]

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the compound of formula (I) has the formula:

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the compound of formula (I) has the formula:

[0221]

[0222] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the compound of formula (I) has the formula:

[0224]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound of formula (I) has the formula:

[0227]

[0228] or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound of formula (I) has the formula:

[0230]

[0231] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound of formula (I) has the formula:

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the compound of formula (I) has the formula:

[0236]

[0237] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound of formula (I) is any one of the following compounds:

[0239]

[0240] or a pharmaceutically acceptable salt thereof.

[0241] Compounds of formula (B)

[0242] In some embodiments, the present disclosure provides compounds of Formula (B):

[0243]

[0244] or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:

[0245] L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0246] L 2 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0247] Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0248] R 1 Selected from CO2R A 、P(O)(OR A )(OR B ), and (C=O)NR A R 10 ;

[0249] Each q is independently 0 or 1;

[0250] Each R A and R B are independently H or C 1-3 alkyl;

[0251] X 2 selected from N and C;

[0252] X 3 Selected from N and CR 3 ;

[0253] X 4 Selected from N and CR 4 ;

[0254] X 5 Selected from N and CR 5 ;

[0255] X 6 Selected from N and CR 6 ;

[0256] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0257] R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ;

[0258] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0259] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0260] In some embodiments, if R 1 is P(O)(OH)(OH), then R 5 Not C 1-3 In some embodiments, R 5 Not C 1-3 In some embodiments, R 5 Not halogen.

[0261] In some embodiments, the compound of Formula (B) is not any of the following compounds:

[0262]

[0263] In some embodiments, X 2 、X 3 、X 4 、X 5 、X 6 、L 1 and R 1 As described herein for Formula (A). In some embodiments, L 2 As described herein for L in formula (A) 1 In some embodiments, L 2 -C 1-3 In some embodiments, L 2 To be R 10 Substituted -C 1-3 In some embodiments, L 2 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 In some embodiments, L 1 For ethylene.

[0264] In some embodiments, the compound has the formula:

[0265]

[0266] or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the compound has the formula:

[0268]

[0269] or a pharmaceutically acceptable salt thereof,

[0270] where R 5 Selected from C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN,-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl)q SO2R 8 、 -(C 1-3 alkyl) q NHSO2R 8 、 -(C 1-3 alkyl) q CO2R A 、 -(C 1-3 alkyl) q NR A R B 、 -(C 1-3 alkyl) q (C=O)NR A R B 、 -(C 1-3 alkyl) q OP(R 8 )O2R B 、 -(C 1-3 alkyl) q OPO3R A R B 、 -(C 1-3 alkyl) q PO3R A R 8 、 and -(C 1-3 alkyl) q (C=O)NHSO2R<00008​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​q CO2R A In some embodiments, R 10 For-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, q is 0. In some embodiments, q is 1.

[0276] In some embodiments, the compound is selected from any one of the following compounds:

[0277] or a salt thereof.

[0278] In some embodiments, the compound of formula (B) is selected from any one of the following compounds:

[0279]

[0280]

[0281] or a salt thereof.

[0282] Compounds of formula (C)

[0283] In some embodiments, the present disclosure provides compounds of Formula (C):

[0284]

[0285] or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:

[0286] L 1 -C 1-3 Alkylene-, or L 1 does not exist;

[0287] R 1 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0288] Each R A and RB are independently H or C 1-3 alkyl;

[0289] X 2 selected from N and C;

[0290] X 3 Selected from N and CR 3 ;

[0291] X 4 Selected from N and CR 4 ;

[0292] X 5 Selected from N and CR 5 ;

[0293] X 6 Selected from N and CR 6 ;

[0294] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0295] X 2a selected from N and C;

[0296] X 3a Selected from N and CR 3a ;

[0297] X 4a Selected from N and CR 4a ;

[0298] X 5a Selected from N and CR 5a ;

[0299] X 6a Selected from N and CR 6a ;

[0300] The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N;

[0301] R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0302] Each q is independently 0 or 1;

[0303] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0304] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0305] In some embodiments, X 2 、X 3 、X 4 、X 5 、X 6 、X 2a 、X 3a 、X 4a 、X 5a 、X 6a 、L 1 and R 1 As described herein for Formula (A) or Formula (B).

[0306] In some embodiments, L 1 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 In some embodiments, L 1 -C substituted by CH2OH, C(O)OH, SO3H or OP(O)(OH)2 1-3 In some embodiments, L 1 To be C 1-3 Alkyl-OPO(OH)(OH), -C 1-3 Alkyl-C(O)(OH), -C 1-3 Alkyl-SO2(OH) or -C 1-3 Alkyl-(C=O)NH2 substituted-C 1-3 Alkylene-.

[0307] In some embodiments, L 1 Selected from methylene, ethylene and propylene.

[0308] In some embodiments, the compound has the formula:

[0309]

[0310] or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound has the formula:

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound has the formula:

[0315]

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound has the formula:

[0318]

[0319] or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the compound has the formula:

[0321]

[0322] or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound has the formula:

[0324]

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound has the formula:

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3alkyl) q CN,-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

[0330] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3alkyl) q PO3R A R 8 .

[0331] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 alkyl, CH2OH, C(O)OH, SO3H, and CH2OP(O)(OH)2. In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the 1-3 Alkyl-OPO(OR A )(OR B ),-C 1-3 Alkyl-CO2R A 、-C 1-3 Alkyl-SO3R A , and -C 1-3 Alkyl-(C=O)NR A R B In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the 1-3 Alkyl-OPO(OH)(OH), -C 1-3 Alkyl-C(O)(OH), -C 1-3 Alkyl-SO2(OR A ), and -C 1-3 Alkyl-(C=O)NH2.

[0332] In some embodiments, q is 0. In some embodiments, q is 1.

[0333] In some embodiments, the compound of formula (C) is selected from any one of the following compounds:

[0334]

[0335] or a salt thereof.

[0336] Compounds of formula (D)

[0337] In some embodiments, the present disclosure provides compounds of Formula (D):

[0338]

[0339] or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein:

[0340] L 1 -C 1-3 Alkylene-, or L 1 does not exist;

[0341] L 2 -C 1-3 Alkylene-;

[0342] R 1 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0343] R 2 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0344] The condition is R 1 and R 2 At least one of them is P(O)(OR A )(OR 8 );

[0345] Each R A and R B are independently H or C 1-3 alkyl;

[0346] X 2 selected from N and C;

[0347] X 3 Selected from N and CR 3 ;

[0348] X 4 Selected from N and CR 4 ;

[0349] X 5 Selected from N and CR 5 ;

[0350] X 6 Selected from N and CR 6 ;

[0351] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0352] R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2RA 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0353] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0354] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0355] In some embodiments, the compound of formula (D) is not:

[0356]

[0357] In some embodiments, X in formula (D) 2 、X 3 、X 4 、X 5 、X6 、L 1 、L 2 、R 1 and R 2 As described herein for Formula (A), Formula (B), or Formula (C). In some embodiments, L 1 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 is selected from methylene, ethylene and propylene. 2 -C 1-3 In some embodiments, L 2 Selected from methylene, ethylene and propylene.

[0358] In some embodiments, the compound has the formula:

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound has the formula:

[0362]

[0363] or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound has the formula:

[0365]

[0366] or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound has the formula:

[0368]

[0369] or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the compound has the formula:

[0371]

[0372] or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the compound has the formula:

[0374]

[0375] or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

[0377] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6aAt least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 .

[0378] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H, and CH2OP(O)(OH)2.

[0379] In some embodiments, q is 0. In some embodiments, q is 1.

[0380] In some embodiments, the compound is selected from any one of the following compounds:

[0381]

[0382] or a salt thereof.

[0383] In some embodiments, the compound of formula (D) is:

[0384]

[0385] or a salt thereof.

[0386] Iron complexes

[0387] In some embodiments, the present application provides Fc 3+ ions and a complex of a compound of any formula described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present application provides Fe 2+ions and a complex of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present application provides a method of treating a compound that does not contain (or substantially does not contain) Fe 2+ Ionic complexes.

[0388] In some embodiments, the compound is present in an amount greater than Fe 3+ Low affinity for transferrin with Fe 3+ Binding (log K at pH 7.4 for the first and second binding sites) cond 20.7 and 19.4, respectively). In some embodiments, Fe 3+ The affinity of the compounds for transferrin is about 1.05 times, about 10 times, about 100 times, about 1000 times, or about 10,000 times greater than the binding affinity of the compounds of the present claims for iron. In some embodiments, the compounds include thermodynamically stable Fe(III) complexes that also bind to Fe with about 10 times, about 100 times, about 1000 times, or about 10,000 times greater affinity than other Fe chelators found in vivo (e.g., citrate, acetate, lactate, phosphate, or carbonate). 3+ Without being bound by any theory, it is believed that the thermodynamic stability of the complex minimizes the concentration of unchelated and dissociated "labile" Fe in the bloodstream upon administration. In some embodiments, the complexes of the present claims are kinetically unstable. Without being bound by any theory or speculation, it is believed that the kinetic instability of the complex enables the Fe to be 3+ In some embodiments, when combined with other metal ions normally present in the bloodstream (e.g., Zn 2+ When compared with other divalent metal ions, the compound selectively binds Fe 3+ For example, the compound is effective for binding Fe 3+ Without being bound by any theory, it is believed that the compounds of the present disclosure are selective for, for example, Zn 2+In some embodiments, the compound described herein is a divalent ion having a low affinity for iron and a divalent ion. The low affinity of divalent ions such as iron complexes allows maintaining serum metal ion concentrations when the compound (iron complex) is applied to anemic patients and avoids redistributing endogenous divalent plasma metals. In some embodiments, the Fe (III) resistance in the complex is reduced to Fe (II) and accidental redox cycles. In some embodiments, the complex does not penetrate the cell membrane and is substantially retained in the extracellular fluid (such as blood and lymph) in which transferrin is present. In some embodiments, the compound described herein is partially eliminated and excreted by the hepatobiliary pathway. For example, at least 10 wt.%, at least 20 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 75 wt.% or at least 90 wt.% of the compound is excreted by the hepatobiliary pathway. Without being bound by any particular theory or speculation, it is believed that hepatobiliary elimination ensures the effective elimination of the compound in patients with end-stage renal disease.

[0389] Other ligands

[0390] In some embodiments, in addition to the ligand compound of formula (A) or formula (I), the coordination compound further comprises at least one other iron ligand. In some embodiments, each other iron ligand is independently selected from HO, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof. In some embodiments, each other iron ligand is a group L as described below.

[0391] In some embodiments, each L is independently selected from H2O and NH3. In some embodiments, each L is H2O. In some embodiments, L is an inorganic anion such as Cl, Br, SO4, HCO3, CO3, PO4, nitrate or nitrite, etc. In some embodiments, each L is an acid or base commonly present in plasma. Examples of such L include organic acids such as citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid or acetic acid. In some embodiments, L is a sugar such as glucose, fructose, mannose or galactose. In some embodiments, any two L can be linked together to form a single iron ligand. In some embodiments, L is an acid or base, or an anion or cation thereof, as described herein in the "Pharmaceutically Acceptable Salts" section.

[0392] Iron complex having a ligand of formula (A)

[0393] In some embodiments, the present disclosure provides Fc 3+ ions and a compound of formula (A) as described herein, which has the following formula:

[0394]

[0395] or a pharmaceutically acceptable salt thereof, wherein:

[0396] --- indicates coordination bond;

[0397] Each L is independently Fe 3+ ligand;

[0398] p is 0, 1, or 2; and

[0399] X 2 、X 3 、X 4 、X 5 、X 6 、X 2a 、X 3a 、X 4a 、X 5a 、X 6a 、L 1 and R 1 As described herein for Formula (A). In some embodiments, the iron complexes can be used in any pharmaceutical formulation and dosage form for treating a disease described herein, such as iron deficiency anemia.

[0400] In some embodiments:

[0401] L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0402] Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2RB 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0403] R 1 Selected from C(O)O, P(O)(O)(OR B ), and (C=O)NR 10 ;

[0404] Each q is independently 0 or 1;

[0405] Each R A and R B are independently H or C 1-3 alkyl;

[0406] X 2 selected from N and C;

[0407] X 3 Selected from N and CR 3 ;

[0408] X 4 Selected from N and CR 4 ;

[0409] X 5 Selected from N and CR 5 ;

[0410] X 6 Selected from N and CR 6 ;

[0411] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0412] X 2a selected from N and C;

[0413] X 3a Selected from N and CR 3a ;

[0414] X 4a Selected from N and CR 4a ;

[0415] X5a Selected from N and CR 5a ;

[0416] X 6a Selected from N and CR 6a ;

[0417] The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N;

[0418] R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ;

[0419] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0420] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN,

[0421] The condition is that if L 1 -R 1is CH2C(O)O or CH2CH2C(O)O, then R 5 and R 5a Not all are S(O)2OH, methyl, halogen or tert-butyl.

[0422] In some embodiments, the compound has the formula:

[0423]

[0424] or a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the compound has the formula:

[0426]

[0427] or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the compound has the formula:

[0429]

[0430] or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 In some embodiments, L 1 Selected from methylene, ethylene and propylene.

[0432] In some embodiments, the compound has the formula:

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments, the compound has the formula:

[0436]

[0437] or a pharmaceutically acceptable salt thereof.

[0438] In some embodiments, the compound has the formula:

[0439]

[0440] or a pharmaceutically acceptable salt thereof.

[0441] In some embodiments, the compound has the formula:

[0442]

[0443] or a pharmaceutically acceptable salt thereof.

[0444] In some embodiments, the compound has the formula:

[0445]

[0446] or a pharmaceutically acceptable salt thereof.

[0447] In some embodiments, the compound has the formula:

[0448]

[0449] or a pharmaceutically acceptable salt thereof, wherein:

[0450] L 1 selected from methylene and ethylene,

[0451] R 5a is H; and

[0452] R 5 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

[0453] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 In some embodiments, R 3 、R 3a、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of them is R 10 .

[0454] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the following are independently selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one, at least two or at least three of the 1-3 Alkyl-OPO(OR A )(OR B ),-C 1-3 Alkyl-CO2R A 、-C 1-3 Alkyl-SO3R A , and -C 1-3 Alkyl-(C=O)NR A R B In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6aAt least one, at least two or at least three of the 1-3 Alkyl-OPO(OH)(OH), -C 1-3 Alkyl-C(O)(OH), -C 1-3 Alkyl-SO2(OH), and -C 1-3 Alkyl-(C=O)NH2.

[0455] In some embodiments, R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 10 For-(C 1-3 alkyl) q CO2R A In some embodiments, q is 0. In some embodiments, q is 1.

[0456] In some embodiments, each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

[0457] In some embodiments, the compound has the formula:

[0458]

[0459] or a pharmaceutically acceptable salt thereof.

[0460] Iron complex having a ligand of formula (I)

[0461] In some embodiments, the present application provides Fc 3+ ions with a compound of formula (I) as described herein. In some embodiments, the complex has a formula selected from any one of the following:

[0462]

[0463]

[0464] or a pharmaceutically acceptable salt thereof, wherein:

[0465] Each --- represents a coordination bond;

[0466] each L is independently an iron ligand; and

[0467] p is 0, 1 or 2.

[0468] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0469] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0470]

[0471] or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0476]

[0477] or a pharmaceutically acceptable salt thereof.

[0478] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0479]

[0480] or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0482]

[0483] or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0485]

[0486] or a pharmaceutically acceptable salt thereof.

[0487] In some embodiments, the present application provides Fc 3+ A complex of an ion and a compound of formula (I) having the following formula:

[0488]

[0489] or a pharmaceutically acceptable salt thereof.

[0490] Iron complex having a ligand of formula (B)

[0491] In some embodiments, the present application provides Fc 3+ ions with a compound of formula (B) as described herein. In some embodiments, the complex has the formula:

[0492]

[0493] or a pharmaceutically acceptable salt thereof, wherein:

[0494] --- indicates coordination bond;

[0495] Each L is independently Fe 3+ ligand;

[0496] p is 0, 1, or 2; and

[0497] X 2 、X 3 、X 4 、X 5 、X 6 , L 1 , L 2 、R 1 and R B As described herein for formula (B).

[0498] In some embodiments:

[0499] L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0500] L 2 -C 1-3 Alkylene-, optionally replaced by R 10 replace;

[0501] Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0502] R 1 Selected from CO2R A 、P(O)(OR A )(OR B ), and (C=O)NR A R 10 ;

[0503] Each R A and R B are independently H or C 1-3 alkyl;

[0504] X 2 selected from N and C;

[0505] X 3 Selected from N and CR 3 ;

[0506] X 4 Selected from N and CR 4 ;

[0507] X 5 Selected from N and CR 5 ;

[0508] X 6 Selected from N and CR 6 ;

[0509] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0510] R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ;

[0511] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0512] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0513] In some embodiments, L 2 -C 1-3 In some embodiments, L 2 To be R10 Substituted -C 1-3 In some embodiments, L 2 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 Alkylene-.

[0514] In some embodiments, L 1 In some embodiments, R 1 (C=O)NR A R 10 .

[0515] In some embodiments, the compound has the formula:

[0516]

[0517] or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, the compound has the formula:

[0519]

[0520] or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the compound has the formula:

[0522]

[0523] or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the compound has the formula:

[0525]

[0526] or a pharmaceutically acceptable salt thereof.

[0527] In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C1-3 alkyl) q CN and R 10 In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of them is R 10 .

[0528] In some embodiments, R 3 、R 4 、R 5 and R 6 At least one, at least two or at least three of the following are independently selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 3 、R 4 、R 5 and R 6 At least one, at least two or at least three of the 1-3 Alkyl-OPO(OR A )(OR B ),-C 1-3 Alkyl-CO2R A 、-C 1-3 Alkyl-SO3R A , and -C 1-3 Alkyl-(C=O)NR A R B In some embodiments, R 3 、R 4 、R 5 and R 6 At least one, at least two or at least three of the 1-3 Alkyl-OPO(OH)(OH), -C 1-3 Alkyl-C(O)(OH), -C 1-3 Alkyl-SO2(OH), and -C 1-3 Alkyl-(C=O)NH2.

[0529] In some embodiments, R10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 10 For-(C 1-3 alkyl) q CO2R A .

[0530] In some embodiments, q is 0. In some embodiments, q is 1.

[0531] In some embodiments, each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

[0532] Iron complex having a ligand of formula (C)

[0533] In some embodiments, the present application provides Fc 3+ ions with a compound of formula (C) as described herein. In some embodiments, the complex has the formula:

[0534]

[0535] or a pharmaceutically acceptable salt thereof, wherein:

[0536] --- indicates coordination bond;

[0537] Each L is independently Fe 3+ ligand;

[0538] p is 0, 1, or 2; and

[0539] X 2 、X 3 、X 4 、X 5 、X 6 , L 1 、R 1 、X 2a 、X 3a、X 4a 、X 5a and X 6a As described herein for formula (C).

[0540] In some embodiments:

[0541] L 1 -C 1-3 Alkylene-, or L 1 does not exist;

[0542] R 1 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0543] Each R A and R B are independently H or C 1-3 alkyl;

[0544] X 2 selected from N and C;

[0545] X 3 Selected from N and CR 3 ;

[0546] X 4 Selected from N and CR 4 ;

[0547] X 5 Selected from N and CR 5 ;

[0548] X 6 Selected from N and CR 6 ;

[0549] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0550] X2a selected from N and C;

[0551] X 3a Selected from N and CR 3a ;

[0552] X 4a Selected from N and CR 4a ;

[0553] X 5a Selected from N and CR 5a ;

[0554] X 6a Selected from N and CR 6a ;

[0555] The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N;

[0556] R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0557] Each q is independently 0 or 1;

[0558] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0559] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0560] In some embodiments, L 1 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 To be R 10 Substituted -C 1-3 In some embodiments, L 1 Selected from methylene, ethylene and propylene.

[0561] In some embodiments, the compound has the formula:

[0562]

[0563] or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound has the formula:

[0565]

[0566] or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the compound has the formula:

[0568]

[0569] or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound has the formula:

[0571]

[0572] or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound has the formula:

[0574]

[0575] or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the compound has the formula:

[0577]

[0578] or a pharmaceutically acceptable salt thereof.

[0579] In some embodiments, the compound has the formula:

[0580]

[0581] or a pharmaceutically acceptable salt thereof.

[0582] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

[0583] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3RA R B , and-(C 1-3 alkyl) q PO3R A R 8 .

[0584] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H, and CH2OP(O)(OH)2.

[0585] In some embodiments, q is 0. In some embodiments, q is 1.

[0586] In some embodiments, each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

[0587] Iron complex having a ligand of formula (D)

[0588] In some embodiments, the present application provides Fc 3+ ions with a compound of formula (D) as described herein. In some embodiments, the complex has the formula:

[0589]

[0590] or a pharmaceutically acceptable salt thereof, wherein:

[0591] --- indicates coordination bond;

[0592] Each L is independently Fe 3+ ligand;

[0593] p is 0, 1, or 2; and

[0594] X 2 、X 3 、X 4 、X 5 、X 6 , L 1 、R 1 , L 2 and R 2 As described herein for Formula (D).

[0595] In some embodiments:

[0596] L 1 -C 1-3 Alkylene-, or L 1 does not exist;

[0597] L 2 -C 1-3 Alkylene-;

[0598] R 1 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0599] R 2 Selected from CO2R A 、P(O)(OR A )(OR 8 ), (C=O)NR A R 10 、SO3R A 、SO2R 8 NHSO2R 8 、

[0600] NR A R B OP(R 8 )O2R B 、OPO3R A R B , and (C=O)NHSO2R 8 ;

[0601] Each R A and R B are independently H or C 1-3 alkyl;

[0602] X 2 selected from N and C;

[0603] X 3 Selected from N and CR3 ;

[0604] X 4 Selected from N and CR 4 ;

[0605] X 5 Selected from N and CR 5 ;

[0606] X 6 Selected from N and CR 6 ;

[0607] The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0608] R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A RB 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ;

[0609] Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and

[0610] Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

[0611] In some embodiments, the compound is not any of the following:

[0612]

[0613]

[0614] In some embodiments, L 1 In some embodiments, L 1 -C 1-3 In some embodiments, L 1 is selected from methylene, ethylene and propylene. 2 -C 1-3 In some embodiments, L 2 Selected from methylene, ethylene and propylene.

[0615] In some embodiments, the compound has the formula:

[0616]

[0617] or a pharmaceutically acceptable salt thereof.

[0618] In some embodiments, the compound has the formula:

[0619]

[0620] or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the compound has the formula:

[0622]

[0623] or a pharmaceutically acceptable salt thereof.

[0624] In some embodiments, the compound has the formula:

[0625]

[0626] or a pharmaceutically acceptable salt thereof.

[0627] In some embodiments, the compound has the formula:

[0628]

[0629] or a pharmaceutically acceptable salt thereof.

[0630] In some embodiments, the compound has the formula:

[0631]

[0632] or a pharmaceutically acceptable salt thereof.

[0633] In some embodiments, the compound has the formula:

[0634]

[0635] or a pharmaceutically acceptable salt thereof.

[0636] In some embodiments, the compound has the formula:

[0637]

[0638] or a pharmaceutically acceptable salt thereof.

[0639] In some embodiments, the compound has the formula:

[0640]

[0641] or a pharmaceutically acceptable salt thereof.

[0642] In some embodiments, R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN,-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

[0643] In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 In some embodiments, R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H, and CH2OP(O)(OH)2.

[0644] In some embodiments, q is 0. In some embodiments, q is 1.

[0645] In some embodiments, each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

[0646] In some embodiments, the compound is selected from any one of the following compounds:

[0647]

[0648] or a pharmaceutically acceptable salt thereof.

[0649] Pharmaceutically acceptable salts

[0650] In some embodiments, a salt of a compound of the present disclosure (e.g., Formula A, Formula (I), Formula B, Formula C, or Formula D, or an iron complex thereof) is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0651] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of the compounds include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, , butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0652] In some embodiments, bases commonly used to form pharmaceutically acceptable salts of compounds include: hydroxides of alkali metals including sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, di- or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine and lysine, among others.

[0653] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are substantially isolated.

[0654] How to use

[0655] In some embodiments, the present disclosure provides a method of treating iron deficiency anemia, comprising administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound of formula (I) as described herein. 3+ In some embodiments, the method comprises treating iron deficiency anemia, vitamin deficiency anemia, anemia of chronic disease, aplastic anemia, anemia associated with bone marrow disease, hemolytic anemia, sickle cell anemia, or thalassemia.

[0656] Some embodiments provide methods of increasing erythropoiesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0657] Some embodiments provide methods of increasing hematocrit in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0658] Some embodiments provide methods of increasing blood iron levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the subject can be determined or identified as needing treatment by, for example, an attending physician (e.g., based on a diagnosis of anemia). Anemia can be diagnosed based on laboratory tests and the clinical manifestations of one or more symptoms associated with anemia. In one example, anemia can be diagnosed based on a hematocrit (red blood cell count) of less than 38% for male subjects and a hematocrit (red blood cell count) of less than 35% for female subjects. In another example, anemia can be diagnosed based on a hemoglobin level of less than 11 g / dL for female subjects and a hemoglobin level of less than 12 g / dL for male subjects. Symptoms commonly associated with anemia include fatigue, weakness, pale skin, irregular heartbeat, shortness of breath, dizziness, lightheadedness, chest pain, headache, or any combination thereof. In yet another example, anemia can be diagnosed based on a mutation in a gene (e.g., a gene encoding hepcidin, iron transporter, or a related biomolecule) associated with anemia. In some embodiments, the method for treating any of the aforementioned conditions includes the step of identifying a subject in need of treatment. In some embodiments, the method comprises identifying a subject diagnosed as having anemia. In some embodiments, the method comprises diagnosing a subject as having anemia.

[0660] In some embodiments, administration of the iron complexing compounds of the present disclosure results in a reduction in symptoms associated with anemia and results in hematocrit and hemoglobin within normal levels.

[0661] Compositions, formulations and routes of administration

[0662] The present application also provides a pharmaceutical composition comprising an effective amount of a compound of the present disclosure disclosed herein (e.g., an iron complex of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also contain any of the other therapeutic agents described herein. In certain embodiments, the present application also provides pharmaceutical compositions and dosage forms comprising any of the other therapeutic agents described herein. The carrier is "acceptable" in the sense that it is compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, the amount used in the drug is harmless to its recipient.

[0663] Pharmaceutically acceptable carriers, adjuvants and solvents that can be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0664] The composition or dosage form may contain any of the compounds and therapeutic agents described herein in the range of 0.005% to 100%, with the remainder being made up of suitable pharmaceutically acceptable excipients. The contemplated composition may contain 0.001%-100% of any of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95% of any of the compounds and therapeutic agents provided herein, in another embodiment 75-85% of any of the compounds and therapeutic agents provided herein, in a further embodiment 20-80% of any of the compounds and therapeutic agents provided herein, wherein the remainder may be made up of any pharmaceutically acceptable excipient described herein or any combination of these excipients.

[0665] Route of administration and dosage form

[0666] The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumor, intrauterine, intravascular, intravenous, nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0667] The compositions and preparations described herein can be conveniently present in unit dosage forms such as tablets, sustained-release capsules, and liposomes, and can be prepared by any method known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th edition, 2000). Such preparation methods include the step of combining the molecule to be administered with components such as carriers constituting one or more auxiliary components. Typically, the active ingredient is uniformly and tightly combined with a liquid carrier, liposomes, or a finely divided solid carrier, or both, and then the product is shaped as needed to prepare the composition.

[0668] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is orally administered. The compositions of the present application suitable for oral administration can exist in, for example, independent units as follows: capsules, sachets, granules or tablets each containing a predetermined amount (e.g., an effective amount) of an active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water liquid emulsions; water-in-oil liquid emulsions; encapsulated in liposomes; or as pills (bolus) etc. Soft gelatin capsules can be used to hold such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, silicic acid and starch. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and gum arabic, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clays, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredient in a flavored matrix (usually sucrose and gum arabic or tragacanth), and pastilles comprising the active ingredient in an inert matrix (e.g., gelatin and glycerin, or sucrose and gum arabic).

[0669] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injections or infusions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The formulations may be present in unit-dose or multi-dose containers such as sealed ampoules and vials and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier such as water for injection, saline (e.g., 0.9% saline solution), or 5% dextrose solution immediately before use. Extemporaneous injections and suspensions can be prepared from sterile powders, granules, and tablets. The injection may be in the form of, for example, a sterile injectable aqueous or oily suspension. The suspension may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. The acceptable solvent and solvent that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oil is usually used as solvent or suspension medium. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof can be used to prepare injections, and natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms can also be used to prepare injections. These oil solutions or suspensions can also include long-chain alcohol diluents or dispersants.

[0670] The pharmaceutical compositions of the present application can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present application with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0671] The pharmaceutical composition of the present application can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical preparations and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbon compounds and / or other solubilizing agents or dispersants known in the art. See, for example, U.S. Patent No. 6,803,031. Other preparations and methods for intranasal administration are described in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0672] The topical compositions of the present disclosure can be prepared and used in the following forms: aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap or other forms commonly used in the field of topical administration and / or cosmetics and skin care formulations. The topical composition can be in the form of an emulsion. When the desired treatment relates to an area or organ that is easy to reach by topical application, the topical administration of the pharmaceutical composition of the present application is especially useful. In some embodiments, topical compositions comprise any one of the compounds disclosed herein and a therapeutic agent in combination with one or more additional ingredients, carriers, excipients, or diluents, including but not limited to absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, moisturizers (humectants), emulsifiers, film formers / setting agents, fragrances, leave-on exfoliants, prescription medications, preservatives, scrub agents, silicones, skin-identical / healing agents, slip agents, sunscreen actives, surfactants / detergents, penetration enhancers, and thickeners.

[0673] The compounds and therapeutic agents of the present application can be introduced into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Patent Nos. 6,099,562, 5,886,026 and 5,304,121. Coatings are typically biocompatible polymer materials, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene-vinyl acetate, and mixtures thereof. Coatings can optionally be further covered with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release properties to the composition. Coatings for invasive devices are included in the definition of pharmaceutically acceptable carriers, adjuvants or solvents (such as those terms used herein).

[0674] According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or therapeutic agent, or a composition containing a compound or therapeutic agent of the present application, such that the compound or therapeutic agent is released from the device and is therapeutically active.

[0675] Dosage and regimen

[0676] In the pharmaceutical compositions of the present application, the compounds of the present disclosure (e.g., iron complexes of compounds of formula (I)) are present in an effective amount (e.g., a therapeutically effective amount). The effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the possibility of combining with other therapeutic therapies (e.g., the use of other agents), and the discretion of the attending physician.

[0677] In some embodiments, an effective amount of a compound (e.g., an iron complex of formula (I)) can be, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; g; about 0.01 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 2 mg / kg; about 0.1 mg / kg to about 1 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, the effective amount of a compound, such as an iron complex of formula (I), is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0678] In some embodiments, the effective amount of the compound (e.g., the iron complex of Formula (I)) can be, for example, in the range of about 1 μg Fe / kg to about 500 μg Fe / kg, about 2 μg Fe / kg to about 300 μg Fe, about 5 μg Fe / kg to about 250 μg Fe / kg / kg, about 1 μg Fe / kg to about 50 μg Fe / kg, about 5 μg Fe / kg to about 100 μg Fe / kg / kg, about 5 μg Fe / kg to about 50 μg Fe / kg / kg, about 1 μg Fe / kg to about 25 μg Fe / kg / kg, or about 1 μg Fe / kg to about 10 μg Fe / kg / kg.

[0679] The above doses can be administered daily (e.g., as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0680] Reagent test kit

[0681] The present invention also includes pharmaceutical kits that can be used for the treatment of, for example, the disorders, diseases, and conditions mentioned herein, comprising one or more containers comprising a pharmaceutical composition containing a therapeutically effective amount of a compound of the present disclosure. Such kits may further include one or more various conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, other containers, and the like, as needed. The kit may also include instructions as an insert or as a label indicating the amount of the component to be administered, administration instructions, and / or mixing instructions for the components. The kit may optionally include other therapeutic agents as described herein. In some embodiments, the present disclosure provides a kit comprising: (i) a container comprising a compound of formula (I) or a salt thereof; (ii) a container comprising an iron salt (e.g., a water-soluble Fe 3+ The insert may further comprise instructions and / or directions for administering the mixed components to a patient with anemia.

[0682] combination

[0683] Compound of the present disclosure can be used in combination with at least one medicine or therapy that can be used for example to treat or alleviate the symptom of iron deficiency anemia. Suitable examples of such medicines include recombinant erythropoietin, vitamin B12, iron sucrose, nandrolone, ferrous fumarate, epoetin and its derivatives, triamcinolone, folic acid, folinic acid, procrin and ferralet etc. Iron complex of the present disclosure can also be used for treating or alleviating the medicine of various comorbidities and be co-administered. Suitable examples of such medicines include anti-inflammatory agents (for example, diclofenac, ibuprofen, indomethacin, ketoprofen, celecoxib, cortisone and prednisone etc.). Compound of the present disclosure and other therapeutic agents can be applied to patient simultaneously (with same pharmaceutical composition or dosage form or with different compositions or dosage forms) or applied to patient successively (can be before or after applying compound of the present disclosure with independent pharmaceutical composition or dosage form and apply other therapeutic agents).

[0684] definition

[0685] As used herein, the term "about" means "approximately" (eg, ± approximately 10% of a specified value).

[0686] At various places in this specification, substituents of compounds of the invention are disclosed in groups or in ranges. The invention is specifically intended to include every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to disclose individually methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0687] It is further understood that certain features of the present invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination.

[0688] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected and can be substituted at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) can replace two hydrogen atoms. It should be understood that substitution on a given atom is limited by valence.

[0689] Throughout this definition, the term “C n-m " represents a range including endpoints, where n and m are integers and represent the number of carbons. Examples include C 1-4 and C 1-6 wait.

[0690] As used herein, the term “C n-m "Alkyl" refers to a saturated hydrocarbon radical having n to m carbons which may be linear or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl; and the like. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. In some embodiments, "alkylene" refers to a divalent alkyl group.

[0691] As used herein, the term “C n-m"Haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s + 1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0692] As used herein, the term “C n-m "Alkylene" refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1,-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methyl-propane-1,3-diyl, etc. In some embodiments, the alkylene portion contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0693] As used herein, the term “C n-m "Alkoxy" refers to a radical of the formula -O-alkyl, where the alkyl radical has n to m carbon atoms. Example alkoxy radicals include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0694] As used herein, “C n-m "Haloalkoxy" refers to a radical of the formula -O-haloalkyl having n to m carbon atoms. An exemplary haloalkoxy radical is OCF3. In some embodiments, the haloalkoxy radical is only fluorinated. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0695] As used herein, the term "amino" refers to a group of formula -NH2.

[0696] As used herein, the term “C n-m "Alkylamino" refers to a radical of the formula -NH(alkyl), wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino radicals include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), and N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

[0697] As used herein, the term "di(C n-m-alkyl)amino" refers to a radical of the formula -N(alkyl)2, wherein each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0698] As used herein, the term “C n-m "Alkoxycarbonyl" refers to a radical of the formula -C(O)O-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

[0699] As used herein, the term “C n-m "Alkylcarbonyl" refers to a radical of the formula -C(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl radicals include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), and butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.

[0700] As used herein, the term “C n-m "Alkylcarbonylamino" refers to a radical of the formula -NHC(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0701] As used herein, the term “C n-m "Alkylsulfonylamino" refers to a radical of the formula -NHS(O)2-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0702] As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2.

[0703] As used herein, the term “C n-m "Alkylaminosulfonyl" refers to a radical of the formula -S(O)2NH(alkyl) where the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0704] As used herein, the term "di(C n-m"(alkyl)aminosulfonyl" refers to a radical of the formula -S(O)2N(alkyl)2 wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0705] As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

[0706] As used herein, the term “C n-m "Alkylaminosulfonylamino" refers to a radical of the formula -NHS(O)2NH(alkyl) where the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0707] As used herein, the term "di(C n-m "(alkyl)aminosulfonylamino" refers to a radical of the formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0708] As used herein, the term "aminocarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0709] As used herein, the term “C n-m "Alkylaminocarbonylamino" refers to a radical of the formula -NHC(O)NH(alkyl) where the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0710] As used herein, the term "di(C n-m "(alkyl)aminocarbonylamino" refers to a radical of the formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0711] As used herein, the term "carbamoyl" refers to a group of formula -C(O)NH2.

[0712] As used herein, the term “C n-m "Alkylcarbamoyl" refers to a radical of the formula -C(O)-NH(alkyl) where the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0713] As used herein, the term "di(C n-m-alkyl)carbamoyl" refers to a radical of the formula -C(O)N(alkyl)2, wherein each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0714] As used herein, the term "thio" refers to a group of formula -SH.

[0715] As used herein, the term “C n-m "Alkylthio" refers to a radical of the formula -S-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0716] As used herein, the term “C n-m "Alkylsulfinyl" refers to a radical of the formula -S(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0717] As used herein, the term “C n-m "Alkylsulfonyl" refers to a radical of the formula -S(O)2-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0718] As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written C(O).

[0719] As used herein, the term "carboxy" refers to a -C(O)OH group.

[0720] As used herein, the term "cyano-C 1-3 "Alkyl" refers to a group of the formula -(C 1-3 alkylene)-CN group.

[0721] As used herein, the term "HO-C 1-3 "Alkyl" refers to a group of the formula -(C 1-3 alkylene)-OH group.

[0722] As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, the halogen is F, Cl, or Br.

[0723] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise indicated, a compound identified herein by name or structure as a particular tautomeric form is intended to include the other tautomeric forms.

[0724] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated into optically active forms or racemic forms. It is known in the art how to prepare optically active forms from optically inactive raw materials, such as by splitting of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and N=N double bonds, etc., may also be present in the compounds described herein, and the present invention encompasses all such stable isomers. Cis and trans geometric isomers of the compounds of the present invention are described and can be separated into mixtures of isomers or individual isomeric forms. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration.

[0725] Compounds provided herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, for example, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into a form by appropriate substitution.

[0726] As used herein, the term "cell" refers to a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a portion of a tissue sample removed from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism, such as a mammal.

[0727] As used herein, the terms "individual," "patient," or "subject," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0728] As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0729] As used herein, the terms "treating" or "treatment" refer to 1) inhibiting a disease; e.g., inhibiting a disease, condition or disorder (i.e., arresting further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition or disorder, or 2) ameliorating a disease; e.g., ameliorating a disease, condition or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition or disorder.

[0730] As used herein, the term "preventing" a disease, condition, or disorder or "prevention" of a disease, condition, or disorder refers to reducing the risk of developing a disease, condition, or disorder in a subject or subject population (e.g., a subject or subject population susceptible to or susceptible to a disease, condition, or disorder). In some embodiments, preventing a disease, condition, or disorder refers to reducing the likelihood of developing a disease, condition, or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition, or disorder refers to completely or almost completely preventing the disease, condition, or disorder from occurring.

[0731] Example

[0732] The following examples are for illustrative purposes only and are not limiting.

[0733] Example 1 - N,N-bis(2-hydroxybenzyl)-L-glutamic acid (BBG)

[0734]

[0735] The reaction scheme is Figure 1A4 equivalents). The mixture was stirred for 1 h at room temperature for 1 h. L-Glutamic acid (0.5 g, 3.4 mmol, 1 equivalent) and NaHCO (2.3 g, 27.2 mmol, 8 equivalents) were mixed in 40 mL of MeOH. Under vigorous stirring, salicylaldehyde (1.7 g, 1.4 mL, 13.6 mmol, 4 equivalents) was slowly added to the resulting suspension. The bright yellow reaction mixture was then treated with sodium cyanoborohydride (1.1 g, 17 mmol, 5 equivalents), which was added four times, 0.275 g each, over a 3 h period. Vigorous stirring was continued at room temperature for a total of 3 h, after which the reaction mixture was filtered and the solvent removed by rotary evaporation to dryness. The crude product was redissolved in H2O / MeCN (1:1, v / v) and purified by preparative RP-HPLC (Phenomenex Luna C5 column (250×2120 mm); eluent A: H2O / 0.1% trifluoroacetic acid (TFA), eluent B: MeCN / 0.1% TFA; gradient: 5-100% B over 30 min, flow rate 15 mL / min). The combined fractions were lyophilized to give BBG·TFA (50 mg, 1×10 -4 mol, 3%). UV-Vis: ε 280 =7,884M -1 cm -1 . For C 19 H 21 Elemental analysis calculated for NO6·0.7TFA·1H2O·0.025MeCN: C, 53.61; H, 5.23; N, 3.13. Found: C, 53.58; H, 5.23; N, 3.13. 19 H 21 NO6+H] + QToF-MS: m / z [M+H] + = 360.1447 (calculated); m / z = 360.1451 (experimental). 1 H NMR (500MHz, D2O): δ, ppm 7.21-7.18(m,4H), 6.82-6.74(m,4H), 4.30(s,4H), 3.70(m,1H), 2.59-2.30(m,2H), 2.21(m,2H). 13 CNMR (125.7MHz, D2O): δ, ppm 176.2, 170.4, 155.2, 132.1, 120.7, 116.2, 115.3, 63.0, 30.4, 20.3. 19 H 21 NO6+H] + ESI-MS: m / z [M+H]+ =360.1 (calculated); m / z =360.1 (experimental).

[0736] Example 2 - Preparation of Fe-BBG

[0737]

[0738] The reaction scheme is Figure 1B BBG (9.5 mg, 2.10 -5 mol, 1 equivalent) was dissolved in 4 mL of water. Under continuous stirring, FeCl3 (35.3 μL of 509.2 mM stock solution, 1.8·10 -5 mol, 0.9 equivalents) was prepared. The wine-red solution of the FeBBG complex was then brought to pH 7.4 using 5 mM NaOH. The neutralized solution was desalted by preparative RP-HPLC (Phenomenex Luna C5 column (250 × 21 × 20 mm); eluent A: H2O, eluent B: MeCN; gradient: 5-100% B over 30 min, flow rate 15 mL / min). The collected fractions were flash-frozen in liquid nitrogen and lyophilized to yield a dark red powder (7.9 mg, 1.7·10 -5 mol, 93%). UV-Vis: ε 462 =2,420M -1 cm -1 . For [C 19 H 18 FeNO6+H] + QToF-MS: m / z [FeBBG+H] + = 413.0578 (calculated); m / z = 413.0562 (experimental). HPLC traces showing the purity of the isolated Fe-BBG detected at 220 nm and 465 nm are shown in FIG. Figure 2A The UV-visible spectrum of Fe-BBG is shown in Figure 2B A photograph of a 0.1 mM Fe-BBG solution in water is shown in the inset.

[0739] Example 3 - In vitro assay to evaluate the stability of Fe-BBG

[0740] Figure 3 shows UV-visible traces of 0.1 mM Fe-BBG in pH 7.4 buffer solution (50 mM HEPES buffer) in the presence of between 0 and 100 molar equivalents of bicarbonate (panel A), acetate (panel B), lactate (panel C), phosphate (panel D), and 0 to 10 molar equivalents of citrate (panel E).

[0741] The UV-visible trace remained unchanged in the presence of up to 100 molar equivalents of bicarbonate, acetate, lactate, and phosphate. For solutions incubated with citrate, the equilibrium product composition was quantified based on absorbance at 465 nm, and from this data we estimated that for Fe-BBG challenged with citrate, K comp = 0.006 ± 0.002. In other words, the ligand BBG binds to Fe with an estimated affinity 230 ± 40 times higher than that of citrate. 3+ combination.

[0742] The data indicate that Fe-BBG is stable to transchelation reactions with endogenously present chelators, which are often found to be associated with the formation of species including non-transferrin-bound iron.

[0743] Example 4 - In vitro assay to evaluate Fe delivery to apotransferrin

[0744] The transport of Fe from Fe-BBG to apotransferrin can be monitored by quenching the intrinsic fluorescence of apotransferrin. Figure 4A Shown are 2 h incubations with 0.5, 1, and 2 molar equivalents of FeBBG (supplemented with 25 mM HCO3 - 50 mM HEPES buffer, pH 7.4; 37°C. Ex =280 nm) after 20 μM apotransferrin fluorescence spectrum.

[0745] The transport of Fe from Fe-BBG to apotransferrin can also be monitored using urea gel electrophoresis. Figure 4B The results show that the slurry containing 0, 1, 2, 5 and 10 molar equivalents of Fe-BBG, or 2 molar equivalents of Fe 3+ (in the form of ferric citrate pyrophosphate) (positive control), or 2 molar equivalents of Fe 3+ Urea gel electrophoresis of apoferric transferrin (apo-Tf), monoferric transferrin (FeC-TF and FeN-TF), and holoferric transferrin (holo-Tf) in a mixture incubated with 10 μM transferrin (in the form of the thermodynamically stable and kinetically inert complex Fe-PyC3A) (negative control).

[0746] Figure 4A and Figure 4B The data in this paper collectively demonstrate how Fe-BBG is able to 3+ Stoichiometrically transported to apotransferrin.

[0747] Example 5 - Fe-BBG rapidly converts Fe 3+ Transported to apotransferrin.

[0748] Figure 5 Fe 3+ Time course of transport from Fe-BBG to transferrin. The reaction was monitored by quenching the intrinsic fluorescence of apotransferrin (conditions: 40 μM Fe-BBG, 20 μM apotransferrin, supplemented with 25 mM HCO3 - 50 mM HEPES buffer, pH 7.4; 25°C. Ex =280nm). Fe 3+ The transport from Fe-BBG to apotransferrin was complete within 6 seconds. The time resolution of the instrument was 6 seconds, and the reaction was too fast for the inventors to quantify the kinetics.

[0749] Example 6 - Fe-BBG cannot be reduced by ascorbate

[0750] Figure 6 Shown are UV-visible spectra of 0.1 mM Fe-BBG incubated in 50 mM HEPES buffer (pH 7.4) in the absence or presence of 0.1 mM sodium ascorbate. Upon challenge with ascorbate, the 462 nm absorbance peak remained unchanged.

[0751] Example 7 - Fe-BBG is robust to reduction and redox cycling.

[0752] To investigate whether Fe-BBG undergoes spontaneous oxidation and reduction under forced conditions, the compound was subjected to the conditions described previously (Methods in Enzymology 1994, 233, 57-66) (5 mM Fe 3+ The complex was incubated with 5-deoxyribose for 1 h at 37°C (2.8 mM H2O2, 2.8 mM deoxyribose, 0.1 mM ascorbic acid, 100 mM pH 7.4 phosphate buffer) to force the generation of harmful hydroxyl radicals, and then the 5-deoxyribose oxidation products were quantified using the thiobarbituric acid reactive species (TBARS) assay. The complexes Fe-NTA and Fe-EDTA, both known to participate in redox cycling and produce Fenton radicals under these reaction conditions, were incubated as positive controls. Reactions were performed in the absence of any Fe as a negative control. Ferric citrate pyrophosphate was also tested. Figure 7 It shows that compared with other Fe 3+Unlike the complex, incubation in the presence of Fe-BBG did not produce TBARS levels above those recorded in the absence of any Fe. Similarly, no TBARS were produced when Fe-BBG was reacted in the presence of physiologically relevant concentrations of citrate (ferric citrate also participates in redox cycling), further emphasizing the stability of Fe-BBG for trans-chelation.

[0753] Example 8 - Pharmacokinetics of Fe-BBG determined using dynamic magnetic resonance imaging

[0754] Fe-BBG is paramagnetic, which enabled the inventors to monitor Fe-BBG blood clearance and excretion by dynamic magnetic resonance imaging. Figure 8 shows coronal abdominal T1-weighted images of mice before, 1 minute after, and 10 minutes after Fe-BBG injection. Sub-panel A shows liver enhancement. The gallbladder (yellow arrow) and intestine begin to enhance contrast at ~10 minutes, consistent with partial hepatobiliary excretion. The image series in sub-panel B shows strong renal enhancement 1 minute after injection, which decreases rapidly and weakens significantly within 10 minutes, which is consistent with rapid urinary excretion. Sub-panel C shows a single exponential fit to the plot of vena cava signal intensity versus time, indicating that the blood MR signal decreases with a half-life of 5.5±2.8 minutes, which is consistent with rapid elimination.

[0755] Example 9 - In vivo assessment of elevated transferrin saturation

[0756] The in vivo efficacy of Fe-BBG as an Fe supplementary drug for transferrin was preliminarily evaluated in normal male C57BL / 6 mice. Mice received 0.01mmol Fe-BBG / kg (0.56μg Fe / g body weight), 0.1mmol Fe-BBG / kg (5.6μg Fe / g body weight) or placebo (saline vehicle) via tail vein injection and were killed 5min, 60min or 100min after injection. Serum non-heme iron parameters were then quantified using spectrophotometric ferroxine assay.

[0757] Fig. 9 compares the serum iron, total iron binding capacity (TIBC) and unconjugated iron binding capacity (UIBC) recorded in the serum collected at 5min, 60min or 100min after Fe-BBG injection in mice treated with placebo. Transferrin saturation percentage (%TSAT) was calculated at 60min and 100min time points, at which point the remaining BBG part after Fe-BBG and apotransferrin chelation was reduced to a level that did not interfere with spectrophotometric determination.

[0758] The data show that Fe-BBG injection increased serum iron and TIBC compared to placebo-treated mice, but did not decrease TIBC. The data also show how Fe-BBG significantly increased %TSAT compared to placebo-treated mice.

[0759] Example 10 - Fe-BBG does not generate labile iron in the body.

[0760] To quantify the labile iron released by Fe-BBG after intravenous injection, male C57BL / 6 mice received 0.01 mmol Fe-BBG / kg (0.56 μg Fe / g body weight), 0.1 mmol Fe-BBG / kg (5.6 μg Fe / g body weight), or placebo (saline vehicle) via tail vein injection and were sacrificed 5 min, 60 min, or 100 min after injection. Serum was collected, and the labile Fe in each sample was quantified by spectrophotometric monitoring of the oxidation rate of dihydrorhodamine 123 under redox-forced conditions as reported in Blood 2003, 102(7), 2670-2677 and described below.

[0761] 20 μL serum was transferred in quadruplicate to a transparent bottom 96-well plate. 180 μL of iron-free HEPES-buffered saline (HBS) containing 40 μM ascorbate and 50 μM dihydrorhodamine 123 (DHR) was added to 2 wells (pre-incubated at 37°C). 180 μL of the same solution containing 50 μM deferiprone was added to the other 2 wells. The reagent was added immediately afterwards. The kinetics of fluorescence enhancement was tracked for 40 minutes at 37°C in a Molecular Devices FlexStation 3 microplate reader with a 485 / 538 nm excitation / emission filter pair, with readings taken every 2 minutes. The slope (R) of the DHR fluorescence intensity over time was calculated from the measured values ​​read between 16 and 40 minutes and recorded as FU min -1 (fluorescence units / min).

[0762] Replicate values ​​of R in the absence (R1) and presence (R2) of deferiprone were averaged, and LPI concentration (μM) was determined from a calibration curve based on the difference in slope relative to iron concentration in the presence and absence of deferiprone.

[0763] A calibration curve was obtained by adding Fe:NTA (1:7 (mol:mol)) to plasma-like medium (PLM) to give a final concentration of 0.2 to 1 μM, followed by serial dilution in PLM and incubation at 37°C for 30 minutes to allow Fe to 3+20 μL of these samples were assayed in quadruplicate for LPI as described in the previous paragraph. A standard curve of ΔDHR oxidation rate versus iron concentration was constructed using data pooled from assays performed in PLM medium.

[0764] Plasma-like medium contains HEPES 20 mM, NaCl 150 mM, sodium citrate 120 μM, sodium ascorbate 40 μM, sodium hydrogen phosphate 1.2 mM, sodium bicarbonate 10 mM, and human serum albumin 40 mg / mL (pH 7.4). Iron-free HEPES-buffered saline (HEPES 20 mM, NaCl 150 mM, pH 7.4) is obtained by treating with 1 g of chelex-100 per 100 mL of solution.

[0765] Figure 10 The data shown in show that Fe-BBG does not release labile iron in vivo (see FIG9 ), even in serum collected 5 min after injection of 5.6 μg Fe / g of Fe-BBG (where total serum non-heme Fe is 25-fold higher than that of placebo-treated mice and far exceeds native TBIC), and the DHR oxidation kinetics are consistent with labile Fe concentrations <0.2 μM.

[0766] In brief, the various part herein forms iron complex, and described iron complex is thermodynamically stable than Transferrins,iron complex, but far more thermodynamically stable than the iron complex formed with the parts such as carbonate, phosphate, acetate, lactate and citrate, can not be reduced by ascorbate, and under mandatory conditions, can not participate in the redox cycle that produces Fenton free radical.The iron complex formed by the various part herein is in vitro with Fe fast transport to Transferrins,iron complex, and when being injected into mice, also causes the remarkable increase of Transferrins,iron complex saturation percentage.The serum collected from the mice that is injected with the iron complex formed by the various part herein shows that there is no detectable unstable iron.In sum, these data support systems are as effective and safe iron supplement medicine for Transferrins,iron complex.

[0767] Example 11 - BBG ligand does not strip Fe from transferrin

[0768] Solutions of 20 μM holotransferrin and solutions of BBG at concentrations between 0 and 100 μM (0-5 molar equivalents) were incubated for 24 h at 37° C. in 50 mM HEPES buffer supplemented with 25 mM carbonate at pH 7.4, and the removal of Fe from transferrin was monitored using fluorescence spectroscopy (excitation wavelength: 280 nm). No evidence of Fe removal from transferrin was observed. Figure 11A .

[0769] In another experiment, 10 μM holotransferrin was incubated with 100 μM BBG (10 molar equivalents) in 50 mM HEPES buffer, pH 7.4, supplemented with 25 mM carbonate at 37° C. for 24 h, and Fe removal was monitored by urea gel electrophoresis. Figure 11B No evidence of Fe removal from transferrin was observed.

[0770] Example 12 - Cyclic Voltammetry of Fe-BBG

[0771] Cyclic voltammograms of pH 7.4 50 mM HEPES buffer solution in the absence of 10 mM Fe-BBG (black trace) and in the presence of 10 mM Fe-BBG (red trace). Glassy carbon working electrode, Pt counter electrode, electrolyte: 0.5 M KNO3, scan rate = 300 mV / s, RT, Figure 12 .

[0772] Example 13 - BBG ligand binds Fe with higher specificity than other endogenous metal ions in vivo 3+ combination.

[0773] In the absence and presence of 1 molar equivalent of Fe 3+ 、Cu 2+ or Zn 2+ The pH potential titration of BBG(L) was used to determine the BBG and its corresponding Fe 3+ 、Cu 2+ and Zn 2+ Thermodynamics of aqueous solutions of complexes, Figure 13A .

[0774] pH potential measurements were performed using an Orion ROSS Ultra pH electrode and a temperature-controlled reaction vessel maintained at 310 K. A 0.10 M NaOH standard solution was used as the titrant. Prior to each titration, the electrode was calibrated by titrating a standard HCl (aqueous) solution having an ionic strength of 0.10 with a standard NaOH titrant using NaCl as the inert electrolyte. A working slope and intercept were generated by plotting mV as a function of the calculated pH, which enabled the electrode reading to be directly converted to [H] during sample titration. + ]. The pH values ​​recorded during the titration refer to the hydrogen ion concentration. All titration samples were prepared in 0.10 M NaCl solutions in distilled deionized water. The ligand solutions were prepared by dissolving weighed amounts in water, and the concentration was determined by the effective weight of the ligand and confirmed by the amount of NaOH required to consume 1 molar equivalent of ligand protons. 1:1 ligand:metal ion (Fe 3+ 、Zn 2+ 、Cu2+ ) solution was prepared by adding an appropriate volume of ICP-MS standard metal ion solution to a weighed amount of ligand. The solution was then adjusted to an ionic strength of I = 0.1 M with water and 1 M NaCl. Data were analyzed using the Hyperquad 2013 software package. Specific experimental conditions were as follows: For BBG The initial titrated mixture contained 0.016 mmol L and 0.0872 mmol H in 2.7 mL. + , the titrant contained 0.1399 M NaOH. For 1:1Fe:BBG The initial titrant was 0.0153 mmol Fe, 0.0153 mmol L, and 0.023 mmol H in 2.5 mL. + , the titrant contained 0.1399 M NaOH. for 1:1Cu:BBG The initial titrated mixture contained 0.0023 mmol Cu, 0.0023 mmol L, and 0.0230 mmol H in 2.6 mL. + , the titrant contained 0.1470 M NaOH. For 1:1Zn:BBG The initial titrant was 0.0025 mmol Zn, 0.0025 mmol L, and 0.024 mmol H in 2.6 mL. + , the titrant contained 0.1470 M NaOH.

[0775] All thermodynamic parameters are Figure 13B The table is listed in the table. FeL pH 7.4 ) at pH 7.4, the stability constant is 19.51, while for Cu-BBG and Zn-BBG, logK CuL pH 7.4 Value and logK ZnL pH 7.4 The values ​​are 10.49 and 4.49 respectively. 2+ 9 orders of magnitude greater stability and 2+ 15 orders of magnitude greater stability than Fe 3+ combination.

[0776] Example 14 - BBG does not strongly compete for endogenously present metals in serum

[0777] Based on Zn 2+ -BBG and Cu 2+ -BBG's logK ML pH 7.4values ​​(4.45 and 10.49, respectively), the inventors expected that BBG ligands would not chelate or redistribute metal ions present in serum and the extracellular space. 2+ The material is mainly composed of Zn bound to albumin, logK ML pH 7.4 =7.0 (Biochim Biophys Acta 2013, 1830(12), 5444-5455), while serum Cu species formation includes Cu bound to proteins including albumin, α-macroglobulin and low molecular weight ligands. 2+ , their respective logK ML pH 7.4 =13 (Coord. Chem. Rev. 2021, 433, 213727). Given the stability constants of Cu-BBG and Zn-BBG and the high abundance of serum albumin (~660 μM), the present inventors speculated that even millimolar concentrations of BBG should not disrupt the homeostasis of these metal ions.

[0778] To illustrate this, human plasma samples containing 0-5 mM BBG were incubated at 37°C for 1 h before ultrafiltration through a 10 kDa molecular weight cutoff filter to separate the low molecular weight solution components. The concentrations of Cu and Zn, as well as Mn, Mg, and Ca, were determined in the plasma concentrate and ultrafiltrate by ICP-MS. Figure 14 Incubation with BBG had little effect on the residual metal ion levels in the plasma concentrate relative to controls not treated with any ligand, nor did BBG significantly increase the concentrations of any metal ions in the ultrafiltrate.

[0779] Example 15 - Treatment with Fe-BBG corrects anemia in a mouse model of iron-refractory iron-deficiency anemia.

[0780] The present inventors evaluated the therapeutic efficacy of Fe-BBG in Tmprss6 knockout mice, which exhibit abnormally high levels of hepcidin and undergo Fe-restricted erythropoiesis, a phenotype that mimics human patients with IRIDA due to TMPRSS6 mutations and reproduces the prominent features of inflammatory anemia. Tmprss6 knockout mice received 29 intraperitoneal injections over 15 days, each of which contained 25 μg Fe (1.3 ± 0.18 μg Fe / g body weight, N = 5 mice, 2 males, 3 females) in the form of Fe-BBG or saline (placebo, N = 5 mice, 2 males, 3 females). The cumulative dose of Fe was 725 μg Fe (37 ± 0.53 μg Fe / g body weight). Mice were sacrificed 120 min after the last injection. Blood was collected for measurement of complete blood count and non-heme Fe parameters. The expression of genes related to erythropoietic activity, Fe exposure, oxidative stress, and inflammation in bone marrow and liver tissues was analyzed by qPCR. Figure 15 Clinical chemistry was also recorded, see Example 16 below. Figure 15 Data are presented as mean ± standard deviation. Statistical differences between groups were determined by two-tailed Student's t-test (for normally distributed values) or Mann-Whitney U test (for non-normally distributed values). Significant differences are indicated by *P < 0.05, **P < 0.01, and ****P < 0.0001.

[0781] Treatment with Fe-BBG resulted in a significant increase in hemoglobin compared to placebo. Hematocrit levels also increased significantly. Fe-BBG treatment significantly increased mean corpuscular volume and erythrocyte width, which the inventors attribute to the increased production of larger hemoglobin-rich erythrocytes. Overall, these changes are consistent with normal hematological recovery. No significant differences were detected between any other hematological parameters.

[0782] Serum Fe levels increased in Fe-BBG-treated mice, as reflected by a concomitant decrease in unbound iron binding capacity (UIBC). Total iron binding capacity (TIBC) levels remained unchanged in Fe-BBG-treated mice relative to placebo, indicating that Fe-BBG was completely cleared by 120 minutes after the last injection and that the increase in serum Fe was due to replenishment of the transferrin Fe pool. At this point, the percentage increase in transferrin saturation (%TSAT) was significantly increased in Fe-BBG-treated mice, with an average %TSAT increase of nearly 7-fold.

[0783] qPCR data showed that bone marrow erythroferrone (Erfe, 5J) was significantly downregulated in Fe-BBG-treated mice, consistent with hemoglobin resynthesis. Transferrin receptor type 1 (Tfrc, 5K) and glycophorin A (GypA), a protein abundantly expressed by erythroid precursor cells, were also downregulated in Fe-BBG-treated mice, consistent with restoration of normal red blood cell maturation.

[0784] Example 16 - Fe-BBG is well tolerated by mice after repeated dosing.

[0785] Repeated administration of Fe-BBG to Tmprss6 knockout mice did not induce significant differences in any clinical chemistry parameters, including serum markers routinely used in drug toxicity screening. Figure 16 . Figure 16 Data are presented as mean ± standard deviation. Statistical differences between groups were determined by two-tailed Student's t-test (for normally distributed values) or Mann-Whitney U test (for non-normally distributed values). Significant differences are indicated by *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

[0786] Fe-BBG did not trigger upregulation of hepatic heme oxygenase 1 (Hmox1), glutamate-cysteine ​​ligase catalytic subunit (Gclc), or NAD(P)H quinone dehydrogenase 1 (Nqo1), which collectively suggests that Fe-BBG does not cause oxidative stress. The expression of serum amyloid A1 (Saa1), a sensitive inflammatory marker, was also unchanged after repeated administration of Fe-BBG. Figure 15 .

[0787] Example 17 - N-(2-Hydroxy-5-sulfobenzyl)-N-(2-hydroxybenzyl)glycine (SBBG).

[0788] The reaction scheme is Figure 17 Shown in.

[0789] (2-Hydroxybenzyl)glycine tert-butyl ester (A). In 50 mL of methanol, glycine tert-butyl ester (0.69 g, 4.1 mmol, 1 eq) and sodium bicarbonate (1.38 g, 16.4 mmol, 4 eq) were mixed for several minutes. Salicylaldehyde (0.5 g, 4.1 mmol, 1 eq) was slowly added while stirring. After 15 minutes, sodium borohydride (0.16 g, 4.1 mmol, 1 eq) was added in four portions over 2 hours. The white mixture was then stirred for an additional 2 hours before being filtered and the solvent removed by rotary evaporation. The crude product was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, and dried under vacuum to give a white powder (0.18 g, 0.7 mmol, 18%). 1 H NMR (500MHz, CD3OD): δ, ppm 6.97-7.09(m,2H), 6.65-6.78(m,2H), 3.77(s,2H), 3.21(s,2H), 1.41(s,9H). 13 C NMR (125.7MHz, CD3OD): δ, ppm171.55,157.09,129.92,128.98,124.36,119.57,115.54,81.59,53.79,52.13,45.81,44.15,27.47.

[0790] N-(2-hydroxy-5-sulfobenzyl)-N-(2-hydroxybenzyl)glycine.

[0791] In 10mL methanol, intermediate A (0.1g, 0.42mmol, 1 equivalent) and sodium bicarbonate (0.13g, 1.6mmol, 4 equivalents) are combined. While stirring, 5-sulfonic acid salicylaldehyde monosodium (prepared as described in Dalton Trans., 2012, 41, 13927-13935) (0.09g, 0.4mmol, 1 equivalent) is slowly added to the mixture. Sodium borohydride (0.016g, 0.4mmol, 1 equivalent) is added four times over 2 hours, and the mixture is then stirred for another 2 hours. The reaction mixture is filtered and the solvent is removed by rotary evaporation. The crude product is dissolved in water and washed with ether. The product is dried in a vacuum and deprotected by stirring in 6M hydrochloric acid (5mL) for 2 hours. SBBG was purified by preparative-scale RP-HPLC using a Phenomenex Luna C5 column (250×2120 mm); eluent A: H 2 O, eluent B: MeCN; gradient: 5-100% B over 30 min; flow rate 15 mL / min. Fractions were analyzed using LC / MS, and fractions containing pure product were combined, frozen with liquid nitrogen, and freeze-dried to dryness to give a beige powder (0.1640 g, 0.39 mmol, 92%). 1 H NMR (500 MHz, D2O): δ, ppm 7.53-7.64 (m, 1H), 7.36-7.41 (m, 1H), 7.24-7.29 (m, 1H), 7.00-7.13 (1H), 6.48-6.63 (m, 3H), 3.65-3.77 (m, 4H), 3.16 (s, 2H). 16 H 16 NO7S] - ESI-MS: m / z [MH] + =366.1 (calculated value); m / z =366.1 (experimental value). LC-MS characterization of SBBG Figure 18 Shown in.

[0792] Example 18 - Preparation of Fe-SBBG.

[0793] The reaction scheme is Figure 19Shown in . A batch of SBBG (15 mg, 0.041 mmol) in 4 mL of water was mixed with Fe2(SO4)3 (8 mg, 0.040 mmol Fe). The solution turned dark red and was adjusted to pH 7.40 using 12.5 mM NaOH (aq.). Fe-SBBG was then purified by preparative-scale RP-HPLC using a Phenomenex Luna C18 column (250×21 20 mm); eluent A: H2O, eluent B: MeCN; gradient: 5-95% B over 30 min; flow rate 15 mL / min. Fractions were analyzed using LC / MS, and fractions containing pure product were combined, frozen with liquid nitrogen, and freeze-dried to dryness to give a dark red powder (15 mg, 0.034 mmol, 84%). For [C 16 H 17 FeNO9S] - ESI-MS: m / z [M-H+2H2O] - = 455.0 (calculated value); m / z = 455.0 (experimental value). LC-MS characterization of SBBG Figure 20 Shown in.

[0794] Example 19-3-(((Carboxymethyl)(2-hydroxybenzyl)amino)methyl))-4-hydroxybenzoic acid (BBG-COOH)

[0795] The reaction scheme is Figure 21 Shown in.

[0796] N-(2-Hydroxy-5-(methoxycarbonyl)benzyl)-N-(2-hydroxybenzyl)glycine) (A).

[0797] N-(2-hydroxymethyl) glycine (0.774g, 4.27mmol) and sodium bicarbonate (2.17g, 25.8mmol) of a batch are stirred in 25mL methyl alcohol.In this mixture, add 3-formyl-4-hydroxybenzoic acid methyl esters (1.08g, 5.99mmol adds with 4 equal portions) and sodium borohydride (110mg, 2.91mmol adds with 4 equal portions, each part all adds after 3-formyl-4-hydroxybenzoic acid ester), and use HPLC to monitor the reaction.When using 280nm to detect, starting raw material was roughly 1:4 with respect to the relative peak area of ​​intermediate A, and the reaction was completed.Then the reaction was concentrated into dry, 50mL H Distribute, separate between O and 50mL EtOAc, then the aqueous part was washed 2 times again with 50mL ethyl acetate.Then use 1MHCl / 1M NaOH that the EtOAc layer is adjusted to pH 6-7 and is saturated into resistates. The concentrated residue was dissolved in 10 mL of 1:1 H2O:MeOH and purified by preparative RP-HPLC (Teledyne ISCO, RediSep C18 Gold column (150 g); eluent A: H2O adjusted to pH 3.0, eluent B: MeCN; gradient: 5-50% B (over 6 column volumes), flow rate 85 mL / min). Fractions were analyzed using LC / MS, and product-containing fractions were combined, frozen with liquid nitrogen, and freeze-dried to dryness to give a white powder (0.42 g, the isolate contained both intermediate A and 4-hydroxy-3-(hydroxymethyl)benzoate by-product). For [C 18 H 19 NO6+H] + ESI-MS: m / z [M+H] + =346.1 (calculated); m / z =356.1 (experimental).

[0798] 3-(((Carboxymethyl)(2-hydroxybenzyl)amino)methyl))-4-hydroxybenzoic acid.

[0799] The solid containing intermediate A (0.42 g) was stirred in 20 mL of 4 M HCl (aq.) and heated to 90° C. for 2 hours. The mixture was then concentrated to dryness and triturated with 25 mL of H O. The resulting solid was dissolved in MeOH and purified by preparative RP-HPLC (Teledyne ISCO, RediSep C18 Gold column (150 g); eluent A: H O adjusted to pH 3.0, eluent B: MeCN; gradient: 5-50% B (over 6 column volumes), flow rate 85 mL / min). Fractions were analyzed using LC / MS, and fractions containing product were combined, frozen with liquid nitrogen, and lyophilized to dryness to give a white powder (0.075 g, 0.227 mmol, 5% overall yield from N-(2-hydroxybenzyl)glycine). 1 HNMR (500MHz, d6-DMSO): δ, ppm 7.78(s,1H),7.73(d,1H),7.11(m 2H),6.85(d,1H),6.77(m,2H),3.83(s,2H),3.77(s,2H),3.23(s,2H). 13 C NMR (500 MHz, d6-DMSO): δ, ppm 172.1, 167.2, 160.8, 156.5, 132.5, 131.2, 130.8, 129.3, 123.1, 122.9, 121.9, 119.5, 115.9, 115.8, 53.7, 53.6, 53.5. 17 H 16 NO6] - ESI-MS: m / z [MH] - =330.1 (calculated value); m / z =330.1 (experimental value). LC-MS characterization of BBG-COOH Figure 22 Shown in.

[0800] Example 20 - Preparation of Fe-BBG-COOH.

[0801] The reaction scheme is Figure 23A batch of BBG-COOH (17 mg, 0.051 mmol) was mixed in 3 mL of water and 12.5 mM NaOH (aq.) was added dropwise until the solid dissolved. To this mixture was added Fe2(SO4)3 (10 mg, 0.050 mmol Fe). The mixture turned dark red and was heterogeneous. The mixture was adjusted to pH 7.10 using 12.5 mM NaOH (aq.) and the solution was filtered to give a dark red homogeneous filtrate. Fe-BBG-COOH was then purified by preparative-scale RP-HPLC using a Phenomenex Luna C18 column (250×21 20 mm); eluent A: H2O, eluent B: MeCN; gradient: 5-95% B over 30 min; flow rate 15 mL / min. Fractions were analyzed using LC / MS, and fractions containing pure product were combined, frozen with liquid nitrogen, and freeze-dried to dryness to give a dark red powder (7.0 g, XX mmol, 68%). 17 H 17 FeNO8] - ESI-MS: m / z [M-H+2H2O] - = 419.0 (calculated value); m / z = 419.0 (experimental value). LC-MS characterization of SBBG Figure 24 Shown in.

[0802] Other implementation plans

[0803] It should be understood that although the present application has been described in conjunction with the detailed description of the present application, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A compound, which is Fe of formula (AI) 3+ Complexes: or a pharmaceutically acceptable salt thereof, wherein: --- indicates coordination bond; Each L is independently Fe 3+ ligand; p is 0, 1, or 2; L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace; Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ; R 1 Selected from C(O)O, P(O)(O)(OR B ) and (C=O)NR 10 ; Each q is independently 0 or 1; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; X 2a selected from N and C; X 3a Selected from N and CR 3a ; X 4a Selected from N and CR 4a ; X 5a Selected from N and CR 5a ; X 6a Selected from N and CR 6a ; The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N; R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN, The condition is that if L 1 -R 1 is CH2C(O)O or CH2CH2C(O)O, then R 5 and R 5a Not all are S(O)2OH, methyl, halogen, or tert-butyl.

2. The compound according to claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein L 1 -C 1-3 Alkylene-.

6. The compound according to any one of claims 1 to 4, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

7. The compound according to any one of claims 1 to 4, wherein L 1 Selected from methylene, ethylene and propylene.

8. The compound according to any one of claims 1 to 7, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 7, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, which has the following formula: or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9, which has the following formula: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11, which has the formula: or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 9, which is selected from: or a pharmaceutically acceptable salt thereof, wherein: L 1 selected from methylene and ethylene, R 5a is H; and R 5 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

14. A compound according to any one of claims 1 to 13, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

15. The compound according to claim 14, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of them is R 10 .

16. A compound according to any one of claims 1 to 15, wherein R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 and-(C 1-3 alkyl) q PO3R A R 8 .

17. A compound according to any one of claims 1 to 15, wherein R 10 For-(C 1-3 alkyl) q CO2R A .

18. The compound according to any one of claims 1 to 17, wherein q is 0.

19. The compound according to any one of claims 1 to 17, wherein q is 1.

20. The compound of any one of claims 1-19, wherein each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

21. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

22. A compound of formula (BI) Fe 3+ Complexes: or a pharmaceutically acceptable salt thereof, wherein: --- indicates coordination bond; Each L is independently Fe 3+ ligand; p is 0, 1, or 2; L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace; L 2 -C 1-3 Alkylene-, optionally replaced by R 10 replace; Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ; R 1 Selected from CO2R A 、P(O)(OR A )(OR B ) and (C=O)NR A R 10 ; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

23. The compound according to claim 22, wherein L 2 -C 1-3 Alkylene-.

24. The compound according to claim 22, wherein L 2 To be R 10 Substituted -C 1-3 Alkylene-.

25. The compound according to claim 22, wherein L 2 Selected from methylene and ethylene.

26. A compound according to any one of claims 22 to 25, wherein L 1 -C 1-3 Alkylene-.

27. A compound according to any one of claims 22 to 25, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

28. A compound according to any one of claims 22 to 25, wherein L 1 Selected from methylene and ethylene.

29. A compound according to any one of claims 22 to 28, wherein R 1 (C=O)NR A R 10 .

30. The compound of any one of claims 22-28, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 22-28, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 22-28, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 22-28, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

34. A compound according to any one of claims 22-33, wherein R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 .

35. A compound according to any one of claims 22-33, wherein R 3 、R 4 、R 5 and R 6 At least one of them is R 10 .

36. A compound according to any one of claims 22 to 35, wherein R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 .

37. The compound according to claim 36, wherein R 10 For-(C 1-3 alkyl) q CO2R A .

38. The compound of any one of claims 22-37, wherein q is 0.

39. The compound of any one of claims 22-37, wherein q is 1.

40. The compound of any one of claims 22-39, wherein each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

41. A compound of formula (CI) Fe 3+ Complexes: or a pharmaceutically acceptable salt thereof, wherein: --- indicates coordination bond; Each L is independently Fe 3+ ligand; p is 0, 1, or 2; L 1 -C 1-3 Alkylene-, or L 1 does not exist; R 1 selected from CO2R A , P(O)(OR A )(OR 8 ), (C=O)NR A R 10 , SO3R A , SO2R 8 , NHSO2R 8 , NR A R B , OP(R 8 )O2R B , OPO3R A R B , and (C=O)NHSO2R 8 ; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; X 2a selected from N and C; X 3a Selected from N and CR 3a ; X 4a Selected from N and CR 4a ; X 5a Selected from N and CR 5a ; X 6a Selected from N and CR 6a ; The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N; R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ; Each q is independently 0 or 1; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

42. The compound according to claim 41, wherein L 1 Does not exist.

43. The compound according to claim 41, wherein L 1 -C 1-3 Alkylene-.

44. The compound according to claim 41, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

45. The compound according to claim 41, wherein L 1 Selected from methylene, ethylene, and propylene.

46. ​​The compound of any one of claims 41-45, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

47. The compound of any one of claims 41-45, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

48. The compound of any one of claims 41-45, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

49. The compound of any one of claims 41-45, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

50. The compound of any one of claims 41-49, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

51. The compound of any one of claims 41-49, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 41-49, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

53. according to the compound described in any one of claims 41-52, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

54. The compound according to claim 53, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 .

55. The compound according to claim 54, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H and CH2OP(O)(OH)2.

56. The compound of any one of claims 41-54, wherein q is 0.

57. A compound according to any one of claims 41-54, wherein q is 1.

58. The compound of any one of claims 41-57, wherein each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

59. A compound of formula (DI) Fe 3+ Complexes: or a pharmaceutically acceptable salt thereof, wherein: --- indicates coordination bond; Each L is independently Fe 3+ ligand; p is 0, 1, or 2; L 1 -C 1-3 Alkylene-, or L 1 does not exist; L 2 -C 1-3 Alkylene-; R 1 selected from CO2R A , P(O)(OR A )(OR 8 ), (C=O)NR A R 10 , SO3R A , SO2R 8 , NHSO2R 8 , NR A R B , OP(R 8 )O2R B , OPO3R A R B , and (C=O)NHSO2R 8 ; R 2 selected from CO2R A , P(O)(OR A )(OR 8 ), (C=O)NR A R 10 , SO3R A , SO2R 8 , NHSO2R 8 , NR A R B , OP(R 8 )O2R B , OPO3R A R B , and (C=O)NHSO2R 8 ; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN, Provided that the compound is not any of the following compounds:

60. The compound according to claim 59, wherein L 1 Does not exist.

61. The compound according to claim 59, wherein L 1 -C 1-3 Alkylene-.

62. The compound according to claim 61, wherein L 1 Selected from methylene, ethylene and propylene.

63. according to the compound described in any one of claims 59-62, wherein L 2 -C 1-3 Alkylene-.

64. The compound according to claim 63, wherein L 2 Selected from methylene, ethylene and propylene.

65. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

66. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

67. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

68. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

69. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

70. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

71. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

72. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

73. The compound of any one of claims 59-64, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

74. according to the compound described in any one of claims 59-73, wherein R 3 、R 4 、R 5 and R 6 At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

75. The compound according to claim 74, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 .

76. The compound according to claim 75, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H and CH2OP(O)(OH)2.

77. The compound of any one of claims 59-75, wherein q is 0.

78. The compound of any one of claims 59-75, wherein q is 1.

79. The compound of any one of claims 59-78, wherein each L is independently selected from H2O, NH3, Cl, Br, SO4, HCO3, CO3, PO4, nitrate, nitrite, citric acid, tartaric acid, ascorbic acid, malic acid, succinic acid, acetic acid, glucose, fructose, mannose and galactose, or any combination thereof.

80. A pharmaceutical composition comprising a compound according to any one of claims 1 to 79 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

81. A method for treating iron deficiency anemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-79, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 80.

82. A compound of formula (A): or a salt thereof, wherein: L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace; Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ; R 1 Selected from CO2R A 、P(O)(OR A )(OR B ), and (C=O)NR A R 10 ; Each q is independently 0 or 1; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; X 2a selected from N and C; X 3a Selected from N and CR 3a ; X 4a Selected from N and CR 4a ; X 5a Selected from N and CR 5a ; X 6a Selected from N and CR 6a ; The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N; R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN, The conditions are: (i) If L 1 R 1 is CH2C(=O)OR A or CH(CH3)C(=O)OR A ,but: X 3 With X 3a different; or X 4 With X 4a different; or X 5 With X 5a different; or X 6 With X 6a different; or X 2 is N; or X 2a is N; and (ii) the compound of formula (A) is not any of the following compounds:

83. The compound of claim 82, having the formula:

84. The compound of claim 82, having the formula:

85. The compound of claim 82, having the formula:

86. according to the compound described in any one of claims 82-85, wherein L 1 -C 1-3 Alkylene-.

87. according to the compound described in any one of claims 82-85, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

88. according to the compound described in any one of claims 82-85, wherein L 1 Selected from methylene and ethylene.

89. A compound according to any one of claims 82-85 having the formula:

90. A compound according to any one of claims 82-89, wherein R 1 P(O)(OR A )(OR B ).

91. according to the compound described in any one of claims 82-89, wherein R 1 CO2R A .

92. according to the compound described in any one of claims 82-89, wherein R 1 (C=O)NR A R 10 .

93. according to the compound described in any one of claim 82-92, wherein R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 .

94. according to the compound described in any one of claims 82-92, wherein R 10 For-(C 1-3 alkyl) q CO2R A .

95. according to the compound described in any one of claims 82-92, wherein R 10 For-(C 1-3 alkyl) q PO3R A R 8 .

96. The compound of any one of claims 82-95, wherein q is 0.

97. The compound of any one of claims 82-95, wherein q is 1.

98. The compound of claim 82, wherein the compound of formula A is selected from any one of the following compounds: or a salt thereof.

99. A compound of formula (B): or a salt thereof, wherein: L 1 -C 1-3 Alkylene-, optionally replaced by R 10 replace; L 2 -C 1-3 Alkylene-, optionally replaced by R 10 replace; Each R 10 Independently -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , or -(C 1-3 alkyl) q (C=O)NHSO2R 8 ; R 1 Selected from CO2R A 、P(O)(OR A )(OR B ), and (C=O)NR A R 10 ; Each q is independently 0 or 1; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN and R 10 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN, The conditions are: (i) If R 1 is P(O)(OH)(OH), then R 5 Not C 1-3 Alkyl or halogen; and (ii) the compound of formula (A) is not any of the following compounds:

100. The compound according to claim 99, wherein L 2 -C 1-3 Alkylene-.

101. The compound according to claim 99, wherein L 2 To be R 10 Substituted -C 1-3 Alkylene-.

102. The compound according to claim 99, wherein L 2 Selected from methylene and ethylene.

103. A compound according to any one of claims 99-102, wherein L 1 -C 1-3 Alkylene-.

104. A compound according to any one of claims 99-102, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

105. A compound according to any one of claims 99-102, wherein L 1 For ethylene.

106. The compound of any one of claims 99-102, wherein the compound has the formula:

107. The compound of any one of claims 99-105, wherein the compound has the formula: where R 5 Selected from C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

108. The compound of any one of claims 99-105, wherein the compound has the formula:

109. A compound according to any one of claims 99-108, wherein R 10 Selected from -(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q (C=O)NHSO2R 8 , and-(C 1-3 alkyl) q PO3R A R 8 .

110. The compound according to claim 109, wherein R 10 For-(C 1-3 alkyl) q CO2R A .

111. The compound according to claim 109, wherein R 10 For-(C 1-3 alkyl) q PO3R A R 8 .

112. The compound of any one of claims 99-111, wherein q is 0.

113. The compound of any one of claims 99-111, wherein q is 1.

114. The compound of claim 99, wherein the compound is selected from any one of the following compounds: or a salt thereof.

115. A compound of formula (C): or a salt thereof, wherein: L 1 -C 1-3 Alkylene-, or L 1 does not exist; R 1 selected from CO2R A 、P(O)(OR A )(OR 8 )、(C=O)NR A R 10 、SO3R A 、SO2R 8 、NHSO2R 8 、NR A R B 、OP(R 8 )O2R B 、OPO3R A R B 、and (C=O)NHSO2R 8 ; Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; X 2a selected from N and C; X 3a Selected from N and CR 3a ; X 4a Selected from N and CR 4a ; X 5a Selected from N and CR 5a ; X 6a Selected from N and CR 6a ; The condition is X 2a 、X 3a 、X 4a 、X 5a and X 6a No more than two of them are N; R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ; Each q is independently 0 or 1; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substituents include haloalkoxy, halogen, OH and CN.

116. The compound according to claim 115, wherein L 1 Does not exist.

117. The compound according to claim 115, wherein L 1 -C 1-3 Alkylene-.

118. The compound according to claim 115, wherein L 1 To be R 10 Substituted -C 1-3 Alkylene-.

119. The compound according to claim 115, wherein L 1 Selected from methylene, ethylene, and propylene.

120. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

121. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

122. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

123. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

124. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

125. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

126. The compound of any one of claims 115-119, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

127. A compound according to any one of claims 115-126, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 .

128. The compound of claim 127, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 .

129. The compound according to claim 128, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H and CH2OP(O)(OH)2.

130. The compound of any one of claims 115-128, wherein q is 0.

131. The compound of any one of claims 115-128, wherein q is 1.

132. The compound of claim 115, wherein the compound of formula (C) is selected from any one of the following compounds: or a salt thereof.

133. A compound of formula (D): or a salt thereof, wherein: L 1 -C 1-3 Alkylene-, or L 1 does not exist; L 2 -C 1-3 Alkylene-; R 1 selected from CO2R A 、P(O)(OR A )(OR 8 )、(C=O)NR A R 10 、SO3R A 、SO2R 8 、NHSO2R 8 、NR A R B 、OP(R 8 )O2R B 、OPO3R A R B 、and (C=O)NHSO2R 8 ; R 2 selected from CO2R A 、P(O)(OR A )(OR 8 )、(C=O)NR A R 10 、SO3R A 、SO2R 8 、NHSO2R 8 、NR A R B 、OP(R<00013'27> )O2R B 、OPO3R A R B 、and (C=O)NHSO2R 8 ; It should be noted that there may be some formatting or symbol issues in the original text that need to be further checked and adjusted in the context of the patent content. Also, the tag <00013'27> seems to have a typo in the original, it should probably be 8 . The condition is R 1 and R 2 At least one of them is P(O)(OR A )(OR 8 ); Each R A and R B are independently H or C 1-3 alkyl; X 2 selected from N and C; X 3 Selected from N and CR 3 ; X 4 Selected from N and CR 4 ; X 5 Selected from N and CR 5 ; X 6 Selected from N and CR 6 ; The condition is X 2 、X 3 、X 4 、X 5 and X 6 No more than two of them are N; R 3 、R 4 、R 5 and R 6 Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN、-(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q SO2R 8 、-(C 1-3 alkyl) q NHSO2R 8 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q NR A R B 、-(C 1-3 alkyl) q (C=O)NR A R B 、-(C 1-3 alkyl) q OP(R 8 )O2R B 、-(C 1-3 alkyl) q OPO3R A R B 、-(C 1-3 alkyl) q PO3R A R 8 , and-(C 1-3 alkyl) q (C=O)NHSO2R 8 ; Each R 8 Selected from C 3-9 Alkyl and -(C 1-3 alkyl) q C 6-10 Aryl, wherein the C 6-10 Aryl is optionally substituted by 1, 2 or 3 independently selected R 11 and Each R 11 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, halogen, OH, CN and C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Substitution with haloalkoxy, halogen, OH and CN, Provided that the compound of formula (D) is not:

134. The compound of claim 133, wherein L 1 Does not exist.

135. The compound of claim 133, wherein L 1 -C 1-3 Alkylene-.

136. The compound of claim 135, wherein L 1 Selected from methylene, ethylene and propylene.

137. A compound according to any one of claims 133-136, wherein L 2 -C 1-3 Alkylene-.

138. The compound of claim 137, wherein L 2 Selected from methylene, ethylene and propylene.

139. The compound of any one of claims 133-138, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

140. The compound of any one of claims 133-138, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

141. The compound of any one of claims 133-138, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

142. The compound of any one of claims 133-141, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

143. The compound of any one of claims 133-141, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

144. The compound of any one of claims 133-141, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

145. A compound according to any one of claims 133-144, wherein R 3 , R 4 , R 5 and R 6 are each independently selected from C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, halogen, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q CN, -(C 1-3 alkyl) q SO3R A , -(C 1-3 alkyl) q SO2R 8 , -(C 1-3 alkyl) q NHSO2R 8 , -(C 1-3 alkyl) q CO2R A , -(C 1-3 alkyl) q NR A R B , -(C 1-3 alkyl) q (C=O)NR A R B , -(C 1-3 alkyl) q OP(R 8 )O2R B , -(C 1-3 alkyl) q OPO3R A R B , -(C 1-3 alkyl) q PO3R A R 8 , and -(C 1-3 alkyl) q (C=O)NHSO2R 8 .

146. The compound according to claim 145, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, -(C 1-3 alkyl) q OH, -(C 1-3 alkyl) q 3R A 、-(C 1-3 alkyl) q CO2R A 、-(C 1-3 alkyl) q OPO3R A R B , and-(C 1-3 alkyl) q PO3R A R 8 .

147. The compound according to claim 146, wherein R 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、R 6 and R 6a At least one of the following is selected from C 1-3 Alkyl, CH2OH, C(O)OH, SO3H and CH2OP(O)(OH)2.

148. The compound of any one of claims 133-146, wherein q is 0.

149. The compound of any one of claims 133-146, wherein q is 1.

150. The compound of claim 133, wherein the compound is selected from any one of the following compounds: or a salt thereof.

Images