Molecular probes for in vivo detection of aldehydes.

Abstract

For example, disclosed herein are methods of molecular magnetic resonance (MR) imaging and positron emission tomography using extracellular probes that target extracellular allicinaldehyde and act as a non-invasive biomarker of fibrogenesis, with high sensitivity and specificity in detecting fibrogenesis in rodent models and human fibrotic tissues.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 188,407, filed May 13, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers HL154125 and DK121789. The government has certain rights in this invention.

[0003] The present disclosure relates to molecular probes for the in vivo detection of aldehydes. [Background technology]

[0004] Many chronic and acute diseases have a fibroproliferative component, i.e., tissue becomes fibrotic or scarred. For example, chronic liver diseases such as nonalcoholic steatohepatitis, chronic kidney disease, inflammatory bowel diseases such as Crohn's disease, cardiac diseases such as heart failure, atrial fibrillation, and myocardial infarction, pulmonary fibrotic diseases such as idiopathic pulmonary fibrosis, and cancers such as pancreatic ductal adenocarcinoma, scleroderma, and atherosclerosis all have fibrotic components. Liver fibrosis plays a crucial role in the progression of most chronic liver diseases (CLDs) and is characterized by the accumulation of extracellular matrix, which can progress to cirrhosis, hepatocellular carcinoma, liver failure, and / or death. During the fibrogenesis (active fibrosis) process, the enzyme lysyl oxidase (LOX) and its paralogs (LOXL1 and LOXL2) are upregulated. LOX oxidizes lysine residues on extracellular matrix proteins, such as collagen and elastin, to aldehydes containing the amino acid allysine. During fibrillogenesis, a protein-associated aldehyde (allysin) accumulates in the extracellular space. Summary of the Invention

[0005] Some embodiments include compounds of formula (I):

[0006] [ka] [In the formula, Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, halogen, -NR A R B , -OH, C 1~6 Alkyl, or -C 1~6 Alkyl-(NR A R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of the groups are -C(=O)OH] or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments provide a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] Some embodiments provide compositions comprising a mixture of compounds of formula (I), or pharmaceutically acceptable salts thereof.

[0009] Some embodiments provide a composition comprising (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or (b) a composition comprising a mixture of compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein the composition is formulated for parenteral administration.

[0010] Some embodiments provide a composition comprising (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or (b) a composition comprising a mixture of compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition is a solid formulated to dissolve in a pharmaceutically acceptable liquid vehicle prior to administration.

[0011] Some embodiments provide a method of magnetic resonance (MR) imaging a subject, comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; and (b) obtaining a magnetic resonance image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0012] Some embodiments provide a method of magnetic resonance (MR) imaging a subject, comprising: (a) obtaining a first magnetic resonance image of a subject; (b) administering to the subject a compound of formula (I) or a composition thereof described herein; (c) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (d) comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject; The present invention provides a method comprising:

[0013] Some embodiments provide a method for imaging liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; and (b) obtaining a magnetic resonance image of the subject's liver after a predetermined period of time; The present invention provides a method comprising:

[0014] Some embodiments provide a method of measuring liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound of formula (I) or a composition thereof described herein; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) measuring liver fibrosis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. The present invention provides a method comprising:

[0015] Some embodiments provide a method for detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; and (b) detecting the presence or absence of liver fibrosis in the subject by obtaining a magnetic resonance image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0016] Some embodiments provide a method of detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound of Formula (I) or a composition thereof described herein; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) detecting the presence or absence of liver fibrosis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. The present invention provides a method comprising:

[0017] Some embodiments provide a method for detecting liver fibrogenesis in a subject, the method comprising obtaining a magnetic resonance image of the subject within a predetermined period of time after the subject has been administered a compound of formula (I) or a composition thereof as described herein.

[0018] Some embodiments provide a method of imaging a subject by positron emission tomography (PET), comprising: (a) administering to a subject a compound of formula (I) or a composition thereof described herein; (b) obtaining a positron emission tomography image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0019] Some embodiments provide a method of imaging a subject by positron emission tomography (PET), comprising: (a) obtaining a first magnetic resonance image of a subject; (b) administering to the subject a compound of formula (I) or a composition thereof described herein; (c) obtaining a second positron emission tomography image of the subject after a predetermined period of time; and (d) comparing the first magnetic resonance image of the subject with the second positron emission tomography image of the subject. The present invention provides a method comprising:

[0020] Some embodiments include a compound of formula (II)

[0021] [ka] [In the formula, M is a metal cation; Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, halogen, -NR A R B , -OH, C 1~6 Alkyl, or -C 1~6 Alkyl-(NRA R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of the groups are -C(=O)OH] or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 shows the percentage r1 change of Gd complexes over time after incubation of allicin-modified bovine serum albumin, BSA-Ald. [Figure 2] Relaxivity values ​​at 60 MHz (PBS, pH 7.40, 24 hours, 37° C.) in the presence or absence of BSA and BSA-Ald are shown. [Figure 3] 1 shows the hydrolysis of BSA-Ald-bound Gd-CHyd and Gd-9 monitored by magnetic relaxation at 60 MHz (PBS, pH 7.40, 37° C.). [Figure 4] Axial images of a CCl4 mouse liver imaged before and 45 min after injection of Gd-CHyd, Gd-10, and Gd-9 (0.1 mmol / kg i.v.) are shown. [Figure 5] Liver-to-muscle contrast-to-noise ratios (ΔCNR) of vehicle and CCl4 mice 45 min after injection of Gd-CHyd, Gd-10, and Gd-9 are shown (n=6 / group). [Figure 6]Shown are Gd-9ΔCNR in CC14 mice before and after pretreatment with a 10-fold dose of MR-inactive Yb-9 (n=3). [Figure 7] Sirius red staining, collagen proportional area (CPA) measured from Sirius red-stained tissue, and hydroxyproline (HYP) in vehicle and CC14 mice (n>15) studied here are shown, all demonstrating that the model results in robust liver fibrosis. ***P<0.001. [Figure 8] A schematic representation of a pairwise experiment for Gd-9 and Gd-10 is shown. Mice were imaged with either Gd-9 or Gd-10 and then imaged again the next day with the other probe (0.1 mmol / kg i.v.). [Figure 9] Liver-to-muscle contrast-to-noise ratio (ΔCNR) 45 min after injection is shown, demonstrating consistently higher ΔCNR in CCl4 mice with Gd-9. ***P<0.001. [Figure 10] A schematic diagram of a blocking experiment using Yb-9 is shown. [Figure 11] Axial DCEMR images of the lungs in pairwise experiments before and 25 min after injection of GdCHyd or Gd-9 are shown. [Figure 12] Quantification of MR signal in the lungs is shown. [Figure 13] Quantification of gadolinium content in the BM or left lung of untreated animals 60 min after injection of Gd-9 is shown. [Figure 14] A schematic representation of the MR imaging and treatment timeline is shown. [Figure 15] Axial DCEMR images of the lungs 25 min after Gd-9 injection in sham-operated mice (Sham), mice receiving intratracheal administration of bleomycin for 10 days (Bleo(D10)), mice receiving PBS for 11 days (Vehicle(D21)), and mice receiving EGCG treatment after injury with Bleo (belo) are shown. [Figure 16]Quantification of lung-to-muscle contrast-to-noise ratio (ΔCNR) in different groups (n=6) is shown. *P<0.05. [Figure 17] Schematic representation of pairwise experiments of Gd-CHyd and Gd-9 at 14 days after bleomycin injury is shown. [Figure 18] The results show that lung allicin content is significantly reduced by treatment with EGCG. **P<0.01. [Figure 19] Lung hydroxyproline content was also shown to be decreased. *p<0.05. [Figure 20] 1 shows the conversion yield of Mn complex (25 μM) over time in reaction with butyraldehyde (100 μM) and characterized by LC-ICP. [Figure 21] Relaxivity values ​​at 60 MHz (PBS, pH 7.40, 2 hours, 37° C.) in the presence or absence of BSA and BSA-Ald are shown. [Figure 22] Axial liver images of CC14 and vehicle mice imaged before and 45 minutes after injection of GdDOTA or Mn-12 (0.1 mmol / kg i.v.) are shown. [Figure 23] Changes in liver-to-muscle contrast-to-noise ratio (ΔCNR) in Sham (n=4) and CCl4 mice (n=6) 45 min after injection of GdDOTA and Mn-12 are shown. *P<0.05, **P<0.01. [Figure 24] Figure 1 shows the lateral relaxivity of H2 17O as a function of temperature in the presence of the corresponding Mn2+ complex. The peak relaxivity indicates the number of water molecules (q) in the inner sphere. [Figure 25] Figure 1 shows the half-life of a 1 mM Mn2+ complex in a transmetallation experiment with 25 mM Zn2+, monitored by relaxivity in 50 mM pH 6.0 MES buffer at 37 °C and 1.4 T, demonstrating the increased kinetic stability of Mn-12 compared to unmodified Mn-1,4-DO2A. [Figure 26]Biodistribution of manganese in the absence (blank) or presence of Mn-12 and Mn-13 (0.1 mmol / kg iv, 60 min post-injection) is shown. Mn-12 shows baseline Mn levels in the liver, whereas Mn-13 shows elevated levels, indicating that Mn-13 is inappropriate for hepatic molecular MR due to a high nonspecific signal. [Figure 27] Figure 1 shows the change over time in liver-to-muscle contrast-to-noise ratio (ΔCNR) in the CCl4 and vehicle groups imaged with Mn-12, demonstrating persistent enhancement in fibrotic liver but rapid washout in healthy liver. [Figure 28] Sirius red staining, collagen proportional area (CPA), and hydroxyproline (HYP) in vehicle and CCl4 mice studied here demonstrate a consistent fibrogenic response in the livers of CCl4-treated mice. ***P<0.001. [Figure 29] The second-order rate constants (k) for the reaction of Mn-15 and Mn-17 with butyraldehyde are shown. [Figure 30] The half-lives (t1 / 2) for hydrolysis of Mn-15 and Mn-17 condensation with butyraldehyde are shown. [Figure 31] Shown are relaxivity values ​​for Mn-15 and Mn-17 in PBS, in BSA solution, in allicin-modified BSA-Ald, and bound to BSAAld. [Figure 32] Axial T1-weighted MR images of a CCl4 mouse imaged before and 20 minutes after injection of Mn-15 (100 μmol / kg, iv, liver labeled with yellow dashed line) are shown. [Figure 33] Shown is the change in liver-to-muscle contrast-to-noise ratio (ΔCNR) in vehicle (n=3) and CC14 (n=3) mice as a function of time after injection of Mn-15 (0.1 mmol / kg, iv). [Figure 34]A significant difference (P=0.02) in the area under the ΔCNR curve (AUC0-40) between vehicle (n=3) and CCl4 (n=3) mice is shown. [Figure 35] 1 shows the blood clearance of 68Ga-7 in untreated animals using distribution and elimination half-lives. [Figure 36] Biodistribution of 68Ga-7 in the lungs, heart, liver, and kidneys at 90 min pi is shown. [Figure 37] PET maximum intensity projection images of bleomycin-injured and untreated mice at 55 minutes pi are shown. [Figure 38] Axial (top) and sagittal (bottom) PET / MR images are shown, demonstrating much higher lung signal in bleomycin-treated mice at 55 minutes pi. [Figure 39] PET lung signal (55 min pi) and lung-to-heart ratio (90 min pi) are shown, demonstrating significant differences between bleomycin-treated and untreated animals. [Figure 40] A schematic diagram of the development of a dual LysAld-conjugated MRI probe for noninvasive detection of liver fibrogenesis is shown. Chronic liver injury leads to stellate cell activation. During extracellular matrix remodeling, closely separated Lys pairs on the α1 chain of collagen telopeptide are oxidized by LOX to LysAld. The dual hydrazine Gd3+ probe precisely targets these LysAld pairs with a high binding on-rate, high binding relaxivity, and low off-rate, resulting in a significant increase in dynamic range and noninvasive detection by MRI. [Figure 41] The chemical structure of the Gd3+ complex is shown. [Figure 42] 1 shows the edge-to-edge distance distributions obtained from molecular dynamics simulations of the OO distance between two α1-N9-LysAld residues in type I collagen and the NN distance of the piperazino-hydrazine groups in Gd-9 and Gd-10. [Figure 43]Figure 43A shows the conversion yield versus time plot of the corresponding Gd3+ (25 μmol) complex in the presence of 100 μmol butyraldehyde. Figure 43B shows the measurement of the affinity of the Gd3+ complex with butyraldehyde. The concentration-dependent binding of the probe to butyraldehyde was determined by HPLC-ICP-MS (in PBS, pH 7.4, 12 h). The corresponding dissociation constants (Kd) were 160, 162, 110, and 110 μM for Gd-CHyd, Gd-11, Gd-9, and Gd-10, respectively. [Figure 44] Shown is a time-course high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) trace of Gd-9 (25 μmol) in the presence of 100 μmol butyraldehyde in PBS at room temperature (peak at 0 and left-most peaks at 13, 25, and 37 min: Gd-9; right-most peaks at 13, 25, and 37 min: product). [Figure 45] HPLC-ICP-MS traces of the reaction of the corresponding Gd 3+ complex (25 μM) with butyraldehyde (100 μM) in PBS at pH 7.4 are shown. [Figure 46] Bar graphs of relaxivity values ​​in PBS, PBS with BSA or BSAAld are shown (10 mg / mL, pH 7.4, 24 h, 37° C., 1.41 T). Data are means ± SD of three independent experiments. [Figure 47] 1 shows a plot of r1 change (percentage) over time for Gd complexes (0.1 mM) after incubation with 10 mg / mL BSAAld in PBS. [Figure 48] Figure 1 shows a plot of the binding yield of the measurement of Gd3+ complex with BSAAld. The binding concentration of the probe to BSAAld (pH 7.4, PBS, 37°C, 12 hours) was determined by ICP-MS after ultrafiltration (5,000 Da cutoff) to separate the protein-bound probe from the unbound probe. The slope gives the binding yield. [Figure 49]Figure 49A shows an HPLC-ICP-MS trace with gadolinium detection for Gd-9 in human plasma at 37°C for 3 hours using Method 23. Figure 49B shows an HPLC-ICP-MS trace with gadolinium detection for Gd-10 in human plasma at 37°C for 3 hours using Method 23. [Figure 50] 1 shows plots of the hydrolysis of BSAAld-bound Gd-CHyd and Gd-9 monitored by longitudinal relaxation in PBS (pH 7.4, 37° C., 1.41 T). [Figure 51] A bar graph of the relaxivity of BSAAld-bound species in PBS (pH 7.4, 37° C., 1.41 T) is shown. Data are the mean ± SD of three independent experiments. [Figure 52] Characterization of bound species using SDS-polyacrylamide gel electrophoresis (SDS-PAGE) is shown. From left to right: a, BSA; b, BSA in the presence of Gd-9; c, BSAAld in the presence of Gd-9. [Figure 53] Schematic representation of relaxivity measurements in the ECM. [Figure 54] A bar graph of relaxivity values ​​in rat fibrous liver ECM with or without the addition of 100-fold excess hydrazine is shown (PBS, pH 7.4, 2 hours, 37°C, 1.41T). [Figure 55] Representative time-dependent coronal T1-weighted 3D-FLASH MR images of a normal mouse before and at the indicated time points after iv injection of 100 μmol / kg of the corresponding probe are shown. The liver enhances slightly with the first blood flow, but after 20 minutes the signal rapidly returns to baseline. Similar results were observed in four animals per probe. [Figure 56] Schematic diagram of the animal experimental design for CCl4-induced liver fibrosis. Mice were gavaged with CCl4 with probe 1 for 12 weeks, then imaged, and then imaged again the next day with probe 2 (100 μmol / kg iv, a probe randomly selected from Gd-DOTA, Gd-CHyd, Gd-9, and Gd-10). [Figure 57]Representative images of Sirius Red, LOX, and LysAld staining (scale bar: 500 μm) are shown. [Figure 58] Collagen proportional area (CPA) measured from tissue stained with Sirius Red is shown (n 10, ***P<0.0001, unpaired t-test, two-tailed). [Figure 59] The percentage of LOX-positive tissue determined from IHC LOX-stained tissue is shown (n≥10, ***P<0.0001, unpaired t-test, two-tailed). [Figure 60] The percentage of LysAld-positive tissues determined from the DNPH reaction assay is shown (n≥10, ***P<0.0001, unpaired t-test, two-tailed). [Figure 61] Shown are plots of probe blood clearance in vehicle- and CCl4-treated mice, as determined by signal intensity changes in T1-weighted 3DFLASH dynamic MRI in the heart (blood pool, n=6). [Figure 62] Shown are axial livers (outlined in white) in MR images of CCl4 mice imaged before and 45 min pi with Gd-CHyd, Gd-10, Gd-9, and Gd-DOTA (100 μmol / kg i.v.). [Figure 63] Liver clearance of the probe in vehicle- and CCl4-treated mice, as determined by the change in ΔCNR on T1-weighted 3DFLASH MRI (n=6). [Figure 64] Changes in liver-to-muscle contrast-to-noise ratio (ΔCNR) at 45 min pi relative to pre-injection images are shown, demonstrating significantly higher ΔCNR in CCl4 mice with Gd-9 (n ≥ 6 per group, *P = 0.0433, **P = 0.0084, ***P < 0.0001, one-way ANOVA, post-injection hoc comparison, two-tailed). [Figure 65]Pairwise comparison of ΔCNR at 45 min for Gd-9 and Gd-10 imaged in the same mice 1 day apart (100 μmol / kg i.v. injection order randomized) shows consistently higher ΔCNR in CCl4 mice imaged with Gd-9 compared with Gd-10 (***P = 0.0003, paired t test, two-tailed). [Figure 66] Schematic of a blocking experiment using Yb-9. [Figure 67] Figure 1 shows a plot of the time course of Gd-9ΔCNR in CCl4 mice before and after pretreatment with a 10-fold dose of MR-inactive Yb-9 (n=3, **P=0.0045). All data are shown as mean ± SD, *P<0.05, **P<0.01, ***P<0.001. [Figure 68] Hepatic hydroxyproline (Hyp, μg / g) in vehicle- and CCl4-treated mice is shown (n10, ***P<0.0001, unpaired t-test, two-tailed). [Figure 69] Figure 69A shows a comparison of α-smooth muscle actin (α-SMA) immunoreactivity in CCl4- and vehicle-treated mice. Representative images of α-SMA immunohistological staining in vehicle- and CCl4-treated mice (scale bar: 500 μm). Figure 69B shows a comparison of α-smooth muscle actin (α-SMA) immunoreactivity in CCl4- and vehicle-treated mice. Percentage of α-SMA-positive tissue determined from IHC-stained tissue in Figure 69A. n>10, ***P<0.001, unpaired t-test, two-tailed. [Figure 70]Experimental design, animal grouping, and in vivo MRI imaging. Adult C57BL / 6 mice fed a standard chow diet served as age-matched controls (n = 10). Mice (n = 6 per group) fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 2, 6, or 10 weeks were used to study nonalcoholic steatohepatitis (NASH) disease progression. Mice fed a CDAHFD for 10 weeks, then switched back to a standard chow diet for 1 or 4 weeks (n = 6 per group) were used to study treatment effects. At each time point, mice underwent Gd-9-enhanced MRI followed by sacrifice for ex vivo liver characterization. [Figure 71] Difference (20 min pi, 100 μmol Gd-9 / kg, pre-injection) T1-weighted images in the control and CDAHFD groups are shown. [Figure 72] Quantitative analysis of liver versus muscle ΔCNR at 20 min in each group is shown (all data are shown as mean ± SD; *P<0.05, **P<0.01, ***P<0.001; ns: not significant; one-way ANOVA, post hoc comparison, two-tailed). [Figure 73] Figure 73A shows representative H&E, Sirius Red, LysAld, and LOX staining of livers from control and CDAHFD-fed mice (scale bar: 100 μm). Figure 73B shows quantitative analysis of fat content expressed as % lipid vacuolation in H&E-stained livers from control and CDAHFD-fed mice (n≧4 per group, all data shown as mean±SD, **P<0.01, ***P<0.001, ns: not significant, one-way ANOVA, post hoc comparison, two-tailed). [Figure 74]Figure 74A shows quantification of total collagen assessed by hepatic hydroxyproline (Hyp) content as a measure of fibrosis (n≧4 per group, all data shown as mean±SD, **P<0.01, ***P<0.001, ns: not significant, one-way ANOVA, post hoc comparison, two-tailed). Figure 74B shows quantitative analysis of collagen proportional area (CPA) measured from Sirius Red-stained livers of control and CDAHFD-fed mice (n≧4 per group, all data shown as mean±SD, *P<0.05, **P<0.01, ***P<0.001, ns: not significant, one-way ANOVA, post hoc comparison, two-tailed). [Figure 75] The percentage of LOX-positive tissue measured from IHC LOX-stained tissues is shown (n ≥ 4 per group, all data are shown as mean ± SD; *P < 0.05, ***P < 0.001; ns: not significant; one-way ANOVA, post hoc comparison, two-tailed). [Figure 76-1] FIG. 76A shows representative images of immunohistochemical staining of α-smooth muscle actin (α-SMA) in control and CDAHFD-fed mice (scale bar: 500 μm). [Figure 76-2] Figure 76B shows quantitative analysis of the percentage of α-SMA-positive tissue measured from IHC-stained tissue (n≧4 per group, all data shown as mean±SD, *P<0.05, **P<0.01, ***P<0.001, ns: not significant, one-way ANOVA, post hoc comparison, two-tailed). [Figure 77-1] Figure 77A shows the correlation analysis between ΔCNR at 20 minutes and hydroxyproline content (R=0.24, P=0.24). Each data point represents one mouse. Figure 77B shows the correlation analysis between ΔCNR at 20 minutes and the percentage of LOX-positive tissue (R=0.92, P<0.0001). Each data point represents one mouse. [Figure 77-2]Figure 77C shows the correlation analysis between ΔCNR at 20 minutes and the integrated intensity of LysAld (R=0.74, P<0.0001). Each data point represents one mouse. [Figure 78] Quantitative analysis of the integrated intensity of LysAld obtained from the DNPH reaction assay as a measure of fibril formation is shown (n ≥ 4 per group, all data are shown as mean ± SD, *P < 0.05, ***P < 0.001, ns: not significant, one-way ANOVA, post hoc comparison, two-tailed). [Figure 79] Correlation analysis between the ΔCNR observed 20 min after Gd-9 injection and the percentage of positive tissue stained for α-SMA as a marker for tissue fibrogenesis is shown (R = 0.85, P < 0.0001). [Figure 80] The experimental design is shown in the figure. Bile duct ligation surgery was performed on male CD rats (n=7) aged 7-9 weeks. Ten days later, the rats were imaged before and 30 minutes after 100 μmol / kg i.v.Gd-9 (n=4 for the sham group). After imaging, the livers were harvested and sectioned. [Figure 81] Coronal MRI (gray scale) of a BDL rat with longitudinal relaxation rate (R1) maps (color scale) before injection and 30 min pi are shown. [Figure 82] Figure 82A shows that at 30 min p.i., the Gd-9-induced change in liver longitudinal relaxation rate (ΔR1) was 5-fold higher in BDL rats than in sham rats (***P=0.0003, unpaired t-test, two-tailed). Figure 82B shows that the liver-to-muscle ΔCNR at 30 min was 4-fold higher in BDL rats than in sham rats (**P=0.008, unpaired t-test, two-tailed). [Figure 83] The percentage of LysAld-positive liver tissue measured by DNPH reaction assay and the percentage of LOX-positive liver tissue measured by LOX IHC were both significantly higher in BDL rats than in sham rats (n = 4, ***P = 0.0014, ***P = 0.0006, respectively, unpaired t-test, two-tailed). [Figure 84-1] Figure 84A shows representative H&E, Sirius Red, LOX, and LysAld staining of livers obtained from sham and BDL rats. Figure 84B shows quantitative analysis of collagen proportional area (CPA) measured from Sirius Red-stained livers in sham and BDL rats. n=4. ***P<0.001, unpaired t-test, two-tailed. [Figure 84-2] Figure 84C shows total collagen quantification assessed by hepatic hydroxyproline (Hyp) content for sham (n=4) and BDL (n=7) rats. ***P<0.001, unpaired t-test, two-tailed. [Figure 85] Figure 85A shows serial liver slices obtained from a BDL rat after Gd-9-enhanced MRI. Left to right: LA-ICP-MS images of gadolinium distribution in freshly harvested BDL liver, BDL liver incubated with Gd-9, BDL liver incubated with Gd-9 + N2H4, and LysAld staining (scale bar: 500 μm). Figure 85B shows a distribution map of gadolinium measured by LA-ICP-MS in fresh sham liver collected 30 minutes after injection of Gd-9 (scale bar: 500 μm). [Figure 86] Gd distribution and co-localization of LysAld are shown along the line indicated by the arrow in Figure 85A. [Figure 87] Figure 87A shows human fibrotic / cirrhotic liver associated with NASH and normal liver samples obtained from surgery and sectioning. Figure 87B shows a representative liver section stained for LysAld by DNPH reaction assay to demonstrate the distribution of extracellular aldehydes (arrows indicate fibrotic bands). Figure 87C shows images of adjacent fibrotic liver sections stained for LOX (immunofluorescence), Sirius Red, or incubated with Gd-9 with or without 100x N2H4 and assessed by LA-ICP-MS. Figure 87D shows images of normal human liver incubated with Gd-9 and assessed by LA-ICP-MS. [Figure 88]Detection of liver fibrogenesis in human NASH fibrotic liver samples. Human fibrotic liver samples from 2-5 patients were stained for LysAld, LOX (immunofluorescence), Sirius Red, or incubated with Gd-9 and assessed by LA-ICP-MS (157Gd). [Figure 89] Detection of liver fibrogenesis in normal human liver samples. Human normal liver samples from 6-9 patients were stained for LysAld, LOX (immunofluorescence), Sirius Red, or incubated with Gd-9 and assessed by LA-ICP-MS (157Gd). [Figure 90] Figure 90A shows the percentage of LysAld-positive tissue for normal and fibrotic human livers as determined from the DNPH reaction assay (*P=0.0232). Figure 90B shows the mean Gd concentration in human fibrotic and normal tissues incubated with Gd-9 and assessed by LA-ICP-MS (**P=0.0023). All data are presented as mean ± SD. *P<0.05, **P<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0023] For example, disclosed herein are methods of molecular magnetic resonance (MR) imaging and positron emission tomography using extracellular probes that target extracellular allicinaldehyde and act as a non-invasive biomarker of fibrogenesis, with high sensitivity and specificity in detecting fibrogenesis in rodent models and human fibrotic tissues.

[0024] Many chronic and acute diseases have a fibroproliferative component, i.e., tissue becomes fibrotic or scarred. For example, chronic liver disease such as nonalcoholic steatohepatitis, chronic kidney disease, inflammatory bowel disease such as Crohn's disease, heart disease such as heart failure, atrial fibrillation, and myocardial infarction, pulmonary fibrotic diseases such as idiopathic pulmonary fibrosis, and cancers such as pancreatic ductal adenocarcinoma, scleroderma, and atherosclerosis all have fibrotic components. As an example, chronic liver disease (CLD) is caused by chronic injury due to alcohol, drug abuse, viral damage, or metabolic disorders (e.g., nonalcoholic steatohepatitis, NASH). CLD accounts for approximately 2 million deaths per year worldwide, with over 2 billion people at risk. If left untreated, CLD results in liver scarring (fibrosis), which can further lead to cirrhosis, primary liver cancer, liver failure, and / or death.

[0025] Biopsy is the gold standard for detecting and staging fibrosis, but it is invasive, subject to sampling error, carries the risk of complications, and is not amenable to continuous monitoring. Noninvasive methods for detecting and staging fibrosis exist, depending on the organ and disease. However, they all have limitations. Primarily, these methods can reliably detect only advanced stages of fibrosis and cannot measure disease activity, i.e., they cannot distinguish between active, ongoing disease (fibrosis) and older damage. For example, in the liver, ultrasound and magnetic resonance (MR) elastography techniques and some blood biomarker panels are effective in detecting advanced fibrosis, but they cannot detect the early onset of liver fibrosis or measure disease activity, i.e., fibrosis. Similar limitations exist in other organs, such as the lung; the high resolution computed by tomography can detect advanced fibrosis but cannot measure disease activity. In the heart, an MRI technique called extracellular volume mapping is used to predict fibrosis. Without wishing to be bound by theory, sensing disease activity provides the best guidance for reversing fibrosis and curing disease, enabling both disease detection and an early readout of treatment efficacy. Sensing fibrogenesis also facilitates drug discovery. For example, drug discovery efforts in nonalcoholic steatohepatitis (NASH) have been hampered by the inability to enroll patients with early-stage fibrosis and instead recruiting patients with advanced disease states, where drug therapy may be less effective. NASH clinical trials also require a reduction in fibrosis stage as an endpoint, but fibrosis regression is a slow process. Early measurement of treatment response allows for early cessation of ineffective treatments and better trial design to detect significant fibrosis reduction in promising therapies.

[0026] In tissue fibrosis, regardless of cause, activated myofibroblasts secrete inflammatory mediators and synthesize extracellular matrix (ECM) components. Excessive accumulation of ECM and ECM cross-linking cause tissue stiffening, disrupt tissue architecture, and lead to liver dysfunction and ultimately liver failure. Collagen is the most abundant protein in the fibrotic ECM. Noninvasive molecular imaging of collagen has been explored in preclinical models and has been shown to be effective in staging fibrosis; however, collagen imaging does not assess fibrosis and cannot distinguish between ongoing disease and old injury.

[0027] Lysyl oxidase (LOX) and its paralogs are established markers of fibrogenesis. During liver fibrogenesis, the secretion and enzymatic activity of lysyl oxidase (LOX) and its paralogs increase. Specifically, LOX binds closely spaced lysine-amino pairs, e.g., two Lys residues (both α1-Lys) in the C-telopeptide of collagen I. 16 ) and three Lys residues in the N-telopeptide (two α1-Lys 9 and one α2-Lys 5 ) to catalyze collagen cross-linking. The oxidation product is allysinaldehyde (Lys Ald ) pair, which then reacts with one ε-amino group [2+1] in the acceptor region of an adjacent collagen molecule to generate an intermolecular pyridinoline crosslink. A similar mechanism is found for all types of collagen and is conserved across species.

[0028] Without wishing to be bound by theory, these extracellular Lys, which are not present in normal liver tissue, Ald or Lys Ald Targeting Lys pairs is believed to provide a highly specific and sensitive biomarker of liver fibrogenesis. During active fibrosis, Lys AldThe concentration increases, but once fibrogenesis ceases, the aldehyde is consumed by degradation. These probe design attributes should result in a high MRI signal at the site of injury, providing a noninvasive and sensitive readout for measuring the early onset of fibrogenesis across various organs and tissues.

[0029] One embodiment is a compound of formula (I)

[0030] [ka] [In the formula, Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from the group consisting of halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, halogen, -NR A R B , -OH, C 1~6 Alkyl, or -C1~6 Alkyl-(NR A R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of the groups are -C(=O)OH] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, when n is 0 and p is 0, R 1 , R 3 , and R 5 At least one of is hydrogen.

[0032] In some embodiments, n is 1, p is 0, and R 1 , R 3 , R 5 , and R 7 are all -C(=O)OH, and R 2 , R 4 , R 6 , and R 8 Three of the are hydrogen, and R 2 , R 4 , R 6 , and R 8 One of them is C 3~25 If it is alkyl, C 3~25 At least one non-adjacent carbon atom of the alkyl is replaced with O.

[0033] In some embodiments, n is 1, p is 0, and R 1 , R 3 , R 5 , and R 7are all -C(=O)OH, and R 2 , R 4 , R 6 , and R 8 Three of the are hydrogen, and R 2 , R 4 , R 6 , and R 8 One of them is C 3~25 If it is alkyl, C 3~25 At least one non-adjacent carbon atom of the alkyl is replaced by O, and C 3~25 Alkyl is one or two -NR A R B is replaced by .

[0034] In some embodiments, the compound of formula (I) is

[0035] [ka]

[0036] [ka]

[0037] [ka] It's surprising.

[0038] In some embodiments, n is 0. In some embodiments, n is 1.

[0039] In some embodiments, p is 0. In some embodiments, p is 1.

[0040] In some embodiments, n is 0 and p is 0. In some embodiments, n is 0 and p is 1. In some embodiments, n is 1 and p is 1. In some embodiments, n is 1 and p is 0.

[0041] In some embodiments, R 2 , R4 , and R 6 are independently hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0042] In some embodiments, R 2 is hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0043] In some embodiments, R 4 is hydrogen and C 3~25 Alkyl (-NR A R B, —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0044] In some embodiments, R 6 is hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0045] In some embodiments, R 2 , R 4 , and R 6 is, independently, hydrogen, 4-10 membered heterocyclyl substituted -NR A R B C is replaced by 3~25 alkyl,3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0046] In some embodiments, R 2 Ha-NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0047] In some embodiments, R 2 teeth, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R BC is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl,3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0048] In some embodiments, R 2 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0049] In some embodiments, R 4 teeth, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH,3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C3~25 Alkyl, -NR A R B substituted with 4- to 10-membered heterocyclyl substituted with C 3~25 Alkyl, substituted with 4- to 10-membered heterocyclyl, C 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A RB C is replaced by 3~25 alkyl, 3~25 wherein one non-adjacent carbon atom of the alkyl is replaced by N; 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C where one non-adjacent carbon atom of an alkyl is replaced by O 3~25 Alkyl is selected from the group consisting of:

[0050] In some embodiments, R 6 teeth, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH,3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C where one non-adjacent carbon atom of an alkyl is replaced by O 3~25 Alkyl is selected from the group consisting of:

[0051] In some embodiments, R 2 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0052] In some embodiments, R 2 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0053] In some embodiments, R 2represents 5- to 10-membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0054] In some embodiments, R 2 -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced by O.

[0055] In some embodiments, R 2 is a C substituted with 4- to 10-membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0056] In some embodiments, R 2 are two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0057] In some embodiments, R 2 -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0058] In some embodiments, R 2 is -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0059] In some embodiments, R 2 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0060] In some embodiments, R 2 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0061] In some embodiments, R 2 is substituted with 4- to 10-membered heterocyclyl 3~25 It is alkyl.

[0062] In some embodiments, R 2 is C 3~25 It is alkyl.

[0063] In some embodiments, R 2 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25One non-adjacent carbon atom of the alkyl is replaced by NH.

[0064] In some embodiments, R 2 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0065] In some embodiments, R 2 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0066] In some embodiments, R 2 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0067] In some embodiments, R 2 C is substituted with OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced by N(CH3).

[0068] In some embodiments, R 2 There are two -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N, and the C 3~25Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of the alkyl are replaced with O.

[0069] In some embodiments, R 2 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0070] In some embodiments, R 4 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0071] In some embodiments, R 4 -NR is a 5- to 10-membered heteroaryl A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0072] In some embodiments, R 4 -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0073] In some embodiments, R 4 is a C substituted with 4- to 10-membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0074] In some embodiments, R 4 are two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0075] In some embodiments, R 4 -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0076] In some embodiments, R 4 is -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0077] In some embodiments, R 4 is -NR A R B and C substituted with -OH3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0078] In some embodiments, R 4 Ha-NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0079] In some embodiments, R 4 is substituted with 4- to 10-membered heterocyclyl 3~25 It is alkyl.

[0080] In some embodiments, R 4 is C 3~25 It is alkyl.

[0081] In some embodiments, R 4 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of the alkyl is replaced by NH.

[0082] In some embodiments, R 4 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0083] In some embodiments, R 4 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25One non-adjacent carbon atom of the alkyl is replaced with O.

[0084] In some embodiments, R 4 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0085] In some embodiments, R 4 C is substituted with OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of the alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced by N(CH3).

[0086] In some embodiments, R 4 There are two -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of the alkyl are replaced with O.

[0087] In some embodiments, R 4 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0088] In some embodiments, R 6 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0089] In some embodiments, R 6 represents 5- to 10-membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0090] In some embodiments, R 6 -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0091] In some embodiments, R 6 is substituted with 4- to 10-membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0092] In some embodiments, R 6 are two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0093] In some embodiments, R 6 -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0094] In some embodiments, R 6 is -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0095] In some embodiments, R 6 is -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0096] In some embodiments, R 6 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0097] In some embodiments, R 6 is substituted with 4- to 10-membered heterocyclyl 3~25 It is alkyl.

[0098] In some embodiments, R 6is C 3~25 It is alkyl.

[0099] In some embodiments, R 6 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of the alkyl is replaced by NH.

[0100] In some embodiments, R 6 is -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0101] In some embodiments, R 6 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0102] In some embodiments, R 6 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0103] In some embodiments, R 6 C is substituted with OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced by N(CH3).

[0104] In some embodiments, R 6 There are two -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of the alkyl are replaced with O.

[0105] In some embodiments, R 6 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0106] In some embodiments, R 2 , R 4 , and R 6 is, independently, hydrogen,

[0107] [ka]

[0108] [ka] is selected from the group consisting of:

[0109] In some embodiments, R 2 teeth, hydrogen,

[0110] [ka]

[0111] [ka] is selected from the group consisting of:

[0112] In some embodiments, R 4 teeth, hydrogen,

[0113] [ka]

[0114] [ka] is selected from the group consisting of:

[0115] In some embodiments, R 6 teeth, hydrogen,

[0116] [ka]

[0117] [ka] is selected from the group consisting of:

[0118] In some embodiments, R 2 , R 4 , and R 6 are all hydrogen. In some embodiments, R 2 is hydrogen. In some embodiments, R 4 is hydrogen. In some embodiments, R 6 is hydrogen.

[0119] In some embodiments, R 2 , R 4 , and R 6 are all -NR A R BC optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0120] In some embodiments, R 2 and R 4 are both hydrogen, and R 6 is -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0121] In some embodiments, R 2 and R 4 are both hydrogen, and R 6 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl,3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 alkyl, and -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 C where four non-adjacent carbon atoms of an alkyl are replaced by O 3~25 Alkyl is selected from.

[0122] In some embodiments, R 2 and R 6 are both hydrogen, and R 4 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0123] In some embodiments, R 2 and R 6 are both hydrogen, and R 4 teeth, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 alkyl, and C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C where one non-adjacent carbon atom of an alkyl is replaced by N(CH3) 3~25 Alkyl is selected from.

[0124] In some embodiments, R 6 and R 4 are both hydrogen, and R 2 is -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0125] In some embodiments, R 1 , R 3 , and R 5 are all -C(=O)OH.

[0126] In some embodiments, R 1 and R 3 are both -C(=O)OH, and R 5 is hydrogen.

[0127] In some embodiments, R 1 and R 5 are both -C(=O)OH, and R 3 is hydrogen.

[0128] In some embodiments, R 5 and R 3 are both -C(=O)OH, and R 1 is hydrogen.

[0129] In some embodiments, R 1 is -C(=O)OH, and R 2 is hydrogen.

[0130] In some embodiments, R 3 is -C(=O)OH, and R 4 is hydrogen.

[0131] In some embodiments, R 3 is hydrogen and R 4is -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0132] In some embodiments, R 3 is hydrogen and R 4 teeth, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 alkyl, and C substituted with OH 3~25 alkyl, 3~25one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl is selected from.

[0133] In some embodiments, R 5 is hydrogen and R 6 is -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0134] In some embodiments, R 5 is hydrogen and R 6 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 alkyl, and -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0135] In some embodiments, R 5 is -C(=O)OH, and R 6 is hydrogen.

[0136] In some embodiments, n is 1.

[0137] In some embodiments, R 2 , R 4 , R 6 , and R 8 are independently hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0138] In some embodiments, R 8is hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0139] In some embodiments, R 2 , R 4 , R 6 , and R 8 is, independently, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH,3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0140] In some embodiments, R 8 teeth, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A RB and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl,3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0141] In some embodiments, R 8 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0142] In some embodiments, R 8 -NR is a 5- to 10-membered heteroaryl A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0143] In some embodiments, R 8 -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0144] In some embodiments, R 8 is substituted with 4- to 10-membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0145] In some embodiments, R 8 There are two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0146] In some embodiments, R 8 -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0147] In some embodiments, R 8 Ha-NRA R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of the alkyl are replaced with O.

[0148] In some embodiments, R 8 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Four non-adjacent carbon atoms of the alkyl are replaced with O.

[0149] In some embodiments, R 8 Ha-NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0150] In some embodiments, R 8 is substituted with 4- to 10-membered heterocyclyl 3~25 It is alkyl.

[0151] In some embodiments, R 8 is C 3~25 It is alkyl.

[0152] In some embodiments, R 8 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of the alkyl is replaced by NH.

[0153] In some embodiments, R 8 Ha-NR A R B and C substituted with -OH 3~25alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0154] In some embodiments, R 8 Ha-NR A R B and C substituted with -OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0155] In some embodiments, R 8 Ha-NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of the alkyl are replaced by NH.

[0156] In some embodiments, R 8 C is substituted with OH 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced by N(CH3).

[0157] In some embodiments, R 8 There are two -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of the alkyl are replaced with O.

[0158] In some embodiments, R 8 Ha-NR A R BC is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, and the C 3~25 One non-adjacent carbon atom of the alkyl is replaced with O.

[0159] In some embodiments, R 2 , R 4 , R 6 , and R 8 is, independently, hydrogen,

[0160] [ka] is selected from the group consisting of:

[0161] In some embodiments, R 8 teeth, hydrogen,

[0162] [ka] is selected from the group consisting of:

[0163] In some embodiments, R 2 , R 4 , R 6 , and R 8 are all hydrogen. In some embodiments, R 8 is hydrogen.

[0164] In some embodiments, R 2 , R 4 , R 6 , and R 8 are all -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A RB , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0165] In some embodiments, R 2 and R 4 are both hydrogen, and R 6 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0166] In some embodiments, R 2 and R 6 are both hydrogen and R 4 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A RB , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0167] In some embodiments, R 2 and R 8 are both hydrogen, and R 4 and R 6 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0168] In some embodiments, R 4 and R 6 are both hydrogen, and R 2 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A RB , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0169] In some embodiments, R 4 and R 8 are both hydrogen, and R 2 and R 6 are both -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0170] In some embodiments, R 6 and R 8 are both hydrogen, and R 2 and R 4 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A RB , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0171] In some embodiments, R 2 , R 4 , and R 6 are all hydrogen, and R 8 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0172] In some embodiments, R 2 , R 4 , and R 8 are all hydrogen, and R 6 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B, -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0173] In some embodiments, R 2 , R 6 , and R 8 are all hydrogen, and R 4 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0174] In some embodiments, R 4 , R 6 , and R 8 are all hydrogen, and R 2 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0175] In some embodiments, R 2 and R 4 is hydrogen and R 6 and R 8 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl is selected from.

[0176] In some embodiments, R 4 and R 8 is hydrogen and R 2 and R 6 is -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0177] In some embodiments, R 2 , R 4 , and R 8 is hydrogen and R 6 teeth, Two -NR A R BC is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from.

[0178] In some embodiments, R 1 , R 3 , R 5 and R 7 are all -C(=O)OH.

[0179] In some embodiments, R 1 and R 3 are both -C(=O)OH, and R 5 and R 7 are both hydrogen.

[0180] In some embodiments, R 1 and R 5 are both -C(=O)OH, and R 3 and R 7 are both hydrogen.

[0181] In some embodiments, R 1 and R 7 are both -C(=O)OH, and R 3 and R 5 are both hydrogen.

[0182] In some embodiments, R 3and R 5 are both -C(=O)OH, and R 1 and R 7 are both hydrogen.

[0183] In some embodiments, R 3 and R 7 are both -C(=O)OH, and R 1 and R 5 are both hydrogen.

[0184] In some embodiments, R 5 and R 7 are both -C(=O)OH, and R 1 and R 3 are both hydrogen.

[0185] In some embodiments, R 1 , R 3 , and R 5 are all -C(=O)OH, and R 7 is hydrogen.

[0186] In some embodiments, R 1 , R 3 , and R 7 are all -C(=O)OH, and R 5 is hydrogen.

[0187] In some embodiments, R 1 , R 5 , and R 7 are all -C(=O)OH, and R 3 is hydrogen.

[0188] In some embodiments, R 3 , R 5 , and R 7 are all -C(=O)OH, and R 1 is hydrogen.

[0189] In some embodiments, R 1 is -C(=O)OH, and R 2 is hydrogen.

[0190] In some embodiments, R 1 is -C(=O)OH and R 2 is -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0191] In some embodiments, R 1 is -C(=O)OH, and R 2 Ha-NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 It is alkyl.

[0192] In some embodiments, R 3 is -C(=O)OH, and R 4 is hydrogen.

[0193] In some embodiments, R 5 is -C(=O)OH, and R 6 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0194] In some embodiments, R 5 is hydrogen and R 6 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced by O, N, NH, or N(CH3).

[0195] In some embodiments, R 5 is -C(=O)OH and R 6 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl is selected from.

[0196] In some embodiments, R 5 is hydrogen and R 6 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl is selected from.

[0197] In some embodiments, R 7 is -C(=O)OH, and R 8 is hydrogen.

[0198] In some embodiments, R 7 is -C(=O)OH, and R 8 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0199] In some embodiments, R 7 is hydrogen and R 8 Ha-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 One to six non-adjacent carbon atoms of an alkyl are optionally replaced with O, N, NH, or N(CH3).

[0200] In some embodiments, R 7 is -C(=O)OH, and R 8 is substituted with 4- to 10-membered heterocyclyl 3~25 It is alkyl.

[0201] In some embodiments, R 7 is hydrogen and R 8 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C 3~25 alkyl, and -NR A R BC is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, is selected from.

[0202] In some embodiments, p is 0.

[0203] In some embodiments, p is 1.

[0204] In some embodiments, R 9 is H, a halogen, or -OH.

[0205] In some embodiments, R 9 is H.

[0206] In some embodiments, R A is hydrogen.

[0207] In some embodiments, R A is C 1~6 In some embodiments, R A is -CH3.

[0208] In some embodiments, R B is hydrogen.

[0209] In some embodiments, R B is C 1~6 In some embodiments, R B is -CH3.

[0210] In some embodiments, R A and R B are both hydrogen.

[0211] In some embodiments, the compound of formula (I) is a compound of formula (IA)

[0212] [ka] or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, R 6 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 alkyl, and -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl is selected from the group consisting of:

[0214] In some embodiments, Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B, —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 At least two of the are -C(=O)OH.

[0215] In some embodiments, the compound of formula (I) is a compound of formula (IB)

[0216] [ka] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, R 6 teeth -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl is selected from the group consisting of:

[0218] In some embodiments, R 8 teeth, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl is selected from the group consisting of:

[0219] In some embodiments, the compound of formula (I) is a compound of formula (IC)

[0220] [ka] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, R 2 teeth, hydrogen, and -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl is selected from the group consisting of:

[0222] In some embodiments, R 6 teeth, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 alkyl, and -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl is selected from the group consisting of:

[0223] In some embodiments, the compound of formula (I) is a compound of formula (ID)

[0224] [ka] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, R 4 teeth, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R BC is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 alkyl, and C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C where one non-adjacent carbon atom of an alkyl is replaced by N(CH3) 3~25 Alkyl is selected from the group consisting of:

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

[0227] [Table 1-1]

[0228] [Table 1-2]

[0229] [Table 1-3]

[0230] [Table 1-4]

[0231] [Table 1-5] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound further comprises a complexed metal cation. In some embodiments, the metal cation is a metal cation used in nuclear magnetic resonance imaging. In some embodiments, the metal cation is a metal cation used in positron emission tomography.

[0233] In some embodiments, the metal cation is Zn, Ga, Gd, Cu, Yb, Mn, Tc, In, Y, or Zr cation. 2+ , Ga 3+ , Gd 3+ , Cu 2+ , Yb 3+ , or Mn 2+ In some embodiments, the metal cation is Zn 2+ In some embodiments, the metal cation is Ga 3+ In some embodiments, the metal cation is Gd 3+ In some embodiments, the metal cation is Cu 2+ In some embodiments, the metal cation is Yb 3+ In some embodiments, the metal cation is Mn 2+ is.

[0234] In some embodiments, the metal cation is 99m Tc, 67 Ga, 68 Ga, 52 Mn, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 89 Zr, 86 Y, or 111 In some embodiments, the metal cation is 68 Ga, 52 Mn, or 64 In some embodiments, the metal cation is 99m In some embodiments, the metal cation is a Tc cation. 67 In some embodiments, the metal cation is 68In some embodiments, the metal cation is 52 In some embodiments, the metal cation is 60 In some embodiments, the metal cation is 60 In some embodiments, the metal cation is 61 In some embodiments, the metal cation is 62 In some embodiments, the metal cation is 64 In some embodiments, the metal cation is 89 In some embodiments, the metal cation is 86 Y is a cation. In some embodiments, the metal cation is 111 It is an In cation.

[0235] In some embodiments, the compound of formula I is

[0236] [Table 2-1]

[0237] [Table 2-2]

[0238] [Table 2-3]

[0239] [Table 2-4]

[0240] [Table 2-5]

[0241] [Table 2-6]

[0242] [Table 2-7] or a pharmaceutically acceptable salt thereof.

[0243] Compound of formula (II)

[0244] [ka] [In formula: M is a metal cation; Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from the group consisting of halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B Optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, halogen, -NR A R B , -OH, C 1~6Alkyl, or -C 1~6 Alkyl-(NR A R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, and p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of is -C(=O)OH] or a pharmaceutically acceptable salt thereof is also provided herein.

[0245] In some embodiments, provided herein is a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the composition comprises a mixture of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is formulated for parenteral administration. In some embodiments, the composition is a solid that is formulated to be dissolved in a pharmaceutically acceptable liquid medium before administration.

[0246] method Some embodiments provide a method for in vivo imaging of a subject, comprising: (a) administering to the subject a compound of any one of Formula (I) or (II), or a mixture of any of the foregoing, or a pharmaceutical composition comprising same; and (b) obtaining an image of the subject after a predetermined period of time. Step (b) can include obtaining an image of the entire subject (e.g., a whole-body scan), imaging specific regions of the subject's body, or both.

[0247] The specific region of the subject's body can be an organ.For example, the organ can be the liver, stomach, esophagus, pancreas, lung, kidney, bladder, thyroid, heart, spleen, intestine or brain.In some embodiments, the organ is the liver, heart, liver and kidney.

[0248] Some embodiments provide methods for measuring fibrogenesis. Some embodiments provide methods for detecting fibrogenesis. Some embodiments provide methods for measuring bile duct ligation. Some embodiments provide methods for detecting bile duct ligation. Some embodiments provide methods for measuring bleomycin injury. Some embodiments provide methods for detecting bleomycin injury.

[0249] Imaging can be, for example, magnetic resonance (MR) imaging, nuclear imaging, positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, optical imaging, or light microscopy.

[0250] Some embodiments provide a method of imaging an object, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining an image of the object after a predetermined period of time. The present invention provides a method comprising:

[0251] In some embodiments, the image obtained in step (b) is indicative of a disease or disorder described herein.

[0252] Some embodiments provide a method of imaging an object, comprising: (a) obtaining a first image of an object; (b) administering to the subject a compound or composition disclosed herein; (c) obtaining a second image of the object after a predetermined period of time; and (d) comparing the first image of the object with the second image of the object. The present invention provides a method comprising:

[0253] In some embodiments, comparing the first image with the second image of step (d) is indicative of a disease or disorder described herein.

[0254] Magnetic resonance imaging Some embodiments provide a method of magnetic resonance (MR) imaging a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining a magnetic resonance image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0255] Some embodiments provide a method of magnetic resonance (MR) imaging a subject, comprising: (a) obtaining a first magnetic resonance image of a subject; (b) administering to the subject a compound or composition disclosed herein; (c) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (d) comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. The present invention provides a method comprising:

[0256] In some embodiments, comparing the first magnetic resonance image with the second magnetic resonance image of step (d) is indicative of a disease or disorder described herein.

[0257] Some embodiments provide a method for imaging liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining a magnetic resonance image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0258] Some embodiments provide a method of measuring liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound or composition disclosed herein; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) measuring liver fibrogenesis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject; The present invention provides a method comprising:

[0259] Some embodiments provide a method for detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) detecting liver fibrosis in the subject by obtaining a magnetic resonance image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0260] Some embodiments provide a method of detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound or composition disclosed herein; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) detecting the presence or absence of liver fibrogenesis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject; The present invention provides a method comprising:

[0261] Some embodiments provide a method for detecting liver fibrogenesis in a subject, the method comprising obtaining a magnetic resonance image of the subject within a predetermined period of time after the subject has been administered a compound or composition disclosed herein.

[0262] Positron Emission Tomography Imaging Positron emission tomography can include measuring the signal in the organ of interest, expressed, for example, as a percent of the injected dose per cubic centimeter (cc) of tissue or as a standardized uptake value (SUV). In some embodiments, the signal in the organ of interest is compared to a reference tissue, such as muscle, and a target-to-background ratio is measured.

[0263] Some embodiments provide a method of imaging a subject by positron emission tomography (PET), comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining a positron emission tomography image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0264] Some embodiments provide a method for imaging liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) after a predetermined period of time, imaging liver fibrosis in the subject by obtaining a PET image of the subject. The present invention provides a method comprising:

[0265] Some embodiments provide a method of measuring liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein; (b) obtaining a first PET image of the subject after a predetermined period of time; (c) after the second period of time, administering to the subject a compound or composition disclosed herein; (d) obtaining a second PET image of the subject after a predetermined period of time; and (e) measuring liver fibrosis in the subject by comparing the first PET image of the subject with the second PET image of the subject. The present invention provides a method comprising:

[0266] Some embodiments provide a method for detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) detecting the presence or absence of liver fibrosis in the subject by obtaining a PET image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0267] Some embodiments provide a method of detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound or composition disclosed herein; (b) obtaining a first PET image of the subject after a predetermined period of time; (c) after the second period of time, administering to the subject a compound or composition disclosed herein; (d) obtaining a second PET image of the subject after a predetermined period of time; and (e) detecting the presence or absence of liver fibrosis in the subject by comparing the first PET image of the subject with the second PET image of the subject. The present invention provides a method comprising:

[0268] Some embodiments provide a method for detecting liver fibrogenesis in a subject, the method comprising obtaining a PET image of the subject within a predetermined period of time after the subject has been administered a compound or composition disclosed herein.

[0269] Nuclear Imaging Some embodiments provide a method of nuclear imaging a subject, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining a nuclear image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0270] Some embodiments provide a method of nuclear imaging a subject, comprising: (a) obtaining a first nuclear image of a subject; (b) administering to the subject a compound or composition disclosed herein; (c) obtaining a second nuclear image of the subject after a predetermined period of time; and (d) comparing the first nuclear image of the subject with the second nuclear image of the subject. The present invention provides a method comprising:

[0271] Single-photon emission tomographic imaging Some embodiments provide a method of imaging a subject by single photon emission computed tomography, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining a single photon emission computed tomography image of the subject after a predetermined period of time. The present invention provides a method comprising:

[0272] optical imaging Some embodiments provide a method of optically imaging an object, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining an optical image of the object after a predetermined period of time; The present invention provides a method comprising:

[0273] Some embodiments provide a method of optically imaging an object, comprising: (a) obtaining a first optical image of an object; (b) administering to the subject a compound or composition disclosed herein; (c) obtaining a second optical image of the object after a predetermined period of time; and (d) comparing the first optical image of the object with the second optical image of the object. The present invention provides a method comprising:

[0274] Optical microscope imaging Some embodiments provide a method of optical microscopy imaging of an object, comprising: (a) administering to a subject a compound or composition disclosed herein, and (b) obtaining an optical microscope image of the object after a predetermined period of time. The present invention provides a method comprising:

[0275] Some embodiments provide a method of optical microscopy imaging of an object, comprising: (a) obtaining a first optical microscope image of an object; (b) administering to the subject a compound or composition disclosed herein; (c) obtaining a second optical microscope image of the object after a predetermined period of time; and (d) comparing the first optical microscope image of the object with the second optical microscope image of the object. The present invention provides a method comprising:

[0276] definition The term "n-membered," where n is an integer, generally describes the number of ring-forming atoms in a moiety, where n is the number of ring-forming atoms in the moiety. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0277] As used herein, the phrase "optionally substituted" means unsubstituted or substituted with the indicated group. The substituents are independently selected, and substitution may occur at any chemically available position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with the indicated substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence.

[0278] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "each occurrence of 'variable' is selected from."

[0279] Throughout the definition, "C n~m The term "" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. For example, C 1~3 , C 1~4 , C 1~6 Examples include:

[0280] As used herein, "C" or "C" used alone or in combination with other terms n~m The term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, alkyl groups contain 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C n~m The carbon atoms of an alkyl group may be optionally substituted with one or more oxo (eg, C(=O)).

[0281] As used herein, "C" or "C" used alone or in combination with other terms n ~ m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0282] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0283] As used herein, the term "carbonyl" or "oxo", employed alone or in combination with other terms, refers to a -C(O)- group.

[0284] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N within the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1, 2, or 3 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring with 5 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, S, and B. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. Exemplary heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b]thiazole, purine, triazine, thieno[3,2-b]pyridine, imidazo[1,2-a]pyridine, 1,5-naphthyridine, 1H-pyrazolo[4,3-b]pyridine, and the like.

[0285] A 5-membered heteroaryl is a heteroaryl group having 5 ring-forming atoms, wherein one or more (e.g., 1, 2, or 3) of the ring-forming atoms are independently selected from N, O, B, and S. Exemplary 5-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and 1,2-dihydro-1,2-azaborine.

[0286] A 6-membered heteroaryl ring is a heteroaryl having a ring with 6 ring-forming atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, S, and B. Exemplary 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0287] As used herein, "heterocyclyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially saturated), in which one or more of the ring-forming carbon atoms of the heterocyclyl are replaced with a heteroatom selected from N, O, S, and B, and the ring-forming carbon atoms and heteroatoms of the heterocyclyl group are optionally substituted with one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)). Heterocyclyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Included in heterocyclyl are monocyclic and polycyclic 3-14-, 4-14-, 3-10-, 4-10-, 5-10-, 4-7-, 5-7-, 5-6-, 5-, or 6-membered heterocyclyl groups. Heterocyclyl groups can also include spirocyclic and bridged rings (e.g., 5- to 14-membered bridged biheterocyclyl rings in which one or more ring-forming carbon atoms are replaced with heteroatoms independently selected from N, O, S, and B). Heterocyclyl groups can be bonded via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocyclyl groups contain 0 to 3 double bonds, i.e., are partially saturated. In some embodiments, heterocyclyl groups contain 0 to 2 double bonds.

[0288] Exemplary heterocyclyl groups include pyrrolidonyl, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholinyl, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolinyl, and the like. Zolidinyl, azepanil, 1,2,3,4-tetrahydroisoquinoline, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro [3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl, and the like. In some embodiments, the heterocyclyl group is pyrrolidonyl, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholinyl, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, or azepanyl.

[0289] In some embodiments, the heterocyclyl group contains 3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocyclyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocyclyl is a monocyclic 4-6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocyclyl is a monocyclic or bicyclic 4-10 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members.

[0290] As used herein, the term "oxo" refers to an oxygen atom (i.e., =0) as a divalent substituent, which when attached to carbon forms a carbonyl group (e.g., C=O or C(O)), or when attached to a nitrogen or sulfur heteroatom forms a nitroso, sulfinyl, or sulfonyl group. "Oxo" can also refer to an oxygen atom as a ligand to a metal atom, e.g., an iron atom.

[0291] "Subject," as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the subject is a human.

[0292] The term "about," when used in connection with numerical values ​​throughout the specification and claims, denotes an interval of accuracy familiar and accepted by those skilled in the art. Such an interval of accuracy is, for example, ±10%.

[0293] The metal cation can include metal cations having atomic numbers of 21-29, 40, 42, or 57-83. For example, the metal cation can include stable or unstable isotopes of the metal. The metal cation can include a mixture of isotopes or a single isotope. In some embodiments, the metal cation is radioactive. In some embodiments, the metal cation is non-radioactive.

[0294] Embodiment Embodiment 1: Compound of Formula (I)

[0295] [ka] [In the formula, Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from the group consisting of halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B Optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R 9 is H, halogen, -NRA R B , -OH, C 1~6 Alkyl, or -C 1~6 Alkyl-(NR A R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of the groups are -C(=O)OH] or a pharmaceutically acceptable salt thereof.

[0296] Embodiment 2: The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0297] Embodiment 3: R 2 , R 4 , and R 6 are independently hydrogen and C 3~25 Alkyl (-NR A R B , —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0298] Embodiment 4: R 2 , R 4 , and R 6 But independently, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, Two -NR A RB C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 four non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 Alkyl, -NR A R B C is replaced by 3~25alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C 3~25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C 3~25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 two non-adjacent carbon atoms of an alkyl replaced by O, C 3~25 Alkyl, -NR A R B C is replaced by3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 one non-adjacent carbon atom of an alkyl is replaced by O, C 3~25 Alkyl or a pharmaceutically acceptable salt thereof.

[0299] Embodiment 5: R 2 , R 4 , and R 6 But independently, hydrogen,

[0300] [ka]

[0301] [ka] or a pharmaceutically acceptable salt thereof.

[0302] Embodiment 6: R 2 , R 4 , and R 6 are all hydrogen, or a pharmaceutically acceptable salt thereof.

[0303] Embodiment 7: R 2 , R 4 , and R 6 All are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NRA R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0304] Embodiment 8: R 2 and R 4 are both hydrogen and R 6 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0305] Embodiment 9:R 2 and R 6 are both hydrogen and R 4 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0306] Embodiment 10:R 6 and R 4 are both hydrogen and R 2 Ga-NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0307] Embodiment 11:R 1 , R 3 , and R 5 are all -C(=O)OH, or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 12:R 1 and R 3 are both -C(=O)OH and R 5 11. The compound of any one of embodiments 2 to 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0309] Embodiment 13:R 1 and R 5 are both -C(=O)OH and R 3 11. The compound of any one of embodiments 2 to 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0310] Embodiment 14:R 5 and R 3 are both -C(=O)OH and R 1 11. The compound of any one of embodiments 2 to 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0311] Embodiment 15:R 1 is -C(=O)OH, and R 2 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0312] Embodiment 16:R 3 is -C(=O)OH, and R 4 16. The compound of embodiment 2 or 15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0313] Embodiment 17:R 3 is hydrogen and R 4 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25The compound of embodiment 2 or 15, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0314] Embodiment 18:R 5 is hydrogen and R 6 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of any one of embodiments 2 and 15 to 17, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH).

[0315] Embodiment 19:R 5 is -C(=O)OH, and R 6 18. The compound of any one of embodiments 2 and 15-17, or a pharmaceutically acceptable salt thereof, wherein:

[0316] Embodiment 20: The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0317] Embodiment 21:R 2 , R 4 , R 6 , and R 8 are independently hydrogen and C 3~25 Alkyl (-NR A R B, —OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is optionally substituted with 1 to 2 substituents independently selected from the group consisting of —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0318] Embodiment 22:R 2 , R 4 , R 6 , and R 8 But independently, hydrogen, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C3~ where four non-adjacent carbon atoms of an alkyl are replaced by O 25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl,3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -C 1~6 Alkyl-(NR A R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 C3-25 alkyl, in which three non-adjacent carbon atoms of the alkyl are replaced by O; -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH,3~25 C3~ where four non-adjacent carbon atoms of an alkyl are replaced by O 25 Alkyl, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl; C 3~25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, C3~ 25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C3~ 25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of alkyl is replaced by O, C3~ 25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C3~ 25 Alkyl, C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C3~ 25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of alkyl is replaced by O, C3~ 25 Alkyl 21. The compound of embodiment 20, selected from the group consisting of:

[0319] Embodiment 23:R 2 , R 4 , R 6 , and R 8 But independently, hydrogen,

[0320] [ka]

[0321] [ka] 21. The compound of embodiment 20, selected from the group consisting of:

[0322] Embodiment 24:R 2 , R 4 , R 6 , and R8 are all hydrogen, or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 25:R 2 , R 4 , R 6 , and R 8 All are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0324] Embodiment 26:R 2 and R 4 are both hydrogen and R 6 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0325] Embodiment 27:R 2 and R 6 are both hydrogen and R 4 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0326] Embodiment 28:R 2 and R 8 are both hydrogen and R 4 and R 6 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A RB and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0327] Embodiment 29:R 4 and R 6 are both hydrogen and R 2 and R 8 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0328] Embodiment 30:R 4 and R 8 are both hydrogen and R 2 and R 6 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0329] Embodiment 31:R 6 and R 8 are both hydrogen and R 2 and R 4 Both are -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0330] Embodiment 32:R 2 , R 4 , and R 6 are all hydrogen, and R 8 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0331] Embodiment 33:R 2 , R 4 , and R 8 are all hydrogen, and R 6 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0332] Embodiment 34:R 2 , R 6 , and R 8 are all hydrogen, and R 4 But, -NR A R BC optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0333] Embodiment 35:R 4 , R 6 , and R 8 are all hydrogen, and R 2 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0334] Embodiment 36:R 1 , R 3 , R 5 and R 7The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein all are -C(=O)OH.

[0335] Embodiment 37:R 1 and R 3 are both -C(=O)OH and R 5 and R 7 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0336] Embodiment 38:R 1 and R 5 are both -C(=O)OH and R 3 and R 7 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0337] Embodiment 39:R 1 and R 7 are both -C(=O)OH and R 3 and R 5 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0338] Embodiment 40:R 3 and R 5 are both -C(=O)OH and R 1 and R 7 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0339] Embodiment 41:R 3 and R 7 are both -C(=O)OH and R 1 and R 5 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0340] Embodiment 42:R 5and R 7 are both -C(=O)OH and R 1 and R 3 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

[0341] Embodiment 43:R 1 , R 3 , and R 5 are all -C(=O)OH, and R 7 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0342] Embodiment 44:R 1 , R 3 , and R 7 are all -C(=O)OH, and R 5 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0343] Embodiment 45:R 1 , R 5 , and R 7 are all -C(=O)OH, and R 3 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0344] Embodiment 46:R 3 , R 5 , and R 7 are all -C(=O)OH, and R 1 The compound of any one of embodiments 20 to 35, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0345] Embodiment 47:R 1 is -C(=O)OH, and R 2 21. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0346] Embodiment 48:R 1 is -C(=O)OH and R2 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0347] Embodiment 49:R 3 is -C(=O)OH, and R 4 The compound of any one of embodiments 20, 47, and 48, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0348] Embodiment 50:R 5 is -C(=O)OH, and R 6 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25The compound of any one of embodiments 20 and 47 to 49, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0349] Embodiment 51:R 5 is hydrogen and R 6 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of any one of embodiments 20 and 47 to 49, or a pharmaceutically acceptable salt thereof, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3).

[0350] Embodiment 52:R 7 is -C(=O)OH, and R 8 The compound of any one of embodiments 20 and 47-51, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0351] Embodiment 53:R 7 is -C(=O)OH and R 8 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR AR B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of any one of embodiments 20 and 47 to 51, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3), or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 54:R 7 is hydrogen and R 8 But, -NR A R B C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl 3~25 alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B and wherein the C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of 3~25 The compound of any one of embodiments 20 and 47 to 51, wherein 1 to 6 non-adjacent carbon atoms of the alkyl are optionally replaced with O, N, NH, or N(CH3), or a pharmaceutically acceptable salt thereof.

[0353] Embodiment 55: A compound of any one of embodiments 1 to 54, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0354] Embodiment 56:R 9 56. The compound of any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, wherein is H, halogen, or —OH.

[0355] Embodiment 57:R 9 56. The compound of any one of embodiments 1 to 55, wherein is H, or a pharmaceutically acceptable salt thereof.

[0356] Embodiment 58: A compound of any one of embodiments 1 to 54, or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0357] Embodiment 59:R A The compound of any one of embodiments 1 to 58, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0358] Embodiment 60:R A C 1~6 59. The compound of any one of embodiments 1 to 58, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0359] Embodiment 61:R B 61. The compound of any one of embodiments 1 to 60, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0360] Embodiment 62:R B C 1~6 61. The compound of any one of embodiments 1 to 60, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0361] Embodiment 63:R A and R B The compound of any one of embodiments 1 to 58, or a pharmaceutically acceptable salt thereof, wherein:

[0362] Embodiment 64: The compound of Formula (I) is a compound of Formula (IA)

[0363] [ka] or a pharmaceutically acceptable salt thereof.

[0364] Embodiment 65:R 6 but, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 C3~ where four non-adjacent carbon atoms of an alkyl are replaced by O 25 Alkyl, 5-10 membered heteroaryl and -NR A R B C is replaced by 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -OH and C 1~6 C substituted with 5-10 membered heteroaryl substituted with alkyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -C 1~6 Alkyl-(NRA R B ) substituted with 4-10 membered heterocyclyl 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 Alkyl, and -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 two non-adjacent carbon atoms of an alkyl are replaced by NH, 3~25 C3~ where four non-adjacent carbon atoms of an alkyl are replaced by O 25 Alkyl 65. The compound of embodiment 64, selected from the group consisting of:

[0365] Embodiment 66: The compound of Formula (I) is a compound of Formula (IB)

[0366] [ka] or a pharmaceutically acceptable salt thereof.

[0367] Embodiment 67:R 6 but, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 alkyl, and -NRA R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, C3~ 25 Alkyl 67. The compound of embodiment 66, selected from the group consisting of:

[0368] Embodiment 68:R 8 but, -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl, C substituted with 4-10 membered heterocyclyl 3~25 Alkyl, C 3~25 alkyl, and -NR A R B C is replaced by 3~25 alkyl, 3~25 One non-adjacent carbon atom of an alkyl is replaced by NH, C3~ 25 Alkyl 68. The compound of embodiment 66 or 67, or a pharmaceutically acceptable salt thereof.

[0369] Embodiment 69: The compound of Formula (I) is a compound of Formula (IC)

[0370] [ka] or a pharmaceutically acceptable salt thereof.

[0371] Embodiment 70:R 2 but, hydrogen, and -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl 70. The compound of embodiment 69, selected from the group consisting of:

[0372] Embodiment 71:R 6 but, Two -NR A R B C is replaced by 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by N, 3~25 Three non-adjacent carbon atoms of an alkyl are replaced by NH, and the C 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by O, C3~ 25 alkyl, and -NR A R B C substituted with 4- to 10-membered heterocyclyl substituted with 3~25 Alkyl 71. The compound of embodiment 69 or 70, selected from the group consisting of:

[0373] Embodiment 72: The compound of formula (I) is a compound of formula (ID)

[0374] [ka] or a pharmaceutically acceptable salt thereof.

[0375] Embodiment 73:R 4 but, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C3~ 25 Alkyl, -NR A R B and C substituted with -OH 3~25 alkyl, 3~25one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of alkyl is replaced by O, C3~ 25 Alkyl, -NR A R B C is replaced by 3~25 alkyl, 3~25 Two non-adjacent carbon atoms of an alkyl are replaced by NH, C3~ 25 alkyl, and C substituted with OH 3~25 alkyl, 3~25 one non-adjacent carbon atom of an alkyl is replaced by NH, 3~25 One non-adjacent carbon atom of an alkyl is replaced by N(CH3), C3~ 25 Alkyl 73. The compound of embodiment 72, selected from the group consisting of:

[0376] Embodiment 74: A compound of Formula (I)

[0377] [Table 3-1]

[0378] [Table 3-2]

[0379] [Table 3-3]

[0380] [Table 3-4]

[0381] [Table 3-5] or a pharmaceutically acceptable salt thereof.

[0382] Embodiment 75: The compound of any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, further comprising a complexed metal cation.

[0383] Embodiment 76: The compound of embodiment 75, or a pharmaceutically acceptable salt thereof, wherein the metal cation is a Zn, Ga, Gd, Cu, Yb, Mn, Tc, or In cation.

[0384] Embodiment 77: The metal cation is Zn 2+ , Ga 3+ , Gd 3+ , Cu 2+ , Yb 3+ , or Mn 2+ 77. The compound of embodiment 75 or 76, wherein:

[0385] Embodiment 78: A compound of Formula (I)

[0386] [Table 4-1]

[0387] [Table 4-2]

[0388] [Table 4-3]

[0389] [Table 4-4]

[0390] [Table 4-5]

[0391] [Table 4-6]

[0392] [Table 4-7] or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 79: A composition comprising a compound of any one of embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0394] Embodiment 80: The composition of embodiment 79, comprising a mixture of compounds of embodiments 1 to 78, or pharmaceutically acceptable salts thereof.

[0395] Embodiment 81: The composition of embodiment 79 or 80, which is formulated for parenteral administration.

[0396] Embodiment 82: The composition of any one of embodiments 79 to 81, which is a solid formulated to be dissolved in a pharmaceutically acceptable liquid vehicle prior to administration.

[0397] Embodiment 83: A method of magnetic resonance (MR) imaging a subject, comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; and (b) obtaining a magnetic resonance image of the subject after a predetermined period of time. A method comprising:

[0398] Embodiment 84: A method of magnetic resonance (MR) imaging a subject, comprising: (a) obtaining a first magnetic resonance image of a subject; (b) administering to the subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (c) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (d) comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. A method comprising:

[0399] Embodiment 85: A method for imaging liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; and (b) obtaining a magnetic resonance image of the subject's liver after a predetermined period of time; A method comprising:

[0400] Embodiment 86: A method of measuring liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) measuring liver fibrosis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. A method comprising:

[0401] Embodiment 87: A method for detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; and (b) detecting the presence or absence of liver fibrosis in the subject by obtaining a magnetic resonance image of the subject after a predetermined period of time. A method comprising:

[0402] Embodiment 88: A method for detecting liver fibrogenesis in a subject, comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (b) after a predetermined period of time, obtaining a first magnetic resonance image of the subject; (c) after the second period of time, administering to the subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (d) obtaining a second magnetic resonance image of the subject after a predetermined period of time; and (e) detecting the presence or absence of liver fibrosis in the subject by comparing the first magnetic resonance image of the subject with the second magnetic resonance image of the subject. Woah, method.

[0403] Embodiment 89: A method for detecting liver fibrogenesis in a subject, comprising obtaining a magnetic resonance image of the subject within a predetermined period of time after the subject has been administered a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82.

[0404] Embodiment 90: A method of imaging a subject by positron emission tomography (PET), comprising: (a) administering to a subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; and (b) obtaining a positron emission tomography image of the subject after a predetermined period of time. A method comprising:

[0405] Embodiment 91: A method of imaging a subject by positron emission tomography (PET), comprising: (a) obtaining a first magnetic resonance image of a subject; (b) administering to the subject a compound of any one of embodiments 1 to 78 or a composition of any one of embodiments 79 to 82; (c) obtaining a second positron emission tomography image of the subject after a predetermined period of time; and (d) comparing the first magnetic resonance image of the subject with the second positron emission tomography image of the subject. A method comprising:

[0406] Embodiment 92: Compound of Formula (II)

[0407] [ka] [In the formula, M is a metal cation; Each R 1 , R 3 , R 5 , and R 7 are independently hydrogen or —C(═O)OH; Each R 2 , R 4 , R 6 , and R 8 are independently hydrogen or C 3~25 alkyl, 3~25 Alkyl is -NR A R B , -OH, halogen, C 1~6 and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each selected from the group consisting of halogen, —NR A R B , -OH, C 1~6 Alkyl, and -C 1~6 Alkyl-(NR A R B Optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 3~25 one or more non-adjacent carbon atoms of the alkyl are optionally replaced by O, N, NH, or N(CH3); R9 is H, halogen, -NR A R B , -OH, C 1~6 Alkyl, or -C 1~6 Alkyl-(NR A R B ) and Each R A and R B are independently hydrogen or C 1~6 is alkyl, n is 0 or 1, p is 0 or 1, If n is 0, R 1 , R 3 , and R 5 At least two of n are -C(=O)OH, and when n is 1, R 1 , R 3 , R 5 , and R 7 wherein at least two of the groups are -C(=O)OH] or a pharmaceutically acceptable salt thereof.

[0408] References

[0409] [Table 5-1]

[0410] [Table 5-2]

[0411] [Table 5-3]

[0412] [Table 5-4]

[0413] [Table 5-5]

[0414] [Table 5-6] [Example]

[0415] The following examples are illustrative and not intended to be limiting.

[0416] Lys Ald Accurate targeting of the pair requires attaching the targeting group to two Lys Ald The distance between the Gd-DOTA core and the Gd-DOTA core must closely match. Here, we designed a probe using a Gd-DOTA core (Figure 41). This Gd-DOTA core distributes extracellularly and is the most thermodynamically stable and kinetically inert Gd core known. 3+ Complexes (21, 22) are known to be Gd-CHyd complexes. Two piperazino-hydrazine moieties were introduced onto the α-carbons of the two Gd-DOTA carboxylate arms to give either cis-1,4-Gd-(CHyd)2 (Gd-9) or trans-1,7-Gd-(CHyd)2 (Gd-10), which differ in the distance between the two hydrazine moieties (Figure 2A). Two control compounds were prepared: Gd-11, which possesses one piperazino-hydrazine and one piperazine arm, and Gd-CHyd, which has only one piperazino-hydrazine moiety (Figure 4I).

[0417] To predict how the positional isomers react with oxidized collagen, we performed molecular dynamics simulations. Two α1-N isomers on oxidized type I collagen were 9 -Lys Ald The OO distance between the residues was found to be centered at 16.5 Å (Figure 42). The NN distance between the two piperazino-hydrazine groups of Gd-9 and Gd-10 was centered at 16.2 and 20.7 Å, respectively. This is because the Lys Ald This suggested that Gd-9 was preferred in paired targeting.

[0418] Abbreviation

[0419] [Table 6-1]

[0420] [Table 6-2]

[0421] [Table 6-3]

[0422] [Table 6-4]

[0423] method NMR: NMR spectra were obtained using a 5 mm broadband probe ( 1 H: 499.81MHz, 13 Recordings were performed on a JEOL ECZ 500R 11.7 T NMR instrument equipped with a 125.68 MHz (C) NMR spectrometer. Gadolinium quantification was performed using an Agilent 8800-QQQICP-MS instrument. Longitudinal (T1) relaxometry was recorded at 1.41 T and 37°C using a Bruker mq60 Minispec. High-resolution electrospray ionization mass spectra (HR-ESI-MS) were acquired using a Bruker Maxis Impact LC-q-TOF mass spectrometer. Animals were imaged on a 4.7 Tesla MRI scanner (Bruker, Billerica MA) using a custom-built volume coil.

[0424] Synthesis protocol (S)-5-Benzyl-1-tert-butyl 2-(methylsulfonyloxy)pentanedioate, 1,4-DO2A-t-Bu, 1,7-DO2A-t-Bu, and Gd-CHyd were obtained as previously described. All other reactants and reagents were of commercial grade and used without further purification. Detailed synthesis and characterization can be found in the Supporting Information.

[0425] Molecular dynamics simulation Based on the crystal structure of Gd-DOTA (CCDC:1882455) and the modeling structure of type I collagen, 3+ In our experiments, we considered all three chains of type I collagen. The missing hydrogen atoms were added using the LEAP module of Amber 18. The Amber ff14SB force field was used for the protein residues. The general AMBER force field (GAFF) was used for Gd 3+ The partial atomic charges were quantified by the RESP method using the HF / 6-31G* level of theory for the ligands of the complexes. 3+ The force field for the complex was then parameterized. + Ions were added to the protein surface to neutralize the overall charge on the protein. Finally, the neutral system was solvated in a TIP3P water cube with a 15 Å water layer.

[0426] After setup, the system was minimized using a combination of steepest descent and conjugate gradient methods. The system was then heated from 0 to 300 K for 0.2 ns under the reference ensemble with a weak constraint of 15 kcal / (mol Å). To achieve uniform density after the heating kinetics, a 1 ns density equilibration was performed under the NPT ensemble with a target temperature of 300 K and a target pressure of 1.0 atm. The system was then further equilibrated for 4 ns under the NPT ensemble to achieve equilibrated pressure and temperature using a Langevin thermostat and a Berendsen barostat. Finally, a 50 ns MD run was performed. Hydrogen-containing covalent bonds were constrained using SHAKE. 5,000 snapshots were sampled from the MD trajectory every 10 ps to calculate the distance distribution between groups of interest. During all minimization, equilibration, and NPT MD processes, a strong constraint of 500 kcal / (mol Å) was imposed to fix both the N- and C-termini of the α1, α1, and α2 chains of type I collagen.

[0427] HPLC-MS: HPLC-MS analysis was performed on an Agilent 1260 instrument (UV detection at 220, 254, and 280 nm) coupled to an Agilent Technologies 6130 Quadrupole MS instrument. Mobile phase: A: 0.1% formic acid (v / v) in HO, B: 0.1% formic acid (v / v) in CHCN, C: 10 mM NHOAc in HO, D: 90% CHCN + 10% solvent C. UV detection at 220, 254, and 280 nm.

[0428] Method 1: Column: Phenomenex LUNA, C18(2), 5 μm, 100 x 2 mm, flow rate: 0.7 mL / min

[0429] [Table 7]

[0430] Method 2: Column: Phenomenex LUNA, C18(2), 5 μm, 100 x 2 mm, flow rate: 0.7 mL / min

[0431] [Table 8]

[0432] Method 3: Column: Restek, Ultra AQ C18, 5 μm, 250 x 4.6 mm column, flow rate: 0.7 mL / min

[0433] [Table 9]

[0434] Method 4: Column: Restek, Ultra AQ C18, 5 μm, 100 x 4.6 mm column, Flow rate: 1.0 mL / min

[0435] [Table 10]

[0436] Method 5: Column: Restek, Ultra AQ C18, 5 μm 100 x 4.6 mm column, flow rate: 1.0 mL / min.

[0437] [Table 11]

[0438] Method 6: Column: Restek, Ultra AQ C18, 5 μm 250 x 4.6 mm column, Flow rate: 1.0 mL / min

[0439] [Table 12]

[0440] Method 7: Column: Restek, Ultra AQ C18, 5 μm, 250 x 10 mm column, Flow rate: 0.7 mL / min

[0441] [Table 13]

[0442] Method 8: Column: Restek, UltraAqueous C18, 5 μm, 250 x 10 mm, flow rate: 0.7 mL / min

[0443] [Table 14]

[0444] Flash chromatography: Large-scale reversed-phase purification was performed on a Teledyne ISCO CombiFlash instrument with UV-Vis detection at 220 and 254 nm. Mobile phase: A: 0.1% formic acid in HO (v / v), B: 0.1% formic acid in CHCN (v / v). UV detection at 220 and 254 nm.

[0445] Method 9: Column: 150g C18, Flow rate: 70mL / min

[0446] [Table 15]

[0447] Method 10: Column 50g C18, flow rate: 40mL / min

[0448] [Table 16]

[0449] Method 11: Column 50g C18-Aq, flow rate: 40mL / min

[0450] [Table 17]

[0451] Method 12: Column: 150g C18 gold, flow rate: 85mL min -1 :

[0452] [Table 18]

[0453] Method 13: Column: 150g Ultra-aqueous gold, flow rate: 70mL / min

[0454] [Table 19]

[0455] Preparative HPLC: Preparative reversed-phase HPLC was performed using an Agilent 1260 instrument with UV detection at 220, 254, and 280 nm. Mobile phase: A: 0.1% formic acid (v / v) in HO, B: 0.1% formic acid (v / v) in CHCN, C: 0.05% trifluoroacetic acid (v / v) in HO, D: 0.05% trifluoroacetic acid (v / v) in CHCN. UV detection at 220, 254, and 280 nm.

[0456] Method 14: Caramel: Phenomenex LUNA C18 (2) 10 μm, 250 × 21.2 mm, flow rate: 15 mL / min

[0457] Table 20

[0458] Method 15: Caramel: Phenomenex LUNA C18 (2) 10 μm, 250 × 21.2 mm, flow rate: 15 mL / min

[0459] Table 21

[0460] Method 16: Caramel: Restek, UltraAqueous C18, 5 μm 250 × 21.2 mm, flow rate: 15 ml / min

[0461] Table 22

[0462] Method 17: Caramel: Restek, UltraAqueous C18, 5μm 250×21.2mm, flow rate: 15ml / min

[0463] Table 23

[0464] Method 18: Caramel: Restek, UltraAqueous C18, 5μm 250×21.2mm, flow rate: 15mL -1 .

[0465] Table 24

[0466] Method 19: Column: Phenomenex LUNA C18(2) 10 μm, 250 x 21.2 mm, flow rate: 15 mL / min

[0467] [Table 25]

[0468] HPLC-ICP-MS: HPLC-ICP-MS was performed on an Agilent 1260 HPLC system coupled to an Agilent 8800-QQQ ICP-MS system. Mobile phases: A: 0.1% trifluoroacetic acid (v / v) in HO, B: 0.1% trifluoroacetic acid (v / v) in CHCN, C: 10 mM NHOAc in HO, D: 90% CHCN + 10% solvent C.

[0469] Method 20: Column: Restek, UltraAqueous C18, 5 μm 250 x 10 mm column. Flow rate: 1 mL / min

[0470] [Table 26]

[0471] Method 21: Column: Restek, UltraAqueous C18, 5 μm 250 x 10 mm column. Flow rate: 1 mL / min

[0472] [Table 27]

[0473] Method 22: Column: XBridge, C18, 3.5 μm 150 x 4.6 mm column. Flow rate: 1 mL / min

[0474] [Table 28]

[0475] Method 23: Column: Restek, UltraAqueous C18, 5 μm 250 x 10 mm column. Flow rate: 1 mL / min

[0476] [Table 29]

[0477] Analytical HPLC: HPLC analysis was performed on an Agilent 1260 instrument. Mobile phase: C: 10 mM NHOAc in H0, D: 90% ACN, 10% solvent C. UV detection at 220 nm, 254 nm and 280 nm.

[0478] Method 24: Column, Xbridge, 5 μm C18 3.5 mm, 150 × 4.6 mm, flow rate: 1.0 mL / min

[0479] [Table 30]

[0480] Method 25: Column, Xbridge, 5 μm C18 3.5 mm, 150 × 4.6 mm, flow rate: 1.0 mL / min

[0481] [Table 31]

[0482] Method 26: Column, Xbridge, 5 μm C18 3.5 mm, 150 × 4.6 mm, flow rate: 1.0 mL / min

[0483] [Table 32]

[0484] Method 27: Column, Xbridge, 5 μm C18 3.5 mm, 150 × 4.6 mm, flow rate: 1.0 mL / min

[0485] [Table 33]

[0486] [Example 1] compound 1

[0487] [ka] Compound 1-1

[0488] [ka] Fmoc-NH-PEG4-acid (120 mg, 0.24 mmol) and HATU (137 mg, 0.36 mmol) were dissolved in anhydrous dimethylformamide (3 mL), and DIPEA (0.05 mL, 0.29 mmol) was added. The solution was stirred at room temperature for 1 hour, and tert-butyl piperazin-1-ylcarbamate (50 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the solution was subjected to preparative HPLC purification (Method 6-1). The residue was dissolved in a DMF / piperazine solution (4:1 v / v) and stirred at room temperature for 30 minutes. The solution was subjected to preparative HPLC purification (Method 6-1) to produce compound 1-1 as an oil (82 mg, 92% yield). 1 H NMR (500 MHz, CDCl3) δ H 3.70 (t, J = 5.0 Hz, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.60 (m, 4H), 3.55 (m, 10H), 3.50 (t, J = 5.0 Hz, 2H), 3.08 (t, J = 5.0 Hz, 2H), 2.75 (t, J = 5.0 Hz, 2H), 2.71 (t, J = 5.2 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.36 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ C 169.8, 154.7, 80.4, 70.4-66.5, 55.3-55.0, 45.1, 41.3, 39.4, 33.2, 28.4. LC-MS (Method 1): tR = 2.41 min, m / z [M + H] + [C 20 H 41 N4O7] + Calculated value: 449.3; measured value: 449.4.

[0489] Compound 1-2

[0490] [ka] NOTA-bis(t-Bu ester) (76 mg, 0.18 mmol) and HATU (103 mg, 0.27 mmol) were dissolved in anhydrous dimethylformamide (4 mL), and DIPEA (0.05 mL, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and compound 1-1 (82 mg, 0.18 mmol) dissolved in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and subjected to preparative HPLC purification (Method 6-1) to produce compound 1-2 (47 mg, 31% yield). 1 H NMR (500 MHz, CDCl3) δ H 3.74 (d, J = 6.7 Hz, 2H), 3.68 (t, J = 5.1 Hz, 2H), 3.57 (m, 14H), 3.51 (m, 4H), 3.41 (m, 2H), 3.33 (s, 4H), 2.89-2.81 (m, 12H), 2.78 (m, 2H), 2.73 (m, 2H), 1.41 (m, 27H); 13 C NMR (126 MHz, CDCl3) δ C 175.7, 171.0, 169.7, 154.5, 81.3, 80.6, 70.6-70.0, 67.5, 60.1, 58.1, 55.5, 55.2-52.9, 45.2, 41.2, 39.3, 33.5, 28.4-28.2. LC-MS (Method 2): t R = 5.72 minutes [M + H] + [C 40 H 76 N7O 12 ] +Calculated value, 846.5; measured value, 846.6.

[0491] compound 1

[0492] [ka] Compound 1-2 (47 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was redissolved in water (4 mL), lyophilized, and then subjected to preparative HPLC purification (Method 7-1) to produce the desired product Compound 1 as a white powder (20 mg, 55% yield). 1 H NMR (500 MHz, DO) δ H 3.88 (s, 4H), 3.74 (s, 2H), 3.64 (br t, J = 6.2 Hz, 4H), 3.53 (m, 8H), 3.52 (s, 4H), 3.50 (br m, 2H), 3.48 (t, J = 5.4 Hz, 2H), 3.32 (m, 4H), 3.28 (m, 6H), 3.20 (m, 4H), 2.98 (m, 4H), 2.60 (t, J = 6.1 Hz, 2H); 13 C NMR (126 MHz, DO) δ C 172.1, 171.5, 169.7, 69.6-68.6, 66.5, 58.1, 56.5, 53.7-53.5, 50.8, 50.5, 50.4, 43.8, 40.0, 39.1, 32.5. LC-MS (Method 3-1): t R = 4.29 minutes, [M + H] + [C 27 H 52 N7O 10 ] + Calculated value: 634.4; measured value: 634.3.

[0493] [Example 2] compound 2

[0494] [ka] Compound 2-1

[0495] [ka] 2-{(tert-butoxy)carbonyl]amino}-3-(1H-pyrrol-1-yl)propanoic acid (200 mg, 0.79 mmol), DCC (280 mg, 1.36 mmol), and N-hydroxysuccinimide (132 mg, 1.15 mmol) were dissolved in dichloromethane (12 mL) and stirred at room temperature for 1 h. NH2-PEG3-NH2 (200 mg, 1.04 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (6 mL) and filtered. The filtrate was purified by CombiFlash (Method 5-1) to produce the desired compound 2-1 (300 mg, 89% yield). 1 H NMR (500 MHz, CD3CN) δ H 6.63 (t, J = 2.1 Hz, 2H), 6.00 (t, J = 2.0 Hz, 2H), 4.31 (m, 1H), 4.21 (dd, J = 14.2, 5.0 Hz, 1H), 4.06 (m, 1H), 3.67 (t, J = 4.9 Hz, 2H), 3.60 (m, 2H), 3.54 (m, 6H), 3.46 (m, 2H), 3.29 (m, 2H), 3.07 (t, J = 5.1 Hz, 2H), 1.34 (s, 9H); 13 C (146 MHz, CD3CN) δ C 170.3, 155.6, 121.4, 108.0, 79.4, 70.0-69.4, 67.0, 56.0, 50.3, 39.2, 27.6. LC-MS (Method 1): t R = 2.59 min, m / z [M + H] + [C 20 H 37 N4O6] + Calculated value, 429.3; measured value, 429.3.

[0496] Compound 2-2

[0497] [ka] NOTA-bis(t-Bu ester) (60 mg, 0.14 mmol) and HATU (100 mg, 0.26 mmol) were dissolved in anhydrous dimethylformamide (4 mL), and DIPEA (0.08 mL, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and compound 2-1 (62 mg, 0.15 mmol) dissolved in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and subjected to preparative HPLC purification (Method 6-1) to produce compound 1-2 (26 mg, 22% yield). 1 H NMR (500 MHz, CDCl3) δ H 6.62 (t, J = 2.2 Hz, 2H), 6.08 (t, J = 2.1 Hz, 2H), 5.43 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 4.11 (m, 1H), 3.58-3.35 (m, 20H), 3.35 (s, 4H), 2.88-2.78 (m, 12H), 1.43 (s, 18H), 1.39 (s, 9H); 13 C (146 MHz, CDCl3) δ C 171.2, 169.7, 155.3, 121.4, 108.7, 81.3, 80.2, 70.6-69.5, 60.4, 58.3, 55.6-55.0, 51.2, 39.6-39.3, 28.4, 28.3. LC-MS (Method 1): t R = 3.27 min, m / z [M + H] + [C 40 H 72 N7O 11 ] + Calculated value: 825.6; measured value: 825.8.

[0498] compound 2

[0499] [ka] Compound 2-2 (20 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was redissolved in water (4 mL) and subjected to preparative HPLC purification (Method 7-1) to produce compound 2 as a white powder after lyophilization (5 mg, 33% yield). 1 H NMR (500 MHz, DO) δ H 6.68 (m, 2H), 6.12 (m, 2H), 4.33 (d, J = 6.2 Hz, 2H), 4.23 (t, J = 6.3 Hz, 1H), 3.61 (br s, 4H), 3.55 (br s, 8H), 3.49 (t, J = 5.9 Hz, 4H), 3.38 (s, 2H), 3.30 (t, J = 5.9 Hz, 4H), 3.17 (m, 4H), 3.03 (t, J = 5.8 Hz, 4H), 2.78 (t, J = 5.8 Hz, 4H); 13 C NMR (126 MHz, DO) δ C 173.8, 173.3, 167.4, 121.9, 109.4, 69.7-68.5, 59.3, 57.3, 54.0, 51.0, 49.4, 48.9, 48.6, 39.3-38.7. LC-MS (Method 3-1): t R = 4.72 min, m / z [M + H] + [C 27 H 48 N7O9] + Calculated value, 614.3; measured value, 614.3.

[0500] [Example 3] compound 3 Compound 3-1

[0501] [ka] (3-Methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)acetic acid hydrochloride (88 mg, 0.45 mmol), DCC (100 mg, 0.49 mmol), N-hydroxysuccinimide (60 mg, 0.52 mmol), and triethylamine (0.1 mL, 0.72 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and Boc-NH-PEG3-NH2 (133 mg, 0.46 mmol) and DIPEA (0.1 mL, 0.56 mmol) were added. The reaction was stirred at room temperature for another 18 hours, and the solution was filtered. The solvent was removed under reduced pressure, and the residue was purified by CombiFlash (Method 5-1) to give the crude product (143 mg, 73% yield), which was used in the next step without further purification. The crude product mixture (143 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The oily residue was redissolved in acetonitrile and purified by CombiFlash (Method 5-2) to produce compound 3-2 (40 mg, 36% yield). 1 H NMR (500 MHz, CD3CN) δ H 5.15 (s, 1H), 4.45 (s, 1.1H, rotamer 1), 4.19 (s, 1.1H, rotamer 2), 3.68 (t, J = 5.1 Hz, 2H), 3.60 (m, 2H), 3.54 (m, 6H), 3.48 (t, J = 5.2 Hz, 2H), 3.31 (q, J = 5.4 Hz, 2H), 3.07 (t, J = 5.1 Hz, 2H); 13 C NMR (126 MHz, CD3CN) δ C 168.3, 160.6, 148.4, 89.6, 70.0-69.3, 66.4, 47.3-46.9, 39.4-49.1, 12.3. LC-MS (Method 3-1): t R = 4.35 min, m / z [M + H] + [C 14 H 27 N4O5] + Calculated value: 331.2; measured value: 331.2.

[0502] compound 3

[0503] [ka] NOTA trihydrochloride (100 mg, 0.24 mmol) was suspended in acetonitrile (5 mL), followed by the addition of pentafluorophenol (61 mg, 0.33 mmol), DCC (70 mg, 0.34 mmol), and triethylamine (0.10 mL, 0.72 mmol). The reaction mixture was stirred for 3 h, and compound 3-1 (40 mg, 0.12 mmol) dissolved in acetonitrile (1 mL) was quickly added under vigorous stirring. The reaction mixture was stirred for another 1 h, and the solution was filtered. The filtrate was concentrated and subjected to preparative HPLC purification (Method 7-1) to produce the desired product compound 3 as a white powder after lyophilization (20 mg, 27% yield). 1 H NMR (500 MHz, DO) δ H 4.46 (s, 1.6H, rotamer 1), 4.27 (s, 0.4H, rotamer 2), 3.69 (s, 4H), 3.55 (br s, 8H), 3.50 (q, J = 5.2 Hz, 4H), 3.45 (br s, 2H), 3.30 (q, J = 5.6 Hz, 4H), 3.21-2.86 (m, 12H), 2.97 (m, 1.6H, rotamer 1), 2.78 (m, 0.4H, rotamer 2), 2.07 (s, 2.4H, rotamer 1), 1.99 (s, 0.6H, rotamer 2); 13 C NMR (126 MHz, DO) δ C 173.0, 172.5, 168.8, 164.1, 149.2, 69.7-68.6, 58.8, 57.1, 51.0-48.9, 49.3 (rotamer 2), 48.3 (rotamer 1), 46.5 (rotamer 2), 46.0 (rotamer 1), 39.1-38.9, 15.8, 11.3. LC-MS (Method 3): t R = 2.12 min, m / z [M + H] + [C 26 H46 N7O 10 ] + Calculated value, 616.3; measured value, 616.3.

[0504] [Example 4] compound 4

[0505] [ka] Compound 4-1

[0506] [ka] Rhodanine-3-acetic acid (100 mg, 0.52 mmol), DCC (160 mg, 0.78 mmol), and N-hydroxysuccinimide (80 mg, 0.70 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 h. NH2-PEG3-NH2 (200 mg, 1.04 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (6 mL) and filtered. The filtrate was purified by CombiFlash (Method 5-1) to produce compound 4-1 (18 mg, 5% yield). 1 H NMR (500 MHz, CDCl3) δ H 4.69 (s, 2H), 4.06 (s, 2H), 3.78 (m, 2H), 3.71 (m, 2H), 3.60 (m, 8H), 3.41 (m, 2H), 3.14 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ C 201.6, 174.2, 165.6, 70.2-69.6, 67.2, 46.5, 39.5-39.4, 35.9. LC-MS (Method 1): t R = 2.19 min, m / z [M + H] + [C 13 H 24 N3O5S2] + Calculated value: 366.1; measured value: 366.3.

[0507] compound 4

[0508] [ka] NOTA trihydrochloride (110 mg, 0.26 mmol) was suspended in acetonitrile (5 mL), followed by the addition of pentafluorophenol (90 mg, 0.49 mmol), DCC (80 mg, 0.39 mmol), and triethylamine (0.20 mL, 1.44 mmol). The reaction mixture was stirred for 3 h, and compound 4-1 (70 mg, 0.19 mmol) dissolved in acetonitrile (1 mL) was quickly added under vigorous stirring. The reaction mixture was stirred for another 1 h, and the solution was filtered. The filtrate was concentrated and subjected to preparative HPLC purification (Method 7-1), which, after lyophilization, produced the desired product compound 4 as a white powder (8 mg, 6% yield). 1 H NMR (500 MHz, DO) δ H 4.57 (s, 2H), 3.69 (s, 4H), 3.55 (m, 8H), 3.49 (m, 4H), 3.46 (s, 2H), 3.30 (m, 4H), 3.21 (s, 4H), 3.08 (t, J = 5.8 Hz, 4H), 2.86 (t, J = 5.9 Hz, 4H); 13 C NMR (126 MHz, DO) δ C 204.5, 176.2, 173.0, 172.5, 168.2, 69.7-68.6, 58.8, 57.1, 50.1, 49.5, 48.9, 46.1, 39.2-38.9. LC-MS (Method 3-1): t R = 5.31 minutes, [M + H] + [C 25 H 43 NO 10 S2] + Calculated value, 651.2; measured value, 651.2.

[0509] [Example 5] compound 5 Compound 5-1

[0510] [ka] Nt-Boc-L-Glu-α-Bz ester (2.0 g, 5.9 mmol), N-hydroxysuccinimide (0.68 g, 5.9 mmol), and DCC (1.5 g, 7.3 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 1 h. Tert-butyl carbazate (0.78 g, 5.9 mmol) and DIPEA (2 mL, 11.5 mmol) were added to the reaction mixture, and the solution was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (10 mL) and filtered. The filtrate was purified by CombiFlash (Method 5) to give the partially purified product (2 g, 4.4 mmol) after solvent evaporation. The solid residue was dissolved in methanol (15 mL), and 2 M KOH (5 mL) was added. The solution was stirred at room temperature for 2 h and then neutralized. The solution was concentrated under reduced pressure and purified by CombiFlash (Method 5) to give compound 5-1 as a white solid (0.4 g, 19% yield over two steps). 1 H NMR (500 MHz, CD3CN) δ H 4.05 (m, 1H), 2.36 (t, J = 7.4 Hz, 1H), 2.22 (t, J = 7.4 Hz, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.39 (m, 18H); 13 C NMR (126 MHz, CD3CN) δ C 173.7-172.2, 155.9-155.6, 80.4-79.2, 53.0-52.4, 29.6-29.4, 27.6-27.4, 27.3-26.9. LC-MS (Method 1): t R = 3.16 min, m / z [M - H] - [C 15 H 26 N3O7] - Calculated value: 360.2; measured value: 360.3.

[0511] Compound 5-2

[0512] [ka] Compound 5-1 (150 mg, 0.42 mmol), DCC (128 mg, 0.62 mmol), and N-hydroxysuccinimide (55 mg, 0.48 mmol) were dissolved in dichloromethane (8 mL) and stirred at room temperature for 1 h. NH2-PEG3-NH2 (220 mg, 1.15 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (6 mL) and filtered. The filtrate was purified by CombiFlash (Method 5-1) to produce compound 5-2 (100 mg, 45% yield). 1 H NMR (500 MHz, CDCl3) δ H 4.14 (m, 1H), 3.74 (m, 2H), 3.60 (m, 10H), 3.43 (m, 2H), 3.13 (m, 2H), 2.28 (m, 2H), 1.97 (m, 2H), 1.40 (2 s, 18H); 13 C NMR (126 MHz, CDCl3) δ C 173.2, 172.1, 156.3-156.2, 81.6-80.0, 70.5-69.6, 67.2, 53.3, 39.3, 32.3-30.5, 30.1-29.2, 28.4-28.3. LC-MS (Method 1): t R = 2.58 min, m / z [M + H] + [C 23 H 46 N5O9] + Calculated value: 536.3; measured value: 536.4.

[0513] Compound 5-3

[0514] [ka] NOTA-bis(t-Bu ester) (30 mg, 0.07 mmol) and HATU (40 mg, 0.11 mmol) were dissolved in anhydrous dimethylformamide (3 mL), and DIPEA (0.15 mL, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and compound 5-2 (34 mg, 0.06 mmol) dissolved in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and subjected to preparative HPLC purification (Method 6-1) to produce compound 5-3 (20 mg, 33% yield). 1 H NMR (500 MHz, CDCl3) δ H 3.58 (m, 8H), 3.51 (t, J = 5.7 Hz, 4H), 3.43 (m, 5H), 3.33 (m, 4H), 3.27 (m, 2H), 2.88-2.81 (m, 12H), 2.23 (m, 4H), 1.41 (m, 36H); 13 C NMR (126 MHz, CDCl3) δ C 173.1-170.8, 156.5-155.8, 81.8-79.6, 81.3, 70.6-69.5, 60.1, 58.2, 55.5-53.2, 39.4-39.1, 32.5-29.1, 28.4-28.2. LC-MS (Method 1): t R = 3.22 min, m / z [M + H] + [C 43 H 81 N8O 14 ] + Calculated value, 933.6; measured value, 933.6.

[0515] compound 5

[0516] [ka] Compound 5-3 (40 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, and the solvent was removed under reduced pressure. The residue was redissolved in water (4 mL) and subjected to preparative HPLC purification (Method 7-1). After lyophilization, the desired product Compound 5 was obtained as a white powder (25 mg, quantitative yield). 1 H NMR (500 MHz, DO) δ H 3.84 (dt, J = 33.6, 6.8 Hz, 1H), 3.61 (s, 4H), 3.53 (m, 8H), 3.48 (m, 4H), 3.45 (s, 2H), 3.29 (m, J = 5.4 Hz, 4H), 3.16 (m, 4H), 3.03 (t, J = 5.8 Hz, 4H), 2.77 (t, J = 5.8 Hz, 4H), 2.25 (m, 2H), 2.02 (m, 2H); 13 C NMR (126 MHz, DO) δ C 174.0, 173.8, 173.2, 169.1, 168.2, 69.6-68.6, 59.3, 57.3, 52.6-51.5, 51.0, 49.4, 48.6, 39.1-38.7, 30.8-28.7, 26.5-26.3. LC-MS (Method 3-1): t R = 7.54 min, m / z [M + H] + [C 25 H 49 N8O 10 ] + Calculated value, 621.3; measured value, 621.3.

[0517] [Example 6] compound 6 Compound 6-1

[0518] [ka] 3-((tert-Butoxycarbonyl)(methyl)amino)propanoic acid (2.0 g, 9.9 mmol) was dissolved in dichloromethane (40 mL). Meldrum's acid (1.4 g, 9.9 mmol), DCC (2.0 g, 9.9 mmol), and DMAP (1.2 g, 9.8 mmol) were added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The solvent was removed under reduced pressure, and the residue was redissolved in ethanol (20 mL) and refluxed for 18 h. The solvent was removed under reduced pressure. The residue was redissolved in dichloromethane and purified by CombiFlash (80 g SiO column) to produce compound 6-1 (1.9 g, 71% yield). 1 H NMR (500 MHz, CDCl3) δ H 4.16 (q, J = 7.0 Hz, 2H), 3.44 (m, 4H), 2.82 (s, 3H), 2.77 (m, 2H), 1.41 (s, 9H), 1.24 (H 11 , t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ C 201.9-201.5, 167.1, 155.7-155.6, 79.7, 61.5, 49.7-49.4, 43.9, 41.6, 35.2-34.7, 28.5, 14.2. LC-MS (Method 1): t R = 3.73 min, m / z [M + Na] + [C 13 H 23 NO5Na] + Calculated value, 296.1; measured value, 296.1.

[0519] Compound 6-2

[0520] [ka] Ethyl 2-hydrazinyl acetate hydrochloride (1.1 g, 7.0 mmol) was suspended in ethanol (20 mL) and triethylamine (2 mL, 14.4 mmol) was added. The solution was stirred for 1 h, and compound 6-1 (1.9 g, 7.0 mmol) was added. The reaction mixture was stirred at 50 °C for 2 h, cooled, and purified via CombiFlash (Method 5-3) to give compound 6-2 (1.2 g, 51% yield) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ H 4.38 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 2.84 (s, 3H), 2.60 (t, J = 6.9 Hz, 2H), 1.41 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ C 173.0-172.6, 157.6-155.9, 79.9, 61.7, 46.2-45.6, 45.5, 40.0, 34.3, 29.6, 28.4, 14.2. LC-MS (Method 1): t R = 3.21 min, m / z [M + H] + [C 15 H 26 N3O5] + Calculated value: 328.2; measured value: 328.3.

[0521] Compound 6-3

[0522] [ka] Compound 6-2 (1.2 g, 3.57 mmol) was dissolved in methanol (15 mL) and 2 M KOH (10 mL) was added. The reaction mixture was stirred at room temperature for 4 h, neutralized, and concentrated under reduced pressure. The residue was redissolved in methanol (6 mL) and purified by CombiFlash (Method 5-1) to yield a crude product mixture (0.7 g). This was used in the next step without further purification. This crude product (200 mg, 0.67 mmol), DCC (180 mg, 0.87 mmol), and N-hydroxysuccinimide (90 mg, 0.79 mmol) were dissolved in dichloromethane (8 mL) and stirred at room temperature for 1 h. NH2-PEG3-NH2 (230 mg, 1.20 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (6 mL) and filtered. The filtrate was purified by CombiFlash (Method 5-1) to give compound 6-4 (123 mg, 25% yield over two steps). 1 H NMR (500 MHz, CDCl3) δ H 7.89 (NH, s, 1H), 5.20 (s, 1H), 4.51 (s, 2H), 3.69 (m, 2H), 3.61 (m, 2H), 3.56 (m, 6H), 3.50 (m, 2H), 3.37 (m, 4H), 3.10 (m, 2H), 2.80 (s, 3H), 2.62 (t, J = 7.2 Hz, 2H), 1.38 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ C 167.8, 155.9, 149.6, 89.2, 79.8, 70.3-69.5, 66.9, 48.0, 47.6, 39.5-39.3, 34.5, 28.4, 26.2. LC-MS (Method 1): t R = 2.47 min, m / z [M + H] + [C 21 H 40 N5O7] + Calculated value, 474.3; measured value, 474.3.

[0523] compound 6

[0524] [ka] NOTA-bis(t-Bu ester) (15 mg, 0.04 mmol), DCC (20 mg, 0.10 mmol), and N-hydroxysuccinimide (14 mg, 0.12 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 h. Compound 6-4 (230 mg, 1.20 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (5 mL) and filtered. The filtrate was subjected to preparative HPLC purification (Method 6-1) to yield a crude product mixture containing some unreacted NOTA-bis(t-Bu ester). The solvent was removed under reduced pressure, and the residue was redissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 18 h, and the solvent was removed under reduced pressure. The residue was redissolved in water (4 mL) and subjected to preparative HPLC purification (Method 7-1) to yield the desired product Compound 6 as a white powder after lyophilization (12 mg, 45% yield). 1 H NMR (500 MHz, DO) δ H 4.51 (s, 1.68H, rotamer 1), 4.32 (s, 0.32H, rotamer 2), 3.65 (s, 4H), 3.55 (br s, 8H), 3.50 (t, J = 5.8 Hz, 4H), 3.40 (s, 2H), 3.30 (m, 6H), 3.20 (m, 6H), 3.05 (t, J = 5.8 Hz, 4H), 2.83 (t, J = 7.1 Hz, 2H), 2.80 (m, 4H), 2.61 (0.55H, rotamer 1), 2.60 (2.45H, rotamer 2); 13 C NMR (126 MHz, DO) δ C173.6, 172.8, 169.5 (rotamer 2), 169.0 (rotamer 1), 161.1, 147.1, 69.6-68.6, 59.1, 57.3, 51.1, 50.8, 49.4, 48.7, 47.4, 46.6 (rotamer 1), 45.0 (rotamer 2), 39.1-38.8, 32.9, 23.7. LC-MS (Method 3-1): t R = 4.37 min, m / z [M + H] + [C 28 H 51 N8O 10 ] + Calculated value: 659.4; measured value: 659.3.

[0525] [Example 7] compound 7 Compound 7-1

[0526] [ka] To a solution of 5-benzyl 1-(tert-butyl) 2-hydroxypentanedioate (2.94 g, 10 mmol) in anhydrous dichloromethane (50 mL) were added 2,6-lutidine (3.21 g, 30 mmol) and TfO (3.38 g, 12 mmol) sequentially at 0 °C, and the reaction mixture was stirred for 1 h. The reaction mixture was added dropwise to a solution of tert-butyl carbazate (6.6 g, 50 mmol) in anhydrous dichloromethane (20 mL) at 0 °C. After stirring for 1 h, the solution was washed with an aqueous solution of citric acid (10%) and brine. The organic layer was dried over NaSO and concentrated under reduced pressure. The crude product was purified by CombiFlash method 5-3 using A and B as solvents to give compound 7-1 (1.76 g, 43%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.40 - 7.29 (m, 5H), 6.15 (s, 1H), 5.11 (s, 2H), 4.21 (s, 1H), 3.53 (s, 1H), 2.52 (t, J = 7.4 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.92 (dd, J = 14.3, 7.2 Hz, 1H), 1.44 (d, J = 11.4 Hz, 18H). 13 C NMR (126 MHz, CDCl3) δ 173.3, 171.9, 156.3, 136.0, 128.6-128.2, 82.0, 80.4, 66.4, 62.45, 30.3, 28.4-28.1, 25.2. LC-MS (Method 1): t R = 4.50 min, m / z [M + H] + [C 21 H 33 N2O6] + Calculated value: 409.2; measured value: 409.3.

[0527] Compound 7-2

[0528] [ka] Compound 7-1 (0.82 g, 2 mmol) and di-tert-butyl dicarbonate (0.88 g, 4 mmol) were dissolved in dichloromethane (30 mL), and a solution of 4-dimethylaminopyridine (24 mg, 0.2 mmol) in dichloromethane (4 mL) was added dropwise. The reaction mixture was stirred at room temperature for 18 h and then extracted with an aqueous solution of citric acid (10%) and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by CombiFlash method 5-3 using A and B as solvents to give compound 7-2 (0.88 g, 87%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.39 - 7.28 (5H), 5.10 (d, J = 3.1 Hz, 2H), 3.53 (t, J = 5.5 Hz, 1H), 2.74 (m, 1H), 2.36 (m, 1H), 2.01 (m, 2H), 1.47 (s, 18H), 1.44 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 173.11, 170.67, 152.16, 136.05, 128.61, 128.29, 128.26, 83.79, 82.33, 66.31, 62.54, 29.81, 28.06, 25.83. LC-MS (Method 1): t R =4.90 min, m / z [M + H] + [C 26 H 41 N2O8] + The calculated value is 509.3; the measured value is 509.3.

[0529] Compound 7-3

[0530]

change

[0531] Compound 7-4

[0532] [ka] NOTA-bis(t-Bu ester) (30 mg, 0.07 mmol) and HATU (30 mg, 0.09 mmol) were dissolved in anhydrous dimethylformamide (3 mL), and DIPEA (0.10 mL, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and compound 7-3 (40 mg, 0.07 mmol) dissolved in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and subjected to preparative HPLC purification (Method 6-1) to produce compound 7-4 (30 mg, 43% yield). 1 H NMR (500 MHz, CDCl3) δ H 3.60 (m, 8H), 3.53 (dt, J = 10.5, 5.5 Hz, 6H), 3.43 (m, 4H), 3.37 (m, 5H), 2.87 (m, 1H), 2.56 (ddd, J = 14.8, 9.7, 5.7 Hz, 1H), 2.18 (ddd, J = 14.4, 9.9, 5.8 Hz, 1H), 1.96 (m, 2H), 1.46 (m, 45H); 13 C NMR (126 MHz, CDCl3) δ C 173.0, 171.2, 171.0, 152.7, 83.6, 82.0-81.5, 70.6-69.9, 62.7, 60.0, 58.0, 55.1-52.7, 39.3-39.2, 31.9, 28.3-28.1, 27.2. LC-MS (Method 1): t R =3.53 min, m / z [M + H] + [C 47 H 88 N7O 15 ] + Calculated value: 990.6; measured value: 990.7.

[0533] compound 7

[0534] [ka] Compound 7-4 (60 mg, 0.06 mmol) was dissolved in concentrated phosphoric acid (0.4 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was diluted with water (4 mL). The solution was subjected to preparative HPLC purification (Method 7-1) to produce compound 7 as a white powder after lyophilization (10 mg, 52% yield). 1 H NMR (500 MHz, DO) δ H 3.66 (s, 4H), 3.51 (m, 9H), 3.46 (t, J = 5.1 Hz, 4H), 3.41 (s, 2H), 3.26 (t, J = 5.7 Hz, 2H), 3.22 (t, J = 5.4 Hz, 2H), 3.19 (m, 4H), 3.05 (t, J = 5.9 Hz, 4H), 2.82 (t, J = 6.0 Hz, 4H), 2.24 (m, 2H), 1.91 (m, 2H); 13 C NMR (126 MHz, DO) δ C 175.1, 174.7, 173.2, 172.5, 69.6-68.6, 62.5, 58.8, 57.2, 51.0, 49.5, 48.8, 39.0-38.8, 31.6, 25.1. LC-MS (Method 3-1): t R = 4.53 min, m / z [M + H] + [C 25 H 48 N7O 11 ] + Calculated value, 622.3; measured value, 622.3.

[0535] [Example 8] compound 8 Compound 8-1

[0536] [ka] To a stirred solution of N-Boc hydroxylamine (1.99 g, 15 mmol) in dimethylformamide (20 mL) was added DBU (3.04 g, 20 mmol) in dimethylformamide (1 mL). 5-Benzyl 1-(tert-butyl) 2-((methylsulfonyl)oxy)pentanedioate (3.72 g, 10 mmol) was then added dropwise. The reaction was allowed to stir at 50 °C for 20 h. The reaction was then concentrated, and the residue was purified via CombiFlash method 5-3 using A and B as solvents to give compound 8-1 (2.17 g, 53%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.40 - 7.29 (m, 5H), 5.11 (s, 2H), 4.24 (dd, J = 9.2, 3.8 Hz, 1H), 2.63 (m, 2H), 2.22 - 2.12 (m, 1H), 2.07 - 1.89 (m, 1H), 1.46 (2 s, 18H). 13 LC-MS (Method 1): t R =4.45 min, m / z = 432.1 [M+Na] + ; Calculated value: 432.2.

[0537] Compound 8-2

[0538] [ka] Compound 8-1 (0.41 g, 1.0 mmol) was added to a slurry of palladium on carbon (50% water, 50 mg) in methanol (10 mL). The mixture was purged with hydrogen twice and then stirred under argon at room temperature for 12 h. Celite was added to the reaction mixture, and the slurry was filtered through a bed of Celite prewetted with methanol. The filtrate was concentrated under reduced pressure to give a colorless oil (0.25 g, 0.5 mmol), which was used in the next reaction without further purification. This crude product (180 mg, 0.57 mmol), DCC (180 mg, 0.87 mmol), and N-hydroxysuccinimide (80 mg, 0.70 mmol) were dissolved in dichloromethane (8 mL) at room temperature for 1 h. NH2-PEG3-NH2 (200 mg, 1.04 mmol) dissolved in dichloromethane (1 mL) was quickly added to the reaction mixture under vigorous stirring. The solvent was evaporated under reduced pressure, and the oily residue was resuspended in acetonitrile (6 mL) and filtered. The filtrate was purified by CombiFlash (Method 5-1) to give compound 8-2 (210 mg, 75% yield). 1 H NMR (500 MHz, CDCl3) δ H 4.28 (dd, J = 8.3, 3.9 Hz, 1H), 3.76 (t, J = 4.9 Hz, 2H), 3.67 (m, 2H), 3.57 (m, 8H), 3.39 (m, 2H), 3.13 (m, 2H), 2.38 (m, 2H), 2.22 (m, 1H), 1.98 (m, 1H), 1.44 (2 s, 18H); 13 C NMR (126 MHz, CDCl3) δ C 173.0-172.9, 171.0, 157.2, 82.8-82.0, 70.3-69.7, 67.3, 39.5-39.1, 31.4, 28.3-28.1, 26.4. LC-MS (Method 1): t R = 2.77 min, m / z [M + H] + [C 22 H 44 N3O9] + Calculated value, 494.3; measured value, 494.3.

[0539] Compound 8-3

[0540] [ka] NOTA-bis(t-Bu ester) (50 mg, 0.12 mmol) and HATU (60 mg, 0.17 mmol) were dissolved in anhydrous dimethylformamide (3 mL), and DIPEA (0.15 mL, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and compound 8-2 (58 mg, 0.12 mmol) dissolved in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 30 min and subjected to preparative HPLC purification (Method 6-1) to produce compound 8-3 (48 mg, 45% yield). 1 H NMR (500 MHz, CDCl3) δ H 4.18 (dd, J = 10.7, 3.2 Hz, 1H), 3.58 (m, 8H), 3.51 (m, 4H), 3.40 (m, 4H), 3.30 (s, 4H), 3.26 (s, 2H), 2.84 (m, 8H), 2.65 (m, 4H), 2.48 (ddd, J = 13.9, 9.4, 6.9 Hz, 1H), 2.34 (ddd, J = 14.0, 7.2, 5.1 Hz, 1H), 2.18 (dddd, J = 14.5, 10.0, 7.2, 3.2 Hz, 1H), 1.88 (dddd, J = 14.5, 9.4, 7.2, 3.8 Hz, 1H), 1.43 (2 s, 36H); 13 C NMR (126 MHz, CDCl3) δ C 172.4, 171.4, 170.7, 156.8, 82.6-82.1, 81.1, 70.5-69.8, 61.1, 58.7, 56.4-56.0, 54.7, 39.2, 32.3, 28.3-28.1, 27.2. LC-MS (method 1): t R = 3.32 min, m / z [M + H] + [C 42 H 79 NO 14 ] + Calculated value, 891.6; measured value, 891.6.

[0541] compound 8

[0542] [ka] Compound 8-3 (22 mg, 0.02 mmol) was dissolved in concentrated phosphoric acid (0.4 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was diluted with water (4 mL). The solution was subjected to preparative HPLC purification (Method 7-1) to produce compound 8 as a white powder after lyophilization (8 mg, 52% yield). 1 H NMR (500 MHz, DO) δ H 4.29 (dd, J = 7.9, 4.0 Hz, 1H),3.69 (s, 4H), 3.54 (m, 8H), 3.49 (t, J = 5.5 Hz, 4H), 3.45 (s, 2H), 3.30 (t, J = 5.7 Hz, 2H), 3.26 (t, J = 5.4 Hz, 2H), 3.22 (m, 4H), 3.08 (t, J = 5.9 Hz, 4H), 2.86 (t, J = 6.0 Hz, 4H), 2.24 (m, 2H), 2.00 (m, 2H); 13 C NMR (126 MHz, DO) δ C 175.5, 175.4, 173.2, 172.6, 82.2, 69.6-68.6, 58.8, 57.2, 51.0, 49.5, 48.6, 39.0-38.8, 31.4, 26.9. LC-MS (Method 3-1): t R = 4.54 min, m / z [M + H] + [C 25 H 47 NO 12 ] + Calculated value, 623.3; measured value, 623.3.

[0543] [Example 9] compound 9

[0544] [ka] Compound 9-1 (S)-5-Benzyl-1-tert-butyl 2-(methylsulfonyloxy)pentanedioate (928 mg, 2.5 mmol) was added as a solution in CHCN (2 mL) to a stirred mixture of 1,4-DO2A-t-Bu (400 mg, 1.0 mmol) and potassium carbonate (345 mg, 2.5 mmol) in CHCN (20 mL) preheated to 60 °C. The reaction was then heated to 80 °C. After 12 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and then purified using Method 9 to give compound 9-1 (180 mg, 19% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm): 7.36 - 7.28 (m, 10H), 5.07 (s, 4H), 3.35 - 3.14 (m, 6H), 2.95 - 2.73 (m, 12H), 2.60 (d, J = 9.3 Hz, 4H), 2.53 - 2.33 (m, 4H), 1.98 (dq, J = 14.5, 7.5, 7.0 Hz, 2H), 1.82 (dq, J = 14.3, 7.8 Hz, 2H), 1.42 (d, J = 2.5 Hz, 36H). 13 C NMR (126 MHz, chloroform-d) δ (ppm): 173.21, 171.98, 170.48, 136.12, 128.60, 128.29, 128.24, 81.23, 81.16, 66.21, 63.53, 55.67, 52.70, 51.96, 50.35, 48.89, 30.99, 28.37, 28.27, 24.92. LC-MS (Method 1, ESI) † ): t R = 3.51 min, m / z [M + H] + [C 52 H 81 N4O 12 ] + Calculated value: 953.6; measured value: 953.5.

[0545] Compound 9-2 Compound 9-1 (150 mg, 0.16 mmol) was dissolved in absolute ethanol (10 mL), and activated palladium on carbon (10%, 15 mg) was added to the solution. The suspension was placed under vacuum and then connected to a balloon containing hydrogen gas. The reaction mixture was stirred for 2 hours. The reaction mixture was then passed through a Celite pad, and the filtrate was subjected to rotary evaporation to give compound 9-2 (119 mg, 98% yield) as a slightly yellow solid. 1 H NMR (500 MHz, acetonitrile-d3) δ (ppm): 3.65 (d, J = 17.2 Hz, 4H), 3.52 (dd, J = 9.8, 3.5 Hz, 2H), 3.15 - 2.89 (m, 12H), 2.80 - 2.67 (m, 4H), 2.35 (septet, J = 8.4, 7.4 Hz, 4H), 2.00 (tt, J = 12.9, 6.3 Hz, 2H), 1.87 (dq, J = 12.4, 7.7 Hz, 2H), 1.46 (d, J = 5.8 Hz, 36H). 13 C NMR (126 MHz, acetonitrile-d3) δ (ppm): 175.25, 170.68, 168.86, 82.05, 82.02, 63.03, 54.51, 51.20, 49.98, 48.47, 48.02, 31.87, 27.53, 27.46, 25.11. LC-MS (Method 2, ESI) † ): t R = 5.67 min, m / z [M + H] + [C 38 H 69 N4O 12 ] + Calculated value, 773.5; measured value, 773.5.

[0546] Compound 9-3 Compound 9-2 (100 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were dissolved in dry CHCN (5 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 98.8 mg, 0.26 mmol) was added. After stirring for another hour, tert-butyl piperazin-1-ylcarbamate (52.3 mg, 0.26 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, and the residue was purified using Method 14 to produce 140 mg (95% yield) of compound 9-3 as a white solid product. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.78 - 3.69 (m, 2H), 3.68 - 3.43 (m, 10H), 3.11 (dt, J = 18.6, 14.1 Hz, 3H), 2.98 (dt, J = 17.4, 12.9 Hz, 2H), 2.85 - 2.59 (m, 16H), 2.52 (d, J = 14.2 Hz, 2H), 2.29 - 2.14 (m, 3H), 2.11 - 1.96 (m, 3H), 1.77 (tt, J = 14.6, 7.9 Hz, 1H), 1.63 - 1.55 (m, 4H), 1.55 - 1.39 (m, 54H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 173.23, 171.29, 165.44, 156.02, 84.60, 81.86, 79.73, 57.89, 55.23, 54.90, 54.58, 53.29, 50.69, 44.32, 42.27, 40.95, 29.47, 27.34, 27.26, 19.27. LC-MS (Method 1, ESI) † ): t R = 3.18 min, m / z [M + H] + [C 56 H 103 N 10 O 14 ] + Calculated value: 1139.8; measured value: 1139.7.

[0547] compound 9 Compound 9-3 (100 mg, 88 μmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 2 mL), triisopropylsilane (150 μL), 1-dodecathiol (150 μL), and water (10 μL). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 16 to give compound 9 (56.5 mg, 90% yield) as a white solid. 1 H NMR (500 MHz, D2O) δ (ppm): 4.33 - 2.37 (m, 50H), 2.06 (d, J = 42.5 Hz, 2H). 13 C NMR (126 MHz, DO) δ (ppm): 175.85, 173.33, 169.57, 58.10, 55.50, 53.51, 51.83, 50.91, 45.11, 43.59, 40.04, 29.52, 19.71. LC-MS (Method 3 or Method 7, ESI † ): t R = 2.28 min, m / z [M + H] + [C 30 H 54 N 10 O 10 ] + Calculated value: 715.4; measured value: 715.3.

[0548] [Example 10] compound 10

[0549] [ka] Compound 10-1 (S)-5-Benzyl-1-tert-butyl 2-(methylsulfonyloxy)pentanedioate (928 mg, 2.5 mmol) was added as a solution in CHCN (2 mL) to a stirred mixture of 1,7-DO2A-t-Bu (400 mg, 1.0 mmol) and potassium carbonate (345 mg, 2.5 mmol) in CHCN (20 mL) preheated to 60 °C. The reaction was then heated to 80 °C. After 12 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and then purified using Method 9 to give compound 9-1 (420 mg, 44% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm): 7.36 - 7.24 (m, 10H), 5.10 - 5.01 (m, 4H), 3.30 (d, J = 16.2 Hz, 2H), 3.25 - 3.14 (m, 4H), 2.94 - 2.69 (m, 12H), 2.62 (d, J = 14.0 Hz, 4H), 2.46 (h, J = 9.6, 8.9 Hz, 4H), 1.95 (dq, J = 14.2, 7.1 Hz, 2H), 1.80 (dq, J = 14.7, 7.9 Hz, 2H), 1.41 (d, J = 2.2 Hz, 36H). 3 C NMR (126 MHz, chloroform-d) δ (ppm): 173.61, 172.25, 170.45, 136.39, 128.89, 128.63, 81.55, 66.51, 63.38, 55.84, 53.50, 49.00, 31.05, 28.64, 28.55, 25.03. LC-MS (Method 1, ESI † ): t R = 3.53 min, m / z [M + H] + [C 52 H 81 N4O 12 ] + Calculated value: 953.6; measured value: 953.5.

[0550] Compound 10-2 Compound 10-1 (150 mg, 0.16 mmol) was dissolved in absolute ethanol (10 mL), and activated palladium on carbon (10%, 15 mg) was added to the solution. The suspension was placed under vacuum and then connected to a balloon containing hydrogen gas. The reaction mixture was stirred for 2 hours. The reaction mixture was then passed through a Celite pad, and the filtrate was subjected to rotary evaporation to give compound 10-2 (119 mg, 99% yield) as a slightly yellow solid. 1 H NMR (500 MHz, acetonitrile-d3) δ (ppm): 3.81 - 3.61 (m, 4H), 3.38 (dd, J = 9.4, 4.5 Hz, 2H), 3.10 (s, 8H), 2.88 (q, J = 14.8 Hz, 8H), 2.37 (d, J = 5.8 Hz, 4H), 2.01 (dq, J = 18.2, 9.7, 8.6 Hz, 2H), 1.83 (dq, J = 12.3, 7.1 Hz, 2H), 1.47 (s, 19H), 1.46 (s, 18H). 13 C NMR (126 MHz, acetonitrile-d3) δ (ppm): 173.83, 171.16, 168.05, 82.94, 81.93, 64.02, 54.42, 53.95, 46.43, 31.06, 27.50, 27.41, 24.14. LC-MS (Method 2, ESI † ): t R = 5.40 min, m / z [M + H] + [C 38 H 69 N4O 12 ] + Calculated value, 773.5; measured value, 773.5.

[0551] Compound 10-3 Compound 10-2 (100 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were dissolved in dry CHCN (5 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 98.8 mg, 0.26 mmol) was added. After stirring for another hour, tert-butyl piperazin-1-ylcarbamate (52.3 mg, 0.26 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, and the residue was purified using Method 14 to produce 143 mg (97% yield) of compound 10-3 as a white solid product. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 4.46 (d, J = 16.8 Hz, 1H), 4.00 (dd, J = 13.6, 7.5 Hz, 3H), 3.84 (dd, J = 14.4, 3.6 Hz, 2H), 3.76 (q, J = 14.1, 13.3 Hz, 4H), 3.64 (dtt, J = 18.7, 10.0, 4.1 Hz, 3H), 3.53 (ddt, J = 12.8, 7.7, 3.9 Hz, 2H), 3.49 - 3.41 (m, 2H), 3.28 (d, J = 11.4 Hz, 4H), 3.20 (d, J = 14.0 Hz, 4H), 2.94 (ddd, J = 16.2, 10.9, 4.4 Hz, 3H), 2.79 (ddd, J = 9.8, 6.0, 3.2 Hz, 3H), 2.72 (tq, J = 7.5, 3.8 Hz, 4H), 2.68 - 2.57 (m, 5H), 2.07 (t, J = 9.8 Hz, 2H), 1.75 (ddt, J = 14.0, 8.8, 4.1 Hz, 1H), 1.62 - 1.41 (m, 58H). 13C NMR (126 MHz, methanol-d4) δ 176.46, 174.47, 173.16, 157.28, 83.44, 82.74, 81.02, 56.73, 55.89, 53.86, 49.17, 45.92, 45.44, 42.21, 32.35, 28.64, 28.37, 20.43. LC-MS (Method 1, ESI) † ): t R = 3.21 min, m / z [M + H] + [C 56 H 103 N 10 O 14 ] + Calculated value: 1139.8; measured value: 1139.7.

[0552] compound 10 Compound 10-3 (100 mg, 88 μmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 2 mL), triisopropylsilane (150 μL), 1-dodecathiol (150 μL), and water (10 μL). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 16 to give compound 10 (57 mg, 90% yield) as a white solid. 1 H NMR (500 MHz, D2O) δ (ppm): 4.30 - 2.38 (m, 50H), 1.96 (m, 4H). 13 C NMR (126 MHz, DO) δ (ppm): 176.73, 173.35, 170.62, 63.21, 56.02, 50.45, 46.61, 44.82, 41.33, 30.21, 25.45. LC-MS (Method 3 or Method 7, ESI † ): t R = 2.29 min, m / z [M + H] + [C 30 H 54 N 10 O 10 ] + Calculated value: 715.4; measured value: 715.3.

[0553] [Example 11] compound 11

[0554] [ka] Compound 11-1 Compound 9-2 (100 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were dissolved in dry CH3CN (20 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 98.8 mg, 0.26 mmol) was added. After stirring for another hour, the solution was incubated on ice. Then, tert-butyl piperazin-1-ylcarbamate (26 mg, 0.13 mmol) dissolved in 10 mL of CH3CN was added slowly over 30 min. The reaction was allowed to warm to room temperature. After 1 h, 1-boc-piperazine (37 mg, 0.2 mmol) was added, and stirring was continued for another 4 h. The solvent was then evaporated and the residue was purified using Method 14 to give 37 mg (25% yield) of a white solid product. 1 H NMR (500 MHz, chloroform-d) δ 3.66 - 3.24 (m, 16H), 3.07 - 2.46 (m, 18H), 2.38 - 1.63 (m, 12H), 1.43 (dd, J = 8.8, 3.7 Hz, 54H). 13 C NMR (126 MHz, methanol-d4) δ 176.61, 174.66, 173.35, 173.01, 157.46, 156.55, 83.56, 82.85, 81.72, 81.21, 81.06, 61.45, 56.83, 56.34, 55.96, 53.96, 49.60, 49.60, 49.43, 46.24, 45.95, 45.47, 44.72, 42.57, 42.26, 32.25, 28.65, 28.42, 20.52. LC-MS (Method 1, ESI) † ): t R= 3.25 min, m / z [M + H] + [C 56 H 103 N9O 14 ] + Calculated value: 1124.8; measured value: 1124.7.

[0555] compound 11 Compound 11-1 (30 mg, 26 μmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 1.5 ml), triisopropylsilane (100 μl), 1-dodecathiol (100 μl), and water (10 μl). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 1 to give compound 11-1 (18 mg, 95% yield) as a white solid. 1 H NMR (500 MHz, D2O) δ (ppm): 3.93 - 3.49 (m, 10H), 3.48 - 3.02 (m, 28H), 2.56 (d, J = 63.5 Hz, 5H), 2.40 - 2.08 (m, 1H), 1.96 (s, 2H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 178.99, 176.75, 176.55, 174.53, 173.26, 172.67, 64.70, 62.03, 61.50, 56.82, 55.96, 53.99, 52.56, 46.36, 45.44, 44.33, 42.61, 35.58, 34.46, 32.77, 32.17, 30.76, 26.28, 22.31, 21.14, 20.49. LC-MS (Method 3 or Method 7, ESI) † ): t R = 2.31 min, m / z [M + H] + [C 30 H 54 N9O 10 ] + Calculated value: 700.4; measured value: 700.3.

[0556] [Example 12] compound 12

[0557] [ka] Compound 12-1 Benzyl 4-bromobutanoate (565 mg, 2.2 mmol) as a solution in CHCN (2 mL) was added to a stirred mixture of 1,4-DO2A-t-Bu (400 mg, 1.0 mmol) and potassium carbonate (345 mg, 2.5 mmol) in CHCN (20 mL) preheated to 80 °C. After 12 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and then purified using Method 9 to give compound 12-1 (692 mg, 92% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm): 7.34 (hd, J = 7.4, 6.5, 1.7 Hz, 10H), 5.10 (s, 4H), 3.29 (s, 4H), 3.14 (s, 4H), 3.06 - 2.96 (m, 4H), 2.95 - 2.81 (m, 8H), 2.70 (s, 4H), 2.49 - 2.38 (m, 4H), 1.89 (p, J = 6.9 Hz, 4H), 1.44 (s, 18H). 13 C NMR (126 MHz, chloroform-d) δ (ppm): 172.65, 170.39, 135.83, 128.88, 128.57, 128.35, 56.11, 53.51, 52.19, 50.94, 50.62, 50.30, 31.10, 28.18, 19.73. LC-MS (Method 1, ESI) † ): t R = 3.29 min, m / z [M + H] + [C 42 H 65 N4O8] + Calculated value: 753.5; measured value: 753.4.

[0558] Compound 12-2 Compound 12-1 (200 mg, 0.26 mmol) was dissolved in absolute ethanol (10 mL), and activated palladium on carbon (10%, 20 mg) was added to the solution. The suspension was placed under vacuum and then connected to a balloon containing hydrogen gas. The reaction mixture was stirred for 2 hours. The reaction mixture was then passed through a Celite pad, and the filtrate was subjected to rotary evaporation to give compound 12-2 as a slightly yellow solid (146 mg, 96% yield). 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.42 (s, 4H), 3.14 (s, 4H), 3.01 (s, 4H), 2.98 - 2.93 (m, 4H), 2.91 (s, 4H), 2.74 (s, 4H), 2.36 (t, J = 6.7 Hz, 4H), 1.89 (p, J = 6.8 Hz, 4H), 1.48 (s, 18H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 176.10, 170.83, 81.32, 55.36, 53.42, 51.46, 50.64, 50.36, 49.99, 31.28, 27.08, 19.62. LC-MS (Method 2, ESI † ): t R = 4.37 min, m / z [M + H] + [C 28 H 53 N4O8] + Calculated value: 573.4; measured value: 573.5.

[0559] Compound 12-3 Compound 12-2 (100 mg, 0.17 mmol) and N,N-diisopropylethylamine (55 mg, 0.42 mmol) were dissolved in dry CHCN (10 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 129.2 mg, 0.34 mmol) was added. After stirring for another hour, tert-butyl piperazin-1-ylcarbamate (68.4 mg, 0.34 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, and the residue was purified using Method 14 to produce 146 mg (92% yield) of compound 12-3 as a white solid product. 1 H NMR (500 MHz, chloroform-d) δ (ppm): 3.69 (s, 2H), 3.55 (dt, J = 10.5, 4.8 Hz, 2H), 3.49 (s, 3H), 3.30 (d, J = 26.1 Hz, 2H), 3.17 (s, 1H), 3.08 - 2.74 (m, 10H), 2.69 (d, J = 20.1 Hz, 2H), 2.42 (t, J = 6.5 Hz, 1H), 1.90 (dt, J = 13.7, 6.1 Hz, 1H), 1.45 (s, 18H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 172.40, 157.13, 85.37, 81.25, 56.22, 55.93, 55.68, 54.48, 51.73, 51.19, 50.21, 45.74, 42.23, 30.76, 28.70, 28.43, 20.78. LC-MS (Method 1, ESI) † ): t R = 2.90 min, m / z [M + H] + [C 46 H 87 N 10 O 10 ] + Calculated value: 939.7; measured value: 939.5.

[0560] compound 12 Compound 12-3 (95 mg, 0.10 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 2 ml), triisopropylsilane (150 μl), 1-dodecathiol (150 μl), and water (10 μl). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 16 to give the product compound 12 as a white solid (56 mg, 90% yield). 1 H NMR (500 MHz, D2O) δ (ppm): 3.68 (d, J = 26.5 Hz, 10H), 3.34 - 2.76 (m, 30H), 2.50 (t, J = 6.1 Hz, 4H), 1.86 (s, 4H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 175.11, 172.59, 57.96, 54.41, 52.14, 51.77, 50.97, 49.74, 45.58, 42.03, 30.50, 20.68. LC-MS (Method 3, ESI † ): t R = 2.33 min, m / z [M + H] + [C 28 H 55 N 10 O6] + Calculated value: 627.4; measured value: 627.5.

[0561] [Example 13] compound 13

[0562] [ka] Compound 13-1 Benzyl 4-bromobutanoate (257 mg, 1.0 mmol) as a solution in CHCN (6 mL) was added dropwise to a stirred mixture of 1,4-DO2A-t-Bu (400 mg, 1.0 mmol) and potassium carbonate (345 mg, 2.5 mmol) in CHCN (20 mL) preheated to 80 °C. After 6 h, 1-bromobutane (137 mg, 1.0 mmol) was added and the reaction was continued for another 2 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and then purified using Method 9 to give compound 13-1 (348 mg, 55% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm): 7.39 - 7.28 (m, 5H), 5.10 (s, 2H), 3.28 (s, 4H), 2.97 - 2.01 (m, 22H), 1.79 (p, J = 8.2, 7.5 Hz, 2H), 1.44 (s, 22H), 1.29 (dp, J = 14.1, 8.4, 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13 C NMR (126 MHz, chloroform-d) δ (ppm): 173.48, 172.07, 170.97, 136.12, 128.68, 128.35, 81.93, 81.11, 66.33, 64.48, 56.59, 56.25, 54.83, 52.39, 52.02, 31.99, 30.75, 28.31, 28.15, 21.13, 20.71, 14.12, 13.82. LC-MS (Method 1, ESI † ): t R = 3.29 min, m / z [M + H] + [C 35 H 61 N4O6] + Calculated value, 633.5; measured value, 633.5.

[0563] Compound 13-2 Compound 13-1 (200 mg, 0.32 mmol) was dissolved in absolute ethanol (10 mL), and activated palladium on carbon (10%, 20 mg) was added to the solution. The suspension was placed under vacuum and then connected to a balloon containing hydrogen gas. The reaction mixture was stirred for 2 hours. The reaction mixture was then passed through a Celite pad, and the filtrate was subjected to rotary evaporation to give compound 13-2 (160 mg, 92% yield) as a slightly yellow solid. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.41 (d, J = 12.4 Hz, 2H), 3.19 - 2.81 (m, 6H), 2.73 (s, 1H), 2.25 (t, J = 6.7 Hz, 1H), 1.86 (dq, J = 13.2, 7.1 Hz, 1H), 1.64 (td, J = 10.7, 10.2, 5.7 Hz, 1H), 1.48 (s, 8H), 1.41 (h, J = 7.3 Hz, 1H), 0.99 (t, J = 7.3 Hz, 1H). 13 C NMR (126 MHz, methanol-d₄) δ (ppm): 179.60, 178.35, 172.09, 82.59, 56.87, 55.37, 55.13, 52.80, 52.69, 52.30, 51.96, 51.81, 51.67, 51.17, 50.83, 49.34, 34.73, 28.55, 28.37, 27.42, 23.01, 21.98, 21.35, 14.33, 14.21. LC-MS (Method 2, ESI†): t R = 6.03 min, m / z [M + H] + [C 28 H 55 N4O6] + Calculated value: 543.4; measured value: 543.5.

[0564] Compound 13-3 Compound 13-2 (100 mg, 0.18 mmol) and N,N-diisopropylethylamine (28 mg, 0.22 mmol) were dissolved in dry CHCN (10 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 68.4 mg, 0.18 mmol) was added. After stirring for another hour, tert-butyl piperazin-1-ylcarbamate (36.2 mg, 0.18 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, and the residue was purified using Method 14 to produce 123 mg (93% yield) of compound 13-3 as a white solid product. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.82 - 3.56 (m, 4H), 3.11 - 2.02 (m, 30H), 1.83 (m, 2H), 1.58 (m, 2H), 1.52 (s, 9H), 1.45 (s, 18H), 1.31 (dq, J = 13.0, 6.7, 6.2 Hz, 2H), 0.96 (t, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, methanol-d4) δ 174.55, 174.27, 172.92, 157.38, 83.28, 83.08, 81.07, 57.16, 56.36, 56.07, 55.61, 54.41, 53.30, 50.97, 50.10, 45.76, 42.29, 31.57, 31.13, 28.68, 28.31, 27.41, 22.06, 21.68, 14.49. LC-MS (Method 1, ESI) † ): t R = 2.86 minutes, [M + H] + [C 38 H 74 N7O7] + Calculated value, 726.5; measured value, 726.5.

[0565] compound 13 Compound 13-3 (100 mg, 0.13 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 2 ml), triisopropylsilane (150 μl), 1-dodecathiol (150 μl), and water (10 μl). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 16 to give the product compound 13 (67 mg, 97% yield) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.61 (s, 6H), 3.37 (s, 4H), 3.11 (m, 16H), 2.89 - 2.66 (m, 6H), 2.45 (t, J = 6.6 Hz, 2H), 1.86 (dq, J = 14.2, 7.6 Hz, 2H), 1.70 (q, J = 8.1, 7.0 Hz, 2H), 1.39 (h, J = 7.3 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, D2O) δ (ppm): 177.23, 173.41, 171.32, 56.39, 53.99, 52.01, 50.58, 50.04, 49.57, 49.22, 48.32, 47.45, 44.77, 41.07, 29.76, 24.92, 13.24, 12.81. LC-MS (Method 3, ESI † ): t R = 3.40 min, m / z [M + H] + [C 24 H 48 N7O5] + Calculated value: 514.4; measured value: 514.3.

[0566] [Example 14] compound 14

[0567] [ka] Compound 14-1 Compound 12-2 (100 mg, 0.17 mmol) and N,N-diisopropylethylamine (55 mg, 0.42 mmol) were dissolved in dry CH3CN (10 mL). After 15 min, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 129.2 mg, 0.34 mmol) was added. After stirring for another hour, tert-butyl carbazate (45 mg, 0.34 mmol) was added and stirring was continued for 4 hours. The solvent was then evaporated, and the residue was purified using Method 14 to produce 129 mg (95% yield) of compound 14-1 as a white solid product. 1 H NMR (500 MHz, methanol-d4) δ (ppm): 3.54 (s, 4H), 3.09 (m, 20H), 2.30 (s, 4H), 1.95 (s, 4H), 1.48 (d, J = 6.1 Hz, 36H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 174.39, 171.60, 157.52, 83.48, 81.71, 56.27, 53.99, 52.05, 51.39, 50.53, 31.39, 28.57, 28.38, 21.12, 0.86. LC-MS (Method 1, ESI) † ): t R = 2.82 min, m / z [M + H] + [C 38 H 73 N8O 10 ] + Calculated value: 801.5; measured value: 801.6.

[0568] compound 14 Compound 14-1 (100 mg, 0.12 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 2 ml), triisopropylsilane (150 μl), 1-dodecathiol (150 μl), and water (10 μl). The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Diethyl acetate was added to the residue to precipitate the product as a white solid. The solid was isolated and washed three times with diethyl acetate. The residue was purified using HPLC method 16 to give compound 14 (55 mg, 90% yield) as a white solid. 1 H NMR (500 MHz, D2O) δ (ppm): 3.27 (td, J = 134.6, 127.1, 71.2 Hz, 26H), 2.28 (d, J = 6.1 Hz, 4H), 1.91 (s, 4H). 13 C NMR (126 MHz, methanol-d4) δ (ppm): 173.67, 173.10, 56.49, 53.01, 50.84, 50.45, 50.00, 48.53, 47.39, 30.49, 20.38. LC-MS (Method 1, ESI † ): t R = 2.50 min, m / z [M + H] + [C 20 H 41 N8O6] + Calculated value, 489.3; measured value, 489.3.

[0569] [Example 15] compound 15

[0570] [ka] Compound 15-1 The starting material, 3,6,9-triaza-1(2,6)-pyridinacyclodecane (1.03 g, 5.0 mmol), was dissolved in a solvent mixture containing 50 mL of deionized water and 25 mL of 1,4-dioxin, and the pH was adjusted to 8.5 with concentrated HCl. tert-Butyl bromoacetate (1.37 g, 7.0 mmol) dissolved in 1,4-dioxin (25 mL) was added dropwise. After 12 and 24 hours, two additional portions of tert-butyl bromoacetate (2 × 0.23 g, 0.48 mmol) were added, and the pH was adjusted to 8.5 with 1 N NaOH. The reaction completion was monitored by LC-MS (Method 1). The reaction mixture was extracted with CHCl3 (3 × 50 mL), and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by CombiFlash (Method 9) to give compound 15-1 (1.37 g, 63%) as a light brown oil. 1 H NMR (500 MHz, CDCl3) δ 7.63 - 7.49 (m, 1H), 7.01 (dd, J = 7.7, 1.7 Hz, 2H), 3.96 (s, 4H), 3.50 (s, 4H), 3.36 (t, J = 5.5 Hz, 4H), 2.98 (t, J = 6.1 Hz, 4H), 1.44 (s, 18H). 13 C NMR (126 MHz, CDCl3) δ 171.20, 160.12, 137.70, 120.42, 81.64, 57.72, 57.45, 51.83, 46.24, 28.29. LC-MS (Method 1): t R =3.35min, m / z = 435.3 [M+H] + ; Calculated value: 435.3.

[0571] Compound 15-2 Compound 15-1 (0.86 g, 2.0 mmol) and K2CO3 (0.54 g, 4.0 mmol) were suspended in dry ACN (40 mL), and N-(3-bromopropyl)phthalimide (0.8 g, 3.0 mmol) in dry ACN (20 mL) was added dropwise. The suspension was refluxed under argon for 12 hours. After removing the precipitate by filtration, the reaction mixture was concentrated under reduced pressure and then purified by CombiFlash (Method 9) to give compound 15-2 (1.18 g, 95%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.82 (dt, J = 5.6, 2.9 Hz, 2H), 7.71 (dt, J = 5.7, 2.8 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 3.97 (s, 4H), 3.79 (q, J = 6.3 Hz, 2H), 3.69 - 3.49 (m, 4H), 3.39 (s, 6H), 3.16 (s, 4H), 2.16 (dt, J = 15.3, 7.0 Hz, 2H), 1.40 (s, 18H). 13 C NMR (126 MHz, CDCl3) δ 169.95, 168.31, 159.29, 138.18, 134.40, 131.86, 123.58, 120.91, 82.10, 58.54, 58.00, 52.39, 50.20, 45.79, 35.59, 28.20, 21.84. LC-MS (Method 1): t R =3.32min, m / z = 622.3 [M+H] + ; Calculated value: 622.4.

[0572] Compound 15-3 Compound 15-2 (0.62 g, 1 mmol) and hydrazine hydrate (2.5 g, 50 mmol) were dissolved in ethanol (20 mL), and the solution was stirred at 45 °C for 1 h. After dilution with 20 mL of CAN, the precipitate was removed by filtration, and the solvent was removed under reduced pressure. The crude product was purified by CombiFlash (Method 9) to give compound 15-3 (0.41 g, 85%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 2H), 3.93 (s, 4H), 3.60 - 3.39 (m, 6H), 3.38 - 3.26 (m, 4H), 3.23 - 3.12 (m, 4H), 3.12 - 3.00 (m, 2H), 2.22 (dd, J = 10.2, 6.5 Hz, 2H), 1.41 (s, 18H). 13 LC-MS (Method 1): t R =2.742min, m / z = 492.5 [M+H] + ; Calculated value: 492.4.

[0573] Compound 15-4 Compound 7-2 (0.51 g, 1 mmol) was added to a slurry of palladium on carbon (50% water, 50 mg) in methanol (20 mL). The mixture was purged with hydrogen twice and then stirred under argon at room temperature for 12 h. Celite was added to the reaction mixture, and the slurry was filtered through a bed of Celite prewetted with methanol. The filtrate was concentrated under reduced pressure to give a colorless oil, which was used in the next step without further purification. The resulting colorless oil, compound 15-3 (0.25 g, 0.5 mmol), and DIPEA (0.13 g, 1.0 mmol) were dissolved in dry ACN (20 mL), and HATU (0.29 g, 0.75 mmol) in dry ACN (10 mL) was added. The reaction mixture was stirred at room temperature for 45 min. After removing the solvent under reduced pressure, the resulting oil was redissolved in dichloromethane and extracted with citric acid (10% in HO) and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by CombiFlash (Method 9) to give compound 15-4 (0.88 g, 87%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.7 Hz, 2H), 5.09 (s, 1H), 3.91 (s, 4H), 3.45 - 3.03 (m, 18H), 2.51 - 2.38 (m, 1H), 2.34 - 2.15 (m, 1H), 2.07 - 1.78 (m, 4H), 1.43 (s, 18H), 1.39 (s, 27H). 13 C NMR (126 MHz, CDCl3) δ 152.47, 139.12, 121.82, 83.54, 82.51, 62.97, 58.05, 52.18, 50.43, 36.72, 31.84, 29.71, 28.18, 28.08, 27.02, 22.46. LC-MS (Method 1): t R =3.67min, m / z = 892.5 [M+H] + ; Calculated value: 892.6.

[0574] compound 15 To compound 9 (178.3 mg, 0.2 mmol) in DCM (5 mL) cooled to 0 °C was added anisole (0.4 mL, 2 mL / mmol), followed by the slow addition of trifluoroacetic acid (5 mL), and the mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 4 h. The solvent and trifluoroacetic acid were carefully evaporated under reduced pressure, and the resulting oily residue was dissolved in water (5 mL). The organic by-products were pipetted with diethyl ether (3 × 5 mL), the aqueous layer was lyophilized, and the resulting crude product was purified by preparative HPLC (Method 7-2, A and B used as solvents) to give compound 15 (88.9 mg, 85%) as a white solid. 1H NMR (500 MHz, D2O) δ 8.16 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 4.39 (s, 4H), 3.75 (s, 4H), 3.62 (t, J = 6.5 Hz, 1H), 3.26 - 2.92 (m, 12H), 2.26 (m, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.84 - 1.74 (m, 2H). 13 C NMR (126 MHz, D2O) δ 175.02, 174.71, 171.25, 150.65, 141.00, 122.98, 62.50, 59.13, 57.44, 52.62, 51.90, 50.15, 37.09, 31.74, 25.17, 24.08. LC-MS (Method 18): t R =5.58 min, m / z = 524.2 [M+H] + ; Calculated value: 524.3.

[0575] [Example 16] Compound 16

[0576]

change

[0577] compound 16 Compound 16-1 (155.5 mg, 0.2 mmol) in DCM (5 mL) cooled to 0 °C was added to anisole (0.4 mL, 2 mL / mmol), followed by the slow addition of trifluoroacetic acid (5 mL). The mixture was stirred at 0 °C for 1 h and then at room temperature for 4 h. The solvent and trifluoroacetic acid were carefully evaporated under reduced pressure, and the resulting oily residue was redissolved in water (5 mL) and decanted with diethyl ether (3 × 5 mL). The aqueous layer was lyophilized, and the resulting crude product was purified by preparative HPLC (Method 18) to give compound 16 (84.9 mg, 81%) as a white solid. 1 H NMR (500 MHz, D2O) δ 7.61 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.8 Hz, 2H), 3.88 (s, 4H), 3.82 (dd, J = 8.1, 4.3 Hz, 1H), 3.27 (s, 4H), 3.21 - 2.84 (m, 13H), 2.25 - 2.10 (m, 2H), 1.90 - 1.77 (m, 3H), 1.74-1.70 (m, 1H). 13 C NMR (126 MHz, D2O) δ 179.23, 179.07, 176.12, 159.03, 138.73, 121.20, 84.38, 60.51, 58.37, 51.45, 49.95, 45.04, 36.56, 32.05, 27.58, 20.98. LC-MS (Method 6): t R =5.58 min, m / z = 525.3 [M+H] + ; Calculated value: 525.3.

[0578] [Example 17] compound 17

[0579] [ka] Compound 17-1 Compound 15-3 (0.25 g, 0.5 mmol), ((tert-butoxycarbonyl)amino)glycine (0.14 g, 0.75 mmol), and DIPEA (0.13 g, 1.0 mmol) were dissolved in dry ACN (20 mL), and HATU (0.29 g, 0.75 mmol) in dry ACN (10 mL) was added. The reaction mixture was stirred at room temperature for 45 min. After removing the solvent under reduced pressure, the resulting oil was redissolved in DCM and extracted with 10% aqueous citric acid and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by CombiFlash (Method 9) to give compound 17-1 (0.26 g, 79%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.61 (t, J = 7.7Hz, 1H), 7.04 (d, J = 7.7 Hz, 2H), 4.08 - 3.86 (m, 4H), 3.54 - 3.30 (m, 12H), 3.28 - 2.96 (m, 6H), 2.05 (m, 2H), 1.42 (m, 27H). 13 C NMR (126 MHz, CDCl3) δ 170.34, 159.65, 138.24, 120.87, 82.19, 58.46, 57.99, 54.99, 51.95, 50.48, 44.47, 36.04, 28.45, 28.23, 28.17, 21.68. LC-MS (Method 1): t R =3.27min, m / z = 664.4 [M+H] + ; Calculated value: 664.6.

[0580] compound 17 To compound 17-1 (132.7 mg, 0.2 mmol) in DCM (5 mL) cooled to 0 °C, anisole (0.4 mL, 2 mL / mmol) was added, followed by the slow addition of trifluoroacetic acid (5 mL). The mixture was stirred at 0 °C for 1 h and at room temperature for 4 h. The solvent and trifluoroacetic acid were carefully evaporated under reduced pressure, and the resulting oily residue was redissolved in water (5 mL). The organic by-products were removed by pipetting with diethyl ether (3 × 5 mL). The aqueous layer was lyophilized, and the resulting crude product was purified by preparative HPLC (Method 18) to give compound 17 (69.5 mg, 77%) as a white solid. 1 H NMR (500 MHz, D2O) δ 8.25 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 4.39 (s, 4H), 3.77 (s, 4H), 3.62 (s, 2H), 3.33 - 2.86 (m, 12H), 2.00 - 1.76 (m, 2H). 13 C NMR (126 MHz, D2O) δ 175.13, 169.90, 152.05, 146.46, 124.00, 57.76, 56.67, 52.85, 51.74, 51.69, 50.96, 50.90, 50.59, 36.34, 22.66. LC-MS (Method 6): t R =2.39min, m / z = 452.2 [M+H] + ; Calculated value: 452.3.

[0581] [Example 18] compound 18

[0582] [ka] Compound 18-1 5-Benzyl 1-(tert-butyl) 2-((methylsulfonyl)oxy)pentanedioate (3.72 g, 10.0 mmol) and diethylamine (2 M in THF, 7.5 mL, 15.0 mmol) were mixed with 40 mL of dry CAN, followed by the addition of KCO (2.76 g, 20.0 mmol) and NaI (0.15 g, 1.0 mmol). The reaction mixture was stirred under reflux for 12 h. The solid was filtered off and washed with DCM. The crude product was purified by CombiFlash (Method 9) to give compound 18-1 (1.70 g, 53%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.39 - 7.25 (m, 5H), 5.09 (s, 2H), 3.03 (t, J = 7.6 Hz, 1H), 2.40 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H), 1.95 (q, J = 7.5 Hz, 2H), 1.44 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 173.14, 171.09, 136.12, 128.62, 128.24, 81.26, 67.05, 66.26, 41.48, 30.90, 28.37, 24.74. LC-MS (Method 1): t R =4.15min, m / z = 322.4 [M+H] + ; Calculated value: 322.2.

[0583] Compound 18-2 Compound 18-1 (0.32 g, 1 mmol) was added to a slurry of palladium on carbon (50% water, 50 mg) in methanol (20 mL). The mixture was purged with hydrogen twice and then stirred under argon at room temperature for 12 hours. Celite was added to the reaction mixture, and the slurry was filtered through a bed of Celite pre-wetted with methanol. The filtrate was concentrated under reduced pressure to give the product as a colorless oil, which was used in the next step without further purification. The resulting colorless oil, compound 4 (0.25 g, 0.5 mmol), and DIPEA (0.13 g, 1.0 mmol) were dissolved in dry ACN (20 mL), and HATU (0.29 g, 0.75 mmol) in dry ACN (10 mL) was added. The reaction mixture was stirred at room temperature for 45 minutes. After removing the solvent under reduced pressure, the resulting oil was redissolved in DCM and extracted with citric acid (10% in HO) and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by CombiFlash (Method 9) to give compound 18-2 (0.27 g, 81%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.58 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 2H), 5.25 (s, 1H), 3.91 (s, 4H), 3.51 - 2.98 (m, 16H), 2.34 - 2.15 (m, 8H), 1.92 (ddt, J = 22.6, 8.4, 6.4 Hz, 4H), 1.40 (d, J = 1.9 Hz, 27H). 13 C NMR (126 MHz, CDCl3) δ 173.88, 170.25, 167.01, 138.23, 120.88, 82.12, 81.12, 67.22, 58.36, 57.95, 52.05, 50.38, 44.89, 41.32, 36.43, 32.62, 28.35, 28.21, 25.46, 21.73. LC-MS (Method 1): t R =2.84 min, m / z = 705.5 [M+H] + ; Calculated value: 705.5.

[0584] compound 18 Compound 18-2 (132.7 mg, 0.2 mmol) in DCM (5 mL) cooled to 0 °C was added to anisole (0.4 mL, 2 mL / mmol), followed by the slow addition of trifluoroacetic acid (5 mL). The mixture was stirred at 0 °C for 1 h and at room temperature for 4 h. The solvent and trifluoroacetic acid were carefully evaporated under reduced pressure, and the resulting oily residue was dissolved in water (5 mL). The organic by-product was pipetted off with diethyl ether (3 × 5 mL). The aqueous layer was lyophilized, and the resulting crude product was purified by preparative HPLC (Method 18) to give compound 18 (89.0 mg, 83%) as a white solid. 1 H NMR (500 MHz, D2O) δ 8.24 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 4.37 (s, 4H), 3.84 (dd, J = 9.6, 3.8 Hz, 1H), 3.75 (s, 4H), 3.28 - 2.88 (m, 12H), 2.78 (d, J = 15.1 Hz, 6H), 2.43 - 2.24 (m, 2H), 2.15 (ddt, J = 15.9, 8.0, 3.9 Hz, 1H), 2.01 (qt, J = 8.0, 5.8 Hz, 1H), 1.90 - 1.77 (m, 2H). 13 C NMR (126 MHz, D2O) δ 175.10, 173.93, 169.94, 151.97, 146.63, 124.08, 66.60, 57.70, 56.60, 52.86, 51.82, 50.83, 42.61, 40.07, 36.40, 31.06, 22.62, 22.00. LC-MS (Method 6): t R =6.64 min, m / z = 537.2 [M+H] + ; Calculated value: 537.3.

[0585] [Example 19] Gd-19

[0586] [ka]

[0587] Compounds 19-1, 19-2 and 19-5 Compounds 19-1, 19-2, and 19-5 were synthesized as previously reported in Akam, EA, et al. Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrosis. Chemical Science 11, 224-231 (2020) and Foillard, S., Rasmussen, MO, Razkin, J., Boturyn, D. & Dumy, P. 1-Ethoxyethylidene, a new group for the stepwise SPPS of aminooxyacetic acid containing peptides. J. Org. Chem. 73, 983-991 (2008).

[0588] Compound 19-3 To a solution of compound 19-2 (70 mg, 0.20 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (DIPEA, 180 μL, 1.0 mmol), followed by compound 19-1 (NHS-DOTAGA, 153 mg, 0.20 mmol). The mixture was stirred for 1 h, then evaporated to dryness, redissolved in acetonitrile, and purified by Combiflash using Method 10 to give compound 19-3 (159 mg, 77%) as a white solid. 1H NMR (500 MHz, クロロホルム-d) δ 3.63 - 3.38 (m, 8H), 3.38 - 3.29 (m, 2H), 3.20 (h, J = 6.6, 6.1 Hz, 2H), 3.13 - 2.76 (m, 21H), 2.57 (ddd, J = 14.8, 7.3, 2.5 Hz, 1H), 2.50 (dt, J = 14.8, 5.2 Hz, 2H), 2.45 - 2.30 (m, 2H), 1.99 (ddt, J = 14.3, 7.3, 3.7 Hz, 1H), 1.93 - 1.81 (m, 1H), 1.43 (dt, J = 3.7, 1.7 Hz, 55H). 13 C NMR (126 MHz, クロロホルム-d) δ 173.15, 171.38, 170.05, 169.81, 168.15, 83.00, 82.66, 82.58, 82.27, 63.43, 55.54, 54.93, 52.76, 52.68, 49.71, 37.66, 36.02, 32.51, 32.37, 28.22, 28.16. LC-MS (Method 1): t R = 2.9 min, purity >90% (220 nm), m / z =1029.65 [M+H]; calculated: 1029.71

[0589] Compound 19-6 Compound 19-3 (208 mg, 0.20 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 3 h with frequent monitoring by LC-MS for reaction completion. The solution was concentrated by rotary evaporation, and the product was precipitated using diethyl ether. The resulting white residue was washed with diethyl ether (3 × 20 mL), isolated by centrifugation, and dried under vacuum to give compound 19-4 as an off-white powder. This powder (113 mg, 0.12 mmol) was suspended in dimethylformamide (1 mL), and DIPEA (80 μL, 0.45 mmol) was added, followed by compound 19-5. The mixture was stirred at room temperature for 1 h and then purified by CombiFash using Method 10 to give compound 19-6 as a white powder, 113 mg, 59.4% yield over two steps. 1 H NMR (500 MHz, methanol-d4) δ 4.41 (d, J = 4.9 Hz, 1H), 4.33 - 4.30 (m, 4H), 4.07 (s, 4H), 3.80 - 3.57 (m, 9H), 3.45 (bm, 16H), 3.10 (m, 5H), 2.79 - 2.39 (m, 3H), 2.04 - 1.88 (m, 1H), 1.45 (m, 18H). LC-MS (Method 4): t R = 5.4 min, purity >95% (220 nm), m / z =951.45 [M+H]; calculated: 951.49 Compound 19-7 To a solution of compound 19-6 (113 mg, 0.12 mmol) in water (1 mL), GdCl3 (50 mg, 0.13 mmol) was added and the pH was adjusted to 6.8 with a solution of 1 M NaOH. The mixture was stirred at room temperature for 1 h and then purified by CombiFlash using Method 11. After lyophilization, compound 19-7 was isolated as a white solid, mass = 105 mg, yield 78%. The product was isolated as a mixture of di- and mono-BOC-protected products. LC-MS (Method 4): R = 6.4 min, mono-BOCt R= 5.2 min. m / z di-BOC = 1106.25 [M+H]; calculated: 1106.38. m / z mono-BOC = 1006.25 [M+H]; calculated: 1006.38. LC-ICP (Method 18): Di-BOCt R =7.4 min, mono-BOCt R =5.7 minutes.

[0590] Gd-19 Compound 19-7 (105 mg, 0.09 mmol) was dissolved in 4 M HCl in dioxane and stirred for 30 min. The solution was evaporated to dryness, redissolved in water, and freeze-dried. The product was then passed through a Chelex column to remove any free gadolinium. After freeze-drying, compound 19-8 (Gd-19) was isolated as a white solid in quantitative yield and used without further purification. LC-MS (Method 4): R =4.5 min, m / z=905.25[M+2H]; Calculated value: 905.28. LC-ICP (Method 11):t R =4.9 minutes, purity >95% [Example 20] Gd-20

[0591] [ka]

[0592] Compound 20-1 To a solution of compound 19-1 (209 mg, 0.26 mmol) in anhydrous dichloromethane (5 mL), a solution of tert-butyl N-(3-aminopropoxy)carbamate (50 mg, 0.26 mmol) and diisopropylethylamine (DIPEA, 180 μL, 1.0 mmol) in 1 mL of dichloromethane was added. The mixture was stirred for 1 h, then evaporated to dryness, redissolved in acetonitrile, and purified by CombiFlash using Method 10 to give compound 20-1 as a white powder. Mass = 206 mg, yield 91%. 1H NMR (500 MHz, chloroform-d) δ 3.90 (t, J = 5.6 Hz, 2H), 3.71 (s, 4H), 3.55 - 3.41 (m, 3H), 3.35 (septet, J = 6.9 Hz, 2H), 3.14 (dt, J = 14.2, 8.1 Hz, 8H), 2.94 (t, J = 5.3 Hz, 8H), 2.33 (dp, J = 29.7, 7.6 Hz, 2H), 2.06 (ddd, J = 12.7, 9.1, 6.5 Hz, 1H), 1.97 - 1.84 (m, 1H), 1.76 (p, J = 6.0 Hz, 2H), 1.44 (d, J = 6.4 Hz, 45H). 13 C NMR (126 MHz, chloroform-D) δ 172.52, 171.36, 169.58, 168.57, 157.50, 83.09, 83.04, 82.53, 82.39, 81.64, 77.38, 77.38, 77.13, 76.87, 75.25, 63.47, 56.35, 55.44, 55.43, 53.19, 52.57, 49.77, 47.24, 37.17, 32.89, 28.33, 28.26, 28.23, 28.15, 27.26, 24.37. LC-MS (Method 1): t R = 3.36 min, purity >90% (220 nm), m / z =873.45 [M+H]; calculated: 873.58

[0593] Compound 20-2 Compound 20-1 (256 mg, 0.21 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 4 h with frequent monitoring by LC-MS for reaction completion. The solution was concentrated by rotary evaporation, and the product was precipitated using diethyl ether. The resulting white residue was washed with diethyl ether (3 × 30 mL), isolated by centrifugation, and dried under vacuum to give compound 20-2 (104 mg, 90% yield) as a white powder, which was used without further purification. 1H NMR (500 MHz, heavy water) δ 3.96 (m, 2H), 3.88 - 3.57 (m, 5H), 3.54 - 2.74 (m, 18H), 2.65 - 2.20 (m, 2H), 1.99 (d, J = 106.3 Hz, 2H), 1.79 - 1.57 (m, 3H), 1.40 - 0.96 (m, 1H). LC-MS (Method 3): t R = 3.23 min, m / z = 873.45 [M+H]; calculated: 873.58

[0594] compound 20 Compound 20-2 (164 mg, 0.29 mmol) was dissolved in water. To this solution was added GdCl3 (123 mg, 0.38 mmol) and the pH was adjusted to 6.8 with a solution of 1 M NaOH. The solution was stirred at room temperature for 1 hour and then purified by CombiFlash using Method 10. After lyophilization, compound 20 was isolated as a white solid. Mass = 187 mg, 89%. LC-MS (Method 3): R =4.5 min, m / z=704.15[M+2H]; Calculated value: 704.18. LC-ICP (Method 11):t R =5.03 min, purity >95%

[0595] [Example 26] Compounds 9, 10, and 11 with Gd 3+ Complex formation with Compounds 9, 10, or 11 (70 or 71 μmol) were dissolved in water (5 mL), and the pH of the solution was adjusted to 5.5 with 0.1 M NaOH. GdCl3·6H2O or YbCl3·6H2O (1.1 equivalents, 77 or 79 μmol) dissolved in water (2 mL) was then added dropwise. The pH of the solution was maintained at 5.5, and the solution was stirred for 2 hours. The solution was then passed through a Chelex column to remove any free metal ions and lyophilized to yield the title compound. A xylenol orange test was negative, demonstrating the absence of unchelated Gd / Yb(III). The corresponding Gd / Yb(III) complexes were characterized by LC-MS and HR-ESI-MS. Purity was further characterized by LC-ICP:

[0596] Gd-9: 60 mg, yield 98%, LC-MS method 3 or method 7, t R =3.77 min, m / z[M] - , [C 30 H 50 GdN 10 O 10 ] - Calculated for 868.3; Found 868.1. HR-ESI-MS m / z (%) [M] - , [C 30 H 50 GdN 10 O 10 ] - Calculated for 868.2958; Found 868.2983. LC-ICP: Method 20 or Method 23, detection of Gd at m / z = 157, t R = 5.09 minutes, purity = 98%.

[0597] Gd-10: 58 mg, 97% yield; LC-MS Method 3 or Method 7, t R =3.79 min, m / z[M] - The calculated value for [C 30 H 50 GdN 10 O 10 ] - , 868.3; Measured value 868.2. HR-ESI-MS m / z (%) [M] - , [C 30 H 50 GdN 10 O 10 ] + Calculated for 868.2958; Found 868.2965. Purity was further characterized by LC-ICP: Method 20 or Method 23, detection of Gd at m / z=157, t R =5.10 minutes, purity=99%.

[0598] Gd-11: 60 mg, 97% yield; LC-MS Method 3 or Method 7, t R =3.78 min, m / z(%)[M] - , [C 30 H 49 GdNO 10 ] -Calculated for 853.3; Found 853.3. HR-ESI-MS m / z (%) [M] - , [C 30 H 49 GdNO 10 Calculated for 853.2849; Found 853.2884. Purity was further characterized by LC-ICP: Method 20 or Method 23, detection of Gd at m / z=157, t R = 5.05 minutes, purity = 98%.

[0599] Yb-9: 95% yield; LC-MS Method 3 or Method 7, t R =3.77 min, m / z[M] - , [C 30 H 50 YbN 10 O 10 ] - Calculated for 884.3; Found 884.1. HR-ESI-MS m / z (%) [M] - , [C 30 H 50 YbN 10 O 10 Calculated value for 884.3105; Found value 884.3115. LC-ICP: Method 20 or Method 23, detection of Yb at m / z = 173, t R = 5.08 minutes, purity = 99%.

[0600] [Example 27] Compounds 12, 13, and 14 with Mn 2+ Complex formation with Compounds 12, 13, or 14 (0.2 mmol) and MnCl2 (0.2 mmol) were dissolved in 4 mL of water. The solution was adjusted to pH 5.5 using 0.1 M NaOH and transferred to a Schelenk tube. After degassing with five N2 pump cycles, the reaction was heated to 60 °C and stirred for 1 h. The solution was then passed through a Chelex column to remove any free metal ions. The concentration of the corresponding Mn complex was determined by ICP-MS. Purity was further characterized by LC-ICP.

[0601] Mn-12: Yield 88%. LC-MS (Method 2, ESI $ ):t R=2.99 min, m / z[M+H] + The calculated value for [C 28 H 53 MnN 10 O6] + , 680.4; Found 680.3. LC-ICP: Method 22, detection of Mn at m / z = 55, t R = 5.42 minutes, purity = 96%.

[0602] Mn-13: Yield 85%. LC-MS (Method 2, ESI $ ):t R =3.57 min, m / z[M+H] + To [C 24 H 46 MnNO5] + Calculated for m / z = 567.3; Found = 567.2. LC-ICP: Method 22, detection of Mn at m / z = 55, t R = 5.97 minutes, purity = 98%.

[0603] Mn-14: Yield 90%. LC-MS (Method 7, ESI $ ):t R =4.89 min, m / z[M+H] + [C 20 H 39 MnN8O6] + Calculated for m / z = 542.2; Found = 542.2. LC-ICP: Method 22, detection of Mn at m / z = 55, t R =3.86 minutes, purity = 95%.

[0604] [Example 28] Compounds 15, 16, 17, and 18 with Mn 2+ Complex formation with Compounds 15, 16, 17, or 18 (0.02 mmol) were dissolved in water (2.0 mL) and the pH was adjusted to 6.5 with 0.1 M NaOH. MnCl 4H O (0.02 mmol) was then added with stirring. The pH was reduced to approximately 3.5, and the completion of complex formation was confirmed by LC-MS. The excess free Mn 2+ was removed with Chelex 100 resin (pH 6.5). The complex was then lyophilized to a powdery solid and redissolved in water as needed.

[0605] Mn-15: Yield 87%. LC-MS (method 6):t R =7.49 min, m / z[M+H] + , [C 23 H 36 MnN7O7] + min, 577.2; actual value 577.2, purity = 96% (250 nm UV detector).

[0606] Mn-16: Yield 91%. LC-MS (method 6):t R =6.58 min, m / z[M+H] + , [C 23 H 35 MnN6O8] + Calculated for 578.2; found 577.1, purity = 97% (250 nm UV detector).

[0607] Mn-17: Yield 85%. LC-MS (method 6):t R =9.53 min, m / z[M+H] + [C 20 H 32 MnNO5] + Calculated for 505.1; Found 505.0, Purity = 92% (250 nm UV detector).

[0608] Mn-18: Yield 90%. LC-MS (method 6):t R =8.01 min, m / z[M+H] + , [C 25 H 39 MnN6O7] + Calculated for 590.2; Found 590.1, Purity = 97% (250 nm UV detector).

[0609] [Example 29] Compounds 15, 16, 17, and 18 with Zn 2+ Complex formation with Compounds 15, 16, 17, or 18 (0.02 mmol) were dissolved in water (2.0 mL) and the pH was adjusted to 6.5 with 0.1 M NaOH. ZnCl2 (0.02 mmol) was then added with stirring. The pH was reduced to approximately 3.5, and the completion of complex formation was confirmed by LC-MS. Excess free Zn 2+ The Zn-15 was removed with Chelex 100 resin (pH 6.5). The complex was then lyophilized to a powdery solid and redissolved in water as needed. Zn-15: Yield 90%. 1 H NMR (500 MHz, D2O) δ 7.88 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.7 Hz, 2H), 4.20-4.01 (m, 4H), 3.64 - 3.39 (m, 4H), 3.23 (t, J = 6.2 Hz, 1H), 3.08 (s, 2H), 2.90 (t, J = 12.2 Hz, 2H), 2.82 - 2.68 (m, 4H), 2.61 (t, J = 13.6 Hz, 2H), 2.36 - 2.21 (m, 2H), 2.01 (s, 2H), 1.90 (q, J = 6.1 Hz, 2H), 1.57 (s, 2H). LC-MS (Method 6): t R =7.19min, m / z [M + H] + [C 23 H 36 N7O7Zn] + Calculated value, 586.2; found value 586.0, purity = 95% (250 nm UV detector).

[0610] Zn-16: Yield 92%. 1H NMR (500 MHz, D2O) δ 7.96 - 7.83 (m, 1H), 7.30 (d, J = 7.8 Hz, 2H), 4.25 - 4.03 (m, 4H), 3.86 (dd, J = 7.9, 4.3 Hz, 1H), 3.66 - 3.38 (m, 4H), 3.04 (t, J = 6.7 Hz, 2H), 2.97 - 2.86 (m, 2H), 2.85 - 2.68 (m, 4H), 2.61 (dt, J = 14.8, 4.3 Hz, 2H), 2.29 - 2.11 (m, 2H), 2.09 - 1.96 (m, 2H), 1.93 - 1.83 (m, 1H), 1.76 (m, 1H), 1.57 (t, J = 8.2 Hz, 2H). LC-MS (Method 6): t R =6.27 min, m / z [M + H] + [C 23 H 35 N6O8Zn] + Calculated value, 587.2; Measured value 587.1, Purity = 96% (250 nm UV extractor).

[0611] Zn-17: yield 90%. 1 H NMR (500 MHz, D2O) δ 7.89 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 4.19 - 4.06 (m, 4H), 3.62 - 3.53 (m, 4H), 3.45 (d, J = 17.0 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.91 (m, 2H), 2.82 - 2.70 (m, 4H), 2.60 (m, 2H), 2.03 (m, 2H), 1.61 (m, 6.5 Hz, 2H). LC-MS (Method 6): t R =9.75 min, m / z [M + H] + [C 20 H 32 N7O5Zn] + Calculated value, 514.2; Measured value 514.0, Purity = 94% (250 nm UV extractor).

[0612] Zn-18: Yield 91%. 1 H NMR (500 MHz, D2O) δ 7.92 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 4.26 - 4.06 (m, 4H), 3.72 - 3.43 (m, 5H), 3.09 (td, J = 6.8, 2.7 Hz, 2H), 2.94 (m, 2H), 2.88 - 2.72 (m, 11H), 2.65 (dt, J = 14.2, 4.1 Hz, 2H), 2.37 - 2.21 (m, 2H), 2.13 (m, 1H), 2.07 - 1.84 (m, 3H), 1.68 - 1.52 (m, 2H). LC-MS (Method 3-3): t R =7.79min, m / z [M + H] + [C 25 H 39 N6O7Zn] + Calculated value, 599.2; found value 599.1, purity = 96% (250 nm UV detector).

[0613] [Example 30] Compounds 1 to 8 68 Radiolabeling with Ga A Bond Elut SCX cartridge (100 mg, Agilent) was washed slowly with 5.5 M HCl (1 mL) and H2O (10 mL). 68 GaCl (6 mCi) was eluted from a Ga-68 generator (Eckert & Ziegler) with 0.1 M HCl and loaded onto the preactivated cartridge. The cartridge was purged with air and 68 GaCl was eluted with 3 M NaCl (0.3 mL in 140 mM HCl). A solution of compound 1-8 (50 μL, 0.5 mg in 1 mL of 10 mM HCl) was diluted with 1.5 M NaOAc (pH = 4.2) and added to 150 μL of 68GaCl was added. The reaction mixture was heated to 60°C (compounds 5, 7, 8) or 90°C (compounds 1, 2, 3, 4, 6) for 10 minutes. The reaction mixture was allowed to cool for 1 minute (compounds 5, 7, 8) or 3 minutes (compounds 1, 2, 3, 4, 6) and then diluted with 0.65 mL of sterile HO.

[0614] [Example 31] Compounds 1 to 8 64 Radiolabeling with Cu From the University of Wisconsin-Madison Cyclotron Facility 64 CuCl (28 mCi) was obtained and diluted to 1 mL with HO. A solution of compound 1-8 (50 μL, 0.5 mg in 1 mL of 10 mM HCl) was diluted with 1.5 M NaOAc (pH = 4.2) and added to 50 μL of 64 CuCl was added. The reaction mixture was heated to 60°C (compounds 5, 7, 8) or 90°C (compounds 1, 2, 3, 4, 6) for 10 minutes. The reaction mixture was allowed to cool for 1 minute (compounds 5, 7, 8) or 3 minutes (compounds 1, 2, 3, 4, 6) and then diluted with 0.65 mL of sterile HO.

[0615] [Example 32] Compounds 15-18 52 Radiolabeling with Mn and 52 / nat Preparation of Mn complexes from the Birmingham, Alabama Cyclotron Facility 52 Obtain MnCl (5 mCi) and dilute to 500 μL with 0.1 M HCl. Add a solution of compounds 1–8 (50 μL, 1.0 mg in 1 mL of 1.5 M NaOAc buffer, pH 4.5) to 50 μL of HCl. 52 The reaction mixture was kept at room temperature for 15 minutes and diluted with 200 μL of sterile PBS. 52 A solution of Mn-labeled compounds 15 to 18 was nat Mn-labeled compounds 15-18 ( nat Mn (final concentration: 30 mM) by mixing with a stock solution. 52 / nat The injection dose of Mn complex was obtained.

[0616] [Example A] In vitro and animal model data In vitro reactivity of compounds Quantitative measurement of reaction rates using aldehydes: Method A: Reaction rate of the compound with 2-formylpyridine measured by HPLC-ICP-MS The reactivity of the aldehyde-conjugated probe was assessed under pseudo-first-order conditions in pH 7.40 phosphate-buffered saline using a 2-formylpyridine concentration of 1000 μM and a probe concentration of 25 μM. Based on their relative integrities, the concentrations of unreacted starting material and condensate were determined at 12-minute intervals. The values ​​were fitted to a standard first-order linear equation, and the rate constant was extracted from the slope.

[0617] Method B: Reaction rate of the compound with butyraldehyde as determined by HPLC-ICP-MS. The reaction was carried out in phosphate buffer at pH 7.40 with a butyraldehyde concentration of 100 μM and a hydrazine probe of 25 μM. Based on their relative integrities, the concentrations of unreacted starting material and condensate were determined at 10-minute intervals over a 2-hour period. The values ​​were fitted to a standard first-order linear equation, and the rate constant was extracted from the slope.

[0618] Method C: Kinetics of reaction of fluorescent compounds with butyraldehyde measured by HPLC with UV-vis and fluorescence detection. Condensation reactions were carried out in pH 7.40 phosphate-buffered saline at a concentration of 100 μM butyraldehyde and 10 μM fluorescent probe. Based on their relative integrities, the concentrations of unreacted starting material and condensate were determined at 10-minute intervals over a 2-hour period. The values ​​were fitted to a standard first-order linear equation, and the rate constant was extracted from the slope.

[0619] Method D: Reaction kinetics using UV-visible measurements. Using the Beer-Lambert law, the ε values ​​of Mn-15, Mn-16, and Mn-17 at 220 nm (ε 220 The molar extinction coefficient at 1000 kJ / cm2 was calculated as follows: 220 = ε220 Cl;(wherein, A220 is the absorbance at a wavelength of 220 nm, C is the concentration (M), and l is the cell path length (cm).

[0620] The extinction coefficients of the reaction products of Mn-15, Mn-16, and Mn-17 with butyraldehyde (Mn-15-Ald, Mn-16-Ald, and Mn-17-Ald) were calculated using the following method: Using Method 24, an HPLC trace of each of 1 mM Mn-N (Mn-N refers to Mn-15, Mn-16, or Mn-17) was first obtained. Then, another batch of Mn-N (final concentration: 1 mM) with 200 equivalents of butyraldehyde was added to drive the reaction to completion. Then, an HPLC trace of the reaction product of Mn-N and butyraldehyde, represented as Mn-N-Ald (Mn-Ald refers to the reaction product with either Mn-15, Mn-16, or Mn-17), was obtained by Method 24. The ε220 value of Mn-N-Ald was calculated using the following equation:

[0621]

number

[0622] [Table 34]

[0623] The kinetics of the reactions of Mn-15, Mn-16, and Mn-17 with butyraldehyde were monitored spectrophotometrically by measuring the change in absorbance at 220 nm. All reactions were carried out in PBS at 25°C. In each experiment, [butyraldehyde] = 1 mM, and the Mn-complex concentrations were varied to 0.04 mM, 0.06 mM, 0.08 mM, and 0.10 mM, to predict the rate laws.

[0624] At the beginning of the reaction (t=0), the concentration of the starting Mn complex is a0 and the concentration of the aldehyde condensate is zero. After t time, the concentration of the product is x and the concentration of the remaining Mn complex starting material is a0-x. The first-order reaction is

[0625]

number

[0626]

number

[0627] The concentration of Mn-N-Ald (where Mn-Ald refers to the reaction product with either Mn-15, Mn-16, or Mn-17) can be predicted by the following equation, where A is the absorbance of Mn-N and A is the absorbance of the reaction mixture after time t: A0=ε MnL a0l (5)

[0628] The absorbance of the reaction mixture is A=ε Mn-N (a0-x)l+εMn-N-Ald xl (6) is.

[0629] After subtraction, ΔA=A-A0=ε MnN (a0-x)l+ε Mn-N-Ald xl-ε Mn-N a 0 l (7) ΔA=(ε Mn-N-Ald- ε Mn-N) xl (8) This becomes:

[0630] [Table 35]

[0631] Quantitative measurement of hydrolysis kinetics: 1 mM solutions of Mn-15-Ald, Mn-16-Ald, and Mn-17-Ald (Mn-Ald refers to the reaction products with either Mn-15, Mn-16, or Mn-17) were prepared as follows: 1 mM (1 mL) of Mn-15, Mn-16, or Mn-17 was prepared in PBS (pH 7.4), followed by the addition of butyraldehyde (14.4 mg, 200 mmol). The mixture was gently shaken at room temperature for 10 minutes and then freeze-dried for 12 hours. The resulting white solid was then redissolved in 1 mL of water.

[0632] The HPLC traces of each butyraldehyde reaction product were measured using Method 25 (Mn-15-Ald) and Method 26 (Mn-16-Ald, Mn-17-Ald). A 37% stock solution of formaldehyde was then added to give a final formaldehyde concentration of 200 mM.

[0633]

number

[0634] The hydrolysis of hydrazones / oximes is reversible. Addition of excess formaldehyde to trap the free nitrogen bases drove the hydrolysis reaction to completion, allowing monitoring of the hydrolysis reaction without interference from the reverse reaction. Thus, the kinetics for the hydrolysis of Mn-15-Ald, Mn-16-Ald, and Mn-17-Ald follow a rate law.

[0635]

number

[0636]

number

[0637]

number

[0638]

number

[0639]

number

[0640]

number

[0641]

number

[0642] [Table 36]

[0643] Preparation of allicin containing bovine serum albumin, BSA-ALD: To a solution of bovine serum albumin (BSA) (100 mg) dissolved in phosphate-buffered saline (4 mL, pH 7.4, 0.25 mM) was added sodium ascorbate (20 mg), ferric chloride (120 μL, 10 mM), and 20 μL of HO (30% w). The reaction mixture was stirred at 37 °C for 24 h, with sodium ascorbate (20 mg) added repeatedly every 8 h. After the reaction, the protein was purified using a PD-10 Sephadex G25 desalting column (GE Healthcare) eluted with PBS. The protein concentration was assessed using a "BCA Protein Assay Kit" (Thermo Scientific). The protein carbonyl concentration was determined using a "Protein Carbonyl Content Assay Kit" (Sigma-Aldrich). BSA-ALD had an aldehyde concentration of 4 aldehydes / protein. BSA had an aldehyde concentration of approximately 0.3 aldehydes / protein.

[0644] Instead, BSA Ald Preparation of Gd 3+ Binding of the probe to the protein was performed according to a modified procedure. To a solution of bovine serum albumin (BSA) (100 mg) dissolved in phosphate-buffered saline (4 mL, pH 7.4, 0.25 mM) was added sodium ascorbate (20 mg), ferric chloride (120 μL, 10 mM), and 20 μL H2O2 (30% w). The reaction was stirred at 37 °C for 24 h, with sodium ascorbate (20 mg) added repeatedly every 8 h. After 24 h, the protein was purified using a PD-10 Sephadex G25 desalting column (GE Healthcare) eluted with PBS. Protein concentration was assessed using the "Micro BCA Protein Assay Kit" (Thermo Scientific, 23235). Protein carbonyl content was determined using the "Protein Carbonyl Content Assay Kit" (Sigma-Aldrich, MAK094-1KT). BSA Ald had an aldehyde concentration of 4 aldehydes / protein. For further use, the protein solution was kept at a concentration of 20 mg / mL.

[0645] Relaxivity measurements: BSA-ALD (10 mg / mL) or BSA (10 mg / mL) was treated with the corresponding Gd or Mn complexes at a concentration range (0.01–0.2 mM) for 24 h at 37 °C, maintaining a total volume of 300 μL for all samples. After 24 h, an aliquot of the solution (50 μL) was used for longitudinal (T1) relaxation measurements, recorded using a Bruker MQ60 Minispec at 1.41 T and 37 °C. Longitudinal (T1) relaxation times were measured via inversion recovery experiments using 10 inversions for periods ranging between 0.05 × T1 and 10 × T1. Solutions in PBS (concentration range: 0.1 mM–1.0 mM) were run in parallel. To measure the relaxivity of BSA-bound species, sodium cyanoborohydride (10 mg) was added to the solution to irreversibly bind the probe to the protein. After an additional 2 hours of incubation at 37°C, the protein-bound and protein-free solutions were separated by ultrafiltration. 200 μL PBS was then added to the residue to dissolve the protein. Longitudinal (T1) relaxation times for the immobilized species were measured at 1.41 T and 37°C using a Bruker mq60 Minispec. After the measurements, the concentrations of the corresponding metal ions (Gd / Mn) in both the residue and the filter were determined using an Agilent 8800 ICP-MS instrument. Relaxivity (r1) was determined from the slope of the plot of 1 / T1 versus metal concentration for five concentrations.

[0646] On / off rates for oxidized BSA-ALD: BSA-ALD (10 mg / mL) was incubated with 200 μM of the corresponding Gd or Mn complex in a total volume of 300 μL at 37°C in pH 7.4 PBS. Dynamic longitudinal (T1) relaxation times were measured at 1.41 T and 37°C using a Bruker mq60 Minis. After 24 h, the protein-bound and protein-free solutions were separated by ultrafiltration. 200 μL PBS was then added to the residue to dissolve the protein-bound species. The change in longitudinal (T1) relaxation time was then measured at 1.41 T and 37°C using a Bruker mq60 Minispec.

[0647] Conjugation of fluorescent compounds to BSA-ALD. BSA-ALD (25 μM) was incubated with 10 μM fluorescent probe in a total volume of 300 μL in pH 7.4 PBS at 37° C. for 3 hours. UV-vis spectra were collected for each solution. Free dye and BSA-Ald-bound dye were then separated by ultrafiltration using a 10 kDa MWCO. UV-vis spectra were then collected for the resulting solutions, yielding a peak intensity of 89,000 nm at 555 nm. -1 cm -1 The concentration of unbound / unreacted dye was determined based on the extinction coefficient of TAMRA of For blocking experiments, BSA-ALD was incubated with 100 molar equivalents of hydrazine and o-methylhydroxylamine at 37°C for 24 hours.

[0648] [Table 37]

[0649] Compound stability in human plasma: A 16 μL aliquot of Gd or Mn complex (1.0 mM) was added to 500 μL of human plasma (Lampire Biological Laboratories). The solution was then incubated at 37°C for 2 or 3 hours. Aliquots (50 μL) were removed at 1, 2, or 3 hours. Proteins were precipitated by the addition of 150 μL of acetonitrile and removed after centrifugation. The supernatant was then analyzed using HPLC-ICP-MS. Neither unchelated gadolinium nor the appearance of any new Gd / Mn-containing species was observed. Figures 49A and 49B show the stability characterization of Gd-9 and Gd-10, demonstrating the absence of dechelation or formation of Gd-containing metabolites after 3 hours.

[0650] [Table 38]

[0651] Animal experiments Animal models: All experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the ARRIVE guidelines and were approved by the MGH Institutional Animal Care and Use Committee. All animals were sacrificed after imaging for biochemical analysis and histological evaluation.

[0652] CCl4 liver fibrosis model: Male C57BL / 6 mice (Charles River Laboratories, Wilmington, MA) were treated with carbon tetrachloride by oral gavage 2-3 times per week for 12 weeks (20% CCl4 in 0.1 ml olive oil week 1, 30% week 2, and 40% week 3-12). Control mice received vehicle (olive oil) only.

[0653] A total of 53 C57BL / 6 mice were used in the CCl4-induced liver fibrosis experiment: A. CCl4 was administered for 12 weeks (n=20). Each mouse was imaged with probe 1, then imaged again 24 hours later with probe 2. Probes 1 and 2 were randomly selected from GdDOTA, GdCHyd, Mn-12, Gd-9, and Gd-10. B. Vehicle-treated control (n=20). Each mouse was imaged with probe 1 and then again 24 hours later with probe 2. Probes 1 and 2 were randomly selected from GdDOTA, Mn-12, GdCHyd, Gd-9, and Gd-10. C. CCl4 was administered for 12 weeks (n=3, three other pairwise comparisons were performed in group A). ​​Each mouse was imaged with probe 1 and then again 24 hours later with probe 2. Probes 1 and 2 were randomly selected from Gd-9 and Gd-10. D. Vehicle-treated controls (n=2, two other pairwise comparisons were performed in group B). Each mouse was imaged with probe 1, then imaged again 24 hours later with probe 2. Probes 1 and 2 were randomly selected from Gd-9 and Gd-10. E. CCl4 was administered for 12 weeks (n=3). Each mouse was imaged with Gd-9. 24 hours later, the same mice were first injected with 1000 μmol / kg Yb-9, followed by 100 μmol / kg Gd-9 15 minutes after the Yb-9 injection.

[0654] Non-alcoholic steatohepatitis liver fibrosis model: A total of 40 C57BL / 6 mice were used and randomly assigned to each study group. To induce NASH, 6-week-old male C57BL / 6 mice (Charles River Labs, Wilmington, MA) were fed a choline-deficient, high-fat diet (CDAHFD) (A06071302; Research Diets, New Brunswick, NJ) consisting of 60 kcal% fat and 0.1% methionine (by weight). No animals were excluded from the study.

[0655] Three groups of mice were studied: Group A, mice were fed dietary CDAHFD for 2 weeks (n = 6), 6 weeks (n = 6), and 10 weeks (n = 6) and imaged with probe Gd-9. Group B, mice were fed diet CDAHFD for 10 weeks, followed by normal chow for 1 week (n = 6) or 4 weeks (n = 6) and imaged with probe Gd-9. Group C, mice were fed normal chow for 2, 6, 10, 11, or 14 weeks (n = 10) and imaged with probe Gd-9.

[0656] Rat liver fibrosis model: Liver fibrosis was induced in male Sprague-Dawley rats (n=7) by common bile duct ligation (CD®, Charles River Labs, Wilmington, MA). Control animals (n=4) underwent sham surgery. Ten days after ligation, BDL and sham rats were imaged using Gd-9 at a dose of 100 μmol / kg based on body surface area.

[0657] Pulmonary fibrosis model: Eight-week-old 57Bl / 6 adult male mice (Jackson Laboratories, Barr Harbor, ME) were given a single intratracheal dose of bleomycin, 1 unit / kg body weight (50 μL total volume) (Fresenius Kabi, Lake Zurich, IL) as previously described in Desogere, P., et al. Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis. J Nuc Med 58, 1991-1996 (2017).

[0658] Combined cardiac and pulmonary fibrosis model: Left ventricular dysfunction accompanied by pulmonary hypertension was induced in 6-month-old senescence-accelerated / resistant mice (SAMP8 / SAMR1) by transverse aortic constriction (TAC) via a left thoracotomy. This mouse model represents a well-established model of pressure overload-induced cardiac hypertrophy, which can induce cardiac and pulmonary fibrosis. The transverse aorta was encircled with 7-0 nylon suture and tightly circumscribed with a pre-sterilized, blunt-ended 27-gauge needle. After the knot was tightly tied, the needle was removed, allowing aortic blood flow to resume. Two other groups of SAMP8 and SAMR1 mice underwent sham surgery as controls. Three weeks after surgery, mice were anesthetized with isoflurane (1.5%) and imaged using a 4.7 Tesla Bruker MRI scanner.

[0659] Renal ischemia-reperfusion (IRI) model: Male C57BL / 6 mice (10-12 weeks old; Charles River Laboratories) were anesthetized with ketamine / xylazine (100 / 10 mg / kg; IP). The animals were then placed in a prone position while maintaining rectal temperature at a strict 37°C using a feedback-regulated heating pad. Strict aseptic procedures were followed while performing a skin incision on the left lower abdominal region. After reaching the retroperitoneal space, the left kidney and its artery and vein were identified. Ischemia was induced by applying microhemostatic forceps clips to the renal artery and vein. Successful ischemia was visually confirmed by a slow, uniform darkening of the kidney. After 26 minutes, the clamps were removed, and successful reperfusion was verified by a rapid change in kidney color from dark maroon to a healthy dark pink. The skin was sealed using surgical staples, and the animals were returned to their home cages. Buprenorphine was administered for analgesia (0.1 mg / kg, SC, bid, for 3 days, starting 1 hour before IRI surgery).

[0660] Fourteen days after IRI, animals were imaged and euthanized. The right and left kidneys were removed, and the cortical and medullary regions of each kidney were isolated for further analysis.

[0661] Tumor xenograft model: Male NU(NCr)-Foxn1nu nude mice, 6–8 weeks old, were provided by Charles River Labs, Wilmington, MA. A total of 1 × 10 7 Patient-derived metastatic pancreatic cancer cells (PDAC6) were injected into the subcutaneous space in the right lower back of mice (n=4 per group). Four weeks after tumor implantation, mice were imaged with Mn-17 (100 μmol / kg) for pretreatment imaging. Another group of mice was imaged 3 days after treatment with FOLFIRINOX (folinate 50 mg / kg, oxaliplatin 2.5 mg / kg, irinotecan 25 mg / kg, fluorouracil 25 mg / kg).

[0662] Imaging and biodistribution studies on the selectivity of allicin-reactive probes in vivo: Fourteen days after injury, bleomycin-injured mice were sedated and then injected with compound 19, compound 20, or Gd-CHyd (formulated to contain an equal concentration of Eu-DOTA as a non-binding control probe) (Akam, EA, et al. Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis. Chemical Science 11, 224-231 (2020)). Animals were then euthanized 30 minutes after injection. Lungs were collected separately along with blood, tail, and liver. Each sample was analyzed for gadolinium and europium content by ICP-MS, and lungs were also assessed for hydroxyproline content. Selectivity was reported as the ratio of Gd to Eu. All animals were dosed via tail vein injection with 100 nmol / g body weight from a 30 mM solution of the gadolinium probe, along with 30 mM Eu-DOTA, as determined by ICP-MS. Compounds 1 to 8 were used for the PET probe. 68 Ga or 64The dose was delivered as a bolus injection via the tail vein. Animals were euthanized 90 minutes after injection, and their organs and tissues were collected and counted using a gamma counter. For imaging studies using PET tracers, animals were injected inside a PET / MRI scanner and dynamically scanned for 60 minutes under anesthesia. Animals were euthanized 90 minutes after injection, and their organs and tissues were counted using a gamma counter. 52 / nat The biodistribution of Mn-15, Mn-16, Mn-17, and Mn-18 was determined by injecting a mixture of Mn complexes into naive mice, and activity in each tissue was measured 24 hours after injection.

[0663] Pairwise comparison between Gd-CHyd and Gd-9 in a pulmonary fibrosis model: A series of baseline images was first acquired. A bolus of Gd-CHyd was then administered intravenously, and imaging was performed for a period of 40 minutes pi. Anesthesia was then removed, and the mouse was allowed to awaken and returned to its cage. Four hours later, the same mouse was anesthetized again. A series of baseline images was acquired, and a bolus of Gd-9 was then administered intravenously, and imaging was performed for a period of 40 minutes pi.

[0664] Pairwise comparison between Mn-15 and Mn-17 in a pulmonary fibrosis model: Bleomycin-injured mice were first randomly imaged with Mn-15 or Mn-17, and then 24 h later, the same imaging protocol was performed on the same mice using the other probe.

[0665] [Table 39]

[0666] [Table 40]

[0667] [Table 41]

[0668] [Table 42]

[0669] MR Imaging and Analysis: Animals were anesthetized with isoflurane (1-2%) and placed supine on a specially designed platform while maintaining body temperature at 37°C. The level of inhaled isoflurane was adjusted to maintain a respiratory rate of 60 ± 5 breaths per minute. While the animal was positioned in the scanner, the tail vein was cannulated to deliver contrast agent intravenously (iv). Imaging was performed at 4.7 T using a small-bore animal scanner with a custom-built volume coil. Mice were imaged using a dose of 100 μmol / kg from a 30 mM stock solution of Gd or Mn complexes.

[0670] For imaging of the mouse liver, a series of baseline images (3D T1-weighted fast low-angle shot magnetic resonance imaging (FLASH)) were first acquired (repetition time / echo time = 15 / 2 ms; flip angle, 30°; field of view, 48 × 30 mm). 2 ;Matrix size: 136 x 136 mm 2 (Slice thickness, 0.25 mm; acquisition time, 3 min 20 s). A bolus of Gd or Mn complex was then administered intravenously, and imaging was performed for 45 min p.i. with repeated acquisition of 3D T1-weighted FLASH sequences. After the imaging session, animals were sacrificed (75 min p.i.), and liver tissue was subjected to histopathological analysis.

[0671] For liver imaging in rats, a series of baseline images (T1-maps and 3D T1-weighted FLASH) were first acquired. Then, a bolus of the molecular probe was administered intravenously, imaging was performed for 30 min, and T1-mapping and 3D T1-weighted FLASH sequences were repeatedly acquired. T1-mapping was performed using a flow-sensitive alternating inversion recovery (FAIR) sequence: repetition time / echo time = 11000 / 33.8 ms; flip angle, 90°; inversion times: 100, 200, 400, 500, 600, 1000, 1500, 2000 ms; field of view, 60 × 60 mm. 2 Matrix size, 140 × 140; slice thickness, 2 mm; acquisition time, 3 minutes 34 seconds. T1-weighted imaging with 3DFLASH: repetition time / echo time = 20 / 2.3 ms; flip angle, 30°; field of view, 60 × 60 mm 2 Matrix size: 127 × 127; slice thickness, 0.5 mm; acquisition time, 3 min 10 s. After the imaging session, the animals were sacrificed (30 min pi) and liver tissue was subjected to histopathological analysis.

[0672] For lung imaging, images were acquired with the following sequences and parameters: 3D Ultrashort TE (3D-UTE, TR / TE / FA = 4 ms / 11.75 μs / 16°, 0.6 mm isotropic spatial resolution, field of view (FOV) 75 mm × 75 mm, single average, acquisition time = 6.1 min) images were acquired before contrast injection and dynamically after injection. Rapid Acquisition with Relaxation Enhancement (RARE, TR / TE / FA = 1.5 s / 8 ms / 180°, 0.3 mm isotropic spatial resolution, field of view (FOV) 60 mm × 50 mm, 4 averages, acquisition time = 6.1 min) and T1-weighted 3D fast low-angle shot (FLASH, TR / TE / FA = 10 ms / 2.5 ms / 30°, 0.6 mm isotropic spatial resolution, field of view (FOV) 60 mm × 50 mm, 1 average, acquisition time = 6.1 min) images were also acquired.

[0673] For combined cardiac and pulmonary imaging, a series of baseline images (2D T1-weighted FLASH for the heart and 3D-UTE for the lungs) were first acquired. 2D T1-weighted FLASH: repetition time / echo time = 18.24 / 3.54 ms; flip angle, 50°; field of view, 36 × 36 mm. 2 ;Matrix size: 138 x 138 mm 2 Slice thickness: 1 mm; Acquisition time: 3 min 50 s. 3D-UTE: Repetition time / Echo time = 4 / 0.01225 ms; Flip angle: 16°; Field of view: 32 × 32 mm 2 ;Matrix size: 128 x 128 mm 2 Slice thickness, 0.25 mm; acquisition time, 3 min 36 s. A bolus of Gd-9 complex was then administered intravenously, and imaging was performed for 40 min pi, with repeated acquisition of 2D T1-weighted FLASH and 3D-UTE sequences. After the imaging session, the animals were sacrificed, and cardiac and pulmonary tissues were subjected to histopathological analysis.

[0674] For kidney imaging, a series of three-dimensional inversion-recovery FLASH images were acquired at baseline and 4 hours after Mn-16 administration using inversion recovery times of 7, 307, 557, 707, 857, 1507, 3007, 5007, and 7007 msec (TR / TE / FA = 5 sec / 72 msec, field of view (FOV) 30 mm × 3 mm, dimensions 128 × 128, slice thickness 0.7 mm).

[0675] For PDAC6 xenograft tumor imaging, images were acquired following the following sequences and parameters: 3D T1-weighted FLASH (TR / TE / FA = 14 ms / 2 μs / 30°, 0.4 mm isotropic spatial resolution, 35 mm x 35 mm FOV, two averages, acquisition time = 4.3 min) images were acquired before and dynamically after contrast injection; 3D RARE (RARE, TR / TE / FA = 1400 s / 57 ms / 180°, 0.3 mm isotropic spatial resolution, 35 mm x 60 mm FOV, one average, acquisition time = 8.1 min) images were also acquired.

[0676] For liver imaging analysis, a region of interest (ROI) encompassing the liver parenchyma was manually traced, avoiding the abundant blood vessels. A second ROI was placed on the visible dorsal muscle in the same image slice to quantify signal intensity in the muscle for comparison. To measure background signal variability, seven ROIs were placed in a tissue-free field (air). More than 20 axial slices per mouse were analyzed in this fashion throughout the entire liver. The same analysis was performed on images acquired with a FLASH sequence before and 45 minutes after injection. The contrast-to-noise ratio (CNR) was calculated by measuring the difference in signal intensity (SI) between the liver and muscle and normalizing this to the standard deviation of the signal in air, Equation 21. Probe injection (CNR) Pre ) was calculated by dividing the CNR measured before injection by the CNR measured after injection (CNR Post ) to calculate ΔCNR. Equation 22.

[0677] CNR=(SI 肝臓 -SI 筋肉 ) / SD 空気 (twenty one) ΔCNR=CNR 注射後 -CNR 注射前 (twenty two)

[0678] For lung imaging analysis, regions of interest (ROIs) were defined within the lungs, excluding blood vessels and airways, using RARE images, pre-contrast FLASH images, and post-contrast FLASH images. A total of six lung ROIs were defined on the axial UTE images to obtain signal intensity (SI). A dorsal muscle ROI was also defined within each slice as a reference. An ROI in a field without any tissue (air) was used to measure background signal variability. The lung-to-muscle ratio (LMR) or contrast-to-noise ratio (CNR) was then averaged from the six slices to calculate the change in LMR (ΔLMR) or CNR (ΔCNR) at each time point.

[0679] For cardiac imaging analysis, a region of interest (ROI) was defined in the myocardium, excluding blood vessels, using...

Claims

1. Compounds of formula (I) 【Chemistry 1】 [In the formula: Each R １ , R ３ , R ５ , and R ７ are independently hydrogen or -C(=O)OH; Each R ２ , R ４ , R ６ , and R ８ are independently hydrogen or C ３～２５ alkyl, ３～２５ Alkyl is —NR Ａ R Ｂ , —OH, halogen, C １～６ and optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, each of which is selected from the group consisting of halogen, —NR Ａ R Ｂ , -OH, C １～６ Alkyl, and -C １～６ Alkyl-(NR Ａ R Ｂ and wherein said C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of ３～２５ One or more non-adjacent carbon atoms of an alkyl may be O, N, NH, or N(CH ３ ) which is sometimes replaced by R ９ is H, halogen, -NR Ａ R Ｂ , -OH, C １～６ Alkyl, or -C １～６ Alkyl-(NR Ａ R Ｂ ) and Each R Ａ and R Ｂ are independently hydrogen or C １～６ is alkyl, n is 0 or 1; p is 0 or 1; When n is 0, R １ , R ３ , and R ５ At least two of n are -C(=O)OH, and when n is 1, R １ , R ３ , R ５ , and R ７ where at least two of are -C(=O)OH, and when n is 0 and p is 0, the compound of formula (I) is a compound of formula (IA) 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof; Here, R ６ teeth, -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH, ３～２５ C, wherein 4 non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, 5-10 membered heteroaryl and -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -OH and C １～６ C substituted with 5-10 membered heteroaryl substituted with alkyl ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, C substituted with 4-10 membered heterocyclyl ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, Two -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ Three non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -C １～６ Alkyl-(NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ Three non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein 4 non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, Two -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ Three non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -C １～６ Alkyl-(NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl ３～２５ Alkyl, ３～２５ Two non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein three non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ Alkyl, C substituted with 4-10 membered heterocyclyl ３～２５ Alkyl, C ３～２５ Alkyl, -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH; ３～２５ Alkyl, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ two non-adjacent carbon atoms of an alkyl are replaced by NH; ３～２５ Alkyl, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by O; ３～２５ Alkyl, -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ two non-adjacent carbon atoms of an alkyl are replaced by NH; ３～２５ Alkyl, C substituted with OH ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH, ３～２５ One non-adjacent carbon atom of the alkyl is N(CH ３ ) has been replaced by C ３～２５ Alkyl, Two -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by N, ３～２５ Three non-adjacent carbon atoms of an alkyl are replaced by NH, ３～２５ C, wherein two non-adjacent carbon atoms of an alkyl are replaced by O; ３～２５ Alkyl, and -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by O; ３～２５ Alkyl is selected from the group consisting of R Ａ and R Ｂ are each independently a hydrogen atom or C １～６ is alkyl. or a pharma- ceutically acceptable salt thereof.

2. R ２ , R ４ , and R ６ But independently, hydrogen, 【Chemistry 3】 or R ２ , R ４ , and R ６ are all hydrogen, or R ２ , R ４ , and R ６ All are -NR Ａ R Ｂ C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl ３～２５ alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each -NR Ａ R Ｂ , -OH, C １～６ Alkyl, and -C １～６ Alkyl-(NR Ａ R Ｂ and wherein said C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of ３～２５ 1 to 6 non-adjacent carbon atoms of an alkyl are O, N, NH, or N(CH ３ ), or R ２ and R ４ are both hydrogen, R ６ -NR Ａ R Ｂ C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl ３～２５ alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each -NR Ａ R Ｂ , -OH, C １～６ Alkyl, and -C １～６ Alkyl-(NR Ａ R Ｂ and wherein said C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of ３～２５ 1 to 6 non-adjacent carbon atoms of an alkyl are O, N, NH, or N(CH ３ ), or R ２ and R ６ are both hydrogen, R ４ -NR Ａ R Ｂ C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl ３～２５ alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each -NR Ａ R Ｂ , -OH, C １～６ Alkyl, and -C １～６ Alkyl-(NR Ａ R Ｂ and wherein said C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of ３～２５ 1 to 6 non-adjacent carbon atoms of an alkyl are O, N, NH, or N(CH ３ ), or R ６ and R ４ are both hydrogen, R ２ -NR Ａ R Ｂ C optionally substituted with 1 to 2 substituents independently selected from the group consisting of -OH, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl ３～２５ alkyl, and the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocyclyl are each -NR Ａ R Ｂ , -OH, C １～６ Alkyl, and -C １～６ Alkyl-(NR Ａ R Ｂ and wherein said C is optionally substituted with 1 to 2 substituents independently selected from the group consisting of ３～２５ 1 to 6 non-adjacent carbon atoms of an alkyl are O, N, NH, or N(CH ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally replaced by:

3. R １ , R ３ , and R ５ are all -C(=O)OH, or R １ and R ３ are both -C(=O)OH and R ５ is hydrogen, or R １ and R ５ are both -C(=O)OH and R ３ is hydrogen, or R ５ and R ３ are both -C(=O)OH and R １ is hydrogen, or R １ is -C(=O)OH, and R ２ is hydrogen, or R ３ is -C(=O)OH, and R ４ is hydrogen, or R ５ is -C(=O)OH, and R ６ is hydrogen, or R ７ is -C(=O)OH, and R ８ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

4. n is 1, or p is 1, or R ９ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is H, a halogen, or -OH.

5. The compound of formula (I) is a compound of formula (IB) 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

6. R ６ but, -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ Alkyl, and -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH; ３～２５ selected from the group consisting of alkyl, or R ８ but, -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ Alkyl, C substituted with 4-10 membered heterocyclyl ３～２５ Alkyl, C ３～２５ Alkyl, and -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH; ３ ~ ２５ Alkyl Selected from the group consisting of:

6. The compound of claim 5, or a pharma- ceutically acceptable salt thereof.

7. The compound of formula (I) is a compound of formula (IC) 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

8. R ２ but, Hydrogen, and -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ alkyl; or R ６ but, Two -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of the alkyl is replaced by N, ３～２５ Three non-adjacent carbon atoms of the alkyl are replaced by NH, ３～２５ C, wherein two non-adjacent carbon atoms of an alkyl are replaced by O; ３ ~ ２５ Alkyl, and -NR Ａ R Ｂ C substituted with 4- to 10-membered heterocyclyl substituted with ３～２５ Alkyl, 8. The compound of claim 7, selected from the group consisting of:

9. The compound of formula (I) is a compound of formula (ID) 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

10. R ４ but, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ two non-adjacent carbon atoms of an alkyl are replaced by NH; ３ ~ ２５ Alkyl, -NR Ａ R Ｂ and C substituted with -OH ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by NH, ３～２５ one non-adjacent carbon atom of an alkyl is replaced by O; ３ ~ ２５ Alkyl, -NR Ａ R Ｂ C substituted with ３～２５ Alkyl, ３～２５ two non-adjacent carbon atoms of an alkyl are replaced by NH; ３ ~ ２５ Alkyl, and C substituted with OH ３～２５ Alkyl, ３～２５ one non-adjacent carbon atom of the alkyl is replaced by NH, ３～２５ One non-adjacent carbon atom of the alkyl is N(CH ３ ) has been replaced by C ３ ~ ２５ Alkyl, 10. The compound of claim 9, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

11. The compound of formula (I) 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 or a pharma- ceutically acceptable salt thereof.

12. 12. A composition comprising a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

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