Fibroblast activation protein inhibitors and uses thereof

Abstract

The present invention relates to compounds of formula (I):

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds; inhibitors of fibroblast activation proteins (FAPs); compositions comprising said compounds or said inhibitors, respectively; said compounds, said inhibitors or said compositions, respectively, for use in a method for diagnosing a disease; said compounds, said inhibitors or said compositions, respectively, for use in a method for treating a disease; said compounds, said inhibitors or said compositions, respectively, for use in a method for diagnosing and treating a disease (also called "ther(g)nosis" or "ther(g)nostics"); said compounds, said inhibitors or said compositions, respectively, for use in a method for delivering an effector to FAP-expressing tissue; said compounds, said inhibitors or said compositions, respectively, for use in a method for stratifying a group of subjects into those likely to respond to a treatment for a disease and those likely not to respond to a treatment for a disease; said compounds, said inhibitors or said compositions, respectively, for use in a method for identifying subjects likely to respond or not to a treatment for a disease; the compound, the inhibitor or the composition, respectively, for use in a method for selecting a subject who is likely to respond or not likely to respond to treatment; a method for diagnosing a disease using the compound, the inhibitor or the composition, respectively; a method for treating a disease using the compound, the inhibitor or the composition, respectively; a method for both diagnosing and treating a disease using the compound, the inhibitor or the composition, respectively (also called "ther(g)nosis" or "ther(g)nostics"); a method for delivering an effector to FAP-expressing tissue using the compound, the inhibitor or the composition, respectively; a method for stratifying a group of subjects into those who are likely to respond to disease treatment and those who are likely to not respond to disease treatment; a method for identifying whether a subject is likely to respond or not likely to respond to disease treatment and a method for selecting from a group of subjects those who are likely to respond or not likely to respond to disease treatment. [Background technology]

[0002] background Despite an increasing number of available treatment options, cancer remains the second leading cause of death worldwide. Treatment strategies have primarily focused on targeting malignant cancer cells themselves, ignoring the ever-present surrounding tumor microenvironment (TME), which limits the access of cancer cell therapeutics. The TME is a part of the tumor mass that consists of a heterogeneous population of cancer cells as well as various resident and infiltrating host cells, secreted factors, and extracellular matrix proteins. The predominant cell type found in the TME is cancer-associated fibroblasts (CAFs). CAFs are often the dominant cell type within solid tumor masses and have been recognized as drivers of tumor progression and homeostasis.

[0003] Fibroblast activation protein (FAP) has become well-known as a marker of CAFs. Due to the ubiquitous presence of CAFs and stroma within tumors, FAP has been identified as a suitable marker for radiopharmaceutical diagnosis and a suitable target for radiopharmaceutical therapy.

[0004] Fibroblast activation protein alpha (FAP) is a type II transmembrane serine protease and a member of the S9 prolyl oligopeptidase family. FAP possesses both post-proline exopeptidase activity (similar to other DPP enzymes, e.g., DPP4, DPP7, DPP8, and DPP9) and endopeptidase activity (similar to prolyl oligopeptidase / endopeptidase (POP / PREP)). Its dipeptidyl peptidase activity cleaves two amino acids at the N-terminus after a proline residue. FAP is primarily found to be localized on the cell surface, although soluble forms of the protein have also been reported.

[0005] FAP expression in the tumor stroma of 90% of epithelial cancers was first reported in 1990 using the monoclonal antibody F19. FAP expression in malignant epithelial cells has also been reported. FAP expression in CAFs has been shown in almost all carcinomas and sarcomas. Furthermore, CAFs are present in hematological malignancies. Therefore, the use of FAP as a therapeutic target is not limited to any particular tumor.

[0006] High levels of FAP-expressing CAFs have been reported to correlate with poor prognosis. Across various human tumor indications, FAP expression has been reported to correlate with high tumor grade and poor overall survival. FAP and FAP-expressing cells present in the tumor microenvironment significantly influence tumor progression. Furthermore, due to its relatively selective expression in tumors, FAP is considered a suitable target for therapeutic and diagnostic agents.

[0007] In addition to cancer, FAP is highly upregulated in interstitial cells at sites of active tissue remodeling, including wound healing, fibrosis, arthritis, and atherosclerosis. Thus, FAP is involved in diseases other than cancer, such as those mentioned herein. FAP expression has been shown to be significantly increased in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Furthermore, FAP is recognized not only as a marker of activated fibroblasts in the injury response but also as an important player in the wound healing process. Upregulated FAP expression has also been observed in fibrotic diseases, such as idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis. Furthermore, FAP is expressed in atherosclerotic lesions and is upregulated in activated vascular smooth muscle cells. Summary of the Invention [Problem to be solved by the invention]

[0008] Shortly after its discovery, FAP was exploited as a therapeutic target for cancer. Various FAP-targeting strategies have been explored, including, for example, inhibition of FAP enzymatic activity, elimination of FAP-positive cells, and targeted delivery of cytotoxic compounds. However, there remains a great need for improved diagnostics and pharmaceuticals for the diagnosis and / or treatment of cancer and other FAP-mediated diseases and conditions. [Means for solving the problem]

[0009] Summary of the Invention One aspect of the present invention is a compound of formula (I) [ka] [In the formula, R1 is H or F; R2 is H or F; R3 is selected from the group consisting of -C(O)-Het1, -B(OH)2, -CN and -C(O)-CH2-OH; where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; B is CH or when A is NH, B is CH or N; E is O or S; R 0 are independently selected from the group consisting of (C1-C4)alkyl, —O—(C1-C4)alkyl, —COO—(C1-C4)alkyl, F, Cl, Br, I, OH, COOH, and CN; m is selected from the group consisting of 0, 1 and 2. selected from the group consisting of R 4 is selected from the group consisting of H, Cl, Br, F and (C1-C2) alkyl; R 5 , R 6 and R 7One of them is R 8 -L- and R 5 , R 6 and R 7 the other two of are each independently selected from the group consisting of H, (C1-C4) alkyl, —O—(C1-C4) alkyl, —O—(C1-C3) alkylidene-(C6) aryl, F, Cl, Br, and O—CF3; R 8 -L- is R 8 -Lin4-Lin3-Lin2-Lin1- [In the formula, Lin1 is [ka] , -O-, N(CH3)- and [ka] selected from the group consisting of However, R 3 If CN, then Lin1 [ka] The condition is that Here, in Lin1, Y is CH or N; [ka] indicates binding to Lin2, and Lin1 [ka] If , Lin2 [ka] is in the meta or para position relative to [ka] indicates the bond to the quinoline, R 9 is selected from the group consisting of halogen, COH, (C1-C6)alkyl, hydroxy-substituted (C1-C6)alkyl, and —O—(C1-C6)alkyl; n is selected from the group consisting of 0, 1 and 2, preferably n is 0 or 1, more preferably n is 0; Lin1, [ka] and [ka] when Lin1 is selected from the group consisting of -C(O)-NH-, -NH-C(O)- and -S(O)2-, and when Lin1 is -O- or -N(CH3)-, Lin2 is absent; Lin3 is a (C2-C4) alkylidene; Lin4, -NR 10 , [ka] selected from the group consisting of Here, in Lin4, [ka] indicates binding to Lin3, [ka] indicates a bond to R8, R 10 is selected from the group consisting of H, CH2-COOH, and (C1-C4) alkyl; [ka] In some cases, [ka] is oxidized to R 8 is a chelating agent or a cytotoxic agent] is] A compound of the formula In formula (I), [ka] is optionally its N-oxide [ka] may be oxidized to Concerning compounds.

[0010] Another aspect of the present invention relates to compounds of formula I that contain a diagnostically or therapeutically active nuclide.

[0011] Another aspect of the present invention relates to a method for treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention. For example, such a compound can be a compound of Formula I:

[0012] The following detailed description is given by way of example and is not intended to limit the invention and is further illustrated by reference to the following figures, from which further features, embodiments and advantages can be seen: [Brief explanation of the drawings]

[0013] [Figure 1(a)]Figures 1(a)-1(p) show the percent uptake of injected dose per gram of tissue (% ID / g) in the kidney, liver, blood pool, and HEK-FAP tumors as determined by SPECT imaging after injection of selected compounds into a Swiss nude mouse model. Figure 1(a): % ID / g uptake of In-3BP-3467 at 1 h, 3 h, 6 h, and 24 h post-injection. [Figure 1(b)] Figure 1(b): % ID / g uptake of 111In-3BP-3581 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(c)] Figure 1(c): % ID / g uptake of 111In-3BP-3621 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(d)] Figure 1(d): % ID / g uptake of 111In-3BP-3631 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(e)] Figure 1(e): % ID / g uptake of 111In-3BP-3622 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(f)] Figure 1(f): % ID / g uptake of 111In-3BP-3772 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(g)] Figure 1(g): % ID / g uptake of 111In-3BP-3785 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(h)] FIG. 1(h): % ID / g uptake of 111In-3BP-4076 at 1 h, 3 h, 6 h and 24 h after injection. [Figure 1(i)] Figure 1(i): % ID / g uptake of 111In-3BP-4808 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 1(j)] Figure 1(j): % ID / g uptake of 111In-3BP-4809 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 1(k)] FIG. 1(k): % ID / g uptake of 111In-3BP-4810 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 1(l)]FIG. 1(l): % ID / g uptake of 111In-3BP-4811 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 1(m)] FIG. 1(m): % ID / g uptake of 111In-3BP-4663 at 1 h, 4 h, 24 h, 48 h and 72 h after injection. [Figure 1(n)] FIG. 1(n): % ID / g uptake of 111In-3BP-4664 at 1 h, 4 h, 24 h, 48 h and 72 h after injection. [Figure 1(o)] Figure 1(o): % ID / g uptake of 111In-3BP-4665 at 1 h, 4 h, 24 h, 48 h and 72 h after injection. [Figure 1(p)] FIG. 1(p): % ID / g uptake of the reference compound 111In-3BP-4200 at 1 h, 4 h, 24 h, 48 h and 72 h after injection. [Figure 2(a)] Figures 2(a)-2(f) show the percent uptake of injected dose per gram of tissue (% ID / g) in kidney, liver, blood pool, HEK-FAP, and / or CHO-FAP tumors as determined by SPECT imaging after injection of select compounds into a SCID-beige mouse model. Figure 2(a): % ID / g uptake of In-3BP-4663 at 1 h, 4 h, 24 h, and 48 h post-injection. [Figure 2(b)] Figure 2(b): % ID / g uptake of 111In-3BP-4664 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 2(c)] Figure 2(c): % ID / g uptake of 111In-3BP-4665 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 2(d)] Figure 2(d): % ID / g uptake of 111In-3BP-4694 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 2(e)] FIG. 2(e): % ID / g uptake of the reference compound 111In-3BP-2929 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 2(f)]Figure 2(f): % ID / g uptake of 111In-3BP-4201 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 3(a)] Figures 3(a)-(d) show SPECT images of selected compounds after injection into Swiss nude mice bearing HEK-FAP tumors. Figure 3(a): SPECT / CT images of In-3BP-4809 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 3(b)] Figure 3(b): SPECT / CT images of 111In-3BP-4810 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 3(c)] Figure 3(c): SPECT / CT images of 111In-3BP-4663 at 1 h, 4 h, 24 h, 48 h, and 72 h after injection. [Figure 3(d)] Figure 3(d): SPECT / CT images of 111In-3BP-4664 at 1 h, 4 h, 24 h, 48 h, and 72 h after injection. [Figure 4(a)] Figures 4(a)-4(f) show SPECT / CT images of selected compounds injected into SCID beige mice bearing HEK-FAP tumors (right shoulder) and CHO-FAP tumors (left shoulder). Figure 4(a): SPECT / CT images of In-3BP-4663 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 4(b)] Figure 4(b): SPECT / CT images of 111In-3BP-4664 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 4(c)] Figure 4(c): SPECT / CT images of 111In-3BP-4665 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 4(d)] Figure 4(d): SPECT / CT images of 111In-3BP-4694 at 1 h, 4 h, 24 h, and 48 h after injection. [Figure 4(e)] FIG. 4(e): SPECT / CT images of the reference compound 111In-3BP-2929 at 1 h, 4 h, 24 h and 48 h after injection. [Figure 4(f)]Figure 4(f): SPECT / CT images of 111In-3BP-4201 at 1 h, 4 h, 24 h, and 48 h after injection. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of the Invention The present invention relates to novel compounds suitable for use as diagnostic and / or pharmaceutical agents for the diagnosis and / or treatment of cancer and other diseases and conditions mediated by FAPs. The present invention provides novel compounds capable of delivering effectors and interacting with FAPs, which effectors can provide for the detection, treatment, and / or management of various diseases associated with one or more FAP-expressing tumors or cells, including cancer.

[0015] Specifically, provided herein are compounds suitable as diagnostic and / or pharmaceutical agents, particularly when conjugated to a diagnostically and / or therapeutically active effector. Furthermore, the compounds provided herein are suitable as diagnostic and / or pharmaceutical agents, particularly when conjugated to a diagnostically and / or therapeutically active effector. This conjugation renders the compounds potent inhibitors of FAP activity, preferably resulting in a pIC50 of 6.0 or greater. Furthermore, the compounds provided herein are suitable as diagnostic and / or pharmaceutical agents, particularly when conjugated to a diagnostically and / or therapeutically active effector, in the diagnosis and / or treatment of diseases in which diseased cells and / or diseased tissues express FAP. Further provided herein are compounds suitable for delivering diagnostically and / or therapeutically effective agents to diseased cells and / or diseased tissues, respectively, particularly to FAP-expressing diseased cells and / or diseased tissues, preferably diseased tissues that include or contain cancer-associated fibroblasts.

[0016] Also provided herein are methods for diagnosing disease, methods for treating and / or preventing disease, and combined methods for diagnosing and treating disease. Preferably, such diseases involve FAP-expressing cells and / or tissues, particularly FAP-expressing diseased cells and / or diseased tissues, preferably diseased tissues that include or contain cancer-associated fibroblasts. Further provided herein are methods for identifying subjects who are likely to respond or not respond to disease treatment, and methods for selecting subjects from a group of subjects who are likely to respond or not respond to disease treatment.

[0017] Additionally, provided herein are pharmaceutical compositions containing compounds having the characteristics outlined above. Further provided herein are kits suitable for use in any of the above methods.

[0018] These and other problems underlying the present invention are solved, for example, by the subject matter of the following embodiments and / or the subject matter of the appended claims.

[0019] Embodiment 1. Formula (I): [ka] [In the formula, R1 is H or F; R2 is H or F; R3 is selected from the group consisting of -C(O)-Het1, -B(OH)2, -CN and -C(O)-CH2-OH; where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; B is CH or when A is NH, B is CH or N; E is O or S; R 0 are independently selected from the group consisting of (C1-C4)alkyl, —O—(C1-C4)alkyl, —COO—(C1-C4)alkyl, F, Cl, Br, I, OH, COOH, and CN; m is selected from the group consisting of 0, 1 and 2. selected from the group consisting of R 4 is selected from the group consisting of H, Cl, Br, F and (C1-C2) alkyl; R 5 , R 6 and R 7 One of them is R 8 -L- and R 5 , R 6 and R 7 the other two of are each independently selected from the group consisting of H, (C1-C4) alkyl, —O—(C1-C4) alkyl, —O—(C1-C3) alkylidene-(C6) aryl, F, Cl, Br, and O—CF3; R 8 -L- is R 8 -Lin4-Lin3-Lin2-Lin1- [In the formula, Lin1 is [ka] , -O-, N(CH3)- and [ka] selected from the group consisting of However, R 3 If CN, then Lin1 [ka] The condition is that Here, in Lin1, Y is CH or N; [ka] indicates binding to Lin2, and Lin1 [ka] If , Lin2 [ka] is in the meta or para position relative to [ka] indicates the bond to the quinoline, R 9 is selected from the group consisting of halogen, COH, (C1-C6)alkyl, hydroxy-substituted (C1-C6)alkyl, and —O—(C1-C6)alkyl; n is selected from the group consisting of 0, 1 and 2, preferably n is 0 or 1, more preferably n is 0; Lin1, [ka] and [ka] when Lin1 is selected from the group consisting of -C(O)-NH-, -NH-C(O)- and -S(O)2-, and when Lin1 is -O- or -N(CH3)-, Lin2 is absent; Lin3 is a (C2-C4) alkylidene; Lin4, -NR 10 , [ka] selected from the group consisting of Here, in Lin4, [ka] indicates binding to Lin3, [ka] indicates a bond to R8, R 10 is selected from the group consisting of H, CH2-COOH, and (C1-C4) alkyl; [ka] In some cases, [ka] is oxidized to R 8 is a chelating agent or a cytotoxic agent] is] is shown by Here, in formula (I), [ka] is optionally its N-oxide [ka] may be oxidized to compound.

[0020] As used in this and other embodiments, and throughout the present invention, the phrase "bond to quinoline" refers to the bond of R5, R6, or R7 to the quinoline ring shown in formula (I), which may optionally be oxidized to its N-oxide, as noted above.

[0021] Embodiment 2. R 3is selected from the group consisting of C(O)-Het1, B(OH)2, and -CO-CH2-OH.

[0022] Embodiment 3. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; When B is CH or A is NH, then B is CH or N; E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 2. The compound of embodiment 1, selected from the group consisting of:

[0023] Embodiment 4. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 2. The compound of embodiment 1, selected from the group consisting of:

[0024] Embodiment 5. The compound has the formula (II): [ka] 2. The compound of embodiment 1, having the structure:

[0025] Embodiment 6. R 4 The compound according to any one of embodiments 1, 2, 3, 4, and 5, wherein is H or —CH 3 .

[0026] Embodiment 7. R 4 The compound of any one of embodiments 1, 2, 3, 4, 5, and 6, wherein is H.

[0027] Embodiment 8. R 4 The compound according to any one of embodiments 1, 2, 3, 4, 5 and 6, wherein is —CH 3 .

[0028] Embodiment 9. R 6 But R 8 -L.

[0029] Embodiment 10. R 5 and R 7 are each independently selected from the group consisting of H and —CH 3 .

[0030] Embodiment 11. R 5 and R 7 is H.

[0031] Embodiment 12. R 7 But R 8 -L.

[0032] Embodiment 13. R 5 and R 6 are each independently selected from the group consisting of H and —CH 3 .

[0033] Embodiment 14. R 5 and R 6 is H.

[0034] Embodiment 15. Lin1, [ka] 15. The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, more preferably any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and most preferably any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, wherein

[0035] Embodiment 16. Lin1, [ka] 15. The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, preferably embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, more preferably embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, and most preferably embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, wherein

[0036] Embodiment 17. 17. The compound of embodiment 15 or 16, wherein Y is CH.

[0037] Embodiment 18. Lin1, [ka] 15. The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, more preferably any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and most preferably any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, wherein

[0038] Embodiment 19. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] exhibits binding to Lin3.

[0039] Embodiment 20. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 20. The compound according to any one of embodiments 15, 16, 17, 18 and 19, wherein:

[0040] Embodiment 21. The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, more preferably any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, and most preferably any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, wherein Lin3 is -(C2-C3)alkylidene.

[0041] Embodiment 22. R 8 -L-, [ka] 15. The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, more preferably any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and most preferably any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, selected from the group consisting of:

[0042] Embodiment 23. R 8 -L-, [ka] 23. The compound of embodiment 22, selected from the group consisting of:

[0043] Embodiment 24. R 8 -L-, [ka] 23. The compound of embodiment 22, selected from the group consisting of:

[0044] Embodiment 25. R 8 Any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24, more preferably, any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, and most preferably, any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0045] Embodiment 26. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99mA compound according to embodiment 25, selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0046] Embodiment 27. 26. The compound of embodiment 25, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa and NODAGA.

[0047] Embodiment 28. 26. The compound of embodiment 25, wherein the chelating agent is DOTA.

[0048] Embodiment 29. 26. The compound of embodiment 25, wherein the chelating agent is DOTAM.

[0049] Embodiment 30. 26. The compound of embodiment 25, wherein the chelating agent is Macropa.

[0050] Embodiment 31. 26. The compound of embodiment 25, wherein the chelating agent is NOTA.

[0051] Embodiment 32. 26. The compound of embodiment 25, wherein the chelating agent is NODAGA.

[0052] Embodiment 33. R 5 but, [ka] 34. The compound according to any one of embodiments 27, 28, 29, 30, 31 and 32, preferably embodiment 28, wherein

[0053] Embodiment 34. R 8 Any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24, preferably any one of embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24, more preferably, any one of embodiments 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, and most preferably, any one of embodiments 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0054] Embodiment 35. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; When B is CH or A is NH, then B is CH or N; E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 2. The compound of embodiment 1, selected from the group consisting of:

[0055] Embodiment 36. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, E is O or S; R 0is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 36. The compound of embodiment 35, selected from the group consisting of:

[0056] Embodiment 37. The compound has the formula (II): [ka] 37. The compound of embodiment 36, having the structure:

[0057] Embodiment 38. R 4 The compound according to any one of embodiments 35, 36 and 37, preferably any one of embodiments 36 and 37, wherein is H or -CH3.

[0058] Embodiment 39. R 4 is H. The compound according to any one of embodiments 35, 36, 37 and 38, preferably any one of embodiments 36, 37 and 38, more preferably any one of embodiments 37 and 38, wherein

[0059] Embodiment 40. R 4 The compound according to any one of embodiments 35, 36, 37 and 38, preferably any one of embodiments 36, 37 and 38, more preferably any one of embodiments 37 and 38, wherein

[0060] Embodiment 41. R 6 But R 8 The compound according to any one of embodiments 35, 36, 37, 38, 39 and 40, preferably any one of embodiments 39 and 40, wherein -L.

[0061] Embodiment 42. R 5 and R 7are each independently selected from the group consisting of H and -CH3.

[0062] Embodiment 43. R 5 and R 7 is H.

[0063] Embodiment 44. R 7 But R 8 The compound according to any one of embodiments 34, 35, 36, 37, 38 and 39, preferably any one of embodiments 38 and 39, wherein R is -L.

[0064] Embodiment 45. R 5 and R 6 are each independently selected from the group consisting of H and —CH 3 .

[0065] Embodiment 46. R 5 and R 6 is H.

[0066] Embodiment 47. Lin1, [ka] 46, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, wherein

[0067] Embodiment 48. Lin1, [ka] 46 and 47, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47, wherein

[0068] Embodiment 49. 49. The compound of embodiment 47 or 48, wherein Y is CH.

[0069] Embodiment 50. Lin1, [ka] 46, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, wherein

[0070] Embodiment 51. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] The compound according to any one of embodiments 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and 47, wherein

[0071] Embodiment 52. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 52. The compound according to any one of embodiments 47, 48, 49, 50 and 51, wherein:

[0072] Embodiment 53. The compound according to any one of embodiments 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52, wherein Lin3 is -(C2-C3)alkylidene.

[0073] Embodiment 52. R 8 -L-, [ka] The compound according to any one of embodiments 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46, selected from the group consisting of:

[0074] Embodiment 55. R 8 -L-, [ka] 55. The compound of embodiment 54, selected from the group consisting of:

[0075] Embodiment 56. R 8 -L-, [ka] 55. The compound of embodiment 54, selected from the group consisting of:

[0076] Embodiment 57. R 8 55, and 56, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, and 56, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, and 56, wherein

[0077] Embodiment 58. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99m 58. The compound of embodiment 57, which is selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0078] Embodiment 59. 58. The compound of embodiment 57, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa, NOTA, and NODAGA.

[0079] Embodiment 60. 58. The compound of embodiment 57, wherein the chelating agent is DOTA.

[0080] Embodiment 61. 58. The compound of embodiment 57, wherein the chelating agent is DOTAM.

[0081] Embodiment 62. 58. The compound of embodiment 57, wherein the chelating agent is Macropa.

[0082] Embodiment 63. 58. The compound of embodiment 57, wherein the chelating agent is NOTA.

[0083] Embodiment 64. The compound of embodiment 57, wherein the chelating agent is NODAGA.

[0084] Embodiment 65. R 5 but, [ka] 65. The compound according to any one of embodiments 60, 61, 62, 63 and 64, preferably embodiment 60, wherein

[0085] Embodiment 66. R 8 51, 52, 53, 54, 55, 56 and 65, preferably any one of embodiments 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 and 56, more preferably any one of embodiments 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 and 56, wherein

[0086] Embodiment 67. R 3 is -CN and Lin1 is [ka] 2. The compound of embodiment 1, selected from the group consisting of:

[0087] Embodiment 68. R 4 68. The compound of embodiment 67, wherein is H or -CH3.

[0088] Embodiment 69. R 4 is H.

[0089] Embodiment 70. R 4 The compound of embodiment 68, wherein is —CH 3 .

[0090] Embodiment 71. R 6 But R 8 The compound according to any one of embodiments 67, 68, 69, 70 and 71, preferably any one of embodiments 69 and 70, wherein -L.

[0091] Embodiment 72. R 5 and R 7 is independently selected from the group consisting of H and -CH3.

[0092] Embodiment 73. R 5 and R 7 is H.

[0093] Embodiment 74. R 7 But R 8 The compound according to any one of embodiments 67, 68, 69 and 70, preferably any one of embodiments 69 and 70, wherein -L.

[0094] Embodiment 75. R 5 and R 6 are each independently selected from the group consisting of H and -CH3.

[0095] Embodiment 76. R 5 and R 6 is H.

[0096] Embodiment 77. Lin1, [ka] 76. The compound according to any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75 and 76, preferably any one of embodiments 68, 69, 70, 71, 72, 73, 74, 75 and 76, wherein

[0097] Embodiment 78. 80. The compound of any one of embodiments 67 and 77, wherein Y is CH.

[0098] Embodiment 79. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 77, preferably any one of embodiments 68, 69, 70, 71, 72, 73, 74, 75 and 76, wherein

[0099] Embodiment 80. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 80. The compound of any one of embodiments 77, 78 and 79, wherein:

[0100] Embodiment 81. The compound according to any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80, preferably any one of embodiments 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, and 80, wherein Lin3 is -(C2-C3)alkylidene.

[0101] Embodiment 82. R 8 -L-, [ka] 77. The compound according to any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75 and 76, selected from the group consisting of:

[0102] Embodiment 83. R 8 -L-, [ka] 77. The compound according to any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75 and 76, selected from the group consisting of:

[0103] Embodiment 84. R 8 84. The compound of any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, and 83, wherein

[0104] Embodiment 85. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99m A compound according to embodiment 84, selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0105] Embodiment 86. The compound of embodiment 84, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa, NOTA, and NODAGA.

[0106] Embodiment 87. The compound of embodiment 84, wherein the chelating agent is DOTA.

[0107] Embodiment 88. The compound of embodiment 84, wherein the chelating agent is DOTAM.

[0108] Embodiment 89. The compound of embodiment 84, wherein the chelating agent is Macropa.

[0109] Embodiment 90. 85. The compound of embodiment 84, wherein the chelating agent is NOTA.

[0110] Embodiment 91. The compound of embodiment 84, wherein the chelating agent is NODAGA.

[0111] Embodiment 92. R 8 84. The compound of any one of embodiments 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, and 83, wherein

[0112] Embodiment 93. Lin1, [ka] , -O-, N(CH3)- and [ka] selected from the group consisting of However, R 3 If , is CN, then Lin1 [ka] The condition is that Here, in Lin1, Y is CH or N; [ka] indicates binding to Lin2, and Lin1 indicates binding to [ka] If Lin2 is [ka] is in the meta or para position relative to [ka] indicates the bond to the quinoline, R 9is selected from the group consisting of halogen, COH, (C1-C6)alkyl, hydroxy-substituted (C1-C6)alkyl, and —O—(C1-C6)alkyl; n is selected from the group consisting of 0, 1 and 2, preferably n is 0 or 1, more preferably n is 0; Lin1, [ka] and [ka] and wherein when Lin1 is -O- or -N(CH3)-, Lin2 is absent.

[0113] Embodiment 94. Lin1, [ka] 94. The compound of embodiment 93, wherein:

[0114] Embodiment 95. Lin1, [ka] 95. The compound of embodiment 93 or 94, wherein

[0115] Embodiment 96. 96. The compound of embodiment 94 or 95, wherein Y is CH.

[0116] Embodiment 97. Lin1, [ka] 97. The compound of any one of embodiments 93, 94, 95 and 96, wherein

[0117] Embodiment 98. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 96. The compound according to any one of embodiments 93, 94 and 95, wherein:

[0118] Embodiment 99. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 99. The compound according to any one of embodiments 93, 94, 95, 96, 97 and 98, wherein:

[0119] Embodiment 100. The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, and 99, wherein Lin3 is -(C2-C3)alkylidene.

[0120] Embodiment 101. R8 -L-, [ka] 94. The compound of embodiment 93, selected from the group consisting of:

[0121] Embodiment 102. R 8 -L-, [ka] 102. The compound of embodiment 101, selected from the group consisting of:

[0122] Embodiment 103. R 8 -L-, [ka] 102. The compound of embodiment 101, selected from the group consisting of:

[0123] Embodiment 104. R 3 The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, wherein is selected from the group consisting of C(O)-Het1, B(OH)2, and -CO-CH2-OH.

[0124] Embodiment 105. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; When B is CH or A is NH, then B is CH or N; E is O or S; R 0is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 104. The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102 and 103, selected from the group consisting of:

[0125] Embodiment 106. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 104. The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102 and 103, selected from the group consisting of:

[0126] Embodiment 107. The compound has the formula (II): [ka] 104. The compound of any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, having the structure:

[0127] Embodiment 108. R 4 The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, and 107, wherein is H or —CH 3 .

[0128] Embodiment 109. R 4is H.

[0129] Embodiment 110. R 4 The compound according to any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, and 108, wherein is —CH3.

[0130] Embodiment 111. R 6 But R 8 107, 108, 109, and 110, preferably any one of embodiments 109 and 110, wherein

[0131] Embodiment 112. R 5 and R 7 are each independently selected from the group consisting of H and -CH3.

[0132] Embodiment 113. R 5 and R 7 is H.

[0133] Embodiment 114. R 7 But R 8 107, 108, 109, and 110, preferably any one of embodiments 109 and 110, wherein

[0134] Embodiment 115. R 5 and R 6are each independently selected from the group consisting of H and -CH3.

[0135] Embodiment 116. R 5 and R 6 is H.

[0136] Embodiment 117. R 8 117. The compound of any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, and 116, wherein

[0137] Embodiment 118. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99m A compound according to embodiment 117, selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0138] Embodiment 119. The compound of embodiment 117, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa, NOTA, and NODAGA.

[0139] Embodiment 120. The compound of embodiment 117, wherein the chelating agent is DOTA.

[0140] Embodiment 121. The compound of embodiment 117, wherein the chelating agent is DOTAM.

[0141] Embodiment 122. The compound of embodiment 117, wherein the chelating agent is Macropa.

[0142] Embodiment 123. The compound of embodiment 117, wherein the chelating agent is NOTA.

[0143] Embodiment 124. The compound of embodiment 117, wherein the chelating agent is NODAGA.

[0144] Embodiment 125. R 5 but, [ka] 124. The compound according to any one of embodiments 119, 120, 121, 122, 123 and 124, preferably claim 120, wherein

[0145] Embodiment 126. R 8 117. The compound of any one of embodiments 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, and 116, wherein

[0146] Embodiment 127. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] 2. The compound of embodiment 1, wherein:

[0147] Embodiment 128. Lin2-Lin1, [ka] wherein: [ka] indicates the bond to the quinoline, [ka] The compound of embodiment 127, wherein:

[0148] Embodiment 129. The compound of embodiment 127 or 128, wherein Lin3 is -(C2-C3)alkylidene.

[0149] Embodiment 130. R 8 -L-, [ka] 128. The compound of embodiment 127, selected from the group consisting of:

[0150] Embodiment 131. R 8 -L-, [ka] 131. The compound according to embodiment 130, selected from the group consisting of:

[0151] Embodiment 132. R 8 -L-, [ka] 131. The compound according to embodiment 130, selected from the group consisting of:

[0152] Embodiment 133. R 3 The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, wherein is selected from the group consisting of C(O)-Het1, B(OH)2, and -CO-CH2-OH.

[0153] Embodiment 134. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; When B is CH or A is NH, then B is CH or N; E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 134. The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, and 133, selected from the group consisting of:

[0154] Embodiment 135. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 134. The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, and 133, selected from the group consisting of:

[0155] Embodiment 136. The compound has the formula (II): [ka] 134. The compound of any one of embodiments 127, 128, 129, 130, 131, 132, and 133, having the structure:

[0156] Embodiment 137. R 4 The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, and 136, wherein is H or —CH 3 .

[0157] Embodiment 138. R 4 The compound of any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137, wherein

[0158] Embodiment 139. R 4 The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, and 137, wherein is —CH3.

[0159] Embodiment 140. R 6 But R 8 138. The compound of any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, and 139, wherein

[0160] Embodiment 141. R 5 and R 7 is each independently selected from the group consisting of H and -CH3.

[0161] Embodiment 142. R 5 and R 7 is H.

[0162] Embodiment 143. R 7 But R 8 -L.

[0163] Embodiment 144. R 5 and R 6 are each independently selected from the group consisting of H and -CH3.

[0164] Embodiment 145. R 5 and R 6 is H.

[0165] Embodiment 146. R 8 146. The compound of any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, and 145, wherein

[0166] Embodiment 147. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99m A compound according to embodiment 146, selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0167] Embodiment 148. The compound of embodiment 146, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa, NOTA, and NODAGA.

[0168] Embodiment 149. The compound of embodiment 146, wherein the chelating agent is DOTA.

[0169] Embodiment 150. The compound of embodiment 146, wherein the chelating agent is DOTAM.

[0170] Embodiment 151. The compound of embodiment 146, wherein the chelating agent is Macropa.

[0171] Embodiment 152. The compound of embodiment 146, wherein the chelating agent is NOTA.

[0172] Embodiment 153. The compound of embodiment 146, wherein the chelating agent is NODAGA.

[0173] Embodiment 154. R 8 146. The compound according to any one of embodiments 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, and 145, wherein

[0174] Embodiment 155. R 8 -L-, [ka] 2. The compound of embodiment 1, selected from the group consisting of:

[0175] Embodiment 156. R 8 -L-, [ka] 156. The compound of embodiment 155, selected from the group consisting of:

[0176] Embodiment 157. R 8 -L-, [ka] 156. The compound of embodiment 155, selected from the group consisting of:

[0177] Embodiment 158. R 3 The compound according to any one of embodiments 155, 156 and 156, wherein is selected from the group consisting of C(O)-Het1, B(OH)2 and -CO-CH2-OH.

[0178] Embodiment 159. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, A is selected from the group consisting of O, S, and NH; When B is CH or A is NH, then B is CH or N; E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 159. The compound according to any one of embodiments 155, 156, 157, and 158, selected from the group consisting of:

[0179] Embodiment 160. R 3 is -C(O)-Het1, where -C(O)-Het1 is [ka] [In the formula, E is O or S; R 0 is selected from the group consisting of -CH3, -O-CH3, -COOCH3, F, Cl and Br. 159. The compound according to any one of embodiments 155, 156, 157, and 158, selected from the group consisting of:

[0180] Embodiment 161. The compound has the formula (II): [ka] 159. The compound of any one of embodiments 155, 156, 157, and 158, having the structure:

[0181] Embodiment 162. R 4 The compound according to any one of embodiments 155, 156, 157, 158, 159, 160, and 161, wherein is H or —CH 3 .

[0182] Embodiment 163. R 4 The compound of any one of embodiments 155, 156, 157, 158, 159, 160, 161, and 162, wherein

[0183] Embodiment 164. R 4 The compound according to any one of embodiments 155, 156, 157, 158, 159, 160, 161, and 162, wherein is —CH 3 .

[0184] Embodiment 165. R 6 But R 8 165. The compound of any one of embodiments 155, 156, 157, 158, 159, 160, 161, 162, 163, and 164, wherein

[0185] Embodiment 166. R 5 and R 7 are each independently selected from the group consisting of H and -CH3.

[0186] Embodiment 167. R 5 and R 7 is H.

[0187] Embodiment 168. R 7 But R 8 The compound according to any one of embodiments 155, 156, 157, 158, 159, 160, 161, 162, 163 and 164, preferably any one of embodiments 162 and 163, wherein

[0188] Embodiment 169. R 5 and R 6 are each independently selected from the group consisting of H and -CH3.

[0189] Embodiment 170. R 5 and R 6 is H.

[0190] Embodiment 171. R 8 161, 162, 163, 164, 165, 166, 167, 168, 169, and 170, wherein

[0191] Embodiment 172. Chelating agents include DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, and N x S 4-x (N4, N2S2, N3S), Hynic, 99m A compound according to embodiment 171, selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA and NODAGA.

[0192] Embodiment 173. The compound of embodiment 171, wherein the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropa, NOTA, and NODAGA.

[0193] Embodiment 174. The compound of embodiment 171, wherein the chelating agent is DOTA.

[0194] Embodiment 175. The compound of embodiment 171, wherein the chelating agent is DOTAM.

[0195] Embodiment 176. The compound of embodiment 171, wherein the chelating agent is Macropa.

[0196] Embodiment 177. The compound of embodiment 171, wherein the chelating agent is NOTA.

[0197] Embodiment 178. The compound of embodiment 171, wherein the chelating agent is NODAGA.

[0198] Embodiment 179. R 5 but, [ka] 177. The compound according to any one of embodiments 173, 174, 175, 176, 177 and 178, preferably embodiment 174, wherein

[0199] Embodiment 180. R 8 161, 162, 163, 164, 165, 166, 167, 168, 169, and 170, wherein

[0200] Embodiment 181. The compound is [ka] TIFF2024527627000125.tif191169 TIFF2024527627000126.tif181169 TIFF2024527627000127.tif191169 TIFF2024527627000128.tif213169 TIFF2024527627000129.tif90169 2. The compound of embodiment 1, selected from the group consisting of:

[0201] Embodiment 182. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22, 23, 24, 2 1, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 1 04, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 , 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180 and 181.

[0202] Embodiment 183. 183. The compound of embodiment 182, wherein the diagnostically active nuclide is a diagnostically active radionuclide.

[0203] Embodiment 184. The diagnostically active radionuclide is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga,68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 177 Lu, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I and 125 The compound according to embodiment 183, selected from the group consisting of I.

[0204] Embodiment 185. The diagnostically active radionuclide is 18 F, 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb and 203 185. The compound of embodiment 184, selected from the group consisting of Pb.

[0205] Embodiment 186. The diagnostically active radionuclide is 18 F, 64 Cu, 68 Ga and 111 In-, ...

[0206] Embodiment 187. The diagnostically active radionuclide is 18 The compound of embodiment 182, wherein R is H.

[0207] Embodiment 188. 188. The compound of embodiment 187, wherein the diagnostically active nuclide is covalently bound to aluminum.

[0208] Embodiment 189. The aluminum is bound to a chelating agent and 18 The compound of embodiment 188, wherein F is covalently bonded.

[0209] Embodiment 190. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22, 23, 24, 2 1, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 1 04, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 , 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180 and 181.

[0210] Embodiment 191. The compound according to embodiment 190, wherein the therapeutically active nuclide is a therapeutically active radionuclide.

[0211] Embodiment 192. The therapeutically active radionuclide 47 Sc, 67 Cu, 89Sr, 90 Y, 111 In, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 226 Th, 227 Th, 131 I and 211 192. The compound according to embodiment 191, selected from the group consisting of At.

[0212] Embodiment 193. The therapeutically active radionuclide 47 Sc, 67 Cu, 90 Y, 161 Tb, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac and 227 The compound according to embodiment 192, selected from the group consisting of Th.

[0213] Embodiment 194. The therapeutically active radionuclide 90 Y, 161 Tb, 177 Lu, 212 Pb, 225 Ac and 227 The compound according to embodiment 193, selected from the group consisting of Th.

[0214] Embodiment 195. 3. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 for use in a method for diagnosing a disease , 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 7, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189.

[0215] Embodiment 196. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, for use in a method for the treatment of a disease 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163 06, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 1 48, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 190, 191, 192, 193 and 194.

[0216] Embodiment 197. 30. For use in a method for identifying a subject, the subject being likely to respond or not likely to respond to treatment of a disease, wherein the method for identifying a subject comprises any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 1 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, The compound according to any one of 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189.

[0217] Embodiment 198. The compound for use according to embodiment 197, wherein the diagnostic method is a method for diagnosing a disease according to any one of embodiments 1 to 198.

[0218] Embodiment 199. 31. The method of claim 30, wherein the subject is selected from a group of subjects who are likely to respond or not likely to respond to treatment of a disease, wherein the method of selecting a subject from a group of subjects comprises the steps of: , 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 9 7, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 1 29, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 16 Any one of 0, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 18 The compound according to any one of claims 8, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189.

[0219] Embodiment 200. The compound for use according to embodiment 199, wherein the diagnostic method is a method for diagnosing a disease according to any one of embodiments 1 to 199.

[0220] Embodiment 201. 10. A compound for use in a method for stratifying a group of subjects into those likely to respond to a treatment of a disease and those likely to not respond to a treatment of a disease, wherein the method for stratifying a group of subjects comprises any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 10 1, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and 189, performing a diagnostic method using the compound. compound.

[0221] Embodiment 202. The compound for use according to embodiment 201, wherein the diagnostic method is a method for diagnosing a disease according to any one of embodiments 1 to 201.

[0222] Embodiment 203. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 , 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 190, 191, 192, 193 and 194, and a pharmaceutically acceptable excipient. A composition, preferably a pharmaceutical composition.

[0223] Embodiment 204. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 1 2, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 6, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 21 61, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193 and 194, one or more optional excipients, and optionally one or more devices; The device is selected from the group consisting of a labeling device, a purification device, a handling device, a radiation protection device, an analytical device, and an administration device. kit.

[0224] One of ordinary skill in the art will recognize that a compound of the present invention is any compound disclosed herein, including (but not limited to) any compound described in any of the above embodiments and any of the below embodiments.

[0225] Those skilled in the art will recognize that a composition of the present invention is any composition disclosed herein, including (but not limited to) any composition described in any of the above embodiments and any of the below embodiments.

[0226] Those skilled in the art will recognize that a kit of the present invention is any kit disclosed herein, including (but not limited to) any kit described in any of the above embodiments and any of the below embodiments.

[0227] The present invention provides compounds that can be used in the diagnosis and / or treatment of cancer and other diseases and conditions mediated by fibroblast activation protein (FAP).

[0228] The present invention provides compounds that can be used in the detection, treatment and / or management of a variety of diseases associated with FAP-expressing tumors or cells, including cancer and non-cancerous diseases.

[0229] The compounds of the present invention provide highly specific and potent binding to FAPs and other desirable properties as described herein.

[0230] The compounds of the present invention have one or more favorable properties, including (but not limited to) rapid tumor uptake, extended tumor residence time, rapid clearance of the compound from non-tumor tissues, improved efficacy and / or favorable biodistribution properties, improved toxicity and side effect profiles.

[0231] The FAP inhibitors of the present invention exhibit properties for effective clinical use, such as rapid uptake and sustained localization at target sites, and negligible retention in non-target tissues.

[0232] Those skilled in the art will recognize that the phrase "an aspect of the invention" is used synonymously with the terms "aspects of the invention" and "aspects of the invention," respectively, and that the phrase "embodiments of the invention" is used synonymously with the terms "embodiments of the invention" and "embodiments of the invention," respectively.

[0233] Unless otherwise specified, all numerical values ​​expressing quantities, conditions, and the like used in the present invention should be understood to be modified in all instances by the term "about." Accordingly, unless otherwise specified, the numerical parameters set forth in the present invention are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding practices.

[0234] Furthermore, the disclosure of a numerical range herein is considered to be a disclosure of all numbers and ranges within that range. For example, if a range is 1 to 10, this is considered to include, for example, 1, 2, 2.2, 3, 4, 5, 6, 7, 7.4, 7.6, 8, 8.7, 9, 9.5, 10, or any other value or range (integer or non-integer) within that range. Furthermore, as used herein, the term "at least" is inclusive of the recited number, for example, "at least 50" includes 50.

[0235] The term "alkyl" as used herein preferably refers to each and every saturated straight-chain or branched-chain hydrocarbon group, usually accompanied by a modifier specifying the number of carbon atoms it may contain. For example, the term (C1-C6) alkyl refers each and every to any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, 3-methylbutyl, 1,2-dimethylpropyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1,1-dimethylbutyl, and any other isoform of an alkyl group containing 6 saturated carbon atoms.

[0236] In one embodiment, and as preferably used herein, (C1-C2) alkyl refers each and individually to either methyl or ethyl.

[0237] In one embodiment, and as preferably used herein, (C1-C3) alkyl refers each and individually to any of methyl, ethyl, n-propyl, and isopropyl.

[0238] In one embodiment, and as preferably used herein, (C1-C4) alkyl refers each and individually to any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0239] In one embodiment and as preferably used herein, (C1-C6) alkyl is each and individually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methyl-butyl, 3-methyl-butyl, 3-pentyl, 3-methyl-but-2-yl, 2-methyl-but-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 2-methyl- pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 3-hexyl, 2-ethyl-butyl, 2-methyl-pent-2-yl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 3-methyl-pent-2-yl, 4-methyl-pent-2-yl, 2,3-dimethyl-butyl, 3-methyl-pent-3-yl, 2-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl and 3,3-dimethyl-but-2-yl.

[0240] In one embodiment, and as preferably used herein, "(C1-C8) alkyl" refers to a saturated or unsaturated, straight or branched chain hydrocarbon group having from 1 to 8 carbon atoms. Representative (C1-C8) alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methyl-butyl, 3-methyl-butyl, 3-pentyl, 3-methyl-but-2-yl, 2-methyl-but-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 3-hexyl, 2-ethyl-but-2-yl, and the like. n-heptyl, 2-heptyl, 2-methyl-hexyl, 3-methyl-hexyl, 4-methyl-hexyl, 5-methyl-hexyl, 3-hexyl, 2-methyl-pent-2-yl, 2,3-dimethyl-butyl, 3-methyl-pent-3-yl, 2-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl, 3,3-dimethyl-but-2-yl, n-heptyl, 2-heptyl, 2-methyl-hexyl, 3-methyl-hexyl, 4-methyl-hexyl, 5-methyl-hexyl, 3-hexyl butyl, 2-ethyl-pentyl, 3-ethyl-pentyl, 4-heptyl, 2-methyl-hex-2-yl, 2,2-dimetyhl-pentyl, 3,3-dimethyl-pentyl, 4,4-dimetyhl-pentyl, 3-methyl-hex-2-yl, 4-methyl-hex-2-yl, 5-methyl-hex-2-yl, 2,3-dimethyl-pentyl, 2,4-dimethyl-pentyl, 3,4-dimethyl-pentyl, 3-methyl-hex-3-yl, 2-ethyl-2-methyl-butyl, 4-methyl-hex-3-yl, 5-methyl-hex-3-yl, 2-ethyl-3-methyl-butyl, 2,3-dimethyl-pent-2-yl, 2,4-dimethyl-pent-2-yl, 3,3-dimethyl-pent-2-yl, 4,4-dimethyl-pent-2-yl, 2,2,3-trimethyl-butyl, 2,3,3-trimethyl-butyl, 2,3,3-trimethyl-but-2-yl, n-octyl, 2-octyl, 2-methyl-heptyl, 3-methyl-heptyl, 4-methyl-heptyl, 5-methyl-heptyl, 6-methyl-heptyl, 3-octyl, 2-ethyl-hexyl, 3-ethyl-hexyl, 4-ethyl-hexyl, 4-octyl, 2-propyl-pentyl, 2-methyl-hept-2-yl, 2,2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 5,5-dimethyl-hexyl, 3-methyl-hept-2-yl, 4-methyl-hept-2-yl, 5 -Methyl-hept-2-yl, 6-methyl-hept-2-yl, 2,3-dimethyl-hex-1-yl, 2,4-dimethyl-hex-1-yl, 2,5-dimethyl-hex-1-yl, 3,4-dimethyl-hex-1-yl, 3,5-dimethyl-hex-1-yl, 3,5-dimethyl-hex-1-yl, 3-methyl-hept-3-yl, 2-ethyl-2-methyl-1-yl, 3-ethyl-3-methyl-1-yl, 4-methyl-hept-3-yl, 5-methyl-hept-3-yl, 6-methyl-hept-3-yl, 2-ethyl-3-methyl-pentyl , 2-ethyl-4-methyl-pentyl, 3-ethyl-4-methyl-pentyl, 2,3-dimethyl-hex-2-yl, 2,4-dimethyl-hex-2-yl, 2,5-dimethyl-hex-2-yl, 3,3-dimethyl-hex-2-yl, 3,4-dimethyl-hex-2-yl, 3,5-dimethyl-hex-2-yl, 4,4-dimethyl-hex-2-yl, 4,5-dimethyl-hex-2-yl, 5,5-dimethyl-hex-2-yl, 2,2,3-trimethyl-pentyl, 2,2,4-trimethyl-pentyl, 2,3,3-trimethyl-pentyl butyl, 2,3,4-trimethylpentyl, 2,4,4-trimethylpentyl, 3,3,4-trimethylpentyl, 3,4,4-trimethylpentyl, 2,3,3-trimethylpent-2-yl, 2,3,4-trimethylpent-2-yl, 2,4,4-trimethylpent-2-yl, 3,4,4-trimethylpent-2-yl, 2,2,3,3-tetramethylbutyl, 3,4-dimethylhex-3-yl, 3,5-dimethylhex-3-yl, 4,4-dimethylhex-3-yl, 4,5-dimethylhex-3-yl, 5,Examples of alkyl groups include, but are not limited to, 5-dimethyl-hex-3-yl, 3-ethyl-3-methyl-pent-2-yl, 3-ethyl-4-methyl-pent-2-yl, 3-ethyl-hex-3-yl, 2,2-diethyl-butyl, 3-ethyl-3-methyl-pentyl, 4-ethyl-hex-3-yl, 5-methyl-hept-3-yl, 2-ethyl-3-methyl-pentyl, 4-methyl-hept-4-yl, 3-methyl-hept-4-yl, 2-methyl-hept-4-yl, 3-ethyl-hex-2-yl, 2-ethyl-2-methyl-pentyl, 2-isopropyl-pentyl, 2,2-dimethyl-hex-3-yl, 2,2,4-trimethyl-pent-3-yl, and 2-ethyl-3-methyl-pentyl. The (C1-C8) alkyl group may be unsubstituted or substituted with one or more groups. Such groups include, but are not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0241] In one embodiment and as preferably used herein, -O-(C1-C6)alkyl refers to an ether oxygen atom to which is attached each and every -(C1-C6)alkyl moiety as defined above, such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 2-methylbutoxy, 3-methylbutoxy, 3-pentoxy, 3-methylbut-2-oxy, 2-methylbut-2-oxy, 2,2 -dimethylpropoxy, n-hexoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-pentoxy, 3-hexoxy, 2-ethyl-butoxy, 2-methyl-pent-2-oxy, 2,2-dimethyl-butoxy, 3,3-dimethyl-butoxy, 3-methyl-pent-2-oxy, 4-methyl-pent-2-oxy, 2,3-dimethyl-butoxy, 3-methyl-pent-3-oxy, 2-methyl-pent-3-oxy, 2,3-dimethyl-but-2-oxy, 3,3-dimethyl-but-2-oxy.

[0242] In one embodiment, and as preferably used herein, -O-(C1-C4)alkyl refers, each and individually, to an ether oxygen atom to which is attached a -(C1-C4)alkyl moiety as defined above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0243] In one embodiment, and as preferably used herein, -COO-(C1-C4)alkyl refers, individually and individually, to an ester group containing a -(C1-C4)alkyl moiety as defined above, for example, a methyl ester, an ethyl ester, a propyl ester, or a butyl ester.

[0244] The term alkylidene, as preferably used herein, refers to a saturated, straight-chain or branched hydrocarbon group with two substitution points designated. Simple alkyl chains with two substitution points at the maximum distance from each other, such as methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl, are also called methylene (also called methane-1,1-diyl), ethylene (also called ethane-1,2-diyl), propylene (also called propane-1,3-diyl), butylene (also called butane-1,4-diyl) and pentylene (also called pentane-1,5-diyl).

[0245] In one embodiment and as preferably used herein, (C1 to C 10 ) Alkylidene is each individually methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,2-diyl, 2-methyl-propane-1,3-diyl, pentane-1,5-diyl, pentane-1,4-diyl, pentane-1,3-diyl, pentane-1,2-diyl, pentane-2,3-diyl, pentane-2,4-diyl hexane-1,6-diyl, any other isomer having 5 carbon atoms, hexane-1,6-diyl, any other isomer having 6 carbon atoms, heptane-1,7-diyl, any other isomer having 7 carbon atoms, octane-1,8-diyl, any other isomer having 8 carbon atoms, nonane-1,9-diyl, any other isomer having 9 carbon atoms, decane-1,10-diyl, and any other isomer having 10 carbon atoms, and preferably (C1-C 10) alkylidene means, each and individually, any of methylene, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, and decane-1,10-diyl. In one embodiment and as preferably used herein, (C2-C4) alkylidene means, each and individually, any of methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,2-diyl, and 2-methyl-propane-1,3-diyl. (C1-C 10 ) Alkylidene groups can be unsubstituted or substituted with one or more groups including, but not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0246] In one embodiment and as preferably used herein, -O-(C1-C3)alkylidene-(C6)aryl refers to, for example, -O-methylene-phenyl, -O-ethylene-phenyl, -O-propylene-phenyl.

[0247] In one embodiment and as preferably used herein, -(C1-C4)alkylidene-C(O)NH- refers to, for example, methylene-C(O)NH-, -ethylene-C(O)NH-, -propylene-C(O)NH-, and -butylene-C(O)NH-.

[0248] In one embodiment, and as preferably used herein, "carbocycle" refers to a saturated, unsaturated, or aromatic monocyclic or bicyclic carbon ring. The carbocycle may be unsubstituted or substituted with one or more groups, including, but not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0249] In one embodiment, and as preferably used herein, "heterocycle" refers to a saturated, unsaturated, or aromatic monocyclic or bicyclic heterocycle. Heterocycle groups can be unsubstituted or substituted with one or more groups, including, but not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0250] In one embodiment, and as preferably used herein, "aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0251] In one embodiment and as preferably used herein, (C5-C6)aryl refers to a carbocyclic aromatic group having 5 or 6 carbon atoms. In one embodiment and as preferably used herein, (C6)aryl refers to a carbocyclic aromatic group having 6 carbon atoms. The carbocyclic aromatic group can be unsubstituted or substituted with one or more groups, including, but not limited to, -(C1-C8)alkyl, -O-[(C1-C8)alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, where each R' is independently selected from -(C1-C8)alkyl and aryl. In one embodiment, and as preferably used herein, "heteroaryl" refers to a heterocyclic aromatic group. Examples of heteroaryl groups include, but are not limited to, furan, thiophene, pyridine, pyrimidine, benzothiophene, benzofuran, and quinoline.

[0252] In one embodiment, and as preferably used herein, "(C5-C6)heteroaryl" refers to a heteroaromatic group consisting of five or six ring atoms, in which at least one atom is different from carbon and includes, for example, nitrogen, sulfur, or oxygen. The heteroaromatic group can be unsubstituted or substituted with one or more groups, including, but not limited to, -(C1-C8)alkyl, -O-[(C1-C8)alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, in which each R' is independently selected from -(C1-C8)alkyl and aryl.

[0253] In one embodiment, and as preferably used herein, atoms in any structural formula or anywhere herein without an atomic mass number designation may be either an undesignated isotopic composition, a mixture of naturally occurring isotopes, or an individual isotope. This applies in particular to atoms of carbon, oxygen, nitrogen, sulfur, phosphorus, halogens, and metals, including, but not limited to, C, O, N, S, F, P, Cl, Br, At, Sc, Cr, Mn, Co, Fe, Cu, Ga, Sr, Zr, Y, Mo, Tc, Ru, Rh, Pd, Pt, Ag, In, Sb, Sn, Te, I, Pr, Pm, Dy, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Sn, Re, Rd, Os, Ir, Au, Pb, Bi, Po, Fr, Ra, Ac, Th, and Fm.

[0254] In one embodiment, and as preferably used herein, the term "effector domain" refers to a chelator or effector.

[0255] In one embodiment, and as preferably used herein, "effector" refers to an active agent that inhibits or interferes with cellular function and / or causes cell death or destruction. Effectors include, but are not limited to, the following active agents: theranostic active agents, diagnostic active agents, therapeutic active agents, theranostic active nuclides, diagnostic active nuclides, therapeutic active nuclides, theranostic active radionuclides, diagnostic active radionuclides, therapeutic active radionuclides, radioisotopes, and cytotoxic agents.

[0256] In one embodiment, and as preferably used herein, a "cytotoxic agent" refers to an agent that damages and / or kills cells, including cancer cells. Cytotoxic agents include, but are not limited to, chemotherapeutic agents or drugs, growth inhibitory agents, enzymes and their fragments, e.g., nucleases, antibiotics; toxins, e.g., small molecule toxins or enzymatically active toxins (including fragments and / or variants thereof) of bacterial, fungal, plant, or animal origin, and various antitumor or anticancer agents disclosed below. In one embodiment, a radioisotope can be the cytotoxic agent. In one embodiment, and as preferably used herein, "amine-reactive" derivatives of cytotoxic agents are utilized to prepare the compounds of the present invention. Amine-reactive derivatives preferably contain at least one functional group. The functional group includes, but is not limited to, a carboxylic acid, an activated carboxylic acid, an isocyanate, or an isothiocyanate.

[0257] In one embodiment, and as preferably used herein, a "chelating agent" refers to a compound capable of forming a chelate, for example, a compound containing a cyclic compound in which a metal or a moiety having an electron gap or lone pair of electrons participates in the formation of a ring. In certain embodiments, a chelating agent is a species of compound in which a single ligand occupies two or more coordination sites on a central atom. A chelating agent refers to an uncomplexed chelating agent or any metal complex partner, i.e., a chelating agent complexed to any metal that can, in principle, be complexed by a chelating agent. The metal complex partner may be a radioactive or non-radioactive metal complex partner. Examples of metal complex partners include, but are not limited to, theranostically active nuclides, diagnostically active nuclides, therapeutically active nuclides, theranostically active radionuclides, diagnostically active radionuclides, therapeutically active radionuclides, and radioisotopes.

[0258] In one embodiment, and as preferably used herein, a "diagnostically active compound" is a compound that is at least suitable or useful for diagnosing a disease.

[0259] In one embodiment, and as preferably used herein, a "diagnostic agent" or "diagnostically active agent" is a compound that is at least suitable or useful for diagnosing a disease.

[0260] In one embodiment, and as preferably used herein, a "diagnostically active radionuclide" is a radionuclide that is suitable or useful for at least diagnosing disease, although those skilled in the art will also recognize that the use of said diagnostically active radionuclide may not be limited to diagnostic purposes, but may also encompass use in therapy and theranostics.

[0261] In one embodiment, and as preferably used herein, a "therapeutically active compound" is a compound that is at least suitable or useful in the treatment of a disease.

[0262] In one embodiment, and as preferably used herein, a "therapeutic agent" or "therapeutically active agent" is at least a compound suitable or useful in the treatment of a disease.

[0263] In one embodiment, and as preferably used herein, a "therapeutically active radionuclide" is a radionuclide that is suitable or useful for at least the treatment of a disease, although those skilled in the art will also recognize that the use of said therapeutically active radionuclide may not be limited to therapeutic purposes, but may also include use in diagnostics and theranostics.

[0264] In one embodiment, and as preferably used herein, a "theranostically active compound" is a compound that is suitable or useful for both the diagnosis and treatment of a disease.

[0265] In one embodiment, and as preferably used herein, a "theranostic agent" or "theranostic active agent" is a compound that is suitable or useful for both the diagnosis and treatment of disease.

[0266] In one embodiment, and as preferably used herein, a "theranostically active radionuclide" is a radionuclide that is suitable or useful for both the diagnosis and treatment of disease.

[0267] In one embodiment, and as preferably used herein, "theranostics" refers to a method for the combined diagnosis and treatment of disease. In certain embodiments, the combination of diagnostically and therapeutically active compounds used in theranostics is radiolabeled.

[0268] In one embodiment, and as preferably used herein, "treatment of a disease" is the treatment and / or prevention of a disease.

[0269] In one embodiment, and as preferably used herein, the terms "treat", "treating" and "treatment" are meant to include alleviating or eliminating one or more of the disorders, diseases or conditions or symptoms associated with the disorders, diseases or conditions, or alleviating or eradicating the cause of the disorders, diseases or conditions themselves.

[0270] In one embodiment, and as preferably used herein, "preventing" or "prevent" refers to reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0271] In one embodiment, and as preferably used herein, the term "subject" or "patient" includes a mammal. The mammal can be, for example, any mammal, such as a human, a companion animal, a pet, a livestock animal, a dog, a cat, a horse, and a cow.

[0272] In one embodiment, and as preferably used herein, a "disease involving a FAP protein" is a disease involving cells that exhibit upregulation of FAP expression, which upregulation is the cause of or part of the underlying pathology of the disease and / or symptoms of the disease.

[0273] In one embodiment, and as preferably used herein, a disease involving a FAP is characterized by cells, including (but not limited to) fibroblasts, expressing a FAP, preferably in an upregulated manner, and tissues containing or comprising cells, such as fibroblasts, that express a FAP or preferably express a FAP in an upregulated manner, respectively, being responsible for the disease and / or the symptoms of the disease or part of the underlying pathology of the disease. A preferred FAP-expressing cell is a cancer-associated fibroblast (CAF). In one disease embodiment, preferably, when used in connection with treatment, the treatment, cure, and / or therapy of the disease, affecting the cells, tissue, and pathology, respectively, results in a cure, treatment, or amelioration of the disease and / or the symptoms of the disease. In one disease embodiment, preferably, when used in connection with diagnosing and / or diagnosing a disease, labeling of FAP-expressing cells and / or FAP-expressing tissue allows the cells and / or tissue to be distinguished or differentiated from healthy or non-FAP-expressing cells and / or healthy or non-FAP-expressing tissue. More preferably, such discrimination or differentiation forms the basis of said diagnosis and diagnosing, respectively. In one embodiment thereof, labeling refers to the interaction, either direct or indirect, of a detectable label with FAP-expressing cells and / or FAP-expressing tissues or tissues containing such FAP-expressing cells, more preferably, such interaction includes or is based on the interaction of the label or a compound bearing such a label with the FAP.

[0274] In one embodiment, and as preferably used herein, a "target cell" or "target tissue" is a cell or tissue that expresses a FAP and is responsible for the disease and / or symptoms of the disease or is part of the underlying pathology of the disease.

[0275] In one embodiment, and as preferably used herein, a "non-target cell" or "non-target tissue" is a cell or tissue that does not express a FAP and / or is not responsible for the disease and / or symptoms of the disease or is not part of the underlying pathology of the disease.

[0276] In one embodiment, and as preferably used herein, a "neoplasm" is an abnormal new growth of cells. Cells in a neoplasm proliferate more rapidly than normal cells and will continue to proliferate if untreated. Neoplasms can be benign or malignant.

[0277] In one embodiment, and as preferably used herein, a "tumor" is a mass lesion that may be benign or malignant.

[0278] In one embodiment, and as preferably used herein, a "cancer" is a malignant neoplasm.

[0279] In one embodiment, and as preferably used herein, "pharmaceutically acceptable excipient" refers to ingredients other than active agents and / or compounds that are suitable for use in pharmaceutical compositions, including, but not limited to, pharmaceutically acceptable adjuvants, diluents, carriers, buffers, binders, colorants, lubricants, fillers, disintegrants, preservatives, surfactants, and stabilizers.

[0280] In one embodiment, and as preferably used herein, a "linkage" is a bond between two atoms of two independent moieties. A preferred linkage is a chemical bond or multiple chemical bonds. Preferably, the chemical bond is a covalent bond or multiple chemical bonds. Preferably, the linkage is a covalent bond or a coordinate bond. As preferably used herein, a coordinate bond embodiment is a bond or group of bonds such as those realized when a metal is bound by a chelating agent. Different types of linkages arise depending on the type of atoms linked and their atomic environment. These types of linkages are defined by the type of atomic arrangement resulting from the linkage. For example, the linkage between an amine-containing moiety and a carboxylic acid-containing moiety results in a linkage termed an amide (also referred to as an amide bond, -CON-, or -NCO). Those skilled in the art will recognize that this example and the following examples of forming linkages are merely typical examples and in no way limit the scope of this application. Those skilled in the art will recognize that linking an isothiocyanate-containing moiety with an amine-containing moiety results in a thiourea (also referred to as a thiourea bond, -NCSN), and linking a C-atom-containing moiety with a thiol group (-C-SH) results in a thioether (also referred to as a thioether bond, -CSC). A non-limiting list of exemplary linkages used in connection with the chelators and linkers of the present invention and their characteristic types of atomic configurations is provided in Table 1.

[0281] [Table 1]

[0282] In some embodiments of the present invention, examples of reactive groups that may be used to form a linkage between a chelator and the remainder of the molecule are provided, although one of skill in the art will recognize that neither the linkages used to form the compounds of the present invention nor the reactive groups that form such linkages are limited to those in Table 2.

[0283] [Table 2]

[0284] In one embodiment, and as preferably used herein, the term "activated carboxylic acid" refers to a carboxylic acid group having the general formula -CO-X, where X is a leaving group. For example, activated carboxylic acid groups may include, but are not limited to, acyl chlorides, symmetrical or asymmetrical anhydrides, and esters. In some embodiments, the activated carboxylic acid group is an ester having pentafluorophenol, nitrophenol, benzotriazole, azabenzotriazole, thiophenol, or N-hydroxysuccinimide (NHS) as the leaving group.

[0285] In one embodiment, and as preferably used herein, the term "mediate a linkage" means that a linkage or a type of linkage, preferably a linkage between two moieties, is established.

[0286] Those skilled in the art will recognize whether stereocenters exist in the compounds disclosed herein. Accordingly, the present invention encompasses possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0287] In the present invention, the structural formula of a compound may conveniently represent a specific isomer in some cases, but the present invention includes all isomers, for example, geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like.

[0288] In one embodiment, the compound of the present invention comprises a chelating agent. In some embodiments, the chelating agent forms a metal chelate, for example, comprising at least one radioactive metal. The at least one radioactive metal is, for example, useful or suitable for diagnostic and / or therapeutic and / or theranostic uses, for example, useful or suitable for imaging and / or radiotherapy.

[0289] Chelators that are useful and / or suitable in principle for the practice of the present invention, including the diagnosis and / or treatment of disease, are known to those skilled in the art. A wide variety of chelators are available and are reviewed, for example, in Banerjee et al. (Banerjee, et al., Dalton Trans, 2005, 24: 3886) and references cited therein (Price, et al., Chem Soc Rev, 2014, 43: 260; Wadas, et al., Chem Rev, 2010, 110: 2858). Such chelating agents include, but are not limited to, linear, cyclic, macrocyclic, tetrapyridine, N3S, N2S2, and N4 chelating agents such as those disclosed in U.S. Pat. Nos. 5,367,080, 5,364,613, 5,021,556, 5,075,099, and 5,886,142.

[0290] In some embodiments, the metal chelator is capable of binding to a radionuclide. This binding can be direct, e.g., the metal chelator may have an ionic, covalent, dipole, or ion-dipole interaction with the radioactive atom. This binding can also be indirect, e.g., the metal chelator binds to a molecule containing the radioactive atom. In some embodiments, the metal chelator comprises or is a macrocycle. In some embodiments, the metal chelator comprises or is DOTA or NOTA. In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle containing O and / or N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine.

[0291] In some embodiments, the metal chelator comprises multiple amines. In some embodiments, the metal chelator comprises four or more N, four or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not contain S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises O and / or N. In some embodiments, the metal chelator is a ring containing three or more N, three or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is multidentate.

[0292] The main ingredients are AAZTA, BAT, CDTA, DTA, C yEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, D TPA-MA, DTPA-BA, BOPA, NTA, NOC, NOTP, CY-DTA , DTCBP , CTA , CB - , , TETA , Pages CPTA, TEAM, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA( PPh) 、DEDPA 、H4オタパ 、H2dedpa 、H5decape 、H2azapa 、H2CHX-DEDPA 、DFO-Chx-MAL 、DFO-p-SCN 、D FO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, scallop, DOTA, DOTAGA, DOTA -MFCO, DOTAM, DOTAM-FREE, DOTA-MA, DOTA-pNB, DOTA-4AMP, ツ-DOTA, ツ-PA-DOTA, p-NCS-Bz- DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN- Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, HOPO, 3,4,3-(Li-1,2-HOPO), TRAIN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, DOXP, p-NCS-DOTA, p-NCS-PADOTA, p- NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-mono-amino DO-DOTA, BCN-DOTA, Butyne-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A(trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)ethanamide, DO3TMP-monoamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimide-monoamide-DOTA, maleimide-DOTA , NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone thylpyridine tetradentate ligand H2L2-4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, deferiprone, THP, HYNIC (2-hydrazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A, IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, macropaquin, macropaquin-SO3, N, x S 4-x、N2S2、N3S、N4、MAG3B、NOTE、NODAGA、SCN-Bz-NOTE-R、NOT-P(NOTMP)、N OTAM, p-NCS-NOTE, TACN, TACN-TM, NETA, NETA-モノアン, pSCN-PhPr-NE3T A、C-NE3TA-NCS、C-NETA-NCS、3p-C-NETA、NODASE、NOPO、NODA、NODA-MP AA, NO2A, N-KNOT-NODA, C-NOTA, BCNOT-KNOT, KNOT-KNOT-NOTE, NO2 A-Synthesis NO2A-Synthesis NO2AP NO3AP N-NOTE DO3A p-NH2-Bn-NOTE p- NH2-Bn-derivative-DO3A p-NO2-Bn-derivative p-SCN-Bn-NOTE p-SCN-Bn-derivative-DO 3A、TRAP、PEPA、BF-PEPA、pycup、pycup2A、pycup1A1Bn、pycup2Bn、SarA r-R, DiAmSar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me) TAM A、TAM B, TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB -TE2A、TE2A、H2CB-TE2A、TE2P、CB-TE2P、MM-TE2A、DM-TE2A、2C-TETA 6C-TETA, BAT, BAT-6, NHS-BAT, SSBAT, SCN-CHX-A-DTPA-P, SCN -TETA, TMT-ミン, p-BZ-HTCP, H4pypa, H4octox, p-NO2-Bn-neunpa, p -SCN-Bn-H4neunpa, TTHA, tBu4pypa-C7-NHS, H4neunpa, H2マロパ, BT- DO3A, DO3A-Nprop, DO3AP, DOTPMB, DOTAMAE, DOTAMAP, DO3AMBu, DEPA, p-NO2-Bn-PCTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA. 99m The Tc(CO)3-dielectric mixture was mixed with MeO-DOTA-NCS.

[0293] HYNIC, DTPA, EDTA, DOTA, TETA, and bisaminobisthiol (BAT) chelators are disclosed in U.S. Pat. No. 5,720,934. Desferrioxamine (DFO) is disclosed in Doulias et al. (Doulias, et al., Free Radic Biol Med, 2003, 35: 719). Tetrapyridines and N3S, N2S2, and N4 chelators are disclosed in U.S. Pat. Nos. 5,367,080, 5,364,613, 5,021,556, 5,075,099, and 5,886,142. All of these references are incorporated herein by reference in their entirety. 6-Amino-6-methylperhydro-1,4-diazepine-N,N',N'',N''-tetraacetic acid (AAZTA) is disclosed by Pfister et al. (Pfister, et al., EJNMMI Res, 2015, 5: 74). Deferiprone, 1,2-dimethyl-3,4-hydroxypyridinone, and hexadentate tris(3,4-hydroxypyridinone) (THP) are disclosed by Cusnir et al. (Cusnir, et al., Int J Mol Sci, 2017, 18). Monoamine-monoamide dithiol (MAMA) chelators are disclosed by Demoin et al. (Demoin, et al., Nucl Med Biol, 2016, 43: 802). Macropa and analogs are disclosed in Thiele et al. (Thiele, et al., Angew Chem Int Ed Engl, 2017, 56: 14712). 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA) and PEPA analogs are disclosed in Price and Orvig (Price, et al., Chem Soc Rev, 2014, 43: 260). Pycup and analogs are disclosed in Boros et al. (Boros, et al., Mol Pharm, 2014, 11: 617).N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCM), 2-[(carboxymethyl)]-[5-(4-nitrophenyl)-1-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane- 1-yl]pentan-2-yl)-amino]acetic acid (3p-C-DEPA), CB-TE2A, TE2A, TE1A1P, DiAmSar, 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr), NETA, tris(2-mercaptoethyl)-1,4,7-triazacyclononane (T ACN-™), {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA), diethylenetriaminepentaacetic acid (DTP), 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphinoylmethyl]-[1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphinoyl)-propionic acid (TRAP), NOPO, H4Octapa, SHBED, BPCA, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA), and 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-hexaacetic acid (PEPA) were purchased from Price Chemical Company. and Orvig (Price, et al., Chem Soc Rev, 2014, 43: 260). 1-Hydroxy-2-pyridone ligands (HOPO) are disclosed by Allott et al. (Allott, et al., Chem Commun (Camb), 2017, 53: 8529). [4-Carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid (DATA) is disclosed by Tornesello et al. (Tornesello, et al., Molecules, 2017, 22: 1282).Tetrakis(aminomethyl)methane (TAM) and analogs are disclosed in McAuley 1988 (McAuley, et al., Canadian Journal of Chemistry, 1989, 67: 1657). Hexadentate tris(3,4-hydroxypyridinone) (THP) and analogs are disclosed in Ma et al. (Ma, et al., Dalton Trans, 2015, 44: 4884).

[0294] Diagnostic and / or therapeutic uses of some of the above chelating agents have been described in the prior art. For example, 2-hydrazinonicotinamide (HYNIC) 99m Tc and 186,188 It has been widely used in the presence of co-ligands for the incorporation of Re (Schwartz, et al., Bioconjug Chem, 1991, 2: 333; Babich, et al., J Nucl Med, 1993, 34: 1964; Babich, et al., Nucl Med Biol, 1995, 22: 25). DTPA is 111 It has been used in Octreoscan® to complex In, and several improvements have been described in the literature (Li, et al., Nucl Med Biol, 2001, 28: 145; Brechbiel, et al., Bioconjug Chem, 1991, 2: 187). DOTA-type chelators for radiotherapy applications are described by Tweedle et al. (US Pat. No. 4,885,363). Other polyazamacrocycles for chelating trivalent metal isotopes are described by Eisenwiener et al. (Eisenwiener, et al., Bioconjug Chem, 2002, 13: 530). N4-chelators, such as 99m Tc-N4-chelators have been used for peptide labeling in the case of minigastrins to target the CCK-2 receptor (Nock, et al., J Nucl Med, 2005, 46: 1727).

[0295] In one embodiment, the metal chelator is selected from the group consisting of DOTA, DOTAGA, DOTAM, DOTP, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A″-DTPA, DFO, macropa, HOPO, TRAP, THP, DATA, NOPO, PCTA, NOTP, sarcofadin, FSC, NETA, NE3TA, H4 octapa, pycup, HYNIC, N x S 4-x (N4, N2S2, N3S), 99mThe compound may be selected from the group including, but not limited to, Tc(CO)3-chelators and their analogs. Here, DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. DOTAGA represents 1,4,7,10-tetraazacyclodosecane,1-(glutaric acid)-4,7,10-triacetic acid. DOTAM (also known as TCMC) represents 1,4,7,10-tetrakis[carbamoylmethyl]-1,4,7,10-tetracyclodecane. DOTP represents 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid). NOTA represents 1,4,7-triazacyclononanetriacetic acid. NODAGA represents 1,4,7-triazacyclononane-N-glutaric acid-N',N''-diacetic acid. NODA-MPAA represents 1,4,7-triazacyclononane-1,4-diacetate-methylphenylacetic acid. HBED represents bis(2-hydroxybenzyl)ethylenediaminediacetic acid. ETA represents 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid. CB-TE2A represents 4,11-bis-(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane. DTPA represents diethylenetriaminepentaacetic acid. CHX-A"-DTPA represents [(2-{[2-(bis-carboxymethyl-amino)-cyclohexyl]-carboxymethyl-amino}-ethyl)-carboxymethyl-amino]-acetic acid. DFO represents the desferal or desferrioxamine type chelating agent group, a non-limiting example chemical name is N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide. Macropa represents N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown. HOPO represents the octadentate hydroxypyridinone type chelating agent group, a non-limiting example structure is shown below.TRAP represents 3-({4,7-bis-[(2-carboxyethyl)-hydroxy-phosphinoylmethyl]-[1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphinoyl)-propionic acid. THP represents hexadentate tris(3,4-hydroxypyridinone). DATA represents [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid. PCTA represents 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9-triacetic acid. NOPO represents 1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]. NOTP represents 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid). Sarcofazine represents 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane. FSC represents 3,15,27-triamino-7,19,31-trihydroxy-10,22,34-trimethyl-1,13,25-trioxa-7,19,31-triaza-cyclohexatriaconta-9,21,33-triene-2,8,14,20,26,32-hexaone. NETA represents {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid. NE3TA represents {4-carboxymethyl-7-[2-(carboxymethyl-amino)-ethyl]-[1,4,7]triazonan-1-yl}-acetic acid. H4octapa represents N,N'-(6-carboxy-2-pyridylmethyl)-N,N'-diacetic acid-1,2-diaminoethane. Pycup represents 1,8-(2,6-pyridinedimethylene)-1,4,8,11-tetraazacyclotetradecane. HYNIC represents 6-hydrazino-nicotinic acid. N. x S 4-x(N4, N2S2, N3S) represent a group of tetradentate chelating agents with an N-atom (basic amine or non-basic amide) and a thiol as donors to stabilize Tc-complexes, especially Tc(V)-oxo complexes. The structure of a representative, non-limiting example N4 is shown below. N4 represents N,N'-bis-(2-amino-ethyl)-propane-1,3-diamine. 99m Tc(CO)3- chelators represent bidentate or tridentate chelators capable of forming stable complexes with technetium tricarbonyl fragments. Their chemical structures are as follows:

[0296] [ka] TIFF2024527627000133.tif199169 TIFF2024527627000134.tif192169

[0297] In some embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic and 99m The compound is selected from the group consisting of Tc(CO)3-chelators and analogs thereof.

[0298] In some embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, and analogs thereof.

[0299] In some embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, and NODAGA and analogs thereof.

[0300] In some embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAM, NOTA, NODAGA, and Macropa and analogs thereof.

[0301] In some embodiments, the metal chelator is DOTA and its analogs.

[0302] Those skilled in the art will recognize that chelating agents can, in principle, be used whether the compounds of the invention are used in or suitable for diagnosis or therapy.

[0303] Those skilled in the art will further recognize that the presence of a chelator in a compound of the invention, unless otherwise specified, includes the possibility that the chelator may be complexed with any metal complex partner, i.e., any metal that, in principle, may be complexed by a chelator. An explicitly mentioned chelator of a compound of the invention, or the general term chelator in relation to a compound of the invention, refers to either the uncomplexed chelator itself or a chelator having any metal complex partner attached, where the metal complex partner is any radioactive or non-radioactive metal complex partner. In some embodiments, the chelator metal complex, i.e., the chelator having the metal complex partner attached, is a stable chelator metal complex.

[0304] Non-radioactive chelator metal complexes have several uses, for example, for assessing properties such as stability or activity that are difficult to determine by other methods. One aspect is that non-radioactive variants of radioactive versions of the metal complex partner (e.g., non-radioactive gallium, lutetium, or indium complexes) can serve as surrogates for radioactive compounds. Furthermore, they are valuable tools for identifying in vitro or in vivo metabolites and for assessing the toxicity of the compounds of the invention. Furthermore, chelator metal complexes can be used in binding assays that take advantage of the fluorescent properties of some metal complexes with different ligands (e.g., europium salts).

[0305] Chelators with a wide variety of (optionally already activated) groups for conjugation to peptides or amino acids can be synthesized or are commercially available. For chelators selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, DTPA, CHX-A″-DTPA, Macropa, HBED, CB-TE2A, DFO, THP, and N4, for example, DOTA, DOTAGA, NODAGA, and Macropa, direct conjugation of the chelator to the amino nitrogen of each compound of the invention is possible. For example, the linkage in this regard is an amide bond.

[0306] For chelators selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, DTPA, CHX-A″-DTPA, DFO and THP, e.g., DOTA, DOTAGA, NOTA, NODAGA, DTPA and CHX-A″-DTPA, direct conjugation of an isothiocyanate-functionalized chelator to the amino-nitrogen of each compound of the invention is possible. For example, the linkage in this regard is a thiourea bond.

[0307] Functional groups on chelators that are ideal precursors for direct conjugation of the chelator to an amino-nitrogen are known to those skilled in the art and include, but are not limited to, carboxylic acids, activated carboxylic acids, active esters such as NHS-esters, pentafluorophenol-esters, HOBt-esters and HOAt-esters, and isothiocyanates.

[0308] Those skilled in the art will recognize that the radionuclide which is or is attached to the compound of the invention will be selected having regard to the characteristics of each disease to be treated and / or diagnosed and / or each patient and patient group to be treated and each patient and patient group to be diagnosed.

[0309] In the present invention, radionuclides are also referred to as radionuclides. Radioactive decay is a process in which the nuclei of unstable atoms lose energy by emitting ionizing particles (ionizing radiation). There are various types of radioactive decay. Decay or energy loss occurs when an atom with one type of nucleus, called a parent radionuclide, transforms into an atom with a nucleus in a different state or into a different nucleus containing a different number of protons and neutrons. Both of these products are called daughter nuclei. In some decays, the parent and daughter are different chemical elements, and thus the decay process results in nuclear transmutation (the creation of atoms of new elements). For example, radioactive decay can be alpha decay, beta decay, or gamma decay. Alpha decay occurs when a nucleus emits an alpha particle (helium nucleus). This is the most common process of emitting nucleons, but in rarer types of decay, the nucleus may emit protons or specific nuclei of other elements (a process called cluster decay). Beta decay occurs when an atomic nucleus loses electrons (β - -decay) or positron (β +-decay) and release of certain neutrinos. In contrast, there are radioactive decay processes that do not result in nuclear transmutation. The energy of an excited nucleus can be released as gamma rays in gamma decay, or can be used to eject an orbital electron by interaction with the excited nucleus in a process called internal conversion, or can be used to absorb an intraatomic electron from an electron shell, thereby changing the nucleus from a proton to a neutron, resulting in the emission of an electron neutrino, in a process called electron capture (EC), or can be emitted without changing the number of protons and neutrons, in a process called isomerization (IT). Another form of radioactive decay, spontaneous fission (SF), is found only in very heavy chemical elements, which spontaneously break down into smaller nuclei and a few isolated nuclear particles.

[0310] In one embodiment, described herein are compounds containing radionuclides. Generally, the type of radionuclide used in therapeutic radiopharmaceuticals can be tailored to the specific type of cancer and the type of targeting moiety. Radionuclides that undergo alpha decay produce particles consisting of two neutrons and two protons, while radionuclides that undergo beta decay release high-energy electrons from their nuclei. Some radionuclides may also emit Auger electrons. In some embodiments, the conjugate comprises a radionuclide that emits alpha particles. Alpha radiation can cause direct, irreparable double-stranded DNA breaks, compared to gamma and beta radiation, which can cause single-strand breaks through indirect DNA damage. The range of these particles in tissues and the half-life of the radionuclide may also be considered when designing a radiopharmaceutical conjugate.

[0311] Alpha-emitter radionuclides are capable of destroying tumors due to the short penetration depth of their alpha particles, while causing very limited damage to surrounding normal tissue. Their high linear energy transfer (LET) results in a relatively high biological effectiveness (RBE) compared to other radionuclide therapies. Furthermore, targeting alpha-emitting radionuclides to specific tumor cells in the body can be highly effective in destroying metastatic lesions that are difficult to treat with currently available technologies (de Kruijff et al, 2015 Pharmaceuticals, 8, 321-336).

[0312] In one embodiment of the present invention, radionuclides may be used to label the compounds of the present invention.

[0313] In one embodiment of the present invention, the radionuclide is suitable for complexation with a chelating agent to form a radionuclide chelate complex.

[0314] In further embodiments, one or more atoms of the compounds of the invention are of non-natural isotopic composition, e.g., they are radionuclides, e.g., radionuclides of carbon, oxygen, nitrogen, sulfur, phosphorus, and halogens. These radioactive atoms are typically part of the amino acids, optionally halogen-containing amino acids and / or building blocks, optionally halogenated building blocks, respectively, of the compounds of the invention.

[0315] In one embodiment of the invention, the radionuclide has a half-life that allows for diagnostic and / or therapeutic medical use, particularly a half-life of between 1 minute and 100 days.

[0316] In one embodiment of the present invention, the radionuclide has a decay energy that allows for diagnostic and / or therapeutic medical use. Specifically, for gamma-emitting isotopes, the decay energy is 0.004 to 10 MeV, e.g., 0.05 to 4 MeV, for diagnostic use. For positron-emitting isotopes, the decay energy is 0.6 to 13.2 MeV, e.g., 1 to 6 MeV, for diagnostic use. For particle-emitting isotopes, the decay energy is 0.039 to 10 MeV, e.g., 0.4 to 6.5 MeV, for therapeutic use.

[0317] In one embodiment of the invention, the radionuclide is industrially produced for medical use, specifically the radionuclide is available in GMP quality.

[0318] In one embodiment of the present invention, the daughter nuclide after radioactive decay of the radionuclide is suitable for diagnostic and / or therapeutic medical use. Furthermore, the daughter nuclide is stable or further decays in a manner that does not interfere with or may even support diagnostic and / or therapeutic medical use. Exemplary radionuclides that can be used in connection with the present invention are well known to those skilled in the art and include, but are not limited to: 11 C. 13 N, 18 F, 24 Na, 28 Mg, 31 Si, 32 P, 33 P, 38 S, 34m Cl, 38 Cl, 39 Cl, 37 Ar, 41 Ar, 44 Ar, 42 K. 43 K. 44 K. 45 K. 47 Ca, 43 Sc, 44 Sc, 44m Sc, 47 Sc, 48 Sc, 49 Sc, 45 Ti, 47 V, 48 V, 48Cr、 49 Cr、 51 Cr、 51 Mn 52 Mn 52m Mn 56 Mn 52 Fe 59 Fe 55 Co. 61 Co. 62m Co. 56 Ni 57 Ni 65 Ni 66 Ni 60 Cu、 61 Cu、 64 Cu、 67 Cu、 62 Zn、 63 Zn、 69 Zn、 69m Zn、 71m Zn、 72 Zn、 65 Ga 66 Ga 67 Ga 68 Ga 70 Ga 72 Ga 73 Ga 66 Ge 67 Ge 69 Ge 71 Ge 75 Ge 77 Ge 78 Ge 69 As 70 As 71 As 72 As 74 As 76 As 77 As 78 As 70 See 72 See 73 See 73m See 81 See 81m See 83 See 74 Bro 74m Bro 75 Bro 76 Bro 77 Bro 80 Bro 80m Bro 82 Bro83 Br、 84 Br、 74 Kr、 76 Kr、 77 Kr、 79 Kr、 85 Kr、 87 Kr、 88 Kr、 78 Rb、 79 Rb、 81 Rb、 82 Rb、 84 Rb、 84m Rb、 86 Rb、 88 Rb、 89 Rb、 80 Sr、 81 Sr、 82 Sr、 83 Sr、 85m Sr、 87 Sr、 91 Sr、 92 Sr、 84 Y、 85 Y、 85m Y、 86 Y、 86m Y、 87 Y、 87m Y、 90 Y、 90m Y、 91m Y、 92 Y、 93 Y、 94 Y、 95 Y、 86 Zr、 87 Zr、 89 Zr、 97 Zr、 88 Nb、 89 Nb、 89m Nb、 90 Nb、 92 Nb、 95 Nb、 95m Nb、 96 Nb、 97 Nb、 98m Nb、 101 Mo、 102 Mo、 90 Mo、 91M o、 93m Mo、 99 Mo、 101 Tc、 104 Tc、 93 Tc、93m Tc、 94 Tc、 94m Tc、 95 Tc、 96 Tc、 99m Tc、 103 Ru、 105 Ru、 94 Ru、 95 Ru、 97 Ru、 100 Rh、 101m Rh、 105 Rh、 106m Rh、 107 Rh、 97 Rh、 97m Rh、 99 Rh、 99m Rh、 100 Pd、 101 Pd、 103 Pd、 109 Pd、 111 Pd、 111m Pd、 112 Pd、 98 Pd、 99 Pd、 101 Ag、 103 Ag、 104 Ag、 104m Ag、 105 Ag、 106 Ag、 106m Ag、 111 Ag、 112 Ag、 113 Ag、 115 Ag、 104 Cd、 105 Cd、 107 Cd、 111 Cd、 115 Cd、 115m Cd、 117 Cd、 117m Cd、 118 Cd、 107 In、 108m In、 109 In、 110 In、 110m In、 111 In、 112 In、 113 In、 114m In、 115m In、 116m In、 117 In、 117m In、 119mIn, 108 Sn、 109 Sn、 110 Sn、 111 Sn、 117 Sn、 121 Sn、 123m Sn、 125 Sn、 127 Sn、 128 Sn、 115 Saturday, 116 Saturday, 116m Saturday, 117 Saturday, 118m Saturday, 119 Saturday, 120 Saturday, 120m Saturday, 122 Saturday, 126 Saturday, 126m Saturday, 127 Saturday, 128 Saturday, 128m Saturday, 129 Saturday, 129m Saturday, 130 Saturday, 131 Saturday, 114 Here, 116 Here, 117 Here, 118 Here, 119 Here, 119m Here, 121 Here, 127 Here, 129 Here, 129m Here, 131 Here, 131m Here, 132 Here, 133 Here, 133m Here, 134 Here, 118 I, 119 I, 120 I, 120m I, 121 I, 123 I, 124 I, 126 I, 128 I, 130 I, 131 I, 132 I, 132m I, 133 I, 134 I, 135 I, 120 Xe, 121 Xe, 122 Xe,123 Xe、 125 Xe、 127 Xe、 133 Xe、 133m Xe、 135 Xe、 135m Xe、 138 Xe、 125 Cs, 127 Cs, 129 Cs, 130 Cs, 131 Cs, 132 Cs, 134 Cs, 135 Cs, 136 Cs, 138 Cs, 124 Well, 126 Well, 127 Well, 128 Well, 129 Well, 129m Well, 131 Well, 131m Well, 133 Well, 135 Well, 139 Well, 140 Well, 141 Well, 142 Well, 129 At, 131 At, 132 At, 133 At, 135 At, 140 At, 141 At, 142 At, 143 At, 130 What, 132 What, 133 What, 133m What, 134 What, 135 What, 137 What, 137m What, 141 What, 143 What, 146 What, 134 Mr. 134m Mr. 136 Mr. 137 Mr. 138m Mr. 139 Mr. 142 Mr. 143 Mr. 144 Mr. 145 Mr. 146Pr 147 Pr 135 Nd、 136 Nd、 137 Nd、 138 Nd、 139 Nd、 139m Nd、 140 Nd、 141 Nd、 147 Nd、 149 Nd、 151 Nd、 152 Nd、 141 PM 148 PM 148m PM 149 PM 150 PM 151 PM 140 Sm、 141 Sm、 141m Sm、 142 Sm、 153 Sm、 155 Sm、 156 Sm、 145 I, 146 I, 147 I, 150 I, 152m I, 154 I, 156 I, 157 I, 158 I, 159 I, 145 Gd、 146 Gd、 147 Gd、 149 Gd、 159 Gd、 147 Also, 148 Also, 149 Also, 150 Also, 151 Also, 152 Also, 153 Also, 154 Also, 154m Also, 155 Also, 156 Also, 156m Also, 161 Also, 163 Also, 151 Dy、 152 Dy、 153 Dy、 155 Dy、 157 Dy、 165 Dy、 166 Dy、154 Hey, 155 Hey, 156 Hey, 157 Hey, 158m Hey, 159 Hey, 161 Hey, 162 Hey, 162m Hey, 164 Hey, 164m Hey, 166 Hey, 167 Hey, 156 Is, 157 Is, 158 Is, 159 Is, 160 Is, 161 Is, 163 Is, 165 Is, 169 Is, 171 Is, 172 Is, 161 Tm, 162 Tm, 163 Tm, 165 Tm, 166 Tm, 167 Tm, 172 Tm, 173 Tm, 175 Tm, 162 Yb、 163 Yb、 164 Yb、 166 Yb、 167 Yb、 169 Yb、 175 Yb、 177 Yb、 178 Yb、 167 Lu, 169 Lu, 170 Hello, 171 Lu, 172 Lu, 176m Lu, 177 Lu, 178 Lu, 178m Lu, 179 Lu, 168 Hf、 170 Hf、 173 Hf、 177m Hf、 179m Hf、 180m Hf、 181 Hf、 182m Hf、 183 Hf、184 Hf, 172 Yes, 173 Yes, 174 Yes, 175 Yes, 176 Yes, 177 Yes, 178 Yes, 180 Yes, 182m Yes, 183 Yes, 184 Yes, 185 Yes, 186 Yes, 174 W、 175 W、 177 W、 178 W、 179 W、 187 W、 190 W、 177 Yes, 178 Yes, 179 Yes, 181 Yes, 182 Yes, 182m Yes, 184 Yes, 186 Yes, 188 Yes, 188m Yes, 189 Yes, 190m Yes, 180 If, 181 If, 182 If, 183 If, 183m If, 191 If, 193 If, 196 If, 182 Yes, 183 Yes, 184 Yes, 185 Yes, 186 Yes, 186m Yes, 187 Yes, 188 Yes, 189 Yes, 190 Yes, 194 Yes, 195 Yes, 195m Yes, 196m Yes, 184 Pt. 186 Pt. 187 Pt. 188 Pt. 189 Pt. 191 Pt. 195 Pt. 197 Pt.197m Pt. 199 Pt. 200 Pt. 202 Pt. 186 I 190 I 191 I 192 I 193 I 194 I 196 I 196m I 198 I 198m I 199 I 200 I 200m I 190 Hg、 191 Hg、 192 Hg、 193 Hg、 195 Hg、 195m Hg、 197 Hg、 197m Hg、 199 Hg、 203 Hg、 194 Tl 194m Tl 195 Tl 196 Tl 196m Tl 197 Tl 198 Tl 198m Tl 199 Tl 200 Tl 201 Tl 202 Tl 194 Pb、 195 Pb、 196 Pb、 197m Pb、 198 Pb、 199 Pb、 199m Pb、 200 Pb、 201 Pb、 202m Pb、 203 Pb、 204 Pb、 209 Pb、 211 Pb、 212 Pb、 214 Pb、 200 Hello 200m Hello 201 Hello 202 Hello 203 Hello 204 Hello 205 Hello 206Bi、 210 Bi、 212 Bi、 212m Bi、 213 Bi、 214 Bi、 200 Month, 201 Month, 202 Month, 203 Month, 204 Month, 205 Month, 206 Month, 207 Month, 205 And、 206 And、 207 And、 208 And、 209 And、 210 And、 211 And、 208 Rn、 209 Rn、 210 Rn、 211 Rn、 212 Rn、 221 Rn、 222 Rn、 223 Rn、 212 Fr、 222 Fr、 223 Fr、 223 Tender, 224 Tender, 225 Tender, 227 Tender, 230 Tender, 224 Ac、 225 Ac、 226 Ac、 228 Ac、 229 Ac、 226 Th、 227 Th、 231 Th、 233 Th、 234 Th、 236 Th、 227 Pa、 228 Pa、 229 Pa、 230 Pa、 232 Pa、 233 Pa、 234 Pa、 235 Pa、 229 U、 230 U、 231 U、 237 U、 239 U、 240 U、 242 U、 231Np, 232 Np, 233 Np, 234 Np, 236m Np, 238 Np, 239 Np, 240 Np, 241 Np, 232 Pu, 235 Pu, 237 Pu, 243 Pu, 245 Pu, 246 Pu, 235 Am, 237 Am, 238 Am, 239 Am, 240 Am, 242 Am, 244 Am, 244m Am, 245 Am, 246 Am, 246m Am, 247 Am, 239 Cm, 240 Cm, 241 Cm, 251 Cm, 245 Bk, 246 Bk, 248 Bk, 250 Bk, 251 Bk, 244 Cf, 245 Cf, 246 Cf, 247 Cf, 253 Cf, 255 Cf, 249 Es, 250 Es, 250m Es, 251 Es, 253 Es, 254m Es, 255 Es, 256m Es, 250 Fm, 251 Fm, 252 Fm, 254 Fm, 255 Fm, 255 Md, 256 Md, 257 Md, 259 No. Their properties are described in detail, for example, in Nuclear Data Sheets (Elsevier, Amsterdam, NL).

[0319] In one embodiment of the invention, the radionuclide is used in diagnosis. In some embodiments, the radioisotope is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 177 Lu, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I and 125 In some embodiments, the radionuclide is selected from the group including, but not limited to, 18 F, 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb and 203 Pb. In some embodiments, the radionuclide is selected from: 18 F, 64 Cu, 68 Ga and 111 In one embodiment of the invention the radionuclide is selected from: 18 F, which means 18 F forms a covalent bond with aluminum, which then complexes with the chelating agent. 18Methods and compositions for F labeling are disclosed, for example, in WO 2012 / 082618. However, those skilled in the art will recognize that the use of such radionuclides is not limited to diagnostic purposes, but also encompasses uses in therapy and theranostics when conjugated to the compounds of the invention.

[0320] In one embodiment of the invention, radionuclides are used in therapy. In some embodiments, the radioisotope is 47 Sc, 67 Cu, 89 Sr, 90 Y, 111 In, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 226 Th, 227 Th, 131 I and 211 In some embodiments, the radioisotope is selected from: 47 Sc, 67 Cu, 90 Y, 161 Tb, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac and 227 In some embodiments, the radionuclide is selected from: 90 Y, 161 Tb, 177 Lu, 212 Pb, 225 Ac and 227 However, those skilled in the art will recognize that the use of said radionuclides is not limited to therapeutic purposes, but also encompasses uses in diagnostics and theranostics when conjugated to the compounds of the invention.

[0321] In one embodiment, the compounds of the invention are present as pharmaceutically acceptable salts.

[0322] In certain embodiments, a "pharmaceutically acceptable salt" of a compound of the present invention is an acid or base salt generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, e.g., without irritation, allergic response, or other problems or complications. Such salts include basic residues, e.g., mineral and organic acid salts of amines, and acidic residues, e.g., alkali or organic acid salts of carboxylic acids. The compounds of the present invention can form internal salts that are also pharmaceutically acceptable salts.

[0323] Suitable pharmaceutically acceptable salts include those derived from acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids such as acetic acid, HOOC-(CH) 2nExamples of pharmaceutically acceptable salts include, but are not limited to, salts of —COOH (where n is an integer from 0 to 4, i.e., 0, 1, 2, 3, or 4, etc.). Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those of ordinary skill in the art will recognize additional pharmaceutically acceptable salts of the compounds provided herein. Generally, pharmaceutically acceptable acid or base salts can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, the use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is preferred.

[0324] In certain embodiments, a "pharmaceutically acceptable solvate" of a compound of the invention is a solvate of a compound of the invention formed by associating one or more solvent molecules with one or more molecules of a compound of the invention. In some embodiments, the solvent is one that is generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, e.g., without irritation, allergic reaction, or other problems or complications. Such solvents include organic solvents, e.g., alcohols, ethers, esters, and amines.

[0325] In certain embodiments, "hydrates" of the compounds of the invention are formed by associating one or more water molecules with one or more molecules of the compounds of the invention. Such hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and tetrahydrates. Regardless of the composition of the hydrate, all hydrates are generally considered to be pharmaceutically acceptable.

[0326] The compounds of the present invention have high binding affinity to FAP and high inhibitory activity against FAP. Due to this high binding affinity, the compounds of the present invention are effective, useful and / or suitable as targeting agents, and when conjugated to another moiety, are effective as targeting moieties, and the target is FAP and / or cells and / or tissues expressing FAP. Thus, with regard to the cells and tissues targeted by the compounds of the present invention, any cells and tissues expressing FAP may be targeted or may be targeted, respectively.

[0327] In one embodiment, the compound interacts with a fibroblast activation protein (FAP), preferably a human FAP having the amino acid sequence of SEQ ID NO: 1, or a homolog thereof, wherein the amino acid sequence of the homolog has at least 85% FAP identity to the amino acid sequence of SEQ ID NO: 1. In a preferred embodiment, the identity is 90%, preferably 95%, 96%, 97%, 98% or 99%.

[0328] The identity between two nucleic acid molecules can be determined as known to those skilled in the art. More specifically, a sequence comparison algorithm can be used to calculate the percent sequence identity of a test sequence relative to a reference sequence based on designated program parameters. The test sequence is preferably a sequence or protein or polypeptide that is said to be identical or, if different, is tested for its degree of identity with a different protein or polypeptide. Such a different protein or polypeptide, also referred to as a reference sequence, is preferably a wild-type protein or polypeptide, more preferably the human FAP of SEQ ID NO: 1.

[0329] Optimal alignment of sequences for comparison can be achieved, for example, by the Smith & Waterman local homology algorithm (Smith, et al., Advances in Applied Mathematics, 1981, 2: 482), by the Needleman & Wunsch homology alignment algorithm (Needleman, et al., J Mol Biol, 1970, 48: 443), by the Pearson & Lipman similarity search method (Pearson, et al., Proc Natl Acad Sci USA, 1988, 85: 2444), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA, the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection.

[0330] An example of a suitable algorithm for determining % sequence identity is the algorithm used in the Basic Local Alignment Search Tool (hereinafter "BLAST"). See, for example, Altschul et al., 1990 (Altschul, et al., J Mol Biol, 1990, 215: 403) and Altschul et al., 1997 (Altschul, et al., Nucleic Acids Res, 1997, 25: 3389). Software for performing BLAST analysis is publicly available from the National Center for Biotechnology Information (hereinafter "NCBI"). The default parameters used to determine sequence identity using software available from NCBI, such as BLASTN (for nucleotide sequences) and BLASTP (for amino acid sequences), are described in McGinnis et al. (McGinnis, et al., Nucleic Acids Res, 2004, 32: W20).

[0331] It is within the scope of the present invention that the compounds of the present invention are used or intended for use in a method for treating the diseases disclosed herein. In certain embodiments, such a method for treating a disease disclosed herein comprises administering a therapeutically effective amount of a compound of the present invention to a subject in need of such treatment. Such a method includes, but is not limited to, curative or adjuvant cancer treatment. The method may be used as a palliative treatment where a cure is not possible, aimed at local disease control or symptomatic relief, or as a therapeutic treatment where the treatment has a survival benefit and a cure is possible.

[0332] The methods for treating diseases disclosed herein include the treatment of diseases disclosed herein, including tumors and cancers, and may be used either as a first-line treatment or as a second-, third-, fourth-, or definitive treatment. It is also within the scope of the present invention to combine the compounds of the present invention with additional therapeutic approaches. It is well known to those skilled in the art that the exact treatment intent, including intent for curative, adjuvant, neoadjuvant, therapeutic, or palliative treatment, will depend on the type, location, and stage of the tumor and the general health of the patient.

[0333] FAP expression in CAFs has been shown in almost all carcinomas and sarcomas (Pure, et al., Oncogene, 2018, 37: 4343; Busek, et al., Front Biosci (Landmark Ed), 2018, 23: 1933). In one embodiment of the present invention, the disease is selected from the group consisting of neoplasms (nos), benign neoplasms, neoplasms of uncertain benign or malignant nature, malignant neoplasms, metastatic neoplasms, malignant neoplasms of uncertain primary or metastatic nature, benign tumor cells, tumor cells of uncertain benign or malignant nature, malignant tumor cells, small cell malignant tumors, giant cell malignant tumors, spindle cell malignant tumors, epithelial neoplasms (nos), benign epithelial tumors, carcinoma in situ (nos), carcinomas (nos), metastatic carcinomas (nos), carcinomatosis, benign epithelioma, malignant epithelioma, large cell Carcinoma (nos), undifferentiated carcinoma (nos), anaplastic carcinoma (nos), pleomorphic carcinoma, giant cell and spindle cell carcinoma, giant cell carcinoma, spindle cell carcinoma, pseudosarcomatous carcinoma, polygonal cell carcinoma, round cell carcinoma, multiple small tumors, small cell carcinoma (nos), oat cell carcinoma, small cell carcinoma, spindle cell, papillary and squamous cell neoplasms, papilloma (nos), non-invasive papilloma, papillary carcinoma (nos), warty papilloma, warty carcinoma (nos), squamous cell papilloma, papillary squamous cell carcinoma , inverted papilloma, papillomatosis (nos), non-invasive squamous cell carcinoma (nos), squamous cell carcinoma (nos), metastatic squamous cell carcinoma (nos), keratinizing squamous cell carcinoma (nos), non-keratinizing large cell squamous cell carcinoma, non-keratinizing small cell squamous cell carcinoma, spindle cell squamous cell carcinoma, adenoid squamous cell carcinoma, non-invasive squamous cell carcinoma with suspicious stromal invasion, microinvasive squamous cell carcinoma, Queyrat's erythroplasia, Bowen's disease, lymphoepithelial carcinoma, basal cell carcinoma basal cell neoplasm, basal cell tumor, basal cell carcinoma (nos), multicentric basal cell carcinoma, morphea basal cell carcinoma, fibroepithelial basal cell carcinoma, basal squamous cell carcinoma, metamorphic carcinoma, Jadassohn intraepithelioma, trichoepithelioma, trichofolliculoma, trichilemmomas, trichilemmomas, transitional cell papilloma and carcinoma, transitional cell papilloma (nos), urothelial papilloma, non-invasive transitional cell carcinoma, transitional cell carcinoma (nos), Schneiderian papilloma, inverted transitional cell papilloma, Schneiderian carcinoma, spindle cell transitional cell carcinoma,Basal cell carcinoma, cloacogenic carcinoma, papillary transitional cell carcinoma, adenoma and adenocarcinoma, adenoma (nos), bronchial adenoma (nos), non-invasive adenocarcinoma, adenocarcinoma (nos), metastatic adenocarcinoma (nos), scirrhous adenocarcinoma, plastic gastritis, superficial spreading adenocarcinoma, intestinal adenocarcinoma, diffuse carcinoma, monomorphic adenoma, basal cell adenoma, islet cell adenoma, islet cell carcinoma, insulinoma (nos), malignant insulinoma, glucagonoma (nos), malignant glucagonoma, gastrinoma (nos), malignant gastrinoma, mixed islet cell and exocrine adenocarcinoma tumor, bile duct adenoma, bile duct carcinoma, bile duct cystadenoma, bile duct cystadenocarcinoma, hepatocellular adenoma, hepatocellular carcinoma (nos), benign hepatic and bile duct cancer, combined hepatocellular carcinoma and bile duct carcinoma, cavernous adenoma, cavernous adenocarcinoma, embryonal adenoma, eccrine dermal cylindroma, adenoid cystic carcinoma, cribriform carcinoma, adenomatous polyp (nos), adenocarcinoma within adenomatous polyps, tubular adenoma (nos), tubular adenocarcinoma, colorectal adenomatous polyp, adenocarcinoma within adenomatous polyps, multiple adenomatous polyps, solid carcinoma (nos), simple carcinoma, carcinoid tumor (nos), malignant carcinoid tumor, carcinoid tumor argenteus argentafine (nos), malignant carcinoid tumor argentafine, carcinoid tumor non-argentafine (nos), malignant carcinoid tumor non-argentafine, malignant mucocarcinoid tumor, composite carcinoid, pulmonary adenomatosis, bronchoalveolar adenocarcinoma, alveolar adenoma, alveolar adenocarcinoma, papillary adenoma (nos), papillary adenocarcinoma (nos), villous adenoma (nos), adenocarcinoma in villous adenoma, choriocarcinoma, ductal alveolar adenoma, chromoadenoma, chromocarcinoma, eosinophilic adenoma, eosinophilic carcinoma, mixed eosinophilic-basophilic adenoma, mixed eosinophilic-basophilic carcinoma, eosinophilic adenoma, eosinophilic adenocarcinoma, basophilic adenoma, basophilic Spheroid carcinoma, clear cell adenoma, clear cell adenocarcinoma (nos), hyperthyroid tumor, renal cell carcinoma, clear cell adenofibroma, granular cell carcinoma, chief cell adenoma, clear cell adenoma, clear cell adenocarcinoma, mixed cell adenoma, mixed cell adenocarcinoma, lipoadenoma, follicular adenoma, follicular adenocarcinoma (nos), well-differentiated follicular adenocarcinoma, spongiform follicular adenocarcinoma, small follicular adenoma, large follicular adenoma, papillary and follicular adenocarcinoma, non-encapsulated sclerosing carcinoma, multiple endocrine adenoma, junctional glomerular tumor, adrenocortical adenoma (nos), adrenocortical carcinoma, small cell adrenocortical adenoma, pigmented variant adrenocortical adenoma, clear cell adrenocortical adenoma,Glomerular cell adrenocortical adenoma, mixed cell adrenocortical adenoma, endometrial adenoma (nos), borderline endometrial adenoma, endometrial carcinoma, endometrial adenofibroma (nos), borderline endometrial adenofibroma, malignant endometrial adenofibroma, adnexal and skin adnexal neoplasms, skin adnexal adenoma, skin adnexal carcinoma, sweat gland adenoma, sweat gland tumor (nos), sweat gland adenocarcinoma, apocrine adenoma, apocrine adenocarcinoma, eccrine acrohidradenoma, eccrine hidradenoma, hydrocele, hydrocele of nipple, hidradenoma of nipple, hidradenoma (nos), lipid adenoma, lipid adenocarcinoma, cerumen adenoma, cerumen adenocarcinoma, mucoepidermoid neoplasm, mucoepidermoid tumor , mucoepidermoid carcinoma, cystic, mucinous and serous neoplasms, cystadenoma (nos), cystadenocarcinoma (nos), serous cystadenoma (nos), borderline-grade serous cystadenoma, serous cystadenocarcinoma (nos), papillary cystadenoma (nos), borderline-grade papillary cystadenoma, papillary cystadenocarcinoma (nos), papillary serous cystadenoma (nos), borderline-grade papillary serous cystadenoma, papillary serous cystadenocarcinoma, serous surface papilloma (nos), borderline-grade serous surface papilloma, serous surface papillary carcinoma, mucinous cystadenoma (nos), borderline-grade mucinous cystadenoma, mucinous cystadenoma ( nos), papillary mucinous cystadenoma (nos), borderline papillary mucinous cystadenoma, papillary mucinous cystadenocarcinoma, mucinous adenoma, mucinous adenocarcinoma, membranous pseudomyxoma, mucin-producing adenocarcinoma, signet ring cell carcinoma, metastatic signet ring cell carcinoma, tubular, lobular and medullary neoplasms, intraductal carcinoma in situ (nos), invasive ductal carcinoma, synovial carcinoma in situ, synovial carcinoma (nos), juvenile breast carcinoma, intraductal papilloma, intraductal papillary adenocarcinoma in situ, intracystic papillary adenoma, intracystic carcinoma in situ, intraductal papillomatosis (nos), subductal papillomatosis, medullary carcinoma (nos), medullary carcinoma with amyloid stroma , medullary carcinoma with lymphoid stroma, lobular carcinoma in situ, lobular carcinoma (nos), invasive ductal carcinoma, inflammatory carcinoma, Paget's disease of the breast, Paget's disease and invasive ductal carcinoma of the breast, extramammary Paget's disease, acinic cell neoplasm, acinic cell adenoma, acinic cell tumor, acinic cell carcinoma, mixed epithelial neoplasm, adenosquamous carcinoma, adenolymphoma, adenocarcinoma with squamous metaplasia, adenocarcinoma with cartilage and bone metaplasia, adenocarcinoma with spindle cell metaplasia, adenocarcinoma with apocrine metaplasia, benign thymoma, malignant thymoma, specialized gonadal neoplasms, sex cord-stromal tumor, theca cell tumor (nos), theca cell carcinoma,Luteoma (nos), granulosa cell tumor (nos), malignant granulosa cell tumor, granulosa cell-theca cell tumor, benign androblastoma, androblastoma (nos), malignant androblastoma, Sertoli-Leydig cell tumor, male germinoma, tubular androblastoma (nos), Sertoli cell carcinoma, tubular androblastoma with lipid storage, benign Leydig cell tumor, Leydig cell tumor (nos), malignant Leydig cell tumor, hilar cell tumor, lipid cell tumor of the ovary, para-adrenal tumor, paraganglioma and glomus tumor, paraganglioma (nos), malignant para Ganglioneuroma, sympathetic paraganglioma, parasympathetic paraganglioma, glomus jugular tumor, aortic body tumor, carotid body tumor, extra-adrenal paraganglioma (nos), malignant extra-adrenal paraganglioma, pheochromocytoma (nos), malignant pheochromocytoma, hemangiosarcoma, glomus tumor, hemangiocytoma, nevus and melanoma, pigmented nevus (nos), malignant melanoma (nos), nodular melanoma, balloon cell nevus, balloon cell melanoma, halo nevus, nasal fibrous papules, nerve nevus, large cell nevus, non-pigmented nevus, amelanotic melanoma, junctional nevus, malignant melanoma in junctional nevus, precancerous melanosis (nos) ), malignant melanoma in precancerous melanosis, Hutchinson's melanoma, malignant melanoma in Hutchinson's melanoma, superficial spreading melanoma, intracutaneous nevi, compound nevi, giant pigmented nevi, malignant melanoma in giant pigmented nevi, epithelioid and spindle cell nevi, epithelioid cell melanoma, spindle cell melanoma (nos), type a spindle cell melanoma, type b spindle cell melanoma, mixed epithelioid and spindle cell melanoma, blue nevi (nos), malignant blue nevi, cellular blue nevi, soft tissue tumors and sarcomas (nos), benign soft tissue tumors, sarcomas (nos), sarcomatosis (n) os), spindle cell sarcoma, giant cell sarcoma, small cell sarcoma, epithelioid cell sarcoma, fibromatous neoplasm, fibroma (nos), fibrosarcoma (nos), fibromyxoma, fibromyxoid sarcoma, periosteal fibroma, periosteal fibrosarcoma, fascial fibroma, fascial fibrosarcoma, childhood fibrosarcoma, elastoma, aggressive fibromatosis, abdominal fibromatosis, anaplastic fibroma, fibrous histiocytoma (nos), atypical fibrous histiocytoma, malignant fibrous histiocytoma, fibroxanthoma (nos), atypical fibroxanthoma, malignant fibroxanthoma, dermatofibroma (nos), nodular dermatofibroma (nos), dermatofibrosarcoma (nos), myxomatous neoplasm, myxoma (nos),Myxosarcoma, lipomatous neoplasm, lipoma (nos), liposarcoma (nos), fibrolipoma, well-differentiated liposarcoma, fibromyxoid liposarcoma, myxoid liposarcoma, round cell liposarcoma, pleomorphic liposarcoma, mixed liposarcoma, intramuscular lipoma, spindle cell lipoma, angiomyolipoma, angiomyoliposarcoma, angiolipoma (nos), infiltrating angiolipoma, myelolipoma, hybernoma, lipoblastomatosis, leiomyomatous neoplasm, leiomyoma (nos), intravascular leiomyomatosis, leiomyosarcoma (nos), epithelioid leiomyoma, epithelioid leiomyosarcoma, cellular leiomyoma, paradoxical leiomyoma, angiomyoma, angiomyosarcoma, fibroid, muscle Sarcoma, rhabdomyoma (nos), rhabdomyosarcoma (nos), pleomorphic rhabdomyosarcoma, mixed rhabdomyosarcoma, embryonal rhabdomyosarcoma, adult rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, composite stromal neoplasm, endometrial stromal sarcoma, endolymphatic stromal myosis, adenomyoma, pleomorphic adenoma, mixed malignant tumor (nos), mixed müllerian tumor, mesodermal mixed tumor, mesodermal nephroblastoma, nephroblastoma (nos), epithelial nephroblastoma, mesenchymal nephroblastoma, hepatoblastoma, carcinosarcoma (nos), embryonic carcinosarcoma, myoepithelioma, benign mesenchymoma, mesenchymoma (nos), malignant mesenchymoma, embryonic sarcoma, fibroepithelial neoplasm, Brenner's tumor tumor (nos), borderline Brenner tumor, malignant Brenner tumor, fibroadenoma (nos), intratubular fibroadenoma (nos), peritubular fibroadenoma, adenofibroma (nos), serous adenofibroma, myxoid adenofibroma, cellular intratubular fibroadenoma, cystosarcoma phyllodes (nos), malignant cystosarcoma phyllodes, juvenile fibroadenoma, synovial neoplasm, benign synovium, synovial sarcoma (nos), spindle cell synovial sarcoma, epithelioid cell synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma of tendons and aponeuroses, mesothelial neoplasm, benign mesothelioma, malignant mesothelioma, benign fibrous mesothelioma, malignant fibrous mesothelioma, benign epithelioid mesothelioma, malignant epithelioid mesothelioma mesothelioma, benign biphasic mesothelioma, malignant biphasic mesothelioma, adenomatous tumor (nos), germ cell neoplasm, dysgerminoma, seminoma (nos), anaplastic seminoma, spermatocytic seminoma, germinoma, germ cell carcinoma (nos), endodermal sinus tumor, polyblastoma, gonadoblastoma, benign teratoma, teratoma (nos), malignant teratoma (nos), teratocarcinoma, undifferentiated malignant teratoma, intermediate malignant teratoma, dermoid cyst, dermoid cyst with malignant transformation, ovarian goiter (nos), malignant ovarian goiter, thyroid carcinoid, chorioneoplasm, hydatidiform mole (nos), invasive hydatidiform mole, choriocarcinoma, Choriocarcinoma with teratoma, malignant choriocarcinoma, mesonephroma, benign mesonephroma, mesonephric tumor, malignant mesonephroma, endosalpingioma, vascular tumor, hemangioma (nos), angiosarcoma, cavernous hemangioma, venous hemangioma, vine hemangioma, Kupffer cell sarcoma, benign hemangioendothelioma, hemangioendothelioma (nos), malignant hemangioendothelioma, capillary hemangioma, intramuscular hemangioma, Kaposi's sarcoma, angiokeratoma, verrucous hemangiomatosis, benign hemangiopericytoma, hemangiopericytoma (nos), malignant hemangiopericytoma, angiofibroma (nos), hemangioblastoma, lymphatic tumor, lymphangioma (nos), lymphangiosarcoma, capillary lymphangioma, cavernous lymphangioma, cyst lymphangioma, lymphangioleiomyoma, lymphangioleiomyomatosis, hemolymphangioma, osteoma and osteosarcoma, osteoma (nos), osteosarcoma (nos), chondroblastic osteosarcoma, fibroblastic osteosarcoma, peripheral telangiectatic osteosarcoma, osteosarcoma in Paget's disease of bone, parosteal sarcoma, osteoid osteoma (nos), osteoblastoma, chondromatous neoplasm, osteochondroma, osteochondromatosis (nos), chondroma (nos), chondromatosis (nos), chondrosarcoma (nos), parosteal chondroma, parosteal chondrosarcoma, chondroblastoma (nos), malignant chondroblastoma, mesenchymal chondrosarcoma, chondroid fibroma, giant cell tumor, giant cell tumor of bone (nos), malignant giant cell tumor of bone, soft tissue Giant cell tumor (nos), malignant giant cell tumor of soft tissue, various bone tumors, Ewing's sarcoma, long bone adamantinoma, ossifying fibroma, odontogenic tumor, benign odontogenic tumor, odontogenic tumor (nos), malignant odontogenic tumor, dentinoma, cementoma (nos), benign cementoblastoma, cementifying fibroma, giant cementoma, odontoma (nos), composite odontoma, composite odontoma, enamel fibroodontoma, amelocytic odontosarcoma, adenomatous odontogenic tumor, calcifying odontogenic cyst, ameloblastoma (nos), malignant ameloblastoma, odontoid ameloblastoma, squamous odontogenic tumor, tooth Odontogenic myxoma, odontogenic fibroma (nos), ameloblastic fibroma, ameloblastic fibrosarcoma, calcifying epithelial odontogenic tumor, various tumors, craniopharyngioma, pinealoma, pineocytoma, pineoblastoma, melanotic neuroectodermal tumor, chordoma, glioma, malignant glioma, gliomatosis cerebri, mixed glioma, subependymal glioma, subependymal giant cell astrocytoma, choroid plexus papilloma (nos), malignant choroid plexus papilloma, ependymoma (nos), anaplastic ependymoma, papillary ependymoma, myxopapillary ependymoma, astrocytoma (nos), anaplastic astrocytoma, protoplasmic astrocytoma, large round cell astrocytoma, fibrillary astrocytoma,Pilocytic astrocytoma, spongioblastoma (nos), multiform spongioblastoma, astroblastoma, glioblastoma (nos), giant cell glioblastoma, glioblastoma with sarcomatous component, primitive unipolar spongioblastoma, oligodendroglioma (nos), anaplastic oligodendroglioma, oligodendroglioma, medulloblastoma (nos), anaplastic medulloblastoma, medullomyoblastoma, cerebellar sarcoma (nos), unicellular sarcoma, neuroepithelioma neoplasm, ganglioneuroma, ganglioneuroblastoma, ganglioneuromatosis, neuroblastoma (nos), medulloepithelioma (nos), teratomatous medulloepithelioma, neuroepithelioma (nos), cavernous neuroblastoma, ganglioneuroma, neurocytoma, Pacinian tumor, omentum Membranoblastoma (nos), differentiated retinoblastoma, undifferentiated retinoblastoma, olfactory neurogenic tumor, sensory neurocytoma, sensory neuroblastoma, sensory neuroepithelioma, meningioma, meningioma (nos), meningiomatosis (nos), malignant meningioma, meningothelial meningioma, fibrous meningioma, psammomatous meningioma, angiomatous meningioma, hemangioblastomatous meningioma, hemangiopericytic meningioma, transitional meningioma, papillary meningioma, meningeal sarcomatosis, nerve sheath tumor, neurofibroma (nos), neurofibromatosis (nos), neurofibrosarcoma, melanotic neurofibroma, plexiform neurofibroma, schwannoma (nos), schwannomatosis, malignant schwannoma, neuroma (nos), granular cell tumor, and Alveolar soft part sarcoma, granular cell tumor (nos), malignant granular cell tumor, alveolar soft part sarcoma, lymphoma (nos or diffuse), benign lymphomatous tumor, malignant lymphoma (nos), non-Hodgkin's malignant lymphoma, anaplastic cell malignant lymphoma (nos), stem cell malignant lymphoma, squamous cell malignant lymphoma (nos), lymphosarcoma (nos), lymphoplasmacytic malignant lymphoma, immunoblastic malignant lymphoma, mixed lymphocytic-histiocytic malignant lymphoma (nos), centroblastic-centrocytic diffuse malignant lymphoma, follicular-centrocytic malignant lymphoma (nos), lymphocytic well-differentiated malignant lymphoma lymphosarcoma (nos), lymphocytic intermediate differentiation malignant lymphoma (nos), centrocytic malignant lymphoma, incisional follicular center cell malignant lymphoma (nos), lymphocytic poorly differentiated malignant lymphoma (nos), prolymphocytic lymphosarcoma, centroblastic malignant lymphoma (nos), non-incisional follicular center cell malignant lymphoma (nos), reticulum cell sarcoma, reticulum cell sarcoma (nos), pleomorphic reticulum cell sarcoma, nodular reticulum cell sarcoma, Hodgkin's disease, Hodgkin's disease (nos), lymphocyte predominant Hodgkin's disease, mixed cell Hodgkin's disease, Hodgkin's disease lymphopenia (nos), Hodgkin's disease lymphopenic diffuse fibrosis,Reticulated Hodgkin's disease lymphocytopenia, Hodgkin's disease nodular sclerosis (NOS), Hodgkin's disease nodular sclerosis cellular phase, Hodgkin's granuloma, Hodgkin's granuloma, Hodgkin's sarcoma, nodular or follicular lymphoma, nodular malignant lymphoma (NOS), mixed lymphocytic-histiocytic nodular malignant lymphoma, centroblastic-centrocytic follicular malignant lymphoma, lymphocytic well-differentiated nodular malignant lymphoma, lymphocytic intermediately differentiated nodular malignant lymphoma, incisional follicular follicular malignant lymphoma, lymphocytic poorly differentiated nodular malignant lymphoma, centroblastic follicular malignant lymphoma, non-incisional follicular follicular malignant lymphoma, mycosis fungoides, fungus Symptoms include: mycoses fungoides, Sézary's disease, various reticuloendothelial neoplasms, microglioma, malignant histiocytosis, histiocytic medullary reticulosis, Letterer-Siwe disease, plasma cell neoplasms, plasma cell myeloma, benign plasma cell neoplasms, plasmacytoma (nos), malignant plasma cell neoplasms, mast cell tumors, mast cell tumors (nos), mast cell sarcoma, malignant mastocytosis, Burkitt's tumor, leukemia, leukemia (nos), leukemia (nos), acute leukemia (nos), subacute leukemia (nos), chronic leukemia (nos), non-leukemia (nos), combined leukemia, combined leukemia, leukemia Lymphoid leukemia, lymphoid leukemia (NOS), acute lymphocytic leukemia, subacute lymphocytic leukemia, chronic lymphocytic leukemia, aleukemic lymphocytic leukemia, prolymphocytic leukemia, plasma cell leukemia, plasma cell leukemia, erythroleukemia, erythroleukemia, acute erythrocyte leukemia, chronic erythrocyte leukemia, lymphosarcoma cell leukemia, lymphosarcoma cell leukemia, myeloid leukemia, myeloid leukemia (NOS), acute myeloid leukemia, subacute myeloid leukemia, chronic myeloid leukemia, aleukemic myeloid leukemia, neutrophilic leukemia, acute promyelocytic leukemia, basophilic leukemia leukemia, basophilic leukemia, eosinophilic leukemia, eosinophilic leukemia, monocytic leukemia, monocytic leukemia (nos), acute monocytic leukemia, subacute monocytic leukemia, chronic monocytic leukemia, aleukemic monocytic leukemia, various leukemias, mast cell leukemia, megakaryocytic leukemia, megakaryocytic myelopathy, myeloid sarcoma, hairy cell leukemia, various myeloproliferative and lymphoproliferative disorders, polycythemia vera, acute panmyelosis, chronic myeloproliferative disorder, myelosclerosis with myelodysplasia, idiopathic thrombocythemia, chronic lymphoproliferative disorder,

[0334] In one embodiment of the invention, the disease is selected from the group consisting of tumors of the pancreas, pancreatic adenocarcinoma, tumors of the head of the pancreas, tumors of the body of the pancreas, tumors of the tail of the pancreas, tumors of the pancreatic duct, tumors of the islets of Langerhans, tumors of the neck of the pancreas, tumors of the prostate, prostate adenocarcinoma, prostate, neuroendocrine tumors, breast cancer, tumors of the central part of the breast, tumors of the inner upper quadrant of the breast, tumors of the inner lower quadrant of the breast, tumors of the outer upper quadrant of the breast, tumors of the outer lower quadrant of the breast, tumors of the axillary process of the breast, double lesions of the breast, juvenile carcinoma of the breast, tumors of the parathyroid gland, myeloma, lung cancer, small cell lung cancer, non-small cell lung cancer, tumors of the main bronchus, tumors of the upper lobe of the lung, Tumors of the middle lobe of the lung, tumors of the lower lobe of the lung, colon carcinoma, tumors of the ascending colon, tumors of the hepatic flexure of the colon, tumors of the transverse colon, tumors of the splenic flexure of the colon, tumors of the descending colon, tumors of the sigmoid colon, tumors of overlapping colon, tumors of the small intestine, tumors of the liver, hepatocellular adenoma, hepatocellular carcinoma, hepatocholangiomas, combined hepatocellular carcinoma and bile duct carcinoma (ombined), hepatoblastoma, ovarian carcinoma, sarcoma, osteosarcoma, fibrosarcoma, gastrointestinal stromal tumors, tumors of the gastrointestinal tract, gastric carcinoma, thyroid carcinoma, medullary thyroid carcinoma, thyroid carcinoma, renal cell carcinoma, renal pelvis carcinoma, tumors of the bladder, bladder carcinoma, tumors of the bladder trigone, tumors of the bladder dome, bladder Tumors of the lateral wall, tumors of the posterior wall of the bladder, tumors of the ureteral orifice, tumors of the urachal tract, tumors of double lesions of the bladder, basal cell carcinoma, basal cell neoplasm, basal cell tumor, basal cell carcinoma, multicentric basal cell carcinoma, basaloid carcinoma, basal cell adenoma, squamous cell carcinoma of the oral cavity, squamous cell carcinoma of the larynx, cervical carcinoma, tumors of the cervix-vaginal region, tumors of double lesions of the cervix, tumors of the uterine isthmus, tumors of the uterus, tumors of the ovary, tumors of the cervical esophagus, tumors of the thoracic esophagus, tumors of the abdominal esophagus, tumors of the upper third of the esophagus, tumors of the middle third of the esophagus, tumors of the lower third of the esophagus, tumors of the esophagus Tumors with multiple lesions, endometrial carcinoma, head and neck cancer, lymphoma, malignant mesothelioma, mesothelial neoplasm, mesothelioma, fibrous mesothelioma, fibrous mesothelioma, epithelioid mesothelioma, epithelioid mesothelioma, duodenal carcinoma, neuroendocrine tumor, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, neuroendocrine tumor of the foregut, neuroendocrine tumor of the midgut, neuroendocrine tumor of the hindgut, gastrointestinal pancreatic neuroendocrine tumor, neuroendocrine carcinoma, neuroendocrine tumor of the breast, neuroendocrine tumor of the ovary, testicular cancer, thymic carcinoma, gastric tumor, tumor of the gastric fundus, tumor of the gastric body, tumor of the gastric cardia, tumor of the pylorus, tumor of the lesser curvature of the stomach, tumor of the greater curvature of the stomach, tumors with multiple lesions in the stomach,The melanoma is selected from the group consisting of paraganglioma, ganglioneuroma, melanoma, malignant melanoma, nodular melanoma, amelanotic melanoma, superficial spreading melanoma, epithelioid melanoma, spindle cell melanoma, and mixed epithelioid and spindle cell melanoma.

[0335] In further embodiments, the aforementioned indications are lateral upper lip, lateral lower lip, lateral lip (nos), upper lip mucosa, lower lip mucosa, labial mucosa (nos), labial commissure, overlapping lesions of the lip, base of the tongue (nos), dorsal surface of the tongue (nos), tongue border, ventral surface of the tongue (nos), anterior two-thirds of the tongue (nos), lingual tonsil, overlapping lesions of the tongue, tongue (nos), upper gingiva, lower gingiva, gingiva (nos), vestibule, lateral vermis, overlapping lesions of the vermis, vermis (nos), hard palate, soft palate, Palate (nos), uvula, overlapping lesions of the palate, palate (nos), buccal mucosa, oral vestibule, retromolar area, overlapping lesions of other parts of the oral cavity and unspecified areas, oral cavity (nos), parotid gland, submandibular gland, sublingual gland, overlapping lesions of the major salivary glands, major salivary glands (nos), tonsillar fossa, tonsillar pillars, overlapping lesions of the tonsils, tonsils (nos), vallecula, anterior surface of the epiglottis, lateral wall of the oropharynx, posterior wall of the oropharynx, pharyngeal cleft, overlapping lesions of the oropharynx, oropharynx (nos), superior wall of the nasopharynx, Posterior wall of the nasopharynx, lateral wall of the nasopharynx, anterior wall of the nasopharynx, overlapping lesions of the nasopharynx, nasopharynx (nos), pyriform sinus, posterior cricoid portion, hypopharyngeal aspect of the aryepiglottic folds, posterior pharyngeal wall, overlapping lesions of the hypopharynx, hypopharynx (nos), pharynx (nos), laryngopharynx, Waldeyer's ring, overlapping lesions of the labio-oral cavity and pharynx, cervical esophagus, thoracic esophagus, abdominal esophagus, upper third of the esophagus, middle third of the esophagus, lower third of the esophagus, overlapping lesions of the esophagus, esophagus (nos), cardia (no s), fundus, body, cardia, pylorus, lesser curvature of the stomach (nos), greater curvature of the stomach (nos), duplication of the stomach, stomach (nos), duodenum, jejunum, ileum, Meckel's diverticulum, duplication of the small intestine, small intestine (nos), cecum, appendix, ascending colon, hepatic flexure of the colon, transverse colon, splenic flexure of the colon, descending colon, sigmoid colon, duplication of the colon, colon (nos), rectosigmoid junction, rectum (nos), anus (nos), anal canal, cloacogenic Zone, anorectal and anal canal overlapping lesions, liver, intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, biliary overlapping lesions, biliary tract (nos), pancreatic head, pancreatic body, pancreatic tail, pancreatic duct, islets of Langerhans, pancreatic neck, pancreatic overlapping lesions, pancreas (nos), intestinal tract (nos), digestive overlapping lesions, digestive tract (nos), nasal cavity, middle ear, maxillary sinus, ethmoid sinus, frontal sinus, sphenoid sinus, paranasal sinus overlapping lesions, paranasal sinus (nos), glottis, supraglottis, subglottis, laryngeal cartilage, laryngeal overlapping lesions, larynx (nos), trachea, main bronchi, upper lobe of lung, middle lobe of lung, lower lobe of lung, lung overlapping lesions, lung (nos), thymus, heart, anterior mediastinum, posterior mediastinum, mediastinum (nos), pleura (nos),Overlapping lesions of the heart, mediastinum and pleura, upper airway (nos), overlapping lesions of the respiratory system and intrathoracic organs, airway (nos), upper limb long bone joints, upper limb short bone joints, lower limb long bone joints, lower limb short bone joints, overlapping lesions of the bones, joints and articular cartilage of the limbs, bones of the limbs (nos), skull and facial bones, mandible, spine, ribs, sternum, clavicle, pelvic bones, overlapping lesions of the bones, joints and articular cartilage, bones (nos), blood, bone marrow, spleen, reticuloendothelial system (nos), hematopoietic system (nos), lip skin (nos), eyelids (nos), external ear, facial skin, neck and scalp, trunk skin, upper limb skin, lower limb skin, head and neck peripheral nerves, shoulder and arm peripheral nerves, leg peripheral nerves meridian, thoracic peripheral nerves, abdominal peripheral nerves, pelvic peripheral nerves, trunk peripheral nerves, overlapping lesions of peripheral nerves and autonomic nervous system, autonomic nervous system (nos), retroperitoneum, peritoneum, peritoneum (nos), overlapping lesions of retroperitoneum and peritoneum, connective tissue of head, connective tissue of arm, connective tissue of leg, connective tissue of chest, connective tissue of abdomen, connective tissue of pelvis, connective tissue of trunk (nos), overlapping lesions of subcutaneous connective tissue and other soft tissues, connective tissue (nos), nipple, central part of breast, inner upper quadrant of breast, inner lower quadrant of breast, outer upper quadrant of breast, outer lower quadrant of breast, axillary process of breast, overlapping lesions of breast, breast (nos), vulva Lips, labia minora, clitoris, overlapping lesions of the vulva, vulva (nos), vagina (nos), internal cervix, external cervix, overlapping lesions of the cervix, cervix, uterine isthmus, endometrium, myometrium, fundus, overlapping lesions of the uterine body, uterine body, uterus (nos), ovaries, fallopian tubes, broad ligament, round ligament, parametrium, uterine adnexa, Wolffian bodies, overlapping lesions of the female genital tract, female genital tract (nos), foreskin, glans penis, body of the penis, overlapping lesions of the penis, penis (nos), prostate, undescended testis, undescended testis, descended testis, testis (nos), epididymis, spermatic cord, scrotum (nos), tunica vaginalis, overlapping lesions of the male genital tract, male genital Reproductive organs (nos), kidneys (nos), renal pelvis, ureters, bladder trigone, bladder dome, lateral wall of the bladder, posterior wall of the bladder, ureteral orifice, urachus, overlapping lesions of the bladder, bladder (nos), urethra, paraurethral glands, overlapping lesions of the urinary system, urinary system (nos), conjunctiva, cornea (nos), retina, choroid, ciliary body, lacrimal gland, orbit (nos), overlapping lesions of the eyeball and adnexa, eyeball (nos), cerebral meninges, spinal meninges, meninges (nos), cerebrum, frontal lobe, temporal lobe, parietal lobe, occipital lobe, ventricles (nos), cerebellum (nos), brainstem, overlapping lesions of the brain, brain (nos), spinal cord, cauda equina, olfactory nerve, optic nerve, acoustic nerve, cranial nerve (nos),May occur in organs and tissues selected from the group including overlapping lesions of the brain and central nervous system, nervous system (nos), thyroid gland, adrenal cortex, adrenal medulla, adrenal glands (nos), parathyroid gland, pituitary gland, craniopharyngeal duct, pineal gland, carotid body, aortic body, overlapping lesions of endocrine glands and related structures, endocrine glands (nos), head, face, or neck (nos), chest (nos), abdomen (nos), pelvis (nos), upper limbs (nos), lower limbs (nos), other unspecified locations, overlapping lesions of unspecified locations, facial, head, and neck lymph nodes, intrathoracic lymph nodes, intraperitoneal lymph nodes, axillary lymph nodes, inguinal lymph nodes, pelvic lymph nodes, lymph nodes in multiple locations, lymph nodes of unknown primary location (nos).

[0336] In some embodiments, the disease is a neoplasm, preferably a cancer or tumor. In some embodiments, the neoplasm, cancer, and tumor is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma, and thyroid cancer, and combinations thereof.

[0337] In some embodiments, the neoplasias, cancers and tumors are individually selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma, and combinations thereof.

[0338] In some embodiments, the disease is a non-neoplastic disease. In some embodiments, the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. In some embodiments, the disease is selected from the group consisting of atherosclerosis, arthritis, rheumatoid arthritis, cardiovascular diseases associated with atherosclerotic plaques, atherosclerotic conditions caused by plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis or vascular obstruction, idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis.

[0339] In some embodiments, subjects treated with the compounds of the present disclosure can be treated in combination with other non-surgical anti-proliferative (e.g., anti-cancer) drug therapies. In some embodiments, the compounds can be administered in combination with anti-cancer compounds, such as cytostatic compounds. Cytostatic compounds are compounds (e.g., small molecules, nucleic acids, or proteins) that suppress cell growth and / or proliferation. In some embodiments, the cytostatic compounds are directed against malignant cells of tumors. In some embodiments, the cytostatic compounds inhibit the growth and / or proliferation of vascular smooth muscle cells or fibroblasts.

[0340] In some embodiments, the compounds described herein are used or are for use in combination with a chemotherapeutic agent, such as a DNA-damaging chemotherapeutic agent. Non-limiting examples of DNA-damaging chemotherapeutic agents include topoisomerase I inhibitors, topoisomerase II inhibitors, alkylating agents, DNA intercalators, DNA intercalators, and free radical generators, such as bleomycin, and nucleoside mimetics.

[0341] In some embodiments, the compounds described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, a combination therapy can include a composition in which a conjugate described herein is co-formulated and / or co-administered with one or more additional therapeutic agents, such as one or more anti-cancer agents, e.g., cytotoxic or cell growth inhibitory agents, immune checkpoint inhibitors, hormonal treatments, vaccines, and / or immunotherapy. In some embodiments, the conjugate is administered in combination with other therapeutic treatment modalities, including surgery, cryosurgery, and / or chemotherapy. Such combination therapy can advantageously utilize lower doses of administered therapeutic agents, thereby avoiding potential toxicities or complications associated with various monotherapies.

[0342] Antiproliferative or cytostatic compounds suitable for use in combination with the compounds of the present disclosure include anticancer agents. Many anticancer agents that can be used are known and include acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacytidine; azaribine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin; bleomycin; Mycobacterium sulfate;Brequinar sodium;Bropirimine;Bryostatin-1;Busulfan;Cactinomycin;Calstosterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelesin;Cedefingol;Celebrex;Chlorambucil;Ciloremycin;Cisplatin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Dactinomycin;Daunorubicin;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Dezagua Ninine; Dexaguanine mesylate; Diazicon; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Doxorubicin glucuronide; Cyanomorpholinodoxorubicin; 2-Pyrrolinodoxorubicin (2P-DOX), Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizin; Epirubicin hydrochloride; Epirubicin glucuronide; Elbrozole; Esorubicin fludarabine hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoposide glucuronide; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine (FUdR); 3',5'-O-dioleoyl-FudR (FUdR-dO); fludarabine; fludarabine phosphate; fluorouracil; fluorocitabine; flutamide; fluoxymesterone; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;Hydroxyurea; Hydroxyprogesterone caproate; Idarubicin; Idarubicin hydrochloride; Ifosfamide; Ilmofosine; Interferon alfa-2a; Interferon alfa-2b; Interferon alfa-n1; Interferon alfa-n3; Interferon beta-Ia; Interferon gamma-Ib; Iproplatin; Irinotecan hydrochloride; L-asparaginase; Lanreotide acetate; Letrozole; Leucovorin, leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine ron; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine; mechlorethamine hydrochloride; medroprogesterone acetate; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; 6-mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mithramycin; mitindomide; mitocalcin; mitochromin; mitogillin; mitomarcine; mitomycin; mitosper; mitotane; mitoxantrone; mitoxantrone hydrochloride Salts; Mycophenolic acid; Niraparib; Nocodazole; Nogalamycin; Olaparib; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Phenylbutyrate, Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Prednisone; Procarbazine; Procarbazine hydrochloride; PSI-341, Puromycin; Puromycin hydrochloride; Pi Lazofurin; Ribopurin; Rogletimide; Rucaparib; Safingol; Safingol hydrochloride; Semustine; Semustine; Streptozocin; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Talazoparib; Tallysomycin; Taxol; Taxotere; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamiprine; Thioguanine;Thiotepa; tiazofurin; tirapazamine; topotecan; topotecan hydrochloride; toremifene citrate; trestron acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; veraparib; velcade; verteporfin; vinblastine; vinblastine sulfate; vincristine; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinylcinate sulfate; vinleurosine sulfate; vinorelbine; vinorelbine tartrate; vinorocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin and zorubicin hydrochloride.

[0343] Other anticancer drugs include 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; acylfulvene; adecipenol; adzelesin; ALL-TK antagonists; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; and anti-dorsalizing morphogenetic protein-1; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atamestane; atlimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists Nist; Benzochlorin; Benzoylstaurosporine; Beta-lactam derivatives; Beta-arrestin; Betaclomicin B; Betulinic acid; bFGF inhibitors; Bisaziridinylspermine; Bisnafide; Bistraten A; Bortezomib; Brefrate; Budotitanium; Buthionine sulfoximine; Caliciamycin; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxamido-aminotriazole; Carboxamidotriazole; CaRest M3; CARN700; cartilage-derived inhibitor; casein kinase inhibitor (ICOS) castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanethraquinone; cycloplatam; sipemycin; cytarabine ocfosfate; cytolytic factors; cytostatin; dacliximab; daunomycin glucuronide; daunorubicin; dehydrodemnin B; diethylstilbestrol;Deslorelin; Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Didemnin B; Didox; Diethylnorspermine; Azacitidine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflomitine; Elemene; Emiteflu; Epirubicin; Epristeride; Estramustine analogues; Estrogen agonist Nist; Estrogen antagonists; Etanidazole; Ethinyl estradiol; Etoposide phosphate; Exemestane; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Fludarabine; Fluorodaunornithine hydrochloride; Forfenimex; Formestane; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronate; Ido Xifene; Idramanton; Ilmofosine; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulating peptides; Insulin-like growth factor-I receptor inhibitors; Interferon agonists; Interferons; Interleukins; Iobenguane; Iododosorbicin; Ipomeanol, 4-; Irinotecan; Ilopract; Irsogladine; Isobengazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinanth Lufate; leptolstatin; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lysocrine amide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; rhizophylline; lytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin;Matrilysin inhibitors; matrix metalloproteinase inhibitors; mervalone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mofalotene; molgramostim; monoclonal antibodies, human chorionic gonadotrophin; monophosphoryl lipid A + Myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multitumor suppressors -1-based therapy; mustard anticancer compounds; mycobacterial peroxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagressip; naloxone + pentazocine; napavine; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrulline; O6-benzylguanine; octreotide; oxenone; oligonucleotides; onapristone; onda Dansetron; Ondansetron; Oracin; Oral cytokine inducers; Osateron; Oxaliplatin; Oxaunomycin; Paclitaxel analogs; Paclitaxel derivatives; Palauamine; Palmitoylrhizoxin; Pamidronic acid; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegaspagase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Pisivany le;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Prasetin A;Prasetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum-triamine complexes;Porfimer sodium;Porfiromycin;Propylbisacridone;Prostaglandin J2;Proteasome inhibitors;Protein A-based immune modulators;Protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;Protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors;Purpurin;Pyrazoloacridines;Pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; demethylated reterliptin; rhenium Re186 etidronate; rhizoxin; ribozyme; RII retinamide; rohitukin; romurtide; roquinimex; rubidinone B1; ruboxil; santopine; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; senescence-derived inhibitor 1; sense oligonucleotide; sigma Signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding proteins; schizofuran; SN-38; sobuzoxane; borocaptate sodium; sodium phenylacetate; sorberol; somatomedin-binding proteins; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitors; stem cell division inhibitors; stypiamide; stromelysin inhibitors; sulfinosines; superactive vasoactive intestinal peptide antagonists; thradista; suramin; swainsonine; synthetic glycosaminoglycans Glycans;Talimustine;Tamoxifen;Tamoxifen methiodide;Tauromustine;Taxanes;Tazarotene;Tecogalan sodium;Tegafur;Telurapyrylium;Telomerase inhibitors;Temozolomide;Testosterone propionate, tetrachlorodecaoxide;Tetrazomine;Saliblastine;Thalidomide;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Tin ethyl etiopurpurin;Titanocene dichloride;Topsentin;Tre Miphen; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; variolin B; vector systems, erythrocyte gene therapy; veraresol; veramine; verdin; vinorelbine; vinxaltine; vitaxin; zanoteron; zilascorub; zinostatin stimalamer; abrin; ricin; ribonuclease; onconase; rapLR1;including, but not limited to, DNase I; Staphylococcal endotoxin-A; pokeweed antiviral protein; gelonin; diphtheria toxin; Pseudomonas exotoxin and Pseudomonas endotoxin or a combination thereof;

[0344] In some embodiments, the agent used in combination with the disclosed compounds is duocarmycin and its analogs, dolastatins, combretastatins, calicheamicin, N-acetyl-γ-calicheamicin (CMC), calicheamicin derivatives, maytansine and its analogs, DM-I, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), tubulysin, disorazole, epothilone, paclitaxel, docetaxel. , topotecan, echinomycin, estramustine, cemadotin, eleutherobin, methopterin, actinomycin, daunorubicin, daunorubicin conjugates, mitomycin C, mitomycin A, vincristine, retinoic acid, camptothecin, camptothecin derivatives, SN38, maytansine, maytansinoid-type derivatives, DM1, DM4, TK1, amanitin, pyrrolobenzodiazepines, pyrrolobenzodiazepine dimers, methotrexate, ilomedin, aspirin, IMID, lenalidomide, and pomalidomide.

[0345] The compounds of the present disclosure may also be used in combination with any of the following treatments:

[0346] Combination therapy with compounds that target the androgen receptor (including androgen deprivation approaches and antiandrogens). Such inhibitors include, but are not limited to, enzalutamide, apalutamide, darolutamide, etc.

[0347] Combination therapy with poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors are a class of chemotherapy drugs that target cancers with defects in DNA damage repair (Yuan, et al., Expert Opin Ther Pat, 2017, 27: 363). Such PARP inhibitors include, but are not limited to, olaparib, rucaparib, velaparib, niraparib, talazoparib, pamiparib, iniparib, E7449, and A-966492.

[0348] Combination therapy with inhibitors of signaling pathways and mechanisms that lead to repair of DNA single-strand and double-strand breaks, such as nuclear factor kappa B signaling (Pilie, et al., Nat Rev Clin Oncol, 2019, 16: 81; Zhang, et al., Chin J Cancer, 2012, 31: 359). Such inhibitors include, but are not limited to, inhibitors of ATM and ATR kinases, checkpoint kinases 1 and 2, DNA-dependent protein kinase, and WEE1 kinase (Pilie, et al., Nat Rev Clin Oncol, 2019, 16: 81).

[0349] These include immune modulators (Khalil, et al., Nat Rev Clin Oncol, 2016, 13: 394), cancer vaccines (Hollingsworth, et al., NPJ Vaccines, 2019, 4: 7), immune checkpoint inhibitors (e.g., PD-1, PD-L1, and CTLA-4 inhibitors) (Wei, et al., Cancer Discov, 2018, 8: 1069), cyclin-D-kinase 4 / 6 inhibitors (Goel, et al., Trends Cell Biol, 2018, 28: 911), antibodies capable of binding to tumor cells and / or metastases and eliciting antibody-dependent cellular cytotoxicity (ADCC) (Kellner, et al., Transfus Med Hemother, 2017, 44: 327), and T cell or NK cell engagers (e.g., bispecific antibodies) (Yu, et al., J Cancer Res Clin Oncol, 2019, 145: 941), and combination therapy with cell therapy using expanded autologous or allogeneic immune cells (e.g., chimeric antigen receptor T (CAR-T) cells) (Khalil, et al., Nat Rev Clin Oncol, 2016, 13: 394). Immune checkpoint inhibitors include, but are not limited to, nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemipilimab.

[0350] According to the present invention, the compound can be administered before, simultaneously with, or after other anti-cancer compounds. The administration schedule may include alternating administration of different agents. In other embodiments, the compound can be delivered before and during, or during and after, or before and after, or before, during, and after treatment with other therapies. In some embodiments, the compound is administered 24 hours or more before the administration of other anti-proliferative treatments. In some embodiments, two or more anti-proliferative therapies can be administered to the subject. For example, the subject may receive the compound in combination with both surgery and at least one other anti-proliferative compound. In some embodiments, the compound can be administered in combination with two or more anti-cancer agents.

[0351] In some embodiments, the compounds of the present invention are used to detect cells and tissues that overexpress FAP. Such detection is achieved by conjugating a detectable label, such as a detectable radionuclide, to the compounds of the present invention. In some embodiments, the detected cells and tissues are diseased cells and tissues and / or are either responsible for a disease and / or disease symptoms or part of the underlying pathology of a disease. In some embodiments, the diseased cells and tissues are responsible for and / or part of an oncological indication (e.g., neoplasms, tumors, and cancer) or a non-oncological indication (e.g., inflammatory disease, cardiovascular disease, autoimmune disease, and fibrotic disease).

[0352] In some embodiments, the compounds of the present invention are used to treat cells and tissues that overexpress a FAP. In some embodiments, the treated cells and tissues are diseased cells and tissues and / or are either responsible for a disease and / or disease symptoms or part of the underlying pathology of a disease. In some embodiments, the diseased cells and tissues are responsible for and / or part of an oncological indication (e.g., neoplasms, tumors, and cancer), and therapeutic activity is achieved by conjugating the compounds of the present invention to a therapeutically active effector, e.g., a therapeutically active radionuclide. In some embodiments, the diseased cells and tissues are responsible for and / or part of a non-oncological indication (e.g., inflammatory disease, cardiovascular disease, autoimmune disease, and fibrotic disease), and therapeutic activity is achieved by inhibiting the enzymatic activity of a FAP.

[0353] In further embodiments, particularly when the disease is a non-oncological disease or non-oncological indication (e.g., inflammatory disease, cardiovascular disease, autoimmune disease, and fibrotic disease), the compounds of the present invention are administered in a therapeutically effective amount, and preferably, the compounds of the present invention do not contain therapeutically active nuclides. An effective amount is a dose of a compound sufficient to provide a therapeutically or medically desired result or effect in the subject to which the compound is administered. The effective amount will vary depending on the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of treatment, the nature of any concurrent or concomitant therapy, the particular route of administration, and factors within the knowledge and expertise of the medical practitioner, etc. For example, in the context of a method directed to treating a subject with a condition characterized by abnormal cell proliferation, an amount effective to inhibit proliferation would be an amount sufficient to reduce or completely halt abnormal cell proliferation, such as slowing or halting the development or progression of a cell mass, e.g., a tumor. As used in the embodiments, "inhibit" encompasses all of the foregoing.

[0354] In some embodiments, a therapeutically effective amount will be the amount necessary to prolong the dormancy of micrometastases or the amount necessary to stabilize any primary tumor cells remaining after surgical or drug therapy.

[0355] Generally, when using unconjugated compounds that do not contain a therapeutically active radionuclide, the therapeutically effective amount may vary based on factors such as the age, condition, and sex of the subject, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. Doses can be adjusted by the individual physician or veterinarian, particularly if any complications arise. In some embodiments, a therapeutically effective amount includes, but is not limited to, amounts ranging from 0.1 μg / kg to about 2000 mg / kg, or 1.0 μg / kg to about 1000 mg / kg, or from about 0.1 mg / kg to about 100 mg / kg, administered once or more times daily for one or more days. If desired, the effective daily amount of the active compound can be administered separately as two, three, four, five, six, or more subdoses, e.g., at appropriate intervals throughout the day, optionally in unit dosage forms. In some embodiments, the compound is administered for 7 or more days, 10 or more days, 14 or more days, or 20 or more days. In some embodiments, the compound is administered for weeks, months, or years. In some embodiments, the compound is delivered every other day, for example, the agent is delivered every 2 days, or every 3 days, or every 4 days, or every 5 days, or every 6 days, or every week, or every month.

[0356] In some embodiments, the compounds of the present invention are for use in the treatment and / or prevention of disease, wherein such treatment is radionuclide therapy.

[0357] For example, radionuclide therapy uses or is based on various forms of radiation emitted by radionuclides. Such radiation includes, for example, photon radiation, β -The radiation can be any one of electron radiation, including (but not limited to) -particles and Auger electrons, proton radiation, neutron radiation, positron radiation, alpha particle radiation, or ion beam. Depending on the type of particle or radiation emitted by the radionuclide, radionuclide therapy can be distinguished, for example, as photon-emitting nuclide therapy, electron-emitting nuclide therapy, proton-emitting nuclide therapy, neutron-emitting nuclide therapy, positron-emitting nuclide therapy, alpha particle radiation, or ion beam radionuclide therapy. All these forms of radionuclide therapy are encompassed by the present invention, and all these forms of radionuclide therapy can be realized by the compounds of the present invention, where a radionuclide bound to the compound of the present invention, for example as an effector, provides this type of radiation.

[0358] Radionuclide therapy preferably exerts its effect by damaging the DNA of cells. Damage is caused by photons, electrons, protons, neutrons, positrons, alpha particles, or ion beams directly or indirectly ionizing the atoms that make up the DNA chain. Indirect ionization occurs as a result of the ionization of water, forming free radicals, particularly hydroxyl radicals, which then damage DNA.

[0359] In the most common forms of radionuclide therapy, the majority of radiation effects are due to free radicals. Because cells have mechanisms for repairing DNA damage, breaking both strands of DNA has proven to be the most important technique for altering cellular properties. Because cancer cells are generally undifferentiated, stem cell-like cells, they replicate more frequently and have a reduced ability to repair sublethal damage compared to most normal, differentiated cells. DNA damage is inherited through cell division, causing cancer cells to accumulate damage and either die or replicate more slowly.

[0360] Oxygen is a potent radiosensitizer, enhancing the effects of a given dose of radiation by forming free radicals that damage DNA. Therefore, hyperbaric oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins such as tirapazamine can be applied.

[0361] Other factors considered in selecting the radiation dose include whether the patient is receiving chemotherapy, whether the radiation therapy is administered before or after surgery, and the degree of success of the surgery.

[0362] For one or more of several important reasons, the total radioactive dose can be fractionated, i.e., spread over time in one or more treatments.For example, fractionation allows normal cells time to recover, while tumor cells generally have a low repair efficiency during fractionation.Also, for example, fractionation can allow tumor cells that are in a relatively radioresistant stage of the cell cycle during one treatment to progress to a sensitive stage of the cycle before the next fraction is administered.Similarly, tumor cells that are chronically or acutely hypoxic and therefore more radioresistant can be reoxygenated during fractionation, which can improve tumor cell killing.

[0363] It is generally known that the response of cancer to radiation therapy varies depending on the cancer. The response of cancer to radiation is expressed by its radiosensitivity. Cancer cells with high radiosensitivity are rapidly killed by an appropriate dose of radiation. These include most leukemias, lymphomas, and germ cell tumors.

[0364] It is important to distinguish between the radiosensitivity of a particular tumor (which is partly a laboratory measurement) and the "cureability" of the cancer with an internally delivered radiation dose in actual clinical practice. For example, leukemia is generally not curable with radiation therapy because it disseminates throughout the body. Lymphoma may be curable if it is confined to one part of the body. Similarly, many common, moderately radioresponsive tumors can be treated with curative doses of radiation if they are developed early. This applies, for example, to nonmelanoma skin cancer, head and neck cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer.

[0365] Tumor response to radiation therapy is also related to its size. For complex reasons, very large tumors do not respond as well to radiation as small tumors or minimal disease. To overcome this effect, various strategies have been used. The most common technique is surgical excision before radiation therapy. This is most commonly seen in the treatment of breast cancer, where wide local excision or mastectomy is followed by adjuvant radiation therapy. Another method is to shrink the tumor with neoadjuvant chemotherapy before definitive radionuclide therapy. A third technique is to enhance the radiosensitivity of the cancer by administering certain drugs during the course of radiation therapy. Examples of drugs that enhance radiosensitivity include, but are not limited to, cisplatin, nimorazole, and cetuximab.

[0366] Intraoperative radiotherapy is a specialized form of radiation therapy given immediately after surgical removal of the cancer. This method is used for breast cancer (targeted intraoperative radiotherapy), brain tumors, and rectal cancer.

[0367] Radionuclide therapy itself is not painful. Many low-dose palliative treatments have minimal or no side effects. High-dose treatments may cause a variety of side effects during treatment (acute side effects), months or years after treatment (long-term side effects), or after further treatment (cumulative side effects). The nature, severity, and duration of side effects vary depending on the organ receiving radiation, the treatment itself (type of radionuclide, dose, fractionation, concurrent chemotherapy), and the patient.

[0368] To the extent that methods for treating the diseases of the present invention are known in the art, it is within the scope of the present invention that each and every one of the above strategies can be implemented, which constitute further embodiments of the present invention.

[0369] It is also within the scope of the present invention that the compounds of the present invention be used in methods for diagnosing the diseases disclosed herein, hi some embodiments, such methods comprise administering to a subject in need thereof a diagnostically effective amount of a compound of the present invention.

[0370] According to the present invention, the imaging method is selected from the group consisting of scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), and combinations thereof.

[0371] Scintigraphy is a form of diagnostic test or method used in nuclear medicine, in which a radiopharmaceutical is internalized into cells, tissues, and / or organs, e.g., in vivo, and radiation emitted from the internalized radiopharmaceutical is captured by an external detector (gamma camera) to form and display a two-dimensional image. In contrast, SPECT and PET form and display a three-dimensional image. For this reason, SPECT and PET are classified as separate techniques from scintigraphy, even though they also use a gamma camera to detect internal radiation. Scintigraphy differs from diagnostic x-rays, in which external radiation is passed through the body to form an image.

[0372] Single-photon emission computed tomography (SPECT) scans are a type of nuclear imaging technique that uses gamma rays. They are very similar to conventional nuclear medicine planar imaging, which uses a gamma camera. Before a SPECT scan, the patient is injected with a radiolabeled chemical that emits gamma rays that can be detected by the scanner. A computer collects information from the gamma camera and converts it into two-dimensional cross-sectional images. These cross-sectional images can be added together to form a three-dimensional image of the organ or tissue. SPECT detects gamma rays emitted singly or sequentially by the radionuclides provided by the radiolabeled chemical. To acquire a SPECT image, the gamma camera rotates around the patient. Typically, projection images are acquired every 3 to 6 degrees at predetermined points during the rotation. In most cases, a full 360-degree rotation is used to obtain an optimal reconstruction. The time required to acquire each projection image also varies, but 15 to 20 seconds is common. This results in a total scan time of 15 to 20 minutes. Multihead gamma cameras are faster. SPECT acquisition is very similar to planar gamma camera imaging, so the same radiopharmaceuticals can be used.

[0373] Positron emission tomography (PET) is a noninvasive diagnostic imaging technique for measuring the biochemical state or metabolic activity of cells in the human body. PET is unique because it produces images of the body's basic biochemistry or function. Traditional diagnostic techniques, such as X-rays, CT scans, and MRIs, produce images of the body's anatomical structures or structures. The premise of these techniques is that they can see any changes in the structures or anatomy associated with disease. Disease also alters biochemical processes, which may occur before visible anatomical changes. PET is an imaging technique that can visualize some of these early biochemical changes. PET scanners use radiation emitted by the patient to create images. Each patient is given a minute amount of a radiopharmaceutical that either mimics a natural substance used in the body or specifically binds to a receptor or molecular structure. When the radioisotope undergoes positron-emitting decay (also known as positive beta decay), it emits a positron, the antiparticle counterpart of the electron. The positrons travel up to a few millimeters before encountering an electron and annihilating, producing a pair of annihilation (gamma) photons traveling in opposite directions. These are detected when they reach the scintillation material in the scanning device, generating a burst of light that is detected by a photomultiplier tube or silicon avalanche photodiode. The technique relies on the coincidence or coincidence detection of pairs of photons. Photons that do not arrive as a pair, i.e., within a few nanoseconds of each other, are ignored. All coincidence counts are forwarded to an image processing unit, which uses image reconstruction techniques to generate the final image data.

[0374] SPECT / CT and PET / CT are the combination of SPECT and PET with computed tomography (CT). The main advantage of combining these modalities is to improve the reliability and accuracy of the reader. With conventional PET and SPECT, the limited number of photons emitted from the abnormal region creates a very low level of background, which makes it difficult to identify the region anatomically. The addition of CT helps determine the location of the abnormal region from an anatomical perspective and classify its likelihood of representing disease.

[0375] To the extent that methods for diagnosing the diseases of the present invention are known in the art, it is within the scope of the present invention that each and every one of the above strategies can be implemented, constituting further embodiments of the present invention.

[0376] In some embodiments, the compounds of the present invention can be advantageously used in methods for identifying subjects, selecting subjects from a group of subjects, or stratifying a group of subjects, where the subjects are likely to respond or not respond to disease treatment, wherein the method comprises performing a diagnostic method using a compound of the present invention. In certain embodiments, such methods can advantageously optimize drug treatment (including minimizing risk and maximizing efficacy), for example, by helping medical professionals identify subjects who are most likely to benefit from a given treatment and avoid unnecessary treatment.

[0377] In some embodiments, the compounds of the invention may be useful for stratifying patients, i.e., creating subsets within a patient population that provide more detailed information about how the patient will respond to a given drug. Stratification may be an important component in transforming a clinical trial from one with a negative or neutral outcome to one with a positive outcome by identifying the subset of the population that is most likely to respond to a new therapy.

[0378] Stratification involves identifying groups of patients who share "biological" characteristics to select the most appropriate management for them and achieve the best possible outcome in terms of risk assessment, risk prevention and achieving optimal treatment outcomes.

[0379] In some embodiments, the compounds of the invention can be used to assess or detect a particular disease as early as possible (this is a diagnostic use), to assess or detect the risk of developing a disease (this is a susceptibility / risk use), to assess or detect the progression of a disease, including low-grade versus high-grade disease (this is a prognostic use), and to predict response and toxicity to a given treatment (this is a predictive use).

[0380] It is also within the scope of the present invention that the compounds of the present invention can be used in theranostics methods. The concept of theranostics is to combine a therapeutic agent with a corresponding diagnostic test that can improve the clinical use of the therapeutic agent. The concept of theranostics is becoming increasingly attractive and is widely considered to be the key to improving the efficiency of drug treatment by helping doctors identify patients who may benefit from a given treatment and thus avoid unnecessary treatment.

[0381] The concept of theranostics is the combination of therapeutic agents and diagnostic tests, which allows physicians to identify patients who will most likely benefit from a given treatment. In one embodiment, the compounds of the present invention are used to diagnose patients, i.e., to identify and locate the primary tumor mass and potential local and distant metastases. Furthermore, tumor volume can be determined, particularly using three-dimensional diagnostic modalities such as SPECT or PET. Only patients with FAP-positive tumor masses and therefore likely to benefit from a given treatment are selected for a specific treatment, thus avoiding unnecessary procedures. For example, such treatment is FAP-targeted therapy using the compounds of the present invention. In some embodiments, chemically identical tumor-targeted diagnostic and radiotherapeutic agents are applied, including, for example, imaging diagnostic agents for scintigraphy, PET, or SPECT. Such compounds differ only in the radionuclide and therefore usually have very similar, if not identical, pharmacokinetic profiles. This can be achieved using chelators and diagnostic or therapeutic radiometals. Alternatively, this can be achieved by using a precursor for the radiolabel and radiolabeling with either a diagnostic or therapeutic radionuclide. In one embodiment, diagnostic imaging is used to quantify the radiation of the diagnostic radionuclide, with subsequent dosimetry known to those skilled in the art and prediction of drug concentration in the tumor relative to organs susceptible to side effects. In this way, a truly personalized drug administration regimen for the patient is achieved.

[0382] In some embodiments, theranostic methods are achieved with only one theranostically active compound, e.g., a compound of the invention labeled with a radionuclide that emits diagnostically detectable radiation (e.g., positrons or gamma rays) and therapeutically effective radiation (e.g., electrons or alpha particles).

[0383] The present invention also contemplates methods for intraoperatively identifying / disclosing diseased tissue expressing FAP in a subject, such methods employing compounds of the present invention, wherein in some embodiments, such compounds of the present invention comprise a diagnostically active agent, e.g., a diagnostically active radionuclide, as an effector.

[0384] According to a further embodiment of the present invention, the compounds of the present invention, particularly when complexed with a radionuclide, can be utilized as an adjuvant or supplement to any other tumor treatment, including surgery as the primary method of treatment for most isolated solid cancers, radiotherapy, including the use of ionizing radiation in an attempt to either cure or ameliorate cancer symptoms using either a sealed internal source in the form of brachytherapy or an external source, chemotherapy, such as alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors and other antitumor agents, hormonal treatments that modulate tumor cell behavior without directly attacking those cells, targeted agents (including monoclonal antibodies) that directly target molecular abnormalities in certain types of cancer, and tyrosine kinase inhibitors, angiogenesis inhibitors, immunotherapy, cancer vaccination, palliative care, including actions to alleviate physical, emotional, spiritual and psychosocial suffering to improve a patient's quality of life, and alternative treatments, including a diverse array of health care systems, practices and products outside of conventional medicine.

[0385] In one embodiment of the methods of the invention, the subject is a patient. In one embodiment, the patient is a subject suffering from, suspected of suffering from, or diagnosed as being at risk of suffering from or developing a disease, wherein the disease is a disease described herein, a disease involving FAP.

[0386] The doses utilized in carrying out the methods for treatment and diagnosis, respectively, in which a radionuclide is used, more particularly one bound to or part of the compounds of the present invention, will vary depending, for example, on the particular condition being treated, e.g., known radiosensitive tumor types, tumor volume, and desired therapy. Generally, the dose is calculated based on the distribution of radioactivity in each organ and the observed target uptake. The gamma-emitting complex can be administered once or several times for imaging. In animals, the indicated dose ranges are, for example, 0.1 ng / kg to 5 mg / kg of the compounds of the present invention (e.g., 1 kBq to 200 MBq of gamma-emitting nuclide ( 111 In or 68g The α- or β-emitting complexes of the compounds of the invention can be administered over several time points, for example, over a period of 1 to 3 weeks or longer. In animals, the indicated dose ranges are, for example, 0.1 ng / kg to 5 mg / kg of the compounds of the invention (e.g., 1 kBq to 200 MBq of α- or β-emitting nuclides ( 225 Ac or 177 For example, in larger mammals, including humans, the indicated dose ranges may be, for example, 0.1 ng / kg to 5 mg / kg or, for example, 0.1 ng / kg to 100 μg / kg of a compound of the invention (e.g., complexed with 10 to 1000 MBq of a gamma-emitting nuclide ( 111 In or 68g For example, in large mammals, including humans, the indicated dose ranges may be, for example, 0.1 ng / kg to 5 mg / kg or, for example, 0.1 ng / kg to 100 μg / kg of a compound of the invention (e.g., 1 to 100,000 MBq of an α- or β-emitting nuclide ( 225 Ac or 177 The compound can be a fluorine-containing compound (including but not limited to fluorine-containing compounds), complexed with fluorine-containing compounds (including but not limited to fluorine-containing compounds).

[0387] In certain embodiments, uptake can be measured in terms of absorbed dose (mGy / MBq), SUVmax, and SUVmean. In animals, uptake throughout tissue is reported as injected dose / gram ID / g. Sensitivity to radiation depends on tumor and non-tumor tissue. The favorable uptake of the compounds in tumor tissue relative to non-tumor tissue allows for the delivery of radionuclides at doses capable of reducing tumor growth or partially or completely destroying tumors. At such doses, no permanent or fatal damage to non-tumor tissues is expected.

[0388] In a further aspect, the present invention relates to compositions, in particular pharmaceutical compositions, comprising the compounds of the present invention.

[0389] The pharmaceutical compositions of the present invention comprise at least one compound of the present invention and, optionally, one or more carrier substances, excipients, and / or adjuvants. The pharmaceutical compositions may further comprise, for example, one or more of water, buffers such as neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates such as glucose, mannose, sucrose, or dextran, mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, and / or preservatives. Furthermore, the pharmaceutical compositions of the present invention may, but do not necessarily, contain one or more other active ingredients.

[0390] The pharmaceutical compositions of the present invention can be formulated for any suitable route of administration, including, for example, topical, e.g., transdermal or ocular, oral, buccal, nasal, vaginal, rectal, or parenteral administration. In one embodiment, and as preferably used herein, the term parenteral includes subcutaneous, intradermal, intravascular, e.g., intravenous, intramuscular, intrathecal, and intraperitoneal injections and any similar injection or infusion technique. In some embodiments, the route of administration is intravenous administration.

[0391] In one embodiment of the invention, the radionuclide-containing compounds of the invention are administered by any conventional route, in particular intravenously, for example in the form of an injectable solution or suspension. The compounds of the invention may also be advantageously administered by infusion, for example by infusion over a period of 30 to 60 minutes.

[0392] In some embodiments, depending on the location of the tumor, the compounds of the present invention can be administered as close as possible to the tumor site, for example, by catheter. Such administration can be directly into the tumor tissue, surrounding tissue, or afferent blood vessels. The compounds of the present invention can also be administered in repeated doses, including divided doses, in some embodiments.

[0393] According to an embodiment of the present invention, the pharmaceutical composition of the present invention includes a stabilizer, e.g., a free radical scavenger, that inhibits the autoradiolysis of the compound of the present invention. Suitable stabilizers include, for example, serum albumin, ascorbic acid, retinol, gentisic acid, or derivatives thereof, or amino acid infusions used in parenteral protein delivery, e.g., electrolyte- and glucose-free, e.g., commercially available amino acid infusions, e.g., Proteinsteril® KE Nephro. In some embodiments, ascorbic acid and gentisic acid are used.

[0394] The pharmaceutical compositions of the present invention can include additional additives, such as agents to adjust the pH to 7.2-7.4, such as sodium or ammonium acetate or NaHPO. In some embodiments, a stabilizer is added to the non-radioactive compound of the present invention, and the introduction of the radionuclide, e.g., complexation with the radionuclide, is carried out in the presence of the stabilizer, either at room temperature or at a temperature of, e.g., 40-120°C. Complexation can conveniently be carried out under air-free conditions, e.g., under N or Ar. In some embodiments, an additional stabilizer can be added to the composition after complexation.

[0395] Elimination of the compounds of the present invention is primarily via the kidney, particularly when the effector is a radionuclide. In some embodiments, further protection of the kidney from radioactivity accumulation can be achieved, particularly when the effector is a radionuclide, by administering lysine or arginine or an amino acid solution with a high lysine and / or arginine content, such as commercially available amino acid solutions, such as Synthamin®-14 or -10, prior to or in conjunction with the infusion of the compounds of the present invention. In some embodiments, kidney protection can also be achieved by administering a plasma expander, such as gelofuscin, either instead of or in addition to the amino acid infusion. In some embodiments, kidney protection can also be achieved by administering a diuretic, which provides a means of forced diuresis to increase the rate of urination. Such diuretics include high-ceiling loop diuretics, thiazides, carbonic anhydrase inhibitors, potassium-sparing diuretics, calcium-sparing diuretics, osmotic diuretics, and low-ceiling diuretics. In some embodiments, the pharmaceutical compositions of the present invention can contain, apart from the compounds of the present invention, at least one of these additional compounds intended for or suitable for nephroprotection, including, for example, protection of the kidneys of a subject to whom the compounds of the present invention are administered.

[0396] Those skilled in the art will understand that the compounds of the present invention are disclosed herein for use in a variety of methods. Those skilled in the art will further understand that the compositions of the present invention and pharmaceutical compositions of the present invention can be equally used in the various methods. Those skilled in the art will also understand that the compositions of the present invention and pharmaceutical compositions of the present invention are disclosed herein for use in a variety of methods. Those skilled in the art will equally understand that the compounds of the present invention can be equally used in the various methods.

[0397] Those skilled in the art will recognize that the compositions and / or pharmaceutical compositions disclosed herein can contain one or more additional compounds in addition to the compounds of the present invention. To the extent that such one or more additional compounds are disclosed herein as being part of the compositions and / or pharmaceutical compositions of the present invention, it will be understood that such one or more additional compounds can be administered to a subject exposed to or in a method of the present invention separately from the compounds of the present invention. Such administration of the one or more additional compounds can occur before, simultaneously with, or after the administration of the compounds of the present invention. Those skilled in the art will also recognize that one or more additional compounds can be administered to a subject in a method of the present invention separately from the compounds of the present invention. Such administration of the one or more additional compounds can occur before, simultaneously with, or after the administration of the compounds of the present invention. To the extent that such one or more additional compounds are disclosed herein as being administered as part of the methods of the present invention, it will be understood that such one or more additional compounds are part of the compositions and / or pharmaceutical compositions of the present invention. It is within the scope of the present invention that the compounds of the present invention and one or more additional compounds may be contained in the same formulation or in different formulations. It is also within the scope of the present invention that the compound of the present invention and one or more additional compounds are not contained in the same formulation, but are contained in the same package containing a first formulation comprising the compound of the present invention and a second formulation comprising one or more additional compounds, wherein the types of formulations may be the same or different.

[0398] It is within the scope of the present invention that more than one compound of the present invention may be included in a composition of the present invention and / or a pharmaceutical composition of the present invention. It is also within the scope of the present invention that more than one compound of the present invention may be used, and preferably administered, in a method of the present invention.

[0399] It will be appreciated that the compositions of the invention and pharmaceutical compositions of the invention may be prepared in a conventional manner.

[0400] Radiopharmaceuticals lose their radioactivity over time as a result of radioactive decay. In diagnostic radiopharmaceuticals, the physical half-life of the radionuclides is often short. In such cases, the final preparation must be carried out immediately before administration to the patient. This is particularly the case for positron-emitting radiopharmaceuticals for tomography (PET radiopharmaceuticals). In many cases, semi-finished products, such as radionuclide generators, radioactive precursors and kits, are used.

[0401] In some embodiments, the kits of the invention, apart from one or more compounds of the invention, typically include at least one of the following: instructions for use, final preparation and / or quality control instructions, one or more optional excipients, one or more optional reagents for labeling procedures, optionally one or more radionuclides with or without shielded containers, and optionally one or more pieces of equipment, wherein the equipment is selected from the group consisting of labeling equipment, purification equipment, analytical equipment, handling equipment, radiation protection equipment, or administration equipment.

[0402] Shielded containers, known as "pigs," for general handling or transport of radiopharmaceutical containers come in a variety of shapes, e.g., bottles, vials, syringes, etc., for holding the radiopharmaceutical containers. One shape includes a removable cover that allows access to the held radiopharmaceutical container. When the pig cover is in place, radiation exposure is permitted.

[0403] In some embodiments, the labeling device is selected from the group of an open reactor, a closed reactor, a microfluidic system, a nanoreactor, a cartridge, a pressure vessel, a vial, a temperature-controllable reactor, a mixing or shaking reactor, and combinations thereof.

[0404] In some embodiments, the purification device is selected from the group of an ion exchange chromatography column or device, a size exclusion chromatography column or device, an affinity chromatography column or device, a gas or liquid chromatography column or device, a solid phase extraction column or device, a filtration device, a centrifuge vial column or device, and combinations thereof.

[0405] In some embodiments, the analytical device is selected from the group of tests or test devices for determining the identity, radiochemical purity, radionuclide purity, radioactivity content and specific activity of a radiolabeled compound, and combinations thereof.

[0406] In some embodiments, the handling device is selected from the group consisting of devices for mixing, diluting, dispensing, labeling, injecting, administering to a subject, and combinations thereof, of radiopharmaceuticals.

[0407] In some embodiments, radiation protection devices are used to protect physicians and other personnel from radiation during the use of therapeutic or diagnostic radionuclides. In some embodiments, the radiation protection device is selected from the group consisting of devices with a protective barrier of a radiation absorbing material selected from the group consisting of aluminum, plastic, wood, lead, iron, lead glass, water, rubber, plastic, and cloth, devices that ensure an appropriate distance from the radiation source, devices that reduce exposure time to the radionuclide, devices that limit inhalation, ingestion, or other modes of entry of radioactive material into the body, and devices that provide a combination of these measures.

[0408] In some embodiments, the administration device is selected from the group of syringes, shielded syringes, needles, pumps, and infusion devices, and combinations thereof. Shielded syringes are generally hollow cylindrical structures that house the cylindrical body of the syringe and are constructed of lead or tungsten with a lead glass window that allows the handler to view the syringe plunger and the fluid level within the syringe.

[0409] Those skilled in the art will recognize that the terms disclosure and invention are used interchangeably in this description.

[0410] Those skilled in the art will further appreciate that in this description, the terms pharmaceutical agent and therapeutic agent are used interchangeably. [Example]

[0411] Example The following examples are included to provide guidance to those skilled in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present invention and the general level of skill in the art, those skilled in the art will recognize that the following examples are intended to be illustrative only, and that numerous changes, modifications, and variations can be utilized without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are intended for illustrative purposes only and should not be construed as in any way limiting the preparation of compounds of the present invention by other methods.

[0412] Abbreviations specifically used in this application and the examples below are as follows:

[0413] [Table 3] TIFF2024527627000136.tif218170 TIFF2024527627000137.tif210170 TIFF2024527627000138.tif212170 TIFF2024527627000139.tif209170 TIFF2024527627000140.tif97170

[0414] Example 1: Materials and Methods The materials and methods and general procedures are further illustrated by the following examples.

[0415] solvent Solvents were used in the specified quality without further purification: acetonitrile (Super Gradient, HPLC, VWR - for analytical purposes; PrepSolv, Merck - for preparative purposes); cyclohexane; dichloromethane (synthesis grade, Roth); N,N-dimethylformamide (peptide synthesis grade, Biosolve); methanol (synthesis grade, Roth); methyl tert-butyl ether (synthesis grade, Roth); tetrahydrofuran (purification grade, Sigma-Aldrich).

[0416] Water: Milli-Q Plus, Millipore, desalted.

[0417] chemicals Chemicals were synthesized according to or analogous to literature procedures or purchased from Sigma-Aldrich-Merck (Deisenhofen, Germany), Bachem (Bubendorf, Switzerland), VWR (Darmstadt, Germany), Novabiochem (Merck Group, Darmstadt, Germany), Iris Biotech (Marktredwitz, Germany), Roth (Karlsruhe, Germany) or other companies and used in the stated quality without further purification.

[0418] HPLC / MS analysis As one typical, non-limiting example, HPLC / MS analysis was performed by injecting 5 μl of sample solution and using a two-step gradient (5-65% B in 12 min, followed by 65-90% in 0.5 min, A: 0.1% TFA in water and B: 0.1% TFA in ACN) for all chromatograms. The typical setup and instrument configuration are as follows: RP column from Agilent (Poroshell 120, 2.7 μm, EC-C18, 50 × 3.00 mm, flow rate 0.8 ml, HPLC, room temperature); mass spectrometer: Agilent 6230 LC / TOF-MS, ESI ionization. MassHunter Qualitative Analysis B.07.00 SP2 software was used. UV detection was performed at λ = 230 nm. Retention time (R t ) are given in decimal notation (e.g., 1.9 min = 1 min 54 s) and are based on detection by UV spectroscopy. The "Find Compounds by Formula" function was used to evaluate the masses of the observed compounds. In particular, the individual "Compound Neutral Mass (in Daltons)" values ​​and the corresponding isotope distribution patterns were used to confirm the compound identities.

[0419] Preparation of compounds Specific embodiments for preparing the compounds of the present invention are provided in the following examples. Unless otherwise specified, all starting materials and reagents are of standard commercial grade and are used without further purification or are easily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that, in light of the present invention, the starting materials and reaction conditions can be varied, including additional steps utilized to prepare compounds encompassed by the present invention.

[0420] Example 2: Synthesis A suitable synthetic strategy for the compounds of the present invention typically involves the late introduction of a chelating agent, with the precursor being a compound bearing a corresponding nitrogen-protecting group. Example 2a illustrates several synthetic routes to the N-Boc-protected precursors (1-8). These precursors are ultimately converted to the compounds of the present invention by applying a general two-step method (Example 2b).

[0421] Example 2a: Synthesis of N-Boc protected precursors shown below as intermediates (1-8) [ka]

[0422] Preparation of intermediate (4), a Boc-protected precursor for the synthesis of DOTA compound 3BP-4663 [ka] The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0423] Step A: Synthesis of 7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (10) 7-Bromoquinoline-4-carboxylic acid (9, 100 mg, 0.397 mmol) and 3-(tert-butoxycarbonyl)phenylboronic acid (105.7 mg, 0.476 mmol) were dissolved in a mixture of DME (4 mL) and 2 M aqueous NaHCO3 (1.190 mL, 2.380 mmol). The flask was evaporated and vented with nitrogen, and the procedure was repeated. After adding bis(triphenylphosphine)palladium(II) dichloride (75.4 mg, 0.198 mmol), the mixture was stirred at 80 °C. After complete conversion, the mixture was cooled to RT, filtered, and evaporated to dryness to yield the title compound. The crude material was used without further purification. MS (m / z): 350.3 [M+H + ].

[0424] Step B: Synthesis of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11) A solution of 7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (10, 138.6 mg, 0.397 mmol) and glycine methyl ester hydrochloride (69.7 mg, 0.555 mmol) was dissolved in anhydrous DMF (10 mL). The solution was cooled to 0 °C, and at this temperature, HATU (226.3 mg, 0.595 mmol) and DIPEA (269.9 μL, 1.587 mmol) were added. The reaction mixture was stirred and warmed to RT. After complete conversion (LCMS), the mixture was evaporated and purified by flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 421.0 [M+H + ].

[0425] Step C: Synthesis of 2-(7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (12) To a solution of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11, 233.5 mg, 0.555 mmol) in a mixture of THF (5.0 mL) and HO (0.5 mL) was added lithium hydroxide monohydrate (46.6 mg, 1.111 mmol). The mixture was stirred for 3 h. After complete conversion, the mixture was neutralized using 1 M aqueous hydrochloric acid and subsequently evaporated to dryness to yield the title compound. This product was used without further purification. MS (m / z): 407.1 [M+H + ].

[0426] Step D: Synthesis of tert-butyl 3-(4-(2-((S)-2-((R)-benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (13) A solution of 2-(7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (12, 129.0 mg, 0.317 mmol) and (2S)-2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidinium 2,2,2-trifluoroacetate (18, 90.1 mg, 0.413 mmol) in anhydrous DMF (3.2 mL) was cooled to 0° C. Subsequently, HATU (181.0 mg, 0.476 mmol) and DIPEA (108 μL, 0.635 mmol) were added. The mixture was stirred and allowed to reach RT. After stirring for 15 min, the volatiles were removed in vacuo and the crude product was purified by chromatography on silica (eluting with DCM / MeOH) to give the title product. MS (m / z): 607.5 [M+H + ].

[0427] Step E: Synthesis of (S)-tert-butyl 3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (14) DMP (107.7 mg, 0.254 mmol) was added to a solution of tert-butyl 3-(4-(2-((S)-2-((R)-benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (13, 77.0 mg, 0.127 mmol) in DCM (1.3 mL). After stirring at RT for 3 h, the mixture was concentrated to dryness and the crude product was subjected to flash column chromatography on silica gel (eluted with DCM / MeOH). MS (m / z): 605.2 [M+H + ].

[0428] Step F: Synthesis of (S)-3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (15) (S)-tert-Butyl 3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (14, 60.0 mg, 0.10 mmol) was dissolved in a mixture of TFA (152.9 μL, 1.99 mmol) and DCM (408 μL) and stirred at RT for 3 h. After complete conversion, the mixture was concentrated to dryness and used without further purification. MS (m / z): 549.1 [M+H + ].

[0429] Step G: Synthesis of (S)-tert-butyl 4-(2-(3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzamido)ethyl)piperazine-1-carboxylate (4) A solution of (S)-3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoic acid (15, 57.9 mg, 0.106 mmol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (33.9 mg, 0.148 mmol) in anhydrous DMF was cooled to 0° C. Subsequently, HATU (60.2 mg, 0.158 mmol) and DIPEA (35.9 μL, 0.211 mmol) were added at this temperature. After stirring at RT for 30 min, the mixture was concentrated to dryness and subjected to reverse-phase HPLC to yield the title compound. MS (m / z): 760.6 [M+H + ].

[0430] Step H: Synthesis of (2S)-tert-butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (17) Benzo[d]oxazole (1.793 g, 15.056 mmol) was dissolved in anhydrous THF (2 mL / mmol) under an argon atmosphere and cooled to −20 °C. At this temperature, isopropylmagnesium chloride (2 M in diethyl ether, 9.034 mL, 18.068 mmol) was added dropwise. Stirring at −20 °C was continued for 1 h before a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (16, 2.359 mL, 12.547 mmol) in anhydrous THF (12.5 mL) was added. The mixture was stirred for 2 h and allowed to reach room temperature. After 2 h, the reaction was quenched by the addition of saturated aqueous NH4Cl (12 mL), and the mixture was stirred for 1 h. The reaction mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (Na2SO4), and evaporated to dryness. The crude mixture was purified by flash column chromatography on silica (eluting with heptane / EA) to give the title compound. MS (m / z): 319.3 [M+H + ].

[0431] Step J: Synthesis of (2S)-2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidinium 2,2,2-trifluoroacetate (18) (2S)-tert-Butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (17, 1.550 g, 4.869 mmol) was dissolved in anhydrous DCM (36 mL) and TFA (7.501 mL, 97.371 mmol) was added dropwise. The mixture was stirred at RT for 1 h. After complete conversion (1 h), the volatiles were removed in vacuo to yield the title compound. This product was used without further purification. MS (m / z): 218.9 [M+H + ].

[0432] The corresponding N-Boc protected precursors, intermediates 1, 2, and 3 (for the synthesis of compounds 3BP-4665, 3BP-4664, and 3BP-4694, respectively), were prepared following a procedure similar to that described for intermediate 4. Those skilled in the art will recognize that simple variations in the substitution pattern of the starting material in Step A will lead to the desired regioisomeric target molecules.

[0433] Additionally, it is straightforward to incorporate various other Boc-protected diamines into the structure by varying the building block introduced in step C. For example, the synthesis of the intermediate for 3BP-3582 was carried out similarly to precursor 4 described above, but in step G, a mono-Boc-protected diamino-propane was coupled instead of the Boc-piperazine building block. Subsequent deprotection and DOTA coupling gave 3BP-3582.

[0434] Preparation of intermediate (6), a Boc-protected precursor for the synthesis of 3BP-4809 [ka] The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0435] Step A: Synthesis of 6-(6-(methoxycarbonyl)pyridin-3-yl)quinoline-4-carboxylic acid (20) 6-Bromoquinoline-4-carboxylic acid (19, 100.0 mg, 0.397 mmol), 2-(methylcarboxy)pyridine-5-boronic acid pinacol ester (125.3 mg, 0.476 mmol), bis(triphenylphosphine)palladium(II) dichloride (75.4 mg, 0.198 mmol), and 2 M aqueous NaHCO (1.190 mL, 2.380 mmol) were reacted according to the synthesis of 7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (10) to give the title compound. This compound was used in the next step without further purification. MS (m / z): 219.8 [M+H + ].

[0436] Step B: Synthesis of 6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxylic acid (21) A mixture of 6-(6-(methoxycarbonyl)pyridin-3-yl)quinoline-4-carboxylic acid (20, 122.3 mg, 0.397 mmol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (207.4 mg, 1.190 mmol) was stirred at 40 °C overnight. After complete conversion, the crude product was purified by flash column chromatography on silica gel (eluted with DCM / MeOH) to give the title compound. MS (m / z): 504.1 [MH + ].

[0437] Step C: Synthesis of tert-butyl 4-(2-(5-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (22) 6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxylic acid (21, 136.0 mg, 0.269 mmol), glycine methyl ester hydrochloride (47.3 mg, 0.377 mmol), HATU (153.4 mg, 0.404 mmol), and DIPEA (183.0 μL, 1.076 mmol) were reacted according to the synthesis of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11) to produce the title compound after flash column chromatography (eluted with DCM / MeOH). MS (m / z): 577.7 [M+H + ].

[0438] Step D: Synthesis of 2-(6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxamide)acetic acid (23) 4-(2-(5-(4-(2-Methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (22, 96.0 mg, 0.166 mmol) was reacted with lithium hydroxide monohydrate (24.5 mg, 0.583 mmol) according to the synthesis of 2-(7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (12) to produce the title compound. This product was used without further purification. MS (m / z): 563.5 [M+H + ].

[0439] Step E: Synthesis of (S)-tert-butyl 4-(2-(5-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (6) 2-(6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxamido)acetic acid (23, 30.9 mg, 0.055 mmol), (S)-benzo[d]oxazol-2-yl(pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (25, 22.2 mg, 0.071 mmol), HATU (31.4 mg, 0.082 mmol), and DIPEA (18.7 μL, 0.110 mmol) were reacted in anhydrous DMF (550 μL) according to the synthesis of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11) to give the title compound after reverse-phase HPLC. MS(m / z):761.5[M+H + ].

[0440] Step F: Synthesis of (S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)pyrrolidine-1-carboxylate (24) (2S)-tert-butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (17, 185.0 mg, 0.581 mmol) was reacted with DMP (492.9 mg, 1.162 mmol) in DCM (5.8 mL) according to the synthesis of (S)-tert-butyl 3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (14) to yield the title compound after flash column chromatography (eluted with EA / heptane). MS (m / z): 316.8 [M+H + ].

[0441] Step G: Synthesis of (S)-benzo[d]oxazol-2-yl(pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (25) (S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)pyrrolidine-1-carboxylate (24, 108.0 mg, 0.341 mmol) was reacted in anhydrous DCM (1.7 mL) with TFA (526.0 μL, 6.828 mmol) according to the synthesis of (2S)-2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidinium 2,2,2-trifluoroacetate to produce the title compound. MS (m / z): 216.6 [M+H + ].

[0442] Preparation of intermediate (7), a Boc-protected precursor for the synthesis of DOTA compound 3BP-4810 [ka] The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0443] Step A: Synthesis of tert-butyl 4-(3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yloxy)propyl)piperazine-1-carboxylate (27) 6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (26, 160 mg, 0.385 mmol), glycine methyl ester hydrochloride (67.7 mg, 0.539 mmol), HATU (219.6 mg, 0.578 mmol), and DIPEA (196.5 μL, 1.155 mmol) were reacted according to the synthesis of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11) to produce the title compound after flash column chromatography (eluted with DCM / MeOH). MS (m / z): 487.3 [M+H + ].

[0444] Step B: Synthesis of 2-(6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxamide)acetic acid (28) tert-Butyl 4-(3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yloxy)propyl)piperazine-1-carboxylate (27, 202.0 mg, 0.415 mmol) was reacted with lithium hydroxide monohydrate (34.9 mg, 0.830 mmol) according to the synthesis of 2-(7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (12) to produce the title compound. This product was used without further purification. MS (m / z): 473.3 [M+H + ].

[0445] Step C: Synthesis of tert-butyl 4-(3-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yloxy)propyl)piperazine-1-carboxylate (7) 2-(6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxamido)acetic acid (28, 100 mg, 0.212 mmol), benzo[d]oxazol-2-yl((2S,4S)-4-fluoropyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (34, 69.4 mg, 0.296 mmol), HATU (112.7 mg, 0.296 mmol), and DIPEA (72.0 μL, 0.423 mmol) were dissolved in (S)-tert-butyl benzoate. The reaction was carried out according to the synthesis of 4-(2-(5-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (6) to yield the title compound after reverse phase HPLC. MS (m / z): 689.2 [M+H + ].

[0446] Step D: Synthesis of (2S,4S)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (30) Lithium aluminum hydride (195.2 mg, 5.140 mmol) was added to a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1000.0 mg, 4.290 mmol) in anhydrous THF (4.3 mL) at 0 °C, and the mixture was allowed to reach rt. After 30 min, sodium sulfate decahydrate was added to quench the reaction, and stirring was continued for 30 min. The mixture was filtered, and the filtrate was carefully evaporated in vacuo (p > 120 mbar). MS (m / z): 219.8 [M+H + ].

[0447] Step E: Synthesis of (2S,4S)-tert-butyl 4-fluoro-2-formylpyrrolidine-1-carboxylate (31) DMP (1021.0 mg, 2.408 mmol) was added to a solution of (2S,4S)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (30, 480.0 mg, 2.189 mmol) in DCM (20 mL). The mixture was stirred at rt for 3 h. After complete conversion, the volatiles were removed in vacuo and the crude product was subjected to flash column chromatography on silica gel (eluting with DCM → EA). MS (m / z): 216.0 [MH + ].

[0448] Step F: Synthesis of (2S,4S)-tert-butyl 2-((R)-benzo[d]oxazol-2-yl(hydroxy)methyl)-4-fluoropyrrolidine-1-carboxylate (32) (2S,4S)-tert-butyl 4-fluoro-2-formylpyrrolidine-1-carboxylate (31, 480.0 mg, 2.210 mmol), benzo[d]oxazole (315.8 mg, 2.651 mmol), and isopropylmagnesium chloride (2 M in diethyl ether, 1590.9 μL, 3.182 mmol) were reacted according to the synthesis of (2S)-tert-butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (17) to produce the title compound after flash column chromatography on silica gel (eluted with heptane / EA). MS (m / z): 337.0 [M+H + ].

[0449] Step G: Synthesis of (2S,4S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidine-1-carboxylate (33) (2S,4S)-tert-butyl 2-((R)-benzo[d]oxazol-2-yl(hydroxy)methyl)-4-fluoropyrrolidine-1-carboxylate (32, 180 mg, 0.535 mmol) was reacted with DMP (249.7 mg, 0.589 mmol) according to the synthesis of (S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)pyrrolidine-1-carboxylate (24) to give the title compound after flash column chromatography (eluted with heptane / EA). MS (m / z): 334.8 [M+H + ].

[0450] Step H: Synthesis of benzo[d]oxazol-2-yl((2S,4S)-4-fluoropyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (34) (2S,4S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidine-1-carboxylate (33, 140 mg, 0.419 mmol) was reacted with TFA (645.2 μL, 8.375 mmol) according to the synthesis of (2S)-2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidinium 2,2,2-trifluoroacetate (18). MS (m / z): 234.9 [M+H + ].

[0451] Intermediate (5), a Boc-protected precursor for preparing 3BP-4808, was prepared according to the procedure described for intermediate (7), except that in step C, building block (25) was used instead of (34).

[0452] Compound 3BP-3412 was prepared analogously to these syntheses by using the corresponding building block bearing two fluorine substituents at the 4-position of the pyrrolidine.

[0453] Preparation of intermediate (8), a Boc-protected precursor for the synthesis of 3BP-4811 [ka] The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0454] Step A: Synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (35) 6-Bromoquinoline-4-carboxylic acid (19, 800.0 mg, 3.174 mmol), 4-(tert-butoxycarbonyl)phenylboronic acid (1057.1 mg, 4.761 mmol), bis(triphenylphosphine)palladium(II) dichloride (603.4 mg, 1.587 mmol), and 2 M aqueous NaHCO (9.5 mL, 19.043 mmol) were reacted according to the synthesis of 7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (10) to give the title compound, which was used in the next step without further purification. MS (m / z): 350.3 [M+H + ].

[0455] Step B: Synthesis of tert-butyl 4-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (36) 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (35, 554.4 mg, 1.587 mmol), glycine methyl ester hydrochloride (278.9 mg, 2.222 mmol), HATU (905.0 mg, 2.380 mmol), and DIPEA (1079.4 μL, 6.347 mmol) were reacted according to the synthesis of tert-butyl 3-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-7-yl)benzoate (11) to produce the title compound after flash column chromatography (eluted with DCM / MeOH). MS (m / z): 421.5 [M+H + ].

[0456] Step C: Synthesis of 2-(6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (37) tert-Butyl 4-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (36, 1334.5 mg, 3.174 mmol) was reacted with lithium hydroxide monohydrate (266.4 mg, 6.348 mmol) according to the synthesis of 2-(7-(3-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxamido)acetic acid (12) to produce the title compound. This product was used without further purification. MS (m / z): 407.0 [M+H + ].

[0457] Step D: Synthesis of tert-butyl 4-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (38) 2-(6-(4-(tert-butoxycarbonyl)phenyl)-quinoline-4-carboxamido)acetic acid (37, 128.9 mg, 0.317 mmol), benzo[d]oxazol-2-yl((2S,4S)-4-fluoropyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (34, 89.1 mg, 0.381 mmol), HATU (180.9 mg, 0.476 mmol), and DIPEA (107.9 μL, 0.634 mmol) were added to (S)-tert-butyl benzoate. The reaction was carried out according to the synthesis of 4-(2-(5-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (6) to yield the title compound after flash chromatography on silica gel (eluted with DCM / MeOH). MS (m / z): 623.1 [M+H + ].

[0458] Step E: Synthesis of 4-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoic acid (39) tert-Butyl 4-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (38, 184.0 mg, 0.296 mmol) was reacted with TFA (455.3 μL, 5.910 mmol) according to the synthesis of (S)-3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzoic acid (15) to give the title compound, which was used in the next step without further purification. MS (m / z): 567.2 [M+H + ].

[0459] Step F: Synthesis of tert-butyl 4-(2-(4-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzamido)ethyl)piperazine-1-carboxylate (8) 4-(4-(2-((2S,4S)-2-(benzo[d]oxazole-2-carbonyl)-4-fluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoic acid (39, 167.4 mg, 0.295 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (115.2 mg, 0.502 mmol), HATU (168.5 mg, 0.443 mmol), and DIPEA (100.5 μL, 0.591 mmol) were dissolved in DMF (2.95 mL) to prepare (S)-tert-butyl The reaction was carried out according to the synthesis of 4-(2-(3-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)benzamido)ethyl)piperazine-1-carboxylate (4) to give the title compound after reverse phase HPLC. MS (m / z): 778.5 [M+H + ].

[0460] Example 2b: Final conversion of eight Boc-protected precursors (intermediates 1-8) to compounds of the invention A general procedure for the conversion of Boc-protected compounds (1-8) to DOTA-functionalized compounds: 1) Boc deprotection and 2) DOTA coupling

[0461] 1) Each compound (1-8) was dissolved in a mixture of 20% TFA and 80% DCM and stirred for 20 minutes. After complete conversion, the mixture was concentrated to dryness and used without further purification.

[0462] 2) The crude material from 1) was dissolved in anhydrous DMSO (typically as a 0.05-0.1 M solution) and adjusted to pH 5-7 with DIPEA. DOTA-NHS ester (1.5 equiv.) was added as a solid and neutralized stepwise to pH 7 by the addition of small amounts of DIPEA. The solution was stirred at RT for 2 h. After complete conversion, the DMSO solution was subjected to HPLC purification to give the respective title compounds.

[0463] Table 3 shows compounds prepared according to the procedures described above, starting from intermediates 1-8.

[0464] [Table 4]

[0465] More detailed results of mass spectrometry (calculated vs. observed) for the title compounds, including compounds of the present invention, are provided in Table 6, which follows Example 8.

[0466] Example 2c: Preparation of Compound 3BP-3376 [ka] (S)—N-(2-(2-(1H-1,2,4-triazole-5-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0467] Step A: Synthesis of methyl 2-(quinoline-4-carboxamido)acetate (40) A solution of quinoline-4-carboxylic acid (3.29 g, 18.99 mmol) and methyl 2-aminoacetate hydrochloride (2.50 g, 19.98 mmol) in anhydrous DMF (25 mL) was cooled to 0 °C. At this temperature, HATU (8.36 g, 21.98 mmol) and DIPEA (13.59 mL, 79.94 mmol) were added, and the resulting solution was stirred at RT overnight. After complete conversion of the starting material, the mixture was evaporated to dryness. The remaining residue was redissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with DCM / MeOH) to give the title compound. MS (m / z): 245.2 [M+H + ].

[0468] Step B: Synthesis of 2-(quinoline-4-carboxamido)acetic acid (41) Methyl 2-(quinoline-4-carboxamido)acetate (40, 4.63 g, 18.96 mmol) was dissolved in methanol (9.8 mL) and water (9.8 mL). 1 M aqueous NaOH solution (28.44 mL, 28.44 mmol) was added and the mixture was stirred at RT overnight. After complete consumption of the starting material, the mixture was concentrated in vacuo. The remaining residue was dissolved in a minimum amount of water. The aqueous solution was washed twice with DCM. The organic phase was subsequently acidified using concentrated HCl. The product was collected by filtration and dried in vacuo. MS (m / z): 230.8 [M+H + ].

[0469] Step C: Synthesis of N-(2-((2S)-2-(hydroxy(1H-1,2,4-triazol-5-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (42) A solution of 2-(quinoline-4-carboxamido)acetic acid (41, 82.1 mg, 0.36 mmol) and (S)-pyrrolidin-2-yl(1H-1,2,4-triazol-5-yl)methanol (45, 50.0 mg, 0.30 mmol) in anhydrous DMF (3 mL) was cooled to 0 °C. At this temperature, HATU (146.9 mg, 0.39 mmol) and DIPEA (202.2 μL, 1.19 mmol) were added, and the solution was stirred at RT overnight. After complete consumption of the starting material, the mixture was evaporated to dryness, and the crude product was purified by flash chromatography on silica gel (eluting with DCM / MeOH) to give the title compound. MS (m / z) 381.1 [M+H + ].

[0470] Step D: Synthesis of (S)—N-(2-(2-(1H-1,2,4-triazole-5-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (3BP-3376) To a solution of N-(2-((2S)-2-(hydroxy(1H-1,2,4-triazol-5-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (42, 88.2 mg, 0.23 mmol) in DCM (820 μL) was added Dess-Martin periodinane (196.7 mg, 0.46 mmol) and the mixture was stirred at RT overnight. After complete consumption of the starting material, a solution of NaHCO3 / Na2S2O3 (10% / 10%; 850 μL) was added and the phases were separated. The organic phase was washed with aqueous Na2S2O3 (25%, 850 μL) and brine (850 μL), dried (Na2SO4), filtered and evaporated to dryness. The crude product was subjected to HPLC purification. MS (m / z) 429.3 [M+H + ].

[0471] Step E: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (43) 3,4-Dihydro-2H-pyran (4.57 mL, 50 mmol) and 4-methylbenzene-1-sulfonic acid (480 mg, 2.5 mmol) were added to a solution of 1H-1,2,4-triazole (1.73 g, 25 mmol) in anhydrous THF (12 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 4 h. After complete consumption of the starting material, the mixture was diluted with EA (6 mL) and washed with aqueous NaHCO (1 M, 10 mL). The organic phase was dried (Na SO), filtered, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (eluted with heptane / EA) to give the title compound. MS (m / z) 153.9 [M+H + ].

[0472] Step F: Synthesis of (2S)-tert-butyl 2-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)methyl)pyrrolidine-1-carboxylate (44) The Schlenk flask was evacuated and ventilated with argon. 1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (43, 490.4 mg, 3.2 mmol) and anhydrous THF (7.5 mL) were added and cooled to −78 °C. At this temperature, BuLi (2.5 M in hexane, 1280 μL, 3.2 mmol) was added, and stirring at −78 °C was continued for 1 h. Then, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (500 mg, 2.7 mmol) in anhydrous THF (2.5 mL) was added, and stirring at −78 °C was continued for 3 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (2 mL) and stirred for 1 h. The mixture was extracted with EA (3 × 3 mL). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (eluting with heptane / EA) to give the title compound. MS (m / z): 353.6 [M+H + ].

[0473] Step G: Synthesis of (S)-pyrrolidin-2-yl(1H-1,2,4-triazol-5-yl)methanol hydrochloride (45) A solution (3 mL) of (2S)-tert-butyl 2-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-yl)methyl)pyrrolidine-1-carboxylate (44, 799.3 mg, 2.27 mmol) in a mixture of 3 M HCl in methanol was stirred at room temperature. After complete consumption of the starting material (4 h, TLC), the mixture was evaporated and used without further purification. MS (m / z) 168.7 [M+H + ].

[0474] Example 2d: Preparation of compound 3BP-3707 [ka] (S)-N-(2-(2-(5-methyl-1,2,4-oxadiazole-3-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0475] Step A: Synthesis of (S)-tert-butyl 2-(acetoxy(cyano)methyl)pyrrolidine-1-carboxylate (46) To a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (200.0 mg, 1.00 mmol) in DME (5 mL) was added acetic anhydride (379.5 μL, 4.02 mmol) and sodium cyanide (59.0 mg, 1.21 mmol). The mixture was stirred at RT overnight. After complete consumption of the starting material, it was extracted with EA (2 × 25 mL). The combined organic phases were washed with water (2 × 10 mL), dried (NaSO) and evaporated to dryness. The crude product was used without further purification. MS (m / z): 286.1 [M+NH + ].

[0476] Step B: Synthesis of (S)-tert-butyl 2-(acetoxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidine-1-carboxylate (47) (S)-tert-Butyl 2-(acetoxy(cyano)methyl)pyrrolidine-1-carboxylate (46, 269.3 mg, 1.00 mmol) was dissolved in EtOH / HO = 5:1 (2.1 mL). Hydroxylamine hydrochloride (97.6 mg, 1.41 mmol) and sodium acetate (205.8 mg, 2.51 mmol) were added, and the mixture was stirred at 40 °C for 4.5 h. The mixture was then evaporated to dryness. The remaining residue was redissolved in EA (2.5 mL) and washed with brine (2 × 5 mL). The organic phase was dried (NaSO) and evaporated to dryness. The resulting intermediate was used without further purification.

[0477] The intermediate was dissolved in toluene (0.7 mL) and acetic anhydride (286.5 μL, 3.01 mmol) was added. The mixture was stirred at 110° C. overnight. After complete conversion, the mixture was evaporated to dryness and the crude product was subjected to flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 225.9 [M-Boc+H + ].

[0478] Step C: Synthesis of (S)-tert-butyl 2-(hydroxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidine-1-carboxylate (48) A solution of (S)-tert-butyl 2-(acetoxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidine-1-carboxylate (47, 218.3 mg, 0.67 mmol) in a mixture of methanolic ammonia / MeOH = 1:1 (2 mL) was stirred at RT overnight. After complete conversion, the solution was concentrated in vacuo. The crude product was used without further purification. MS (m / z): 283.9 [M+H + ].

[0479] Step D: Synthesis of (S)-(5-methyl-1,2,4-oxadiazol-3-yl)(pyrrolidin-2-yl)methanol 2,2,2-trifluoroacetate (49) To a solution of (S)-tert-butyl 2-(hydroxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidine-1-carboxylate (48, 190.1 mg, 0.67 mmol) in DCM (1.34 mL) was added 2,2,2-trifluoroacetic acid (1.03 mL, 13.42 mmol) and stirred at RT overnight. After complete conversion, the solution was concentrated in vacuo to yield the title compound. MS (m / z): 184.0 [M+H + ].

[0480] Step E: Synthesis of (S)—N-(2-(2-(hydroxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (50) (S)-(5-Methyl-1,2,4-oxadiazol-3-yl)(pyrrolidin-2-yl)methanol 2,2,2-trifluoroacetate (49, 100 mg, 0.42 mmol) was reacted with 2-(quinoline-4-carboxamido)acetic acid (41, 121.63 mg, 0.35 mmol) according to the synthesis of N-(2-((2S)-2-(hydroxy(1H-1,2,4-triazol-5-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (42) to give the title compound, which was used without further purification. MS (m / z): 396.2 [M+H + ].

[0481] Step F: Synthesis of (S)-N-(2-(2-(5-methyl-1,2,4-oxadiazole-3-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (3BP-3707) (S)—N-(2-(2-(hydroxy(5-methyl-1,2,4-oxadiazol-3-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (50, 137.6 mg, 0.35 mmol) was reacted with Dess-Martin periodinane (295.2 mg, 0.70 mmol) according to the synthesis of (S)—N-(2-(2-(1H-1,2,4-triazole-5-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (3BP-3376). The crude product was purified by HPLC. MS (m / z): 394.3 [M+H + ].

[0482] Example 2e: Preparation of Compound 3BP-3295 [ka] ((S)-4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoic acid The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0483] Step A: Synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51) 6-Bromoquinoline-4-carboxylic acid (50.0 mg, 0.20 mmol), 4-(tert-butoxycarbonyl)phenylboronic acid (66.1 mg, 0.30 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.8 mg, 0.01 mmol) were placed in a flask and evacuated. The flask was then vented with nitrogen. The solid was dissolved in DME (2 mL), 2 M aqueous NaHCO3 (595.1 μL, 1.19 mmol) was added, and the resulting mixture was stirred at 80 °C overnight. After complete consumption of the starting material, the mixture was cooled to RT and evaporated to dryness. The crude product was used without further purification. MS (m / z): 350.3 [M+H +].

[0484] Step B: Synthesis of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52) A solution of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51, 69.3 mg, 0.20 mmol), (S)-2-(2-cyanopyrrolidin-1-yl)-2-oxoethanaminium 4-methylbenzenesulfonate [J. Med. Chem. 2017, 60, 8385] (118.4 mg, 0.24 mmol), HATU (117.6 mg, 0.31 mmol), and DIPEA (202.4 μL, 1.19 mmol) in anhydrous DMF (1.25 mL) was stirred overnight at RT. After complete conversion of the starting material, the mixture was concentrated in vacuo. The crude product was used without further purification. MS (m / z): 485.4 [M+H + ].

[0485] Step C: Synthesis of ((S)-4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoic acid (3BP-3295) To a solution of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52) in EtO (1450 μL) was added water (475 μL). The mixture was cooled to 0° C., concentrated HCl (475 μL) was added over 10 min, and stirring at 0° C. was continued for 1 h. The mixture was then evaporated to dryness (bath temperature 25° C.). The residue was suspended in EtO, sonicated, and evaporated. The crude product was purified by reverse-phase HPLC to give the title compound. MS (m / z): 429.1 [M+H + ].

[0486] Example 2f: Preparation of compound 3BP-4084 [ka] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(hydroxymethyl)-4-(methylsulfonyl)phenyl)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0487] Step A: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (53) To a solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylthio)phenyl)-1,3,2-dioxaborolane (200.0 mg, 0.76 mmol) in methanol (22.5 mL) was added a solution of NaIO4 (300.0 mg, 1.40 mmol) in water (9 mL). The mixture was stirred at RT overnight. After complete conversion, the mixture was filtered. KMnO4 was added to the filtrate and stirred for 10 min. Subsequently, the mixture was filtered again. Methanol was removed in vacuo and the aqueous solution was extracted with EA. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica (eluent: heptane / EA) to give the title compound. MS (m / z): 296.7 [M+H + ].

[0488] Step B: Synthesis of 2-(2-(bromomethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54) 4,4,5,5-Tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (53, 58.0 mg, 0.20 mmol). 53, NBS (36.6 mg, 0.21 mmol), and AIBN (0.5 mg, 3 μmol) were dissolved in CCl4 and refluxed overnight. After cooling to RT, the mixture was filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica (eluent: heptane / EA). MS (m / z): 418.7 [M+HCOO - ].

[0489] Step C: Synthesis of 5-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (55) 2-(2-(bromomethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54, 62.0 mg, 0.17 mmol) was suspended in 1 M aqueous NaOH (248 μL) and THF (248 μL) was added until a clear solution was obtained. The solution was stirred at RT overnight. After complete conversion of the starting material, the pH was adjusted to 6 by adding 1 M aqueous hydrochloric acid, and it was concentrated in vacuo to give the title compound. MS (m / z): 310.9 [MH + ].

[0490] Step D: Synthesis of 6-(2-(hydroxymethyl)-4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (56) (5-(Methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (55, 51.6 mg, 0.17 mmol) was reacted with 6-bromo-4-carboxylic acid (45.8 mg, 0.18 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31.4 mg, 0.08 mmol) according to the synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51). The crude product was purified by flash chromatography on silica (eluent: DCM / MeOH / AcOH). MS (m / z): 357.9 [M+H+ ].

[0491] Step E: Synthesis of (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(hydroxymethyl)-4-(methylsulfonyl)phenyl)quinoline-4-carboxamide (3BP-4084) 6-(2-(hydroxymethyl)-4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (28.8 mg, 0.08 mmol) 56 was reacted with (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (31.8 mg, 0.11 mmol) according to the synthesis of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52). The crude product was purified by HPLC to give the title compound. MS (m / z): 529.1 [M+H + ].

[0492] Example 2g: Preparation of Compound 3BP-4152 [ka] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(cyclopropylmethoxy)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0493] Step A: Synthesis of cyclopropylmethyl 8-(cyclopropylmethoxy)quinoline-4-carboxylate (57) Cesium carbonate (387.5 mg, 1.19 mmol) and TBAI (7.3 mg, 0.02 mmol) were added to a solution of 8-hydroxy-quinoline-4-carboxylic acid (75.0 mg, 0.40 mmol) in acetonitrile (10 mL). Subsequently, bromomethylcyclopropane (267.6 μL, 1.98 mmol) was added, and the mixture was stirred at RT overnight. After complete conversion of the starting material, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound. MS (m / z): 297.8 [M+H + ].

[0494] Step B: Synthesis of 8-(cyclopropylmethoxy)quinoline-4-carboxylic acid (58) To a solution of cyclopropylmethyl 8-(cyclopropylmethoxy)quinoline-4-carboxylate (57, 117.9 mg, 0.40 mmol) in THF (4.0 mL) was added a solution of lithium hydroxide monohydrate (17.5 mg, 0.42 mmol) in water (0.2 mL), and the solution was stirred at RT for 2 h. After complete conversion of the starting material, the solution was concentrated in vacuo to give the title compound. MS (m / z): 243.8 [M+H + ].

[0495] Step C: Synthesis of (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(cyclopropylmethoxy)-quinoline-4-carboxamide (3BP-4152) 8-(Cyclopropylmethoxy)quinoline-4-carboxylic acid (58, 25.0 mg, 0.10 mmol) was reacted with (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (34.3 mg, 0.11 mmol) according to the synthesis of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52). The crude product was purified by HPLC to give the title compound. MS (m / z): 415.0 [M+H + ].

[0496] Example 2h: Preparation of compound 3BP-4025 [ka] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-5-methyl-6-(4-(methylsulfonyl)phenyl)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0497] Step A: Synthesis of 5-bromo-4-methylindoline-2,3-dione and 5-bromo-6-methylindoline-2,3-dione (59) A mixture of 4-bromo-3-methylaniline (10.00 g, 53.75 mmol), 2,2,2-trichloroethane-1,1-diol (9.42 g, 46.97 mmol), hydroxylamine hydrochloride (5.83 g, 83.85 mmol), concentrated HCl (6.90 mL, 83.31 mmol), and NaSO (61.60 g, 433.68 mmol) in water (206 mL) was stirred at 80 °C overnight. After complete consumption of 4-bromo-3-methylaniline and cooling to room temperature, the precipitated crude product was filtered off. This crude product was carefully dissolved in a mixture of concentrated HSO (27.4 mL) and water (9.6 mL), maintaining the temperature at 50–60 °C. After complete addition, the solution was stirred at 80 °C for 1 h. After complete consumption of the starting material, the mixture was filtered, redissolved in 2M NaOH (137 mL), and stirred at RT for 1.5 h. The undissolved solid was filtered off. The filtrate was acidified to pH 1 with concentrated HCl and extracted with EA to give the title compound. MS (m / z): 239.9 [M+H + ].

[0498] Step B: Synthesis of 6-bromo-4-(butoxycarbonyl)-5-methylquinoline-2-carboxylic acid (60) A solution of 5-bromo-4-methylindoline-2,3-dione and 5-bromo-6-methylindoline-2,3-dione (59, 56.0 mg, 2.33 mmol) and pyruvic acid (194.4 μL, 2.80 mmol) in 20% aqueous NaOH (5 mL) was refluxed overnight. After complete consumption of the starting material and cooling to RT, the mixture was filtered. The filter cake was washed with n-BuOH. The filtrate was subsequently acidified to pH 2 with 2 M HCl. The aqueous solution was extracted with n-BuOH. The combined organic phase was concentrated in vacuo, and the crude product was purified by HPLC to give 6-bromo-4-(butoxycarbonyl)-7-methylquinoline-2-carboxylic acid and the title compound. MS (m / z): 365.7 [M+H + ].

[0499] Step C: Synthesis of 6-bromo-5-methylquinoline-2,4-dicarboxylic acid (61) To a solution of 6-bromo-4-(butoxycarbonyl)-5-methylquinoline-2-carboxylic acid (60, 26.2 mg, 72 μmol) in MeOH (2 mL) was added lithium hydroxide monohydrate (6.0 mg, 143 μmol) at 0° C. The solution was stirred at RT overnight. Subsequently, the solution was quenched with Amberlyst IR120 (H + The resin was filtered off and carefully washed with MeOH. The filtrate was evaporated to give the title compound. MS (m / z): 309.7 [M+H + ].

[0500] Step D: Synthesis of 6-bromo-5-methylquinoline-4-carboxylic acid (62) A solution of 6-bromo-5-methylquinoline-2,4-dicarboxylic acid (61, 22.9 mg, 74 μmol) in water (2 mL) was heated to 200° C. for 5 min using a microwave. After complete conversion of the starting material, the solution was lyophilized to give the title compound. MS (m / z): 265.6 [M+H + ].

[0501] Step E: Synthesis of 5-methyl-6-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (63) 6-Bromo-5-methylquinoline-4-carboxylic acid (62, 30.0 mg, 0.11 mmol) was reacted with 4-(methylsulfonyl)phenylboronic acid (45.8 mg, 0.18 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31.4 mg, 0.08 mmol) according to the synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51). The crude product was purified by flash chromatography on silica (eluent: DCM / MeOH / AcOH). MS (m / z): 357.9 [M+H + ].

[0502] Step F: Synthesis of (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-5-methyl-6-(4-(methylsulfonyl)phenyl)quinoline-4-carboxamide (3BP-4025) 5-Methyl-6-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (63, 16.8 mg, 49 μmol) was reacted with (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (16.4 mg, 54 μmol) according to the synthesis of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52). The crude product was purified by HPLC to give the title compound. MS (m / z): 513.0 [M+H + ].

[0503] Example 2i: Preparation of Compound 3BP-4197 [ka] (S)-N-(2-(2-(2-hydroxyacetyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0504] Step A: Synthesis of (S)-tert-butyl 2-vinylpyrrolidine-1-carboxylate (64) KO t Bu (2.0 g, 18.82 mmol) was added to a solution of methyltriphenylphosphonium iodide (7.6 g, 18.82 mmol) in anhydrous THF (33.5 mL) under a nitrogen atmosphere, and the mixture was stirred at RT for 15 min. Subsequently, a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (2.5 g, 12.5 mmol) in anhydrous THF (22.2 mL) was added, and the reaction mixture was stirred at RT overnight. After complete conversion of the starting material, water (33.5 mL) was added, and the mixture was extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica (eluent: heptane / EA) to give the title compound.

[0505] Step B: Synthesis of (S)-tert-butyl 2-(1,2-dihydroxyethyl)pyrrolidine-1-carboxylate (65) Potassium osmate dihydrate and 4-methylmorpholine N-oxide were added to a solution of (S)-tert-butyl 2-vinylpyrrolidine-1-carboxylate (64) in a mixed solvent of acetone / water (10 mL / mmol). The mixture was stirred at RT overnight. 10% aqueous NaSO was then added, and stirring at RT was continued for 1 h. The organic layer was separated, and the aqueous solution was extracted with EA. The combined organic phases were washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by flash chromatography (eluent: heptane / EA) to give the title compound. MS (m / z): 231.9 [M+H + ].

[0506] Step C: Synthesis of (S)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)pyrrolidine-1-carboxylate (66) A solution of (S)-tert-butyl 2-(1,2-dihydroxyethyl)pyrrolidine-1-carboxylate (65, 2.6 g, 11.18 mmol) and imidazole (1.1 g, 16.77 mmol) (3.5 mL / mmol (S)-tert-butyl 2-(1,2-dihydroxyethyl)pyrrolidine-1-carboxylate (65)) in anhydrous DCM was cooled to 0° C. At this temperature, a solution of TBSCl (1.9 mg, 12.29 mmol) in anhydrous DCM (1.5 mL / mmol TBSCl) was added slowly. The mixture was stirred overnight and allowed to reach RT. After complete conversion, the mixture was washed with saturated aqueous NH4Cl and water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica (eluent: heptane / EA) to give the title compound. MS (m / z): 346.0 [M+H + ].

[0507] Step D: Synthesis of (S)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)acetyl)pyrrolidine-1-carboxylate (67) A solution of oxalyl chloride (35.3 μL, 0.42 mmol) in anhydrous DCM (972 μL) was cooled to −78 °C. At this temperature, DMSO (59.2 μL, 0.83 mmol) was added. After stirring at −78 °C for 30 min, a solution of (S)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)pyrrolidine-1-carboxylate (66, 120.0 mg, 0.35 mmol) in anhydrous DCM (324 μL) was slowly added. After stirring for 50 min, NEt (293.3 μL, 2.08 mmol) was added and stirring was continued overnight. During this time, the mixture was allowed to reach RT. After complete conversion, the reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried (NaSO), and evaporated to dryness. The crude product was purified by flash chromatography on silica (eluent: heptane / EA) to give the title compound. MS (m / z): 344.0 [M+H + ].

[0508] Step E: Synthesis of (S)-2-hydroxy-1-(pyrrolidin-2-yl)ethanone (68) (S)-tert-Butyl 2-(2-(tert-butyldimethylsilyloxy)acetyl)pyrrolidine-1-carboxylate (67, 35.4 mg, 0.10 mmol) was dissolved in 1 M HCl in methanol (300.0 μL) and stirred at RT for 1 h. After complete conversion, the mixture was evaporated to dryness. The crude product was used without further purification.

[0509] Step F: Synthesis of (S)-N-(2-(2-(2-hydroxyacetyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (3BP-4197) (S)-2-Hydroxy-1-(pyrrolidin-2-yl)ethanone (68, 13.3 mg, 0.10 mmol) and 2-(quinoline-4-carboxamido)acetic acid (41, 25.6 mg, 0.10 mmol) were dissolved in DMF (1 mL) and cooled to 0 °C. At this temperature, HATU (58.8 mg, 0.16 mmol) was added and the pH was adjusted to pH 6 using DIPEA. The mixture was stirred for 2 h and allowed to reach RT. After complete conversion, the mixture was evaporated to dryness and purified by HPLC to give the title compound. MS (m / z): 342.1 [M+H + ].

[0510] Example 2j: Preparation of Compound 3BP-3581 [ka] (S)-2,2',2''-(10-(2-(3-(4-(4-(2-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tolyl)triacetic acid The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0511] Step A: Synthesis of 4-(3-(tert-butoxycarbonylamino)propylthio)phenylboronic acid (69) To a mixture of 4-mercaptophenylboronic acid (500.0 mg, 3.25 mmol), cesium carbonate (2.12 g, 6.49 mmol), and sodium iodide (486.7 mg, 3.25 mmol) in acetonitrile (12 mL) was slowly added a solution of tert-butyl 3-bromopropylcarbamate (773.2 mg, 3.25 mmol) in acetonitrile (1.2 mL). The mixture was stirred at RT overnight. After complete conversion, the mixture was filtered and the filtrate was evaporated to give the title compound. MS (m / z): 310.0 [MH + ].

[0512] Step B: Synthesis of 4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenylboronic acid (70) A solution of 4-(3-(tert-butoxycarbonylamino)propylthio)phenylboronic acid (69, 1.01 g, 3.25 mmol) in methanol (43.7 mL) was added to a solution of sodium periodate (2.08 g, 9.74 mmol) in water (17 mL). The solution was stirred at RT overnight. After complete conversion, the mixture was filtered. Sodium permanganate (0.31 g, 1.95 mmol) was added and stirring at RT was continued for 2 h. After complete conversion, methanol was evaporated and the remaining aqueous phase was extracted with EA. The combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (eluent: DCM / MeOH) to yield the title compound. MS (m / z): 243.3 [M-Boc+H + ].

[0513] Step C: Synthesis of 6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxylic acid (71) 4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenylboronic acid (70, 310.4 mg, 0.91 mmol) was reacted with 6-bromoquinoline-4-carboxylic acid (190.0 mg, 0.75 mmol) using bis(triphenylphosphine)palladium(II) dichloride (28.7 mg, 0.08 mmol) according to the synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51). The crude product was used without further purification. MS (m / z): 470.9 [M+H + ].

[0514] Step D: Synthesis of methyl 2-(6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxamido)acetate (72) 6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxylic acid (71, 282.1 mg, 0.60 mmol) was reacted with methyl 2-aminoacetate hydrochloride (150.0 mg, 1.20 mmol) according to the synthesis of 2-(quinoline-4-carboxamido)acetate (40) to produce the title compound. MS (m / z): 542.4 [M+H + ].

[0515] Step E: Synthesis of 2-(6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxamido)acetic acid (73) A solution of methyl 2-(6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxamido)acetate (72, 146.3 mg, 0.27 mmol) in 1,4-dioxane (8.4 mL) was cooled to 0 °C, and a solution of lithium hydroxide monohydrate (22.7 mg, 0.54 mmol) was added. The mixture was stirred at room temperature for 4 h. Subsequently, 1,4-dioxane was evaporated, and the remaining aqueous solution was carefully acidified (pH 1-2) with 2 M HCl at 0 °C and directly extracted with DCM (3 × 5 mL). The combined organic phases were dried (NaSO) and concentrated in vacuo to give the title compound. MS (m / z): 428.1 [M-Boc+H + ].

[0516] Step F: Synthesis of (S)-tert-butyl 3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylcarbamate (74) A solution of (S)-benzo[d]oxazol-2-yl(pyrrolidin-2-yl)methanone (78, 55.4 mg, 0.26 mmol) and 2-(6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxamido)acetic acid (73, 123.0 mg, 0.23 mmol) in anhydrous DMF (1.2 mL) was cooled to 0 °C. At this temperature, HATU (115.2 mg, 0.30 mmol) and 2,4,6-trimethylpyridine (90.1 μL, 0.70 mmol) were added, and the mixture was stirred at RT overnight. After complete conversion, the mixture was evaporated to dryness, redissolved in DCM, and washed with water. The organic phase was dried (NaSO) and concentrated in vacuo. The crude product was purified by HPLC to give the title product. MS(m / z): 726.5 [M + H + ].

[0517] Step G: Synthesis of (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-N-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (75) TFA (50.3 μL, 0.44 mmol) was added to a solution of (S)-tert-butyl 3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylcarbamate (74, 16.0 mg, 0.02 mmol) in DCM (260 μL), and the solution was stirred at RT for 1 h. Subsequently, the volatiles were removed in vacuo to give the title compound. MS (m / z): 626.1 [M+H + ].

[0518] Step H: Synthesis of (S)-2,2',2''-(10-(2-(3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tolyl)triacetic acid (3BP-3581) A solution of (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-N-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (75, 13.8 mg, 18.7 μmol), DOTA-NHS ester (25.7 mg, 31.8 μmol) in DMSO (0.7 mL) was neutralized with DIPEA to pH 7. The solution was stirred at RT for 2 h. After complete conversion, the DMSO solution was subjected to HPLC purification to give the title compound. MS (m / z): 1012.3 [M+H + ].

[0519] Step I: Synthesis of (S)-tert-butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (76) The Schlenk flask was evacuated and ventilated with argon. Benzoxazole (762.5 mg, 6.40 mmol) and anhydrous THF (13.3 mL) were added and cooled to -20 °C. At this temperature, isopropylmagnesium chloride (2.0 M in diethyl ether, 3.84 mL, 7.68 mmol) was added, and stirring at -20 °C was continued for 1 h. Then, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (1000.0 mg, 5.34 mmol) in anhydrous THF (5.0 mL) was added at -20 °C. The mixture was stirred overnight and allowed to reach RT. After complete conversion, the reaction was quenched by the addition of saturated aqueous NH4Cl (9 mL) and stirred for 1 h. The mixture was extracted with EA (3 × 9 mL). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (eluting with heptane / EA) to give the title compound. MS (m / z): 353.6 [M+H + ].

[0520] Step J: Synthesis of (S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)pyrrolidine-1-carboxylate (77) Dess-Martin periodinane (199.8 mg, 0.47 mmol) was added to a solution of (S)-tert-butyl 2-(benzo[d]oxazol-2-yl(hydroxy)methyl)pyrrolidine-1-carboxylate (76, 100.0 mg, 0.31 mmol) in CHCl (300 μL), and the mixture was stirred at RT for 4 h. After complete consumption of the starting material, a solution of NaHCO / NaSO (10% / 10%; 3 mL) was added and the phases were separated. The organic phase was washed with aqueous NaSO (25%, 3 mL) and brine (3 mL), dried (NaSO), filtered, and evaporated to dryness to give the title compound. MS (m / z): 317.1 [M+H + ].

[0521] Step K: Synthesis of (S)-benzo[d]oxazol-2-yl(pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (78) TFA (486.5 μL, 6.32 mmol) was added dropwise to a solution of (S)-tert-butyl 2-(benzo[d]oxazole-2-carbonyl)pyrrolidine-1-carboxylate (77, 100.0 mg, 0.32 mmol) in DCM (630 μL). The reaction mixture was stirred at RT for 1 h. After complete conversion, the solution was concentrated in vacuo to give the title compound. MS (m / z): 216.9 [M+H + ].

[0522] Example 2k: Preparation of Compound 3BP-3622 [ka] (S)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)-6-(4-(3-(2-(4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propylsulfonyl)phenyl)quinoline 1-oxide The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0523] Step A: Synthesis of (S)-tert-butyl 3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylcarbamate (79) 6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxylic acid (71, 391.4 mg, 0.44 mmol) was reacted with (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (110.0 mg, 0.36 mmol) according to the synthesis of (S)-tert-butyl 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52). The crude product was purified by flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 640.0 [MH + ].

[0524] Step B: Synthesis of (S)-6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide (80) mCPBA (20.7 mg, 0.12 mmol) was added portionwise to a solution of (S)-tert-butyl 3-(4-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylcarbamate (79, 70.0 mg, 0.11 mmol) in DCM (1.1 mL), and the mixture was stirred at RT overnight. The mixture was filtered, and the residue was washed with DCM (1 mL). The filtrate was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 658.2 [M+H + ].

[0525] Step C: Synthesis of (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide 4-methylbenzenesulfonate (81) A solution of (S)-6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide (80, 80.5 mg, 0.12 mmol) and 4-methylbenzenesulfonic acid monohydrate (32.6 mg, 0.17 mmol) in acetonitrile was stirred at RT overnight. After complete conversion, the volatiles were evaporated to give the title compound. MS (m / z): 558.0 [M+H + ].

[0526] Step D: Synthesis of (S)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)-6-(4-(3-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propylsulfonyl)phenyl)quinoline 1-oxide (3BP-3622) (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide 4-Methylbenzenesulfonate (81, 33.8 mg, 0.05 mmol) was reacted with DOTA-NHS ester (83.1 mg, 0.09 mmol) according to the synthesis of (S)-2,2',2''-(10-(2-(3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3BP-3581) to give the title compound. MS (m / z): 982.6 [M+K + ].

[0527] 3BP-3467 was prepared following a similar procedure as described for 3BP-3622, without the oxidation step B.

[0528] Example 2l: Preparation of compound 3BP-3951 [ka] (S)-2,2',2''-(10-(2-(3-(1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxamido)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0529] Step A: Synthesis of 6-azidoquinoline-4-carboxylic acid (82) Sodium azide (515.8 mg, 7.94 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (1.25 mL, 7.94 mmol) were added to a solution of 6-bromoquinoline-4-carboxylic acid (1000.0 mg, 3.97 mmol) in a 7:1 mixture of ethanol and water (52.8 mL). Sodium ascorbate (1 M in ethanol, 396.7 μL, 0.4 mmol) and CuI (1 M in ethanol, 396.7 μL, 0.4 mmol) were subsequently added, and stirring was continued at 80 °C for 15 min. After complete consumption of the starting material, the mixture was diluted with water and extracted with EA. The combined organic phases were dried (NaSO) and concentrated in vacuo to yield the title compound. MS (m / z): 214.8 [M+H + ].

[0530] Step B: Synthesis of methyl 2-(6-azidoquinoline-4-carboxamido)acetate (83) 6-Azidoquinoline-4-carboxylic acid (82, 832.5 mg, 3.89 mmol) was reacted with methyl 2-aminoacetate hydrochloride (610.0 mg, 4.86 mmol) according to the synthesis of 2-(quinoline-4-carboxamido)acetate (40) to produce the title compound. MS (m / z): 285.9 [M+H + ].

[0531] Step C: Synthesis of tert-butyl 1-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate (84) Copper(II) sulfate pentahydrate (48.6 mg, 0.19 mmol) and sodium ascorbate (77.0 mg, 0.39 mmol) were dissolved in water and t To a solution of tert-butyl propiolate (640.6 μL, 4.67 mmol) and methyl 2-(6-azidoquinoline-4-carboxamido)acetate (83, 1109.4 mg, 3.89 mmol) in a 1:1 mixture of 20 mL of BuOH was added. The mixture was stirred under a nitrogen atmosphere. After complete consumption of the starting material, the mixture was evaporated to dryness and purified by flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 412.0 [M+H + ].

[0532] Step D: Synthesis of 1-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylic acid 2,2,2-trifluoroacetate (85) tert-Butyl 1-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate (84, 490.0 mg, 1.19 mmol) was dissolved in anhydrous DCM (5 mL) and TFA (1.84 mL, 23.82 mmol) was added dropwise. The mixture was stirred at RT for 4 h. After complete conversion of the starting material, the mixture was concentrated in vacuo to yield the title compound. MS (m / z): 355.9 [M+H + ].

[0533] Step E: Synthesis of methyl 2-(6-(4-(3-(tert-butoxycarbonylamino)propylcarbamoyl)-1H-1,2,3-triazol-1-yl)quinoline-4-carboxamide)acetate (86) A solution of 1-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylic acid 2,2,2-trifluoroacetate (85, 560.0 mg, 1.19 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (312.4 μL, 1.79 mmol) was dissolved in DMF (7.95 mL) and cooled to 0 °C. Subsequently, HATU (680.5 mg, 1.79 mmol) and DIPEA (811.6 μL, 4.77 mmol) were added at this temperature. The mixture was stirred overnight at RT. After complete consumption, the mixture was diluted with DCM and washed with water. The organic phase was dried (NaSO) and evaporated to dryness. The crude product was purified by flash chromatography on silica (eluent: DCM / MeOH) to give the title compound. MS(m / z):512.1[M+H + ].

[0534] Step F: Synthesis of 2-(6-(4-(3-(tert-butoxycarbonylamino)propylcarbamoyl)-1H-1,2,3-triazol-1-yl)quinoline-4-carboxamide)acetic acid (87) 3-(tert-Butoxycarbonylamino)propyl 1-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate (86, 457.5 mg, 0.89 mmol) was reacted with lithium hydroxide monohydrate (75.1 mg, 1.79 mmol) according to the synthesis of 2-(6-(4-(3-(tert-butoxycarbonylamino)propylsulfonyl)phenyl)quinoline-4-carboxamido)acetic acid (73) to give the title compound. MS (m / z): 498.2 [M+H + ].

[0535] Step G: Synthesis of (S)-3-(tert-butoxycarbonylamino)propyl 1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate (88) 2-(6-(4-(3-(tert-butoxycarbonylamino)propylcarbamoyl)-1H-1,2,3-triazol-1-yl)quinoline-4-carboxamide)acetic acid (87, 50.0 mg, 0.10 mmol) was reacted with (2S)-pyrrolidine-2-carbonitrile hydrochloride (20.0 mg, 0.15 mmol) according to the synthesis of N-(2-((2S)-2-(hydroxy(1H-1,2,4-triazol-5-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (42) to give the title compound. MS (m / z): 576.2 [M+H + ].

[0536] Step H: Synthesis of (S)-3-aminopropyl 1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate 4-methylbenzenesulfonate (89) (S)-3-(tert-Butoxycarbonylamino)propyl 1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate (88, 48.6 mg, 0.08 mmol) was reacted with 4-methylbenzenesulfonic acid monohydrate (22.5 mg, 0.12 mmol) according to the synthesis of (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide 4-methylbenzenesulfonate (81) to give the title compound. MS (m / z): 476.1 [M+H + ].

[0537] Step K: Synthesis of (S)-2,2',2''-(10-(2-(3-(1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)-quinolin-6-yl)-1H-1,2,3-triazole-4-carboxamido)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3BP-3951) (S)-3-Aminopropyl 1-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-1H-1,2,3-triazole-4-carboxylate 4-Methylbenzenesulfonate (89, 55.1 mg, 0.09 mmol) was reacted with DOTA-NHS ester (116.0 mg, 0.14 mmol) according to the synthesis of (S)-2,2',2''-(10-(2-(3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3BP-3581) to give the title compound. MS (m / z): 1012.2 [M+H + ].

[0538] Example 2m: Preparation of Compound 3BP-4076 [ka] (S)-2,2',2''-(10-(2-(4-(2-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tolyl)triacetic acid 3BP-4076 The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0539] Step A: Synthesis of 6-(6-(methoxycarbonyl)pyridin-3-yl)quinoline-4-carboxylic acid (90) 6-Bromoquinoline-4-carboxylic acid (100 mg, 0.40 mmol) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (313.1 mg, 1.19 mmol) were reacted using bis(triphenylphosphine)palladium(II) dichloride (150.8 mg, 0.40 mmol) according to the synthesis of 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51). The crude product was used without further purification. MS (m / z): 309.0 [M+H + ].

[0540] Step B: Synthesis of 6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxylic acid (91) 6-(6-(methoxycarbonyl)pyridin-3-yl)quinoline-4-carboxylic acid (20.0 mg, 0.065 mmol) (90), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (113.0 mg, 0.65 mmol), and 1,2-dimethoxyethane (150 μL) were stirred overnight at 40 °C. After complete conversion, the mixture was evaporated to dryness and purified by flash chromatography on silica gel (eluent: DCM / MeOH → DCM / MeOH / acetic acid). MS (m / z): 506.5 [M+H + ].

[0541] Step C: Synthesis of (S)-tert-butyl 4-(2-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (92) 6-(6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxylic acid (91, 38.8 mg, 0.073 mmol) was reacted with (S)-2-(2-cyanopyrrolidin-1-yl)-2-oxoethanaminium 4-methylbenzenesulfonate [J. Med. Chem. 2017, 60, 8385] (26.5 mg, 0.087 mmol), HATU (36.0 mg, 0.095 mmol), and DIPEA (49.5 μL, 0.291 mmol) in the presence of (S)-tert-butyl The reaction was carried out according to the synthesis of 4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (52). The crude product was purified by flash chromatography on silica gel (eluent: DCM / MeOH) to give the title compound. MS (m / z): 677.7 [M+H + ].

[0542] Step D: Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(6-(2-(piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxamide 4-methylbenzenesulfonate (93) (S)-tert-Butyl 4-(2-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazine-1-carboxylate (23.2 mg, 0.034 mmol) 92 was reacted with p-toluenesulfonic acid monohydrate (13.0 mg, 0.069 mmol) according to the synthesis of (S)-6-(4-(3-aminopropylsulfonyl)phenyl)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinoline 1-oxide 4-methylbenzenesulfonate (81). The crude product was used without further purification. MS (m / z): 577.2 [M+H + ].

[0543] Step E: Synthesis of (S)-2,2',2''-(10-(2-(4-(2-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)picolinamido)ethyl)piperazin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tolyl)triacetic acid (3BP-4076) (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(6-(2-(piperazin-1-yl)ethylcarbamoyl)pyridin-3-yl)quinoline-4-carboxamide 4-Methylbenzenesulfonate (93, 19.8 mg, 0.034 mmol) was reacted with DOTA-NHS ester (47.1 mg, 0.058 mmol) according to the synthesis of (S)-2,2',2''-(10-(2-(3-(4-(4-(2-(2-(benzo[d]oxazole-2-carbonyl)pyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenylsulfonyl)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3BP-3581). The crude product was purified by HPLC. MS (m / z): 1001.6 [M+K + ].

[0544] The synthesis of 3BP-3772 was carried out following a similar procedure as described for 3BP-4076, utilizing another mono-Boc protected diamine compound in step B, namely, (3-amino-propyl)-carbamic acid tert-butyl ester.

[0545] Example 2n: Preparation of Compound 3BP-3954 [ka] (S)-2,2',2''-(10-(2-((carboxymethyl)(3-(4-(4-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)benzamido)propyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tolyl)triacetic acid The synthesis of the title compound is shown in the following reaction scheme. [ka]

[0546] Step A: Synthesis of tert-butyl 4-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)benzoate (94) 6-(4-(tert-butoxycarbonyl)phenyl)quinoline-4-carboxylic acid (51, 1987.3 mg, 6.07 mmol) was reacted with methyl 2-aminoacetate hydrochloride (635.0 mg, 5.06 mmol) according to the synthesis of 2-(quinoline-4-carboxamido)acetate (40) to produce the title compound. MS (m / z): 421.3 [M+H + ].

[0547] Step B: Synthesis of 4-(4-(2-methoxy-2-oxoethylcarbamoyl)quinolin-6-yl)benzoic acid trifluoroacetate (95) To a solution of tert-butyl 4-(4-(2-methox...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is H or F; R2 is H or F; R3 is —C(O)-Het1; Here, —C(O)-Het1 is 【Chemistry 2】 [In the formula, E is O or S; R ０ is (C １ ~C ４ ) alkyl, —O—(C １ ~C ４ ) alkyl, —COO—(C １ ~C ４ ) independently selected from the group consisting of alkyl, F, Cl, Br, I, OH, COOH, and CN; m is selected from the group consisting of 0, 1 and 2. and R ４ is H, Cl, Br, F and (C １ ~C ２ ) alkyl; R ５ , R ６ and R ７ One of them is R ８ -L- and R ５ , R ６ and R ７ The other two of each independently represent H, (C １ ~C ４ ) alkyl, —O—(C １ ~C ４ ) alkyl, —O—(C １ ~C ３ ) alkylidene-(C ６ ) aryl, F, Cl, Br and O—CF ３ selected from the group consisting of R ８ -L- is R ８ -Lin4-Lin3-Lin2-Lin1- [In the formula, Lin1 is, 【Transformation 3】 , -O-, -N(CH ３ ) - and 【Chemistry 4】 selected from the group consisting of Here, in Lin1, Y is CH or N; 【Transformation 5】 indicates binding to Lin2, and Lin1 indicates binding to 【Transformation 6】 Then Lin2 is 【Transformation 7】 is in the meta or para position relative to 【Transformation 8】 indicates the bond to the quinoline, R ９ is halogen, CO ２ H, (C １ ~C ６ ) alkyl, hydroxy-substituted (C １ ~C ６ ) alkyl and —O—(C １ ~C ６ ) alkyl; n is selected from the group consisting of 0, 1 and 2, preferably n is 0 or 1, more preferably n is 0; Lin1, 【Chemistry 9】 and 【Chemistry 10】 When Lin2 is selected from the group consisting of —C(O)—NH—, —NH—C(O)—, and —S(O) ２ -, and Lin1 is selected from the group consisting of -O- or -N(CH ３ )-, then Lin2 is absent; Lin3 is (C ２ ~C ４ ) alkylidene, Lin4 is -NR １０ , 【Chemistry 11】 selected from the group consisting of Here, in Lin4, 【Chemistry 12】 indicates binding to Lin3, 【Chemistry 13】 is R ８ indicates the bond to R １０ is H, CH ２ -COOH and (C １ ~C ４ ) alkyl; 【Chemistry 14】 In some cases, 【Chemistry 15】 is oxidized to R ８ is a chelating agent or a cytotoxic agent. is] A compound of the formula: In formula (I), 【Chemistry 16】 is optionally its N-oxide 【Chemistry 17】 may be oxidized to The compound, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

2. -C(O)-Het1 is the following: [Chemistry 18] [In the formula, E is O or S; R ０ But -CH ３ , —O—CH ３ , -COOCH ３ , F, Cl and Br] 10. The compound of claim 1 selected from the group consisting of: Preferably, the compound of formula (II): 【Chemistry 19】 or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, having the structure:

3. R ４ is H or -CH ３ and preferably R 4 is H, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

4. R ６ But, R ８ -L, preferably R ５ and R ７ are each independently H and —CH ３ and more preferably, R 5 and R 7 are each H, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

5. R ７ But, R ８ -L, preferably R ５ and R ６ are each independently H and —CH ３ and more preferably, R 5 and R 6 are each H, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

6. Lin1, 【Chemistry 20】 2. The compound of claim 1, wherein:

7. Lin1, 【Chemistry 21】 Preferably, Y is CH, and more preferably, Lin1 is 【Chemistry 22】 2. The compound of claim 1, wherein:

8. The compound of claim 7, wherein n is 0, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

9. Lin2-Lin1 is as follows: 【Chemistry 23】 [In the formula, 【Chemistry 24】 indicates the bond to the quinoline, 【Chemistry 25】 indicates binding to Lin3] and preferably, Lin2-Lin1 is selected from the group consisting of: 【Chemistry 26】 [In the formula, 【Chemistry 27】 indicates the bond to the quinoline, 【Chemistry 28】 indicates binding to Lin3] selected from the group consisting of More preferably, Lin2-Lin1 is: 【Chemistry 29】 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, selected from the group consisting of:

10. Lin3 is -(C ２ ~C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, wherein R is 1 or 2;

11. R ８ -L- is the following: 【Transformation 30】 and preferably R ８ -L- is the following: 【Chemistry 31】 and more preferably, R ８ -L- is the following: 【Chemistry 32】 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, selected from the group consisting of:

12. R 8 -L- is one of the following: 【Transformation 33】 2. The compound of claim 1, wherein:

13. The compound of formula (II): 【Transformation 34】 (In the formula, R 4 , R 5 and R 6 are H; R 7 is R 8 -L-; R 8 -L- is one of the following: 【Chemistry 35】 is) 2. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

14. The compound of formula (II): 【Transformation 36】 (In the formula, R 4 , R 5 and R 7 are H; R 6 is R 8 -L-; R 8 -L- is one of the following: 【Chemistry 37】 is) 2. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof.

15. R ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, wherein:

16. The chelating agent may be DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, DOTAM, HOPO, TRAP, THP, DATA, NOTP, Sarcofadin, FSC, NETA, H4 Octapa, Pycup, N ｘ S ４－ｘ (N4, N2S2, N3S), Hynic, ９９ｍ Tc(CO) ３ 16. The compound of claim 15, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the chelating agent is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropas, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropas, NOTA, and NODAGA, preferably the chelating agent is selected from the group consisting of DOTA, DOTAM, Macropas, NOTA, and NODAGA.

17. R ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, wherein:

18. below 【Transformation 38】 【change】 selected from the group consisting of Preferably, the following: 【Chemistry 39】 【change】 【change】 selected from the group consisting of More preferably, 【Chemistry 40】 2. The compound of claim 1, or a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate, or a pharmaceutically acceptable solvate thereof, selected from the group consisting of:

19. 2. The compound of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, comprising a therapeutically active nuclide, preferably wherein the therapeutically active nuclide is a therapeutically active radionuclide.

20. The compound of claim 19, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the therapeutically active radionuclide is a particle-emitting isotope for therapeutic use and has a decay energy of 0.039 to 10 MeV, preferably 0.4 to 6.5 MeV.

21. The therapeutically active radionuclide is 177 Lu, 225 Ac, 161 Tb, 212 Pb, 90 Y, 47 Sc, 67 Cu, 111 In, 227 Th, 149 Tb, 67 Ga, 211 At, 125 I, 131 I, 186 Re, 188 Re, 153 Sm, 89 Sr, 213 Bi, 223 Ra, 224 Ra and 226 Th, preferably 177 Lu, 225 Ac, 161 Tb, 212 Pb, 90 Y, 47 Sc, 67 Cu, 111 In, 227 20. The compound of claim 19, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the compound is selected from the group consisting of 177 Lu, 225 Ac, 161 Tb, 212 Pb, and 90 Y, more preferably 177 Lu, 225 Ac, 161 Tb, 212 Pb, and 90 Y.

22. The compound of claim 19, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the therapeutically active radionuclide is a therapeutically active radiometal, preferably the therapeutically active radionuclide is selected from the group consisting of 177 Lu, 225 Ac, 161 Tb, 212 Pb, and 90 Y.

23. A compound according to claim 19, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the therapeutically active nuclide is complexed to a chelating agent, preferably wherein the chelating agent is DOTA.

24. A radionuclide chelate complex comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, and a radionuclide, wherein the radionuclide is complexed to a chelating agent, preferably the chelating agent is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent, and preferably the radionuclide is a therapeutically active radionuclide as defined in claim 19.

25. A radionuclide chelate complex according to claim 24, wherein the therapeutically active radionuclide is 177 Lu, 225 Ac, 161 Tb, 212 Pb or 90 Y.

26. A compound according to claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, comprising a diagnostically active nuclide, preferably wherein the diagnostically active nuclide is a diagnostically active radionuclide.

27. The compound according to claim 26, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the diagnostically active radionuclide is a gamma-emitting isotope for diagnostic use and has a decay energy of 0.004 to 10 MeV, preferably 0.05 to 4 MeV, or wherein the diagnostically active radionuclide is a positron-emitting isotope for diagnostic use and has a decay energy of 0.6 to 13.2 MeV, preferably 1 to 6 MeV.

28. The compound of claim 26, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the diagnostically active radionuclide is a diagnostically active radiometal.

29. The compound of claim 28, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the diagnostically active radionuclide is 68 Ga, 64 Cu, 177 Lu, or 111 In.

30. The compound of claim 26, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the diagnostically active nuclide is complexed to a chelating agent, preferably the chelating agent is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent.

31. A radionuclide chelate complex comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, and a radionuclide, wherein the radionuclide is complexed to a chelating agent, preferably the chelating agent is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent, and the radionuclide is a diagnostically active radionuclide as defined in claim 26.

32. A radionuclide chelate complex according to claim 31, wherein the diagnostically active radionuclide is 68 Ga, 64 Cu, 177 Lu or 111 In.

33. 10. A composition, preferably a pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient.

34. A composition, preferably a pharmaceutical composition, comprising the radionuclide chelate complex of claim 24 and a pharmaceutically acceptable excipient.

35. A composition, preferably a pharmaceutical composition, comprising the radionuclide chelate complex of claim 31 and a pharmaceutically acceptable excipient.

36. A compound according to claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, for use in the treatment of a disease.

37. The compound of claim 36, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is a neoplasm, preferably a cancer or tumor.

38. The compound of claim 37, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

39. The compound of claim 37, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma, and thyroid cancer, preferably the disease is selected from the group comprising breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma.

40. The compound of claim 36, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases.

41. A radionuclide chelate complex according to claim 24 for use in the treatment of disease.

42. A radionuclide chelate complex according to claim 41, wherein the disease is a neoplasm, preferably a cancer or a tumor.

43. A radionuclide chelate complex according to claim 42, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

44. The radionuclide chelate complex of claim 42, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably the disease is selected from the group comprising breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

45. The radionuclide chelate complex of claim 41, wherein the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

46. ​​The composition of claim 33 for use in treating a disease.

47. The composition of claim 46, wherein the disease is a neoplasm, preferably a cancer or tumor.

48. The composition of claim 47, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

49. The composition of claim 47, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

50. The composition of claim 46, wherein the disease is selected from the group including inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

51. The composition of claim 34 for use in treating a disease.

52. The composition of claim 51, wherein the disease is a neoplasm, preferably a cancer or tumor.

53. The composition of claim 52, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

54. The composition of claim 52, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably, the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

55. The composition of claim 51, wherein the disease is selected from the group including inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

56. The composition of claim 35 for use in treating a disease.

57. The composition of claim 56, wherein the disease is a neoplasm, preferably a cancer or tumor.

58. The composition of claim 57, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

59. The composition of claim 57, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably, the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

60. The composition of claim 56, wherein the disease is selected from the group including inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

61. A compound according to claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, for use in diagnosing a disease.

62. The compound of claim 61, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is a neoplasm, preferably a cancer or tumor.

63. The compound of claim 62, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

64. The compound of claim 62, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma, and thyroid cancer, preferably the disease is selected from the group comprising breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma.

65. The compound of claim 61, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, wherein the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases.

66. A radionuclide chelate complex according to claim 31 for use in diagnosing disease.

67. A radionuclide chelate complex as described in claim 66, wherein the disease is a neoplasm, preferably a cancer or tumor.

68. A radionuclide chelate complex according to claim 67, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

69. The radionuclide chelate complex of claim 67, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

70. The radionuclide chelate complex of claim 66, wherein the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

71. The composition of claim 33 for use in diagnosing a disease.

72. The composition of claim 71, wherein the disease is a neoplasm, preferably a cancer or tumor.

73. The composition of claim 72, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

74. The composition of claim 72, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma, and thyroid cancer; preferably, the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma.

75. The composition of claim 71, wherein the disease is selected from the group including inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

76. The composition of claim 34 for use in diagnosing a disease.

77. The composition of claim 76, wherein the disease is a neoplasm, preferably a cancer or tumor.

78. The composition of claim 77, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

79. The composition of claim 77, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably, the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

80. The composition described in claim 76, wherein the disease is selected from the group including inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

81. The composition of claim 35 for use in diagnosing a disease.

82. The composition of claim 81, wherein the disease is a neoplasm, preferably a cancer or tumor.

83. A radionuclide chelate complex according to claim 82, wherein the disease is (a) a neoplasm, preferably a cancer or tumor, and / or the disease involves cells that exhibit upregulated fibroblast activation protein (FAP) expression, preferably the disease involves diseased tissue comprising cells that exhibit upregulated FAP expression, more preferably the disease involves cancer-associated fibroblasts.

84. The radionuclide chelate complex of claim 82, wherein the disease is selected from the group consisting of solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland carcinoma, sarcoma, squamous cell carcinoma and thyroid cancer, preferably the disease is selected from the group including breast cancer, colorectal cancer, bile duct carcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

85. The radionuclide chelate complex of claim 81, wherein the disease is selected from the group consisting of inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

86. A kit comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable hydrate, or pharmaceutically acceptable solvate thereof, one or more optional excipients, and optionally one or more apparatus, wherein the apparatus is selected from the group consisting of labeling apparatus, purification apparatus, handling apparatus, radiation protection apparatus, analytical apparatus, and administration apparatus.

87. A kit comprising a radionuclide chelate complex as defined in claim 24, one or more optional excipients, and optionally one or more devices, wherein the devices are selected from the group consisting of labeling devices, purification devices, handling devices, radiation protection devices, analytical devices, and administration devices.

88. A kit comprising a radionuclide chelate complex as defined in claim 31, one or more optional excipients, and optionally one or more devices, wherein the devices are selected from the group consisting of labeling devices, purification devices, handling devices, radiation protection devices, analytical devices, and administration devices.

Images