NTSR1-targeted radiopharmaceutical and checkpoint inhibitor combination therapy

Abstract

A method for treating or ameliorating cancer comprising administering to a mammal an NTSR1-targeted radiopharmaceutical comprising a radionuclide chelated to a compound of formula I and one or more checkpoint inhibitors. The present disclosure encompasses the insight that combining the inhibition of checkpoint proteins with treatments that target damage to cancer cells can provide less toxic treatments with improved efficacy.Radioactive decay can cause direct physical damage (such as single- or double-stranded DNA breaks) or indirect damage (such as bystander or crossfire effects) to the biomolecules that make up cells.Drugs that deliver radionuclides to cancer cells, i.e., radiopharmaceuticals, provide a mechanism for generating DNA damage that has anticancer therapeutic effects.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,173, filed January 28, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Cancer cells exploit various mechanisms to evade immune surveillance, including the suppression of T cell activation.

[0003] The mammalian immune system relies on checkpoint molecules to distinguish normal cells from foreign cells. Checkpoint molecules expressed on specific immune cells need to be activated or inactivated to initiate an immune response. Inhibition of checkpoint proteins results in increased activation of the immune system.

[0004] Checkpoint inhibition has been investigated as an immunotherapeutic method for cancer. Upregulation of checkpoint molecules such as programmed death 1 (PD-1), programmed death ligand-1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is naturally intended to limit the magnitude of tumor-specific immune responses. Thus, blockade of these checkpoint molecules results in more robust and sustained T cell activation. However, checkpoint inhibition may also allow the immune system to attack some normal cells in the body, which may result in adverse side effects. Furthermore, only a limited number of cancer types, such as melanoma, lung cancer, bladder cancer, and head and neck tumors, show inherent sensitivity to checkpoint inhibition. Within the tumor types that respond, the typical overall response rate across patients is only 20-25%.

[0005] Thus, there is a need for improved treatments for cancer, particularly increased efficacy without increased toxicity in patients. Summary of the Invention [Means for solving the problem]

[0006] overview The present disclosure encompasses the insight that combining the inhibition of checkpoint proteins with treatments that target damage to cancer cells can provide less toxic treatments with improved efficacy. Radioactive decay can cause direct physical damage (such as single- or double-stranded DNA breaks) or indirect damage (such as bystander or crossfire effects) to the biomolecules that make up cells. Drugs that deliver radionuclides to cancer cells, i.e., radiopharmaceuticals, provide a mechanism to generate DNA damage with anti-cancer therapeutic effects. The present disclosure provides a combination of radiopharmaceuticals, specifically small molecule-based radiopharmaceuticals that target neurotensin receptor 1 (NTSR1)-positive tumors and target cancer cells using actinium-225, lutetium-177 or other suitable therapeutic radionuclides, with checkpoint inhibitors to treat or ameliorate cancer.

[0007] More specifically, a method of treating or ameliorating cancer, said method comprising: (i) administering a radiopharmaceutical to a mammal, said mammal having been or currently being treated with one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or (iii) administering to the mammal one or more checkpoint inhibitors simultaneously with administering to said mammal the radiopharmaceutical. Including, In each occurrence, the radiopharmaceutical comprises a compound of formula I: [ka] comprising a radionuclide chelated by During the ceremony, R 1is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 selected from the group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 are each independently hydrogen and C 1-4 selected from the group consisting of alkyl; L1 is C 2-5 is alkylidene; L2 is C 2-20 Alkylidene, C 2-20 heteroalkylidene, (C=O)O, (C=O)NR, or a combination thereof, where R is hydrogen or C 1-4 is alkyl; W is a chelator selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; Radionuclides are 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 A method is provided in which the method is selected from the group consisting of:

[0008] In some embodiments, the methods include administering one or more checkpoint inhibitors to a mammal, where the mammal has received or is receiving a radiopharmaceutical.

[0009] In some embodiments, the method comprises administering a radiopharmaceutical to a mammal, wherein the mammal has received or is receiving one or more checkpoint inhibitors.

[0010] In some embodiments, the methods include administering one or more checkpoint inhibitors to the mammal simultaneously with administering the radiopharmaceutical to said mammal.

[0011] In some embodiments, the chelating agent is selected from the group consisting of DOTA, DOTA-GA, NOTA, NODA-GA and NODA-SA.

[0012] In some embodiments, the chelating agent is selected from the group consisting of DTPA, EDTA, CDTA, DFO, BAT, and HYNIC.

[0013] In some embodiments, the radiopharmaceutical is chelated with a compound of formula I 225 Contains Ac 225 Ac radiopharmaceutical. 225 The Ac radiopharmaceutical was chelated with the following structure (compound A): 225 Ac containing: [ka]

[0014] In some embodiments, the one or more checkpoint inhibitors comprise a PD-1 or PD-L1 inhibitor or a CTLA-4 inhibitor.

[0015] In some embodiments, the PD-1 or PD-L1 inhibitor or the CTLA-4 inhibitor is an antibody.

[0016] In some embodiments, the one or more checkpoint inhibitors include both a PD-1 or PD-L1 inhibitor and a CTLA-4 inhibitor.

[0017] In some embodiments, the PD-1 or PD-L1 inhibitor is selected from the group consisting of camrelizumab, cemiplumab, dostallimab, nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, RMP1-14, atezolizumab, avelumab, and durvalumab.

[0018] In some embodiments, the CTLA-4 inhibitor is selected from the group consisting of BMS-986218, BMS-986249, ipilimumab, tremelimumab (formerly ticilimumab, CP-675,206), MK-1308, REGN-4659 and 4F10-11.

[0019] In some embodiments, the mammal is a human.

[0020] In some embodiments, the above 225 The Ac radiopharmaceutical is administered at a dosage of less than 1 MBq / kg of body weight of said mammal.

[0021] In some embodiments, the above 225 The Ac radiopharmaceutical is administered at a dosage of less than 250 kBq / kg of body weight of said mammal.

[0022] In some embodiments, the above 225 The Ac radiopharmaceutical is administered at a dosage of less than 100 kBq / kg of body weight of said mammal.

[0023] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 15 MBq.

[0024] In some embodiments, the above 225The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 10 MBq.

[0025] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 5 MBq.

[0026] In some embodiments, the checkpoint inhibitor is administered at a dosage of about 1 mg / kg to about 10 mg / kg of body weight of the mammal.

[0027] In some embodiments, the checkpoint inhibitor is administered at a dosage of about 5 mg / kg of body weight of the mammal.

[0028] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, small cell lung cancer, prostate cancer, breast cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, head and neck cancer, gastrointestinal stromal tumor, uterine leiomyoma, sarcoma, adrenocortical carcinoma, neuroendocrine carcinoma, multiple myeloma, acute myeloid leukemia, and cutaneous T-cell lymphoma.

[0029] In some embodiments, the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

[0030] In some embodiments, the administration results in a reduction in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume.

[0031] In some embodiments, the administration results in a reduced incidence of recurrence or metastasis.

[0032] In some embodiments, the method includes administering one or more checkpoint inhibitors to a mammal, wherein the mammal has the following structure: [ka] Chelated by 225 Contains Ac 225Have received or are receiving Ac radiopharmaceuticals; The one or more checkpoint inhibitors include both a PD-1 inhibitor and a CTLA-4 inhibitor, 225 The Ac radiopharmaceutical is administered at a dosage of 100-600 kBq / kg of body weight of the mammal. Also provided herein is the use of a compound of formula I for the manufacture of a medicament for a method of treating or ameliorating cancer in a subject in need thereof, said method comprising: (i) administering a radiopharmaceutical to a mammal, said mammal having been or currently being treated with one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or (iii) administering to the mammal one or more checkpoint inhibitors simultaneously with administering to said mammal the radiopharmaceutical. Including, The compound of formula I is [ka] is represented by During the ceremony, R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 selected from the group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 are each independently hydrogen and C 1-4selected from the group consisting of alkyl; L1 is C 2-5 is alkylidene; L2 is C 2-20 Alkylidene, C 2-20 heteroalkylidene, (C=O)O, (C=O)NR, or a combination thereof, where R is hydrogen or C 1-4 is alkyl; W is a chelator selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; Radionuclides are 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Selected from the group consisting of Th; In each occurrence, the radiopharmaceutical comprises a radionuclide chelated by a compound of formula I.

[0033] In another aspect, there is provided herein a compound of formula I for use in treating or ameliorating cancer in a subject in need thereof, said use comprising: (i) administering a radiopharmaceutical to a mammal, said mammal having been or currently being treated with one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or (iii) administering to the mammal one or more checkpoint inhibitors simultaneously with administering to said mammal the radiopharmaceutical. Including, The compound of formula I is [ka] is represented by During the ceremony, R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 selected from the group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 are each independently hydrogen and C 1-4 selected from the group consisting of alkyl; L1 is C 2-5 is alkylidene; L2 is C 2-20 Alkylidene, C 2-20 heteroalkylidene, (C=O)O, (C=O)NR, or a combination thereof, where R is hydrogen or C 1-4 is alkyl; W is a chelator selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; In each occurrence, the radiopharmaceutical comprises a radionuclide chelated by a compound of formula I, the radionuclide being 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213Bi, 223 Ra, 225 Ac, and 227 Th. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 shows the biodistribution of the radiopharmaceutical [177Lu]-Compound A in the CT-26 syngeneic model.

[0035] [Diagram 2] FIG. 2 shows the in vivo efficacy of the radiopharmaceutical [225Ac]-Compound A at different dosages in the CT-26-mNTSR1 syngeneic immunocompetent mouse model.

[0036] [Figure 3A] Figures 3A and 3B show increased therapeutic efficacy from the combination of radiopharmaceutical [225Ac]-Compound A with α-CTLA-4 / PD-1 in the CT-26-mNTSR1 syngeneic mouse model. [Figure 3B] Figures 3A and 3B show increased therapeutic efficacy from the combination of radiopharmaceutical [225Ac]-Compound A with α-CTLA-4 / PD-1 in the CT-26-mNTSR1 syngeneic mouse model.

[0037] [Figure 4A] FIG. 4A and FIG. 4B show improved overall survival in mice treated with [225Ac]-Compound A co-administered with α-CTLA-4, α-PD-1, or both. [Figure 4B] FIG. 4A and FIG. 4B show improved overall survival in mice treated with [225Ac]-Compound A co-administered with α-CTLA-4, α-PD-1, or both. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Detailed Description The present disclosure relates to combination therapies for treating or ameliorating cancer using a combination of certain radiopharmaceuticals and checkpoint inhibitors. In particular, the radiopharmaceuticals are small molecules chelated with radionuclides that target neurotensin receptor 1 (NTSR1).

[0039] NTSR1 is a transmembrane receptor that binds to the neurotransmitter neurotensin (Vincent et al., Trends Pharmacol. Sci., 1999, 20, 302-309; Pelaprat, Peptides, 2006, 27, 2476-2487). NTSR1 is mainly expressed in the central nervous system and intestine (smooth muscle, mucosa and nerve cells). Apart from the central nervous system, NTSR1 is highly expressed in some neoplastic cells in mammalian and human bodies, especially in some tumor indications, whereas the expression of NTSR1 in most other tissues of mammalian and human bodies is either absent or low. See, e.g., Bugni et al., Int. J. Cancer, 2012, 130, 1798-1805; Wang et al., Neuropeptides, 2011, 45, 151-156; and Taylor et al., Prostate, 2012, 72, 523-32.

[0040] These NTSR1 expressing tumor indications include, but are not limited to, pancreatic ductal adenocarcinoma, small cell lung cancer, prostate cancer, colorectal cancer, breast cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, head and neck cancer, non-small cell lung cancer, gastrointestinal stromal tumor, uterine leiomyoma, and cutaneous T-cell lymphoma. A preferred group of NTSR1 expressing tumor indications is pancreatic ductal adenocarcinoma, small cell lung cancer, prostate cancer, colorectal cancer, breast cancer, meningioma, and Ewing's sarcoma.

[0041] Radiolabeled targeting moieties (also known as radiopharmaceuticals) are designed to target proteins or receptors (e.g., NTSR1) that are upregulated in disease states and / or specific to diseased cells (e.g., tumor cells) in order to deliver a radioactive payload to damage and kill the cells of interest. definition Chemical terms:

[0042] The term "alkyl," as used herein, unless otherwise specified, includes both straight and branched chain saturated groups of 1 to 20 carbons (e.g., 1 to 10 or 1 to 6). Alkyl groups are exemplified by methyl, ethyl, n-propyl and iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or in the case of alkyl groups having two or more carbons, four substituents independently selected from the group consisting of: (1) C 1-6 Alkoxy; (2) C 1-6 (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH) or substituted amino (i.e., -N(R N1 )2(where R N1 is as defined for amino);(4)C 6-10 Aryl-C 1-6 Alkoxy; (5) Azido; (6) Halo; (7) (C 2-9 (8) hydroxy optionally substituted with an O-protecting group; (9) nitro; (10) oxo (e.g., carboxaldehyde or acyl); (11) C 1-7 Spirocyclyl; (12) Thioalkoxy; (13) Thiol; (14) -COR optionally substituted with an O-protecting group A’ (where R A’ (a)C 1-20 Alkyl (e.g., C 1-6 alkyl), (b) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 Aryl, (d) hydrogen, (e) C1-6 Alka-C 6-10 Aryl, (f) Amino-C 1-20 Alkyl, (g)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (15) -C(O)NR B’ R C’ (where R B’ and R C’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 aryl); (16) -SO2R D’ (where R D’ (a)C 1-6 Alkyl, (b) C 6-10 Aryl, (c) C 1-6 Alka-C 6-10 (17) -SO2NR E’ R F’ (where R E’ and R F’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C6-10 Aryl and (d) C 1-6 Alka-C 6-10 (18) -C(O)R G’ (where R G’ (a)C 1-20 Alkyl (e.g., C 1-6 alkyl), (b) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 Aryl, (d) hydrogen, (e) C 1-6 Alka-C 6-10 Aryl, (f) Amino-C 1-20 Alkyl, (g)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (19) -NR H’ C(O)R I’ (where R H’ is (a1) hydrogen and (b1) C 1-6 alkyl; R I’ is (a2)C 1-20 Alkyl (e.g., C 1-6 (b2) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c2) C6-10 Aryl, (d2) hydrogen, (e2) C 1-6 Alka-C 6-10 Aryl, (f2) Amino-C 1-20 Alkyl, (g2)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h2)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (20) -NR J’ C(O)OR K’ (where R J’ is (a1) hydrogen and (b1) C 1-6 alkyl; R K’ is (a2)C 1-20 Alkyl (e.g., C 1-6 (b2) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c2) C 6-10 Aryl, (d2) hydrogen, (e2) C 1-6 Alka-C 6-10 Aryl, (f2) Amino-C 1-20 Alkyl, (g2)-(CH2) s2 (OCH2CH2) s1 (CH2) s3OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h2) -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of C1-alkaryl can be further substituted with an oxo group to provide the respective aryloyl substituent.

[0043] The terms "alkylene," "alkylidene," and the prefix "alk-," as used herein, refer to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and are exemplified by methylene, ethylene, isopropylene, and the like. x-y Alkyl, C x-y Alkylene", "C x-y Alkylidene" and the prefix "C x-y "Alk-" refers to an alkyl or alkylene group having x to y carbons. Exemplary values ​​of x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C 1-6 , C 1-10 , C 2-5 , C 2-8 , C 2-10 , or C 2-20 Alkyl or C1-6 , C 1-10 , C 2-5 , C 2-8 , C 2-10 , or C 2-20 In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.

[0044] The term "alkenyl," as used herein, unless otherwise specified, represents a monovalent straight or branched chain group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl includes both cis and trans isomers. Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituents described herein.

[0045] The term "alkynyl," as used herein, refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituents described herein.

[0046] As used herein, the term “amino” refers to —N(R N1 )2, where each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, e.g., an optionally substituted arylalkoxycarbonyl group or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, e.g., an optionally substituted arylalkoxycarbonyl group or any described herein), heterocyclyl (e.g., heteroaryl) or alkheterocyclyl (e.g., alkheteroaryl), and these enumerated R N1 Each of the groups may be optionally substituted as defined herein for each group; or two R N1 are linked to form a heterocyclyl or N-protecting group, where each R N2 are independently H, alkyl, or aryl. The amino group may be an unsubstituted amino (i.e., -NH) group or a substituted amino (i.e., -N(R N1 )2) groups. In a preferred embodiment, amino can be -NH2 or -NHR N1 where R N1 are independently OH, NO2, NH2, and NR N2 2. SO2OR N2 , SO2R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl), or aryl, and each R N2 , H, C 1-20 Alkyl (e.g., C 1-6 Alkyl) or C 6-10 It may be aryl.

[0047] The term "amino acid" as used herein refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of -CO2H or a sulfo group of -SO3H), where the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). In some embodiments, the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkaheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. The amino acid group may be optionally substituted with one, two, three, or in the case of amino acid groups having two or more carbons, four substituents independently selected from the group consisting of: (1) C 1-6 Alkoxy; (2) C 1-6 (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH) or substituted amino (i.e., -N(R N1 )2(where R N1 is as defined for amino);(4)C 6-10 Aryl-C 1-6 Alkoxy; (5) Azido; (6) Halo; (7) (C 2-9 (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxaldehyde or acyl); (11) C 1-7 Spirocyclyl; (12) Thioalkoxy; (13) Thiol; (14) -CO2R A’ (where R A’ (a)C 1-20 Alkyl (e.g., C 1-6 alkyl), (b) C 2-20Alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 Aryl, (d) hydrogen, (e) C 1-6 Alka-C 6-10 Aryl, (f) Amino-C 1-20 Alkyl, (g)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (15) -C(O)NR B’ R C’ (where R B’ and R C’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 aryl); (16) -SO2R D’ (where R D’ (a)C 1-6 Alkyl, (b) C 6-10 Aryl, (c) C 1-6 Alka-C 6-10 (17) -SO2NR E’ R F’ (where R E’and R F’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 Aryl and (d) C 1-6 Alka-C 6-10 (18) -C(O)R G’ (where R G’ (a)C 1-20 Alkyl (e.g., C 1-6 alkyl), (b) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 Aryl, (d) hydrogen, (e) C 1-6 Alka-C 6-10 Aryl, (f) Amino-C 1-20 Alkyl, (g)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (19) -NR H’ C(O)R I’ (where R H’ is (a1) hydrogen and (b1) C 1-6 alkyl; R I’ is (a2)C 1-20 Alkyl (e.g., C 1-6(b2) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c2) C 6-10 Aryl, (d2) hydrogen, (e2) C 1-6 Alka-C 6-10 Aryl, (f2) Amino-C 1-20 Alkyl, (g2)-(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h2)-NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (20) -NR J’ C(O)OR K’ (where R J’ is (a1) hydrogen and (b1) C 1-6 alkyl; R K’ is (a2)C 1-20 Alkyl (e.g., C 1-6 (b2) C 2-20 Alkenyl (e.g., C 2-6 alkenyl), (c2) C 6-10 Aryl, (d2) hydrogen, (e2) C 1-6 Alka-C 6-10 Aryl, (f2) Amino-C 1-20 Alkyl, (g2)-(CH2) s2 (OCH2CH2) s1 (CH2)s3 OR', where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and R' is H or C 1-20 (h2) -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 (wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), s2 and s3 are each independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 (21) amidine. In some embodiments, each of these groups may be further substituted as described herein.

[0048] The term "aryl" as used herein refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having one or two aromatic rings, exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: (1) C 1-7 Acyl (e.g., carboxaldehyde); (2) C 1-20 Alkyl (e.g., C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylsulfinyl-C 1-6 Alkyl, Amino-C 1-6 Alkyl, azido-C 1-6 Alkyl, (Carboxaldehyde)-C 1-6 Alkyl, halo-C 1-6Alkyl (e.g., perfluoroalkyl), hydroxy-C 1-6 Alkyl, nitro-C 1-6 Alkyl, or C 1-6 Thioalkoxy-C 1-6 (3) C 1-20 Alkoxy (e.g., C 1-6 Alkoxy, for example perfluoroalkoxy; (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl;(6)Amino;(7)C 1-6 Alka-C 6-10 Aryl;(8)Azide;(9)C 3-8 Cycloalkyl; (10)C 1-6 Alka-C 3-8 Cycloalkyl;(11)Halo;(12)C 1-12 Heterocyclyl (e.g., C 1-12 Heteroaryl; (13) (C 1-12 (14) Hydroxy; (15) Nitro; (16) C 1-20 Thioalkoxy (e.g., C 1-6 Thioalkoxy;(17)-(CH2) q CO2R A’ (where q is an integer from 0 to 4, and R A’ (a)C 1-6 Alkyl, (b) C 6-10 aryl, (c) hydrogen, and (d) C 1-6 Alka-C 6-10 aryl);(18)-(CH2) q CONR B’ R C’ (where q is an integer from 0 to 4, and R B’ and R C’ is (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 aryl; (19)-(CH2) q SO2R D’ (where q is an integer from 0 to 4, and R D’ is (a) alkyl, (b) C 6-10aryl, and (c) alk-C 6-10 aryl);(20)-(CH2) q SO2NR E’ R F’ (where q is an integer from 0 to 4, and R E’ and R F’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 (21) thiol; (22) C 6-10 Aryloxy; (23)C 3-8 Cycloalkoxy; (24)C 6-10 Aryl-C 1-6 Alkoxy; (25)C 1-6 Alka-C 1-12 Heterocyclyl (e.g., C 1-6 Alka-C 1-12 Heteroaryl;(26)C 2-20 alkenyl; and (27) C 2-20 Alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of C1-alkaryl or C1-alkheterocyclyl can be further substituted with an oxo group to give the respective aryloyl and (heterocyclyl)oyl substituents.

[0049] The term "arylalkyl" as used herein refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkylene group, as defined herein. Exemplary unsubstituted arylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 1-6 Alka-C 6-10 Aryl, C 1-10 Alka-C 6-10 Aryl or C 1-20 Alka-C 6-10In some embodiments, alkylene and aryl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group. Other groups preceded by the prefix "alk-" are similarly defined, where "alk" is any group that is selected from the group consisting of C, C-, C-aryl, C-alkyl, C-alkylene, C-aryl ...aryl, C-alkylene, C-aryl, C-aryl, C-aryl, 1-6 Refers to alkylene and the attached chemical structures as defined herein.

[0050] The term "carbonyl" as used herein refers to a C(O) group, which also can be represented as C=O.

[0051] The term "carboxy" as used herein means -CO2H.

[0052] The term "cyano" as used herein refers to a -CN group.

[0053] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of 3 to 8 carbons, exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclic heptyl, and the like. When a cycloalkyl group contains one carbon-carbon double bond or one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkenyl" or "cycloalkynyl" group, respectively. Exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like. Cycloalkyl groups include (1) C 1-7 Acyl (e.g., carboxaldehyde); (2) C 1-20 Alkyl (e.g., C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylsulfinyl-C 1-6 Alkyl, Amino-C 1-6 Alkyl, azido-C 1-6 Alkyl, (Carboxaldehyde)-C 1-6 Alkyl, halo-C 1-6Alkyl (e.g., perfluoroalkyl), hydroxy-C 1-6 Alkyl, nitro-C 1-6 Alkyl, or C 1-6 Thioalkoxy-C 1-6 (3) C 1-20 Alkoxy (e.g., C 1-6 Alkoxy, for example perfluoroalkoxy; (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl;(6)Amino;(7)C 1-6 Alka-C 6-10 Aryl;(8)Azide;(9)C 3-8 Cycloalkyl; (10)C 1-6 Alka-C 3-8 Cycloalkyl;(11)Halo;(12)C 1-12 Heterocyclyl (e.g., C 1-12 Heteroaryl; (13) (C 1-12 (14) Hydroxy; (15) Nitro; (16) C 1-20 Thioalkoxy (e.g., C 1-6 Thioalkoxy;(17)-(CH2) q CO2R A’ (where q is an integer from 0 to 4, and R A’ (a)C 1-6 Alkyl, (b) C 6-10 aryl, (c) hydrogen, and (d) C 1-6 Alka-C 6-10 aryl);(18)-(CH2) q CONR B’ R C’ (where q is an integer from 0 to 4, and R B’ and R C’ is (a) hydrogen, (b) C 6-10 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 aryl; (19)-(CH2) q SO2R D’ (where q is an integer from 0 to 4, and R D’ (a)C 6-10Alkyl, (b) C 6-10 aryl, and (c) C 1-6 Alka-C 6-10 aryl);(20)-(CH2) q SO2NR E’ R F’ (where q is an integer from 0 to 4, and R E’ and R F’ each of which is independently (a) hydrogen, (b) C 6-10 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 (21) thiol; (22) C 6-10 Aryloxy; (23)C 3-8 Cycloalkoxy; (24)C 6-10 Aryl-C 1-6 Alkoxy; (25)C 1-6 Alka-C 1-12 Heterocyclyl (e.g., C 1-6 Alka-C 1-12 Heteroaryl;(26)oxo;(27)C 2-20 alkenyl; and (28) C 2-20 The alkynyl can be optionally substituted. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of C1-alkaryl or C1-alkheterocyclyl can be further substituted with an oxo group to obtain the respective aryloyl and (heterocyclyl)oyl substituents.

[0054] The term "diastereomers" as used herein means stereoisomers that are not mirror images of one another and are not superimposable with respect to one another.

[0055] As used herein, the term "enantiomer" refers to each individual optically active form of a compound having an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0056] The term "halogen" as used herein refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0057] The terms "heteroalkyl" and "heteroalkylidene" as used herein each refer to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur, respectively. In some embodiments, the heteroalkyl group can be further substituted with one, two, three, or four substituents, as described herein for alkyl groups. The terms "heteroalkenyl" and "heteroalkynyl" as used herein each refer to an alkenyl and alkynyl group, as defined herein, in which one or two of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur, respectively. In some embodiments, the heteroalkenyl and heteroalkynyl groups can be further substituted with one, two, three, or four substituents, as described herein for alkyl groups.

[0058] The term "heteroaryl" as used herein refers to the subset of heterocyclyl, as defined herein, that is aromatic (i.e., containing 4n+2 pi-electrons in a monocyclic or polycyclic ring system). Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiments, heteroaryl is substituted with 1, 2, 3, or 4 substituents as defined for heterocyclyl groups.

[0059] The term "heteroarylalkyl" refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted heteroarylalkyl groups include those having 2 to 32 carbons (e.g., 2 to 22, 2 to 18, 2 to 17, 2 to 16, 3 to 15, 2 to 14, 2 to 13, or 2 to 12 carbons, such as C 1-6 Alka-C 1-12 Heteroaryl, C 1-10 Alka-C 1-12 Heteroaryl or C 1-20 Alka-C 1-12 In some embodiments, alkylene and heteroaryl may each be further substituted with 1, 2, 3, or 4 substituents as defined for each group herein. Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.

[0060] The term "heterocyclyl" as used herein, unless otherwise specified, refers to a 5-, 6-, or 7-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0-2 double bonds, and 6- and 7-membered rings have 0-3 double bonds. Exemplary unsubstituted heterocyclyl groups have 1-12 (e.g., 1-11, 1-10, 1-9, 2-12, 2-11, 2-10, or 2-9) carbons. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbons and / or heteroatoms bridge two non-adjacent members of a monocyclic ring (e.g., quinuclidinyl groups). The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings are fused to one, two, or three carbocyclic rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, etc. Examples of fused heterocyclyls include tropane and 1,2,3,5,8,8a-hexahydroindolizine. The heterocyclic compound may be pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolyl Dinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl), purinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl), tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like, including dihydro and tetrahydro forms thereof, where one or more double bonds have been reduced and replaced with hydrogen. Still other exemplary heterocyclyls include 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl; aryl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino 5-oxo-1H-triazolyl; 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl); 2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl); 1,6-dihydro-6-oxopyriminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g., 2-(methylthio)-1,6-dihydro-4-oxo-5- methylpyrimidin-1-yl;1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl);1,6-dihydro-6-oxo-pyridazinyl (e.g., 1,6-dihydro-6-oxo-3-ethylpyridazinyl);1,6-dihydro-6-oxo-1,2,4-triazinyl (e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl);2,3-Dihydro-2-oxo-1H-indolyl (e.g., 3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and 2,3-dihydro-2-oxo-3,3'-spiropropane-1H-indol-1-yl); 1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl; 1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl). );2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g., 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl);2,3-dihydro-2-oxo-benzoxazolyl (e.g., 5-chloro-2,3-dihydro-2-oxo-benzoxazolyl);2,3-dihydro-2-oxo-benzoxazolyl;2-oxo-2H-benzopyranyl;1,4-benzodioxanyl;1,3-benzodioxanyl;2 ,3-Dihydro-3-oxo,4H-1,3-benzothiazinyl; 3,4-Dihydro-4-oxo-3H-quinazolinyl (e.g., 2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl); 1,2,3,4-Tetrahydro-2,4-dioxo-3H-quinazolyl (e.g., 1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl); 1,2,3,6-Tetrahydro-2,6-dioxo-7H-purinyl (e.g., For example, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl; 1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g., 1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl); 2-oxobenzo[c,d]indolyl; 1,1-dioxo-2H-naphtho[1,8-c,d]isothiazolyl; and 1,8-naphthylene dicarboxamide. Additional heterocyclic compounds include 3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl and 2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl and thiocanyl. Heterocyclic groups also include groups of the formula: [ka] During the ceremony, E' is selected from the group consisting of -N- and -CH-; F' is selected from the group consisting of -N=CH-, -NH-CH2-, -NH-C(O)-, -NH-, -CH=N-, -CH2-NH-, -C(O)-NH-, -CH=CH-, -CH2-, -CH2CH2-, -CHO-, -OCH2-, -O- and -S-; and G' is selected from the group consisting of -CH- and -N-. Any of the heterocyclyl groups mentioned herein may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: (1) C 1-7 Acyl (e.g., carboxaldehyde); (2) C 1-20 Alkyl (e.g., C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylsulfinyl-C 1-6 Alkyl, Amino-C 1-6 Alkyl, azido-C 1-6 Alkyl, (Carboxaldehyde)-C 1-6 Alkyl, halo-C 1-6 Alkyl (e.g., perfluoroalkyl), hydroxy-C 1-6 Alkyl, nitro-C 1-6 Alkyl, or C 1-6 Thioalkoxy-C 1-6 (3) C 1-20 Alkoxy (e.g., C 1-6 Alkoxy, for example perfluoroalkoxy; (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl;(6)Amino;(7)C 1-6 Alka-C 6-10 Aryl;(8)Azide;(9)C 3-8 Cycloalkyl; (10)C 1-6 Alka-C 3-8 Cycloalkyl;(11)Halo;(12)C 1-12 Heterocyclyl (e.g., C 2-12Heteroaryl; (13) (C 1-12 (14) Hydroxy; (15) Nitro; (16) C 1-20 Thioalkoxy (e.g., C 1-6 Thioalkoxy;(17)-(CH2) q CO2R A’ (where q is an integer from 0 to 4, and R A’ (a)C 1-6 Alkyl, (b) C 6-10 aryl, (c) hydrogen, and (d) C 1-6 Alka-C 6-10 aryl);(18)-(CH2) q CONR B’ R C’ (where q is an integer from 0 to 4, and R B’ and R C’ is (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 aryl; (19)-(CH2) q SO2R D’ (where q is an integer from 0 to 4, and R D’ (a)C 1-6 Alkyl, (b) C 6-10 aryl, and (c) C 1-6 Alka-C 6-10 aryl);(20)-(CH2) q SO2NR E’ R F’ (where q is an integer from 0 to 4, and R E’ and R F’ each of which is independently (a) hydrogen, (b) C 1-6 Alkyl, (c) C 6-10 aryl, and (d) C 1-6 Alka-C 6-10 (21) thiol; (22) C 6-10 Aryloxy; (23)C 3-8 Cycloalkoxy; (24) Arylalkoxy; (25) C 1-6 Alka-C1-12 Heterocyclyl (e.g., C 1-6 Alka-C 1-12 Heteroaryl; (26) oxo; (27) (C 1-12 Heterocyclyl)imino;(28)C 2-20 alkenyl; and (29) C 2-20 Alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of C1-alkaryl or C1-alkheterocyclyl can be further substituted with an oxo group to give the respective aryloyl and (heterocyclyl)oyl substituents.

[0061] The term "hydrocarbon" as used herein refers to a group consisting solely of carbon and hydrogen atoms.

[0062] The term "hydroxyl" as used herein refers to an -OH group. In some embodiments, the hydroxyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein for alkyl (e.g., O-protecting groups).

[0063] The term "isomer" as used herein refers to any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that compounds can have one or more chiral centers and / or double bonds and thus exist as stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Unless otherwise indicated, chemical structures depicted herein encompass all of the corresponding stereoisomers, i.e., both stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomeric and stereoisomeric mixtures (e.g., racemates). Enantiomeric and stereoisomeric mixtures of compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent, etc. Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0064] The term "N-protected amino" as used herein refers to an amino group, as defined herein, having one or two N-protecting groups, as defined herein, attached thereto.

[0065] The term "N-protecting group" as used herein refers to a group intended to protect an amino group against undesired reactions during synthetic procedures. Commonly used N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis", 3, incorporated herein by reference. rdEdition (John Wiley & Sons, New York, 1999). N-protecting groups include acyl, aryloyl or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries, such as protected or unprotected D,L or D,L-amino acids, such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups, such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy ...6-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,7-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,8-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,9-dimethoxybenzyloxycarbonyl, 3,10-dimethoxybenzyloxycarbonyl, 3,11-dimethoxybenzyloxycarbonyl, 3,12 ,4-Dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxyca Examples of such alkyl groups include aryl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkaryl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl, and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0066] The term "O-protecting group" as used herein refers to a group intended to protect an oxygen-containing (e.g., phenol, hydroxyl, or carbonyl) group from undesired reactions during synthetic procedures. Commonly used O-protecting groups are described in detail in Greene, "Protective Groups in Organic Synthesis", 3, incorporated herein by reference. rdEdition (John Wiley & Sons, New York, 1999). Exemplary O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-isopropylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups such as acyl, acetyl, propionyl, pivaloyl, and the like; optionally substituted arylcarbonyl groups such as benzoyl; silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), and the like; aryl groups with hydroxyl groups such as ... ester-forming groups, such as methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, trityl, etc.; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, methyloxycarbonyl, etc.; alkoxyalkoxycarbonyl, alkoxy groups, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, 3-methyl-2-butenoxycarbonyl, etc.; haloalkoxycarbonyl, such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.;Optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, fluorenylmethyloxycarbonyl, and the like; and optionally substituted aryloxycarbonyl groups, such as phenoxycarbonyl, p-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and the like. o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methyl-phenoxycarbonyl, m-methylphenoxycarbonyl, o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, p-chlorophenoxycarbonyl, 2-chloro-4-nitrophenoxycarbonyl, etc.; substituted alkyl, aryl and alkaryl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; ethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl and nitrobenzyl; silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and and diphenylmethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl); carbonyl protecting groups (e.g., acetal and ketal groups, such as dimethylacetal, 1,3-dioxolane, and the like; acylal groups; and dithiane groups, such as 1,3-dithiane, 1,3-dithiolane, and the like);Carboxylic acid protecting groups (e.g., ester groups, such as methyl esters, benzyl esters, t-butyl esters, orthoesters, etc.); and oxazoline groups.

[0067] The term "oxo" as used herein refers to =O.

[0068] The term "polyethylene glycol" as used herein refers to an alkoxy chain composed of one or more monomeric units, each of which consists of -OCH2CH2-. Polyethylene glycol (PEG) may also be referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms may be considered interchangeable for purposes of this disclosure. For example, polyethylene glycol has the structure -(CH2) s2 (OCH2CH2) s1 (CH2) s3 O-, where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10). Polyethylene glycol may also have -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R N1 are independently hydrogen or optionally substituted C 1-6 It is an alkyl.

[0069] The term "stereoisomer" as used herein refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, in particular all possible stereochemical and conformational isomeric forms of the basic molecular structure, all diastereomers, enantiomers and / or conformers. Some compounds may exist in different tautomeric forms, all of the latter being included within the scope of the present disclosure.

[0070] The term "sulfonyl" as used herein refers to the group -S(O)2-.

[0071] The term "thiol" as used herein refers to a --SH group. Other Terms

[0072] As used herein, the terms "about" or "approximately" refer to a ±10% variation from the recited quantitative value (including the recited quantitative value itself), unless otherwise indicated or inferred from the context. For example, a dose of about 100 kBq / kg indicates a dose range of 100±10% kBq / kg, i.e., 90 kBq / kg to 110 kBq / kg (both inclusive), unless otherwise indicated or inferred from the context.

[0073] As used herein, the terms "administered in combination," "administration in combination," or "co-administered" mean that two or more agents are administered to a subject at the same time or within such an interval that there may be an overlap of the effects of each agent on the patient. Thus, two or more agents administered in combination do not have to be administered together. In some embodiments, they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 days), within 28 days (e.g., within 14, 7, 6, 5, 4, 3, 2, or 1 days), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hours), or within about 60, 30, 15, 10, 5, or 1 minute of each other. In some embodiments, the administration of the agents is spaced apart and close enough together to achieve a combined effect.

[0074] As used herein, "administering" an agent to a subject includes contacting cells of the subject with the agent.

[0075] The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias and lymphomas. "Solid tumor cancers" are cancers that include abnormal tissue masses, such as sarcomas, carcinomas and lymphomas. "Blood cancers" or "liquid cancers", used interchangeably herein, are cancers that are present in bodily fluids, such as lymphomas and leukemias.

[0076] The term "checkpoint inhibitors," also known as "immune checkpoint inhibitors" or "ICIs," refers to agents that block the action of immune checkpoint proteins, e.g., agents that block the binding of such immune checkpoint proteins to their partner proteins.

[0077] The term "chelate" as used herein refers to an organic compound or portion thereof that is capable of binding to a central metal or radioactive metal atom at two or more points.

[0078] As used herein, the term "conjugate" refers to a molecule containing a chelating group or a metal complex thereof, a linker group, and optionally a therapeutic or targeting moiety.

[0079] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0080] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, can also exist in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0081] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of proton transfer tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed in one form by appropriate substitution.

[0082] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1-6The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. As used herein, phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) are intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where said alkyl is optionally substituted"). It is not intended to imply that the feature "X" (e.g., alkyl) itself is optionally present.

[0083] As used herein, the terms "reduce", "reduced", "increase", "increase", or "reduce", "reduced" (e.g., with respect to therapeutic outcome or effect) have a meaning relative to a reference level. In some embodiments, the reference level is a level determined by using the above method with a control in an experimental animal model or clinical trial. In some embodiments, the reference level is a level in the same subject before or at the start of treatment. In some embodiments, the reference level is the average level in a population not treated by the treatment method.

[0084] As used herein, the term "effective amount" of an agent (e.g., any of the conjugates described above) is an amount sufficient to effect beneficial or desired results, such as clinical results, and thus, an "effective amount" will depend on the context in which it is applied.

[0085] The term "lower effective dose" when used in combination with an agent (e.g., a therapeutic agent) refers to a dosage of the agent that is therapeutically effective in the combination therapy of the present invention and that is lower than the dose that has been determined to be therapeutically effective when the agent is used as a monotherapy in reference experiments or by other therapeutic guidance.

[0086] The term "pharmaceutical composition" as used herein refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelcap or syrup); for topical administration (e.g., as a cream, gel, lotion or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use that does not contain particulate emboli); or any other formulation described herein.

[0087] As used herein, "pharmaceutical acceptable excipient" refers to any component that is other than the compounds described herein (e.g., a vehicle that can suspend or dissolve active compounds) and has the characteristics of being non-toxic and non-inflammatory in patients.Excipients can include, for example, anti-adhesive agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radiation protection agents, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0088] The term "pharmaceutically acceptable salt" as used herein refers to a salt of the compound described herein that is suitable for use in contact with human and animal tissues without undue toxicity, irritation or allergic reaction within the scope of sound medical judgment.Pharmaceutically acceptable salts are well known in the art.For example, pharmaceutically acceptable salts are described in Berge et al., J.Pharmaceutical Sciences 66:1-19,1977 and in Pharmaceutical Salts:Properties, Selection, and Use,(Eds.P.H. Stahl and C.G. Wermuth),Wiley-VCH,2008.Said salts can be prepared in situ during the final isolation and purification of the compound described herein or separately by reacting the free base group with a suitable organic acid.

[0089] Compounds may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compound is in acidic form. In many cases, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid to form acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines to form base salts. Methods for preparing suitable salts are well established in the art.

[0090] Representative acid addition salts include, inter alia, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0091] As used herein, the term "radiopharmaceutical" or "radioconjugate" refers to any compound or conjugate that contains a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.

[0092] As used herein, the term "radionuclide" refers to an atom capable of undergoing radioactive decay (e.g., 3 H, 14 C. 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu, 61Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br, 77 Br, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, 99 Tc, 99m Tc 105 Rh, 109 Pd, 111 In, 123 I, 124 I, 125 I, 131 I, 149 Pm, 149 Tb, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229Th、66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn, 201 The term radionuclide refers to 1,2-difluoromethane (Tl). The terms radionuclide, radioisotope, or radioisotope may also be used to describe a radionuclide. A radionuclide may be used as a detection agent. In some embodiments, the radionuclide is an alpha-emitting radionuclide. Exemplary radionuclides for use in the methods of the present invention include: 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi,223 Ra, 225 Ac, and 227 Examples of such antibodies include, but are not limited to, Th.

[0093] As used herein and well understood in the art, "treating" a condition or "treatment" of a condition (e.g., a condition described herein, such as cancer) is an approach to obtain a beneficial or desired result, such as a clinical result. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; reduction in the severity of a disease, disorder, or condition; a stabilized (i.e., not worsening) state of a disease, disorder, or condition; preventing the spread of a disease, disorder, or condition; delaying or slowing the progression of a disease, disorder, or condition; amelioration or remission of a disease, disorder, or condition; and alleviation (whether partial or total), whether detectable or undetectable. In the context of cancer treatment, "improving" can include, for example, reducing the incidence of metastasis, reducing tumor volume, reducing tumor angiogenesis, and / or reducing tumor growth rate. "Ameliorating" a disease, disorder, or condition means lessening the severity and / or undesirable clinical signs of the disease, disorder, or condition and / or slowing or prolonging the time course of progression compared to the severity or time course without treatment. Chelating Agents

[0094] The compounds of formula I include a chelating moiety or chelator. Exemplary chelators include, but are not limited to, DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC, which are defined as follows: DOTA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA stands for 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid; NOTA stands for 1,4,7-triazacyclononanetriacetic acid. DTPA stands for diethylenetriaminepentaacetic acid; TETA stands for 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid, EDTA stands for ethylenediamine-N,N'-tetraacetic acid; NODAGA stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N''-diacetic acid; NODASA stands for 1,4,7-triazacyclononane-1-succinic-4,7-diacetic acid; TRITA stands for 1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid; CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; DFO represents the desferal or desferrioxamine type group of chelating agents, 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; BAT represents the bisaminobisthiol group of chelating agents, a non-limiting example chemical name is 1-[2-(2-mercapto-2-methyl-propylamino)-ethylamino]-2-methyl-propane-2-thiol; HYNIC stands for 6-hydrazino-nicotinic acid; Their chemical structures are as follows: [ka] Radiopharmaceuticals

[0095] Radiopharmaceuticals suitable for use according to the present disclosure generally comprise a radionuclide chelated to a compound of Formula I, where each variable is as defined in the Summary section above. [ka] Chelate part

[0096] Examples of suitable chelating moieties include DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid), NOTA (1,4,7-triazacyclononane triacetic acid), DTPA (diethylenetriaminepentaacetic acid), TETA (1,4,8,11-tetraacetate), and the like. 1,4,7-Triazacyclododecane-1,4,8,11-tetraacetic acid), EDTA (Ethylenediamine-N,N'-tetraacetic acid), NODAGA (1,4,7-triazacyclononane-N-glutaric acid-N',N''-diacetic acid), NODASA (1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid), TRITA (1,4,7,10-tetraazacyclotridecane-1,4,7,10- tetraacetic acid), CDTA (trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid), DFO (the desferal or desferrioxamine type group of chelators, 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), BAT (the bisaminobisthiol group of chelators, a non-limiting example chemical name is 1-[2-(2-mercapto-2-methyl-propylamino)-ethylamino]-2-methyl-propane-2-thiol), and HYNIC (6-hydrazino-nicotinic acid).

[0097] In some embodiments, the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Radionuclides

[0098] The present disclosure includes the use of radiopharmaceuticals, each of which contains a radionuclide. Examples of suitable radionuclides include: 47 Sc, 55 Co, 60 Cu, 61 Cu,62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 69 Er, 77 As, 82 Rb, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, 99 Tc, 99m Tc, 105 Rh, 109 Pd, 111 In, 111 Ag, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 Pm, 149 Tb, 151 Pm, 159 Gd, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 169 Yb, 172 Tm, 175 Yb, 177 Lu, 117m Sn, 177m Sn, 186 Re, 188 Re, 188 Rd., 198 Au, 199 Au, 201 Tl, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, and 229 Examples of such antibodies include, but are not limited to, Th.

[0099] In some embodiments, the radionuclide is 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb,153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.

[0100] In some embodiments, the radionuclide is an alpha emitter, such as astatine-211 ( 211 At), Bismuth-212( 212 Bi), Bismuth-213( 213 Bi), Actinium-225( 225 Ac), Radium-223( 223 Ra), lead-212( 212 Pb), Thorium-227( 227 Th), or terbium-149 ( 149 Tb).

[0101] Linker The radiopharmaceuticals used in the methods of the present disclosure comprise a linker as shown in the structure of Formula I, comprising L1 and L2: [ka] Here, L1 is C 2-5 alkylidene; L2 is C 2-20 Alkylidene, C 2-20 heteroalkylidene, (C=O)O, (C=O)NR, or a combination thereof, where R is hydrogen or C 1-4 It is an alkyl.

[0102] An exemplary L1 is: [ka] each of which can be optionally substituted with substituents described herein.

[0103] L2 typically contains at least one heteroatom (e.g., O or N), an amide moiety, or both. Exemplary L2 include, but are not limited to, the following: [ka] each of which can be optionally substituted with substituents described herein. Checkpoint inhibitors

[0104] In some embodiments, the checkpoint inhibitor is co-administered with the radiopharmaceutical. In general, suitable checkpoint inhibitors inhibit immunosuppressive checkpoint proteins. In some embodiments, the checkpoint inhibitor inhibits a protein selected from the group consisting of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1), programmed death-ligand-1 (PD-L1), LAG-3, T-cell immunoglobulin mucin 3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and killer immunoglobulin-like receptor (KIR).

[0105] In some embodiments, the checkpoint inhibitor can bind to CTLA-4, PD-1, or PD-L1. In some embodiments, the checkpoint inhibitor disrupts the interaction (e.g., disrupts the binding) between PD-1 and PD-L1.

[0106] In some embodiments, the checkpoint inhibitor is a small molecule.

[0107] In some embodiments, the checkpoint inhibitor is an antibody or antigen-binding fragment thereof, such as a monoclonal antibody. In some embodiments, the checkpoint inhibitor is a human or humanized antibody or antigen-binding fragment thereof. In some embodiments, the checkpoint inhibitor is a murine antibody or antigen-binding fragment thereof.

[0108] In some embodiments, the checkpoint inhibitor is a CTLA-4 antibody.Non-limiting examples of CTLA-4 antibodies include BMS-986218, BMS-986249, ipilimumab, tremelimumab (previously ticilimumab, CP-675,206), MK-1308 and REGN-4659.Another example of a CTLA-4 antibody is the mouse monoclonal antibody 4F10-11.

[0109] In some embodiments, the checkpoint inhibitor is a PD-1 antibody.Non-limiting examples of PD-1 antibodies include camrelizumab, cemiplumab, dostarlimab, nivolumab, pembrolizumab, sintilimab, tislelizumab and toripalimab.Another example of a PD-1 antibody is the mouse monoclonal antibody RMP1-14.

[0110] In some embodiments, the checkpoint inhibitor is a PD-L1 antibody. Non-limiting examples of PD-L1 antibodies include atezolizumab, avelumab, and durvalumab.

[0111] In some embodiments, a combination of more than one checkpoint inhibitor is used, for example, in some embodiments, both a CTLA-4 inhibitor and a PD-1 or PD-L1 inhibitor are used. Subject

[0112] In some disclosed methods, a therapy (including, for example, a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, for example a human.

[0113] In some embodiments, the subject has received or is receiving another treatment. For example, in some embodiments, the subject has received or is receiving a radiopharmaceutical. In some embodiments, the subject has received or is receiving a checkpoint inhibitor.

[0114] In some embodiments, the subject has cancer or is at risk of developing cancer. For example, the subject may have been diagnosed with cancer. The cancer may be primary or metastatic cancer. The subject may have cancer at any stage (e.g., stage I, stage II, stage III, or stage IV), with or without lymph node involvement, with or without metastasis. The provided compositions may prevent or reduce further growth of the cancer and / or otherwise ameliorate the cancer (e.g., prevent or reduce metastasis). In some embodiments, the subject does not have cancer but has been determined to be at risk of developing cancer due to the presence of one or more risk factors, such as, for example, environmental exposure, the presence of one or more genetic mutations or variants, family history, etc. In some embodiments, the subject has not been diagnosed with cancer.

[0115] In some embodiments, the cancer is a solid tumor.

[0116] In some embodiments, the solid tumor cancer is breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, neuroendocrine carcinoma, Ewing's sarcoma, multiple myeloma, or acute myeloid leukemia.

[0117] In some embodiments, the cancer is a non-solid (e.g., liquid (e.g., hematological)) cancer. Administration and Dosage Effective doses and lower effective doses

[0118] The present disclosure provides combination therapy, in which the amount of each therapeutic agent may or may not be therapeutically effective alone.For example, a method is provided that includes administering a first treatment and a second treatment in an amount that is effective together to treat or improve a disorder, such as cancer.In some embodiments, at least one of the first and second treatments is administered to the subject at a lower effective dose.In some embodiments, both the first and second treatments are administered at a lower effective dose.

[0119] In some embodiments, the first treatment comprises a radiopharmaceutical and the second treatment comprises a checkpoint inhibitor.

[0120] In some embodiments, the first treatment comprises a checkpoint inhibitor and the second treatment comprises a radiopharmaceutical.

[0121] In some embodiments, the therapeutic combinations disclosed herein are administered to a subject in a manner (e.g., dosage and timing) sufficient to cure or at least partially halt the symptoms of the disorder and its complications. In the context of a single treatment ("monotherapy"), an amount sufficient to achieve this purpose is defined as a "therapeutically effective amount", an amount of compound sufficient to substantially improve at least one symptom associated with a disease or medical condition. A "therapeutically effective amount" typically varies depending on the therapeutic agent. In the case of a known therapeutic agent, the relevant therapeutically effective amount may be known to or easily determined by a person skilled in the art.

[0122] For example, in the treatment of cancer, the agent or compound that reduces, prevents, delays, inhibits or stops any symptoms of disease or condition is therapeutically effective.The therapeutically effective amount of agent or compound is not required to cure disease or condition, but provides treatment for disease or condition, such that the onset of disease or condition is delayed, hindered or prevented, or the symptoms of disease or condition are improved, or the duration of disease or condition is changed, or for example, the severity is reduced or recovery is accelerated in an individual.For example, treatment can be therapeutically effective if it causes cancer to regress or the growth of cancer to be delayed.

[0123] Effective dosing regimens for these uses (e.g., amounts of each therapeutic agent, relative timing of treatment, etc.) may depend on the severity of the disease or condition as well as the weight and general condition of the subject. For example, the therapeutically effective amount of a particular composition containing a therapeutic agent to be applied to a mammal (e.g., a human) may be determined by one of skill in the art, taking into account individual differences in the age, weight, and condition of the mammal. Because certain conjugates of the present disclosure exhibit enhanced ability to target and remain in cancer cells, the dosage of these compounds may be lower than the equivalent dose required for the therapeutic effect of the unconjugated agent (e.g., equal to or lower than about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%). Therapeutically effective amounts and / or optimal amounts may be empirically determined by one of skill in the art. Thus, lower effective doses may also be determined by one of skill in the art.

[0124] Single or multiple administrations of the radiopharmaceutical or composition (e.g., a pharmaceutical composition comprising a therapeutic agent or radiopharmaceutical) may be administered at dose levels and patterns selected by the treating physician. The dose and administration schedule may be determined and adjusted based on the severity of the subject's disease or condition, and may be monitored throughout the course of treatment according to methods commonly practiced by clinicians or as described herein.

[0125] In the disclosed combination therapy method, the first and second treatments can be administered to the subject sequentially or simultaneously.For example, the first composition comprising the first therapeutic agent and the second composition comprising the second therapeutic agent can be administered to the subject sequentially or simultaneously.Alternatively, the composition comprising the combination of the first therapeutic agent and the second therapeutic agent can be administered to the subject.

[0126] In some embodiments, the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., multiple times. When the radiopharmaceutical is administered more than once, the dose of each administration may be the same or different.

[0127] In some embodiments, the checkpoint inhibitor is administered in a single dose. In some embodiments, the checkpoint inhibitor is administered more than once (e.g., at least twice, at least three times, etc.). In some embodiments, the checkpoint inhibitor is administered multiple times according to a regular or semi-regular schedule, such as approximately once every two weeks, once a week, twice a week, three times a week, or more than three times a week. When the checkpoint inhibitor is administered more than once, the dose of each administration may be the same or different. For example, the checkpoint inhibitor may be administered in the amount of an initial dose, and then the dosage of the checkpoint inhibitor in subsequent doses may be higher or lower than the amount of the initial dose.

[0128] In some embodiments, the first dose of the checkpoint inhibitor is administered simultaneously with the first dose of the radiopharmaceutical. In some embodiments, the first dose of the checkpoint inhibitor is administered prior to the first dose of the radiopharmaceutical. In some embodiments, the first dose of the checkpoint inhibitor is administered after the first dose of the radiopharmaceutical. In some embodiments, a subsequent dose of the checkpoint inhibitor is administered.

[0129] In some embodiments, the present disclosure provides: 225 The method includes administering an Ac radiopharmaceutical to a mammal at a dosage of less than 1 MBq / kg (e.g., less than 800 kBq / kg, less than 600 kBq / kg, less than 500 kBq / kg, less than 400 kBq / kg, less than 300 kBq / kg, less than 250 kBq / kg, less than 200 kBq / kg, less than 150 kBq / kg, less than 100 kBq / kg, or less than 50 kBq / kg) of body weight of said mammal. Each dose may be administered multiple times to the mammal.

[0130] In certain embodiments, the above 225The Ac radiopharmaceutical may be administered in dosages of 900 kBq / kg to 800 kBq / kg, 800 kBq / kg to 700 kBq / kg, 700 kBq / kg to 600 kBq / kg, 600 kBq / kg to 500 kBq / kg, 500 kBq / kg to 400 kBq / kg, 400 kBq / kg to 300 kBq / kg, 300 kBq / kg to 200 kBq / kg, 200 kBq / kg to 100 kBq / kg, or 100 kBq / kg to 50 kBq / kg. Each dose may be administered multiple times to the mammal.

[0131] In certain embodiments, the above 225 The Ac radiopharmaceutical may be administered in a dosage of about 2MBq / kg, about 1.9MBq / kg, about 1.8MBq / kg, about 1.7MBq / kg, about 1.6MBq / kg, about 1.5MBq / kg, about 1.4MBq / kg, about 1.3MBq / kg, about 1.2MBq / kg, about 1.1MBq / kg, about 1MBq / kg, about 0.9MBq / kg, about 0.8MBq / kg, about 0.7MBq / kg, about 0.6MBq / kg, about 0.5MBq / kg, about 0.4MBq / kg, about 0.3MBq / kg, about 0.2MBq / kg, about 0.1MBq / kg, or about 0.05MBq / kg. Each dose may be administered multiple times to the mammal.

[0132] In some embodiments, the above 225 The Ac radiopharmaceutical is administered at a dosage of less than 250 kBq / kg (e.g., about 240 kBq / kg, about 220 kBq / kg, about 200 kBq / kg, about 180 kBq / kg, about 160 kBq / kg, about 150 kBq / kg, about 140 kBq / kg, about 130 kBq / kg, about 120 kBq / kg, about 110 kBq / kg, or about 100 kBq / kg) of body weight of the mammal. Each dose may be administered multiple times to the mammal.

[0133] In some embodiments, the above 225The Ac radiopharmaceutical is administered at a dosage of less than 100 kBq / kg (e.g., about 90 kBq / kg, about 80 kBq / kg, about 70 kBq / kg, about 60 kBq / kg, about 50 kBq / kg, about 40 kBq / kg, about 30 kBq / kg, about 20 kBq / kg, or about 10 kBq / kg) of body weight of the mammal. Each dose may be administered multiple times to the mammal.

[0134] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 15MBq (e.g., about 14MBq, about 13MBq, about 12MBq, about 11MBq, about 10MBq, about 9MBq, about 8MBq, about 7MBq, about 6MBq, about 5MBq, about 4MBq, about 3MBq, about 2MBq, about 1MBq). Each unit dosage may be administered multiple times to the mammal.

[0135] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 10 MBq. Each unit dosage may be administered to the mammal multiple times.

[0136] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 5MBq, and each unit dosage may be administered to the mammal multiple times.

[0137] In some embodiments, the radiopharmaceutical (or composition thereof) and the checkpoint inhibitor (or composition thereof) are administered within 28 days (eg, within 14, 7, 6, 5, 4, 3, 2, or 1 day) of each other.

[0138] In some embodiments, the radiopharmaceutical (or composition thereof) and the checkpoint inhibitor (or composition thereof) are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day) of each other. In various embodiments, the checkpoint inhibitor is administered simultaneously with the radiopharmaceutical. In various embodiments, the checkpoint inhibitor is administered multiple times after a first administration of the radiopharmaceutical.

[0139] In some embodiments, the composition (such as a composition comprising a radiopharmaceutical) is administered for radiation treatment planning or diagnostic purposes. When administered for radiation treatment planning or diagnostic purposes, the composition can be administered to the subject in an amount effective to determine a diagnostically effective dose and / or a therapeutically effective dose. In some embodiments, a first dose of the disclosed conjugate or a composition thereof (e.g., a pharmaceutical composition) is administered in an amount effective for radiation treatment planning, followed by a combination therapy comprising a conjugate disclosed herein and another therapeutic agent.

[0140] Pharmaceutical compositions containing one or more agents (e.g., radiopharmaceuticals and / or checkpoint inhibitors) can be formulated for use according to the disclosed methods and systems in various drug delivery systems.For suitable formulation, one or more physiologically acceptable excipients or carriers can also be included in the composition.Examples of suitable formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.For a brief review of methods for drug delivery, see, for example, Langer (Science 249:1527-1533, 1990). formulation

[0141] The pharmaceutical composition may be formulated for local administration, such as parenteral, intranasal, topical, oral, or transdermal means, for prophylactic and / or therapeutic treatment. The pharmaceutical composition may be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by local application or intraarticular injection in the area affected by a blood vessel or cancerous condition. Examples of additional routes of administration include intravascular, intraarterial, intratumoral, intraperitoneal, intraventricular, intraepidural, as well as nasal, ocular, intrascleral, intraorbital, rectal, topical, or aerosol inhalation administration. Sustained release administration, such as by means of depot injection or erodible implants or components, is also specifically contemplated. Suitable compositions include compositions that include an agent (e.g., a compound disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier (e.g., water, buffered water, saline, or PBS, among others), for example, parenteral administration. The composition may contain pharma- ceutically acceptable auxiliary substances for approaching physiological conditions, such as pH adjusting and buffering agents, isotonicity adjusting agents, wetting agents or detergents, among others.In some embodiments, the composition is formulated for oral delivery; for example, the composition may contain inactive ingredients such as binders or fillers for the formulation of unit dosage forms such as tablets or capsules.In some embodiments, the composition is formulated for topical administration; for example, the composition may contain inactive ingredients such as solvents or emulsifiers for the formulation of creams, ointments, gels, pastes or eye drops.

[0142] The composition may be sterilized, for example, by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the preparation is typically 3-11, more preferably 5-9 or 6-8, most preferably 6-7, for example 6-6.5. In some embodiments, the composition in solid form is packaged in a plurality of single-dose units, each containing a fixed amount of the agent(s), for example in a sealed package of tablets or capsules. In some embodiments, the composition in solid form is packaged in a container for flexible quantities, such as a squeezable tube designed for topically applicable creams or ointments. effect

[0143] In some embodiments, the methods of the present disclosure provide a therapeutic benefit.

[0144] In some embodiments, the therapeutic effect comprises a reduction in tumor volume, a stable tumor volume, or a reduction in the rate of increase in tumor volume, hi some embodiments, the therapeutic effect comprises a reduction in the incidence of recurrence or metastasis. Other drugs

[0145] In some embodiments, the disclosed methods further comprise administering an antiproliferative agent, a radiosensitizing agent, or an immunosuppressant or immunomodulatory agent.

[0146] "Antiproliferative" or "antiproliferative agent," as used interchangeably herein, means any anticancer agent, including those antiproliferative agents listed in Table 1, any of which may be used in combination with a radiopharmaceutical to treat a condition or disorder. Antiproliferative agents also include organoplatinum derivatives, naphthoquinone and benzoquinone derivatives, chrysophanic acid and its anthroquinone derivatives.

[0147] "Immunoregulatory agent" or "immunomodulatory agent," as used interchangeably herein, means any immune modulator, including those listed in Table 1, any of which may be used in combination with the radiopharmaceuticals provided herein.

[0148] As used herein, "radiosensitizer" includes any agent that increases the sensitivity of cancer cells to radiation therapy.Radiosensitizers can include, but are not limited to, 5-fluorouracil, platinum analogs (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesyltransferase inhibitors, COX-2 inhibitors, bFGF antagonists and VEGF antagonists. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] EXAMPLES

[0149] Example 1. Synthesis of radiopharmaceuticals containing compounds of formula I

[0150] The compounds of formula I are small molecule antagonists that target NTSR1 and are 177 Lu) or Actinium-225 ( 225The compounds of formula I can be radiolabeled with radionuclides such as Ac) to form radiopharmaceuticals with chelated radionuclides. The synthesis of the compounds of formula I or their radionuclides with chelated radiopharmaceuticals can be found in U.S. Pat. No. 10,961,199 B2.

[0151] The following exemplary compound, Compound A, prepared according to US Pat. No. 10,961,199 B2, was used in the in vivo studies provided in Examples 2-5 below. [ka] Example 2. 177 Lu]-Compound A biodistribution in the CT-26 syngeneic model

[0152] Compound A of formula I is radiolabeled with Lu-177 using methods well known in the art to give 177 Lu]-Compound A was formed. 177 The ability of [Lu]-Compound A to target antigen-expressing murine NTSR1-overexpressing tumors in vivo was demonstrated using the CT-26 syngeneic model. Tumor uptake was sustained at 2.5-7% injected dose / g (ID / g) for 6-48 hours post-injection. See Figure 1. Example 3. CT-26-mNTSR1 Syngeneic Immunocompetent Mouse Model 225 Ac]-Enhanced efficacy of Compound A

[0153] Compound A of formula I is radiolabeled using standard techniques to give 225 Ac]-Compound A was formed. 225 Ac]-Compound A efficacy test was performed at different doses of [ 225 Ac]-Compound A was used. 225 It was found that [Ac]-Compound A had enhanced efficacy in reducing tumor volume in CT-26-mNTSR1 syngeneic mice with healthy immune systems. See Figure 2. Example 4. 225Combination of Ac]radiopharmaceutical and α-CTLA-4 / PD-1 treatment demonstrates increased therapeutic efficacy in the CT-26-mNTSR1 syngeneic mouse model

[0154] In vivo studies were performed to evaluate the effect of α-CTLA-4 and α-PD-1 antibodies in combination with checkpoint inhibitors on relative tumor volume in the CT-26-mNTSR1 mouse model [ 225 The effect of [Ac]-Compound A (described in Example 3) was tested. Mice treated with either the CTLA-4 inhibitor alone or the PD-1 inhibitor alone showed a modest reduction in relative tumor volume when compared to the vehicle control group. 225 Mice treated with [Ac]-Compound A showed a greater reduction in tumor volume compared to the vehicle control group. 225 Increased efficacy, including tumor inhibition, was observed when [Ac]-Compound A was co-administered at 0.185MBq / kg or 0.555MBq / kg doses (single dose, intravenous) with either CTLA-4 or PD-1 at 5mg / kg or both. At the 0.555MBg / kg dose, co-administration with both CTLA-4 and PD-1 was superior to the vehicle control group and 225 This resulted in not only significantly smaller tumor volumes but also tumor regression for at least 40 days after treatment when compared to the Ac radiopharmaceutical group, see Figures 3A and 3B. Example 5. 225 Improved overall survival in mice treated with Ac]-Compound A

[0155] In vivo studies were performed to assess the effect of checkpoint inhibitors, α-CTLA-4 and α-PD-1 antibodies in combination on survival in the CT-26-mNTSR1 mouse model [ 225 Ac]-Compound A (described in Example 3) was tested. 225 Increased overall survival was observed when Compound A was co-administered at a dose of 0.185 MBq / kg (single dose, intravenous) with 5 mg / kg of α-CTLA-4 or α-PD-1 (or both) - co-administration was no different from vehicle control or [225 Ac]-resulted in increased survival when compared to Compound A alone. See Figure 4A.

[0156] Separately, in vivo studies were performed to evaluate the effect of different dosages of α-CTLA-4 and α-PD-1 antibodies in combination with checkpoint inhibitors on survival in the CT-26-mNTSR1 mouse model. 225 Ac]-Compound A (described in Example 4) was tested. 225 When [Ac]-Compound A was co-administered at a dose of 0.555 MBq / kg (single dose, intravenous) with 5 mg / kg of α-CTLA-4 or α-PD-1, an increase in overall survival was observed (compared to vehicle and 225 Ac]-Compound A single treatment group) was observed. 225 Coadministration of Compound A with both α-CTLA-4 and α-PD-1 in the presence or absence of either α-CTLA-4 or α-PD-1 antibodies resulted in a reduction in the efficacy of either vehicle control or [ 225 Ac]-resulted in increased survival when compared to Compound A. See Figure 4B. Other embodiments

[0157] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. A combination comprising a radiopharmaceutical and a checkpoint inhibitor, 1. A combination for use in a method of treating or ameliorating cancer, said method comprising: (i) administering said radiopharmaceutical to a mammal, wherein said mammal has received or is receiving one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving the radiopharmaceutical; or (iii) administering one or more checkpoint inhibitors to the mammal simultaneously with administering the radiopharmaceutical to the mammal; Including, The radiopharmaceutical comprises a compound of Formula I: 【Chemistry 13】 a radionuclide chelated by During the ceremony, R １ is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine, and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R ２ is C １－６ Alkyl, C ３－８ Cycloalkyl, C ３－８ selected from the group consisting of cycloalkylmethyl, halogen, nitro, and trifluoromethyl; R ３ and R ４ are each independently hydrogen and C １－４ selected from the group consisting of alkyl; L １ is C ２－５ is alkylidene; L ２ is C ２－２０ Alkylidene, C ２－２０ heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or C １－４ is alkyl; W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; The radionuclide is ６４ Cu, ６７ Cu, ６８ Ga, ９０ Y. １４９ Tb, １５３ Sm, １７７ Lu, ２１１ At, ２１２ Bi, ２１２ Pb, ２１３ Bi, ２２３ Ra, ２２５ Ac, and ２２７ A combination selected from the group consisting of Th.

2. The combination described in claim 1, characterized in that one or more checkpoint inhibitors are administered to a mammal, and the mammal has received or is receiving a radiopharmaceutical.

3. The radiopharmaceutical has the following structure: 【Chemistry 14】 Chelated by ２２５ Contains Ac ２２５ 3. The combination according to claim 1 or 2, which is an Ac radiopharmaceutical.

4. 2. The combination of claim 1, wherein the one or more checkpoint inhibitors comprise a PD-1 or PD-L1 inhibitor or a CTLA-4 inhibitor.

5. The combination of claim 4, wherein the PD-1 or PD-L1 inhibitor or the CTLA-4 inhibitor is an antibody.

6. 2. The combination of claim 1, wherein the one or more checkpoint inhibitors comprise both a PD-1 or PD-L1 inhibitor and a CTLA-4 inhibitor.

7. 7. The combination of any one of claims 4 to 6, wherein the PD-1 or PD-L1 inhibitor is selected from the group consisting of camrelizumab, cemiplumab, dostallimab, nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, RMP1-14, atezolizumab, avelumab, and durvalumab.

8. 7. The combination of any one of claims 4 to 6, wherein the CTLA-4 inhibitor is selected from the group consisting of BMS-986218, BMS-986249, ipilimumab, tremelimumab (formerly ticilimumab, CP-675,206), MK-1308, REGN-4659 and 4F10-11.

9. The combination of claim 1, wherein the mammal is a human.

10. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered at a dosage of less than 1 MBq / kg of body weight of the mammal.

11. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered at a dosage of less than 250 kBq / kg of body weight of the mammal.

12. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered at a dosage of less than 100 kBq / kg of body weight of the mammal.

13. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 15 MBq.

14. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 10 MBq.

15. The aforementioned ２２５ 4. The combination of claim 3, wherein the Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 5 MBq.

16. 2. The combination of claim 1, wherein the cancer is selected from the group consisting of colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, small cell lung cancer, prostate cancer, breast cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, head and neck cancer, gastrointestinal stromal tumor, uterine leiomyoma, sarcoma, adrenocortical carcinoma, neuroendocrine carcinoma, multiple myeloma, acute myeloid leukemia, and cutaneous T-cell lymphoma.

17. 17. The combination of claim 16, wherein the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

18. 2. The combination of claim 1, wherein said administration results in a reduction in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume.

19. 19. The combination of claim 18, wherein said administration results in a reduced incidence of recurrence or metastasis.

20. The method of claim 20, wherein one or more checkpoint inhibitors are administered to a mammal, wherein the mammal has a compound having the following structure: 【Chemistry 15】 Chelated by ２２５ Contains Ac ２２５ have received or are receiving Ac radiopharmaceuticals, the one or more checkpoint inhibitors include both a PD-1 inhibitor and a CTLA-4 inhibitor; ２２５ 2. The combination of claim 1, wherein the Ac radiopharmaceutical is administered at a dosage of 100 to 600 kBq / kg of body weight of the mammal.

21. A composition comprising a radiopharmaceutical comprising a radionuclide chelated by a compound of Formula I, for use in a method of treating or ameliorating cancer, said method comprising: (i) administering said radiopharmaceutical to a mammal, wherein said mammal has received or is receiving one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving the radiopharmaceutical; or (iii) administering one or more checkpoint inhibitors to the mammal simultaneously with administering the radiopharmaceutical to the mammal; Including, Formula I 【Chemistry 13】 and During the ceremony, R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine, and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R 2 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; L 1 is a C 2-5 alkylidene; L 2 is C 2-20 alkylidene, C 2-20 heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or C 1-4 alkyl; W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; 10. A composition wherein said radionuclide is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.

22. A composition comprising a checkpoint inhibitor for use in a method of treating or ameliorating cancer, said method comprising: (i) administering a radiopharmaceutical to a mammal, wherein said mammal has received or is receiving one or more checkpoint inhibitors; (ii) administering one or more checkpoint inhibitors to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or (iii) administering to the mammal one or more checkpoint inhibitors simultaneously with administering to said mammal a radiopharmaceutical; Including, The radiopharmaceutical comprises a compound of Formula I: 【Chemistry 13】 a radionuclide chelated by During the ceremony, R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine, and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R 2 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; L 1 is a C 2-5 alkylidene; L 2 is C 2-20 alkylidene, C 2-20 heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or C 1-4 alkyl; W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA, DTPA, TETA, EDTA, NODAGA, NODASA, TRITA, CDTA, BAT, DFO, and HYNIC; 10. A composition wherein said radionuclide is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 90 Y, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.

Images