NTSR1-targeted radiopharmaceutical and DNA damage response 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 a DNA damage response inhibitor. The disclosure encompasses the insight that inhibition of DNA damage repair mechanisms used in combination with a therapy that specifically targets DNA breaks to cancer cells (but not normal tissues) may result in better 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 the cell. Drugs that deliver radioisotopes, radiopharmaceuticals, to cancer cells provide a mechanism for generating DNA damage with anti-cancer therapeutic effects.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,178, filed January 28, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background DNA single- and double-stranded breaks occur for a variety of reasons, including cellular exposure to exogenous sources of DNA damaging agents, such as radiopharmaceuticals, or due to genetic mutations in pathways involving the BRCA, PTEN and ATR proteins. Such DNA breaks are repaired through multiple pathways, and inhibition of these repair pathways results in the accumulation of single- and / or double-stranded breaks (e.g., PARP inhibition (PARPi) or ATM inhibition).

[0003] Existing PARP inhibitors act through both inhibition of PARP enzyme inhibitory activity and through trapping of PARP proteins inside chromatin ("DNA trapping"). Tumor cells with BRCA and / or PTEN mutations are sensitive to PARPi, but ATR inhibition (ATRi) is unable to repair double-strand breaks, thus resulting in the accumulation of double-strand breaks. Similarly, inhibitors of ATM (ATMi) or DNA-PK (DNA-PKi) or inhibitors of other DNA repair pathways can result in increased accumulation of DNA damage in cells. Increased single- or double-strand DNA breaks in tumors result in higher cell death. DNA damage repair inhibitors (DDRi) have been investigated as cancer therapeutics based on this mechanism. However, the presence of mutations that allow DDRi monotherapy in cancer cells and are also found in non-cancerous somatic cells can result in undesirable normal tissue toxicity. Furthermore, many DDRi have shown only modest efficacy in vivo when used as monotherapy, and their use may be limited to cancer types that are already deficient in some aspect of DNA repair capacity (e.g., PARPi for the treatment of BRCA1 / 2-deficient cancers).

[0004] 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]

[0005] overview The present disclosure encompasses the insight that inhibition of DNA damage repair mechanisms used in combination with treatments that specifically target DNA breaks to cancer cells (but not normal tissues) can result in better 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 the cell. Drugs that deliver radioisotopes, radiopharmaceuticals, to cancer cells provide a mechanism to generate DNA damage with anti-cancer therapeutic effects. The present disclosure provides methods of combining 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 radionuclides, with DDRi to treat or ameliorate cancer. More specifically, there is provided 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 a DNA damage response inhibitor (DDRi); (ii) administering a DDRi to a mammal, the mammal having received or having received a radiopharmaceutical; or (iii) administering a DDRi to the mammal simultaneously with administering the radiopharmaceutical to said mammal. Including, In each occurrence, the radiopharmaceutical comprises a compound of formula I: [ka] comprising 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; 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:

[0006] In some embodiments, the method comprises administering a DDRi to a mammal, said mammal having received or having received a radiopharmaceutical.

[0007] In some embodiments, the method comprises administering a radiopharmaceutical to a mammal, said mammal having undergone or having undergone one or more DDRi's.

[0008] In some embodiments, the method comprises administering one or more DDRi to the mammal simultaneously with administering the radiopharmaceutical to said mammal.

[0009] In some embodiments, the chelating agent is selected from the group consisting of DOTA, DOTA-GA, NOTA, NODA-GA and NODA-SA.

[0010] In some embodiments, the chelating agent is selected from the group consisting of DTPA, EDTA, CDTA, DFO, BAT, and HYNIC.

[0011] 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 Contains Ac. [ka]

[0012] In some embodiments, the DDRi is a PARP inhibitor. In certain embodiments, the PARP inhibitor is a small molecule PARP inhibitor. In certain embodiments, the small molecule PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, talazoparib, pamiparib, rucaparib (camsylate) and veliparib, or analogs thereof. In certain embodiments, the small molecule PARP inhibitor is olaparib or an analog thereof.

[0013] In some embodiments, the DDRi is an ATR or ATM inhibitor. In certain embodiments, the ATR or ATM inhibitor is a small molecule ATR or ATM inhibitor. In certain embodiments, the small molecule ATR or ATM inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541, M4344, M6620 (previously known as VE-922 or VX-970), NU6027 and VE-821, or analogs thereof. In certain embodiments, the small molecule ATR or ATM inhibitor is AZD1390, BAY-1895344, or analogs thereof.

[0014] In some embodiments, the DDRi is a DNA-protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor.In certain embodiments, the DDRi is a DNA-PK inhibitor selected from the group consisting of AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCI, PP121 and SF2523, or analogs thereof.In certain embodiments, the DNA-PK inhibitor is AZD7648 or an analog thereof.

[0015] In some embodiments, the mammal is a human.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 15 MBq.

[0020] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 10 MBq.

[0021] In some embodiments, the above 225 The Ac radiopharmaceutical is administered to the mammal in a unit dosage of less than 5 MBq.

[0022] In some embodiments, the DDRi is administered at a dosage of about 5 mg / kg to about 30 mg / kg of body weight of the mammal.

[0023] In some embodiments, the DDRi is administered at a dosage of about 25 mg / kg of body weight of the mammal.

[0024] 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.

[0025] In some embodiments, the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

[0026] 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.

[0027] In some embodiments, the administration results in a reduced incidence of recurrence or metastasis.

[0028] In some embodiments, the method comprises administering to a mammal a DDRi, wherein the mammal has the following structure: [ka] Chelated by 225 Contains Ac 225 Have received or are receiving Ac radiopharmaceuticals; The DDRi is a PARP inhibitor or an ATR or ATM 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 a DNA damage response inhibitor (DDRi); (ii) administering a DDRi to a mammal, the mammal having received or having received a radiopharmaceutical; or (iii) administering a DDRi to the mammal simultaneously with administering the radiopharmaceutical to said mammal. 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; 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.

[0029] 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 a DNA damage response inhibitor (DDRi); (ii) administering a DDRi to a mammal, the mammal having received or having received a radiopharmaceutical; or (iii) administering a DDRi to a mammal simultaneously with administering a radiopharmaceutical to said mammal; 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, 213 Bi, 223 Ra, 225 Ac, and 227 Th. [Brief description of the drawings]

[0030] [Figure 1] FIG. 1 shows the biodistribution of the radiopharmaceutical [177Lu]-Compound A in the CT-26-mNTSR1 syngeneic immunocompetent mouse model.

[0031] [Diagram 2] FIG. 2 shows the in vivo efficacy of the radiopharmaceutical [225Ac]-Compound A at different dosages in the CT-26-mNTSR1 xenograft model.

[0032] [Diagram 3] FIG. 3 shows increased therapeutic efficacy from the combination of the radiopharmaceutical [225Ac]-Compound A with olaparib in the CT-26-mNTSR1 xenograft model.

[0033] [Figure 4] FIG. 4 shows improved overall survival in mice treated with a combination of [225Ac]-Compound A and olaparib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description The present disclosure relates to combination therapies for treating or ameliorating cancer using a combination of a particular radiopharmaceutical and a DNA damage response inhibitor. In particular, the radiopharmaceutical is a small molecule chelated with a radionuclide that targets neurotensin receptor 1 (NTSR1).

[0035] 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.

[0036] 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.

[0037] 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:

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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 for each group herein. 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 ... 1-6 Refers to alkylene and the attached chemical structures as defined herein.

[0046] The term "carbonyl" as used herein refers to a C(O) group, which also can be represented as C=O.

[0047] The term "carboxy" as used herein means -CO2H.

[0048] The term "cyano" as used herein refers to a -CN group.

[0049] 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.

[0050] 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.

[0051] 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%.

[0052] The term "halogen" as used herein refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] The term "hydrocarbon" as used herein refers to a group consisting solely of carbon and hydrogen atoms.

[0058] 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).

[0059] 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.

[0060] 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.

[0061] 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).

[0062] 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.

[0063] The term "oxo" as used herein refers to =O.

[0064] 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.

[0065] 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.

[0066] The term "sulfonyl" as used herein refers to the group -S(O)2-.

[0067] The term "thiol" as used herein refers to a --SH group. biological terms ATM stands for ataxia telangiectasia mutated. ATR stands for ataxia telangiectasia and Rad3-related. BRCA stands for breast cancer gene. Chk1 stands for checkpoint kinase 1. Chk2 stands for checkpoint kinase 2. DDR stands for DNA damage response. DNA stands for deoxyribonucleic acid. DNA-PK stands for DNA-dependent protein kinase. NTSR1 stands for neurotensin receptor 1. PARP stands for poly ADP ribose polymerase. PTEN stands for phosphatase and tensin homolog deleted on chromosome 10. WEE1 stands for WEE1 G2 checkpoint kinase. Other Terms

[0068] 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.

[0069] 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.

[0070] As used herein, "administering" an agent to a subject includes contacting cells of the subject with the agent.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0075] 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.

[0076] 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.

[0077] 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 1-6 The 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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

[0089] 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

[0090] 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

[0091] 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).

[0092] In some embodiments, the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Radionuclides

[0093] 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.

[0094] 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.

[0095] 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).

[0096] 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.

[0097] An exemplary L1 is: [ka] each of which can be optionally substituted with substituents described herein.

[0098] 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. DNA Damage and Repair Inhibitors (DDRi)

[0099] As disclosed herein, the terms "DNA damage response inhibitor" and "DNA damage and repair inhibitor" are used interchangeably. In various embodiments, a DNA damage and repair inhibitor (DDRi) is co-administered with a radiopharmaceutical.

[0100] DNA repair involves multiple molecular pathways that repair DNA single-strand breaks (e.g., the PARP pathway) and double-strand breaks (e.g., other genes such as BRCA and ATR / ATM). PARP inhibition (PARPi) results in failure to repair single-strand breaks, which further leads to double-strand breaks. Available PARP inhibitors act through both PARP enzyme inhibition and DNA trapping. Tumor cells with BRCA and / or PTEN mutations are sensitive to PARPi. ATR inhibition (ATRi) results in failure to repair double-strand breaks, and the accumulation of double-strand breaks leads to cell death. These inhibitors act by preventing homologous recombination and non-homologous end joining mechanisms.

[0101] The present disclosure relates to combination therapy with radiopharmaceuticals and DNA damage and repair inhibitors.It has been found that this type of combination therapy provides unexpected improvements in cancer treatment, especially in cancers that are not expected to respond to DDRi.

[0102] In some embodiments, the DDRi is a PARP inhibitor (PARPi). In some embodiments, the PARPi is selected from the group consisting of niparib, niraparib, olaparib, pamiparib, rucaparib (camsylate), talazoparib, and veliparib, or analogs thereof. In some embodiments, the PARPi is adavosertib, AZD2811, or analogs thereof.

[0103] In some embodiments, the DDRi is an ATM / ATR inhibitor. In some embodiments, the ATM / ATR inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541, M4344, M6620 (previously known as VE-922 or VX-970), NU6027 and VE-821, or analogs thereof. In certain embodiments, the ATM / ATR inhibitor is AZD1390 or an analog thereof.

[0104] In some embodiments, the DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. Examples of WEE1 inhibitors, Chk1 inhibitors, and Chk2 inhibitors include those known in the art.

[0105] In some embodiments, DDRi is DNA-dependent protein kinase (DNA-PK) inhibitor.Non-limiting examples of DNA-PK inhibitor include but are not limited to AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCI, PP121, SF2523 and their analogs.In certain embodiments, DNA-PK inhibitor is AZD7648 or its analogs. Subject

[0106] In some disclosed methods, a therapy (e.g., including a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, such as a human.

[0107] 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 DDRi.

[0108] 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.

[0109] In some embodiments, the cancer is a solid tumor.

[0110] 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.

[0111] 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

[0112] 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.

[0113] In some embodiments, the first treatment comprises a radiopharmaceutical and the second treatment comprises a DDRi.

[0114] In some embodiments, the first treatment comprises a DDRi and the second treatment comprises a radiopharmaceutical.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] In some embodiments, the DDRi is administered in a single dose. In some embodiments, the DDRi is administered more than once (e.g., at least twice, at least three times, etc.). In some embodiments, the DDRi is administered multiple times according to a regular or semi-regular schedule, for example, approximately once every two weeks, once a week, twice a week, three times a week, or more than three times a week. When the DDRi is administered more than once, the dosage of each administration may be the same or different. For example, the DDRi may be administered in the amount of an initial dose, and then the dosage of the DDRi afterwards may be higher or lower than the amount of the initial dose.

[0122] In some embodiments, the first dose of DDRi is administered simultaneously with the first dose of radiopharmaceutical. In some embodiments, the first dose of DDRi is administered before the first dose of radiopharmaceutical. In some embodiments, the first dose of DDRi is administered after the first dose of radiopharmaceutical. In some embodiments, a subsequent dose of DDRi is administered.

[0123] In some embodiments, the present disclosure provides: 225The 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.

[0124] In certain embodiments, the above 225 The 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.

[0125] 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.

[0126] In some embodiments, the above 225The 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.

[0127] In some embodiments, the above 225 The 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] In some embodiments, the radiopharmaceutical (or a composition thereof) and the DDRi (or a composition thereof) are administered within 28 days (eg, within 14, 7, 6, 5, 4, 3, 2, or 1 day) of each other.

[0132] In some embodiments, the radiopharmaceutical (or composition thereof) and the DDRi (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 DDRi is administered simultaneously with the radiopharmaceutical. In various embodiments, the DDRi is administered multiple times after a first administration of the radiopharmaceutical.

[0133] 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.

[0134] Pharmaceutical compositions containing one or more agents (e.g., radiopharmaceuticals and / or DDRi) 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

[0135] 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.

[0136] 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

[0137] In some embodiments, the methods of the present disclosure provide a therapeutic benefit.

[0138] 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

[0139] In some embodiments, the disclosed methods further comprise administering an antiproliferative agent, a radiosensitizing agent, or an immunosuppressant or immunomodulatory agent.

[0140] "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.

[0141] "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.

[0142] 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

[0143] Example 1. Synthesis of radiopharmaceuticals containing compounds of formula I

[0144] 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.

[0145] 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. CT-26-mNTSR1 Syngeneic Immunocompetent Mouse Model 177 Lu]-Compound A biodistribution

[0146] Compound A of formula I is radiolabeled with Lu-177 using methods well known in the art to produce [ 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 7-2.85% injected dose / g (ID / g) for 6-48 hours post-injection. See Figure 1. Example 3. CT-26-mNTSR1 xenograft model 225 Ac]-Compound A single agent efficacy

[0147] Compound A of formula I is radiolabeled using standard techniques to give 225 Ac]-Compound A was formed. 225 Ac]-Compound A efficacy study was performed using various doses ranging from 0.185 to 5.555 MBq / kg (single dose, intravenous) 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 xenograft-bearing mice compared to the efficacy of cold Compound A. See Figure 2. Example 4. CT-26-mNTSR1 xenograft model 225 Combination of Ac]-Compound A and Olaparib Treatment Results in Increased Therapeutic Efficacy

[0148] In CT-26-mNTSR1 tumor-bearing mice, in combination with olaparib [ 225 An in vivo study was conducted to test the effect of Compound A (described in Example 3) at 0.555MBq / kg [Ac]- 225 Mice treated with either [Ac]-Compound A or 50 mg / kg of olaparib showed slight or negligible reduction in tumor growth compared to control mice. However, 225 Ac]-Compound A was coadministered at a dose of 0.555 MBq / kg (single dose, intravenous) with olaparib (25 mg / kg QD; oral), whereas vehicle alone or monotherapy ([ 225 Ac]-Compound A alone or Olaparib alone) treatment groups, increased therapeutic efficacy, including tumor regression, was observed. See FIG. 3. Example 5. 225 Improved overall survival in mice treated with Ac]-Compound A

[0149] Effects on survival in the CT-26-mNTSR1 mouse model 225 In vivo studies were conducted to test the effects of [Ac]-Compound A (described in Example 3) and Olaparib. 225 Improved overall survival was observed when Compound A was co-administered with olaparib (25 mg / kb, QD, oral) at a dose of 0.555 MBq / kg (single dose, intravenous) - co-administration was superior to vehicle controls, [ 225 Ac]-Compound A treatment group, or Olaparib treatment group, resulted in a significant improvement in survival rate. See Figure 4. Other embodiments

[0150] 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. 1. A combination for use in a method of treating or ameliorating cancer, said combination comprising a radiopharmaceutical and a DNA damage response inhibitor (DDRi), said method comprising: (i) administering said radiopharmaceutical to a mammal, said mammal having undergone or having undergone said DDRi; (ii) administering said DDRi to a mammal, wherein said mammal has received or is receiving said radiopharmaceutical; or (iii) administering said DDRi to a mammal simultaneously with administering said radiopharmaceutical to said mammal. Including, In each occurrence, the radiopharmaceutical is 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 -C ６ ) alkyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) selected from the group consisting of cycloalkylmethyl, halogen, nitro, and trifluoromethyl; R ３ and R ４ are each independently hydrogen and (C １ -C ４ ) alkyl; L １ is (C ２ -C ５ ) alkylidene; L ２ is (C ２ -C ２０ ) alkylidene, (C ２ -C ２０ ) heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or (C １ -C 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; 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. 2. The combination of claim 1, wherein the DDRi is administered to a mammal, the mammal having received or having received 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 DDRi is a PARP inhibitor.

5. The combination of claim 4, wherein the PARP inhibitor is a small molecule PARP inhibitor.

6. 6. The combination of claim 5, wherein the small molecule PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, talazoparib, pamiparib, rucaparib (camsylate), and veliparib, or analogs thereof.

7. 7. The combination of claim 6, wherein the small molecule PARP inhibitor is olaparib or an analog thereof.

8. 2. The combination of claim 1, wherein the DDRi is an ATR or ATM inhibitor.

9. 9. The combination of claim 8, wherein the ATR or ATM inhibitor is a small molecule ATR or ATM inhibitor.

10. 10. The combination of claim 9, wherein the small molecule ATR or ATM inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541, M4344, M6620 (formerly known as VE-922 or VX-970), NU6027 and VE-821, or analogs thereof.

11. 11. The combination of claim 10, wherein the small molecule ATR or ATM inhibitor is AZD1390, BAY-1895344 or an analogue thereof.

12. 2. The combination of claim 1, wherein the DDRi is a DNA-protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor.

13. 13. The combination of claim 12, wherein the DDRi is a DNA-PK inhibitor selected from the group consisting of AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCl, PP121 and SF2523, or analogs thereof.

14. 14. The combination of claim 13, wherein the DNA-PK inhibitor is AZD7648 or an analogue thereof.

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

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 23. The combination of claim 22, wherein the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

24. 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.

25. 25. The combination of claim 24, wherein said administration results in a reduced incidence of recurrence or metastasis.

26. The DDRi is administered to a mammal, wherein the mammal has the following structure: 【Chemistry 15】 Chelated by ２２５ Contains Ac ２２５ have received or are receiving Ac radiopharmaceuticals, the DDRi is a PARP inhibitor or an ATR or ATM 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.

27. A composition for use in a method for treating or ameliorating cancer, said composition comprising a radiopharmaceutical comprising a radionuclide chelated by a compound of formula I, said method comprising: (i) administering said radiopharmaceutical to a mammal, wherein said mammal has received or is receiving a DNA damage response inhibitor (DDRi); (ii) administering a DDRi to a mammal, wherein the mammal has received or is receiving the radiopharmaceutical; or (iii) administering a DDRi to a mammal simultaneously with administering said radiopharmaceutical to said 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 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylmethyl, halogen, nitro, and trifluoromethyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen and (C 1 -C 4 ) alkyl; L 1 is (C 2 -C 5 ) alkylidene; L 2 is (C 2 -C 20 )alkylidene, (C 2 -C 20 )heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or (C 1 -C 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.

28. A composition for use in a method for treating or ameliorating cancer, said composition comprising a DNA damage response inhibitor (DDRi), said method comprising: (i) administering a radiopharmaceutical to a mammal, said mammal having undergone or having undergone said DDRi; (ii) administering said DDRi to a mammal, wherein said mammal has received or is receiving a radiopharmaceutical; or (iii) administering said DDRi to a mammal simultaneously with administering a radiopharmaceutical to said 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 selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylmethyl, halogen, nitro, and trifluoromethyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen and (C 1 -C 4 ) alkyl; L 1 is (C 2 -C 5 ) alkylidene; L 2 is (C 2 -C 20 )alkylidene, (C 2 -C 20 )heteroalkylidene, (C═O)O, (C═O)NR, or a combination thereof, where R is hydrogen or (C 1 -C 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.

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