Combination therapy of NTSR1 targeted radiopharmaceutical

Abstract

The present invention relates to a method of treating or ameliorating cancer comprising administering to a mammal an NTSR1-targeting radiopharmaceutical comprising a radionuclide chelated with a compound of formula I, and a DNA damage response inhibitor.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,178, filed on January 28, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] DNA single-strand breaks and double-strand breaks occur for a variety of reasons, including exposure of cells to exogenous DNA damaging agents such as radiopharmaceuticals, or due to genetic mutations in pathways including BRCA, PTEN and ATR proteins. Such DNA breaks are repaired via multiple pathways and inhibition of these repair pathways results in accumulation of single-strand and / or double-strand breaks (e.g., PARP inhibition (PARPi) or ATM inhibition).

[0004] Existing PARP inhibitors work both through inhibitors of PARP enzyme inhibition activity and through the capture of PARP proteins within chromosomes ("DNA capture"). Tumor cells with BRCA and / or PTEN mutations are sensitive to PARPi, while ATR inhibition (ATRi) results in double-strand breaks that cannot be repaired - and therefore cause accumulation of double-strand breaks. Similarly, ATM inhibitors (ATMi) or DNA-PK inhibitors (DNA-PKi) or other DNA repair pathways cause an increase in the accumulation of DNA damage in cells. The increase in single-strand or double-strand DNA breaks in tumors leads to higher cell death. DNA damage repair inhibitors (DDRi) have been studied as cancer therapeutics based on this mechanism. However, the presence of mutations that enable DDRi monotherapy in cancer cells and are also present in non-cancerous somatic cells can produce undesirable normal tissue toxicity. In addition, many DDRi only exhibit appropriate in vivo efficacy when used as monotherapy and their use may be limited to cancer types that are already defective in some aspects of DNA repair capacity (e.g., PARPi for the treatment of BRCA1 / 2-deficient cancers).

[0005] Therefore, there is a need for improved treatments for cancer. In particular, there is a need to increase efficacy without increasing toxicity in patients. Summary of the invention

[0006] The present invention encompasses the understanding that therapies that use inhibition of DNA damage repair mechanisms and targeting DNA breaks specifically to cancer cells (rather than normal tissues) in a combined manner can produce better therapies with improved efficacy. Radioactive decay can cause direct physical damage (such as single or double strand DNA breaks) or indirect damage (such as bystander effect or crossfire effect) to the biomolecules that make up the cell. Drugs that deliver radioisotopes, radiopharmaceuticals to cancer cells provide a mechanism for producing DNA damage that has anti-cancer therapeutic effects. The present invention provides methods for combining radiopharmaceuticals, particularly small molecule-based radiopharmaceuticals, with DDRi to treat or ameliorate cancer, wherein such small molecule-based radiopharmaceuticals target neurotensin receptor 1 (NTSR1) positive tumors and use actinium-225, lutetium-177 or other suitable radionuclides to target cancer cells.

[0007] More specifically, the present application provides a method for treating or improving cancer, the method comprising:

[0008] (i) administering a radiopharmaceutical to a mammal, wherein the mammal has received or is receiving a DNA damage response inhibitor (DDRi);

[0009] (ii) administering a DDRi to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or

[0010] (iii) administering DDRi to a mammal and concurrently administering a radiopharmaceutical to the mammal,

[0011] wherein the radiopharmaceutical comprises, in each occurrence, a radionuclide chelated to a compound of formula I:

[0012]

[0013] in

[0014] R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl;

[0015] 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;

[0016] R 2 Is to choose free C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl;

[0017] R 3 and R4 Each independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0018] L1 is C 2-5 Alkylene;

[0019] L2 is C 2-20 Alkylene, C 2-20 heteroalkylene, (C=O)O, (C=O)NR or a combination thereof, R is hydrogen or C 1-4 Alkyl; and

[0020] 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,

[0021] Wherein the 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.

[0022] In some embodiments, the method comprises administering a DDRi to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical.

[0023] In some embodiments, the method comprises administering a radiopharmaceutical to a mammal, wherein the mammal has received or is receiving one or more DDRi's.

[0024] In some embodiments, the method comprises administering to the mammal one or more DDRi's concurrently with administering to the mammal a radiopharmaceutical.

[0025] In some embodiments, the chelating agent is selected from the group consisting of DOTA, DOTA-GA, NOTA, NODA-GA, and NODA-SA.

[0026] In some embodiments, the chelating agent is selected from the group consisting of DTPA, EDTA, CDTA, DFO, BAT, and HYNIC.

[0027] In some embodiments, the radiopharmaceutical is a compound comprising225 Ac 225 Ac radiopharmaceuticals. Exemplary 225 The Ac radiopharmaceutical comprises a chelated compound of the following structure (Compound A): 225 Ac:

[0028]

[0029] 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 an analog thereof. In certain embodiments, the small molecule PARP inhibitor is olaparib or an analog thereof.

[0030] In some embodiments, 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 (formerly VE-922 or VX-970), NU6027 and VE-821 or its analogs. In certain embodiments, the small molecule ATR or ATM inhibitor is AZD1390, BAY-1895344 or its analogs.

[0031] In some embodiments, DDRi is a DNA protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. In certain embodiments, DDRi is a DNA-PK inhibitor selected from the group consisting of AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75HCI, PP121, and SF2523, or an analog thereof. In certain embodiments, the DNA-PK inhibitor is AZD7648 or an analog thereof.

[0032] In some embodiments, the mammal is a human.

[0033] In some embodiments, the drug is administered at a dose of less than 1 MBq / kg body weight of the mammal.225 Ac radiopharmaceuticals.

[0034] In some embodiments, the drug is administered at a dose of less than 250 kBq / kg body weight of the mammal. 225 Ac radiopharmaceuticals.

[0035] In some embodiments, the drug is administered at a dose of less than 100 kBq / kg body weight of the mammal. 225 Ac radiopharmaceuticals.

[0036] In some embodiments, the mammal is administered the drug at a unit dose of less than 15 MBq. 225 Ac radiopharmaceuticals.

[0037] In some embodiments, the mammal is administered the drug at a unit dose of less than 10 MBq. 225 Ac radiopharmaceuticals.

[0038] In some embodiments, the mammal is administered the drug at a unit dose of less than 5 MBq. 225 Ac radiopharmaceuticals.

[0039] In some embodiments, the DDRi is administered at a dose of about 5 mg / kg to about 30 mg / kg body weight of said mammal.

[0040] In some embodiments, the DDRi is administered at a dose of about 25 mg / kg body weight of said mammal.

[0041] 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 cancer, multiple myeloma, acute myeloid leukemia and cutaneous T-cell lymphoma.

[0042] In some embodiments, the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

[0043] In some embodiments, the administration results in a reduction in tumor volume, a stabilization of tumor volume, or a reduction in the rate of increase in tumor volume.

[0044] In some embodiments, the administration results in a reduced incidence of recurrence or metastasis.

[0045] In some embodiments, the method comprises administering a DDRi to a mammal, wherein the mammal has received or is receiving 225 Ac radiopharmaceuticals, the 225Ac radiopharmaceuticals contain chelated 225 Ac:

[0046]

[0047] wherein DDRi is a PARP inhibitor or an ATR or ATM inhibitor, and wherein the DDRi is administered at a dose of 100 to 600 kBq / kg body weight of the mammal 225 Ac radiopharmaceuticals.

[0048] 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 an individual in need thereof, the method comprising:

[0049] (i) administering a radiopharmaceutical to a mammal, wherein the mammal has received or is receiving a DNA damage response inhibitor (DDRi);

[0050] (ii) administering a DDRi to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or

[0051] (iii) administering DDRi to a mammal and concurrently administering a radiopharmaceutical to the mammal,

[0052] Wherein the compound of formula I is represented by:

[0053]

[0054] in

[0055] R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl;

[0056] 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;

[0057] R 2 Is to choose free C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl;

[0058] R 3 and R 4 are each independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0059] L1 is C 2-5 Alkylene;

[0060] L2 is C 2-20 Alkylene, C2-20 heteroalkylene, (C=O)O, (C=O)NR or a combination thereof, R is hydrogen or C 1-4 Alkyl; and

[0061] 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,

[0062] Wherein the 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; and

[0063] wherein the radiopharmaceutical comprises a radionuclide chelated to a compound of formula I in each occurrence.

[0064] In another aspect, provided herein is a compound of formula I for use in treating or ameliorating cancer in an individual in need thereof, the use comprising:

[0065] (i) administering a radiopharmaceutical to a mammal, wherein the mammal has received or is receiving a DNA damage response inhibitor (DDRi);

[0066] (ii) administering a DDRi to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical; or

[0067] (iii) administering DDRi to a mammal and concurrently administering a radiopharmaceutical to the mammal,

[0068] Wherein the compound of formula I is represented by:

[0069]

[0070] in

[0071] R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl;

[0072] 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;

[0073] R 2 Is to choose free C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 The group consisting of cycloalkylmethyl, halogen, nitro and trifluoromethyl;

[0074] R 3 and R 4 are each independently selected from hydrogen and C 1-4 The group consisting of alkyl groups;

[0075] L1 is C 2-5 Alkylene;

[0076] L2 is C 2-20 Alkylene, C 2-20 heteroalkylene, (C=O)O, (C=O)NR or a combination thereof, R is hydrogen or C 1-4 Alkyl; and

[0077] 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; and

[0078] wherein the radiopharmaceutical comprises, in each occurrence, a radionuclide chelated to a compound of formula I, wherein the 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 Draw the radiopharmaceutical 177 Biodistribution of Lu]-Compound A in the CT-26-mNTSR1 isogenic immunocompetent mouse model.

[0080] Figure 2Plotting different doses of radiopharmaceuticals[ 225 Ac]-Compound A in vivo efficacy in the CT-26-mNTSR1 xenograft model.

[0081] Figure 3 Shown is the enhanced therapeutic efficacy of the combination of radiopharmaceutical [225Ac]-Compound A and olaparib in the CT-26-mNTSR1 xenograft model.

[0082] Figure 4 For illustration 225 Ac]-Compound A and olaparib combination-treated mice showed improvement in overall survival.

[0083] Implementation

[0084] The present invention relates to combination therapy for treating or ameliorating cancer using certain radiopharmaceuticals and DNA damage response inhibitors in combination. Specifically, the radiopharmaceutical is a small molecule chelated with a radionuclide targeting neurotensin receptor 1 (NTSR1).

[0085] NTSR1 is a transmembrane receptor that binds the neurotransmitter neuromodulator (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 the intestine (smooth muscle, mucosa and nerve cells). In addition to the central nervous system, NTSR1 is highly expressed in the mammalian body and the human body, especially in some neoplastic cells in some tumor indications, while NTSR1 is not expressed or expressed at low levels in most other tissues of mammals and humans. See, for example, 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.

[0086] These tumor indications expressing NTSR1 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 tumors, uterine leiomyoma, and cutaneous T-cell lymphoma. A preferred group of tumor indications expressing NTSR1 is pancreatic ductal adenocarcinoma, small cell lung cancer, prostate cancer, colorectal cancer, breast cancer, meningioma, and Ewing's sarcoma.

[0087] 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 are specific to diseased cells (e.g., tumor cells) to deliver a radioactive payload to damage and kill the cells of interest.

[0088] definition

[0089] Chemical terms

[0090] Unless otherwise specified, as used herein, the term "alkyl" includes both straight and branched chain saturated groups of 1 to 20 (e.g., 1 to 10 or 1 to 6) carbons. Alkyl is exemplified by methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or (in the case of an alkyl group having two or more carbons) four substituents independently selected from the group consisting of: (1) C 1-6 Alkoxy; (2) C 1-6 (3) an amino group as defined herein (e.g., an unsubstituted amino group (ie, -NH2) or a substituted amino group (ie, -N(R N1 )2, where R N1 is as defined herein for amino); (4) C 6-10 Aryl-C 1-6 Alkoxy; (5) azido; (6) halo; (7) (C 2-9 (8) hydroxyl optionally substituted with an O-protecting group; (9) nitro; (10) oxo (eg, carboxaldehyde or acyl); (11) C 1-7 Spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO2R A' , which is optionally substituted with an O-protecting group and wherein R A' is selected from the group consisting of: (a) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b) C 2-20 Alkenyl (e.g. C 2-6 (c) C 6-10 Aryl, (d) Hydrogen, (e) C 1-6 Alkane-C 6-10 Aryl, (f) amino-C 1-20 Alkyl, (g) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3OR', 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 R' is H or C 1-20 alkyl, and (h) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (15)-C(O)NR B' R C' , where R B' and R C' are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (16)-SO2R D' , where R D' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl, (c)C 1-6 Alkane-C 6-10 Aryl and (d) hydroxyl; (17)-SO2NR E' R F' , where R E' and R F' are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (18)-C(O)R G' , where R G' is selected from the group consisting of: (a) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b) C 2-20 Alkenyl (e.g. C 2-6 (c) C 6-10 Aryl, (d) Hydrogen, (e) C 1-6 Alkane-C 6-10 Aryl, (f) amino-C 1-20Alkyl, (g) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C 1-20 alkyl, and (h) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (19)-NR H' C(O)R I' , where R H' is selected from the group consisting of: (a1) hydrogen and (b1) C 1-6 Alkyl, and R I' is selected from the group consisting of: (a2) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b2) C 2-20 Alkenyl (e.g. C 2-6 alkenyl), (c2)C 6-10 Aryl, (d2) Hydrogen, (e2) C 1-6 Alkane-C 6-10 Aryl, (f2)amino-C 1-20 Alkyl, (g2) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C 1-20 alkyl, and (h2) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (20)-NR J' C(O)OR K' , where R J' is selected from the group consisting of: (a1) hydrogen and (b1) C 1-6 Alkyl, and R K' is selected from the group consisting of: (a2) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b2) C 2-20 Alkenyl (e.g. C 2-6 alkenyl), (c2)C 6-10 Aryl, (d2) Hydrogen, (e2) C 1-6 Alkane-C 6-10 Aryl, (f2)amino-C 1-20 Alkyl, (g2) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C 1-20 alkyl, and (h2) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 alkyl; and (21) amidine. In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of the C1-alkaryl group may be further substituted with oxo to obtain the respective aroyl substituent.

[0091] As used herein, the terms "alkylene," "alkylidene," and the prefix "alk-" refer to a saturated divalent hydrocarbon radical derived from a straight or branched chain saturated hydrocarbon by removing two hydrogen atoms, and are exemplified by methylene, ethylene, isopropylene, and the like. The term "Cx-y Alkyl", "C x-y Alkylene, "C x-y Alkylidene" and the prefix "C x-y "Alk-" means an alkyl or alkylene group having between x and y carbon atoms. 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 In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.

[0092] Unless otherwise specified, as used herein, the term "alkenyl" means a monovalent straight or branched chain group of 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 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.

[0093] As used herein, the term "alkynyl" 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 may 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.

[0094] As used herein, the term "amino" refers to -N(R N1 )2, where R N1 Each independently is H, OH, NO2, N(R N2 2. SO2OR N2 、SO2R N2 , SOR N2, N-protecting groups, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkancycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group such as optionally substituted arylalkoxycarbonyl or any group described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other groups described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group such as optionally substituted arylalkoxycarbonyl or any group described herein), heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), wherein the R listed above N1 Each of the groups may be optionally substituted as defined herein for each group; or both R N1 to form a heterocyclic group or an N-protecting group, and wherein R N2 Each is independently H, alkyl or aryl. The amino group may be an unsubstituted amino group (ie, -NH2) or a substituted amino group (ie, -N(R N1 )2). In a preferred embodiment, the amino group is -NH2 or -NHR N1 , where R N1 OH, NO2, NH2, NR N2 2. SO2OR N2 、SO2R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other acyl described herein), alkoxycarbonylalkyl (e.g., tert-butoxycarbonylalkyl), or aryl, and R N2 Can be H, C 1-20 Alkyl (e.g. C 1-6 Alkyl) or C 6-10 Aryl.

[0095] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group and an acid group (e.g., a carboxyl group of -CO2H or a sulfonic acid group of -SO3H), wherein the amino acid is connected to the parent molecular group by a side chain, an amino group or an acid group (e.g., a side chain). In some embodiments, the amino acid is connected to the parent molecular group by a carbonyl group, wherein the side chain or the amino group is connected to the carbonyl group. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkaryl, aminoalkyl, carbamoylalkyl and carboxylalkyl groups. 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 carbon atoms) four substituents independently selected from the group consisting of: (1) C 1-6 Alkoxy; (2) C 1-6 (3) an amino group as defined herein (e.g., an unsubstituted amino group (ie, -NH2) or a substituted amino group (ie, -N(R N1 )2, where R N1 As defined for amino group); (4) C 6-10 Aryl-C 1-6 Alkoxy; (5) azido; (6) halo; (7) (C 2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (such as formaldehyde or acyl); (11) C 1-7 Spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO2R A' , where R A' is selected from the group consisting of: (a) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b) C 2-20 Alkenyl (e.g. C 2-6 (c) C 6-10 Aryl, (d) Hydrogen, (e) C 1-6 Alkane-C 6-10 Aryl, (f) amino-C 1-20 Alkyl, (g) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C1-20 alkyl, and (h) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (15)-C(O)NR B' R C' , where R B' and R C' Each is independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (16)-SO2R D ', where R D' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl, (c)C 1-6 Alkane-C 6-10 Aryl and (d) hydroxyl; (17)-SO2NR E' R F' , where R E' and R F' are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (18)-C(O)R G' , where R G' is selected from the group consisting of: (a) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b) C 2-20 Alkenyl (e.g. C 2-6 (c) C 6-10 Aryl, (d) Hydrogen, (e) C 1-6 Alkane-C 6-10 Aryl, (f) amino-C 1-20 Alkyl, (g) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3OR', 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 R' is H or C 1-20 alkyl, and (h) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (19)-NR H' C(O)R I' , where R H' is selected from the group consisting of: (a1) hydrogen and (b1) C 1-6 Alkyl, and R I' is selected from the group consisting of: (a2) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b2) C 2-20 Alkenyl (e.g. C 2-6 alkenyl), (c2)C 6-10 Aryl, (d2) Hydrogen, (e2) C 1-6 Alkane-C 6-10 Aryl, (f2)amino-C 1-20 Alkyl, (g2) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C 1-20 alkyl, and (h2) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 Alkyl; (20)-NRJ' C(O)OR K' , where R J' is selected from the group consisting of: (a1) hydrogen and (b1) C 1-6 Alkyl, and R K' is selected from the group consisting of: (a2) C 1-20 Alkyl (e.g. C 1-6 Alkyl), (b2) C 2-20 Alkenyl (e.g. C 2-6 alkenyl), (c2)C 6-10 Aryl, (d2) Hydrogen, (e2) C 1-6 Alkane-C 6-10 Aryl, (f2)amino-C 1-20 Alkyl, (g2) is -(CH2) s2 (OCH2CH2) s1 (CH2) s3 OR', 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 R' is H or C 1-20 alkyl, and (h2) is -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2) s3 NR N1 An amino-polyethylene glycol, 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 R N1 are each independently hydrogen or an optionally substituted C 1-6 and (21) amidine. In some embodiments, each of these groups may be further substituted as described herein.

[0096] As used herein, the term "aryl" refers to a monocyclic, bicyclic or polycyclic carbocyclic ring system having one or two aromatic rings, and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, dihydroindenyl, indanyl and the like, and 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. formaldehyde); (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-C1-6 Alkyl, Azide-C 1-6 Alkyl, (formaldehyde)-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 Alkyl); (3) C 1-20 Alkoxy (e.g. C 1-6 Alkoxy, such as perfluoroalkoxy); (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl; (6) amino; (7) C 1-6 Alkane-C 6-10 Aryl; (8) Azide; (9) C 3-8 Cycloalkyl; (10)C 1-6 Alkane-C 3-8 Cycloalkyl; (11) halo; (12) C 1-12 Heterocyclic groups (such as C 1-12 Heteroaryl); (13) (C 1-12 heterocyclyl)oxy; (14)hydroxyl; (15)nitro; (16)C 1-20 Thioalkoxy (e.g. C 1-6 Thioalkoxy); (17)-(CH2) q CO2R A' , where q is an integer from zero to four, and R A' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl, (c) hydrogen and (d) C 1-6 Alkane-C 6-10 Aryl; (18)-(CH2) q CONR B' R C' , wherein q is an integer from zero to four and wherein R B' and R C' are independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (19)-(CH2) q S02R D' , wherein q is an integer from zero to four and wherein R D' is selected from the group consisting of: (a) alkyl, (b) C 6-10 Aryl and (c) alkane-C 6-10 Aryl; (20)-(CH2)q SO2NR E' R F' , wherein q is an integer from zero to four and wherein R E' and R F' are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (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 Alkane-C 1-12 Heterocyclic groups (such as C 1-6 Alkane-C 1-12 Heteroaryl); (26) C 2-20 alkenyl; and (27)C 2-20 In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of a C1-alkaryl or C1-alkarylheterocyclyl group may be further substituted with oxo to obtain an aroyl and (heterocyclyl)acyl substituent, respectively.

[0097] As used herein, the term "arylalkyl" refers to an aryl group, as defined herein, attached to a parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted arylalkyl groups have 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C 1-6 Alkane-C 6-10 Aryl, C 1-10 Alkane-C 6-10 Aryl or C 1-20 Alkane-C 6-10 In some embodiments, the alkylene and aryl groups may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group. Unless otherwise indicated, other groups preceded by the prefix "alk-" are defined in the same manner, wherein "alkane" refers to C 1-6 The alkylene group and the attached chemical structure are as defined herein.

[0098] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0099] As used herein, the term "carboxyl" means -CO2H.

[0100] As used herein, the term "cyano" refers to a -CN group.

[0101] Unless otherwise specified, as used herein, the term "cycloalkyl" means a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon radical of three to eight carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, and the like. When the cycloalkyl includes one carbon-carbon double bond or one carbon-carbon triple bond, the cycloalkyl may be referred to as a "cycloalkenyl" or "cycloalkynyl," respectively. Exemplary cycloalkenyl and cycloalkynyl radicals include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like. The cycloalkyl may be optionally substituted by: (1) C 1-7 Acyl (e.g. formaldehyde); (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, Azide-C 1-6 Alkyl, (formaldehyde)-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 Alkyl); (3) C 1-20 Alkoxy (e.g. C 1-6 Alkoxy, such as perfluoroalkoxy); (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl; (6) amino; (7) C 1-6 Alkane-C 6-10 Aryl; (8) Azide; (9) C 3-8 Cycloalkyl; (10)C 1-6 Alkane-C 3-8 Cycloalkyl; (11) halo; (12) C 1-12 Heterocyclic groups (such as C 1-12 Heteroaryl); (13) (C 1-12 heterocyclyl)oxy; (14)hydroxyl; (15)nitro; (16)C 1-20 Thioalkoxy (e.g. C 1-6 Thioalkoxy); (17)-(CH2) q CO2R A' , where q is an integer from zero to four, and R A' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl, (c) hydrogen and (d) C 1-6 Alkane-C 6-10 Aryl; (18)-(CH2) qCONR B' R C' , wherein q is an integer from zero to four and wherein R B' and R C' are independently selected from the group consisting of: (a) hydrogen, (b) C 6-10 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (19)-(CH2) q S02R D' , wherein q is an integer from zero to four and wherein R D' is selected from the group consisting of: (a) C 6-10 Alkyl, (b)C 6-10 Aryl and (c)C 1-6 Alkane-C 6-10 Aryl; (20)-(CH2) q SO2NR E' R F' , wherein q is an integer from zero to four and wherein R E' and R F' are each independently selected from the group consisting of: (a) hydrogen, (b) C 6-10 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (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 Alkane-C 1-12 Heterocyclic groups (such as C 1-6 Alkane-C 1-12 Heteroaryl); (26) oxo; (27) C 2-20 alkenyl; and (28)C 2-20 In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of a C1-alkaryl or C1-alkarylheterocyclyl group may be further substituted with oxo to obtain an aroyl and (heterocyclyl)acyl substituent, respectively.

[0102] As used herein, the term "diastereomers" means stereoisomers that are not mirror images of each other and are not superimposable on each other.

[0103] As used herein, the term "enantiomer" means each individual optically active form of a compound having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by standard methods in the art).

[0104] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine or fluorine.

[0105] As used herein, the terms "heteroalkyl" and "heteroalkylene" each refer to an alkyl group as defined herein, wherein one or both of the constituent carbon atoms are each replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for the alkyl group. As used herein, the terms "heteroalkenyl" and "heteroalkynyl" refer to alkenyl and alkynyl groups, respectively, as defined herein, wherein one or both of the constituent carbon atoms are each replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups may be further substituted with 1, 2, 3, or 4 substituents as described herein for the alkyl group.

[0106] As used herein, the term "heteroaryl" refers to a subset of heterocyclyl groups as defined herein that are aromatic: that is, they contain 4n+2 π 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, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents as defined for heterocyclyl.

[0107] 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 have 2 to 32 carbon atoms (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 carbon atoms, such as C 1-6 Alkane-C 1-12 Heteroaryl, C 1-10 Alkane-C 1-12 Heteroaryl or C 1-20 Alkane-C 1-12 In some embodiments, alkylene and heteroaryl may each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups. Heteroarylalkyl is a subset of heterocyclylalkyl.

[0108] Unless otherwise specified, as used herein, the term "heterocyclyl" refers to a 5-, 6-, or 7-membered ring containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclyls 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. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a single ring, such as quinuclidinyl. The term "heterocyclyl" includes bicyclic, tricyclic and tetracyclic groups, wherein any of the above heterocyclic rings is fused to one, two or three carbon rings, for example, an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocycle, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuranyl, benzothienyl and the like. Examples of fused heterocyclic groups include tropane and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclic groups include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, furanyl, 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 their dihydro and tetrahydro forms in which one or more double bonds are reduced and replaced with hydrogen. Other exemplary heterocyclic groups 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 (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl); 2,3-dihydro-2-thione-1,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thione-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-oxopyrimidinyl; 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-quinazolinyl (e.g., 1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolinyl); 1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g., 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 dicarboxamido. Additional heterocyclic groups 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, oxepanyl and thiocanyl. Heterocyclic groups also include groups of the formula:

[0109] in

[0110] 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-, -CH2O-, -OCH2-, -O- and -S-; and G' is selected from the group consisting of -CH- and -N-. Any of the heterocyclic groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C 1-7 Acyl (e.g. formaldehyde); (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, Azide-C 1-6 Alkyl, (formaldehyde)-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 Alkyl); (3) C 1-20 Alkoxy (e.g. C 1-6 Alkoxy, such as perfluoroalkoxy); (4) C 1-6 Alkylsulfinyl; (5)C 6-10 Aryl; (6) amino; (7) C 1-6 Alkane-C 6-10 Aryl; (8) Azide; (9) C 3-8 Cycloalkyl; (10)C 1-6 Alkane-C 3-8 Cycloalkyl; (11) halo; (12) C 1-12 Heterocyclic groups (such as C 2-12Heteroaryl); (13) (C 1-12 heterocyclyl)oxy; (14)hydroxyl; (15)nitro; (16)C 1-20 Thioalkoxy (e.g. C 1-6 Thioalkoxy); (17)-(CH2) q CO2R A' , where q is an integer from zero to four, and R A' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl, (c) hydrogen and (d) C 1-6 Alkane-C 6-10 Aryl; (18)-(CH2) q CONR B' R C' , wherein q is an integer from zero to four and wherein R B' and R C' are independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (19)-(CH2) q S02R D' , wherein q is an integer from zero to four and wherein R D' is selected from the group consisting of: (a) C 1-6 Alkyl, (b)C 6-10 Aryl and (c)C 1-6 Alkane-C 6-10 Aryl; (20)-(CH2) q SO2NR E' R F' , wherein q is an integer from zero to four and wherein R E' and R F' Each is independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 Alkyl, (c)C 6-10 Aryl and (d)C 1-6 Alkane-C 6-10 Aryl; (21) Thiol; (22) C 6-10 Aryloxy; (23)C 3-8 Cycloalkoxy; (24) arylalkoxy; (25) C 1-6 Alkane-C 1-12 Heterocyclic groups (such as C 1-6 Alkane-C 1-12 Heteroaryl); (26) oxo; (27) (C 1-12 Heterocyclyl)imino; (28)C 2-20 alkenyl; and (29)C2-20 In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of a C1-alkaryl or C1-alkarylheterocyclyl group may be further substituted with oxo to obtain an aroyl and (heterocyclyl)acyl substituent, respectively.

[0111] As used herein, the term "hydrocarbon" refers to a group consisting only of carbon and hydrogen atoms.

[0112] As used herein, the term "hydroxy" refers to an -OH group. In some embodiments, the hydroxy group may be substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group (eg, an O-protecting group).

[0113] As used herein, the term "isomer" means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It should be recognized that compounds may have one or more pairs of chiral centers and / or double bonds, and therefore exist in the form of stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers) or non-isomer enantiomers (e.g., isomeric enantiomers (i.e., (+) or (-)) or cis / trans isomers). Unless otherwise indicated, chemical structures depicted herein encompass all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomeric and stereoisomeric mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of compounds can usually be separated into their component enantiomers, enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0114] As used herein, the term "N-protected amino" refers to an amine group as defined herein attached to one or two N-protecting groups as defined herein.

[0115] As used herein, the term "N-protecting group" refers to those groups intended to protect amino groups from undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis", 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups include acyl, aroyl or carbamoyl groups, such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral adjuvants 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 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, dibenzyloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, The N-protecting groups include, for example, cyclopentyloxycarbonyl, cyclopentyloxycarbonyl, cyclopentyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, alkylaryl (such as benzyl, trityl, benzyloxymethyl, and the like) and silyl (such as trimethylsilyl, and the like). Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, benzylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0116] As used herein, the term "O-protecting group" refers to those groups intended to protect oxygen-containing (e.g., phenol, hydroxyl or carbonyl) groups from undesired reactions during synthetic procedures. Commonly used O-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis", 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O-protecting groups include acyl, aroyl or carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, tert-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylamino aminomethylamino and 4-nitrobenzoyl; alkylcarbonyl such as acyl, acetyl, propionyl, pivaloyl and the like; optionally substituted arylcarbonyl such as benzoyl; silyl such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), triisopropylsilyl (TIPS) and the like; ether groups formed with hydroxyl such as methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, trityl and the like alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, methoxycarbonyl and the like; alkoxyalkoxycarbonyl such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenyloxy alkyloxycarbonyl, such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and the like; optionally substituted arylalkyloxycarbonyl such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxy-carbonyl, fluorenylmethoxycarbonyl, and the like;and optionally substituted aryloxycarbonyl such as phenoxycarbonyl, p-nitrophenoxycarbonyl, o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methyl-phenoxycarbonyl, m-methylphenoxycarbonyl, o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, p-chlorophenoxycarbonyl, 2-chloro-4-nitrophenoxy-carbonyl, and the like; substituted alkyl, aryl and alkylaryl ethers (e.g., triphenylmethane); 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; tert-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl and nitrobenzyl); silyl ethers (e.g., trimethyl and nitrobenzyl). ;

[0117] As used herein, the term "oxo" means =0.

[0118] As used herein, the term "polyethylene glycol" refers to an alkoxy chain comprising one or more monomer units, each of which consists of -OCH2CH2-. Polyethylene glycol (PEG) is sometimes also referred to as polyethylene oxide (PEO) or polyethylene oxide (POE), and for the purposes of the present invention, these terms are considered interchangeable. For example, polyethylene glycol can have the structure -(CH2) s2 (OCH2CH2) s1 (CH2) s3 O-, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and 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). Polyethylene glycol may also be considered to include -NR N1 (CH2) s2 (CH2CH2O) s1 (CH2)s3 NR N1 An amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and 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 N1 are each independently hydrogen or an optionally substituted C 1-6 alkyl.

[0119] As used herein, the term "stereoisomer" refers to all possible different isomeric and configurational forms that a compound (e.g., a compound of any chemical formula described herein) may have, in particular all possible stereochemical and configurational isomeric forms of the basic molecular structure, all diastereomers, enantiomers and / or configurational isomers. Some compounds may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0120] As used herein, the term "sulfonyl" refers to a -S(O)2- group.

[0121] As used herein, the term "thiol" refers to a -SH group.

[0122] Biological terms

[0123] ATM stands for ataxia telangiectasia mutated gene

[0124] ATR stands for ataxia telangiectasia and Rad3-related gene

[0125] BRCA stands for breast cancer gene

[0126] Chk1 stands for checkpoint kinase 1

[0127] Chk2 stands for checkpoint kinase 2

[0128] DDR stands for DNA damage response

[0129] DNA stands for deoxyribonucleic acid

[0130] DNA-PK stands for DNA-dependent protein kinase

[0131] NTSR1 stands for neurotensin receptor 1

[0132] PARP stands for poly ADP ribose polymerase

[0133] PTEN stands for phosphatase and tensin homolog deleted on chromosome 10

[0134] WEE1 indicates WEE1 G2 checkpoint kinase

[0135] Other terms

[0136] Unless otherwise indicated or inferred from the context, as used herein, the term "about" or "approximately" refers to a ±10% variation relative to the recited quantitative value (and including the recited quantitative value itself). For example, unless otherwise indicated or inferred from the context, a dose of about 100 kBq / kg represents a dose range of 100±10% kBq / kg (i.e., 90 kBq / kg to 110 kBq / kg), including endpoints.

[0137] As used herein, the terms "administered in combination," "combined administration," or "co-administered" mean that two or more agents are administered to a subject simultaneously or within an interval so that the effects of each agent on the patient may overlap. 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., 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day), within 28 days (e.g., 14, 7, 6, 5, 4, 3, 2, or 1 day), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour), or within about 60, 30, 15, 10, 5, or 1 minute of each other. In some embodiments, the administration of the agents is spaced sufficiently close to each other so that a combined effect is achieved.

[0138] As used herein, "administering" an agent to a subject includes contacting cells of the subject with the agent.

[0139] The term "cancer" refers to any cancer caused by malignant neoplastic cell proliferation, such as tumors, neoplasms, carcinomas, sarcomas, leukemias and lymphomas. "Solid tumor cancers" are cancers that contain abnormal tissue masses, such as sarcomas, carcinomas and lymphomas. As used interchangeably herein, "hematological cancers" or "liquid cancers" are cancers that are present in body fluids, such as lymphomas and leukemias.

[0140] As used herein, the term "chelate" refers to an organic compound, or a portion thereof, which can bind to a central metal or radiometal atom at two or more points.

[0141] As used herein, the term "conjugate" refers to a molecule containing a chelating group or a metal complex thereof, a linking group, and optionally a therapeutic moiety or a targeting moiety.

[0142] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, and tautomers of the depicted structure.

[0143] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended to be encompassed. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are encompassed in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be separated in the form of isomeric mixtures or in separated isomeric forms.

[0144] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the concomitant 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 keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imidic acid pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-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 spatially locked into one form by appropriate substitution.

[0145] At various places in this specification, substituents of the compounds of the invention are disclosed in groups or ranges. Specifically, the invention is intended to include each and every individual subcombination of the members within such groups and ranges. For example, the term "C 1-6 "C alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. In the present context, phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) are intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to indicate that the feature "X" (e.g., alkyl) itself is optional.

[0146] As used herein, the terms "decrease", "decreased", "increase", "increased", or "reduction", "reduced" (e.g., with reference to a treatment outcome or effect) have meanings relative to a reference level. In some embodiments, the reference level is a level determined under control in an experimental animal model or clinical trial by using the method. In some embodiments, the reference level is the 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.

[0147] As used herein, the term "effective amount" of an agent (eg, any of the aforementioned conjugates) is an amount sufficient to achieve beneficial or desired results, such as clinical results, and thus an "effective amount" depends on the context in which it is applied.

[0148] When used as a term in conjunction with an agent (e.g., a therapeutic agent), the term "lower effective dose" refers to a dose of the agent that is therapeutically effective in the combination therapy of the present invention and is lower than the dose that has been determined to be therapeutically effective when the agent is used as a monotherapy in a reference experiment or with the aid of other treatment guidelines.

[0149] As used herein, the term "pharmaceutical composition" means a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is manufactured or sold under the approval of a governmental regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical composition may be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., in the form of a cream, gel, lotion, or ointment); for intravenous administration (e.g., in the form of a sterile solution free of particulate emboli and in the form of a solvent system suitable for intravenous use); or in the form of any other formulation described herein.

[0150] As used herein, "pharmaceutically acceptable excipients" refers to any ingredient other than the compounds described herein that is non-toxic and non-sexual in the patient (e.g., a vehicle capable of suspending or dissolving the active compound). Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radiation protectants, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. 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 polyvinyl pyrrolidone, citric acid, cross-linked povidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, 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.

[0151] As used herein, the term "pharmaceutically acceptable salt" means those salts of the compounds described herein that are suitable for use in contact with human and animal tissues without unusual toxicity, irritation or allergic reaction within the scope of reasonable 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 Pharmaceutical Salts: Properties, Selection, and Use, (P. H. Stahl and C. G. Wermuth, eds.), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or isolated by reacting the free base with a suitable organic acid.

[0152] The compound may have an ionizable group so that it can be prepared in the form of a pharmaceutically acceptable salt. Such salts may be acid addition salts involving inorganic or organic acids, or in the case of an acidic form of the compound, the salt may be prepared from an inorganic or organic base. Typically, the compound is prepared or used in the form of a pharmaceutically acceptable salt prepared as a pharmaceutically acceptable acid or base addition product. 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 for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming alkaline salts. Methods for preparing suitable salts are well-known in the art.

[0153] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and others. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0154] As used herein, the term "radiopharmaceutical" or "radioconjugate" refers to any compound or conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.

[0155] As used herein, the term "radionuclide" refers to an atom that is capable of radioactive decay (e.g. 3 H. 14 C. 15 N. 18 F. 35 S. 47 Sc, 55 Co. 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67Cu, 75 Br, 76 Br, 77 Br, 89 Zr, 86 Y. 87 Y. 90 Y. 97 Such as 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, 229 Th, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn, 201 Tl). The terms radionuclide, radioactive nuclide, radioisotope, or radioactive isotope may also be used to describe a radionuclide. A radionuclide may be used as a detection agent. In some embodiments, the radionuclide may be an alpha-emitting radionuclide. Exemplary radionuclides used in the methods of the present invention include, but are not limited to: 64 Cu, 67 Cu, 68 Ga, 90 Y. 149 Tb, 153 Sm, 177 Lu, 211 At 212 Bi, 212 Pb, 213Bi, 223 Ra, 225 Ac and 227 Th.

[0156] As used herein and as well understood in the art, "treatment" to "treat" a disorder or condition (e.g., a disorder described herein, such as cancer) is an approach for obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; lessening of the extent of a disease, disorder, or condition; stabilization of the state of a disease, disorder, or condition (i.e., not worsening); prevention of the spread of a disease, disorder, or condition; delay or slowing of the progression of a disease, disorder, or condition; amelioration or palliation of a disease, disorder, or condition; and remission (whether partial or complete), whether detectable or undetectable. In the context of cancer treatment, "improvement" may include, for example, a reduction in the incidence of cancer metastasis, a reduction in tumor volume, a reduction in tumor vascularization, and / or a reduction in tumor growth rate. "Palligate" a disease, disorder, or condition means that the extent and / or reduction in undesirable clinical manifestations of the disease, disorder, or condition and / or the time course of progression are slowed or prolonged compared to the extent or time course in the absence of treatment.

[0157] Chelating agents

[0158] The compounds of Formula I comprise a chelating moiety or chelating agent. Exemplary chelating agents 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:

[0159] DOTA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0160] DOTAGA stands for 1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid,

[0161] NOTA stands for 1,4,7-triazacyclononane triacetic acid,

[0162] DTPA stands for diethylenetriaminepentaacetic acid,

[0163] TETA stands for 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid.

[0164] EDTA stands for ethylenediamine-N,N'-tetraacetic acid.

[0165] NODAGA stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid,

[0166] NODASA stands for 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid,

[0167] TRITA stands for 1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid.

[0168] CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid,

[0169] DFO stands for a chelating agent of the Desferal or Desferrioxamine type group, a non-limiting example of which is chemically named N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide,

[0170] BAT represents a chelating agent of the bisamino-bisthiol group, a non-limiting example of which is 1-[2-(2-mercapto-2-methyl-propylamino)-ethylamino]-2-methyl-propane-2-thiol,

[0171] HYNIC stands for 6-hydrazino-nicotinic acid,

[0172] And its chemical structure is as follows:

[0173]

[0174] Radiopharmaceuticals

[0175] Radiopharmaceuticals suitable for use in accordance with the present invention generally comprise a radionuclide chelated to a compound of formula I, with the variables being as defined above in the Summary of the Invention section:

[0176]

[0177] Chelated part

[0178] Examples of suitable chelating moieties include, but are not limited to, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid), NOTA (1,4,7-triazacyclononane triacetic acid), DTPA (diethylenetriaminepentaacetic acid), TETA (1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid), EDTA (ethylenediamine-N,N'-tetraacetic acid), NODAGA (1,4,7-triazacyclononane-N-pentanedioic 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 (chelating agent of the deferoxamine or desferrioxamine type group, a non-limiting example of which is the chemical name N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide), BAT (chelating agent of the bisamino-bisthiol group, a non-limiting example of which is the chemical name 1-[2-(2-mercapto-2-methyl-propylamino)-ethylamino]-2-methyl-propane-2-thiol) and HYNIC (6-hydrazino-nicotinic acid).

[0179] In some embodiments, the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid).

[0180] Radionuclides

[0181] The present invention includes the use of radiopharmaceuticals each containing a radionuclide. Examples of suitable radionuclides include (but are not limited to) 47 Sc, 55 Co. 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 69 2. 77 As, 82 Rb, 89 Zr, 86 Y. 87 Y. 90 Y. 97 Such as 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, 117 mSn, 177 mSn, 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 Th.

[0182] In some embodiments, the 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.

[0183] In some embodiments, the radionuclide is an alpha emitter, such as astatine-211 ( 211 At), Bismuth-212( 212 Bi), bismuth-213( 213Bi), Actinium-225( 225 Ac), radium-223 ( 223 Ra), lead-212( 212 Pb), Thorium-227( 227 Th) or terbium-149( 149 Tb).

[0184] Connector

[0185] The radiopharmaceutical used in the methods of the present invention comprises a linker as shown in the structure of Formula I, comprising L1 and L2:

[0186]

[0187] Where L1 is C 2-5 Alkylene; L2 is C 2-20 Alkylene, C 2-20 heteroalkylene, (C=O)O, (C=O)NR or a combination thereof, R is hydrogen or C 1-4 alkyl.

[0188] An exemplary L1 is Each of which may be optionally substituted with substituents described herein.

[0189] L2 typically contains at least one heteroatom (eg, O or N), an amide moiety, or both. Exemplary L2 include, but are not limited to, the following:

[0190] and Each of which may be optionally substituted with substituents described herein.

[0191] DNA Damage and Repair Inhibitors (DDRi)

[0192] 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.

[0193] DNA repair involves multiple molecular pathways that repair single strand breaks (e.g., the PARP pathway) and double strand breaks (e.g., BRCA and other genes such as ATR / ATM) of DNA. PARP inhibition (PARPi) results in the failure to repair single strand breaks, which further result in double strand breaks. Available PARP inhibitors work 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 the failure to repair double strand breaks - accumulation of double strand breaks results in cell death. These inhibitors work by preventing homologous recombination and non-homologous end joining mechanisms.

[0194] The present invention relates to combination therapies using radiopharmaceuticals and inhibitors of DNA damage and repair. It has been found that this type of combination therapy produces unexpected improvements in cancer treatment, particularly in cancers that would not be expected to respond to DDRi.

[0195] In some embodiments, DDRi is a PARP inhibitor (PARPi). In some embodiments, PARPi is selected from the group consisting of: niparib, niraparib, olaparib, pamipanib, rucaparib (camphorsulfonate), tararaparib and veliparib or their analogs. In some embodiments, PARPi is adavosertib, AZD2811 or its analogs.

[0196] 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 (formerly VE-922 or VX-970), NU6027, and VE-821, or an analog thereof. In certain embodiments, the ATM / ATR inhibitor is AZD1390 or an analog thereof.

[0197] In some embodiments, the DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. Examples of WEE1 inhibitors, Chk1 inhibitors, or Chk2 inhibitors include inhibitors known in the art.

[0198] In some embodiments, DDRi is a DNA-dependent protein kinase (DNA-PK) inhibitor. Non-limiting examples of DNA-PK inhibitors include, but are not limited to, AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75HCI, PP121, SF2523, and analogs thereof. In certain embodiments, the DNA-PK inhibitor is AZD7648 or an analog thereof.

[0199] Subjects

[0200] In some disclosed methods, a therapy (eg, comprising a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, eg, a human.

[0201] In some embodiments, the subject has received or is receiving another therapy. For example, in some embodiments, the subject has received or is receiving a radiopharmaceutical. In some embodiments, the subject has received or is receiving DDRi.

[0202] In some embodiments, the subject suffers from cancer or is at risk of developing cancer. For example, the subject may have been diagnosed with cancer. Cancer may be primary cancer or metastatic cancer. The subject may suffer from cancer at any stage, such as Phase I, Phase II, Phase III, or Phase IV, with or without lymph node involvement and with or without cancer metastasis. The composition provided can prevent or reduce the further growth of cancer and / or otherwise improve cancer (e.g., prevent or reduce cancer metastasis). In some embodiments, the subject does not suffer from cancer, but has been determined to be at risk of suffering from cancer, for example, because there are one or more risk factors, such as environmental exposure, the presence of one or more genetic mutations or variants, family medical history, etc. In some embodiments, the subject has not yet been diagnosed with cancer.

[0203] In some embodiments, the cancer is a solid tumor.

[0204] 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 cancer, Ewing's sarcoma, multiple myeloma, or acute myeloid leukemia.

[0205] In some embodiments, the cancer is a non-solid (eg, liquid (eg, hematological)) cancer.

[0206] Administration and dosage

[0207] Effective and lower effective doses

[0208] The present invention provides combination therapy, wherein the amount of each therapeutic agent itself may be therapeutically effective or may not be therapeutically effective. For example, the methods provided by the present invention include a first therapy and a second therapy administered in an amount that is effective together to treat or improve a condition (e.g., cancer). In some embodiments, at least one of the first and second therapies is administered to a subject at a lower effective dose. In some embodiments, both the first and second therapies are administered at a lower effective dose.

[0209] In some embodiments, the first therapy comprises a radiopharmaceutical and the second therapy comprises DDRi.

[0210] In some embodiments, the first therapy comprises DDRi and the second therapy comprises a radiopharmaceutical.

[0211] In some embodiments, the therapeutic combination as disclosed herein is administered to a subject in a manner (e.g., an amount and timing of administration) sufficient to cure or at least partially arrest the symptoms of the disorder and its complications. In the case of a single therapy ("monotherapy"), an amount sufficient to achieve this purpose is defined as a "therapeutically effective amount" (an amount of a compound sufficient to substantially improve at least one symptom associated with a disease or medical condition). A "therapeutically effective amount" generally varies depending on the therapeutic agent. For known therapeutic agents, the relevant therapeutically effective amount may be known to or readily determined by those skilled in the art.

[0212] For example, in cancer treatment, an agent or compound that reduces, prevents, delays, inhibits or suppresses any symptom of a disease or condition will be therapeutically effective. A therapeutically effective amount of an agent or compound does not need to cure a disease or condition, but should provide treatment for a disease or condition so as to delay, hinder or prevent the onset of the disease or condition, or to ameliorate the symptoms of the disease or condition, or to change the stage of the disease or condition or, for example, to reduce severity or speed up recovery in a subject. For example, a treatment may be therapeutically effective if it causes cancer regression or slows cancer growth.

[0213] The dosage regimen effective for such uses (e.g., the amount of each therapeutic agent, the relative timing of the therapy, etc.) may depend on the severity of the disease or disorder and the weight and overall state of the subject. For example, the therapeutically effective amount of a specific composition comprising a therapeutic agent applied to a mammal (e.g., a human) may be determined by a general technician taking into account differences in the age, weight, and disorder of the mammal. Because certain conjugates of the present invention are directed to exhibiting enhanced targeting cancer cells and residualization, the dose of such compounds may be lower than the equivalent dose required for the uncombined agent to achieve a therapeutic effect (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%). The therapeutically effective and / or optimal amount may also be determined empirically by a person skilled in the art. Therefore, a lower effective dose may also be determined by a person skilled in the art.

[0214] Single or multiple administrations of a radiopharmaceutical or composition (e.g., a pharmaceutical composition comprising a therapeutic agent or radiopharmaceutical) may be performed using a dose level and pattern selected by the treating physician. The dose and administration regimen may be determined and adjusted based on the severity of the subject's disease or condition, which may be monitored throughout the course of treatment according to methods commonly practiced by clinicians or as described herein.

[0215] In the disclosed combination therapy methods, the first and second therapies can be administered to the subject sequentially or concurrently. For example, a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent can be administered to the subject sequentially or concurrently. Alternatively, a composition comprising a combination of a first therapeutic agent and a second therapeutic agent can be administered to the subject.

[0216] In some embodiments, the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., multiple doses. When the radiopharmaceutical is administered more than once, the doses administered each time may be the same or different.

[0217] 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 conventional or semi-conventional schedule, e.g., 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 doses of each administration may be the same or different. For example, a DDRi may be administered in the amount of an initial dose, and subsequent doses of the DDRi may be higher or lower than the amount of the initial dose.

[0218] In some embodiments, the first dose of DDRi is administered simultaneously with the first dose of the radiopharmaceutical. In some embodiments, the first dose of DDRi is administered before the first dose of the radiopharmaceutical. In some embodiments, the first dose of DDRi is administered after the first dose of the radiopharmaceutical. In some embodiments, subsequent doses of DDRi are administered.

[0219] In some embodiments, the methods provided herein comprise administering to a mammal a dose 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 the mammal's body weight. 225 Ac radiopharmaceutical. Each of the doses may be administered to the mammal multiple times.

[0220] In certain embodiments, the drug may be administered at a dose of between 900 kBq / kg and 800 kBq / kg, between 800 kBq / kg and 700 kBq / kg, between 700 kBq / kg and 600 kBq / kg, between 600 kBq / kg and 500 kBq / kg, between 500 kBq / kg and 400 kBq / kg, between 400 kBq / kg and 300 kBq / kg, between 300 kBq / kg and 200 kBq / kg, between 200 kBq / kg and 100 kBq / kg, or between 100 kBq / kg and 50 kBq / kg. 225 Ac radiopharmaceutical. Each of the doses may be administered to the mammal multiple times.

[0221] In certain embodiments, the drug may be administered at a dose of about 2 MBq / kg, about 1.9 MBq / kg, about 1.8 MBq / kg, about 1.7 MBq / kg, about 1.6 MBq / kg, about 1.5 MBq / kg, about 1.4 MBq / kg, about 1.3 MBq / kg, about 1.2 MBq / kg, about 1.1 MBq / kg, about 1 MBq / kg, about 0.9 MBq / kg, about 0.8 MBq / kg, about 0.7 MBq / kg, about 0.6 MBq / kg, about 0.5 MBq / kg, about 0.4 MBq / kg, about 0.3 MBq / kg, about 0.2 MBq / kg, about 0.1 MBq / kg, or about 0.05 MBq / kg. 225 Ac radiopharmaceutical. Each of the doses may be administered to the mammal multiple times.

[0222] In some embodiments, the drug is administered at a dose 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 the mammal's body weight. 225 Ac radiopharmaceutical. Each of the doses may be administered to the mammal multiple times.

[0223] In some embodiments, the drug is administered at a dose 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 the mammal's body weight. 225 Ac radiopharmaceutical. Each of the doses may be administered to the mammal multiple times.

[0224] In some embodiments, the mammal is administered the drug at a unit dose of less than 15 MBq (e.g., about 14 MBq, about 13 MBq, about 12 MBq, about 11 MBq, about 10 MBq, about 9 MBq, about 8 MBq, about 7 MBq, about 6 MBq, about 5 MBq, about 4 MBq, about 3 MBq, about 2 MBq, about 1 MBq). 225 Ac radiopharmaceutical. Each of the unit doses may be administered to the mammal multiple times.

[0225] In some embodiments, the mammal is administered the drug at a unit dose of less than 10 MBq. 225 Ac radiopharmaceutical. Each of the unit doses may be administered to the mammal multiple times.

[0226] In some embodiments, the mammal is administered the drug at a unit dose of less than 5 MBq. 225 Ac radiopharmaceutical. Each of the unit doses may be administered to the mammal multiple times.

[0227] In some embodiments, the radiopharmaceutical (or composition thereof) and DDRi (or composition thereof) are administered within 28 days (eg, 14, 7, 6, 5, 4, 3, 2, or 1 day) of each other.

[0228] In some embodiments, the radiopharmaceutical (or a composition thereof) and DDRi (or a composition thereof) are administered within 90 days (e.g., 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day) of each other. In various embodiments, DDRi is administered simultaneously with the radiopharmaceutical. In various embodiments, DDRi is administered multiple times after the first administration of the radiopharmaceutical.

[0229] In some embodiments, the composition (such as a composition comprising a radiopharmaceutical) is administered for radiation therapy planning or diagnostic purposes. When administered for radiation therapy planning or diagnostic purposes, the composition can be administered to a subject in an amount effective for diagnosis and / or for determination of a therapeutically effective dose. In some embodiments, a first dose of a disclosed conjugate or a composition thereof (e.g., a pharmaceutical composition) is administered in an amount effective for radiation therapy planning, followed by administration of a combination therapy comprising a conjugate as disclosed herein and another therapeutic agent.

[0230] Pharmaceutical compositions comprising one or more medicaments (e.g., radiopharmaceuticals and / or DDRi) can be prepared for use according to the disclosed methods and systems in various drug delivery systems. For proper preparation, one or more physiologically acceptable excipients or carriers may also be included in the composition. Examples of suitable formulations are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th edition, 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249: 1527-1533, 1990).

[0231] Preparation

[0232] The pharmaceutical composition can be formulated for parenteral, intranasal, topical, oral or local administration, such as for preventive and / or therapeutic treatment by transdermal means. The pharmaceutical composition can be administered parenterally (e.g., by intravenous, intramuscular or subcutaneous injection), or by oral ingestion, or by topical administration or intraarticular injection at an area affected by a vascular or cancer condition. Examples of additional routes of administration include intravascular, intraarterial, intratumoral, intraperitoneal, intraventricular, intradural, and nasal, intraocular, intrascleral, intraorbital, rectal, topical or aerosol inhalation administration. In particular, sustained release administration by means such as depot injection or erodible implants or components is also contemplated. Suitable compositions include compositions comprising a medicament (e.g., a compound as disclosed herein) dissolved or suspended in an acceptable carrier (preferably an aqueous carrier, such as water, buffered water, saline or PBS, etc.), for example, for parenteral administration. The composition may contain pharmaceutically acceptable auxiliary substances (such as pH adjusters and buffers, tonicity adjusters, wetting agents or detergents, etc.) to approximate physiological conditions. In some embodiments, the composition is formulated for oral delivery; for example, the composition may contain inert 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 inert ingredients such as solvents or emulsifiers for the formulation of creams, ointments, gels, pastes, or eye drops.

[0233] The composition can be sterilized, for example, by known sterilization techniques or aseptic filtration. The aqueous solution can be packaged to be used as is or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the preparation will generally be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and optimally between 6 and 7, such as 6 to 6.5. In some embodiments, the composition in solid form is packaged in a plurality of single dose units, each unit containing a fixed amount of one or more medicaments mentioned above, such as in a sealed package form of a tablet or capsule. In some embodiments, a flexible amount of the composition in solid form is packaged in a container, such as packaged in a squeezable tube designed for an externally applied cream or ointment.

[0234] effect

[0235] In some embodiments, the methods of the invention produce a therapeutic effect.

[0236] In some embodiments, the therapeutic effect comprises a reduction in tumor volume, a stabilization of tumor volume, or a reduction in the rate of tumor volume increase. In some embodiments, the therapeutic effect comprises a reduction in the incidence of recurrence or metastasis.

[0237] Other medicines

[0238] In some embodiments, the disclosed methods further comprise administering an antiproliferative agent, a radiosensitizer, or an immunoregulatory agent.

[0239] As used interchangeably herein, "antiproliferative" or "antiproliferative agent" means any anticancer agent, including those listed in Table 1, any of which can be used in combination with a radiopharmaceutical to treat a disorder or condition. Antiproliferative agents also include organoplatinum derivatives, naphthoquinone and benzoquinone derivatives, rhubarb acid and its anthraquinone derivatives.

[0240] As used interchangeably herein, "immunoregulatory agent" or "immunomodulatory agent" means any immunomodulator, including those listed in Table 1, any of which can be used in combination with a radiopharmaceutical provided herein.

[0241] As used herein, "radiosensitizers" include any agent that increases the sensitivity of cancer cells to radiation therapy. Radiosensitizers may include, but are not limited to, 5-fluorouracil, platinum analogs (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesyl transferase inhibitors, COX-2 inhibitors, bFGF antagonists, and VEGF antagonists.

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253] Examples

[0254] Example 1. Synthesis of Radiopharmaceuticals Containing Compounds of Formula I

[0255] The compounds of formula I are small molecule antagonists targeting NTSR1, which can be antagonized with radionuclides such as lutetium-177 ( 177 Lu) or actinium-225( 225 Ac)) is radiolabeled to form a radioactive nuclide chelated radiopharmaceutical. The synthesis of the compound of formula I or its radioactive nuclide chelated radiopharmaceutical can be referred to U.S. Patent No. 10,961,199 B2.

[0256] The following exemplary compound (ie, 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.

[0257]

[0258] Example 2.[ 177 Biodistribution of Lu]-Compound A in the CT-26-mNTSR1 isogenic immunocompetent mouse model

[0259] Compound A of Formula I was radiolabeled with Lu-177 using methods well known in the art to form [177Lu]-Compound A. The CT-26 isogenic model was used to confirm [ 177 Lu]-Compound A's ability to target antigens expressing mouse NTSR1-overexpressing tumors in vivo. Tumor uptake was maintained at 7 to 2.85% injected dose / g (ID / g) from 6 to 48 hours after injection. Figure 1 .

[0260] Example 3.[ 225 Single agent efficacy of [Ac]-Compound A in the CT-26-mNTSR1 xenograft model

[0261] Compound A of Formula I is radiolabeled using standard techniques to form [ 225 Ac]-Compound A. Various doses of [ 225 Ac]-Compound A was tested in immunocompetent mice [ 225 Ac]-Compound A efficacy study. It was found that relative to the efficacy of cold Compound A, [ 225 Ac]-Compound A has enhanced efficacy in reducing tumor volume in mice bearing CT-26-mNTSR1 xenografts. Figure 2 .

[0262] Example 4.[ 225 The combination of [Ac]-Compound A and olaparib treatment produces enhanced therapeutic efficacy in the CT-26-mNTSR1 xenograft model

[0263] In vivo studies were conducted to test [ 225 Effect of the combination of [Ac]-Compound A (described in Example 3) and olaparib in mice bearing CT-26-mNTSR1 tumors. Compared with control mice, the effect of [ 225 Mice treated with [Ac]-Compound A or 50 mg / kg of olaparib showed slight or negligible reductions in tumor growth. 225 Ac]-compound A or olaparib alone) treatment groups, when [ 225When [Ac]-Compound A was co-administered with olaparib (25 mg / kg QD; oral) at a dose of 0.555 MBq / kg (single dose, intravenous), enhanced therapeutic efficacy, including tumor regression, was observed. Figure 3 .

[0264] Example 5.[ 225 Improvement in overall survival of mice treated with [Ac]-Compound A

[0265] In vivo studies were conducted to test [ 225 Ac]-Compound A (described in Example 3) and Olaparib on the survival rate in the CT-26-mNTSR1 mouse model. 225 Ac]-Compound A-treated group or olaparib-treated group compared with 225 Improved overall survival was observed when [Ac]-Compound A was co-administered at a dose of 0.555 MBq / kg (single dose intravenous) with olaparib (25 mg / kb, QD, oral) - co-administration resulted in a significant improvement in survival. Figure 4 .

[0266] Other embodiments

[0267] Those skilled in the art will recognize or be able to ascertain using only routine experimentation many equivalent technical solutions to the specific embodiments described herein. Such equivalent technical solutions are intended to be covered by the claims of this application.

Claims

1. A method for treating or ameliorating cancer, the method comprising: (i) administering a radiopharmaceutical to a mammal, wherein the 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 a radiopharmaceutical; or (iii) administering DDRi to a mammal and concurrently administering a radiopharmaceutical to the mammal, wherein the radiopharmaceutical comprises, in each occurrence, a radionuclide chelated to a compound of formula I: in 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 (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl, halogen, nitro and trifluoromethyl; R 3 and R 4 Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl; L1 is (C2-C5) alkylene; L2 is (C2-C 20 )alkylene, (C2-C 20 )heteroalkylene, (C=O)O, (C=O)NR or a combination thereof, R is hydrogen or (C1-C4)alkyl; and 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, Wherein the 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.

2. The method of claim 1, comprising administering DDRi to a mammal, wherein the mammal has received or is receiving a radiopharmaceutical.

3. The method of claim 1 or 2, wherein the radiopharmaceutical is a chelated 225 Ac 225 Ac radiopharmaceuticals:

4. The method of any one of claims 1 to 3, wherein the DDRi is a PARP inhibitor.

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

6. The method of claim 5, wherein the small molecule PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, tarapanib, pamiparib, rucaparib (camphosulfonate) and veliparib, or an analog thereof.

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

8. The method of any one of claims 1 to 3, wherein the DDRi is an ATR or ATM inhibitor.

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

10. The method 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 an analog thereof.

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

12. The method of any one of claims 1 to 3, wherein the DDRi is a DNA protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor or a Chk2 inhibitor.

13. The method 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-75HCI, PP121 and SF2523, or an analog thereof.

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

15. A method as claimed in any preceding claim, wherein the mammal is a human.

16. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered at a dose of less than 1 MBq / kg body weight of said mammal.

17. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered at a dose of less than 250 kBq / kg body weight of said mammal.

18. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered at a dose of less than 100 kBq / kg body weight of said mammal.

19. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered to the mammal in a unit dose of less than 15 MBq.

20. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered to the mammal in a unit dose of less than 10 MBq.

21. The method according to any one of claims 3 to 15, wherein said 225 The Ac radiopharmaceutical is administered to the mammal in a unit dose of less than 5 MBq.

22. The method of any of the preceding claims, 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 cancer, multiple myeloma, acute myeloid leukemia, and cutaneous T-cell lymphoma.

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

24. The method of any of the preceding claims, wherein the administration results in a reduction in tumor volume, a stabilization of tumor volume, or a reduction in the rate of increase in tumor volume.

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

26. The method of claim 1, comprising administering a DDRi to a mammal, wherein the mammal has received or is receiving 225 Ac radiopharmaceuticals, the 225 Ac radiopharmaceuticals contain chelated 225 Ac: Wherein the DDRi is a PARP inhibitor or an ATR or ATM inhibitor, and wherein 225 The Ac radiopharmaceutical is administered at a dose of 100 to 600 kBq / kg body weight of said mammal.

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