Boron containing PSMA ligand for use in the treatment of cancer

Abstract

The present document describes compound of structural formula I, or a pharmaceutically acceptable salt thereof, stereoisomer thereof, and ester thereof and pharmaceutical compositions comprising the compounds of formula I, as well as methods and / or uses of the compounds of formula I for radiation therapy, wherein the radiation therapy is a boron-proton capture therapy or a boron-neutron capture therapy; and for imaging; or for a combination thereof.

Description

BORON CONTAINING PSMA LIGAND FOR USE IN THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of United States Provisional Patent Application No. 63 / 559,606 filed on February 29, 2024, the specification of which is hereby incorporated by reference in its entirety.BACKGROUND(a) Field

[0002] The subject matter disclosed generally relates to PSMA ligands, and more specifically the subject matter disclosed relates to boron containing PSMA ligands for use in the treatment and / or diagnosis of cancers.(b) Related Prior Art

[0003] Radiation therapy for prostate cancer can be delivered using photons in the form of X- ray beams, or charged particles, such as protons. X-ray beams release radiation along the length of the beam as it penetrates through the body and the tumor. Proton therapy more precisely targets the tumor, limiting radiation exposure to normal organs and tissues due to physical characteristics of the charged particle radiation. The proton beam energy deposition is characterized by a “Bragg Peak” with a rapid fall-off, resulting in a more precisely shaped high-dose treatment volume. Furthermore, as the energy of protons falls off, the interaction cross-section for proton-boron capture increases, leading to release of alpha particles to augment the radiobiological effects of the proton radiation therapy.

[0004] The proton-boron nuclear reaction is described as p +11B — > 3Q with complete absorption of the proton by the boron 1 1 (11B) nucleus and is referred to as “proton-boron fusion reaction” (Cirrone et al 2018) underlying proton boron capture therapy (PBCT).

[0005] Historically, boron-neutron capture therapy (BNCT) had been investigated for cancer treatment due to the release of a and Li particles underlying high Linear Energy Transfer (LET) radiation effects to enhance the relative biological effectiveness (RBE) of the treatment beam (Barth, 2005). In the BNCT interaction the boron 10 isotope (10B) presents a large interaction cross-section to thermal neutrons (Coderre, 1999), resulting in enhanced RBE for cell killing. However, technical challenges relating to beam shaping have limited clinical applications.

[0006] Therefore, boron has demonstrated potential for enhancing the RBE of radiation therapy through the release of high-LET a particles following interactions with protons or neutrons. Boron exists in nature as a mixture of isotopes, 20%10B and 80%11B (i.e., the “wild-type” ratio). Purified10B is commercially available for applications with neutron radiation therapy. Purified11B is availablefor applications with proton therapy. The “wild-type” ratio offers potential applications with either type of radiation. Furthermore, the ability to utilize10B or11B in purified form permits targeting boron neutron capture or boron proton capture, respectively, for enhancement of radiation effects in cancer therapy. Previous publications support concentration dependence of respective boron isotopes for the PBCT and for the BNCT interactions for increasing the RBE for therapeutic purposes.

[0007] Prostate cancer is the most common cancer among men, except for skin cancer. In 2024, an estimated 299,010 men in the United States will have been diagnosed with prostate cancer. Worldwide, an estimated 1 ,414,259 people were diagnosed with prostate cancer in 2020. It is the fourth most commonly diagnosed cancer in the world.

[0008] Prostate cancer incidence rates dropped steeply from 2007 to 2014 because screening guidelines at the time resulted in less prostate-specific antigen (PSA) testing. But since 2014, overall incidence rates have gone up by around 3% each year, and incidence rates for advanced-stage prostate cancer rose by 5% each year. Around 60% of cases are diagnosed in people age 65 or older. The average age at the time of diagnosis is 66 years. The disease is rarely identified in those younger than 40. The number of new cases diagnosed in Black men is 70% higher than the number of new cases diagnosed in White men. Black men in the United States and the Caribbean have the highest incidence rates of prostate cancer around the globe.

[0009] Prostate cancer is the second leading cause of cancer death in men in the United States. It is estimated that 35,250 deaths from this disease will occur in the United States in 2024. In 2020, an estimated 375,304 people worldwide died from prostate cancer.

[0010] However, the death rate dropped by half from 1993 to 2013 as a result of advances in screening and treatment. From 2016 to 2020, the decline in the death rate slowed to just over a half of a percent each year, likely as a result of the increase in prostate cancers diagnosed at an advanced stage. There are more than 3.3 million survivors of prostate cancer in the United States today. The relative 5-year survival rate for prostate cancer diagnosed in its earliest stages is over 99%. However, the 5-year survival rate for advanced or metastatic prostate cancer drops to 34%.

[0011] Prostate-specific membrane antigen (PSMA) is an enzyme that in humans is encoded by the FOLH1 (folate hydrolase 1 ) gene. It is also known as Glutamate carboxy peptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I) and NAAG peptidase. PSMA is a zinc metalloenzyme that resides in membranes, and it is highly expressed in prostate. Most of the enzyme resides in the extracellular space. PSMA is a class II membrane glycoprotein. It catalyzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartate (NAA). PSMA is the second-most upregulated gene product, with an 8- to 12-fold increase over levels in noncancerousprostate cells. Because of this high expression, PSMA is a potential biomarker for therapy and imaging of some cancers.

[0012] The compounds of the present invention are novel PSMA ligands that inhibit PSMA enzymatic activity through binding of the ligand to the PSMA enzyme. Hence, the PSMA ligands of the present invention are thought to increase the concentration levels of boron that may be achieved on prostate cancer cells expressing PSMA, thus allowing one to exploit these high levels of boron for both therapeutic and imaging benefits. The PSMA-boron molecules of the present invention are suitable for manufacture as A10B and11B mixture, or they can be synthesized using the individual isotopes.SUMMARY

[0013] According to an embodiment, there is provided a compound of structural formula I, or a pharmaceutically acceptable salt thereof, stereoisomer thereof, and ester thereof:wherein: m = 1-2; n = 0-5;R1= H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), ora and c are independently absent or selected from C-i-Ce alkylene, C1-C4 oligomethylene, and C1-C6 alkyl-substituted C1-C4 oligomethylene; b is absent or selected from the group consisting of a cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; phenylene optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; naphthylene optionally substituted with 0-5 heteroatoms, C Ce alkyl, or C3-C7 cycloalkyl; a monocyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; and a bicyclic heteroarylene, each ring of the bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; wherein a, b, and c together provide at least 2 carbon atoms between the attached N and B atoms; wherein R1and a, or R1and b, may together form a four- to seven-membered ring consisting of N and 3 to 6 further atoms, 0-2 of which are heteroatoms, while the others are C;R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, C1-C8 alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N(C1-C6 alkyl)CH2C(O), C(O)CMe2N(C1- C6alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2;R4is H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3- C7 heterocyclyl)( C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl);X is C2-C10 oligomethylene carrying 0-4 substituents selected independently from the group consisting of H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl) and represents a bond to X.

[0014] R2and R3may be each H.

[0015] The C1-C8 alkyl-substituted C2-C4 oligomethylene may be selected from the group consisting of Me2C-CMe2, Et2C-CEt2, and CH2-CMe2-CH2.

[0016] In the compound of the present invention, in the cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms; in the phenylene optionally substituted with 0-3 heteroatoms; in the naphthylene optionally substituted with 0-5 heteroatoms; in the monocyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-3 heteroatoms, and / or in the bicyclic heteroarylene, each ring of the bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, the heteroatoms may comprise a halogen, a radiohalogen, or a combination thereof.

[0017] In the compound of the present invention, the heteroatoms may be radiohalogen.

[0018] The radiohalogen may be a radioisotope of At, I, Br, Cl, or F.

[0019] The radiohalogen may be At-211 , 1-123, 1-124, 1-125, 1-131, Br-75, Br-77, and F-18.

[0020] The compound of the present invention may be a compound having one of the following formulae:

[0021] The compound of the present invention may be a compound of formula XXVII:XXVII wherein R5is a monocyclic heteroarylene having 5 or 6 ring atoms, substituted with 1-3 heteroatoms and at least one R6, or a bicyclic heteroarylene, each ring of the bicyclic heteroarylene having 5 or 6 ring atoms, substituted with 1-5 heteroatoms and at least one R6, wherein the heteroatoms comprise at least one radioisotope of At, I, Br, Cl and F; andwherein R6is, wherein R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, Ci-Cs alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N( C1-C6 alkyl)CH2C(O), C(O)CMe2N( C1-C6 alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2.

[0022] The compound of formula XXVII may be one of the following compounds:

[0023] In the compound of the present invention, B may be boron-10 (10B), boron-11 (11B), or a combination thereof.

[0024] The radiohalogen may be an imaging radiohalogen.

[0025] The radiohalogen may be a therapeutic radiohalogen.

[0026] According to another embodiment, there is provided a pharmaceutical composition comprising the compound of the present invention, and a pharmaceutically acceptable carrier.

[0027] The compound of of the present invention, or the pharmaceutical composition of the present invention, may be for use in the treatment of prostate cancer in a patient in need thereof.

[0028] According to another embodiment, there is provided the use of the compound of the present invention, or the pharmaceutical composition of the present invention, for the treatment of prostate cancer in a patient in need thereof.

[0029] The compound for use of the present invention, or the use of the present invention, may further comprise use of radiation therapy.

[0030] According to another embodiment, there is provided a method of treating prostate cancer comprising administering to a patient an effective amount of the compound of the present invention, or the pharmaceutical composition of the present invention, followed by one or more rounds of radiation therapy.

[0031] The compound for use of the present invention, the use of the present invention, or the method of the present invention, wherein the R1may bebinding an atom of177Lu,68Ga, or a combination thereof, for imaging of a tumor in a subject in need thereof.

[0032] The compound for use or the use of the present invention, or the method of the present invention, wherein the radiation therapy may be a boron-proton capture therapy, a boron-neutron capture therapy, or a combination thereof.

[0033] The compound of the present invention, or the pharmaceutical composition of the present invention, may be for use in medical imaging in a patient in need thereof.

[0034] According to another embodiment, there is provided a use of the compound of the present invention, or the pharmaceutical composition of the present invention, for medical imaging in a patient in need thereof.

[0035] According to another embodiment, there is provided a method of medical imaging comprising administering to a patient an effective amount of the compound of the present invention, or the pharmaceutical composition of the present invention, followed by one or more rounds of image acquisition with an imaging apparatus.

[0036] The following terms are defined below.

[0037] For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here.

[0038] The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.” Any element expressed in the singular form also encompasses its plural form. Any element expressed in the plural form also encompasses its singular form. The term “plurality”as used herein means more than one, for example, two or more, three or more, four or more, and the like.

[0039] As used herein and unless otherwise specified, the term “about”, when used to describe a recited value, means within 10% of the recited value.

[0040] As used herein and unless otherwise specified, the term “substituted” refers to a compound in which one or more hydrogen atoms have been replaced by other atoms or groups.

[0041] The term “NAALADase” as used herein refers to N-acetyl-L-aspartyl-L-glutamate peptidase. The enzyme was originally named for its substrate specificity for hydrolyzing N-acetylated alpha-linked acidic dipeptides. Currently, it is known that the enzyme has a broader range of substrate specificity than originally discovered, particularly that the enzyme does not require N-acetylation or alpha-linkage. Thus, as used herein “NAALADase” encompasses other names used in the literature such as NAAG hydrolyzing enzyme, NAALA dipeptidase, and PSMA.

[0042] The term “inhibition”, in the context of enzyme inhibition, is intended to relate to reversible enzyme inhibition such as competitive, uncompetitive, and noncompetitive inhibition. This can be experimentally distinguished by the effects of the inhibitor on the reaction kinetics of the enzyme, which may be analyzed in terms of the basic Michaelis-Menten rate equation. Competitive inhibition occurs when the inhibitor can combine with the free enzyme in such a way that it competes with the normal substrate for binding at the active site. A competitive inhibitor reacts reversibly with the enzyme to form an enzyme-inhibitor complex [El], Following the Michaelis-Menten formalism, we can define the inhibitor constant, K[i], as the dissociation constant of the enzyme-inhibitor complex. Thus, in accordance with the above and as used herein, K[i] is essentially a measurement of affinity between a molecule and its receptor, or in relation to the present invention, between the present inventive compounds and the enzyme to be inhibited. It should be noted that IC50 is a related term used when defining the concentration or amount of a compound which is required to cause a 50% inhibition of the target enzyme.

[0043] The term “treatment” is intended to mean any process, action, application, therapy, or the like, wherein an animal, including a human being, is subject to medical aid with the object of improving the animal’s condition, directly or indirectly. The method of this invention for treating cancer and particularly prostate cancer comprises administering internally to a subject expected to be benefitted thereby, an effective amount of a PSMA inhibitor compound of the present invention. Doses of this compound of the present invention included in the present methods and pharmaceutical compositions are an efficacious, nontoxic quantity. Persons skilled in the art using routine clinical testing are able to determine optimum doses. The desired dose is administered to a subject from 1 to6 or more times daily, orally, rectally, parenterally, or topically and may follow a higher initial amount administered as a bolus dose.

[0044] As used herein and unless otherwise specified, the term “alkenyl'” refers to a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon (CC) double bond. Examples of alkenyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 1 ,3-butadien-2-yl, 2,4-pentadien-1-yl, 1 ,4-pentadien-3-yl, and the like.

[0045] As used herein and unless otherwise specified, the term “alkoxy”, used alone or as part of a larger moiety, refers to the groups -O-alkyl and -O-cycloalkyl. As used herein and unless otherwise specified, the term “substituted alkoxy”, used alone or as part of a larger moiety, refers to the groups - □-(substituted alkyl) and -O-(substituted cycloalkyl).

[0046] As used herein and unless otherwise specified, the term “alkyl”, used alone or as part of a larger moiety, means a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain that is completely saturated. Unless otherwise specified, an alkyl group contains 1 to 7 carbon atoms (“C1-C7 alkyl”). For example, in some embodiments, alkyl groups contain 1 to 6 carbon atoms (“C1-C6 alkyl”); in some embodiments, alkyl groups contain 1 to 5 carbon atoms (“C1-C5 alkyl”); in some embodiments, alkyl groups contain 1 to 4 carbon atoms (“C1-C4 alkyl”, alternatively “lower alkyl”); and in some embodiments, alkyl groups contain 3 to 7 carbon atoms (“C3-C7 alkyl”). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl. A substituted alkyl group is one having at least one or more substituents, and no more substituents than the number of hydrogen atoms in the unsubstituted group. In some embodiments, the substituents are fluorine atoms. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF2, CF3, CH2CF3, CF2CF3, 4-fluorobutyl, and the like.

[0047] As used herein and unless otherwise specified, the term “alkynyl” refers to a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butyn-1-yl, and the like.

[0048] As used herein and unless otherwise specified, the term “aryl”, used alone or as part of a larger moiety (for example, “(aryl)alkyl”) refers to a univalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, aryl groups contain 6 or 10 ring members. Non- limiting examples of aryl include phenyl, naphthyl, and the like. The term “aryl” also refers to aryl groupsthat may be unsubstituted or substituted. For example, aryl groups can be unsubstituted or can be substituted with one, two, three, or more groups selected independently from the group consisting of halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1- Ce alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkyl), C(N-OH)(C1-C6 alkyl), C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(0)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), cyano, B(OH)2, and esterified B(OH)2, such as Bpinacolyl.

[0049] As used herein and unless otherwise specified or clear from context, the term “chemical entity” refers to a compound having the indicated structure, whether in its “free” form (e g., “free compound” or “free base” or “free acid” form, as applicable), or in a salt form, particularly a pharmaceutically acceptable salt form, and furthermore whether in solid state form or otherwise. In some embodiments, a solid state form is an amorphous (i.e., non-crystalline) form; in some embodiments, a solid state form is a crystalline form (e.g., a polymorph, pseudohydrate, hydrate, or solvate). Similarly, the term encompasses the compound whether provided in solid form or otherwise. Unless otherwise specified, all statements made herein regarding “compounds” apply to the associated chemical entities, as defined.

[0050] As used herein and unless otherwise specified, the terms “comprising”, “having”, “including”, “containing”, and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, un-recited elements and / or method steps. For example, “A includes 1 , 2, and 3” means that A includes but is not limited to 1 , 2, and 3.

[0051] As used herein and unless otherwise specified, the term “consisting essentially of’ when used herein in connection with a composition, use, or method, denotes that additional elements, method steps or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method, or use functions.

[0052] As used herein and unless otherwise specified, the term “consisting of’ when used herein in connection with a composition, use, or method, excludes the presence of additional elements and / or method steps.

[0053] As used herein and unless otherwise specified, the term “cycloalkyl”, used alone or as part of a larger moiety, for example “(cycloalkyl)alkyl”, refers to: (i) a substituted or unsubstituted, univalent monocyclic hydrocarbon radical that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic; or (ii) bicyclo[m.n.o]alkyl wherein each of “m”, “n”, and “0" is independently an integer ranging from zero to 5, and the sum “m”+”n"+”o" ranges from 2 to 6. In some embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like, as well as bicyclo[2.2.1 ]heptyl (also called norbornyl) and bicyclo[1 .1 .1 ]pentyl. A substituted cycloalkyl group is one having at least one or more substituents. In some embodiments, the substituents are fluorine atoms. Non-limiting examples of substituted cycloalkyl groups include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, 4,4- difluorocyclohexyl, and the like.

[0054] As used herein and unless otherwise specified, the term “halogen” or “halo”, used alone or as part of a larger moiety, refers to fluoro (F), chloro (Cl), bromo (Br), iodo (I), or astato (At).

[0055] As used herein and unless otherwise specified, the term radiohalogen is a radioactive halogen. Radioactive halogens include radioactive isotopes of F, Cl, Br, and I, and particularly18F (F- 18),36CI (CI-36),75Br (Br-75),76Br (Br-76),77Br (Br-77),123l (1-123),124l (1-124),125l (1-125),131l (1-131), and211At (At-211 ).

[0056] As used herein and unless otherwise specified, the term “heteroalkyl” refers to a substituted or unsubstituted, saturated or unsaturated alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.

[0057] The term “heteroatom” is intended to mean an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), fluorine (F), chlorine (Cl), bromine (Br), and iodine (I) as well as the metals lithium (Li) and magnesium (Mg).

[0058] As used herein and unless otherwise specified, the term “heteroaryl”, used alone or as part of a larger moiety, e.g., “(heteroaryl)alkyl”, refers to a univalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6 or 10 n electrons shared in a cyclic array, and having, in addition to ring carbon atoms, from one to four ring heteroatoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, naphthyridinyl, pteridinyl, and the like. Heteroaryl groups may be unsubstituted or may be substituted with one, two, three, or more groups selected independently from halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C5cycloalkyl, substituted C3-C6cycloalkyl, C(O)OH, C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(CI-C4alkyl)(C1-C4 alkyl), C(O)- heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), cyano, B(OH)2, and esterified B(OH)2, such as Bpinacolyl.

[0059] As used herein and unless otherwise specified, the term “heterocyclyl”, used alone or as part of a larger moiety (for example, (“heterocyclyl)alkyl”) refers to a univalent stable 4- to 7- membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and has, in addition to ring carbon atoms, one to four heteroatoms. Non-limiting examples of heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like. Heterocyclyl groups can be unsubstituted or can be substituted. For example, heterocyclyl groups can be unsubstituted or can be substituted with one, two, three, or more groups selected independently from the group consisting of halogen, OH, O(C1-C6 alkyl), O(substituted C1-C6 alkyl), C1-C6 alkyl, substituted C1-C6 alkyl, and C3-C6cycloalkyl.

[0060] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0061] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0062] As used herein and unless otherwise specified, the term “inactive” (and all related terms thereto including “inactivity”), when used the context of “EC50 (nM)” and “Eff%” as such terms would be understood by a person skilled in the art or equivalent skilled person, and when used in reference to the activity of the PSMA ligand, means a concentration of greater than 10,000 nM (when used in the context of “ECso (nM)”) or an efficacy of 30% or lower (when used in the context of “Eff%”).

[0063] As used herein and unless otherwise specified, the term “isotopologue” refers to a species that differs from a specific compound only in the isotopic composition thereof. For example, all hydrogen atoms in a compound are independently of natural isotopic composition or of any isotopic composition enriched or depleted in one or both of the heavy isotopes,2H (D, deuterium) and3H (T, tritium), ranging from a depletion to zero% to an enrichment to 100%. Deuterium may be incorporated into the compounds described herein in various ways, using deuterated versions of reagents andbuilding blocks under the same or similar conditions as those employed for their counterparts with natural hydrogen isotope composition.

[0064] The term “time sufficient for / to” or is intended to mean any period of time suitable to effect treatment with the method of the present invention.

[0065] The term “a therapeutically effective amount” is intended to mean an amount that is effective in therapy, or an amount sufficient to provide a therapeutic effect. An amount that is effective in therapy is an amount which produces a biological activity and will relieve to some extent one or more symptoms of the disorder being treated, or result in inhibition of the progress or at least partial reversal of the condition. It will depend, among other things, on the individual. The typical daily dose of the active substance(s) may vary and will depend on various factors such as the individual requirements of the patients (e.g., the age, weight, etc. of the subject to be treated), the mode of administration, and the disease or condition and its severity.

[0066] As used herein and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds provided in this disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include salts of compounds comprising an amino group that are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, orwith organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydriodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Other pharmaceutically acceptable salts include those that are derived from appropriate bases such as alkali metal, alkaline earth metal, ammonium, and N+(Ci. 4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further non-limiting examples of pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium and quaternary ammonium cations.

[0067] As used herein and unless otherwise specified, the term “subject" includes a mammal (e.g., a human, and in some embodiments including prenatal human forms). In some embodiments, a subject suffers from a relevant disease, disorder, or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder, orcondition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a mammal with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered. In some embodiments, a subject is a fetus, an infant, a child, a teenager, an adult, or a senior citizen (i.e., the subject is of advanced age, such as older than 50). In some embodiments, a child refers to a human that is between two and 18 years of age. In some embodiments, an adult refers to a human that is eighteen years of age or older.

[0068] As used herein and unless otherwise specified, the phrase “such as” is intended to be open-ended. For example, the phrase “A can be a halogen, such as chlorine or bromine” means that “A” can be, but is not limited to, chlorine or bromine.

[0069] Reference to specific moieties, functional groups, or substituents contemplates (where applicable) tautomers thereof.

[0070] Unless otherwise stated, structures depicted herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure (e.g., the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers). Unless otherwise stated, the compounds disclosed, taught, or otherwise suggested in this disclosure contemplate all single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise stated, the compounds disclosed, taught, or suggested in this disclosure contemplate all tautomeric forms thereof. Additionally, unless otherwise stated, structures depicted herein include compounds that differ only in the presence of one or more isoto pica I ly enriched atoms. Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. Additionally, incorporation of heavier isotopes such as deuterium (2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.

[0071] Chemical entities described herein are further illustrated by the classes, subclasses, and species disclosed herein. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as describedtherein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. In this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope, or any mixture of stable isotopes, of that atom.

[0072] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature, and not as restrictive, and the full scope of the subject matter is set forth in the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Further features and advantages of the present disclosure will become apparent from the following detailed description, taken in combination with the appended drawings, in which:

[0074] Fig. 1 illustrates the inhibition of PSMA with the compound of formula II and positive control (phosphonomethyl)pentanedioic acid (2-PMPA). The calculated IC50 of the compound of formula II is about 1.18 nM.DETAILED DESCRIPTION

[0075] In embodiments there are disclosed compounds of structural formula I, or pharmaceutically acceptable salts thereof, stereoisomers thereof, and esters thereof:wherein: m = 1-2; n = 0-5;R1= H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), ora and c are independently absent or selected from C-i-Cs alkylene, C1-C4 oligomethylene, and C1-C6 alkyl-substituted C1-C4 oligomethylene; b is absent or selected from the group consisting of a cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; phenylene optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; naphthylene optionally substituted with 0-5 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; a monocyclic heteroarylene having 5 or6 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; and a bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; wherein a, b, and c together provide at least 2 carbon atoms between the attached N and B atoms; wherein R1and a, or R1and b, may together form a four- to seven-membered ring consisting of N and 3 to 6 further atoms, 0-2 of which are heteroatoms, while the others are C;R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, Ci-Cs alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N(CI-C6 alkyl)CH2C(O), C(O)CMe2N(Ci- C6alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2;R4is H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3- C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl);X is C2-C10 oligomethylene carrying 0-4 substituents selected independently from the group consisting of H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl) and ‘nnn' represents a bond to X.

[0076] According to embodiments of compounds of structural formula I, or a pharmaceutically acceptable salt thereof, and stereoisomer thereof, and ester thereof, R2and R3are each H.

[0077] According to embodiments of compounds of structural formula I, or a pharmaceutically acceptable salt thereof, and stereoisomers thereof, and ester thereof, the Ci-Cs alkyl-substituted C2- C4 oligomethylene is selected from the group consisting of Me2C-CMe2, Et2C-CEt2, and CH2-CMe2- CH2.

[0078] In embodiment, the compound of formula I may be a compound having one of the following formulae:

[0079] In the compounds of the present invention, in the cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms; the phenylene optionally substituted with 0-3 heteroatoms; the naphthylene optionally substituted with 0-5 heteroatoms; the monocyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-3 heteroatoms, and / or the bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, the heteroatoms comprise a halogen, a radiohalogen, or a combination thereof. According to some embodiments, the heteroatoms are radiohalogen.

[0080] Fluorine may be fluorine-19 (19F), fluorine-18 (18F), or a combination thereof. Chlorine may be chlorine-35 (35CI), chlorine-37 (37CI), chlorine-36 (36CI), or a combination thereof. Bromine maybe bromine-79 (79Br), bromine-81 (81Br), bromine-75 (75Br), bromine- 76 (76Br), bromine-77 (77Br) , or a combination thereof. Iodine may be iodine-127 (127l), iodine-123 (123l), iodine-124 (124l), iodine-125 (125l), iodine-131 (131l), or a combination thereof.

[0081] The invention also encompasses mono-, oligo-, or polymeric anhydride-like derivatives of boronic acids, such as compounds containing the following moieties:

[0082] as well as mixtures of such anhydride-like derivatives with their parent boronic acids. Anhydride-like derivatives may be formed by loss of water from their parent boronic acids and may revert to those in a water-containing medium, such as a drug formulation or a biological environment.

[0083] According to an embodiment, the radiohalogen is an imaging radiohalogen. In such embodiments, the radiohalogen may be used in medical imaging studies such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). Examples of imaging radiohalogen include fluorine-18 (18F), iodine-123 (123l), iodine-124 (124l), and iodine-125 (125l).

[0084] According to another embodiment, the radiohalogen is a therapeutic radiohalogen. Therapeutic radiohalogens are unstable isotopes of halogens that emit radiation and are used in medical therapy. An example of a therapeutic radiohalogen is iodine-131 (131l).

[0085] According to another embodiment, the radiohalogen is an imaging and a therapeutic radiohalogen. Examples of imaging and therapeutic radiohalogen are iodine-125 (125l) and iodine-131 (131l).

[0086] According to another embodiment, the compound of formula I of the present invention may be a compound of formula XXVII:XXVII wherein R5is said monocyclic heteroarylene having 5 or6 ring atoms, substituted with 1-3 heteroatoms and at least one R6, or said bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, substituted with 1-5 heteroatoms and at least one R6, wherein said heteroatoms comprise at least one radioisotope of At, I, Br, Cl and F; andwherein R6is, wherein R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, Ci-Cs alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N(C1-C6 alkyl)CH2C(O), C(O)CMe2N(C1-C6 alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2.

[0087] In embodiment, the compound of formula XXVII may be a compound having one of the

[0088] In embodiments, the radiohalogen may be an imaging radiohalogen, a therapeutic radiohalogen, and / or both an imaging radiohalogen and a therapeutic radiohalogen.

[0089] According to embodiments of compounds of structural formula I, or a pharmaceutically acceptable salt thereof, and stereoisomers thereof, the B is boron-10 (10B), boron-11 (11B), or a combination thereof.Methods of use

[0090] The compounds of formula I described herein are believed to be useful in the treatment of cancer, and particularly of prostate cancer in a patient in need thereof.

[0091] Therefore, and according to embodiments, the compounds of formula I of the present invention are suitable to be used in the treatment of cancer, particularly prostate cancer. Thus, embodiments encompass the use of the compounds of formula I, in the treatment of cancer, particularly prostate cancer. Embodiments also encompass the compounds of formula I, for use in the treatment of cancer, particularly prostate cancer. Also encompassed are the use of the compounds of formula I, for the preparation of medicaments for use in the treatment of cancer, particularly prostate cancer. According to further embodiments, there is also provided a method of treating prostate cancer comprising administering to a patient an effective amount of the compound of the present invention, or the pharmaceutical composition of the present invention. According to embodiments, the use of the present invention, the compounds for use of the present invention, or the methods of the present invention may be, or are followed by one or more rounds of radiation therapy. In embodiments, the radiation therapy is a boron-proton capture therapy, a boron-neutron capture therapy, or a combination thereof.

[0092] According to other embodiments, the compounds of formula I according to the present invention may be used for imaging (i.e., medical imaging) and diagnostic purposes.

[0093] For example, and according to embodiments, when the R1is

[0094] and is binding an atom of177Lu,68Ga, or a combination thereof, the compounds may be used for imaging of a tumor and as diagnostics in a subject in need thereof.

[0095] Therefore, according to further embodiments, the compounds of formula I according to the present invention, and / or or pharmaceutical composition of the present invention may be for use in medical imaging in a patient in need thereof. According to yet further embodiments, there is provided the use of compounds of formula I or the pharmaceutical composition of according to the present invention comprising a compound of formula I, for medical imaging in a patient in need thereof. According to yet further embodiments, there is provided a method of medical imaging comprising administering to a patient an effective amount of the compound of formula I or the pharmaceutical composition of according to the present invention comprising a compound of formula I followed by one or more rounds of image acquisition with an imaging apparatus.Methods of Administration

[0096] As contemplated herein, a therapeutically effective amount of a compound of formula I described herein is administered to a subject in need thereof. Whether such treatment is indicated depends on the subject case, and is further subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and / or malfunctions that are present, the risks of developing particular signs, symptoms and / or malfunctions, and other factors.

[0097] As contemplated herein, a compound of formula I described herein may be administered by any suitable route known in the art. Such routes include, but are not limited to, oral, buccal, inhalation, topical, sublingual, rectal, vaginal, intracisternal, or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, transdermal, and parenteral administration (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a particular site). Parenteral administration may be accomplished using a needle and syringe or using a high-pressure technique.

[0098] Pharmaceutical compositions include those wherein a compound of formula I described herein is present in a sufficient amount to be administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by a qualified medical practitioner in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound of formula I described herein that are sufficient to maintain the desired therapeutic effects. It is possible that the compound of formula I described herein may only require infrequent administration (e.g. monthly, as opposed to daily) to achieve the desired therapeutic effect.

[0099] As contemplated herein, a therapeutically effective amount of a compound of formula I described herein adapted for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound of formula I that are sufficient to maintain the desired therapeutic effects. The desired amount conveniently may be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four, or more subdoses per day. Multiple doses often may be desired or required. For example, a compound of formula I described herein may be administered at a frequency of: four doses delivered as one dose per day atfour-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days’ rest, and another five daily doses (5 / 2 / 5); or, any dose regimen determined to be appropriate for the circumstance.

[0100] As contemplated herein, the compounds of formula I described herein may be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the compounds of formula I described herein are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the compounds described herein.

[0101] Water is a preferred carrier when a compound of formula I described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0102] These pharmaceutical compositions may be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of a compound of formula I described herein is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of formula I described herein. When administered in liquidform, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound described herein.

[0103] When a therapeutically effective amount of a compound of formula I described herein is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains an isotonic vehicle. A compound of formula I described herein can be infused with other fluids over a 10-30 minute span or over several hours.

[0104] The compounds of formula I described herein may be readily combined with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient to be treated.

[0105] Pharmaceutical preparations for oral use can be obtained by adding a compound of formula I described herein to a solid excipient, with or without grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.

[0106] A compound of formula I described herein may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0107] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compound of formula I described herein can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.

[0108] In some embodiments, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0109] A compound of formula I described herein also may be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, a compound of formula I described herein also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of formula I described herein may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

[0110] A compound of formula I described herein may be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. The compounds of formula I described herein also may be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compounds of formula I described herein may be best used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

[0111] The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.EXAMPLE 1SYNTHESIS OF THE COMPOUND OF FORMULA II

[0112] The synthesis of the compound of Formula II comprises several steps, namely: (1) construction of the urea core; (2) amide formation; and (3) functional group transformations.L-2-aminoadipic acid (S)-2-amino-6-(benzyloxy)- 6-oxohexanoic acid hydrochloride1- Synthesis of (S)-2-amino-6-(benzyloxy)-6-oxohexanoic acid hydrochloride

[0113] To a stirred solution of L-2 -aminoadipic acid (25.0 g, 155 mmol, 1.0 equiv) in benzyl alcohol (16.8 g, 155 mmol, 1 .0 equiv) was added hydrochloric acid (12M, 13 mL, 156 mmol, 1 .0 equiv), The mixture was stirred for 1 h at 100 °C. Upon completion of the reaction, the mixture was cooled to room temperature. Diethyl ether (200 mL) was added, and the precipitate was collected by filtration and dried to afford (S)-2-amino-6-(benzyloxy)-6-oxohexanoic acid hydrochloride (15.0 g, 34% yield) as a white solid.1H NMR (400 MHz, D2O) δ 7.02-6.74 (m, 5H), 4.07 (s, 2H), 3.63-3.49 (m, 1 H), 1.97-1 .84 (m, 2H), 1.56-1 .29 (m, 2H), 1.28-1 .08 (m, 2H).2- Synthesis of (S)-6-(benzyloxy)-2-(3-f(S)-1,5-di-tert-butoxy-1 ,5-dioxopentan-2-yl)ureido)-6- oxohexanoic acid(S)-2-amino-6-(benzyloxy)- >4go / o(S)-6-(benzyloxy)-2-(3-((S)-1,5-di-6-oxohexanoic acidy 0tert-butoxy-1,5-dioxopentan-2-yl)- hydrochloride ureido)-6-oxohexanoic acid

[0114] To a solution of L-glutamic acid di-tert-butyl ester (15.0 g, 59.8 mmol, 1.19 equiv), 1 ,1'- carbonyldiimidazole (11.6 g, 71.7 mmol, 1.42 equiv), and A / ,A / -diisopropylethylamine (23.1 g, 179 mmol, 3.55 equiv) in 100 mL of N,N -dimethylformamide was added (S)-2-amino-6-(benzyloxy)-6- oxohexanoic acid hydrochloride (14.5 g, 50.4 mmol, 1.00 equiv). The mixture was stirred for 4 h at 80 °C. Upon completion of the reaction, water (200 mL) was added, and the pH value of the solution was adjusted to 5 with HCI (1M). The product was extracted into ethyl acetate (3 x 200 mL), and thecombined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluting with 40% of acetonitrile in water containing 0.5% of NH4HCO3 to obtain (S)-6- (benzyloxy)-2-(3-((S)-1 ,5-di-tert-butoxy-1 ,5-dioxopentan-2-yl)ureido)-6-oxohexanoic acid (12.4 g, 46% yield) as a yellow oil. MS calcd. for C27H41N2O9 (M + H+) m / z 537.28, found 537.15.3- Synthesis of 6-benzyl 1-tert-butyl(S)-2-(3-((S)-1,5-di-tert-butoxy-1 ,5-dioxopentan-2- yljureidojhexanedioate(S)-6-(benzyloxy)-2-(3-(( S)-1 ,5-di- y = 93% 6-benzyl l-(fert-butyl) (S)-2-(3-((S)- fert-butoxy-1 ,5-dioxopentan-2-yl)- 1 ,5-di-tert-butoxy-1 ,5-dioxopentan- ureido)-6-oxohexanoic acid 2-yl)ureido)hexanedioate

[0115] To a stirred solution of (S)-6-(benzyloxy)-2-(3-((S)-1 ,5-di-fert-butoxy-1 ,5-dioxopentan- 2-yl)ureido)-6-oxohexanoic acid (12.4 g, 23.1 mmol, 1.00 equiv) in 100 mL of dichloromethane was added 2-fert-butyl-1 ,3-diisopropylisourea (13.9 g, 69.4 mmol, 3.00 equiv). The mixture was stirred overnight at 50 °C. Upon completion of the reaction, the mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to afford 6-benzyl 1 -tert-butyl (S)-2-(3-((S)-1 ,5-di-fert-butoxy-1 ,5-dioxopentan-2- yl)ureido)hexanedioate (8.60 g, 93% yield) as a colorless oil. MS calcd. for C31H49N2O9 (M + H+) m / z 593.34, found 593.30.4- Synthesis of ( S)-6-(tert-butoxy)-5-( 3-((S)-1, 5-di-tert-butoxy- 1 , 5-dioxopentan-2-yl) ureido)-6- oxohexanoic acid6-benzyl 1 -(tert-butyl) (S)-2-(3-((S)- y = 55% (S)-6-(tert-butoxy)-5-(3-((S)-1 ,5-di- 1 ,5-di-tert-butoxy-1 ,5-dioxopentan- tert-butoxy-1 ,5-dioxopentan-2-yl)- 2-yl)ureido)hexanedioate ureido)-6-oxohexanoic acid

[0116] To a stirred solution of 6-benzyl 1-fert-butyl (S)-2-(3-((S)-1 ,5-di-fert-butoxy-1 ,5- dioxopentan-2-yl)ureido)hexanedioate (8.60 g, 23.1 mmol, 1.00 equiv) in methanol (50 mL) was added 10% palladium on carbon (860 mg). The mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. Upon completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with 10% methanol in dichloromethane to afford (S)-6-(tert-butoxy)-5-(3-((S)-1 ,5-di-tert-butoxy-1 ,5-dioxopentan- 2-yl)ureido)-6-oxohexanoic acid (4.00 g, 55% yield) as a colorless oil. MS calcd. for C24H43N2O9 (M + H+) m / z 503.30, found 503.20.5- Synthesis of di-tert-butyl (((S)-6-((3-bromoDhenyl)(methyl)amino)-1-(tert-butoxy)-1.6-dioxohexan- 2-yl)carbamoyl)-L- glutamate(S)-6-(tert-butoxy)-5-(3-((S)-1,5-di- > di-tert-butyl (((S)-6-((3-bromophenyl)- tert-butoxy-1 ,5-dioxopentan-2-yl)- y - o / o (methyl)amino)-1 -(tert-butoxy)-l ,6- ureido)-6-oxohexanoic acid dioxohexan-2-yl)carbamoyl)-Z_-glutamate

[0117] To a stirred solution of (S)-6-(tert-butoxy)-5-(3-((S)-1 ,5-di-fert-butoxy-1 ,5-dioxopentan- 2-yl)ureido)-6-oxohexanoic acid (1.00 g, 23.1 mmol, 1 .00 equiv), 3-bromo-N-methylaniline (1 .00 g, 23.1 mmol, 1 .00 equiv), and 1 -methylimidazole (1.00 g, 23.1 mmol, 1.00 equiv) in acetonitrile (100 mL) was added / V,A / ,M) / V-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 13.9 g, 69.4 mmol, 3.00 equiv). After stirring for 4 h at room temperature, the reaction was found to be completed. The mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give di-tert-butyl (((S)-6-((3-bromophenyl)(methyl)amino)- 1-(tert-butoxy)-1 ,6-dioxohexan-2-yl)carbamoyl)-L-glutamate (1.10 g, 82% yield) as a yellow solid. MS calcd. for C3iH49BrN3O8 (M + H+) m / z 672.27, found 672.15.6- Synthesis of di-tert-butyl (((S)-1-(tert-butoxy)-6-(methyl(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)amino)-1 ,6-dioxohexan-2-yl)carbamoyl)-L-glutamatedi-tert-butyl (((S)-6-((3-bromophenyl)- di-tert-butyl (((S)-1 -(tert-butoxy)-6-(methyl(3-(4,4,5,5- (methyl)amino)-1-(tert-butoxy)-1 ,6- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)amino)-1 ,6- dioxohexan-2-yl)carbamoyl)-L-glutamate dioxohexan-2-yl)carbamoyl)-L-glutamate

[0118] To a stirred solution of di-tert-butyl (((S)-6-((3-bromophenyl)(methyl)amino)-1-(tert- butoxy)-1 ,6-dioxohexan-2-yl)carbamoyl)-L-glutamate (1 .00 g, 1 .49 mmol, 1 .00 equiv) in 1 ,4-dioxane (20 mL) were added bis(pinacolato)diboron (757 mg, 2.98 mmol, 2.00 equiv), 1 ,1'- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride dichloromethane complex (241 mg, 0.30 mmol, 0.20 equiv), and potassium acetate (439 mg, 4.47 mmol, 3.00 equiv). The mixture was stirred for 1 h at 80 °C under a nitrogen atmosphere. Upon completion of the reaction, the mixture was evaporated, and the residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to afford di-terf-butyl (((S)-1-(tert-butoxy)-6-(methyl(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)amino)-1 ,6-dioxohexan-2-yl)carbamoyl)-L-glutamate (850 mg, 79% yield) as a yellow solid. MS calcd. for C37H61BN3O10 (M + H+) m / z 718.45, found 718.55.d i-tert-butyl (((S)-1 -(tert-butoxy)-6-(methyl(3-(4,4,5,5-(((S)-5-((3-boronophenyl)(methyl)- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)amino)-1 ,6- amino)-1-carboxy-5-oxopentyl)- dioxohexan-2-yl)carbamoyl)-L-glutamate carbamoyl)-L-glutamic acid(Compound of formula II)

[0119] To a stirred solution of di-tert-butyl (((S)-1-(tert-butoxy)-6-(methyl(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)amino)-1 ,6-dioxohexan-2-yl)carbamoyl)-L-glutamate (850 mg, 1.18 mmol, 1.00 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred for 4 h at room temperature. Upon completion of the reaction, the mixture was concentrated, and the residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep Phenyl OBD, 19 x250 mm, 5 μm particle size. Mobile Phase A: water containing0.1 % trifluoroacetic acid. Mobile Phase B: acetonitrile. Flow rate: 60 mL / min. Gradient: 3% B to 20% B in 10 min. UV detector wavelengths: 254 and 220 nm. The peak eluting at a retention time of 7.02 min was collected and evaporated to afford (((S)-5-((3-boronophenyl)(methyl)amino)-1-carboxy-5- oxopentyl)carbamoyl)-L-glutamic acid (147 mg, 98.7% purity, 25% yield) as a colorless solid. MS calcd. for C19H26BN30IO (M + H+) m / z 467.18, found 468.10.1H NMR (400 MHz, CD3OD, TMS) δ 7.77 (d, 1 H, J = 7.2 Hz), 7.61 (s, 1 H), 7.47 (t, 1 H, J = 7.6 Hz), 7.32 (d, 1 H, J = 8.0 Hz), 4.29 (dd, 1 H, J = 8.4, 5.2 Hz), 4.14 (dd, 1 H, J = 7.6, 4.4 Hz), 3.24 (s, 3H), 2.44-2.38 (m, 2H), 2.18-2.08 (m, 3H), 1.91 (m, 1 H), 1.84-1.49 (m, 4H).EXAMPLE 2 INHIBITION OF PSMA ACTIVITY BY COMPOUND OF FORMULA 2

[0120] The potency of the compound of formula II of the present invention is tested in an in vitro PSMA enzyme inhibition assay. The inhibition constants of the studied inhibitors were determined using the radioenzymatic assay with3H-NAAG (radiolabeled at the terminal glutamate) as a substrate. Briefly, rhGCPII (30 ng / mL) was preincubated in the presence of increasing concentrations of inhibitors (PH-SHU-A001_1 and PH-SHU-A001_2 are duplicates), or the positive control compound (phosphonomethyl)pentanedioic acid (2-PMPA) in 20 mM Tris, 150 mM NaCI, pH 8.0, for 15 min at 37°C in the total volume of 80 pL. The reaction was initiated by addition of 40 pL of 0.31 pM NAAG (Sigma™) and 15 nM3H-NAAG (50 Ci / mmol, Perkin Elmer™) mixture (120 μL total reaction volume). The reaction was terminated after 20 min by 120 pL of 200 mM potassium phosphate, 50 mM EDTA, 2 mM β-mercaptoethanol, pH 7.4. The released glutamate was separated from the reaction mixture by ion-exchange chromatography and quantified by liquid scintillation. Duplicate reactions were carried out for each experimental point. The data were fitted using the GraphPad Prism software (GraphPad Software, San Diego, CA, USA), and IC50 values were calculated from the inhibition curves of three independent experiments using a non-linear analysis protocol. Fig. 1 shows the results of this inhibition assay, which confirms that the compound of formula II is a potent inhibitor of PSMA, having an average IC50 of about 1 .44 nM.EXAMPLE 3SYNTHESIS OF THE COMPOUND OF FORMULA XXIV

[0121] The synthetic route used is the following:

[0122] To a stirred solution of tert-butyl / V-(tert-butoxycarbonyl)carbamate (20.0 g, 92.0 mmol, 1 equiv) in EtOH (500 mL) was added KOH (6.20 g, 1 10.5 mmol, 1.2 equiv) in portions at room temperature. The resulting mixture was stirred at 60 °C for 12 h, then concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (500 mL). The precipitated solids were collected by filtration and washed with diethyl ether (3 x 50 mL). This resulted in tert-butyl N-(tert- butoxycarbonyl)carbamate potassium salt (21 .0 g, 89% yield) as a white solid.2- Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-[(3,4-dibromophenyl)methyl]carbamate (2)

[0123] A stirred mixture of tert-butyl / V-(tert-butoxycarbonyl) carbamate potassium salt (5.98 g, 23.4 mmol, 1.1 equiv), 1 ,2-dibromo-4-(bromomethyl)benzene (7.00 g, 21.3 mmol, 1 .00 equiv), and DMF (300 mL) was stirred at 50 °C for 4 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (5 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to afford tert-butyl A / -(tert-butoxycarbonyl)- / V-[(3,4- dibromophenyl)methyl]carbamate (10.2 g, 82% yield, 80% purity) as a light yellow solid. MS calcd. for Ci7H24Br2NO4 (M + H+) m / z 464, found 464.3- Synthesis of tert-butyl N-[3,4-bis(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)benzyll-N-(tert-

[0124] A mixture of tert-butyl A / -(tert-butoxycarbonyl)-A / -(3,4-dibromobenzyl)carbamate (10.0 g, 21.5 mmol, 1 equiv), Pd(dppf)CI2(1.57 g, 2.10 mmol, 0.1 equiv) , B2pin2(13.65 g, 53.7 mmol, 2.5 equiv), and potassium acetate (6.33 g, 64.5 mmol, 3.0 equiv) in 1 ,4-dioxane (500 mL) was stirred at 100 °C for 4 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 33% ethyl acetate in petroleum ether to afford tertbutyl A / -[3,4-bis(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]- / V-(tert-butoxycarbonyl)carbamate(6.0 g, 50% yield, 80% purity) as a yellow solid. MS calcd. for C29H42B2NO8 (M + H+) m / z 560, found560.4- Synthesis of 3,4-bis(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzylamine hydrochloride (4)

[0125] A solution of fert-butyl / V-[3,4-bis(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]- A / -(fert-butoxycarbonyl)carbamate (6.0 g, 10.7 mmol) in anhydrous HCI in 1 ,4-dioxane (4.0 M, 100 mL) was stirred at 25 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 80% ethyl acetate in petroleum ether to afford 3,4-bis(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzylamine hydrochloride (2.50 g, 59% yield, 90% purity) as a light yellow solid. MS calcd. for C19H32B2NO4 (M + H+of the free amine) m / z 360, found 360.5- Synthesis of di-tert-butyl f[(S)-6-[[3.4-bis(4.4.5.5-tetramethyl-1.S^-dioxaborolan^- yDbenzyllaminol-l -tert-butoxy-1,6-dioxohexan-2-yllcarbamoyll-L-Qlutamate (5), ferf-butoxy-1 ,5-dioxopentan-2-yl)- 1 ,3,2-dioxaborolan-2-yl)- ureidoJ-6-oxohexanoic acid benzylamine hydrochlorideXXIV, di-tert-butyl [[(S)-6-[[3,4-bis(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl]amino]-1 -terf-butoxy- 1 ,6-dioxohexan-2-yl)carbamoyl]-L-glutamate

[0126] To a stirred mixture of (S)-6-(te / Y-butoxy)-5-(3-((S)-1 ,5-di-te / Y-butoxy-1 ,5-dioxopentan- 2-yl)ureido)-6-oxohexanoic acid (3.00 g, 6.0 mmol, 1 equiv) and 1-[3,4-bis(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methanamine (2.57 g, 7.2 mmol, 1.2 equiv) in acetonitrile (200 mL) were added A / -methylimidazole (NMI, 1.47 g, 17.9 mmol, 3.0 equiv) and A / ,A / , / V’, / \ / ’- tetramethylchloroformamidinium hexafluorophosphate (TCFH, 2.51 g, 8.9 mmol, 1.5 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 4 h, then extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (5 x 100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, Cis silica gel; mobile phase, acetonitrile in water, from 10% to 100% in 20 min; UV detection at 254 nm to afford crude product (1.7 g, 90% purity). The crude product was purified by column chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to afford di-fert-butyl [[(S)-6-[[3,4-bis(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]amino]-1-tert-butoxy-1 ,6-dioxohexan-2-yl]carbamoyl]-L- glutamate (compound XXIV, 950 mg, 19% yield, 98.7% purity) as a white solid. MS calcd. for C43H72B2N3O12 (M + H+) m / z 844.53, found 844.65.1H NMR (400 MHz, DMSO-d6) δ 8.33 (t, J = 6.0 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 1 .7 Hz, 1 H), 7.26 (dd, J = 7.8, 1 .8 Hz, 1 H), 6.29 (dd, J = 17.9, 8.3 Hz, 2H), 4.24 (d, J = 5.9 Hz, 2H), 4.1 1 -3.94 (m, 2H), 2.27-2.18 (m, 2H), 2.18-2.05 (m, 2H), 1 .92-1 .80 (m, 1 H), 1 .72-1 .61 (m, 1 H), 1 .53 (q, J = 5.7 Hz, 4H), 1 .42-1 .35 (m, 27H), 1 .29 (d, J = 3.6 Hz, 24H).

[0127] While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be evident to those skilled in the art that modifications may be made without departing from this disclosure. Such modifications are considered as possible variants comprised in the scope of the disclosure.References1 . Blaha, P., Feoli, C., Agosteo, S., Calvaruso, M., Cammarata, F. P., Catalano, R., Ciocca, M., Cirrone, G. A. P., Conte, V., & Cuttone, G. (2021). The proton-boron reaction increases the radiobiological effectiveness of clinical low-and high-energy proton beams: novel experimental evidence and perspectives. Frontiers in oncology, 2122.2. Brooks, A., Newton, G., Shyr, L.-J., Seiler, F., & Scott, B. (1990). The combined effects of a-particles and X-rays on cell killing and micronuclei induction in lung epithelial cells. International journal of radiation biology, 58(5), 799-811.3. Cirrone, G., Manti, L., Margarone, D., Petringa, G., Giuffrida, L., Minopoli, A., Picciotto, A., Russo, G., Cammarata, F., & Pisciotta, P. (2018). First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness. Scientific reports, 8(1), 1-15.4. Cirrone, G., Petringa, G., Attili, A., Chiappara, D., Manti, L, Bravata, V., Margarone, D., Mazzocco, M., & Cuttone, G. (2018). Study of the discrepancy between analytical calculations and the observed biological effectiveness in proton boron capture therapy (PBCT). Rad. Applic., 3(3), 147-151.

Claims

CLAIMS:

1. A compound of structural formula I, or a pharmaceutically acceptable salt thereof, stereoisomers thereof, and ester thereof:wherein: m = 1 -2; n = 0-5;R1= H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), ora and c are independently absent or selected from C1-C6 alkylene, C1-C4 oligomethylene, and C1-C6 alkyl-substituted C1-C4 oligomethylene; b is absent or selected from the group consisting of a cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; phenylene optionally substituted with 0-3 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; naphthylene optionally substituted with 0-5 heteroatoms, C1-C6 alkyl, or C3-C7 cycloalkyl; a monocyclic heteroarylene having 5 or6 ring atoms, optionally substituted with 0-3 heteroatoms, C1-C6 alkyl,or C3-C7 cycloalkyl; and a bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, C1-C6 alkyl, or C3-C7cycloalkyl; wherein a, b, and c together provide at least 2 carbon atoms between the attached N and B atoms; wherein R1and a, or R1and b, may together form a four- to seven-membered ring consisting of N and 3 to 6 further atoms, 0-2 of which are heteroatoms, while the others are C;R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, Ci-Cs alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N(CI-C6 alkyl)CH2C(O), C(O)CMe2N(Ci- C6alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2;R4is H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3- C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl);X is C2-C10 oligomethylene carrying 0-4 substituents selected independently from the group consisting of H, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)(C1-C6 alkyl), C3-C7 heterocyclyl, (C3-C7 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), or heteroaryl(C1-C6 alkyl) and ll'M‘ represents a bond to X.

2. The compound of claim 1 , wherein R2and R3are each H.

3. The compound of claim 1 , wherein said Ci-Cs alkyl-substituted C2-C4 oligomethylene is selected from the group consisting of Me2C-CMe2, Et2C-CEt2, and CH2-CMe2-CH2.

4. The compound of any one of claims 1 - 3, wherein in said cycloalkylene having 3-7 ring atoms, optionally substituted with 0-3 heteroatoms; in said phenylene optionally substituted with 0-3 heteroatoms; in said naphthylene optionally substituted with 0-5 heteroatoms; in said monocyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-3 heteroatoms, and / or in said bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, optionally substituted with 0-5 heteroatoms, said heteroatoms comprise a halogen, a radiohalogen, or a combination thereof.

5. The compound of claim 4, wherein said heteroatoms are radiohalogen.

6. The compound of claim 4 or 5, wherein said radiohalogen is a radioisotope of At, I, Br, Cl, orF.

7. The compound of claims 4 - 6, wherein said radiohalogen is At-211 , 1-123, 1-124, 1-125, 1-131 , Br-75, Br-77, and F-18.

8. The compound of any one of claims 1 - 3, wherein said compound is a compound having one of the following formulae:

9. The compound of any one of claims 4 to 7, wherein said compound is a compound of formulaXXVII:XXVII wherein R5is said monocyclic heteroarylene having 5 or 6 ring atoms, substituted with 1-3 heteroatoms and at least one R6, or said bicyclic heteroarylene, each ring of said bicyclic heteroarylene having 5 or 6 ring atoms, substituted with 1-5 heteroatoms and at least one R6, wherein said heteroatoms comprise at least one radioisotope of At, I, Br, Cl and F; andwherein R6is, wherein R2and R3are each H, or R2and R3together are C2-C4 oligomethylene, C1-C8 alkyl-substituted C2-C4 oligomethylene, C3-C7 cycloalkylene, C(O)CH2N(C1-C6 alkyl)CH2C(O), C(O)CMe2N(C1-C6 alkyl)CMe2C(O), (CH2)2NH(CH2)2, or (CH2)2N(C1-C6 alkyl)(CH2)2.

10. The compound of claim 9, wherein said compound of formula XXVII is one of the following compounds:

11. The compound of any one of claims 1 - 10, wherein B is boron-10 (10B), boron-11 (11B), or a combination thereof.

12. The compound of any one of claims 6 to 11 , wherein said radiohalogen is an imaging radiohalogen.

13. The compound of any one of claims 6 to 11 , wherein said radiohalogen is a therapeutic radiohalogen.

14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13, and a pharmaceutically acceptable carrier.

15. The compound of any one of claims 1 to 13, or the pharmaceutical composition of claiml 4, for use in the treatment of prostate cancer in a patient in need thereof.

16. Use of the compound of any one of claims 1 to 13, or the pharmaceutical composition of claim 14, for the treatment of prostate cancer in a patient in need thereof.

17. The compound for use of claim 15, or the use of claim 16, further comprising use of radiation therapy.

18. A method of treating prostate cancer comprising administering to a patient an effective amount of the compound of any one of claims 1 to 13, or the pharmaceutical composition of claim 14, followed by one or more rounds of radiation therapy.

19. The compound for use of claims 15, the use of claims 16-17, orthe method of claim 18, wherein said R1isbinding an atom of177Lu,68Ga, or a combination thereof, for imaging of a tumor in a subject in need thereof.

20. The compound for use or the use of claim 17, or the method of claim 18, wherein said radiation therapy is a boron-proton capture therapy, a boron-neutron capture therapy, or a combination thereof.

21. The compound of any one of claims 4 to 13, orthe pharmaceutical composition of claim 14, for use in medical imaging in a patient in need thereof.

22. Use of the compound of any one of claims 4 to 13, or the pharmaceutical composition of claim 14, for medical imaging in a patient in need thereof.

23. A method of medical imaging comprising administering to a patient an effective amount of the compound of any one of claims 4 to 13, or the pharmaceutical composition of claim 14, followed by one or more rounds of image acquisition with an imaging apparatus.

Images