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WO2024016071A1 - Composés radiomarqués ciblant l'antigène membranaire spécifique de la prostate - Google Patents

Composés radiomarqués ciblant l'antigène membranaire spécifique de la prostate Download PDF

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Publication number
WO2024016071A1
WO2024016071A1 PCT/CA2023/050959 CA2023050959W WO2024016071A1 WO 2024016071 A1 WO2024016071 A1 WO 2024016071A1 CA 2023050959 W CA2023050959 W CA 2023050959W WO 2024016071 A1 WO2024016071 A1 WO 2024016071A1
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Prior art keywords
compound
aromatic
branched
linear
group
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PCT/CA2023/050959
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English (en)
Inventor
Kuo-Shyan LIN
François BÉNARD
Zhengxing Zhang
Fei Yuan LU
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Provincial Health Services Authority
The University Of British Columbia
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Publication of WO2024016071A1 publication Critical patent/WO2024016071A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids

Definitions

  • the present invention relates to radiolabeled compounds for in vivo imaging or treatment of diseases or conditions characterized by expression of prostate-specific membrane antigen, particularly compounds with low uptake in salivary glands and/or kidneys.
  • Prostate cancer is the second most prevalent cancer diagnosis in men with a GLOBOCAN estimate of 1,276,106 new cases reported in 2018 and is the fifth leading cause of death worldwide.
  • Prostate cancer is the second most prevalent cancer diagnosis in men with a GLOBOCAN estimate of 1,276,106 new cases reported in 2018 and is the fifth leading cause of death worldwide.
  • PSA prostate specific antigen
  • PSMA prostate-specific membrane antigen
  • PSMA also known as folate hydrolase 1 and glutamate carboxypeptidase II, is a transmembrane protein that catalyzes the hydrolysis of N-acetylaspartylglutamate to glutamate and N-acetylaspartate.
  • Small urea-based molecules such as glutamate-urea-glutamate have been identified to target the catalytic site of glutamate carboxypeptidase II and serve as the basis for many PSMA radiopharmaceuticals including 18 F-PSMA-1007 and the recently FDA-approved 18 F-DCFPyL for imaging of prostate cancer.
  • 18 F-DCFPyL A limitation of 18 F-DCFPyL is its high liver uptake which reduces its sensitivity for detecting metastatic lesions in liver.
  • 18 F-PSMA-1007 has an even higher nonspecific uptake level in most normal tissues when compared to 18 F-DCFPyL, leading to more false positive diagnosis for this tracer.
  • PET positron emission tomography
  • R 0 is O or S
  • R 1a is —CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2 , –OPO 3 H 2 , –OSO 3 H, –B(OH) 2
  • R 1b is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2, –B(OH) 2
  • R 1c is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2, –B(OH) 2
  • R 2 is —CH 2 –, –CH(OH)–, –CHF–, –CF 2 –, –CH(CH 3 )–, –C(CH 3
  • the present disclosure relates to methods of imaging prostate specific membrane antigen (PSMA)-expressing tissues in a subject, comprising administering a compound disclosed herein to a subject in need thereof, wherein the compound comprises a positron or gamma emitting radioisotope; and imaging the PSMA-expressing tissue.
  • PSMA prostate specific membrane antigen
  • FIG. 2 shows maximum intensity projection PET images of 18 F-KL01120 in LNCaP tumor-bearing mice acquired at 1 h post-injection without (left) and with (right) the co-injection of 2-PMPA (0.5 mg).
  • FIG. 3 shows maximum intensity projection PET images of 18 F-KL01130 in LNCaP tumor-bearing mice acquired at 1 h post-injection without (left) and with (right) the co-injection of 2-PMPA (0.5 mg).
  • compositions, use or method excludes the presence of additional elements and/or method steps in that feature.
  • a compound, composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
  • a use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
  • a “diagnostic radiometal” includes radiometals that are suitable for use as imaging agents.
  • the term “subject” refers to an animal (e.g., a mammal or a non-mammal animal).
  • the subject may be a human or a non-human primate.
  • the subject may be a laboratory mammal (e.g., mouse, rat, rabbit, hamster and the like).
  • the subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, camelid and the like) or a domestic animal (e.g., canine, feline and the like).
  • the subject is a human.
  • the compounds disclosed herein may also include base-free forms, salts or pharmaceutically acceptable salts thereof. Unless otherwise specified, the compounds claimed and described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are explicitly represented herein. [0052] The compounds disclosed herein may be shown as having one or more charged groups, may be shown with ionizable groups in an uncharged (e.g., protonated) state or may be shown without specifying formal charges.
  • the ionization state of certain groups within a compound is dependent, inter alia, on the pKa of that group and the pH at that location.
  • a carboxylic acid group i.e., COOH
  • COOH carboxylic acid group
  • OSO 3 H i.e., SO 4 H
  • SO 2 H groups SO 3 H groups
  • OPO 3 H 2 i.e., PO 4 H 2
  • PO 3 H groups would generally be deprotonated (and negatively charged) at neutral and physiological pH values.
  • salt and solvate have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid.
  • a suitable base e.g., without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two.
  • Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography.
  • the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject.
  • suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes enantiomers and diastereomer.
  • the expression “Xy-Xz”, where y and z are integers e.g.
  • X 1 -X 15 , X 1 -X 30 , X 1 -X 100 , and the like) refers to the number of carbons (for alkyls, whether saturated or unsaturated, or aryls) in a compound, R-group or substituent, or refers to the number of carbons plus heteroatoms (for heteroalkyls, whether saturated or unsaturated, or heteroaryls) in a compound, R-group or substituent.
  • Heteroatoms may include any, some or all possible heteroatoms.
  • the heteroatoms are selected from N, O, S, P and Se.
  • the heteroatoms are selected from N, O, S and P. Such embodiments are non-limiting.
  • Alkyls and aryls may alternatively be referred to using the expression “Cy-Cz”, where y and z are integers (e.g., C 3 -C 15 and the like).
  • y and z are integers (e.g., C 3 -C 15 and the like).
  • Cy-Cz when used in association with heteroalkyl, heteroalkenyl, heteroalkynyl, and the like, it is understood that one or more carbon atoms of Cy-Cz alkyl is replaced with a heteroatom, such as N, O, S, P and Se.
  • C4 heteroalkyl can include CH 3 CH 2 OCH 3 .
  • alkyl and heteroalkyl each includes any reasonable combination of the following: (1) saturated alkyls as well as unsaturated (including partially unsaturated) alkyls (e.g., alkenyls and alkynyls); (2) linear or branched; (3) acyclic or cyclic (aromatic or nonaromatic), the latter of which may include multi-cyclic (fused rings, multiple non-fused rings or a combination thereof); and (4) unsubstituted or substituted.
  • an alkyl or heteroalkyl may be saturated, branched and cyclic, or unsaturated, branched and cyclic, or linear and unsaturated, or any other reasonable combination according to the skill of the person of skill in the art. If unspecified, the size of the alkyl/heteroalkyl is what would be considered reasonable to the person of skill in the art.
  • the size of an alkyl may be 1 2 3 4 5 6 7 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100 carbons in length, subject to the common general knowledge of the person of skill in the art.
  • alkyl can be C 1 -C 12 alkyl or C 1 -C 6 alkyl.
  • the size of a heteroalkyl may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100 carbons and
  • alkyl, alkenyl or alkynyl In the context of the expression “alkyl, alkenyl or alkynyl” and similar expressions, the “alkyl” would be understood to be a saturated alkyl. Likewise, in the context of the expression “heteroalkyl, heteroalkenyl or heteroalkynyl” and similar expressions, the “heteroalkyl” would be understood to be a saturated heteroalkyl. [0058] As used herein, in the context of an alkyl/heteroalkyl group of a compound, the term “linear” may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that does not split off into more than one contiguous chain.
  • Non-limiting examples of linear alkyls include methyl, ethyl, n-propyl, and n-butyl.
  • the term “branched” may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that splits off into more than one contiguous chain. The portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof.
  • Non-limiting examples of a branched alkyl group include tert-butyl and isopropyl.
  • cyclic alkyl/heteroalkyl refers to saturated, unsaturated, or partially unsaturated cycloalkyl and cycloheteroalkyl groups as well as combinations with linear or branched alkyl/heteroalkyl – for example: -(alkylene) 0-1 -(cycloalkylene)-(alkylene) 0-1 -, -(alkylene) 0-1 -(cycloheteroalkylene)-(alkylene) 0-1 -, -(alkylene) 0-1 -(arylene)-(alkylene) 0-1 -, and -(alkylene) 0-1 -(heteroarylene)-(alkylene) 0-1 - are included in said term.
  • a divalent aromatic heteroalkyl group can be and a divalent saturated cycloalkyl group can be .
  • alkylenyl refers to a divalent analog of an alkyl group.
  • alkylenyl, alkenylenyl or alkynylenyl alkylenyl or alkenylenyl
  • the “alkylenyl” would be understood to be a saturated alkylenyl.
  • heteroalkylenyl refers to a divalent analog of a heteroalkyl group.
  • heteroalkylenyl In the context of the expression “heteroalkylenyl, heteroalkenylenyl or heteroalkynylenyl”, “heteroalkylenyl or heteroalkenylenyl” and similar expressions, the “heteroalkylenyl” would be understood to be a saturated heteroalkylenyl.
  • saturated when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises only single bonds, and may include linear, branched, and/or cyclic groups.
  • Non-limiting examples of a saturated C 1 -C 20 alkyl group may include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl
  • the saturated alkyl can be a C 1 -C 12 saturated alkyl or C 1 -C 6 saturated alkyl. Unless otherwise specified, a C1-C20 alkylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed saturated alkyl groups.
  • the term “unsaturated” when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises at least one double or triple bond, and may include linear, branched, and/or cyclic groups.
  • Non-limiting examples of a C 2 -C 20 alkenyl group may include vinyl, allyl, isopropenyl, l-propene-2-yl, 1-butene-l-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, cyclodecanenyl, and the like.
  • the alkenyl group can be a C 2 -C 12 alkenyl or C 2 -C 6 alkenyl. Unless otherwise specified, a C 1 -C 20 alkenylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkenyl groups.
  • Non-limiting examples of a C 2 -C 20 alkynyl group may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.
  • the alkynyl group can be a C 2 -C 12 alkynyl or C 2 -C 6 alkynyl. Unless otherwise specified, a C 1 -C 20 alkynylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkynyl groups.
  • the alkynylenyl group can be a C 2 -C 12 alkynyl or C 2 -C 6 alkynylenyl.
  • the above-defined saturated C 1 -C 20 alkyl groups, C 2 -C 20 alkenyl groups and C 2 -C 20 alkynyl groups are all encompassed within the term “C 1 -C 20 alkyl”, unless otherwise indicated.
  • the above-defined saturated C 1 -C 20 alkylenyl groups, C 2 -C 20 alkenylenyl groups and C 2 -C 20 alkynylenyl groups are all encompassed within the term “C 1 -C 20 alkylenyl”, unless otherwise indicated.
  • the term “X 1 -X 20 heteroalkyl” would encompass each of the above-defined saturated C 1 -C 20 alkyl groups, C 2 -C 20 alkenyl groups and C 2 -C 20 alkynyl groups, where one or more of the carbon atoms is independently replaced with a heteroatom.
  • X 1 -X 20 heteroalkylenyl would encompass each of the above-defined saturated C 1 -C 20 alkylenyl groups, C 2 -C 20 alkenylenyl groups and C 2 -C 20 alkynylenyl groups, where one or more of the carbon atoms is independently replaced with a heteroatom.
  • the X 1 -X 20 heteroalkyl can be a C 1 -C 12 heteroalkyl or C 1 -C 6 heteroalkyl. The person of skill in the art would understand that various combinations of different heteroatoms may be used.
  • Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolydinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, and the like.
  • an “aryl” group includes both single aromatic rings as well as fused rings containing at least one aromatic ring.
  • C 3 -C 20 aryl groups include phenyl (Ph), pentalenyl, indenyl, naphthyl and azulenyl.
  • Non-limiting examples of X 3 -X 20 aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pirazinyl, quinolinyl, isoquinolinyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl, benzofu
  • substituted is used as it would normally be understood to a person of skill in the art and generally refers to a compound or chemical entity that has one chemical group replaced with a different chemical group.
  • a substituted alkyl is an alkyl in which one or more hydrogen atom(s) are independently each replaced with an atom that is not hydrogen.
  • chloromethyl is a non-limiting example of a substituted alkyl, more particularly an example of a substituted methyl.
  • Aminoethyl is another non-limiting example of a substituted alkyl, more particularly an example of a substituted ethyl.
  • a substituted compound or group may be substituted with any chemical group reasonable to the person of skill in the art.
  • a hydrogen bonded to a carbon or heteroatom e.g., N
  • halide e.g., F, I Br Cl
  • unsubstituted is used as it would normally be understood to a person of skill in the art.
  • Non-limiting examples of unsubstituted alkyls include methyl, ethyl, tert-butyl, pentyl and the like.
  • the expression “optionally substituted” is used interchangeably with the expression “unsubstituted or substituted”.
  • hydrogen may or may not be shown.
  • hydrogens may be protium (i.e. 1 H), deuterium (i.e. 2 H) or combinations of 1 H and 2 H. Methods for exchanging 1 H with 2 H are well known in the art.
  • Xaa refers to an amino acid residue in a peptide chain or an amino acid that is otherwise part of a compound. Amino acids have both an amino group and a carboxylic acid group, either or both of which can be used for covalent attachment.
  • the amino group and/or the carboxylic acid group may be converted to an amide or other structure; e.g. a carboxylic acid group of a first amino acid is converted to an amide (i.e. a peptide bond) when bonded to the amino group of a second amino acid.
  • Xaa may have the formula –N(R a )R b C(O)–, where R a and R b are R-groups. R a will typically be hydrogen or methyl.
  • the amino acid residues of a peptide may comprise typical peptide (amide) bonds and may further comprise bonds between side chain functional groups and the side chain or main chain functional group of another amino acid.
  • the side chain carboxylate of one amino acid residue in the peptide may be bonded to and the amine of another amino acid residue in the peptide (e.g. Dap, Dab, Orn, Lys). Further details are provided below.
  • “Xaa” may be any amino acid, including proteinogenic and nonproteinogenic amino acids.
  • Non-limiting examples of nonproteinogenic amino acids are shown in Table 1 and include: D-amino acids (including without limitation any D-form of the following amino acids), ornithine (Orn), 3-(1-naphtyl)alanine (Nal), 3-(2-naphtyl)alanine (2-Nal), ⁇ aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, beta-(1,2,3-triazol-4-yl)-L-alanine, 1,2,4-triazole-3-alanine, Phe(4-F), Phe(4-Cl), Phe(4-Br), Phe(4-I), Phe(4-NH 2 ), Phe(4-NO 2 ), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), ⁇ -alanine, 4-amino
  • an amino acid shall be understood to encompass both L- and D-amino acids.
  • TABLE 1 List of non-limiting examples of non-proteinogenic amino acids.
  • the wavy line “ ” symbol shown through or at the end of a bond in a chemical formula is intended to define the R group on one side of the wavy line, without modifying the definition of the structure on the opposite side of the wavy line.
  • any atoms shown outside the wavy lines are intended to clarify orientation of the R group. As such, only the atoms between the two wavy lines constitute the definition of the R group.
  • chemical groups with more than one point of attachment are understood to be placed in any direction a skilled artisan would understand as chemically possible – e.g., –C(O)NH– and –NHC(O)– are interchangeable unless otherwise noted.
  • the compound of the present disclosure relates to a compound of Formula I: [0074] or a salt or a solvate thereof, wherein: [0075] R 0 is O or S; [0076] R 1a is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2 , –OPO 3 H 2 , –OSO 3 H, –B(OH) 2 , N [0077] R 1b is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2, –B(OH) 2 , or [0078] R 1c is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2, –B(OH) 2 , or [0079] R 2 is –CH 2 –, –CH(OH)–, –CHF–, –CF 2 –, –CH(CH 3
  • the compound of the present disclosure relates to a compound of Formula II: [00107] or is a salt or a solvate thereof; wherein: [00108] R 0 is O or S; [00109] R 1a is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2 , –OPO 3 H 2 , or –OSO 3 H; [00110] R 1b is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, or –PO 3 H 2 ; [00111] R 1c is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, or –PO 3 H 2; [00112] R 2 is –CH 2 –, –(CH 2 ) 2 –, –(CH 2 ) 3 –, –CH 2 CHF–, –CHFCH 2 –, –CH 2 OCH 2
  • the compound of the present disclosure relates to a compound of Formula III: [00138] or is a salt or a solvate thereof; wherein: [00139] R 0 is O; [00140] R 1a is –CO 2 H; [00141] R 1b is –CO 2 H; [00142] R 1c is —CO 2 H; [00143] R 2 is –(CH 2 ) 3 –; [00144] R 3 is –CH 2 –, –(CH 2 ) 2 –, –(CH 2 ) 3 , –(CH 2 ) 4 –, –(CH 2 ) 5 –, –CH 2 -O-CH 2 –, –CH 2 -O-CH 2 -CH 2 –, –CH 2 -CH 2 -O-CH 2 –, or —CH 2 –S-CH 2 -; [00145] R 4 is –NHC(O)– or –C(O)
  • the compound of is a salt or solvate of Formula I, II, and/or III.
  • R 0 is O. In other embodiments, R 0 is S.
  • R 1a is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, –PO 3 H 2 , –OPO 3 H 2 , or –OSO 3 H.
  • R 2a is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, or –PO 3 H 2 .
  • R 3a is –CO 2 H, –SO 2 H, –SO 3 H, –PO 2 H, or –PO 3 H 2 .
  • R 1a is –CO 2 H.
  • R 1b is –CO 2 H.
  • R 1c is —CO 2 H.
  • R 1a and R 1b are each –CO 2 H.
  • R 1a and R 1c are each –CO 2 H.
  • R 1b and R 1c are each –CO 2 H.
  • R 1a , R 1b and R 1c are each –CO 2 H.
  • R 1a , R 1b and R 1c are each –CO2H.
  • R 1a , R 1b and R 1c are anionic or metalated salts of the foregoing.
  • R 2 is –CH 2 –.
  • R 2 is —CH(OH)–.
  • R 2 is –CHF–.
  • R 2 is –CF 2 –.
  • R 2 is –CH(CH 3 )–.
  • R 2 is –C(CH 3 ) 2 –.
  • R 2 is –(CH 2 ) 2 –.
  • R 2 is –CH 2 CH(OH)–.
  • R 2 is –CH 2 CHF–. In some embodiments, R 2 is –CHFCH 2 –. In some embodiments, R 2 is –CF 2 CH 2 –. In some embodiments, R 2 is –CH 2 CF 2 –. In some embodiments, R 2 is —CH(OH)CH 2 –. In some embodiments, R 2 is –CH(CH 3 )CH 2 –. In some embodiments, R 2 is –CH 2 CH(CH 3 ) –. In some embodiments, R 2 is –C(CH 3 ) 2 CH 2 –. In some embodiments, R 2 is –CH 2 C(CH 3 ) 2 –.
  • R 2 is –CH 2 –, –CH(OH)–, –CHF–, –CF 2 –, –CH(CH 3 )–, –C(CH 3 ) 2 –, –(CH 2 ) 2 –, –CH 2 CH(OH)–, –CH 2 CHF–, –CHFCH 2 –, –CF 2 CH 2 –, –CH 2 CF 2 –, –CH(OH)CH 2 –, –CH(CH 3 )CH 2 –, –CH 2 CH(CH 3 )–, –C(CH 3 ) 2 CH 2 –, –CH 2 C(CH 3 ) 2 –, –CH 2 CH(OH)CH 2 –, –CH 2 CHFCH 2 –, –(CH 2 ) 2 CH(OH)–, –(CH 2 ) 2 CHF–, –(CH 2 ) 3 –, –CH 2 O
  • R 2 is —CH 2 CH(OH)CH 2 –, –CH 2 CHFCH 2 –, –(CH 2 ) 2 CH(OH)–, –(CH 2 ) 2 CHF–, –(CH 2 ) 3 –, –CH 2 OCH 2 –, –CH 2 SCH 2 –, –CHFCH 2 CH 2 –, –CH(OH)CH 2 CH 2 –, –CH(CH 3 )CH 2 CH 2 –, –CH 2 CH(CH 3 )CH 2 –, –CH 2 CH 2 CH(CH 3 )—, –C(CH 3 ) 2 CH 2 CH 2 –, –CH 2 C(CH 3 ) 2 CH 2 –, –CH 2 CH 2 C(CH 3 ) 2 –, –CH(CH 3 )–O–CH 2 –, –C(CH 3 ) 2 –, –CH 2 –, –CH 2 –O–CH 2 –, –C(CH 3
  • R 2 is –CH 2 OCH 2 – or –CH 2 SCH 2 –.
  • R 2 is –CH 2 –, –CH(OH)–, –CHF–, –CF 2 –, –CH(CH 3 )–, –C(CH 3 ) 2 –, –(CH 2 ) 2 –, –CHFCH 2 –, –CF 2 CH 2 –, –CH(OH)CH2–, –CH(CH3)CH2–, –C(CH3)2CH2–,–(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH 2 OCH 2 –,–CH 2 SCH 2 –, –CHFCH 2 CH 2 –, –CH(OH)CH 2 CH 2 –, –CH(CH 3 )CH 2 CH 2 –, –CH 2 CH 2 CH(CH 3 )
  • R 2 is –(CH 2 ) 2 CHF–, –(CH 2 ) 3 –, –CH 2 OCH 2 –, –CH 2 SCH 2 –, –CHFCH 2 CH 2 –, –CH(OH)CH 2 CH 2 –, –CH(CH 3 )CH 2 CH 2 –, –CH 2 CH 2 CH(CH 3 )–, –C(CH 3 ) 2 CH 2 CH 2 –, –CH 2 CH 2 C(CH 3 ) 2 –, –CH(CH 3 )–O–CH 2 –, –C(CH 3 ) 2 –O–CH 2 –, –CH 2 –O–CH(CH 3 )–, –CH 2 –O–C(CH 3 ) 2 –, –CH 2 –S(O)–CH 2 –, –CH 2 –S(O) 2 –CH 2 –, –CH(CH 3 ) 2 –, –CH(CH 3 ) 2
  • R 2 is –CH 2 CH(OH)–, –CH 2 CHF– –CH 2 CH(CH 3 )– –CH 2 CH(COOH)– –CH 2 CH(OH)CH 2 – –CH 2 CH(F)CH 2 – or –CH 2 CH(CH 3 )CH 2 –, wherein the second carbon in R 2 has R-configuration.
  • R 2 is –CH 2 CH(OH)–, –CH 2 CHF–, or –CH 2 CH(CH 3 )–, wherein the second carbon in R 2 has R-configuration.
  • R 2 is –CH 2 CHF–, wherein the second carbon in R 2 has R-configuration.
  • R 2 is —CHOH–.
  • R 2 is –CH 2 CHOH–.
  • R 2 is –CH 2 CHOHCH 2 –.
  • R 2 is –CH 2 CHFCH 2 .
  • R 2 is –(CH 2 ) 2 CHOH–.
  • R 2 is –(CH 2 ) 2 CHF–.
  • R 2 is –(CH 2 ) 3 –.
  • R 2 is –CH 2 OCH 2 –.
  • R 2 is –CH 2 SCH 2 –.
  • R 2 is –CH 2 CH(OH)CH 2 –.
  • R 2 is –CH 2 CHFCH 2 –.
  • R 2 is –(CH 2 ) 2 CH(OH)–.
  • R 2 is –CHFCH 2 CH 2 –.
  • R 2 is –CH(OH)CH 2 CH 2 –.
  • R 2 is –CH(CH 3 )CH 2 CH 2 –.
  • R 2 is –CH 2 CH(CH 3 )CH 2 –.
  • R 2 is –CH 2 CH 2 CH(CH 3 )–. In some embodiments, R 2 is –C(CH 3 ) 2 CH 2 CH 2 –. In some embodiments, R 2 is –CH 2 C(CH 3 ) 2 CH 2 –. In some embodiments, R 2 is –CH 2 CH 2 C(CH 3 ) 2 –. In some embodiments, R 2 is –CH(CH 3 )–O–CH 2 –. In some embodiments, R 2 is –C(CH 3 ) 2 –O–CH 2 –. In some embodiments, R 2 is –CH2–O–CH(CH3)–. In some embodiments, R 2 is –CH2–O–C(CH3)2–.
  • R 2 is –CH 2 –S(O)–CH 2 –. In some embodiments, R 2 is –CH 2 –S(O) 2 –CH 2 –. In some embodiments, R 2 is –CH(CH 3 )–S–CH 2 –. In some embodiments, R 2 is –C(CH3)2–S–CH2–. In some embodiments, R 2 is –CH2–S–CH(CH3)–. In some embodiments, R 2 is –CH 2 –S–C(CH 3 ) 2 –. In some embodiments, R 2 is –CH(CH 3 )–S(O)–CH 2 –.
  • R 2 is –C(CH 3 ) 2 –S(O)–CH 2 –. In some embodiments, R 2 is –CH 2 –S(O)–CH(CH 3 )–. In some embodiments, R 2 is –CH 2 –S(O)–C(CH 3 ) 2 –. In some embodiments, R 2 is –CH(CH 3 )–S(O) 2 –CH 2 –. In some embodiments, R 2 is –C(CH 3 ) 2 –S(O) 2 –CH 2 –. In some embodiments, R 2 is –CH 2 –S(O) 2 –CH(CH 3 )–.
  • R 2 is –CH 2 –S(O) 2 –C(CH 3 ) 2 –. In some embodiments, R 2 is –CH 2 –NH–C(O)–. In some embodiments, R 2 is –C(O)–NH–CH 2 –. In some embodiments, R 2 is –C(O)–NH–CH(CH 3 )–. In some embodiments, R 2 is –C(O)–NH–C(CH 3 ) 2 –.
  • R 2 is -CH 2 -, –(CH 2 ) 2 –, –(CH 2 ) 3 –, -CH 2 CHF-, -CHFCH 2 -, -CH 2 OCH 2 -, or -CH 2 SCH 2 -.
  • R 2 is –(CH 2 ) 2 – or –(CH 2 ) 3 –.
  • R 1a is –CO 2 H and R 2 is –(CH 2 ) 2 – or –(CH 2 ) 3 –.
  • R 1a is –CO 2 H and R 2 is –CH 2 –.
  • R 1a is –CO 2 H
  • R 1b is –CO 2 H
  • R 1c is —CO 2 H
  • R 2 is –(CH 2 ) 2 – or –(CH 2 ) 3 –.
  • R 1a is –CO 2 H and R 2 is –CH 2 –.
  • R 3 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 10 alkylenyl, alkenylenyl, or alkynylenyl, or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 10 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl.
  • R 3 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 20 alkylenyl or alkenylenyl, or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 20 heteroalkylenyl or heteroalkenylenyl.
  • R 3 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 10 alkylenyl or alkenylenyl, or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 10 heteroalkylenyl or heteroalkenylenyl.
  • R 3 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 6 alkylenyl or alkenylenyl, or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 6 heteroalkylenyl or heteroalkenylenyl.
  • R 3 is a linear acyclic C 3 -C 15 alkylenyl.
  • R 3 is a linear acyclic C 3 -C 15 heteroalkylenyl in which 1-5 carbons are replaced with N, S and/or O heteroatoms.
  • R 3 is a linear acyclic saturated C 3 -C 10 alkylenyl, optionally substituted with 1-5 amine, amide, oxo, hydroxyl, thiol, methyl or ethyl groups.
  • R 3 is –(CH2)3-15–.
  • R 3 is –(CH 2 ) 3-10 –.
  • R 3 is –(CH 2 ) 3-6 –.
  • R 3 is a linear C 3 -C 5 alkenylenyl and/or alkynylenyl. [00183] In some embodiments of the compounds of the invention, R 3 is –CH 2 –; –(CH 2 ) 2 –; –(CH 2 ) 3 ; –(CH 2 ) 4 –; –(CH 2 ) 5 –; –CH 2 -O-CH 2 –; –CH 2 -O-CH 2 -CH 2 –; –CH 2 -CH 2 -O-CH 2 –; or —CH 2 –S-CH 2 -.
  • R 3 is –(CH 2 ) 4 –; –CH 2 -O-CH 2 -CH 2 –; or –CH 2 -CH 2 -O-CH 2 –. In some embodiments, R 3 is –(CH 2 ) 4 –. In some embodiments, R 3 is –CH 2 -O-CH 2 -CH 2 –. In some embodiments, R 3 is –CH 2 -CH 2 -O-CH 2 –. In some embodiments, R 3 is –CH 2 -O-CH 2 -CH 2 –**, where ** end connects to R 4 .
  • R 3 is –CH 2 -CH 2 -O-CH 2 –**, where ** end connects to R 4 .
  • R 3 is –(CH 2 ) 4 – or –CH 2 -O-CH 2 -CH 2 –**, where ** end connects to R 4 .
  • R 4 is –O–.
  • R 4 is –S–.
  • R 4 is —NHC(O)–.
  • R 4 is –C(O)NH–.
  • R 4 is .
  • R 4 is .
  • R 4 is .
  • R 4 is –S(O)–.
  • R 4 is –S(O)2–. In some embodiments, R 4 is –C(O)–(NH) 2 –C(O)–. In some embodiments, R 4 is –OC(O)NH–. In some embodiments, R 4 is –NHC(O)C–. In some embodiments, R 4 is –NHC(O)NH–. In some embodiments, R 4 is –OC(S)NH. In some embodiments, R 4 is –NHC(S)O–. In some embodiments, R 4 is –NHC(S)NH–. In some embodiments, R 4 is –NHC(O)C(O)NH–. In some embodiments, R 4 is –S-S–.
  • R 4 is –S-CH 2 -S–. In some embodiments, R 4 is -NH-NH-C(O)-. In some embodiments, R 4 is or –C(O)-NH-NH–. [00185] In some embodiments of the compounds of the invention, R 4 is –O–, –S–, –S(O)–, –S(O) 2 –, –NHC(O)–, –C(O)NH–, [00186] In some embodiments of the compounds of the invention, R 3 is –(CH 2 ) 3-15 – and R 4 is –NHC(O)–.
  • R 3 is –(CH 2 ) 3-10 – and R 4 is —NHC(O)–. In some embodiments, R 3 is –(CH 2 ) 3-6 – and R 4 is –NHC(O)–. In some embodiments, R 3 is –(CH 2 ) 3-5 – and R 4 is –NHC(O)–. In some embodiments, R 3 is –(CH 2 ) 4 – and R 4 is –NHC(O)–. In some embodiments, R 3 is –(CH2)4– and R 4 is –NHC(O)–**, where ** end connects to R 5 .
  • R 3 is –(CH 2 ) 3-15 – and R 4 is –C(O)NH–. In some embodiments, R 3 is –(CH 2 ) 3-10 – and R 4 is –C(O)NH–. In some embodiments, R 3 is –(CH2)3-6– and R 4 is –C(O)NH–. In some embodiments, R 3 is –(CH2)3-5– and R 4 is –C(O)NH–. In some embodiments, R 3 is –(CH 2 ) 4 – and R 4 is –C(O)NH–.
  • R 3 is –(CH 2 ) 4 – and R 4 is –C(O)NH–**, where ** end connects to R 5 .
  • R 5 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 30 alkylenyl or alkenylenyl, or is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 30 heteroalkylenyl or heteroalkenylenyl.
  • R 5 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 20 alkylenyl or alkenylenyl, or is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 20 heteroalkylenyl or heteroalkenylenyl.
  • R 5 is a C 1 -C 6 alkylenyl substituted with C 5 -C 20 aryl, C 5 -C 20 arylalkyl, C 5 -C 20 heteroaryl or C 5 -C 20 heteroarylalkyl.
  • R 5 is a C 1 -C 3 alkylenyl substituted with C 10 -C 20 aryl, C 10 -C 20 arylalkyl, C 10 -C 20 heteroaryl or C 10 -C 20 heteroarylalkyl. In some embodiments, R 5 is a C 1 -C 3 alkylenyl substituted with C 10 -C 16 aryl, C 10 -C 16 arylalkyl, C 10 -C 16 heteroaryl or C 10 -C 16 heteroarylalkyl.
  • R 5 is a C 1 alkylenyl substituted with C 10 -C 16 aryl, C 10 -C 16 arylalkyl, C 10 -C 16 heteroaryl or C 10 -C 16 heteroarylalkyl.
  • R 5 is –(CH 2 ) 0-3 CH(R 10 )(CH 2 ) 0-3 –.
  • R 5 is –(CH 2 ) 0-1 CH(R 10 )(CH 2 ) 0-1 –.
  • R 5 is –CH(R 10 )–.
  • R 5 is –CH 2 CH(R 10 )–.
  • R 5 is –CH(R 10 )CH 2 –. In some embodiments, R 5 is –CH(R 10 )–.
  • R 10 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 19 alkyl, alkenyl or alkynyl; a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 19 heteroalkyl, heteroalkenyl or heteroalkynyl having only 1-3 heteroatoms.
  • R 10 is C 5 -C 20 aryl, C 5 -C 20 arylalkyl, C 5 -C 20 heteroaryl or C 5 -C 20 heteroarylalkyl. In some embodiments, R 10 is C 10 -C 20 aryl, C 10 -C 20 arylalkyl, C 10 -C 20 heteroaryl or C 10 -C 20 heteroarylalkyl. In some embodiments, R 10 is C 10 -C 16 aryl, C 10 -C 16 arylalkyl, C 10 -C 16 heteroaryl or C 10 -C 16 heteroarylalkyl.
  • R 10 is –CH 2 R 23 , in which R 23 is an optionally substituted C 4 -C 16 aromatic ring or partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced with N, S and/or O heteroatoms, and wherein the optional substitutions are selected from OH, NH 2, NO2, halogen, C1-C6 alkyl, and/or C1-C6 alkoxyl groups.
  • R 10 is optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH 2 , NO 2 , CN, OH, or one or more additional endocyclic ring nitrogen atoms.
  • R 10 is an alkenyl containing either a C6-C16 aryl or C6-C16 heteroaryl having 1-3 heteroatoms independently selected from N, S and/or O.
  • the C 6 -C 16 aryl is benzyl.
  • the C 6 -C 16 heteroaryl is benzyloxyl or benzylthio.
  • R 10 is: or . In some embodiments, R 10 is In some embo 10 diments, R is In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is In some embodiments, R 10 is In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is In some embodiments, R 10 is In some embodiments, R 10 is . In some embodiments, R 10 is . In some embodiments, R 10 is: , .
  • R 10 is [00196] In some embodiments of the compounds of the invention, R 5 is –CH(R 10 )– wherein R 10 is , , In some embodiments, R 5 is –CH(R 10 )– wherein R 10 is , or . In some embodiments, R 5 is –CH(R 10 )– wherein R 10 is , or [00197] In some embodiments of the compounds of the invention, R 5 is –CH(R 10 )– and R 10 is .
  • R is –CH(R )– and R is [00198] In some embodiments of the compounds of the invention, R 5 is –(CH 2 ) 0-3 CH(R 10 )(CH 2 ) 0-3 – and R 10 is –(CH 2 ) 5 CH 3 . In some embodiments, R 5 is –CH(R 10 )– and R 10 is –(CH 2 ) 5 CH 3 . In some embodiments, R 5 is –(CH 2 ) 0-3 CH(R 10 )(CH 2 ) 0-3 –. [00199] In some embodiments of the compounds of the invention, R 10 is –CH 2 -R 23 .
  • R 23 is phenyl substituted with 1 or 2 iodo groups and optionally further substituted with 1 oxy group.
  • R 5 is –(CH 2 ) 0-3 CH(R 10 )(CH 2 ) 0-3 – wherein R 10 is –CH 2 R 23 and R 23 is phenyl substituted with 1 or 2 iodo groups and optionally further substituted with 1 oxy group.
  • R 23 is In some embodiments, R 23 is In some embodiments, R 23 is . In some embodiments, R 23 is In some embodiments, R 23 is . In some embodiments, R 23 is . In some embodiments, R 23 is . In some embodiments, R 23 is .
  • R 23 is [00200] In some embodiments of the compounds of the invention, R 6 is hydrogen. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. [00201] In some embodiments of the compounds of the invention, Xaa 1 is an amino acid of formula –N(R 8 )R 9 C(O)–. [00202] In some embodiments of the compounds of the invention, m is 1. In some embodiments, m is 2 and each Xaa 1 may be the same or different. In some embodiments, m is 3 and each Xaa 1 may be the same, different or a combination thereof.
  • each R 8 is independently hydrogen or methyl. In some embodiments, at least one R 8 is methyl.
  • R 9 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 30 alkylenyl or alkenylenyl, or is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 30 heteroalkylenyl or heteroalkenylenyl.
  • R 9 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 20 alkylenyl or alkenylenyl, or is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 20 heteroalkylenyl or heteroalkenylenyl.
  • R 9 is a C 1 -C 6 alkylenyl substituted with C 5 -C 20 aryl, C 5 -C 20 arylalkyl, C 5 -C 20 heteroaryl or C 5 -C 20 heteroarylalkyl.
  • R 9 is a C 1 -C 3 alkylenyl substituted with C 10 -C 20 aryl, C 10 -C 20 arylalkyl, C 10 -C 20 heteroaryl or C 10 -C 20 heteroarylalkyl. In some embodiments, R 9 is a C 1 -C 3 alkylenyl substituted with C 10 -C 16 aryl, C 10 -C 16 arylalkyl, C 10 -C 16 heteroaryl or C 10 -C 16 heteroarylalkyl.
  • R 9 is a C 1 alkylenyl substituted with C 10 -C 16 aryl, C 10 -C 16 arylalkyl, C 10 -C 16 heteroaryl or C 10 -C 16 heteroarylalkyl.
  • R 9 is –(CH 2 ) 0-3 CH(R 10 )(CH 2 ) 0-3 –.
  • R 9 is –(CH 2 ) 0-1 CH(R 10 )(CH 2 ) 0-1 –.
  • R 9 is –CH(R 10 )–.
  • R 9 is –CH 2 CH(R 10 )–.
  • R 9 is –CH(R 10 )CH 2 –. In some embodiments, R 9 is –CH(R 10 )–. [00207] In some embodiments of the compounds of the invention, R 9 is -(C 1 -C 6 alkylenyl)-(C 3 -C 10 cycloalkylenyl)-, -(C 1 -C 6 alkylenyl)-(C 3 -C 10 cycloalkylenyl)-(C 1 -C 6 alkylenyl)-, -(C 1 -C 6 alkylenyl)-(C 6 -C 12 arylene)-, or -(C 1 -C 6 alkylenyl)-(C 6 -C 12 arylene)-(C 1 -C 6 alkylenyl)-.
  • R 9 is -(C 1 -C 3 alkylenyl)-(C 3 -C 10 cycloalkylenyl)-, -(C 1 -C 3 alkylenyl)-(C 3 -C 10 cycloalkylenyl)-(C 1 -C 3 alkylenyl)-, -(C 1 -C 3 alkylenyl)-(C 6 -C 12 arylene)-, or -(C 1 -C 3 alkylenyl)-(C 6 -C 12 arylene)-(C 1 -C 3 alkylenyl)-.
  • R 9 is -(C 1 -C 3 alkylenyl)-(C 3 -C 10 cycloalkylenyl)- or -(C 1 -C 3 alkylenyl)-(C 6 -C 12 arylene)-. In some embodiments, R 9 is -(C 1 -C 3 alkylenyl)-(C 3 -C 10 cycloalkylenyl)-. [00208] In some embodiments of the compounds of the invention, R 9 is . In some emb 9 odiments, R is or .
  • At least one R 9 is R 24 -R 25 -R 26 , wherein R 24 -R 25 -R 26 are independently selected from: –(CH 2 ) 0-3 –; C 3 -C 8 cycloalkylene in which 0-3 carbons are replaced with N, S or O heteroatoms, and optionally substituted with one or more OH, NH 2 , NO 2 , halogen, C 1 -C 6 alkyl and/or C 1 -C 6 alkoxyl groups; and C 4 -C 16 arylene in which 0-3 carbons are replaced with N, S or O heteroatoms, and optionally substituted with one or more OH, NH 2 , NO 2 , halogen, C 1 -C 6 alkyl and/or C 1 -C 6 alkoxyl groups.
  • (Xaa 1 ) 1-4 is (Xaa 1 ) 0-3 NHR 27 C(O), wherein R 27 is , or .
  • at least one R 9 is In some embodiments, at least one R 9 is .
  • at least one R 9 is In some embodiments, at least one R 8 is hydrogen. In some embodiments, all R 8 are hydrogen.
  • at least one Xaa 1 is a tranexamic acid residue.
  • (Xaa 1 ) 1-4 consists of a single tranexamic acid residue.
  • at least one R 9 or R 5 is In some embodiments, at least one R 9 or R 5 is .
  • R 5 is [00211] In some embodiments, R 5 is In some embodiments, R 5 is . In some embodiments, R 5 is . [00212] In some embodiments, R 3 is –(CH 2 ) 4 – and –(Xaa 1 ) m N(R 6 )R 5 R 4 – is . In some embodiments, R 10 is .
  • R 3 is –CH 2 -CH 2 -O-CH 2 – and –(Xaa 1 ) m N(R 6 )R 5 R 4 – is
  • R 10 is [00214]
  • R 7 may include a radiolabeling group optionally spaced apart using an amino acid or peptide linker and a nitriloacetic acid or derivative thereof.
  • R 7 is [00216]
  • Xaa 2 is –N(R 13 )R 14 C(O)–.
  • n is 1.
  • n is 2 and each Xaa 2 may be the same or different. In some embodiments, n is 3 and each Xaa 2 may be the same, different or a combination thereof. In some embodiments, n is 4 and each Xaa 2 may be the same, different or a combination thereof. In some embodiments, each Xaa 2 is independently selected from proteinogenic amino acids and the non-proteinogenic amino acids listed in Table 1, wherein each peptide backbone amino group is optionally methylated. [00218] In some embodiments of the compounds of the invention, each R 13 is independently hydrogen or methyl. In some embodiments, at least one R 13 is methyl.
  • each R 14 is independently: a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C1-C15 alkylenyl, alkenylenyl or alkynylenyl; or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 15 heteroalkylenyl, heteroalkenylenyl or heteroalkynylenyl; wherein each R 14 is optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, or an amide; each R 14 is optionally substituted with one R x ; and at least one R 14 is substituted with one R X.
  • each R 14 is independently: a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 10 alkylenyl, alkenylenyl or alkynylenyl; or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 10 heteroalkylenyl, heteroalkenylenyl or heteroalkynylenyl; wherein each R 14 is optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, or an amide; each R 14 is optionally substituted with one R x ; and at least one R 14 is substituted with one R X.
  • each R 14 is independently: a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 6 alkylenyl, alkenylenyl or alkynylenyl; or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 6 heteroalkylenyl, heteroalkenylenyl or heteroalkynylenyl; wherein each R 14 is optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, or an amide; each R 14 is optionally substituted with one R x ; and at least one R 14 is substituted with one R X.
  • each R 14 is independently a linear or branched, acyclic C 1 -C 15 alkylenyl. In some embodiments, each R 14 is independently a linear or branched, acyclic C 1 -C 10 alkylenyl. In some embodiments, each R 14 is independently a linear or branched, acyclic C 1 -C 6 alkylenyl.
  • each R 14 is optionally substituted with one R x and further optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, or any functional group found in an amino acid side chain. In some embodiments of the compounds of the invention, each R 14 is optionally substituted with one R x and further optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, or any functional group found in a natural or non-natural amino acid side chain.
  • each R 14 is optionally substituted with one R x and further optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, an amide, an amine, hydrazine, hydrazide, thiohydrazide, urea, thiourea, guanidine, imidazole, pyrrolidine, or methylthiol.
  • each R 14 is optionally substituted with one R x and further optionally substituted with a carboxylic acid, a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, or an amide.
  • a carboxylic acid a sulfonic acid, a sulfinic acid, a phosphoric acid, a hydroxyl, or an amide.
  • –N(R 13 )R 14 C(O)– is an amino acid residue.
  • –N(R 13 )R 14 C(O)– is a natural amino acid residue or a non-natural amino acid residue.
  • each Xaa 2 is independently selected from: O I n some embodiments, each Xaa 2 is independently selected from: , or [00224] In some embodiments of the compounds of the invention, n is 1 and Xaa 2 is O 2 . In some embodiments, n is 1 and Xaa is In some embodiments, n is 2 and each Xaa 2 is independently selected from: , , or .
  • n is 3 and each Xaa 2 is independently selected from: [00225] In some embodiments of the compounds of the invention, R 7 is O [00226] In some embodiments of the compounds of the invention, R X i –(C(O)) p –(CH 2 ) q -(radiolabeling group), or –(N(R)C(O)) p –(CH 2 ) q -(radiolabeling group), wherein the radiolabeling group is independently selected from: an aryl or heteroaryl substituted with a radioisotope or a prosthetic group comprising a trifluoroborate, wherein r is 0 or 1; and wherein m1, m2, m3 and m4 are each independently 1, 2, 3, or 4.
  • R X can form bonds to the N-terminus of the N-terminal Xaa 2 or an amino acid group of Xaa 2 capable of forming an amide bond (e.g., a side chain of an alpha amino acid).
  • An example of a Xaa 2 sidechain capable of forming an amide bond with R X is an amino group.
  • Non-limiting examples of amino acid residues capable of forming an amide with R X include Lys, Orn, Dab, Dap, Arg, homo-Arg, and the like.
  • R X forms a bond to the N-terminus of the N-terminal Xaa 2 .
  • R X may bond to different Xaa 2 side chains or other functional groups.
  • at least one R X is , wherein r is 0 or 1; and wherein m1, m2, and m3 are each independently 1, 2, 3, or 4.
  • O H [00229]
  • at least one R X is , wherein m4 is 1, 2, 3, or 4.
  • at least one R X is , wherein r is 0 or 1; and wherein m1, m2, and m3 are each independently 1, 2, 3, or 4.
  • at least one R X is , wherein m4 is 1, 2, 3, or 4.
  • the radioisotope is a radiohalogen.
  • the term “radiohalogen” refers to a radioactive isotope of a halogen.
  • the term “radiohalogen” includes radioactive isotopes of F, Cl, Br, and I, such as 18 fluorine, 76 bromine, 123 iodine, 124 iodine, and 131 iodine.
  • a radiohalogen is 18 fluorine, 123 iodine, or 124 iodine.
  • one or more R X may comprise an aryl group substituted with a radioisotope.
  • one or more R X is , wherein A, B, C, D and E are independently CH or N, and R 15 is a radioisotope.
  • one or more R X may comprise an aryl group substituted with a radioisotope.
  • one or more R X is wherein A, B, C, D and E are independently CH or N, and R 15 is a radioisotope.
  • one or more R X is .
  • one or more R X is .
  • one or more R X is .
  • one or X more R R is .
  • one or X more R R is .
  • one or more R X is .
  • one or X more R R is In some embodiments, one or more R X is .
  • one or more R X is . In some embodiments, one or more R X is . In some embodiments, one or more R X is In 1 5 ently 2 some of these embodiments, R is independ 11 At, 131 I, 124 I, 123 I, 77 Br or 18 F. In some of these embodiments, R 15 is a radioisotope. In some of these embodiments, R 15 is 18 F. [00235] In some embodiments, one or more R X may comprise an aryl group substituted C with a radioisotope. In some embodiments, one or more R X is R , wherein A, B, C, D and E are independently CH or N, and R 15 is a radioisotope.
  • one or more R X is In some embodiments, one or more R X is . In some embodiments, one or more R X is . In some embodiments, one or more R X is In some embodiments, one or more R X is In some embodiments, one or more R X is In some embodiments, one or more R R X is . In some embodiments, one or more R X is In some embodiments, one or more R X is In some embodiments, R 15 is independently 211 At, 131 I, 124 I, 123 I, 77 Br or 18 F. In some of these embodiments, R 15 is a radioisotope. In some of these embodiments, R 15 is 18 F.
  • one or more R X may comprise a prosthetic group containing a trifluoroborate (BF 3 ), capable of 18 F/ 19 F exchange radiolabeling.
  • one or more R X is –(N(R)C(O)) p –(CH 2 ) q -(R 16 R 17 BF 3 ); each R 16 is independently absent, or .
  • R X is –(N(R) 16 17 16 C(O)) p –(CH 2 ) q -(R R BF 3 ); each R is independently absent, ; each R 17 BF 3 is independently selected from Table 2 (below), Table 3 (below), or and R 19 and R 20 are independently C 1 -C 5 linear or branched alkyl.
  • R in the pyridine substituted with –OR, –SR, –NR–, –NHR or –NR 2 groups is C 1 -C 5 branched or linear alkyl.
  • one or more –R 17 BF 3 is independently selected from one or a combination of those listed in Table 2.
  • one or more –R 17 BF 3 is independently selected from one or a combination of those listed in Table 3.
  • one fluorine is 18 F. In some embodiments, all three fluorines are 19 F.
  • one or more R X is each R 16 is independently absent, or [00239] TABLE 2: Exemplary R 17 BF 3 groups.
  • R 17 BF 3 may form
  • R in which the R (when present) in the pyridine substituted –OR, –SR, –NR–, –NHR or –NR 2 is a branched or linear C 1 -C 5 alkyl.
  • R is a branched or linear C 1 -C 5 saturated alkyl.
  • R is methyl.
  • R is ethyl.
  • R is propyl.
  • R is isopropyl.
  • R is n-butyl.
  • one fluorine is 18 F. In some embodiments, all three fluorines are 19 F.
  • R 17 BF 3 may form , in which the R (when present) in the pyridine substituted –OR, –SR, –NR– or –NR 2 is branched or linear C 1 -C 5 alkyl. In some embodiments, R is a branched or linear C 1 -C 5 saturated alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is is isopropyl. In some embodiments, R is n-butyl. In some embodiments, one or more –R 17 BF 3 is In some embodiments, one fluorine is 18 F.
  • all three fluorines are 19 F.
  • one or more –R 17 BF3 is In some embodiments, R 19 is methyl. In some embodiments, R 19 is ethyl. In some embodiments, R 19 is propyl. In some embodiments, R 19 is isopropyl. In some embodiments, R 19 is butyl. In some embodiments, R 19 is n-butyl. In some embodiments, R 19 is pentyl. In some embodiments, R 20 is methyl. In some embodiments, R 20 is ethyl. In some embodiments, R 20 is propyl. In some embodiments, R 20 is is isopropyl. In some embodiments, R 20 is butyl.
  • R 20 is n-butyl. In some embodiments, R 20 is pentyl. In some embodiments, R 19 and R 20 are both methyl. In some embodiments, one fluorine is 18 F. In some embodiments, all three fluorines are 19 F. [00244] In some embodiments, one or more R X may comprise a prosthetic group containing a silicon-fluorine-acceptor moiety. In some embodiments, the fluorine of the silicon-fluorine acceptor moiety is 18 F.
  • the prosthetic groups containing a silicon-fluorine-acceptor moiety may be independently selected from one or a combination of the following: wherein R 21 and R 22 are independently a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1-C10 alkyl, alkenyl or alkynyl group. In some embodiments, R 21 and R 22 are independently selected from the group consisting of phenyl, tert-butyl, sec-propyl or methyl.
  • the prosthetic group i some embodiments, the prosthetic group i some embodiments, the prosthetic group is In some embodiments, the prosthetic group is [00245] In some embodiments, one or more R X comprise a prosthetic group containing a fluorophosphate. In some embodiments, one or more R X comprise a prosthetic group containing a fluorosulfate. In some embodiments, one or more R X comprise a prosthetic group containing a sulfonylfluoride. Such prosthetic groups are well known and are commercially available, and are facile to attach (e.g., via an amide linkage).
  • the fluorine atom in the fluorophosphate, fluorosulfate or sulfonylfuloride is 18 F. In some embodiments, the fluorine atom in the fluorophosphate, fluorosulfate or sulfonylfuloride is 19 F. [00246] In some embodiments of the compounds of Formula I, II, or III, the compound is selected from the group consisting of:
  • the compound is:
  • the present disclosure also relates to the compounds selected from the group consisting of: KL01007-pyridine-BF 3 ; KL01040;
  • the compound is radiolabeled with 18 F.
  • Methods of Use [00249]
  • the radiolabeling group comprises or is conjugated to a diagnostic radioisotope
  • the radiolabeling group comprises or is conjugated to a diagnostic radioisotope
  • the method comprises: administering to the subject a composition comprising certain embodiments of compounds of Formula I, II, or III or salt or solvate thereof and a pharmaceutically acceptable excipient; and imaging tissue of the subject, e.g., using PET or SPECT.
  • PSMA-targeted treatment may then be selected for treating the subject.
  • PSMA expression has been detected in various cancers (e.g., Rowe et al., 2015, Annals of Nuclear Medicine 29:877-882; Sathekge et al., 2015, Eur J Nucl Med Mol Imaging 42:1482–1483; Verburg et al., 2015, Eur J Nucl Med Mol Imaging 42:1622–1623; and Pyka et al., J Nucl Med November 19, 2015 jnumed.115.164442).
  • the PSMA-expressing cancer may be prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neuroendocrine tumor, ovarian cancer or sarcoma.
  • the cancer is prostate cancer.
  • Solid-phase peptide synthesis methods and technology are well-established in the art. For example, peptides may be synthesized by sequential incorporation of the amino acid residues of interest one at a time. In such methods, peptide synthesis is typically initiated by attaching the C-terminal amino acid of the peptide of interest to a suitable resin.
  • reactive side chain and alpha amino groups of the amino acids are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with a functional group such as an amine group, a hydroxyl group, or an alkyl halide group on the solid support.
  • a functional group such as an amine group, a hydroxyl group, or an alkyl halide group on the solid support.
  • the protecting group on the side chain and/or the alpha amino group of the amino acid is selectively removed, allowing the coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point the peptide can be cleaved from the support and purified.
  • Fmoc protecting groups may be removed from the amino acid on the solid support, e.g., under mild basic conditions, such as piperidine (20-50% v/v) in DMF.
  • the amino acid to be added must also have been activated for coupling (e.g., at the alpha carboxylate).
  • Non-limiting examples of activating reagents include without limitation 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP).
  • HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluor
  • Racemization is minimized by using triazoles, such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling may be performed in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA/DIEA) and the like. For long peptides or if desired, peptide synthesis and ligation may be used.
  • a suitable base such as N,N-diisopropylethylamine (DIPEA/DIEA) and the like.
  • peptides may be elongated in a branched fashion by attaching to side chain functional groups (e.g., carboxylic acid groups or amino groups), either: side chain to side chain; or side chain to backbone amino or carboxylate. Coupling to amino acid side chains may be performed by any known method, and may be performed on-resin or off-resin. Non-limiting examples include: forming an amide between an amino acid side chain containing a carboxyl group (e.g. Asp, D-Asp, Glu, D-Glu, and the like) and an amino acid side chain containing an amino group (e.g.
  • Lys(N 3 ), D-Lys(N 3 ), and the like) and an alkyne group e.g. Pra, D-Pra, and the like.
  • the protecting groups on the appropriate functional groups must be selectively removed before amide bond formation, whereas the reaction between an alkyne and an azido groups via the click reaction to form an 1,2,3-triazole does not require selective deprotection.
  • selectively removable protecting groups include 2-phenylisopropyl esters (O-2-PhiPr) (e.g.
  • O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mild acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM.
  • mild acidic conditions such as 2.5% trifluoroacetic acid (TFA) in DCM.
  • Alloc protecting groups can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenyl silane in DCM.
  • Dde and ivDde protecting groups can be selectively deprotected using 2-5% of hydrazine in DMF.
  • Deprotected side chains of Asp/Glu (L- or D-forms) and Lys/Orn/Dab/Dap (L- or D-forms) can then be coupled, e.g., by using the coupling reaction conditions described above.
  • Peptide backbone amides may be N-methylated (i.e., alpha amino methylated).
  • N-methylation under Mitsunobu conditions may be performed.
  • Ns-Cl 4-nitrobenzenesulfonyl chloride
  • TMD diisopropyl azodicarboxylate
  • N-deprotection may be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • HATU For coupling protected amino acids to N-methylated alpha amino groups, HATU, HOAt and DIEA may be used.
  • the PSMA-binding moiety e.g., Lys-ureido-Aad, and the like
  • the PSMA-binding moiety may be constructed on solid phase via the formation of a ureido linkage between the amino groups of two amino acids.
  • Fmoc-protecting amino acid for example Fmoc-Lys(ivDde)-OH
  • Wang resin using standard activation/coupling strategy (for example, Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and N,N-diisopropylethylamine (7 eq.) in N,N-dimethylformamide).
  • Fmoc-protecting group is then removed by 20% piperidine in N,N-dimethylformamide.
  • the activation and conversion of an amino group to an isocyanate group can be achieved by reacting the amino group with phosgene or triphosgene.
  • the side chain functional group of the amino acid for example ivDde on Lys
  • the linker, albumin-binding motif, and/or radiolabeling group e.g., radiometal chelator and the like
  • the linker, albumin-binding motif, and/or radiolabeling group e.g., radiometal chelator and the like
  • the formation of the thioether (-S-) and ether (-O-) linkages (e.g., for R 4 ) can be achieved either on solid phase or in solution phase.
  • thioether (-S-) linkage can be achieved by coupling between a thiol-containing compound (such as the thiol group on cysteine side chain) and an alkyl halide (such as 3-(Fmoc-amino)propyl bromide and the like) in an appropriate solvent (such as N,N-dimethylformamide and the like) in the presence of base (such as NN-diisopropylethylamine and the like)
  • an ether (-O-) linkage can be achieved via the Mitsunobu reaction between an alcohol (such as the hydroxyl group on the side chain of serine or threonine, for example) and a phenol group (such as the side chain of tyrosine, for example) in the presence of triphenylphosphine and diisopropyl azidicarboxylate (DIAD) in an aprotic solvent (such as 1,4-dioxane and the like).
  • the reactants used are preferably in equivalent molar ratio (1 to 1), and the desired products can be purified by flash column chromatography or high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • the reactions are carried out on solid phase, meaning one reactant has been attached to a solid phase, then the other reactant is normally used in excess amount ( ⁇ 3 equivalents of the reactant attached to the solid phase).
  • the excess unreacted reactant and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents, such as N,N-dimethylformamide, methanol and dichloromethane, for example.
  • Non-peptide moieties e.g., radiolabeling groups, albumin-binding groups and/or linkers
  • a bifunctional chelator such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) may be activated in the presence of N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) for coupling to a peptide.
  • NDS N-hydroxysuccinimide
  • DCC N,N'-dicyclohexylcarbodiimide
  • a non-peptide moiety may be incorporated into the compound via a copper-catalyzed click reaction under either liquid or solid phase conditions. Copper-catalyzed click reactions are well established in the art.
  • 2-azidoacetic acid is first activated by NHS and DCC and coupled to a peptide. Then, an alkyne-containing non-peptide moiety may be clicked to the azide-containing peptide in the presence of Cu 2+ and sodium ascorbate in water and organic solvent, such as acetonitrile (ACN) and DMF and the like.
  • ACN acetonitrile
  • radiometal chelators are well-known and many chelators are commercially available (e.g., from Sigma-Aldrich TM /Milipore Sigma TM and others). Protocols for conjugation of radiometals to the chelators are also well known (e.g., see Example 1, below).
  • the synthesis of the silicon-fluorine-acceptor moieties can be achieved following previously reported procedures (e.g., Bernard-Gauthier et al. Biomed Res Int. 2014 2014:454503; Kostikov et al. Nature Protocols 20127:1956–1963; Kostikov et al. Bioconjug Chem.201218:23:106-114; each of which is incorporated by reference in its entirety).
  • the synthesis or acquisition of radioisotope-substituted aryl groups is likewise facile.
  • the synthesis of the R 16 R 17 BF 3 component on the PSMA-targeting compounds can be achieved following previously reported procedures (Liu et al.
  • the BF 3 -containing motif can be coupled to the linker via click chemistry by forming a 1,2,3-triazole ring between a BF 3 -containg azido (or alkynyl) group and an alkynyl (or azido) group on the linker, or by forming an amide linkage between a BF 3 -containg carboxylate and an amino group on the linker.
  • a boronic acid ester-containing azide, alkyne or carboxylate is first prepared following by the conversion of the boronic acid ester to BF 3 in a mixture of HCl, DMF and KHF 2 .
  • the boronic acid ester-containing azide, alkyne or carboxylate can be prepared by coupling boronic acid ester-containing alkyl halide (such as iodomethylboronic acid pinacol ester) with an amine-containing azide, alkyne or carboxylate (such as N, N-dimethylpropargylamine).
  • boronic acid ester-containing alkyl halide such as iodomethylboronic acid pinacol ester
  • an amine-containing azide, alkyne or carboxylate such as N, N-dimethylpropargylamine.
  • the boronic acid ester can be prepared via Suzuki coupling using aryl halide (iodine or bromide) and bis(pinacolato)diboron.
  • the desired product can be purified by solid phase extraction or by reversed high performance liquid chromatography (HPLC) using a mixture of water and acetonitrile as the mobile phase.
  • HPLC high performance liquid chromatography
  • the desired peptide may be cleaved from the solid support using suitable reagents, such as TFA, tri-isopropylsilane (TIS) and water.
  • EXAMPLE 1 Synthesis of KL01007-pyridine-BF 3 , KL01040, KL01060, KL01074 KL01090 KL01108 KL01120 and KL01130 [00265]
  • General methods [00266] PSMA-targeting ligands were synthesized on solid phase synthesis via either AAPPTec (Louisville, KY) Endeavor 90 Peptide Synthesizer or CEM Corporation (Matthews, NC) Liberty Blue Automated Microwave Peptide Synthesizer starting with commercially obtained resins via standard Fmoc chemistry.
  • HPLC columns used were a semi-preparative column (Luna C18, 5 ⁇ m particle size, 100 ⁇ pore size, 250 x 10 mm) and an analytical column (Luna C18, 5 ⁇ m particle size, 100 ⁇ pore size, 250 x 4.6 mm) from Phenomenex (Torrance, CA) to collected desired peaks and to verify purity, respectively. Collected peaks with the desired product were then lyophilized using Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze drier. Identity of PSMA-targeting ligands was verified with mass via AB SCIEX (Framingham, MA) 4000 QTRAP mass spectrometer system with an ESI ion source.
  • Fmoc deprotection Following Fmoc deprotection, the following sequences were added: Fmoc-tranexamic acid and followed by Fmoc-Lys(ivDde). Then the Fmoc from the Lys residue is first deprotected to add N,N-bis[2-(tert-butoxy)-2-oxoethyl]glycine and then ivDde deprotection to add an activated azidoacetic acid. The peptides were then cleaved and deprotected by 95% TFA and 5% TIS for 2 hr at room temperature. Resin was filtered and the peptide precipitated via addition to cold diethyl ether.
  • the radiolabeling precursor and non-radioactive standard of KL01040 were then generated by coupling N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid respectively.
  • Non-radioactive KL01040 standard prepared by adding 6-fluoronicotinic acid was completed via microwave method at 75°C for 10 min.
  • the radiolabeling precursor was formed via room temperature coupling by dissolving 3 equivalents of N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride in 2 mL of DMF and 3 equivalents of triethylamine (TEA) and then conducting coupling for 2 hr. Both compounds were purified with HPLC semi-preparative column: 42% MeCN and 0.1% formic acid in water with retention around 9 min for the non-radioactive KL01040 standard; 29% MeCN and 0.1% formic acid in water with retention around 8.6 min for the radiolabeling precursor.
  • urea bond to Aad was synthesized via solid-phase peptide chemistry starting with 1 equivalent of Fmoc-Oxalysine(Alloc)-2-chlorotrityl resin. After swelling in N,N-dimethylformamide (DMF), Fmoc was removed from resin via the treatment of 20% piperidine in DMF. The isocyanate of 2-aminoadipyl component was generated by combining 3-4 equivalents L-2-aminoadipic acid di-tertbutyl ester in dichloromethane and diisopropylethylamine (DIPEA) in dry ice/acetone bath.
  • DIPEA diisopropylethylamine
  • Fmoc-L-9-anthrylalanine (5 equivalents) was coupled to resin with 5 equivalents of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and 10 equivalents of DIPEA under microwave for 10 min at 75°C. Following Fmoc deprotection, the following sequences were added: Fmoc-tranexamic acid and followed by Fmoc-Lys(ivDde). Then the Fmoc from the Lys residue is first deprotected to add N,N-bis[2-(tert-butoxy)-2-oxoethyl]glycine.
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • ivDde is then deprotected and the radiolabeling precursor and non-radioactive standard of KL01060 were then generated by coupling N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid, respectively, according to previous methods.
  • the precursor was purified with HPLC semi-preparative column: 28% MeCN and 0.1% formic acid in water with retention around 10.6 min. The final yield was 13% for the radiolabeling precursor.
  • the calculated ESI-MS for the radiolabeling precursor [M+H] + was 1186.6; found 1186.1.
  • the resin then underwent ivDde deprotection, followed by addition of the following sequence Fmoc-L-9-anthrylalanine (5 equivalents), Fmoc-tranexamic acid, Fmoc-Gly, Fmoc-L-cysteic acid, and Fmoc-Lys(ivDde). Then the Fmoc from the Lys residue is first deprotected to add N,N-bis[2-(tert-butoxy)-2-oxoethyl]glycine.
  • ivDde is then deprotected and the radiolabeling precursor and non-radioactive standard of KL01090 were then generated via coupling N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid, respectively, according to previous methods.
  • Precursor was purified with QC column: 27% MeCN and 0.1% formic acid in water with retention around 8 min for the radiolabeling precursor. The final yield was 30% for the radiolabeling precursor.
  • the calculated ESI-MS for the nonradioactive KL01090 standard [M+2H] 2+ was 676.8; found 675.4.
  • the Fmoc from the Dab residue is first deprotected to add N,N-bis[2-(tert-butoxy)-2-oxoethyl]glycine.
  • ivDde is then deprotected and the radiolabeling precursor and non-radioactive standard of KL01108 were then generated via coupling N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid, respectively, according to previous methods.
  • the non-radioactive standard is purified via QC column at 31% MeCN and 0.1% formic acid in water with retention around 10 min.
  • the radiolabeling precursor was purified via HPLC semi-preparative column 30% MeCN and 0.1% formic acid in water with retention around 7 min. The final yields were 10% and 32% for the non-radioactive KL01108 standard and radiolabeling precursor, respectively.
  • the calculated ESI-MS for the non-radioactive KL01108 standard [M+H] + was 1102.4; found 1102.5.
  • the calculated ESI-MS for the radiolabeling precursor [M+H] + was 1142.5; found 1142.3.
  • ivDde is then deprotected and the radiolabeling precursor and non-radioactive standard of KL01120 were then generated via coupling of N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid, respectively, according to previous methods.
  • the non-radioactive KL01120 standard was purified with HPLC semi-preparative column: 30% MeCN and 0.1% formic acid in water with retention around 7 min.
  • the radiolabeling precursor was purified on QC column with 25% MeCN and 0.1% formic acid in water with retention around 11.6 min.
  • the final yields were 36% and 22% for the non-radioactive KL01040 standard and radiolabeling precursor, respectively.
  • the calculated ESI-MS for the non-radioactive KL01120 standard [M+H] + was 1144.5; found 1144.5.
  • the calculated ESI-MS for the radiolabeling precursor [M+H] + was 1184.5; found 1184.6.
  • the isocyanate of 2-aminoadipyl component was generated by combining 3-4 equivalents L-2-aminoadipic acid di-tertbutyl ester in dichloromethane and diisopropylethylamine (DIPEA) in dry ice/acetone bath.
  • DIPEA diisopropylethylamine
  • Triphosgene (3 equivalents) dissolved in dichloromethane (DCM) was added dropwise to the reaction and then warmed to room temperature and stirred for 30 min to generate the isocyanate of 2-aminoadipyl component for addition to resin.
  • the activated Aad was then added to the resin and reacted for 24 hr to form urea linkage.
  • the ivDde-protection group was removed with 5% hydrazine in DMF, followed by addition of the following sequence Fmoc-L-9-anthrylalanine (5 equivalents), Fmoc-tranexamic acid, and Fmoc-Lys(ivDde). Then the Fmoc from the Lys residue is first deprotected to add Fmoc-Gly and then 4-[bis[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]-4-oxobutanoic acid.
  • ivDde is then deprotected and the radiolabeling precursor and non-radioactive standard of KL01130 were then generated via coupling of N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)-carbonyl-pyridine-2-aminiumchloride and 6-fluoronicotinic acid, respectively, according to previous methods.
  • the non-radioactive KL01130 standard was purified with HPLC semi-preparative column: 40% MeCN and 0.1% formic acid in water with retention around 8.8 min.
  • the radiolabeling precursor was purified on HPLC sem-preparative column with 27% MeCN and 0.1% formic acid in water with retention around 9.6 min.
  • the final yields were 23% and 38% for the non-radioactive KL01130 standard and radiolabeling precursor, respectively.
  • the calculated ESI-MS for the non-radioactive KL01120 standard [M+2H] 2+ was 601.3; found 601.6.
  • the calculated ESI-MS for the radiolabeling precursor [M+2H] 2+ was 621.3; found 621.3.
  • the radiolabeling precursor of KL01040 (2 mg) in 0.4 mL anhydrous DMF was added, and the mixture was incubated at 70 o C for 15 min. The reaction mixture was quenched with 1 mL water and then purified with HPLC (C18 semi-prep column, 4.5 mL/min, 35% MeCN and 0.1% formic acid in water, retention time 14.1 min). Decay corrected radiochemical yield: 25%.
  • EXAMPLE 2 Biodistribution and PET/CT Imaging Studies in Tumor-Bearing Mice [00292] All imaging and biodistribution studies used male NOD-scid IL2Rg null (NSG) mice and conducted according to the guidelines established by the Canadian Council on Animal Care and approved by Animal Ethics Committee of the University of British Columbia.
  • mice were anesthetized via inhalation of 2% isoflurane in oxygen and implanted subcutaneously with 5 ⁇ 10 6 LNCaP cells below the left shoulder. Imaging and biodistribution studies were performed only after tumors grew to 5 ⁇ 8 mm in diameter.
  • approximately 5 MBq of the 18 F-labeled tracer was injected through the tail vein. While for ex vivo biodistribution studies, mice were injected with around 2 MBq of the 18 F-labeled tracer through the tail vein. Mice were allowed to recover and roam freely in the cages after injecting the tracer. At 45 min post-injection, imaging mouse were sedated again and positioned on the scanner.
  • a 10 min CT scan was conducted first to allow for localization and attenuation correction for later reconstruction of PET images.
  • a 10 min PET image was acquired following CT scan. Heating pads were used during the entire procedure to keep the mice warm and circulate the blood.
  • All mice for biodistribution study were euthanized with blood drawn from heart and all tissues of interest were collected, rinsed with PBS, blotted dry, weighed, and counted using an automated gamma counter. The uptake in each organ/tissue was normalized to the injected dose and expressed as the percentage of the injected dose per gram of tissue (%ID/g).
  • Representative maximum intensity projection PET images of 18 F-KL01007-pyridine-BF 3 and 18 F-KL01040 acquired at 1 h post-injection from LNCaP tumor-bearing mice is enumerated in Table 4 and shown in FIG.1.
  • Representative maximum intensity projection PET images of 18 F-KL01120 and 18 F-KL01130 acquired at 1 h post-injection from LNCaP tumor-bearing mice is also enumerated in Table 5 and shown in FIG.2 ( 18 F-KL01120) and enumerated in Table 6 and shown in FIG.3 ( 18 F-KL01130).
  • TABLE 4 Biodistribution (at 1 h post-injection) of 18 F-KL01007-pyridine-BF 3 and 18 F-KL01040 in mice bearing LNCaP tumor xenografts. Data are presented as mean ⁇ SD %ID/g.
  • TABLE 5 Biodistribution and tumor-to-background uptake ratios of 18 F-KL01120 in LNCaP tumor-bearing mice. Data are presented as mean ⁇ SD %ID/g.
  • TABLE 6 Biodistribution and tumor-to-background uptake ratios of 18 F-KL01130 in LNCaP tumor-bearing mice. Data are presented as mean ⁇ SD %ID/g.

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Optics & Photonics (AREA)
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Abstract

La présente invention concerne des composés ciblant l'antigène membranaire spécifique de la prostate (PSMA) représentés par la formule (I) ou un sel ou un solvate de ceux-ci. Les composés ciblant le PSMA selon la présente invention peuvent être utiles comme agents d'imagerie pour des maladies/états pathologiques exprimant le PSMA.
PCT/CA2023/050959 2022-07-18 2023-07-17 Composés radiomarqués ciblant l'antigène membranaire spécifique de la prostate WO2024016071A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020252598A1 (fr) * 2019-06-21 2020-12-24 Provincial Health Services Authority Composés radiomarqués ciblant l'antigène membranaire spécifique de la prostate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020252598A1 (fr) * 2019-06-21 2020-12-24 Provincial Health Services Authority Composés radiomarqués ciblant l'antigène membranaire spécifique de la prostate

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry CAS; 23 February 2010 (2010-02-23), ANONYMOUS : "L-Glutamic acid, N-[[[(1S)-1-car boxy-5-[[[6-(fluoro-18F)-3- pyridinyl]carbonyl]amino]p entyl]amino]carbonyl]-", XP093132222, retrieved from STN Database accession no. 1207181-29-0 *
DATABASE Registry CAS; 26 April 2017 (2017-04-26), ANONYMOUS : ".", XP093132225, retrieved from STN Database accession no. 2093321-18-5 *
KUO, HSIOU-TING ET AL.: "177u-Labeled Albumin-Binder Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio", THE JOURNAL OF NUCLEAR MEDICINE, vol. 62, no. 4, 28 August 2020 (2020-08-28), pages 521 - 527, XP093065403, Retrieved from the Internet <URL:https://doi.org/10.2967/jnumed.> DOI: 10.2967/jnumed.120.250738 *
KUO, HSIOU-TING ET AL.: "One-Step 18F-Labeling and Preclinical Evaluation of Prostate- Specific Membrane Antigen Trifluoroborate Probes for Cancer Imaging", THE JOURNAL OF NUCLEAR MEDICINE, vol. 60, no. 8, 8 February 2019 (2019-02-08), pages 1160 - 1166, XP055813073, Retrieved from the Internet <URL:https://doi.org/10.2967/jnumed.118.216598> DOI: 10.2967/jnumed.118.216598 *

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