Radioactive tracers and therapeutic agents that bind to fibroblast activation protein (FAP)

Abstract

The present invention relates to ligand-SIFA conjugates that contain two separate moieties within a single molecule: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), and (b) a silicon fluoride acceptor (SIFA) moiety that contains a covalent bond between a silicon atom and a fluorine atom.

Description

[Technical field]

[0001] The present invention relates to therapeutically and / or diagnostically useful compounds, in particular compounds useful in a variety of therapeutic and / or diagnostic fields related to elevated FAP expression, including the treatment and / or diagnosis of various cancers. Advantageously, the present invention relates to a compound comprising, in a single molecule, (a) one or more ligands capable of binding to fibroblast activation protein (FAP), and (b) a covalent bond between a silicon and a fluorine atom, 18 By F 19 By isotopic exchange of F 18 may be labeled with F or 18 The present invention relates to a ligand-SIFA conjugate (i.e., a compound) that includes a F-labeled silicon fluoride acceptor (SIFA) moiety. [Background technology]

[0002] Fibroblast Activation Protein (FAP) Fibroblast activation protein (FAP) is best known for its increased expression in tumor stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activity, cleaving substrates at post-proline bonds. FAP expression is difficult to detect in non-diseased adult organs, but is significantly upregulated at sites of tissue remodeling, including liver fibrosis, pulmonary fibrosis, atherosclerosis, arthritis, tumors, and embryonic tissues. FAP is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. FAP expression is found in activated stromal fibroblasts in over 90% of all human cancers. Stromal fibroblasts play a key role in cancer development, growth, and metastasis. Due to its restricted expression pattern and dual enzymatic activity, FAP has emerged as a unique therapeutic target, and several approaches for targeting FAP are currently being tested, primarily in cancer treatment (Rui L. et al., Cancer Biology & Therapy, 2012, 13:3, 123-129).

[0003] 18 F sign 18 F labeling is a well-known radiolabeling technique and has been used, for example, in conjugates targeting prostate-specific membrane antigen (PSMA) for positron emission tomography (PET) imaging. 18 An attractive approach to introduce F-label is the use of fluorinated silicon acceptors (SIFA). Fluorinated silicon acceptors are described, for example, in Lindner et al., Bioconjugate Chemistry 25, 738-749 (2014). To preserve the silicon-fluoride bond, the use of fluorinated silicon acceptors creates the need for sterically bulky groups around the silicon atom. This in turn makes fluorinated silicon acceptors highly hydrophobic. For binding to PSMA, the hydrophobic moiety provided by fluorinated silicon acceptors can be exploited to establish the interaction of radioactive diagnostic or therapeutic compounds with the hydrophobic pocket of PSMA, as described in Zhang et al., Journal of the American Chemical Society 132, 12711-12716 (2010). However, the higher degree of lipophilicity introduced into the molecule prior to conjugation poses serious problems for the development of radiopharmaceuticals with suitable in vivo biodistribution, i.e. low non-specific binding in non-target tissues.

[0004] WO2019 / 020831 and WO2020 / 157184 disclose ligand-SIFA-chelator conjugates. WO2019 / 083990, WO2019 / 154886, WO2018 / 111989, WO2021 / 005131 and WO2021 / 005125 disclose compounds comprising FAP ligands. Summary of the Invention

[0005] There is a need for imaging agents that can identify the presence of diseases associated with elevated FAP expression in human tissues, which may include cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders.

[0006] The present invention seeks to provide FAP-targeted radiodiagnostic and / or radiotherapeutic agents that contain silicon-fluorine containing moieties and are characterized by advantageous in vivo properties.

[0007] Furthermore, the present invention seeks to provide improved radiotherapeutic and / or radiodiagnostic agents for medical indications associated with elevated FAP expression. Furthermore, the present invention seeks to provide combination FAP-targeted and PSMA-targeted radiodiagnostic and / or radiotherapeutic agents that contain silicon-fluorine containing moieties and are characterized by advantageous in vivo properties.

[0008] Furthermore, the present invention seeks to provide improved radiotherapeutic and / or radiodiagnostic agents for medical indications associated with elevated FAP expression and elevated prostate specific membrane antigen (PSMA) expression.

[0009] Summary of the Invention According to a first aspect of the invention, there is provided a method for producing a medicament comprising the steps of: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), and (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, the SIFA being 18 Optionally labeled with F, a SIFA moiety or a pharma- ceutically or diagnostically acceptable salt or solvate thereof, These conjugates, jointly referred to herein as "conjugates of the invention" or "conjugates of some embodiments of the invention," may also optionally include additional moieties.

[0010] Suitably, the conjugates of the invention comprise a single chemical entity that includes both (a) the one or more FAP ligands and (b) the SIFA moiety within a single molecule. Suitably, the SIFA moiety in the conjugate of the invention is 18 It may be optionally radiolabeled with an F label. 18 F radiolabeling can be accomplished by techniques well known to those of skill in the art, for example by isotope-linking the SIFA moiety as disclosed in PCT / EP2020 / 052268. 19 F- 18 The SIFA moiety may be introduced by F exchange. Preferably, the conjugate of the present invention comprises 18 The SIFA moiety is preferably radiolabeled with F. 18 The inclusion of an F radiolabel allows the conjugates of the invention to be used as radioactive diagnostic tracers, for example in PET imaging.

[0011] The term "pharmaceutically or diagnostically acceptable salt or solvate" includes the salts and solvates described herein. In some embodiments, the conjugates of the present invention may further comprise (c) one or more chelating moieties (CM). When present, said one or more chelating moieties (CM) may optionally contain a chelated non-radioactive or radioactive cation. Preferred conjugates of the present invention further comprise said (c) one or more chelating moieties (CM) containing a chelated non-radioactive or radioactive cation as specified herein.

[0012] In some embodiments, the conjugates of the invention may further comprise (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA). Suitably, moieties (a) and (b), and, where present, (c) and (d), each represent separate moieties within a single molecule of the conjugate of the invention.

[0013] Thus, the conjugates of the invention comprise two distinct moieties (a) and (b) within a single molecule, where (a) is one or more ligands capable of binding to a fibroblast activation protein (FAP), and (b) is a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, wherein the SIFA is 18 A ligand-SIFA conjugate, which is a SIFA moiety, optionally labeled with F, comprising within said single molecule: (c) one or more chelating moieties (CM), optionally containing a chelated non-radioactive or radioactive cation; or (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA); or (e) a combination of both (c) said one or more chelating moieties (CM) and (d) said one or more PSMA ligands. or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0014] Thus, the conjugates of the invention include: Within a single molecule, there are two distinct parts: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), and (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, the SIFA being 18 Optionally labeled with F, a SIFA moiety or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0015] Within a single molecule, there are three distinct parts: (a) one or more ligands capable of binding to fibroblast activation protein (FAP); (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, the SIFA being 18 a SIFA moiety, optionally labeled with F; and (c) one or more chelating moieties (CM), optionally containing a chelated non-radioactive or radioactive cation; or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0016] Within a single molecule, there are three distinct parts: (a) one or more ligands capable of binding to fibroblast activation protein (FAP); (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, the SIFA being 18 a SIFA moiety, optionally labeled with F; and (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA). or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0017] Within a single molecule, there are four distinct parts: (a) one or more ligands capable of binding to fibroblast activation protein (FAP); (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, the SIFA being 18 a SIFA moiety, optionally labeled with F; (c) one or more chelating moieties (CM), optionally containing a chelated non-radioactive or radioactive cation; and (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA). or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0018] Suitably, the conjugates of the present invention that contain three or more distinct moieties selected from FAP, SIFA and PSMA as specified herein; FAP, SIFA and CM; and FAP, SIFA, PSMA and CM in a single molecule may each be prepared independently from the conjugates of the present invention that contain two distinct moieties selected from FAP and SIFA as specified herein in a single molecule.Thus, the conjugates of the present invention that contain two distinct moieties selected from FAP and SIFA as specified herein in a single molecule may be considered as intermediates for the synthesis of the conjugates of the present invention that contain three or more distinct moieties selected from FAP, SIFA and PSMA as specified herein; FAP, SIFA and CM; and FAP, SIFA, PSMA and CM in a single molecule.

[0019] Suitably, when a conjugate of the invention comprises two or more FAP ligands, each FAP ligand may be the same or different. Suitably, the FAP ligands in the conjugates of the invention each independently comprise one or more 4-12 membered heterocyclic groups, which contain at least one nitrogen atom and optionally contain one or more additional heteroatoms selected from nitrogen, oxygen or sulfur. Suitably, each of the 4-12 membered heterocyclic groups specified herein represents a ring system which may be fully aromatic, partially aromatic or non-aromatic in nature. Thus, the term "4-12 membered heterocyclic group" which each FAP ligand may comprise includes optionally substituted azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, tetrazolyl, indolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, pyrazinyl, morpholinyl, Included are groups such as pyrimidinyl, purinyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, decahydroisoquinolinyl, quinolzinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, and pteridinyl.

[0020] Suitably, the 4-12 membered heterocyclic groups specified herein that may be included in each FAP ligand may be optionally substituted with one or more optional substituents. Preferred optional substituents include halo, cyano, OH, B(OH), 2 , CO 2 H, C 1~6 Alkyl, -OC 1~6 Alkyl, SC 1~6 Highly preferred optional substituents are selected from halo, especially fluoro, and cyano.

[0021] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more 4-12 membered heterocyclic groups as specified herein, which heterocyclic groups contain one or more nitrogen atoms as the only heteroatoms.

[0022] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more 4-12 membered heterocyclic groups as specified herein, which groups contain at least one nitrogen atom and optionally contain one or more additional nitrogen atoms.

[0023] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more 5-10 membered heterocyclic groups containing at least one nitrogen atom and optionally containing one or more additional nitrogen atoms.

[0024] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more 5- or 10-membered heterocyclic groups as specified herein, which groups contain at least one nitrogen atom and optionally contain one or more additional nitrogen atoms.

[0025] Preferably, said one or more 5- to 10-membered heterocyclic groups, which contain at least one nitrogen atom, and optionally contain one or more further nitrogen atoms, include nitrogen as the only heteroatom.

[0026] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, tetrazolyl, indolyl, pyridazinyl, pyrazinyl, pyrimidinyl, purinyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, decahydroisoquinolinyl, quinoldinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, and pteridinyl.

[0027] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, tetrazolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, decahydroisoquinolinyl, quinoldinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, and pteridinyl.

[0028] Suitably, each FAP ligand in a conjugate of the invention independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, decahydroisoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, and naphthyridinyl.

[0029] Preferably, each FAP ligand in a conjugate of the invention independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyridinyl, in particular optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, quinazolinyl.

[0030] The silicon fluoride acceptor (SIFA) moiety in the conjugates of the invention is typically essentially C 4 ~C 20 The SIFA moiety comprises a hydrocarbyl group substituted with one or more silicon fluoride functional groups, the silicon fluoride functional groups comprising a silicon atom covalently bonded to one or more fluorine atoms. Exemplary SIFA moieties are identified herein.

[0031] Suitably, the SIFA moiety as specified herein is essentially C 4 ~C 20 The hydrocarbyl group is C 6 ~C 10 C containing essentially hydrocarbyl groups, preferably aryl groups 6 ~C 10 essentially hydrocarbyl groups, more preferably C containing a phenyl ring 6 ~C 10 The aryl group essentially contains hydrocarbyl groups.

[0032] Suitably, the SIFA moiety as defined herein is essentially C 4 ~C 20 , especially C 6 ~C 10 Each of the one or more fluorosilicon functional group substituents of the hydrocarbyl moiety is covalently bonded to one or more fluorine atoms and one or more C 3 ~C 10 Preferably, one or more of the silicon fluoride functional group substituents are covalently bonded to a single fluorine atom and have two C 3 ~C 10Preferably, one or more of the silicon fluoride functional group substituents are covalently bonded to a single fluorine atom and have two C 3 ~C 10 Contains a silicon atom covalently bonded to an alkyl group, and these C 3 ~C 10 The alkyl groups can be the same or different.

[0033] Preferred SIFA moieties in the conjugates of the invention include phenyl groups substituted with one or more silicon fluoride functional groups as specified herein, particularly where said phenyl groups are para-substituted with silicon fluoride functional groups as specified herein. Highly preferred SIFA moieties in the conjugates of the invention include phenyl groups covalently bonded to a single fluorine atom and having two C 3 ~C 10 These Cs include phenyl groups para-substituted with silicon fluoride functional groups that contain a silicon atom covalently bonded to an alkyl group. 3 ~C 10 The alkyl groups can be the same or different.

[0034] In some embodiments, the conjugates of the invention may comprise (c) one or more optional chelating moieties (CM). Suitably, when the conjugates of the invention comprise two or more chelating moieties (CM), each CM may be the same or different.

[0035] Exemplary chelating moieties that may be present in the conjugate of the present invention are specified herein.Preferably, when the conjugate of the present invention comprises one or more of the optional chelating moieties (CM), each of the one or more chelating moieties is independently selected from TRAP, DOTA and DOTAGA, in particular DOTA and DOTAGA.

[0036] Suitably, one or more optional chelating moieties (CM) may each independently comprise a radioactive or non-radioactive cation as specified herein, preferably a radioactive metal or non-radioactive metal cation. Preferably, when one or more chelating moieties comprises a radioactive or non-radioactive cation, the cation is selected from Ga, Cu, Lu, Y and Ac cations, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y and 225 In some preferred embodiments, the radioactive or non-radioactive cation is selected from the group consisting of indium, technetium, gallium, gadolinium, copper, lutetium, and rhenium cations. In some preferred embodiments, the radioactive or non-radioactive cation is selected from the group consisting of indium, technetium, gallium, gadolinium, copper, lutetium, and rhenium cations. 111 In, 99m Tc, 64 Cu, 67 Cu, 67 Ga or 68 Ga. In some embodiments, the one or more optional chelating moieties (CM) may include a cation that binds to a radioactive element. In some embodiments, the one or more optional chelating moieties (CM) are 18 In some embodiments, one or more optional chelating moieties (CM) may include a cation that is bonded to F. In some embodiments, one or more optional chelating moieties (CM) may include Al 18 F 3 or Sc 18 F 3 Suitably, the one or more chelating moieties (CM) may comprise a radioactive cation, e.g., for use in diagnostic agents as radiotracers. 68 Ga or 64 Alternatively, one or more of the chelating moieties may be labeled with a therapeutic isotope, e.g. 177 Lu, 90 Y or 225 It may be labeled with Ac.

[0037] For some embodiments of the invention, the conjugate comprises 18F, and for some embodiments of the invention, the conjugate comprises one or more other radioisotopes (e.g., associated with a chelating moiety). 18 It contains both F and one or more other radioisotopes.

[0038] therefore, 18 The conjugates of the invention, comprising a SIFA moiety radiolabeled with F and one or more chelating moieties (CM) containing appropriate radioactive cations, allow the conjugates of the invention to be used as "paired" tracers bridging diagnostic and therapeutic radiopharmaceutical applications.

[0039] In some embodiments, the conjugates of the invention comprise (d) one or more optional PSMA ligands. Suitably, when the conjugates of the invention comprise two or more PSMA ligands, each PSMA ligand may be the same or different.

[0040] Exemplary PSMA ligands that may optionally be present in the conjugates of the invention are identified herein and / or disclosed in WO2019 / 020831, WO2020 / 157177 and WO2020 / 157184.

[0041] Suitably, if present, the one or more optional PSMA ligands (d) are each independently selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 specified herein.

[0042] Suitably, the conjugate of the present invention has the formula I

[0043] [ka]

[0044] or a pharma- ceutically or diagnostically acceptable salt or solvate thereof, (i) each FAP independently represents a ligand capable of binding to a fibroblast activation protein (FAP) identified herein; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a silicon fluoride acceptor (SIFA) moiety containing a covalent bond between a silicon and a fluorine atom as defined herein, wherein the SIFA is 18 represents a SIFA moiety, optionally labeled with F; (iv) each C independently represents a chelating moiety optionally containing a chelated non-radioactive or radioactive cation as specified herein; (v) each PSMA independently represents a ligand capable of binding to prostate-specific membrane antigen (PSMA) as identified herein; a is an integer from 1 to 3, b is an integer from 0 to 2, and c is an integer from 0 to 2.

[0045] Suitably, each FAP ligand in a compound of formula (I) may be the same or different, preferably each FAP ligand is the same. Suitably, when present, each C M in a compound of formula (I) may be the same or different, preferably each C M is the same.

[0046] Suitably, if present, each PSMA ligand in a compound of formula (I) may be the same or different, preferably each PSMA ligand is the same. Suitably, the optionally substituted linker group L in the conjugates of formula (I) and formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG) specified herein below represents a polyvalent organic linker group capable of forming separate covalent bonds with (a) each of said one or more FAP ligands, (b) said silicon fluoride acceptor (SIFA), (c) if present, each of said one or more optional chelating moieties (CM), and (d) if present, each of said one or more optional PSMA ligands (d). Suitably, each of said one or more FAP ligands, said SIFA, if present, said one or more optional CM, and if present, said one or more optional PSMA ligands are each independently covalently bonded to L.

[0047] Suitably, each of said one or more FAP ligands, said SIFA, if present, said one or more optional CMs, and if present, said one or more optional PSMA ligands may each independently be covalently attached to a common atom of the linker group L (i.e. at the same position). Suitably, each of said one or more FAP ligands, said SIFA, if present, said one or more optional CMs, and if present, said one or more optional PSMA ligands may each independently be covalently attached to one or more different atoms (i.e. at one or more different positions) of the linker group L. Preferably, each of said one or more FAP ligands, said SIFA, if present, said one or more optional CMs, and if present, said one or more optional PSMA ligands are each independently covalently attached to one or more different positions of the linker group L.

[0048] Suitably, L in the conjugates of formula (I), and formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG) specified herein below, represents an optionally substituted polyvalent linking group comprising a structure selected from oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide, oligo(thioester-amide), oligo(urea-amide), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioetherurea), oligo(ester-thioester), oligo(ester-urea), oligo(thioester-urea).

[0049] Preferably, L in the conjugates of formula (I), and formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG) specified herein below, represents an optionally substituted polyvalent linking group having a structure selected from oligoamide and oligo(ester-amide).

[0050] Preferably, the optional substituents of the polyvalent linking group are -OH, -OCH 3 , -COOH, -COOCH 3 , -NH 2 , and -NHC(NH)NH 2 may be selected from: The term "oligo" as used in oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea) should be understood to refer to a group preferably having from 2 to 20, more preferably from 2 to 10, subunits linked by bonds of the type specified in the term. As will be understood by one of ordinary skill in the art, when two different types of bonds are shown in parentheses, both types of bonds are contained in the associated group (e.g., "oligo(ester-amide)" contains ester and amide bonds).

[0051] The linker group preferably has a structure selected from optionally substituted oligoamide and oligo(ester-amide) and contains in its backbone a total of 1 to 5, more preferably a total of 1 to 3, and most preferably a total of 1 or 2 amide and / or ester bonds, preferably amide bonds.

[0052] Thus, the term oligoamide refers to a CH group interrupted by groups selected from NHCO or CONH. 2 or a moiety having a chain of CHR groups. Each occurrence of the R moiety can be, for example, -OH, -OCH 3 , -COOH, -COOCH 3 , -NH 2 , and -NHC(NH)NH 2 is an optional substituent selected from:

[0053] Suitably, the (a) one or more FAP ligands, the (b) SIFA, if present, the (c) one or more optional CMs, and, if present, the (d) one or more optional PSMAs may each independently be covalently attached to a linker group (L) by a covalent bond that forms part of a functional group, e.g., an ether group, an ester group, a thioester group, a thioether group, an amide group, a carbamate group.

[0054] A preferred conjugate of formula I is (i) each FAP ligand independently comprises one or more 4-12 membered heterocyclic groups as identified herein, which heterocyclic groups contain at least one nitrogen atom and optionally contain one or more additional heteroatoms selected from nitrogen, oxygen, or sulfur; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is essentially C 4 ~C 20 a hydrocarbyl group substituted by one or more silicon fluoride functional groups as specified herein, the silicon fluoride group comprising a silicon atom covalently bonded to one or more fluorine atoms, the SIFA moiety comprising: 18 Optionally labeled with F, (iv) CM; (v) PSMA, including the conjugates wherein a, b and c are each as defined for the compound of formula I.

[0055] A more preferred conjugate of formula I is (i) each FAP ligand independently comprises one or more 5- or 10-membered heterocyclic groups as identified herein, which heterocyclic groups contain at least one nitrogen atom and optionally contain one or more additional nitrogen atoms, each of said one or more heterocyclic groups containing only nitrogen heteroatoms; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6~C 10 wherein the aryl group is substituted by one or more silicon fluoride functional groups as specified herein, the silicon fluoride groups comprising a silicon atom covalently bonded to one or more fluorine atoms, and the SIFA moiety is 18 Optionally labeled with F, (iv) CM; (v) PSMA, including the conjugates where a, b and c are each as defined for the conjugate of formula I.

[0056] Even more preferred conjugates of formula I are (i) each FAP ligand independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, decahydroisoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, and naphthyridinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 wherein the phenyl group is substituted, preferably para-substituted, by one or more silicon fluoride functional groups as specified herein, the silicon fluoride groups being covalently bonded to one or more fluorine atoms and one or more C 3 ~C 10 wherein the SIFA moiety comprises a silicon atom covalently bonded to a hydrocarbyl group essentially of the formula: 18 Optionally labeled with F, (iv) CM; (v) PSMA, including the conjugates where a, b and c are each as defined for the conjugate of formula I.

[0057] Even more preferred conjugates of formula I are (i) each FAP ligand independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, and naphthyridinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 Optionally labeled with F, (iv) CM; (v) PSMA, including the conjugates where a, b and c are each as defined for the conjugate of formula I.

[0058] Even more preferred conjugates of formula I are (i) each FAP ligand independently comprises one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, and quinazolinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 Optionally labeled with F, (iv) CM; (v) PSMA, including the conjugates where a, b and c are each as defined for the conjugate of formula I.

[0059] It will be appreciated that in the conjugates of formula I, and similarly of formulae IA to IG specified herein, each of said one or more FAP ligands, said SIFA, if present, said one or more optional CMs, and if present, said one or more optional PSMA ligands may each independently be covalently bonded to a common atom (i.e., at the same position) of the linker group L, or each independently be covalently bonded at one or more different atoms (i.e., at one or more different positions) of the linker group L.

[0060] In a preferred embodiment, the conjugates of the invention include conjugates of formula I, where a is 1 or 2, b is 0, and c is 0, and are represented by formulas IA and IB:

[0061] [ka]

[0062] [Wherein, if present, FAP 1 and FAP 2 each independently represents a FAP ligand as defined for the conjugates of formula I, and SIFA and L are each as defined for the conjugates of formula I, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0063] Preferred conjugates of formula IA and IB are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand as defined for the preferred conjugates of formula I specified herein; (iii) L represents an optionally substituted linker group as specified herein; (iii) The SIFA comprises a conjugate, wherein the SIFA is as defined for the preferred conjugates of formula I specified herein.

[0064] Suitably, highly preferred conjugates of formula IA and IB are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand comprising one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, and quinazolinyl; (ii) L represents an optionally substituted linker group as defined for the conjugate of formula I; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 F.

[0065] In an alternative preferred embodiment, the conjugates of the invention include conjugates of formula I, where a is 1 or 2, b is 1, and c is 0, and are represented by formulas IC and ID:

[0066] [ka]

[0067] [Wherein, if present, FAP 1 and FAP 2 , SIFA and L are as defined for the conjugates of formulas IA and IB, and CM is as defined for the conjugates of formula (I), or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0068] Preferred conjugates of formula IC and ID are those in which CM is selected from TRAP, DOTA and DOTAGA, and which CM is optionally substituted with a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0069] More preferred conjugates of formula IC and ID are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand as defined for the preferred conjugates of formulae IA and IB specified herein; (ii) SIFA is as defined for the preferred conjugate of formula IA specified herein; (iii) L represents an optionally substituted linker group as defined for the conjugate of formula I; (iv) CM is selected from TRAP, DOTA and DOTAGA, which CM is optionally substituted with a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0070] Suitably, highly preferred conjugates of formula IC and ID are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand comprising one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, and quinazolinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 Optionally labeled with F, (iv) CM is selected from TRAP, DOTA and DOTAGA, which CM is optionally substituted with a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0071] In a further alternative preferred embodiment, the conjugate of the invention comprises a conjugate of formula I, where a is 1, b is 1, and c is 1, and has the formula IE:

[0072] [ka]

[0073] [In the formula, FAP 1 , SIFA, CM and L are each as defined for the conjugates of formula IC, and PSMA is as defined for the compound of formula I, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0074] Preferred conjugates of formula IE include those in which PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5, as defined herein.

[0075] More preferred conjugates of formula IE are those in which PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as specified herein, and CM is selected from TRAP, DOTA and DOTAGA, and the CM is selected from a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0076] An even more preferred conjugate of formula IE is (i) FAP 1 represents independently a FAP ligand as defined for the preferred conjugates of formula IC specified herein; (iii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is as defined for the preferred conjugates of formula IC specified herein; (iv) PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as defined herein; (v) the CM is selected from TRAP, DOTA and DOTAGA, and the CM is a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0077] Suitably, the highly preferred conjugate of formula IE is (i) FAP 1 represents a FAP ligand comprising one or more heterocyclic groups independently selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, and quinazolinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 Optionally labeled with F, (iv) PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as defined herein; (v) CM is selected from TRAP, DOTA and DOTAGA, which CM is optionally substituted with a radioactive metal cation or a non-radioactive cation as specified herein, in particular 68 Ga, 64 Cu, 177 Lu, 90 Y or 225 The conjugates include those optionally substituted with Ac cations.

[0078] In a further alternative embodiment, alternative preferred conjugates of the invention include conjugates of formula I, where a is 1 or 2, b is 0, and c is 1, and are represented by formulas IF and IG:

[0079] [ka]

[0080] [Wherein, if present, FAP 1 and FAP 2 , SIFA and L are as defined for the conjugates of formulas IA and IB, and PSMA is as defined for the conjugates of formula IE], or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0081] Preferred conjugates of formula IF and IG are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand as defined for the preferred conjugates of formulae IA and IB specified herein; (iii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is as defined for the preferred conjugates of formulae IA and IB specified herein; (iv) Conjugates in which the PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as defined herein.

[0082] Suitably, highly preferred conjugates of formula IF and IG are (i) FAP, if present 1 and FAP 2 each independently represents a FAP ligand comprising one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, and quinazolinyl; (ii) L represents an optionally substituted linker group as specified herein; (iii) SIFA is a C 6 ~C 10 The phenyl group is covalently bonded to a single fluorine atom and has two C 3 ~C 10 is para-substituted with a silicon fluoride functional group that contains a silicon atom covalently bonded to an alkyl group, the SIFA moiety being 18 Optionally labeled with F, (iv) Conjugates in which the PSMA is selected from the structures represented by the formulas PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as defined herein.

[0083] Highly preferred conjugates of the present invention include conjugates of formula I where a is 1 or 2, b is 0 or 1, and c is 0, as represented by conjugates of formula IA, IB, IC, and ID. Particularly preferred conjugates of the present invention include conjugates of formula I where a is 1, b is 1, and c is 0, as represented by conjugates of formula IC.

[0084] The conjugates of the present invention may comprise a single FAP ligand, as exemplified by the conjugates of formulas IA, IC, IE and IF, two FAP ligands, as exemplified by the conjugates of formulas IB, ID and IG, or three or more FAP ligands. When the conjugate comprises two or more FAP ligands, each of the FAP ligands may be the same or different, and preferably each of the FAP ligands is identical. Thus, in the conjugates of formulas IB, IC and IG, the FAP 1 is preferably a FAP 2 is the same as:

[0085] In some embodiments of the invention, as exemplified by the conjugates of formulae IE, IF and IG, the conjugates may contain one or more ligands capable of binding to PSMA in addition to one or more ligands capable of binding to a FAP. Such conjugates are useful as "dual" radiotherapeutic and / or radiodiagnostic agents for medical indications associated with elevated FAP expression and elevated prostate specific membrane antigen (PSMA) expression.

[0086] According to a further aspect of the invention there is provided a process for preparing the conjugates of the invention as exemplified below. The following processes illustrate the general synthetic procedures that may be adopted to obtain the conjugates of the present invention.

[0087] Conjugates of the invention comprising two separate moieties within a single molecule: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), and (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, as exemplified by the conjugates of formulas IA and IB, may be prepared by coupling each of (a) the one or more FAP ligands and (b) the SIFA moiety with a common linker group, L, to form a single molecule.

[0088] Conjugates of the invention comprising three separate moieties within a single molecule: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, and (c) one or more chelating moieties (CM) optionally containing a chelated non-radioactive or radioactive cation, as exemplified by conjugates of formulas IC and ID, may be prepared by coupling each of (a) said one or more FAP ligands, (b) said SIFA moiety, and (c) said one or more chelating moieties (CM) to a common linker group, L, to form a single molecule.

[0089] Conjugates of the invention comprising three separate moieties within a single molecule: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, and (d) one or more ligands capable of binding to a prostate-specific membrane antigen (PSMA), as exemplified by conjugates of formulae IF and IG, may be prepared by coupling each of (a) the one or more FAP ligands, (b) the SIFA moiety, and (d) the one or more PSMA ligands to a common linker group, L, to form a single molecule.

[0090] Conjugates of the invention comprising four separate moieties within a single molecule: (a) one or more ligands capable of binding to a fibroblast activation protein (FAP), (b) a silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, (c) one or more chelating moieties (CM) optionally containing a chelated non-radioactive or radioactive cation, and (d) one or more ligands capable of binding to a prostate-specific membrane antigen (PSMA), as exemplified by a conjugate of formula IE, may be prepared by coupling each of (a) said one or more FAP ligands, (b) said SIFA moieties to a common linker group, and (c) said one or more chelating moieties (CM) and (d) said one or more PSMA ligands to a common linker group, L, to form a single molecule.

[0091] A preferred process for preparing the conjugates of the present invention comprises the steps of providing a conjugate precursor compound comprising a FAP ligand as identified herein covalently bound to a common linker group L, and then coupling (b) said SIFA moiety, (c) said one or more optional chelating moieties (CM), said one or more optional PSMA ligands, and said one or more further optional additional FAP ligands to the linker group conjugate precursor compound.

[0092] The coupling reaction of the one or more FAP ligands and the SIFA moiety, and, if present, the one or more optional CM moieties and / or the one or more optional PSMA ligands with a linker group may be accomplished by using conventional bond formation techniques well known to those skilled in the art, such as conventional amide, ester, ether, thioether, thioester bond formation techniques. Exemplary procedures that may be used include those described herein. Furthermore, it will be recognized that the coupling reaction of the one or more FAP ligands and the SIFA moiety, and, if present, the optional one or more CM moieties and / or the optional one or more PSMA ligands with a linker group may be performed in any order. The conjugate of the present invention may be isolated from its reaction mixture using conventional techniques, such as crystallization, chromatography, including column chromatography and HPLC.

[0093] The conjugates of the invention are useful in a variety of therapeutic and / or diagnostic areas related to elevated FAP expression, including the treatment and / or diagnosis of various cancers in an animal or human subject. Suitably, a therapeutically and / or diagnostically effective amount of the conjugates of the invention is administered to an animal or human subject.

[0094] The conjugates of the present invention may be useful in the treatment or diagnosis of medical indications associated with elevated FAP expression in human tissues.The conjugates of the present invention may be useful in the treatment or diagnosis of cancer.

[0095] The conjugate of the present invention may be useful in the diagnosis or treatment of diseases characterized by overexpression of fibroblast activation protein (FAP) in animals or human subjects. The diseases characterized by overexpression of fibroblast activation protein (FAP) may be selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders. The cancer may be selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer. Thus, conjugates of the invention having a FAP binding moiety (ie, a FAP ligand) can be used in the diagnosis, imaging or treatment of cancers having FAP expression.

[0096] Suitably, when the conjugate of the present invention further comprises the optional (d) one or more PSMA ligands, the conjugate of the present invention can be useful in the diagnosis or treatment of diseases characterized by overexpression of fibroblast activation protein (FAP), or overexpression of PSMA, or overexpression of both FAP and PSMA in animals or human subjects.Diseases characterized by overexpression of PSMA do not only include prostate cancer.Non-prostate cancers known to demonstrate PSMA expression include breast cancer, lung cancer, colorectal cancer, and renal cell carcinoma.Therefore, any conjugate of the present invention identified herein with a PSMA binding moiety (i.e., PSMA ligand) can be used in the diagnosis, imaging, or treatment of cancers with PSMA expression.

[0097] The conjugates of the present invention can be useful in (i) detecting smaller primary tumors, thereby enabling earlier diagnosis; (ii) detecting smaller metastases, thereby enabling better assessment of tumor stage; (iii) providing accurate intraoperative guidance and facilitating complete surgical removal of tumor tissue; (iv) providing better discrimination between inflammation and tumor tissue; (v) providing more accurate staging of tumor-bearing patients; (vi) providing better follow-up of tumor lesions after antitumor treatment; and (vii) as a theranostic agent for diagnosis and treatment.Furthermore, the conjugates of the present invention can be used for the diagnosis and treatment of non-malignant diseases, such as chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, and keloid disorders.

[0098] In a further aspect, the present invention provides a pharmaceutical composition comprising or consisting of one or more conjugates of the invention disclosed herein. Suitably, the pharmaceutical composition may comprise a pharma- ceutically acceptable carrier, excipient and / or diluent.

[0099] In a further aspect, the present invention provides a diagnostic composition comprising or consisting of one or more conjugates of the invention disclosed herein. Suitably, the diagnostic composition may comprise a diagnostically acceptable carrier, excipient and / or diluent.

[0100] In a further aspect, the present invention provides said one or more conjugates of the invention or a composition comprising said conjugates of the invention, in particular a pharmaceutical or diagnostic composition, for use in medicine.

[0101] A preferred use in medicine is in nuclear medicine, e.g. in nuclear diagnostic imaging and / or staging of diseases associated with preferably overexpression of FAP in diseased tissue (also named nuclear molecular imaging), and / or in targeted radiotherapy.

[0102] It will be appreciated that when the conjugate of the present invention further comprises said optional (d) one or more PSMA ligands, said preferred use in medicine may further extend to nuclear diagnostic imaging and / or staging of diseases associated with preferably overexpression of FAP and / or PSMA in diseased tissue, and / or targeted radiotherapy.Thus, such conjugate of the present invention is useful for combination of diagnostic imaging and / or staging of diseases associated with preferably overexpression of both FAP and PSMA in diseased tissue, and / or combination of targeted radiotherapy.

[0103] In a further aspect, the present invention provides said one or more conjugates of the invention as defined herein, or a composition comprising said conjugates of the invention as defined herein, for use in the treatment of cancer in an animal or human subject.

[0104] In a further aspect, the present invention provides said one or more conjugates of the invention as defined herein, or a composition comprising said conjugates of the invention as defined herein, for use in the treatment of a disease characterized by overexpression of a FAP in an animal or human subject, in particular for use in the treatment of a cancer in an animal or human subject characterized by overexpression of a FAP.

[0105] In a further aspect, the present invention provides said one or more conjugates of the invention as defined herein comprising said optional (d) one or more PSMA ligands, or a composition comprising said conjugates of the invention, for use in the treatment of a disease characterised by overexpression of a FAP, or overexpression of PSMA, or overexpression of both a FAP and PSMA in an animal or human subject, in particular for use in the treatment of a cancer in an animal or human subject characterised by overexpression of both a FAP and PSMA.

[0106] In a further aspect, the present invention provides said one or more conjugates of the invention as defined herein, or a composition comprising said conjugates of the invention, for use as a diagnostic or imaging agent in an animal or human subject, in particular for use as a diagnostic or imaging agent for a disease associated with the overexpression of a FAP, preferably cancer.

[0107] In a further aspect, the present invention provides said one or more conjugates of the invention as defined herein comprising said optional (d) one or more PSMA ligands, or a composition comprising said conjugate of the invention as defined herein, for use as a diagnostic or imaging agent in an animal or human subject, in particular for use as a diagnostic or imaging agent for a disease associated with overexpression of FAP and / or overexpression of PSMA, preferably cancer.

[0108] Suitably, in a further aspect, the present invention provides said one or more conjugates of the invention as defined herein, or a composition comprising said conjugates of the invention, for use as a cancer diagnostic or imaging agent.

[0109] A preferred indication is the detection or staging of cancers associated with overexpression of FAP, with prostate cancer being a particularly preferred indication. Advantageously, in a further aspect, the present invention provides a method for treating the human or animal body by surgery or therapy or a diagnostic method performed on the human or animal body, comprising administering to a human or animal subject a therapeutically or diagnostically effective amount of said one or more conjugates of the invention as defined herein or a composition comprising said conjugates of the invention as defined herein. Advantageously, the method for treatment is of cancer.

[0110] definition The following definitions are provided for purposes of illustration and not limitation. "FAP ligand" means a chemical moiety that includes one or more functional groups, e.g., organic functional groups, that are capable of binding to fibroblast activation proteins (FAPs) expressed in mammalian, particularly human, tissue. Exemplary FAP ligands of the conjugates of the invention are identified herein.

[0111] A "SIFA moiety" refers to a moiety that contains a covalent bond between a silicon and a fluorine atom, 18 It means a silicon fluoride acceptor moiety, optionally labeled with F. Exemplary SIFA moieties of the conjugates of the invention are identified herein.

[0112] "Chelating moieties" (CM) include, inter alia, (i) macrocyclic ring structures having 8 to 20 ring atoms, of which at least two are heteroatoms selected from oxygen and nitrogen atoms, (ii) acyclic open-chain chelating structures having 8 to 20 main chain atoms, of which at least two are heteroatoms selected from oxygen and nitrogen atoms, (iii) branched chelating structures containing a quaternary carbon atom. Exemplary chelating moieties of the conjugates of the invention are identified herein.

[0113] "PSMA ligand" refers to a chemical moiety that includes one or more functional groups, e.g., organic functional groups, that can bind to prostate specific membrane antigen expressed in mammalian, particularly human, tissue. Exemplary PSMA ligands in the conjugates of the invention are identified herein and / or disclosed in WO2019 / 020831, WO2020 / 157177 and WO2020 / 157184.

[0114] "Hydrocarbyl" means a group or radical containing carbon and hydrogen atoms and bonded to the remainder of the molecule through a carbon atom. It may contain heteroatoms, i.e., atoms other than carbon and hydrogen, provided that the essentially hydrocarbon nature and characteristics of the group are not altered. Preferred hydrocarbyl groups and radicals contain only hydrogen and carbon. Suitably, the term hydrocarbyl encompasses aliphatic and aromatic groups and radicals. Preferred hydrocarbyl groups include aliphatic groups and radicals, such as alkyl, alkylene, alkenyl groups and radicals.

[0115] "Alkyl" refers to a monovalent hydrocarbyl group that does not contain double or triple bonds. The alkyl group may be linear, branched, cyclic, acyclic, and / or partially cyclic / acyclic. The alkyl group may be optionally substituted with one or more substituents. Preferably, C 1 ~C 10 The term alkyl group encompasses methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl and decyl. Preferred alkyl groups are non-cyclic alkyl groups.

[0116] "Aryl" refers to a 6- to 10-membered carbocyclic aromatic group, such as phenyl and naphthyl. Each "aryl" group specified herein includes halo, cyano, nitro, C 1 ~C 6 Alkyl, C(O)R 21 , C(O)OR 22 , C(O)NR 23 R 24 , N.R. 25 R 26 wherein R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are each independently hydrogen or C 1 ~C 6Represents alkyl.

[0117] "Halo" refers to fluoro, chloro, bromo and iodo. The term "comprising" or any cognate specifies the presence of a stated feature, step or integer or component, but does not exclude the presence or addition of one or more other features, steps, integers, components or groups thereof, and the expressions "consisting of" and "consisting essentially of" or cognate terms may be subsumed within the scope of "comprising" or cognate terms, where "consisting essentially of" permits the inclusion of substances that do not substantially affect the properties of the compound, composition or other characteristics it refers to.

[0118] The conjugates of the invention may exhibit tautomerism, and all tautomeric forms of the conjugates of the invention are included within the scope of the invention. The conjugates of the present invention may also contain one or more asymmetric carbon atoms and may exhibit optical and / or diastereoisomerism. Diastereoisomers may be separated by conventional techniques, for example by fractional crystallization or chromatography. Various stereoisomers may be isolated by separating racemic or other mixtures using conventional techniques, for example by fractional crystallization and high performance liquid chromatography (HPLC). All stereoisomers are included within the scope of the conjugates of the present invention.

[0119] Moreover, the upper and lower quantity, range and ratio limits set forth herein may be independently combined and are understood to be inclusive of "about" that quantity, range or ratio limit.

[0120] It will also be understood that any feature of each aspect of the invention, e.g., of the conjugates of the invention, may be considered to represent a preferred feature of any other said aspect of the invention. [Brief description of the drawings]

[0121] [Figure 1] FIG. 1 shows the quality control of Example 11 ([18F]-Ga-(S,R,R)-SiFA-FAP-1) at the end of radiosynthesis. [Diagram 2] Figure 2 shows PET imaging uptake of Example 11 ([18F]-Ga-(S,R,R)-SiFA-FAP-1) in U87-MG tumor-bearing mice (Table 2). Mice were injected with [18F]-Ga-(S,R,R)-SiFA-FAP-1 (8±1.5MBq) and imaged 60 minutes after radiotracer administration. The average uptake (%ID / cm3) of the radiotracer in muscle and tumor, mean±SD, is shown (n=3). Radiotracer uptake was more than 4-fold higher in tumor compared to muscle. [Diagram 3] Figure 3 shows the biodistribution of Example 11 ([18F]-Ga-(S,R,R)-SiFA-FAP-1) in U87-MG tumor-bearing mice (Tables 3a and 3b). Mice were injected with Example 11 ([18F]-Ga-(S,R,R)-SiFA-FAP-1) (8±1.5MBq). 80 minutes after radiotracer injection, radioactivity in tissues was measured by gamma counting. Radiotracer biodistribution (%ID / g), mean±SD, is shown (n=4). Biodistribution analysis demonstrated 8-fold higher radiotracer uptake in tumors compared to muscle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0122] Detailed Description of the Invention In particular, the present invention relates to a compound represented by formula (1), (1a) or (1b):

[0123] [ka]

[0124] or a pharma- ceutically or diagnostically acceptable salt or solvate thereof, wherein FAP refers to a ligand capable of binding to fibroblast activation protein (FAP) as defined herein; L is an optionally substituted polyvalent linker group as defined herein; Q in the conjugates of formula 1a and 1b 1 and Q 2 are optionally substituted linker groups, which may be the same or different; SIFA is a silicon fluoride acceptor (SIFA) moiety that contains a covalent bond between a silicon and a fluorine atom, wherein the SIFA is 18 represents a SIFA moiety, optionally including F; CM represents a chelating moiety optionally containing a chelated non-radioactive or radioactive cation as defined herein.

[0125] A conjugate of the invention may comprise a single FAP ligand (i.e., a conjugate of formula (1)), two FAP ligands (i.e., formulas (1a) or (1b)) or three or more FAP ligands, which may be the same or different.

[0126] In some embodiments of the invention, the conjugate may include one or more ligands capable of binding to PSMA in addition to one or more ligands capable of binding to the FAP.

[0127] Collectively, Q in the conjugates of formula 1a and 1b 1 -LQ 2 It is understood that together, represent a multivalent linker group as defined herein. The conjugate may be represented by formula (4), (4a) or (4b):

[0128] [ka]

[0129] or a pharma- ceutically or diagnostically acceptable salt or solvate thereof, 1 , X 2 and X 3represents a divalent linking group, where X 1 , X 2 and X 3 together with the groups to which they are attached contain one or more amide bonds.

[0130] X 1 X may be an optionally substituted linker of 5 to 30 atoms containing one or more amide bonds. 1 may be an optionally substituted linker of 5 to 30 atoms containing one or more amide bonds, where the optional substituents are -X 3 -FAP, CO 2 H and CH 2 OH. X 1 X may be an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds. 1 may be an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds, where the optional substituents are -X 3 -FAP, CO 2 H and CH 2 OH.

[0131] X 2 may be an optionally substituted linker of 1 to 30 atoms containing one or more amide bonds. 2 may be an optionally substituted linker of 1 to 10 atoms containing one or more amide bonds. 2 may be an optionally substituted 1-5 atom linker containing one or more amide bonds. In compounds of formula (4) or (4b), X 2 may also be -NH- or represent a bond.

[0132] X 3 X may be an optionally substituted linker of 5 to 30 atoms containing one or more amide bonds. 3may be an optionally substituted linker of 5 to 30 atoms containing one or more amide bonds, where the optional substituents are CO 2 H and CH 2 OH. X 3 X may be an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds. 3 may be an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds, where the optional substituents are CO 2 H and CH 2 OH.

[0133] X 1 is the expression: -[(CR 11 R 12 ) n (NHCO) m (CONH) p ] q - [In the formula, each repeating unit independently n is 1 to 10; m is 0 or 1; p is 0 or 1, where m and p are not both 1; q is 1 to 8; R 11 and R 12 In each occurrence, H, CO 2 H and CH 2 is independently selected from OH, Here, R 11 and R 12 One occurrence of -X 3 -FAP].

[0134] X 2 is the expression: -[(CR 11 R 12 ) n (NHCO) m (CONH) p ] q - [In the formula, each repeating unit independently n is 1 to 10; m is 0 or 1; p is 0 or 1, where m and p are not both 1; q is 1 to 8; R 11 and R 12 In each occurrence, H, CO 2 H and CH 2 is independently selected from OH, Here, R 11 and R 12 One occurrence of -X 3 -FAP].

[0135] X 3 is the expression: -[(CR 11 R 12 ) n (NHCO) m (CONH) p ] q - [In the formula, each repeating unit independently n is 1 to 10; m is 0 or 1; p is 0 or 1, where m and p are not both 1; q is 1 to 8; R 11 and R 12 In each occurrence, H, CO 2 H and CH 2 OH].

[0136] Independently within each repeat unit, n can be 1 to 10. n can be 1 to 5. n can be 1 to 3. n can be 1. n can be 2. n can be 3. n can be 4. n can be 5. n can be 6. n can be 7. n can be 8. n can be 9. n can be 10.

[0137] Independently within each repeat unit, m can be 0 and p can be 1. m can be 1 and p can be 0. m and p can both be 0. q can be 1 to 8. q can be 1 to 5. q can be 1 to 3. q can be 1. q can be 2. q can be 3. q can be 4. q can be 5. q can be 6. q can be 7. q can be 8.

[0138] X 1 teeth, -R 13 -NH-C(O)-R 14 -C(O)-NH-R 15 -NH-C(O)-, and -R 13 -NH-C(O)-R 14 -NH-C(O)-R 15 -NH-C(O)-R 16 -NH-C(O)- [In the formula, R 13 , R 14 , R 15 and R 16 is independently 1~10 These alkyl groups are, respectively, -H, -OH, -OCH 3 , -CH 2 OH, -CO 2 H, -CO 2 CH 3 , -NH 2 , -CH 2 NH 2 and -NHC(NH)NH 2 wherein R 13 , R 14 , R 15 and R 16 One of them is -X 3 -optionally substituted with -FAP.

[0139] X 1 teeth, -CH(COOH)-R 17 -NH-C(O)-R18 -C(O)-NH-R 19 -CH(COOH)-NH-C(O)-, and -CH(COOH)-R 17 -NH-C(O)-R 18 -NH-C(O)-R 19 -NH-C(O)-CH(CH 2 OH)-NH-C(O)- [In the formula, R 17 , R 18 and R 19 is independently 1~6 It can be selected from the group consisting of alkyl.

[0140] X 3 teeth, -R 13 -NH-C(O)-R 14 -C(O)-NH-R 15 -NH-C(O)-, and -R 13 -NH-C(O)-R 14 -NH-C(O)-R 15 -NH-C(O)-R 16 -NH-C(O)- [In the formula, R 13 , R 14 , R 15 and R 16 is independently 1~10 These alkyl groups are, respectively, -H, -OH, -OCH 3 , -CH 2 OH, -CO 2 H, -CO 2 CH 3 , -NH 2 , -CH 2 NH 2 and -NHC(NH)NH 2 wherein R 13 , R 14 , R 15 and R 16 One of them is -X 3 -optionally substituted with -FAP.

[0141] X 2 is -NH-, -NH-C(O)-, -NH-C(O)-CH 2 -, -NH-C(O)-CH 2 CH 2 - or -NH-C(O)-CH 2 CH 2 -CH(COOH)-, each of which may be -X 3 In the compound of formula (4) or (4b), X 2 may be a bond.

[0142] X 3 teeth, -CH(COOH)-R 17 -NH-C(O)-R 18 -C(O)-NH-R 19 -CH(COOH)-NH-C(O)-, and -CH(COOH)-R 17 -NH-C(O)-R 18 -NH-C(O)-R 19 -NH-C(O)-CH(CH 2 OH)-NH-C(O)- [In the formula, R 17 , R 18 and R 19 is independently 1~6 It can be selected from the group consisting of alkyl.

[0143] The conjugate may be represented by formula (5), (5a), (5b), (5c) or (5d):

[0144] [ka]

[0145] or a salt thereof, wherein FAP represents a ligand capable of binding to a fibroblast activation protein (FAP), SIFA represents a silicon fluoride acceptor (SIFA) moiety, CM represents a chelating moiety, and the linker connecting the FAP and CM is -X 3- optionally substituted with FAP.

[0146] The conjugate may be represented by formula (5), (5a), (5b), (5c) or (5d):

[0147] [ka]

[0148] or a salt thereof, wherein FAP represents a ligand capable of binding to fibroblast activation protein (FAP), SIFA represents a silicon fluoride acceptor (SIFA) moiety, and CM represents a chelating moiety.

[0149] FAP Ligand In the conjugate of the present invention, the ligand that can be bound to fibroblast activation protein (FAP) can be a functional group that comprises a moiety that can be bound to FAP.The ligand that can be bound to fibroblast activation protein (FAP) can comprise a substituted pyrrolidine ring.The ligand that can be bound to fibroblast activation protein (FAP) can comprise a pyrrolidine ring that is substituted with CN and optionally one or more F atoms.

[0150] A compound may contain multiple FAP binding domains per conjugate, and thus a compound may contain two or more ligands capable of binding to a fibroblast activation protein (FAP).

[0151] The ligand capable of binding to fibroblast activation protein (FAP) has the formula (2):

[0152] [ka]

[0153] [In the formula, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 and R 8 are H, OH, and B(OH) 2 , CO 2 H, CN, Halo, C 1~6 Alkyl and -OC 1~6 independently selected from alkyl, R 9 and R 10 are independently H or C 1~6 The moiety may include a moiety having the formula:

[0154] The ligand capable of binding to fibroblast activation protein (FAP) has the formula (2a):

[0155] [ka]

[0156] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are H, OH, and B(OH) 2 , CO 2 H, CN, Halo, C 1~6 Alkyl and -OC 1~6 independently selected from alkyl, R 9 and R 10 are independently H or C 1~6 is alkyl, n is 0 to 3; X is a 5-10 membered N-containing monocyclic or bicyclic heterocycle, which optionally further contains 1, 2 or 3 heteroatoms selected from O, N and S; C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl and -NR 20 R 21and optionally substituted with 1 to 3 substituents selected from 20 and R 21 H and C 1~6 The moiety may include a group having an alkyl group independently selected from the group consisting of aryl, ... and alkyl.

[0157] In a conjugate comprising a moiety having formula (2) or (2a), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be independently selected from H, CN, and F. 1 can be H, CN or F. 2 can be H, CN or F. 3 can be H, CN or F. 4 can be H, CN or F. 5 can be H, CN or F. 6 can be H, CN or F. 7 can be H, CN or F. 8 can be H, CN or F. Certain compounds have R 7 and R 8 One of the groups is CN and the other is H, and R 3 and R 4 is H or F, and R 1 , R 2 , R 5 and R 6 Including those where H.

[0158] In a conjugate comprising a moiety having formula (2) or (2a), R 9 and R 10 are independently H or C 1~6 R can be alkyl. 9 and R 10 may independently be H or methyl.

[0159] In conjugates that include a moiety having formula (2a), n can be 0 to 3. n can be 0. n can be 1. n can be 2. n can be 3. In the conjugates that include a moiety having formula (2a), X is

[0160] [ka]

[0161] may be selected from: Certain conjugates are

[0162] [ka]

[0163] [ka]

[0164] wherein m is 0 to 10. In the conjugate of the present invention, the ligand capable of binding to fibroblast activation protein (FAP) may comprise a cyclic peptide moiety. The ligand may comprise a cyclic peptide moiety described in WO2021 / 005125 or WO2021 / 005131.

[0165] Certain conjugates are

[0166] [ka]

[0167] It may comprise a moiety selected from the group consisting of: PSMA Ligand Some embodiments of the invention include the PSMA ligands disclosed in WO2019 / 020831. In some embodiments of the invention, the one or more ligands capable of binding to prostate specific membrane antigen (PSMA ligands) have the following formula PSMA1:

[0168] [ka]

[0169] The structure includes: In the formula, m is an integer from 2 to 6, preferably from 2 to 4, more preferably from 2, n is an integer from 2 to 6, preferably from 2 to 4, more preferably from 2 or 3, and R 1L is CH 2 , NH or O, preferably NH; R 3L is CH 2 , NH or O, preferably NH; R 2L is C or P(OH), preferably C, and the ligand is

[0170] [ka]

[0171] The conjugate is attached to the remainder of the conjugate via the bond marked with In some embodiments of the invention, the one or more ligands capable of binding to prostate specific membrane antigen (PSMA ligands) have the following formula PSMA2:

[0172] [ka]

[0173] wherein n is an integer from 2 to 6, and the ligand is

[0174] [ka]

[0175] The conjugate is attached to the remainder of the conjugate via the bond marked with In some embodiments of the invention, the one or more ligands capable of binding to prostate specific membrane antigen (PSMA ligands) have the following formula PSMA3:

[0176] [ka]

[0177] The present invention includes a structure represented by: In some embodiments of the invention, the one or more ligands capable of binding to prostate specific membrane antigen (PSMA ligands) have the following formula PSMA4:

[0178] [ka]

[0179] The present invention includes a structure represented by: In some embodiments of the invention, the one or more ligands capable of binding to prostate specific membrane antigen (PSMA ligands) have the following formula PSMA5:

[0180] [ka]

[0181] The present invention includes a structure represented by: The conjugates of the present invention include a silicon fluoride acceptor (SIFA) moiety that includes a covalent bond between silicon and a fluorine atom. In the SIFA moiety, the fluorine atom can be any known isotope of F or any combination thereof. In particular, the fluorine atom of the SIFA moiety is 19 F or 18 For diagnostic imaging and therapy, the fluorine atom of the SIFA moiety may be: 18 It may be F. 18 F is19 It can be introduced by isotopic exchange with F.

[0182] Certain ligands that can bind to disease-related target molecules can be cyclic peptides, but such cyclic peptides are not chelating groups as envisaged herein, because without additional chelating moieties the problem of hydrophobic SIFA moiety is not solved.Therefore, the compounds of the present invention require hydrophilic chelating groups in addition to the ligands that can bind to disease-related target molecules.Hydrophilic chelating groups are required to reduce the hydrophobicity of compounds caused by the presence of SIFA moiety.

[0183] SIFA part The silicon fluoride acceptor (SIFA) moiety has the formula (3):

[0184] [ka]

[0185]

[0033] In the formula, F is 19 F and 18 F, R 1S and R 2S are independently linear, branched or cyclic C 3 ~C 10 is an alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, R 3S may contain one or more aromatic and one or more aliphatic units and / or up to three heteroatoms selected from O and S; 1 ~C 20 A hydrocarbon group, preferably R 3S C contains an aromatic ring and may contain one or more aliphatic units 6 ~C10 More preferably, R 3S is a phenyl ring, and most preferably R 3S is a Si-containing substituent

[0186] [ka]

[0187] The bond marked with is in the para position on the phenyl ring, and the SIFA moiety is

[0188] [ka]

[0189] The conjugate is attached to the remainder of the conjugate via the bond marked with The silicon fluoride acceptor (SIFA) moiety has the formula (3):

[0190] [ka]

[0191]

[0033] In the formula, F is 19 F and 18 F, R 1S and R 2S are independently linear, branched or cyclic C 3 ~C 10 is an alkyl group, R 3S is a C containing one or more aromatic and / or aliphatic units and / or up to three heteroatoms selected from O and S 1 ~C 20 is a hydrocarbon group, The SIFA part is

[0192] [ka]

[0193] The conjugate is attached to the remainder of the conjugate via the bond marked with In the conjugate containing the SIFA moiety of formula (3), R 1S and R 2S is a linear or branched C 1~6 Alkyl group or C 3~6 R may be independently selected from cycloalkyl groups. 1S and R 2S R may be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1S and R 2S R can be methyl. 1S and R 2S R can be isopropyl. 1S and R 2S R can be t-butyl. 1S R may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 1S R can be methyl. 1S R can be isopropyl. 1S R can be t-butyl. 2S R may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 2S R can be methyl. 2S R can be isopropyl. 2S can be t-butyl.

[0194] In the conjugate containing the SIFA moiety of formula (3), R 3S is a C containing one or more aromatic and / or aliphatic units and / or up to three heteroatoms selected from O and S 1 ~C 20 R is a hydrocarbon group. 3SR may be a phenyl ring. 3S teeth,

[0195] [ka]

[0196] may be also possible. The silicon fluoride acceptor (SIFA) moiety has the formula (3a) or (3b):

[0197] [ka]

[0198] In the formula, t-Bu represents a tert-butyl group, and F represents 19 F and 18 F] which is understood to include both Chelate part In the conjugates herein, preferred chelating moieties (CM) include at least one of the following (i), (ii) or (iii): (i) A macrocyclic ring structure having 8 to 20 ring atoms, of which at least 2, more preferably at least 3, are selected from oxygen or nitrogen atoms. Preferably, up to 6 ring atoms are selected from oxygen or nitrogen atoms. Particularly preferred are 3 or 4 ring atoms that are nitrogen or oxygen atoms. Of the oxygen and nitrogen atoms, nitrogen atoms are preferred. In combination with the macrocyclic ring structure, the preferred chelating group may contain at least 2, for example 2 to 6, preferably 2 to 4, carboxyl and / or hydroxyl groups. Of the carboxyl and hydroxyl groups, carboxyl groups are preferred. (ii) Acyclic open-chain chelate structures having 8 to 20 backbone (skeletal) atoms, of which at least 2, more preferably at least 3, are heteroatoms selected from oxygen or nitrogen atoms. Preferably, no more than 6 backbone atoms are selected from oxygen or nitrogen atoms. Of the oxygen and nitrogen atoms, nitrogen atoms are preferred. More preferably, the open-chain chelate structures are structures that contain a combination of at least 2, more preferably at least 3, heteroatoms selected from oxygen or nitrogen atoms, and at least 2, for example 2 to 6, preferably 2 to 4, carboxyl and / or hydroxyl groups. Of the carboxyl and hydroxyl groups, carboxyl groups are preferred. (iii) Branched chelating structures containing a quaternary carbon atom. Preferably, the quaternary carbon atom is replaced with three identical chelating groups in addition to the remainder of the conjugate. The substituted chelating group may include an amide. The substituted chelating group may include an aromatic group. The substituted chelating group may include a hydroxypyridinone.

[0199] The chelate part is (i) macrocyclic ring structures having from 8 to 20 ring atoms, at least two of which are heteroatoms selected from oxygen and nitrogen atoms; (ii) an acyclic open-chain chelate structure having 8 to 20 backbone atoms, at least two of which are heteroatoms selected from oxygen and nitrogen atoms; or (iii) Branched chelating structures containing quaternary carbon atoms may include at least one of the following:

[0200] The chelating moiety (CM) was selected from the group consisting of bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2b).2]Hexadecane (DO2A), 1,4,7,10-tetracyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphonic acid) diethylenetriamine-N,N',N''-penta(methylene)phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethyleneglycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)- 1,4,7,10-Tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), and the tetra-3-hydroxy-N-methyl-2-pyridinone chelator abbreviated as Me-3,2-HOPO (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino) ... 2-Dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N' The phosphoryl group may be selected from 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA), 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (Triamine-1-yl)-1,4-diaze ...

[0201] A specific chelating moiety (CM) is shown below:

[0202] [ka]

[0203] The specific chelating moiety (CM) is

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] Includes. The specific chelating moiety (CM) is

[0208] [ka]

[0209] Includes. Of the above exemplary chelating agents, particular preference is given to chelating moieties selected from TRAP, DOTA and DOTAGA.

[0210] The chelating moiety (CM) is 1,4,7,10-tetracyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA):

[0211] [ka]

[0212] or α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA):

[0213] [ka]

[0214] may be also possible. The chelating portion (CM) is

[0215] [ka]

[0216] wherein M represents a chelated metal cation. Metal or cation chelating macrocyclic and acyclic compounds are well known in the art and are available from several manufacturers. The chelating moieties according to the present invention are not particularly limited, but it will be understood that many moieties can be readily used in an off-the-shelf manner by one of ordinary skill in the art.

[0217] The chelating moiety may comprise a chelated cation, which may be radioactive or non-radioactive, preferably a chelated metal cation, which may be radioactive or non-radioactive. The chelating moiety may comprise a chelated cation that is radioactive. The chelating moiety may comprise a chelated cation that is non-radioactive.

[0218] It is particularly preferred that CM represents a chelating moiety selected from DOTA and DOTAGA, linked by one of its carboxyl groups to the remainder of the conjugate via an amide bond.

[0219] Preferred examples of cations that can be chelated by the chelating group are radioactive or non-radioactive cations of Sc, Cr, Mn, Co, Fe, Ni, Cu, Ga, Zr, Y, Tc, Ru, Rh, Pd, Ag, In, Sn, Te, Pr, Pm, Tb, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Re, Pt, Hg, Au, Pb, Bi, Ra, Ac, Th, more preferably cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th and Er. The cation may be Ga. The cation may be Lu.

[0220] The chelate part is 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 90 Y, 89 Y, <Tc、 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag,110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 Pm, 151 Pm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 a chelated cation or cationic species selected from the cations of Th; 18 F or 211 cationic molecules containing At, or 18 F-[AlF] 2+ Cations such as: 44 Sc, 47 Sc, 61 Cu, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 161 Tb, 166 Ho, 177 Lu, 188 Re, 212 Pb, 212 Bi, 213 Bi, 225Ac, and 227 Th cation or 18 It may contain F-containing cationic molecules.

[0221] The chelate part is 43 Sc, 44 Sc, 47 Sc, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 90 Y, 111 In, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 or a chelated cation selected from the cations of Th 18 The chelating moiety may contain a cationic molecule that contains F. 68 Ga or 177 The chelating moiety may contain a chelated cation selected from the cations of Lu. 68 The chelating moiety may contain a Ga cation. 177 M may contain a Lu cation. 43 Sc, 44 Sc, 47 Sc, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 90 Y, 111 In, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 212Pb, 212 Bi, 213 Bi, 225 Ac, and 227 M may be selected from the cations of 68 Ga, 64 Cu, 177 Lu, 90 Y and 225 M may be selected from the cations of 68 Ga and 177 M may be selected from the cations of chelated 68 M may be a chelated Ga cation. 177 M may be a chelated Lu cation. 64 M may be a chelated Cu cation. 90 Y may be a cation. M may be a chelated 225 It may also be an Ac cation.

[0222] In the compounds herein, the chelated non-radioactive or radioactive cation of the chelating moiety is one or more COO - The non-radioactive or radioactive cations of the chelating moiety may be chelated to one or more N atoms. The non-radioactive or radioactive cations of the chelating moiety may be chelated to one or more N atoms or one or more COO - The non-radioactive or radioactive cation chelated to the chelating moiety may be chelated to one or more N atoms and one or more COO - In the structures provided herein, where chelated non-radioactive or radioactive cations are shown, the groups to which they are chelated are shown only as representative. For example, the disclosure of compounds containing chelating moieties shown below includes Ga 3+ Included within its scope are all complex or chelate forms that are chemically possible between the cation and the entire conjugate:

[0223] [ka]

[0224] The main aspect of the present invention is the combination of silicon fluoride acceptor and chelating group (chelator) or chelate in a single molecule.These two structural elements, i.e., SIFA and chelator, are in close spatial proximity.Preferably, the shortest distance between two atoms of the two elements is 25 Å or less, more preferably less than 20 Å, even more preferably less than 15 Å.Alternatively or additionally, it is preferred that 25 or less covalent bonds, preferably 20 or less chemical bonds, even more preferably 15 or less chemical bonds separate the atom of SIFA moiety and the atom of chelator.

[0225] Suitably, the cation is a radioactive or non-radioactive cation. It is preferably a radioactive or non-radioactive metal cation, more preferably a radioactive metal cation. Examples are given further below.

[0226] As a result, conjugates that are radiolabeled on both the SIFA moiety and the chelating group, molecules that are radiolabeled on only one of the two sides, as well as molecules that are not radiolabeled at all fall under the term of the first embodiment. In the last case, the chelating group may be a complex of a cold (non-radioactive) ion or may be devoid of any ion.

[0227] Placement of a silicon fluoride acceptor near a hydrophilic chelator, such as, but not limited to, DOTAGA or DOTA, can effectively mask or counteract the lipophilicity of the SIFA moiety to such an extent that the overall hydrophobicity of a radiotherapeutic or diagnostic compound is shifted into a range that makes the compound suitable for in vivo administration.

[0228] In addition, the use of chelators and 18Combination of isotopic exchange at SIFA with F-fluoride is also possible with centres with on-site cyclotrons or by shipment from cyclotron centres. 18 In the F-fluoride obtaining center [ 18 F][ nat while producing a "pair" diagnostic tracer that can be used as a [ion] tracer. 18 In centers where F-fluoride is not available but radioisotope generators, e.g. Ge-68 / Ga-68 generators, the corresponding versions, e.g. nat F][ 68 Ga] tracer can be used.

[0229] Importantly, in both cases, chemically identical radiopharmaceuticals were injected, and therefore differences in in vivo behavior are not expected. Currently, due to chemical differences, the radiopharmaceuticals delivered by patient cohorts at a given institution are not 18 Clinical data for F-labeled compounds will be provided by a separate group at a separate institution. 68 Although not directly comparable with the clinical data of Ga-analogues, the radiopharmaceuticals and / or diagnostic agents according to the invention can be directly compared and thus make it possible to correlate such data (e.g. data from a centre in Europe working with F-18 and another centre in India working with Ga-68). Furthermore, if suitably selected, the chelates can also be used for labelling with therapeutic isotopes, e.g. the beta-emitting isotopes Lu-177, Y-90, or the alpha-emitting isotope Ac-225, thereby enabling diagnostic ([ 18 F][ nat Lu] tracers) and therapeutic radiopharmaceuticals ([ nat F][ 177 This may allow us to extend the concept of “paired” tracers that bridge the [Lu] gap.

[0230] Also provided are pharmaceutical imaging compositions comprising or consisting of one or more of the conjugates of the invention disclosed herein. Diagnostic compositions comprising or consisting of one or more of the conjugates of the invention disclosed herein are also provided.

[0231] Therapeutic compositions comprising or consisting of one or more of the conjugates of the invention disclosed herein are also provided. The pharmaceutical composition may further comprise a pharma- ceutically acceptable carrier, excipient and / or diluent. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline solution, water, emulsions, such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. Compositions containing such carriers may be formulated by well-known conventional methods. These pharmaceutical compositions may be administered to a subject in a suitable dose. The administration of suitable compositions may be performed in different ways, for example, by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchial administration. It is particularly preferred that the administration is performed by injection and / or delivery, for example, to a site in the pancreas or into a cerebral artery or directly into brain tissue. The composition may also be administered directly to the target site, for example, by biolistic delivery to an external or internal target site, such as the pancreas or brain. The dosing regimen is determined by the attending physician and clinical factors. As is well known in the medical arts, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs administered concomitantly. Pharmaceutically active agents may be present in an effective therapeutic amount, which may be between 0.1 ng and 10 mg / kg body weight per dose, although doses below or above this exemplary range are envisioned, particularly taking into account the aforementioned factors.

[0232] Also provided is one or more of the conjugates, compounds or compositions of the invention disclosed herein for use in diagnostic medicine. The conjugates of the present invention may be useful in the treatment or diagnosis of medical indications associated with elevated FAP expression in human tissues. The conjugates of the present invention may be useful in the treatment or diagnosis of cancer. The conjugates of the present invention may be useful in (i) detecting smaller primary tumors, thereby enabling earlier diagnosis; (ii) detecting smaller metastases, thereby enabling better assessment of tumor stage; (iii) providing accurate intraoperative guidance and facilitating complete surgical removal of tumor tissue; (iv) providing better discrimination between inflammation and tumor tissue; (v) providing more accurate staging of tumor-bearing patients; (vi) providing better follow-up of tumor lesions after antitumor treatment; and (vii) as theranostic agents for diagnosis and treatment. In addition, the molecules may be used for the diagnosis and treatment of non-malignant diseases, such as chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, and keloid disorders.

[0233] The conjugate of the present invention may be for use in the diagnosis or treatment of diseases characterized by overexpression of fibroblast activation protein (FAP) in animals or human subjects. The diseases characterized by overexpression of fibroblast activation protein (FAP) may be selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders. The cancer may be selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer.

[0234] A preferred use in medicine is in nuclear medicine, for example in nuclear diagnostic imaging (also named nuclear molecular imaging) of diseases associated with overexpression of FAP in diseased tissue, and / or in targeted radiotherapy.

[0235] There is also provided a conjugate, compound or composition of the invention as defined herein for use in a method of diagnosing and / or staging cancer. The term "treatment" with respect to the use of any of the conjugates or compounds described herein is used to refer to any form of intervention in which a compound is administered to a subject suffering from, at risk of suffering from, or potentially at risk of suffering from, the disease or disorder in question. Thus, the term "treatment" encompasses both prophylactic (preventative) treatment and treatment in the event of measurable or detectable symptoms of the disease or disorder.

[0236] The term "effective therapeutic amount" (eg, with respect to methods of treating a disease or condition) refers to an amount of a compound that is effective in producing the desired therapeutic effect. Terms such as "alkyl," "hydrocarbon," and "cycloalkyl" are all used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted" attached to any group means that said group may be substituted, if desired, with one or more substituents which may be the same or different.

[0237] Insofar as any of the compounds described have chiral centers, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers.The invention described herein relates to all crystal forms, solvates and hydrates of any of the compounds disclosed, prepared in any manner.Insofar as any of the compounds disclosed herein have acidic or basic centers, such as carboxylate or amino groups, all salt forms of said compounds are included herein.In the case of pharmaceutical use, the salts should be considered as pharma-ceutically acceptable salts.

[0238] The salts or pharma- ceutically acceptable salts that may be mentioned include acid addition salts and base addition salts, as well as salt forms that arise due to the presence of chelated non-radioactive or radioactive cations.Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing said solvent or said medium using standard techniques (for example, in vacuum, by lyophilization or by filtration).Salts may also be prepared by exchanging the counterion of the compound in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0239] In addition to the suitable chelated non-radioactive or radioactive cations described hereinabove, further examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium.

[0240] Examples of acid addition salts are acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., , D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, Includes acid addition salts formed with 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0241] Also included are any solvates of conjugates or compounds and their salts.Preferred solvates are those formed by incorporating molecules of non-toxic pharma- ceutically acceptable solvents (hereinafter referred to as solvating solvents) into the solid-state structure (e.g., crystalline structure) of the compounds of the present invention.Examples of such solvents may include water, alcohol (e.g., ethanol, isopropanol and butanol) and dimethylsulfoxide.Solvates may be prepared by recrystallizing the compounds of the present invention with a solvent or mixture of solvents that contain a solvating solvent.Whether or not a solvate is formed in any given case may be determined by subjecting the crystals of the compound to analysis using well-known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.

[0242] Solvate can be stoichiometric or non-stoichiometric solvate.Particular solvate can be hydrate, and examples of hydrate include hemihydrate, monohydrate and dihydrate.For more detailed discussion of solvate and the methods used to make and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, 2nd Edition, published by SSCI, Inc., West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0243] The conjugates of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes, 1 H, 2 H(D), and 3 H(T). Similarly, references to carbon and oxygen are 12 C. 13 C and 14 C and 16 O and 18In a similar manner, reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also encompasses variations in which one or more of the hydrogen atoms in the group are in the form of a deuterium or tritium isotope, such as an ethyl group (perdeuteroethyl group) in which all five hydrogen atoms are in the form of a deuterium isotope, or a methoxy group (trideuteromethoxy group) in which all three hydrogen atoms are in the form of a deuterium isotope. Isotopes may be radioactive or non-radioactive.

[0244] Selected Embodiments Some embodiments of the invention include: 1. A method for the preparation of a fibroblast activating protein (FAP) comprising the steps of: 1. preparing a fibroblast activating protein (FAP) comprising administering to said fibroblast activating protein (FAP) a fluorine-containing silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom; 18 A ligand-SIFA conjugate, which is a SIFA moiety, optionally labeled with F, optionally comprising within said single molecule: (c) one or more chelating moieties (CM) optionally containing a chelated non-radioactive or radioactive cation, or (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA), or (e) a combination of both (c) said one or more chelating moieties (CM) and (d) said one or more PSMA ligands, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0245] 2. A method for producing a compound comprising the steps of: (a) forming a fibroblast activating protein (FAP) having a fluorine atom and a silicon fluoride acceptor (SIFA) moiety, the compound comprising: 18A ligand-SIFA conjugate according to embodiment 1, comprising a SIFA moiety, optionally labeled with F, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0246] 3. A method for producing a compound comprising the steps of: (a) forming a fibroblast activating protein (FAP) having a fluorine atom and a fluorine atom; and (b) forming a fluorine atom and a silicon fluoride acceptor (SIFA) having a fluorine atom and a silicon fluoride atom. 18 A ligand-SIFA conjugate as described in embodiment 1, comprising a SIFA moiety, optionally labeled with F, and (c) one or more chelating moieties (CM) optionally containing chelated non-radioactive or radioactive cations, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0247] 4. A method for producing a compound comprising the steps of: (a) forming a fibroblast activating protein (FAP) having a fluorine atom and a fluorine atom; and (b) forming a fluorine atom and a silicon fluoride acceptor (SIFA) having a fluorine atom and a silicon fluoride atom; 18 A ligand-SIFA conjugate as described in embodiment 1, or a pharma- ceutically or diagnostically acceptable salt or solvate thereof, comprising a SIFA portion, optionally labeled with F, and (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA).

[0248] 5. A method comprising the steps of: (a) forming a fibroblast activating protein (FAP) from a fluorine atom; and (b) forming a fluorine atom; and (c) forming a fluorine atom; and (d) forming a fluorine atom; and (e) forming a fluorine atom. 18A ligand-SIFA conjugate according to embodiment 1, comprising a SIFA portion, optionally labeled with F; (c) one or more chelating moieties (CM) optionally containing chelated non-radioactive or radioactive cations; and (d) one or more ligands capable of binding to prostate-specific membrane antigen (PSMA), or a pharma- ceutically or diagnostically acceptable salt or solvate thereof.

[0249] 6. The ligand-SIFA conjugate of any one of embodiments 1 to 5, wherein the one or more FAP ligands are as defined in any one of claims 3, and 13 to 21.

[0250] 7. A ligand-SIFA conjugate according to embodiments 1 to 6, wherein the SIFA moiety is as defined in any one of claims 6, 7 and 12. 8. The ligand-SIFA conjugate according to embodiments 1, 3, 5, 6 and 7, wherein one or more chelating moieties (CM) are as defined in any one of claims 8, 9, 10 and 11.

[0251] 9. The ligand-SIFA conjugate according to embodiments 1, 4, 5, 6, 7 and 8, wherein the one or more PSMA ligands are selected from the structures of the formulae PSMA1, PSMA2, PSMA3, PSMA4 and PSMA5 as specified herein.

[0252] 10. A pharmaceutical or diagnostic composition comprising or consisting of one or more conjugates or compounds according to any one of embodiments 1 to 9. 11. A ligand-SIFA conjugate according to any one of embodiments 1 to 10 for use in medicine.

[0253] 12. A ligand-SIFA conjugate according to any one of embodiments 1 to 10 for use as a cancer diagnostic or imaging agent. 13. A method for imaging and / or diagnosing cancer, comprising administering to a patient in need thereof a ligand-SIFA conjugate described in any one of embodiments 1 to 10.

[0254] 14. A ligand-SIFA conjugate according to any one of embodiments 1 to 10 for use in the treatment of cancer. 15. A ligand-SIFA conjugate according to any one of embodiments 1 to 10 for use in the diagnosis or treatment of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders.

[0255] 16. The ligand-SIFA conjugate according to any one of embodiments 1 to 10 for use in the diagnosis or treatment of a cancer selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer.

[0256] Highly preferred conjugates of the present invention include the conjugates of Examples 1 to 13a shown in Table 1 below. EXAMPLES

[0257] Examples and Preparations The following non-limiting examples are illustrative of the invention. The synthesis of conjugates of some embodiments of the invention and intermediates for use therein are illustrated by the following non-limiting examples and preparations.

[0258] Examples of conjugates of the invention include those shown in Table 1 below. A conjugate of the invention may be selected from any one of Examples 1 to 13a shown in Table 1.

[0259]

Table 1-1

[0260]

Table 1-2

[0261]

Table 1-3

[0262]

Table 1-4

[0263]

Table 1-5

[0264]

Table 1-6

[0265]

Table 1-7

[0266]

Table 1-8

[0267]

Table 1-9

[0268]

Table 1-10

[0269] General method Certain conjugates of the invention may be prepared according to the following general scheme, where FAP comprises a FAP-binding moiety, PSMA comprises a PSMA-binding moiety, L represents a linker moiety, SIFA represents a SIFA-containing moiety, CM comprises a chelating moiety, and CM(M) comprises a chelating moiety having a chelated metal cation.

[0270] [ka]

[0271] material and method Where preparative routes are not included, relevant intermediates are commercially available. Unless otherwise stated, commercial grade reagents were utilized without further purification. Purity of compounds was determined by HPLC, and all final target compounds had a purity of >95% unless otherwise stated. Proton nuclear magnetic resonance ( 1 H NMR spectra were recorded in the specified deuterated solvents on a Varian 400 spectrometer operating at 400 MHz. Mass spectra were determined using a Shimadzu LCMS2020 with an N series DUIS (ESI) system using positive-negative switching. HPLC spectra were determined using an Agilent 1200 series.

[0272] Room temperature includes 20 to 25°C. Synthesis of silicon fluoride acceptor reagents (SiFA-BA) The silicon fluoride acceptor reagent used herein was 4-(di-tert-butylfluorosilyl)benzoic acid (SiFA-BA):

[0273] [ka]

[0274] SiFA-BA was synthesized according to a previously published procedure (L. Iovkova et al., Chem. Eur. J. 2009, 15, 2140-2147), as depicted in the scheme below: All reactions were carried out in a dry reaction vessel under argon using a vacuum gas manifold.

[0275] [ka]

[0276] Synthesis of SiFA-BA: a) TBDMSCl, imidazole (DMF); b) tBuLi, di-tert-butyldifluorosilane (THF); c) HCl (MeOH); d) pyridinium chlorochromate (DCM); e) KMnO 4 (DCM, tert-butanol, NaH 2 PO 4 buffer solution).

[0277] Synthesis of the conjugates of Examples 1 and 2 Exemplary synthetic procedures for obtaining the conjugates of the invention of Examples 1 and 2 detailed in Table 1 are shown in the schemes below.

[0278] [ka]

[0279] Synthesis of intermediates Preparation 1 6-Hydroxyquinoline-4-carboxylic acid (2) 6-Methoxyquinoline-4-carboxylic acid (5 g, 0.0246 mol; BLD-pharma) and HBr solution (48% in water, 75 ml) in a sealed tube were heated to 140° C. for 4 h under vigorous stirring. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (20 ml) and the resulting solution was basified (pH=7.5) using 4N aqueous sodium hydroxide (NaOH). The precipitate formed was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was triturated with methanol (20 ml×3) and diethyl ether (20 ml). The resulting slurry was dissolved in acetonitrile (20 ml) and water (60 ml). The resulting mixture was lyophilized to give the title compound as a light brown solid (yield: 4.0 g, 86%). The title compound was identified by LC-MS and 1 Characterized by H NMR analysis. LC-MS, C 10 H 7 NO 3 Calculated 189.04; Observed 190.25 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 8.46 (d, J= 4.0 Hz, 1H), 8.10 (s, 1H), 7.70 (d, J= 9.2 Hz, 1H), 7.32 (d, J= 4.0 Hz, 1H), 7.17-7.14 (m, 1H).

[0280] Preparation 2 (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)-6-hydroxyquinoline-4-carboxamide (4) N,N-Diisopropylethylamine (3.5 ml, 0.0198 mol), 1-hydroxy-7-azabenzotriazole (4.0 g, 0.264 mol; Spectrochem) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (6.0 g, 0.0158 mol; Spectrochem) were added to a stirred solution of the title compound of Preparation 1 (2.5 g, 0.0132 mol) and (S)-1-glycylpyrrolidine-2-carbonitrile (3.0 g, 0.0198 mol, BLD-pharma) in dry N,N-dimethylformamide (DMF, 50 ml) under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis. After completion of the reaction, water (30 ml) was added and the resulting mixture was extracted with ethyl acetate (50 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 silica) column chromatography using 5% methanol in dichloromethane to give the title compound as a yellow solid (yield: 1.9 g, 45%). The title compound was characterized by LC-MS analysis. LC-MS, C 17 H 16 N 4 O 3 Calculated 324.12; Observed 325.30 [M+H] + .

[0281] Preparation 3 tert-Butyl-(S)-(3-((4-((2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)carbamate (6) tert-Butyl (3-bromopropyl)carbamate (0.87 g, 0.0037 mol) was added portionwise to a solution of the title compound of Preparation 2 (1 g, 0.0031 mol) and potassium carbonate (0.51 g, 0.0037 mol) in N,N-dimethylformamide (DMF, 10 ml) under nitrogen. The resulting mixture was stirred at 60° C. for 16 hours. The progress of the reaction was monitored by TLC analysis. After completion, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated under reduced pressure to give the light brown crude compound. The crude compound was purified by silica gel (230-400 mesh) eluting with 0-5% methanol in dichloromethane to give the title compound as a yellow solid (yield: 0.75 g, 50%). The title compound was analyzed by LC-MS and HPLC. 1 Characterized by H NMR analysis. LC-MS, C 25 H 31 N 5 O 5 Calculated 481.23; Observed 482.40 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 8.79 (d, J= 4.4 Hz, 1H), 7.99 (d, J= 9.2 Hz, 1H), 7.62 (bs, 1H), 7.51 (d, J= 4.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.30 (bs, 1H), 5.17 (bs, 1H), 4.80 (bs, 1H), 4.46-4.40 (m, 1H), 4.31-4.27 (m, 1H), 4.17 (m, 2H), 3.73 (bs, 1H), 3.58-3.54 (m, 1H), 3.38-3.37 (m, 2H), 2.37-2.26 (m, 4H), 2.05 (bs, 2H), 1.44 (s, 9H).

[0282] Preparation 4 (S)-6-(3-aminopropoxy)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (7) Trifluoroacetic acid (0.25 ml, 0.0032 mol) was added to a solution of the title compound of Preparation 3 (0.75 g, 0.0016 mol) in dichloromethane (7.5 ml) under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis. The reaction mixture was then concentrated under reduced pressure and the residue was co-distilled with fresh dichloromethane (three times). Finally, the resulting residue was triturated first with diethyl ether (10 ml) and then with n-pentane (10 ml) and then dried under vacuum to give the title compound as a light brown solid in quantitative yield. The crude title compound was used without further purification. The title compound was identified by LC-MS and 1 Characterized by H NMR analysis. LC-MS, C 20 H 23 N 5 O 3 Calculated 381.18; Observed 382.35 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 9.09 (d, J= 5.2 Hz, 1H), 8.84 (d, J= 4.0 Hz, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.96-7.87 (m, 4H), 7.56-7.49 (m, 2H), 4.82 (d, J= 4.0 Hz, 1H), 4.23 (s, 4H), 3.74 (bs, 1H), 3.59-3.53 (m, 1H), 3.04-3.03 (m, 2H), 2.23-2.09 (m, 5H).

[0283] Preparation 5 (9H-Fluoren-9-yl)methyl((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-3-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)-1-oxopropan-2-yl)carbamate (8) 2,4,6-Collidine (1.65 mL, 12.30 mmol), 1-hydroxy-7-azabenzotriazole (0.51 g, 3.674 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (1.18 g, 3.674 mmol) were added to a stirred solution of the title compound of Preparation 4 (0.7 g, 1.84 mmol) and N-alpha-(9-fluorenylmethyloxycarbonyl)-N-beta-[(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl]-D-2,3-diaminopropionic acid (0.99 g, 2.02 mmol, ACT-China) in dry N,N-dimethylformamide (DMF, 14 ml) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC analysis. After completion of the reaction, water (30 ml) was added and the resulting mixture was extracted with ethyl acetate (50 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude title compound was purified by silica gel (230-400 silica) column chromatography using 5% methanol in dichloromethane to give the title compound as an off-white solid (yield: 0.90 g, 51%). The title compound was characterized by LC-MS analysis. LC-MS, C 48 H 51 N 7 O 8 Calculated 853.38; Observed 854.50 [M+H] + .

[0284] Preparation 6 (9H-Fluoren-9-yl)methyl-((R)-3-amino-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-1-oxopropan-2-yl)carbamate (9) Hydrazine hydrate (25%, 1.3 ml) was added to a stirred solution of the title compound of Preparation 5 (2.6 g, 0.0027 mol) in ethanol (25 ml) and the resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis. After completion of the reaction, water (20 ml) was added and the resulting mixture was extracted with dichloromethane (100 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude title compound was purified by silica gel (230-400 silica) column chromatography using 10% methanol in dichloromethane to give the title compound as an off-white solid (yield: 1.50 g, 78%). The title compound was analyzed by LC-MS and HPLC. 1 Characterized by H NMR analysis. LC-MS, C 38 H 39 N 7 O 6 Calculated 689.30; Observed 690.45 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 9.03 (t, J= 5.6 Hz, 1H), 8.81 (d, J= 4.4 Hz, 1H), 8.12 (bs, 1H), 7.97 (d, J= 8.8 Hz, 1H), 7.89-7.88 (m, 3H), 7.68 (d, J= 7.6 Hz, 2H), 7.51 (d, J= 4.4 Hz, 1H), 7.46-7.39 (m, 3H), 7.32 (t, J= 7.2 Hz, 3H), 4.83-4.81 (m, 1H), 4.30-4.17 (m, 8H), 3.72 (bs, 4H), 3.57-3.51 (m, 1H), 3.06-2.99 (m, 2H), 2.22-2.16 (m, 2H), 2.09-2.05 (m, 2H), 1.97-1.94 (m, 3H).

[0285] Preparation 7 (9H-Fluoren-9-yl)methyl-((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)carbamate (10) N,N-Diisopropylethylamine (1.8 ml, 9.79 mmol), 1-hydroxy-7-azabenzotriazole (0.44 g, 3.27 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (1.0 g, 3.27 mmol) were added to a stirred solution of the title compound of Preparation 6 (1.5 g, 2.18 mmol) and 4-(di-tert-butylfluorosilyl)benzoic acid (0.92 g, 3.27 mmol) in dry N,N-dimethylformamide (DMF, 15 ml) under nitrogen. The resulting mixture was stirred at room temperature for 24 hours and the progress of the reaction was monitored by thin layer chromatography (TLC) analysis. After completion of the reaction, water (100 ml) was added and the resulting mixture was extracted with ethyl acetate (300 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude title compound was purified by silica gel (230-400 silica) column chromatography using 1-10% methanol in dichloromethane to give the title compound as an off-white solid (yield: 1.2 g, 60%). The title compound was characterized by LC-MS analysis. LC-MS, C 53 H 60 FN 7 O 7 S calculated 953.43; observed 954.65 [M+H] + .

[0286] Preparation 8 6-(3-((R)-2-amino-3-(4-(di-tert-butylfluorosilyl)benzamido)propanamido)propoxy)-N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (11) (Example 12) A solution of piperidine (0.15 ml, 1.51 mmol) in N,N-dimethylformamide (DMF, 1 ml) was added dropwise to a stirred solution of the title compound of Preparation 7 (1.2 g, 1.26 mmol) in N,N-dimethylformamide (DMF, 12 ml). The resulting mixture was stirred at room temperature for 1 hour and the reaction was monitored by TLC analysis. After completion of the reaction, water (100 ml) was added and the resulting mixture was extracted with ethyl acetate (70 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude title compound was purified by silica gel (230-400 silica) column chromatography using 5-12% methanol in dichloromethane to give the title compound as an off-white solid (yield: 0.90 g, 98%). The title compound was analyzed by LC-MS and 1 Characterized by H NMR analysis. LC-MS, C 38 H 50 FN 7 O 5 Si calculated: 731.36; Observed: 732.45 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 9.06 (t, J= 6.0 Hz, 1H), 8.81-8.77 (m, 2H), 8.26 (t, J= 4.8 Hz, 1H), 8.03-7.95 (m, 3H), 7.87 (bs, 1H), 7.67 (d, J= 7.6 Hz, 2H), 7.51 (d, J= 4.4 Hz, 1H), 7.45 (d, J= 8.8 Hz, 1H), 6.01 (bs, 2H), 4.84 (bs, 1H), 4.60 (bs, 1H), 4.25-4.16 (m, 4H), 3.74 (bs, 1H), 3.57-3.37 (m, 1H), 3.17-3.14 (m, 2H), 3.13-3.08 (m, 2H), 3.06-3.02 (m, 1H), 2.50 (s, 8H), 2.30-1.94 (m, 6H), 1.30-1.14 (m, 1H), 1.08 (s, 18 H).

[0287] Preparation 9 Tri-tert-butyl 2,2',2''-(10-((R)-1-(tert-butoxy)-5-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (12) N,N-Diisopropylethylamine (0.70 ml, 3.69 mmol) was added to a stirred solution of the title compound of Preparation 8 (0.90 g, 1.23 mmol) and 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoic acid (0.86 g, 1.23 mmol, Argonix Reagents & Intermediates) in dichloromethane (18 ml) under nitrogen. This was followed by the addition of 1-propanephosphonic anhydride solution (50% in ethyl acetate, 1.2 ml, 3.69 mmol). The resulting mixture was stirred at room temperature for 3 hours and the reaction was monitored by TLC analysis. After completion of the reaction, water (50 ml) was added and the resulting mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude title compound was purified by silica gel (230-400 silica) column chromatography using 5-14% methanol in dichloromethane to give the title compound as an off-white solid (yield: 1.0 g, 57%). The product (12) was carried on to the next step without further characterization.

[0288] Synthesis of the conjugates of Examples 1 and 2 Preparation 10 - Compound of Example 1 2,2',2''-(10-((R)-1-carboxy-4-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (13) A solution of the title compound of Preparation 9 (1.0 g, 0.71 mmol) in trifluoroacetic acid:triisopropylsilane:water (95:2.5:2.5, 15 ml) was stirred at room temperature for 16 hours under nitrogen. The progress of the reaction was monitored by LC-MS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a sticky liquid residue. The residue was triturated with methyl tert-butyl ether (10 ml x 3 times) followed by n-pentane (10 ml) to produce a solid. The solid was dried under vacuum to give the crude title compound as an off-white solid (yield: 0.83 g, 99%). The crude title compound (70 mg) was purified by reverse phase high performance liquid chromatography (HPLC) (mobile phase A: 0.1% formic acid in water; and mobile phase B: acetonitrile - column: Inertsil ODS3V 250 x 20 mm, 5.0 μm) to give 20 mg of the title compound as a pale yellow solid. LC-MS, C 57 H 80 FN 11 O 14 Si calculated value 1189.56; observed value 1188.35 [MH] - . 1 H NMR (400 MHz, DMSO): δ 11.80 (bs, 4H), 9.03 (bs, 1H), 8.80 (s, 1H), 8.47-8.33 (m, 2H), 8.14 (bs, 1H), 7.96-7.85 (m, 4H), 7.64-7.62 (m, 2H), 7.51-7.44 (m, 1H), 4.83 (bs, 1H), 4.44 (bs, 2H), 4.21-4.16 (m, 4H), 3.72 (bs, 1H), 3.53-3.40 (m, 10H), 3.10-2.80 (m, 13H), 2.33-1.71 (m, 14H), 1.02 (s, 18H).High performance liquid chromatography (HPLC): 10.361 min, 98.46%, (column: Inertsil ODS 3V-C18 4.6×250 mm, 5 μm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile).

[0289] Preparation 11 - Compound of Example 2 2-(16-((R)-1-carboxy-4-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-4-oxobutyl)-3,6-dioxo-4,5-dioxa-1,8,11,16-tetraazabicyclo[6.5.5]octadecane-11-yl)gallium(I)acetate (14, Ga-(S,R,R)-SiFA-FAP-1) Gallium(III) nitrate (0.236 g, 0.925 mmol) was added to a stirred solution of the title compound of Preparation 10 (0.55 g, 0.462 mmol) in tert-butanol:water (3:1, 20 ml) under nitrogen and the resulting mixture was heated at 75° C. for 3 hours. The progress of the reaction was monitored by LC-MS analysis. After completion, the reaction was cooled to room temperature and water (20 ml) was added. The resulting mixture was filtered through a microfilter and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with methyl tert-butyl ether (5×3 ml) and diethyl ether (10 ml) to produce a sticky solid which was dried under vacuum to give the crude title compound as a pale yellow solid. The crude title compound was purified by reverse phase HPLC (mobile phase A: 0.1% formic acid in water; and mobile phase B: acetonitrile - column: Inertsil ODS3V 250 x 20 mm, 5 μm) to give the title compound as an off-white solid (yield: 78 mg, 13.4%). LC-MS, C 57 H 77 FGaN 11 O 14 Si calculated value 1255.47; observed value 1254.40 [MH] - . 1 H NMR (400 MHz, DMSO): δ 9.03 (bs, 1H), 8.80 (d, J= 4.0 Hz, 1H), 8.59 (bs, 1H), 8.12 (bs, 2H), 7.97-7.85 (m, 4H), 7.67 (d, J= 7.6 Hz, 2H), 7.51 (d, J= 4.4 Hz, 1H), 7.46-7.44 (m, 1H), 4.84 (d, J= 4.8 Hz, 1H), 4.56 (bs, 1H), 4.47 (bs, 1H), 4.21-4.16 (m, 4H), 3.75 (bs, 1H), 3.56-3.41 (m, 14H), 3.20-2.70 (m, 16H), 2.17 (bs, 1H), 2.07 (bs, 1H), 1.95 (bs, 2H), 1.07 (s, 18H).

[0290] Synthesis of the conjugates of Examples 3 and 4 An exemplary synthetic procedure for obtaining the conjugates of Examples 3 and 4 detailed in Table 1 is shown in the scheme below.

[0291] [ka]

[0292] Synthesis of intermediates Preparation 1 4-Hydroxyquinazolin-6-yl acetate (2) A mixture of quinazoline-4,6-diol (5 g, 30.86 mmol; Combi-blocks), acetic anhydride (46.6 mL, 49.38 mmol; Spectrochem) and pyridine (8 mL; Spectrochem) was heated at 100° C. for 2 h under nitrogen. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (5% methanol in dichloromethane). After completion, the reaction was cooled to room temperature and the reaction mixture was poured onto crushed ice (50 mL). This resulted in a pale yellow precipitate. The solid was collected by filtration, washed with fresh ice-cold water (200 mL) and dried under vacuum to give the desired compound as a pale yellow solid. The title compound was determined by LC-MS and NMR (Hz) NMR (Hz): δ 1.0 (1H), 1.5 (1H), ... 1 Characterized by H NMR analysis. Yield: 6.3 g (100%). LC-MS C 10 H 8 N 2 O 3 Calculated 204.05; Observed 205.25 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.74 (bs, 1H), 8.06-8.02 (m, 2H), 7.80 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 2.37 (s, 3H).

[0293] Preparation 2 4-Chloroquinazolin-6-yl acetate (3) To a mixture of 4-hydroxyquinazolin-6-yl acetate (6.3 g, 30.86 mmol) and thionyl chloride (43.05 g, 26.25 mL, 361.8 mmol; Spectrochem) was added a catalytic amount of dry N,N-dimethylformamide (DMF, 0.3 mL) under nitrogen. The resulting mixture was heated at 90° C. for 3 h. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (5% methanol in dichloromethane). Upon completion, the reaction was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (50 mL) and dried under vacuum to give the desired compound as a pale yellow solid. The title compound was identified by LC-MS and NMR (Hz) NMR (Hz): δ 1.0 (1H), 1.5 (1H), ...0 (1H), 1.5 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H 1 Characterized by H NMR analysis. Yield: 6.8 g (100%). LC-MS, C 10 H 7 ClN 2 O 2 Calculated 222.02; Observed 223.15 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 9.08 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.76 (d, J=9.2 Hz, 1H), 2.42 (s, 3H).

[0294] Preparation 3 4-Chloroquinazolin-6-ol (4) A mixture of 4-chloroquinazolin-6-yl acetate (19 g, 85.30 mmol) and ammonia (7N in methanol; 400 mL; Hychem laboratories) was stirred at room temperature for 1 h. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (5% methanol in dichloromethane). After completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether (10 mL) and dried under vacuum to give the desired compound as a dark brown solid, which was carried on to the next step without further purification. The title compound was characterized by LC-MS analysis. Yield: 13.3 g (86.6%). LC-MS C 8 H 5 ClN2 Calculated: 180.01; Observed: 181.20 [M+H] + .

[0295] Preparation 4 Methyl 6-hydroxyquinazoline-4-carboxylate (5) A stirred solution of 4-chloroquinazolin-6-ol (13.3 g, 73.6 mmol), triethylamine (30.6 mL, 220.9 mmol; Spectrochem) in dry methanol (200 mL) was purged with nitrogen for 20 minutes at room temperature. 2 dppf (5.3 g, 7.36 mmol; Chempure) was added and the resulting mixture was heated at 60° C. under CO pressure (5 kg). The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (5% methanol in dichloromethane). After completion, the reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to give the crude compound. The crude was subjected to silica gel (100-200) column chromatography using 10-50% ethyl acetate in n-hexane to give the desired compound as a pale yellow solid. The title compound was purified by LC-MS and 1 Characterized by H NMR analysis. Yield: 8.6 g (57.3%). LC-MS C 10 H 8 N 2 O 3 Calculated 204.05; Observed 205.25 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 10.76 (s, 1H), 9.21 (s, 1H), 8.01 (d, J=9.2 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=9.2 Hz, 1H), 4.02 (s, 3H).

[0296] Preparation 5 6-Hydroxyquinazoline-4-carboxylic acid (6) To a stirred solution of methyl 6-hydroxyquinazoline-4-carboxylate (8.6 g, 42.1 mmol) in tetrahydrofuran:methanol:water (6:1:0.5; 75 mL) was added sodium hydroxide (4.2 g, 105.3 mmol) and the mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC analysis (5% methanol in dichloromethane). After completion, the reaction mixture was concentrated to one third of the volume under reduced pressure. The pH of the solution was adjusted to 7 using concentrated hydrochloric acid (HCl). The initially formed solid was removed by filtration and the filtrate was further acidified to pH=1 using concentrated HCl. The yellow solid formed was filtered off, washed with fresh water and dried under vacuum to give the desired compound as a pale yellow solid. The title compound was identified by LC-MS and NMR (Hz) NMR (Hz): δ 1.0 (1H), 1.5 (1H), ...0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1H), 1.0 (1 1 Characterized by H NMR analysis. Yield: 5.3 g (66.6%). LC-MS C 9 H 6 N 2 O 3 Calculated 190.04; Observed 191.20 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 14.12 (bs, 1H), 10.69 (s, 1H), 9.19 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J=9.6 Hz, 1H).

[0297] Preparation 6 (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)-6-hydroxyquinazoline-4-carboxamide (8) To a stirred solution of HBTU (9.09 g, 24.0 mmol; Spectrochem) in dry N,N-dimethylformamide (DMF, 70 mL) was added 6-hydroxyquinazoline-4-carboxylic acid (3.8 g, 20.0 mmol), hydroxybenzotriazole (HOBt, 6.1 g, 40.0 mmol; Spectrochem) and diisopropylethylamine (8.9 mL, 50.0 mmol; Spectrochem). Following this, (S)-1-glycylpyrrolidine-2-carbonitrile (4.8 g, 30.0 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (10% methanol in dichloromethane). After completion of the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude compound was subjected to silica gel (230-400) column chromatography using 5-10% methanol in dichloromethane to give the desired compound as a pale yellow solid. The title compound was characterized by LC-MS analysis. Yield: 3.2 g (49.0%). LC-MS C 16 H 15 N 5 O 3 Calculated 325.12; Observed 326.05 [M+H] + .

[0298] Preparation 7 tert-Butyl (S)-(3-((4-((2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)carbamate (10) To a solution of (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)-6-hydroxyquinazoline-4-carboxamide (3.2 g, 9.8 mmol) in dry DMF (32 mL) under nitrogen was added K 2 CO 3(1.6 g, 11.81 mmol; Spectrochem) and tert-butyl (3-bromopropyl)carbamate (2.8 g, 11.81 mmol; BLD-pharma) were added. The resulting mixture was stirred at 60° C. for 24 h. The progress of the reaction was monitored by TLC analysis (10% methanol in dichloromethane). After completion, the reaction was cooled to room temperature and water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude compound was purified by flash silica gel (230-400) column chromatography using 5-6% methanol in dichloromethane to give the desired compound as a pale yellow solid. The desired compound was purified by LC-MS and HPLC. 1 Characterized by H NMR analysis. Yield: 3.4 g (72.0%). LC-MS C 24 H 30 N 6 O 5 Calculated value 482.23; observed value 481.15 [MH] - . 1 H NMR (400 MHz, DMSO): δ 9.30-9.28 (m, 2H), 8.44 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 6.96 (s, 1H), 4.83 (bs, 1H), 4.25 (d, J=5.2 Hz, 2H), 4.15 (s, 2H), 3.74 (bs, 1H), 3.58-3.54 (m, 1H), 3.14 (d, J=5.6 Hz, 2H), 2.19-2.07 (m, 4H), 1.95-1.92 (m, 2H), 1.37 (s, 9H).

[0299] Preparation 8 (S)-6-(3-aminopropoxy)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinazoline-4-carboxamide (11) To a solution of tert-butyl (S)-(3-((4-((2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)carbamate (3.4 g, 7.0 mmol) in dichloromethane (DCM, 34 mL) under inert atmosphere was added trifluoracetic acid (2.1 mL, 28.2 mmol; Spectrochem). The resulting mixture was stirred at room temperature for 24 h. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (15% methanol in dichloromethane). After completion, the reaction mixture was concentrated under reduced pressure and the residue was co-distilled with fresh dichloromethane (20 mL×3). Finally, the residue was triturated with diethyl ether (20 mL) and dried under vacuum to give the desired compound as a light brown solid in quantitative yield. The crude compound was carried to the next step without further purification. The desired compound was characterized by LC-MS analysis. 19 H 22 N 6 O 3 Calculated 382.18; Observed 383.35 [M+H] + .

[0300] Preparation 9 (9H-Fluoren-9-yl)methyl((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)-1-oxopropan-2-yl)carbamate (12) (S)-6-(3-aminopropoxy)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinazoline-4-carboxamide (1.8 g, 4.71 mmol) and Fmoc-(n-beta-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-l-alpha,beta-diaminopropionic acid (2.5 g, 5.1 mmol; Argonix Reagents & Chemicals) in dry N,N-dimethylformamide (DMF, 20 mL). To a stirred solution of 2,4,6-collidine (4.2 mL, 31.4 mmol; Spectrochem), 1-hydroxy-7-azabenzotriazole (HOAt, 1.2 g, 9.4 mmol; Spectrochem) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 3.0 g, 9.4 mmol; Spectrochem) were added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (15% methanol in dichloromethane). After completion of the reaction, ice-cold water (100 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 silica) column chromatography using 5-10% methanol in dichloromethane to give the desired compound as an off-white solid. 1 Characterized by H NMR analysis. Yield: 1.3 g (30%). LC-MS C 47 H 50 N 8 O 8 Calculated 854.38; Observed 855.65 [M+H] + . 1H NMR (400 MHz, DMSO): δ 13.48 (d, J=7.6 Hz, 1H), 9.27 (s, 1H), 8.55-8.46 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.71-7.62 (m, 4H), 7.40-7.37 (m, 2H), 7.30-7.28 (m, 2H), 4.81 (bs, 1H), 4.58 (bs, 1H), 4.28-4.18 (m, 8H), 3.71 (bs, 1H), 3.53-3.51 (m, 1H), 3.37 (bs, 1H), 2.46 (s, 3H), 2.22-1.98 (m, 11H), 1.09 (t, J=6.4 Hz, 2H), 0.91 (s, 6H).

[0301] Preparation 10 (9H-Fluoren-9-yl)methyl((R)-3-amino-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-1-oxopropan-2-yl)carbamate (13) To a stirred solution of (9H-fluoren-9-yl)methyl((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)-1-oxopropan-2-yl)carbamate (0.62 g, 0.65 mmol) in ethanol (6 mL) was added hydrazine hydrate (25%, 0.3 mL; Spectrochem). The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (15% methanol in dichloromethane). After completion of the reaction, water (30 mL) was added and the resulting mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (100-200 silica) column chromatography using 5-10% methanol in dichloromethane to give the desired compound as an off-white solid. The desired compound was identified by LC-MS and HPLC. 1 Characterized by H NMR analysis. Yield: 0.42 g (100%). LC-MS C 37H 38 N 8 O 6 Calculated value 690.29; Observed value 691.50 [M+H] + 。 1 H NMR (400 MHz, ): δ 9.29 - 9.27 (m, 2H), 8.45 (s, 1H), 8.11 (bs, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.73 - 7.66 (m, 3H), 7.40 - 7.31 (m, 4H), 4.82 (bs, 1H), 4.27 - 4.17 (m, 8H), 3.72 (bs, 1H), 3.53 - 3.52 (m, 1H), 3.29 - 3.27 (m, 4H), 3.02 (bs, 1H), 2.17 - 1.91 (m, 6H), 1.09 (t, J = 6.0 Hz, 2H).

[0302] Preparation 11 (9H-Fluoren-9-yl)methyl ((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)carbamate (14) (Example 13) (9H-fluoren-9-yl)methyl ((R)-3-amino-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-1-oxopropan-2-yl)carbamate (0.42 g, 0.61 mmol) and 4-(di-tert-butylfluorosilyl)benzoic acid (SiFA-BA, 0.25 g) in dry N,N-dimethylformamide (DMF, 5 mL), To a stirred solution of 1,2-dichloromethane (0.89 mmol), N,N-diisopropylethylamine (DIPEA, 0.72 mL, 4.0 mmol; Spectrochem), 1-hydroxy-7-azabenzotriazole (0.122 g, 0.9 mmol; Spectrochem) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 0.28 g, 0.9 mmol; Spectrochem) were added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC analysis (10% methanol in dichloromethane). After completion of the reaction, water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 silica) column chromatography using 1-10% methanol in dichloromethane to give the desired compound as an off-white solid. The desired compound was characterized by LC-MS analysis. Yield: 0.4 g (70%). LC-MS C 52 H 59 FN 8 O 7 Si calculated 954.43; observed 955.65 [M+H] + .

[0303] Preparation 12 6-(3-((R)-2-amino-3-(4-(di-tert-butylfluorosilyl)benzamido)propanamido)propoxy)-N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinazoline-4-carboxamide (15) To a stirred solution of (9H-fluoren-9-yl)methyl ((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)carbamate (0.4 g, 0.41 mmol) in dimethylformamide (DMF, 3 mL) was added dropwise a solution of piperidine (0.04 mL, 0.50 mmol; Spectrochem) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by thin layer chromatography (TLC) analysis (15% methanol in dichloromethane). After completion of the reaction, water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (70 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 silica) column chromatography using 5-12% methanol in dichloromethane to give the desired compound as an off-white solid. The desired compound was identified by LC-MS and HPLC. 1 Characterized by H NMR analysis. Yield: 0.22 g (73%). LC-MS C 37 H 49 FN 8 O 5 Si calculated 732.36; observed 733.65 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 9.31-9.26 (m, 2H), 8.84 (bs, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 8.01 (d, J=7.6 Hz, 3H), 7.74-7.64 (m, 3H), 7.10 (bs, 3H), 4.82 (bs, 1H), 4.66 (bs, 1H), 4.25-4.13 (m, 4H), 3.73 (bs, 1H), 3.53-3.52 (m, 1H), 3.35-3.09 (m, 3H), 2.50-2.07 (m, 6H), 1.23 (s, 18H).

[0304] Preparation 13 Tri-tert-butyl 2,2',2''-(10-((R)-1-(tert-butoxy)-5-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (16) A mixture of 6-(3-((R)-2-amino-3-(4-(di-tert-butylfluorosilyl)benzamido)propanamido)propoxy)-N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinazoline-4-carboxamide (0.22 g, 0.30 mmol) and 1,4,7,10-tetraazacyclodosecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA(tBu)) in dichloromethane (4 mL). 4 To a stirred solution of N,N-diisopropylethylamine (DIPEA, 0.16 mL, 0.90 mmol; Spectrochem) was added under nitrogen. This was followed by the addition of 1-propanephosphonic anhydride (50% in ethyl acetate, 0.28 mL, 0.90 mmol; Spectrochem). The resulting mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC analysis (15% methanol in dichloromethane). After completion of the reaction, water (30 mL) was added and the resulting mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 silica) column chromatography using 10-15% methanol in dichloromethane to give the desired compound as an off-white solid. The desired compound was identified by LC-MS and NMR (Hz) NMR (Hz) δ 100-150 Hz, 400-400 Hz, 500-500 Hz, 600-650 Hz, 700-750 Hz). 1 Characterized by H NMR analysis. Yield: 0.29 g (69.0%). LC-MS C 72 H 111 FN 12 O 14 Si calculated value 1414.81; observed value 1413.85 [MH] - . 1H NMR (400 MHz, DMSO): δ 9.31-9.28 (m, 2H), 8.56-8.47 (m, 2H), 8.16 (bs, 1H), 8.09 (bs, 1H), 8.02-7.90 (m, 3H), 7.73-7.63 (m, 3H), 4.81 (bs, 1H), 4.47 (bs, 1H), 4.24-4.13 (m, 5H), 3.72 (bs, 1H), 3.54-3.52 (m, 2H), 3.30 (bs, 3H), 3.16 (d, J=5.2 Hz, 2H), 3.03-3.00 (m, 5H), 2.85-2.70 (m, 4H), 2.33-1.83 (m, 21H), 1.40 (s, 36H), 1.08 (s, 18H).

[0305] Synthesis of the conjugates of Examples 3 and 4 Preparation 14 - Compound of Example 3 2,2',2''-(10-((R)-1-carboxy-4-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (17) Tri-tert-butyl 2,2',2''-(10-((R)-1-(tert-butoxy)-5-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazo in trifluoroacetic acid (TFA):triisopropylsilane (TIS):water (95:2.5:2.5, 22 mL; Spectrochem). A solution of (4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (0.29 g, 0.20 mmol) was stirred at room temperature for 36 hours under nitrogen. The progress of the reaction was monitored by LC-MS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous liquid. The residue was triturated with methyl tert-butyl ether (20 mL x 3) followed by n-pentane (10 mL) resulting in the formation of a solid. The solid was dried under vacuum to give the desired compound as a light brown solid. The desired compound was characterized by LC-MS analysis. Yield: 0.19 g (77.8%, crude). LC-MS C56 H 79 FN 12 O 14 Si calculated value 1191.56; observed value 1189.70 [MH] - .

[0306] Preparation 15 - Compound of Example 4 2-(16-((R)-1-carboxy-4-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-4-oxobutyl)-3,6-dioxo-4,5-dioxa-1,8,11,16-tetraazabicyclo[6.5.5]octadecane-11-yl)gallium(I)acetate (18, Ga-(S,R,R)-SiFA-FAP-2) To a stirred solution of 2,2',2''-(10-((R)-1-carboxy-4-(((R)-1-((3-((4-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinazolin-6-yl)oxy)propyl)amino)-3-(4-(di-tert-butylfluorosilyl)benzamido)-1-oxopropan-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (crude, 0.19 g, 0.16 mmol) in tert-butanol:water (3:1, 7.3 mL) under nitrogen was added gallium(III) nitrate (0.082 g, 0.32 mmol; Sigma Aldrich) and the resulting mixture was heated at 75°C for 3 h. The progress of the reaction was monitored by LC-MS analysis. After completion, the reaction was cooled to room temperature and water (10 mL) was added. The resulting mixture was filtered through a microfilter and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with methyl tert-butyl ether (10 mL x 3) and diethyl ether (10 mL). The sticky residue was dried under high vacuum to give a pale yellow solid. The crude compound was purified by reverse phase HPLC; mobile phase A: A: 0.1% formic acid in water and mobile phase B: acetonitrile; column: Waters XBridge Prep C18 250 x 19 mm, 5 μm to give the desired compound as an off-white solid. Yield: 13 mg (6.5%). LC-MS C 56 H 76 FGaN 12 O 14 Si calculated 1256.46; observed 1257.80 [M+H] + . 1H NMR (400 MHz, DMSO): δ 9.33-9.27 (m, 2H), 8.61 (m, 1H), 8.46 (bs, 1H), 8.16 (bs, 2H), 8.02-7.91 (m, 3H), 7.75-7.65 (m, 3H), 4.84 (bs, 1H), 4.57 (bs, 1H), 4.45 (bs, 1H), 4.25-4.17 (m, 4H), 3.73 (bs, 1H), 3.48 (m, 4H), 3.30-2.70 (m, 23H), 2.18-1.83 (m, 11H), 1.02 (s, 18H); HPLC: 7.730 min; 90.6%, Column: XBridge C18 250×4.6, 5 μm, Mobile phase A: H 2 0.1% formic acid in O; mobile phase B: acetonitrile.

[0307] Synthesis of conjugates of Examples 5 to 10 The conjugates of Examples 5 to 10 may be prepared according to the following schemes.

[0308] [ka]

[0309] The above steps 1 to 5 can be carried out according to a published method (WO2019 / 020831): Step 1: a) 20% piperidine, (DMF); b) (tBuO)EuE(OtBu) 2, HOBt, TBTU, DIPEA, (DMF); Step 2: a) 2% hydrazine (DMF); b) succinic anhydride, DIPEA, (DMF); c) Fmoc-D-Lys-OAll-HCl, HOBt, TBTU, DIPEA, (DMF); Step 3: a) 20% piperidine, (DMF); b) Fmoc-D-Dap(Dde)-OH, HOBt, TBTU, DIPEA, (DMF); c) Imidazole, hydroxylamine hydrochloride, (NMP, DMF); Step 4: a) SIFA-BA (WO2019 / 020831), HOBt, TBTU, DIPEA (DMF); b) 20% piperidine, (DMF); Step 5: DOTAGA anhydride, DIPEA, (DMF).

[0310] Example 5

[0311] [ka]

[0312] Example 6

[0313] [ka]

[0314] Example 7 The synthesis of (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (step 6 above) is carried out according to the method described by Jansen et al. (ACS Med. Chem. Lett. 2013, 4, 491-496).

[0315] [ka]

[0316] [ka]

[0317] Step 6: a) HATU, DIPEA, (DMF); b) cleavage: TFA TIS, water; c) final deprotection: TFA. Examples 8 and 8a

[0318] [ka]

[0319] Examples 9 and 10

[0320] [ka]

[0321] The synthesis of (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile (step 6) is carried out according to the method described by Jansen et al. (ACS Med. Chem. Lett. 2013, 4, 491-496).

[0322] [ka]

[0323] radioactive label General information Carrier-free Fluorine-18 is available from Curium Pharma at a concentration of over 97%. 18 O]H 2 The O target (Bruce Technology) 2.8 mL was irradiated with a PETtrace cyclotron (16 MeV proton beam, GE Healthcare) 18 O(p,n) 18 Radioactive instant thin layer chromatography (radioactive ITLC) analysis was performed using a mini GITA Dual radioactive TLC instrument (Elysia-Raytest). 2 CO 3Measurements were performed using silica gel impregnated chromatography paper (Varian Inc.) eluted with 0.1 M aqueous solution for 4 min. Analytical HPLC measurements were performed on a system consisting of an Agilent HP Series 1100 (Hewlett Packard, Les Ulis, France) coupled with a Flo-one A500 Radiomatic detector (Packard, Canberra, Australia). Separation was performed on a C-18 column (Kinetex® EVO C18, 5 μm, 4.6 × 150 mm, 100 Å, equipped with a guard column) using the following solvent conditions: water containing 0.1% trifluoroacetic acid (solvent A) and acetonitrile containing 0.1% trifluoroacetic acid (solvent B); 0 to 10 min: gradient elution from 99% to 0% A at a flow rate of 1 mL / min, λ = 254 and 214 nm. Anhydrous K[ 18 Preparation of [F]F-K222-carbonate complexes was carried out using a SynChrom R&D EVOI synthesis module (Raytest). Oasis HLB Plus LP cartridges (60 μm), Sep-Pak® Light Accell Plus QMA carbonate cartridges (46 mg, 45 μm) and Sep-Pak® light C18 Plus cartridges (130 mg, 55-105 μm) were purchased from Waters. All radiolabeled compounds were compared to standard non-radioactive material by TLC or analytical HPLC and should be free of significant UV-absorbing chemical and radiochemical impurities.

[0324] Example 11 ([ 18 Radiosynthesis of [F]-Ga-(S,R,R)-SiFA-FAP-1) In the SynChrom R&D EVOI synthesis module, 18 O]H 2 [ 18 F]F -An aqueous solution of (2.67 GBq in 12 h 16 min) was passed through an anion exchange resin (Sep-Pak® Light Accell Plus QMA carbonate ion cartridge 46 mg) preconditioned with deionized water (10 mL) and air (10 mL). A solution of potassium carbonate (2.8 mg) and Kryptofix (K222, 21 mg) in a mixture of water (200 μL) and acetonitrile (700 μL) was then passed through the cartridge to elute the radioactivity into the reactor. After 30 s of helium bubbling, azeotropic drying of the mixture was carried out under vacuum and helium flow at 100 °C for 3 min. After cooling to 30 °C, acetonitrile (1 mL) was added to the reactor. After 30 s of helium bubbling, the reaction mixture was evaporated to dryness under vacuum and helium flow at 110 °C for 3 min. After cooling to 30° C., a freshly prepared solution of the compound of Example 2 (66 μg, 52 nmol) and acetic acid (9 μL) in anhydrous DMSO (500 μL) was added to the dried reactor. The solution was stirred for 10 s and transferred into a closed glass vial containing a magnetic stirrer. The reaction mixture was then stirred for 10 min at room temperature, diluted with water (20 mL) and passed through an Oasis HLB Plus cartridge. It was washed with water (10 mL), dried with air (20 mL) and the radioactivity was recovered from the cartridge using absolute ethanol (2 mL) and air (3 mL). After evaporation under vacuum, the final product was formulated in saline (0.9% NaCl, 0.5 mL). Total synthesis time: 61 min. Decay-corrected radiochemical yield: 57%. At the end of the radiosynthesis, the radiochemical purity of the radiotracer was confirmed using analytical radioactive RP-HPLC measurements (>99%, FIG. 1).

[0325] biological activity The studies on binding affinity in vitro and biodistribution in vivo were carried out.

[0326] In vivo PET imaging and biodistribution Human glioblastoma U87-MG cell line was purchased from ATCC. Cells were cultured in EMEM (supplemented with 2 mM L-glutamine, 10% fetal bovine serum and 0.1 mM NEAA) at 37° C. in a humidified atmosphere (5% CO2, 95% air).

[0327] All animal experiments were performed in accordance with the guidelines of the Federation for Laboratory Animal Science Associations. Healthy female Swiss nude (Crl:NU(Ico)-Foxn1nu) mice (5-6 weeks old) were purchased from Charles River. Mice were irradiated 24-72 hours before tumor cell inoculation (total body irradiation, 2 Gy / mouse) and then inoculated with U87-MG cells (1 × 10 in 200 μL of RPMI1640). 7 1 piece) was injected subcutaneously into the right shoulder flank.

[0328] Female Swiss nude (Crl:NU(Ico)-Foxn1nu) mice (n=4), each bearing a subcutaneous U87-MG tumor in the right flank, were administered the radiolabeled compound of Example 11 ([ 18 [F]-Ga-(S,R,R)-SiFA-FAP-1) (8 ± 1.5 MBq, 100 μL per mouse) was administered intravenously into the tail vein (approximately 3 weeks after inoculation of U87-MG cells). Static PET imaging was performed under anesthesia (2% isoflurane) using a small animal PET scanner (eXploreVISTA, GE) 60 min after radiotracer administration (n = 3). Whole-body PET imaging was performed for 20 min across two bed positions. Regions of interest were created and radiotracer uptake in tissues was calculated as % injected dose per volume of region of interest (%ID / cm). 3 Immediately after PET imaging, mice (n=4) were sacrificed and selected tissues (blood, tumor, heart, lung, liver, kidney, spleen, pancreas, intestine, bone, muscle, tail) were harvested and weighed. Radioactivity in collected samples was determined using gamma counting (Packard). Radiotracer uptake was calculated as % injected dose per gram of tissue (%ID / g).

[0329] result The radiolabeled compound of Example 11 ([ 18 Tumor uptake of [F]-Ga-(S,R,R)-SiFA-FAP-1) was monitored using both PET imaging (Table 2, Figure 2) and biodistribution analysis by gamma counting of excised tissues (Tables 3a and 3b, Figure 3). PET imaging demonstrated more than four-fold higher radiotracer uptake in tumor compared to muscle (Table 2, Figure 2). Biodistribution analysis demonstrated eight-fold higher radiotracer uptake in tumor compared to muscle (Tables 3a and 3b, Figure 3).

[0330] [Table 2]

[0331] [Table 3a]

[0332] [Table 3b]

[0333] In vitro FAP binding affinity The binding affinity of non-radiolabeled compounds Example 2 (Ga-(S,R,R)-SiFA-FAP-1) and Example 1 ((S,R,R)-SiFA-FAP-1) was assessed in vitro using grating binding interferometry (GCI) and waveRAPID kinetics assays (Kartal O et al., SLAS Discov. 2021 Sep;26(8):995-1003).

[0334] To assess target binding of compounds, FAPs were immobilized on a streptavidin sensor chip. Briefly, streptavidin chips were conditioned with borate buffer and activated with EDC-NHS solution. Immobilization was achieved by amine coupling to the surface on the amine-reactive sensor chip (NeutrAvidin sensor chip), and unused amine-reactive groups were deactivated with ethanolamine. FAPs were immobilized by NeutrAvidin capture of biotinylated FAPs, and the remaining NeutrAvidin was quenched with biocytin. Compound binding to immobilized FAPs was assessed using a waveRAPID kinetics assay with different concentrations of each compound in 1x PBS pH 7.4, 1 mM DTT, 0.005% Tween, 2% DMSO. Binding affinity to FAPs was measured using the K D reported as.

[0335] result The binding affinities for both compounds were in the pM range (Table 4).

[0336] [Table 4]

Claims

1. In a single molecule, two distinct moieties: (a) one or more ligands capable of binding to fibroblast activation protein (FAP), and (b) A silicon fluoride acceptor (SIFA) moiety comprising a covalent bond between silicon and a fluorine atom, wherein the SIFA is １８ the SIFA moiety optionally labeled with F A ligand-SIFA conjugate comprising, or a pharmaceutically or diagnostically acceptable salt or solvate thereof.

2. (c) one or more chelate moieties optionally containing chelated non-radioactive or radioactive cations The conjugate according to claim 1, further comprising.

3. One or more ligands capable of binding to fibroblast activation protein (FAP) are each independently one or more heterocyclic groups selected from optionally substituted pyrrolidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyridinyl. The conjugate according to claim 1, comprising.

4. Formula (4), (4a) or (4b): 【Chemical 1】 [wherein, X １ , X ２ and X ３ represent a divalent linking group, where X １ , X ２ and X ３ together with the groups to which they are attached contain one or more amide bonds, FAP represents a ligand capable of binding to fibroblast activation protein (FAP), L is an optionally substituted linker group, SIFA represents a silicon fluoride acceptor (SIFA) moiety containing a covalent bond between silicon and a fluorine atom, CM represents a chelate moiety optionally containing chelated non-radioactive or radioactive cations] The conjugate according to claim 2, which is a conjugate of, or a salt thereof.

5. X １ is an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds, wherein the optional substituent is -X ３ -FAP, CO ２ H and CH ２ OH, and is selected from X ２ is an optionally substituted linker of 1 to 5 atoms containing one or more amide bonds, where, in the compound of formula (4) or (4b), X ２ may also be —NH— or represent a bond, X ３ is an optionally substituted linker of 10 to 20 atoms containing one or more amide bonds, wherein the optional substituent is CO ２ H and CH ２ OH, the conjugate according to claim 4, wherein the conjugate is selected from the group consisting of

6. The silicon fluoride acceptor (SIFA) moiety has the formula (3): 【Chemical 2】 [wherein, R １Ｓ and R ２Ｓ are each independently a linear, branched or cyclic C ３ -C １０ alkyl group, R ３Ｓ is a C １ -C ２０ hydrocarbon group containing one or more aromatic and / or aliphatic units and / or up to three heteroatoms selected from O and S, The SIFA moiety is 【Chemical 3】 The conjugate according to claim 1, comprising a structure represented by being attached to the remainder of the conjugate via a marked bond].

7. The silicon fluoride acceptor (SIFA) moiety has the formula (3a): 【Chemical Formula 4】 Wherein t-Bu represents a tert-butyl group]. The conjugate according to claim 6, comprising a structure represented by

8. The chelate moiety is (i) a macrocyclic ring structure having 8 to 20 ring atoms, at least two of which are heteroatoms selected from oxygen atoms and nitrogen atoms, (ii) an acyclic open-chain chelate structure having 8 to 20 main chain atoms, at least two of which are heteroatoms selected from oxygen atoms and nitrogen atoms, or (iii) a branched chelate structure containing a quaternary carbon atom The conjugate according to claim 2, comprising at least one of.

9. The chelating moiety is bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A) 1,4,7,10-tetracyclododecane-N,N',N'',N''' -tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), 1,4,7,10 tetraazacyclododecane N,N',N'',N''' 1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP), diethylenetriamine N,N',N'' penta(methylene)phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), the tetra 3-hydroxy-N-methyl-2-pyridinone chelator abbreviated as Me-3,2-HOPO (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,(2-Dihydropyridine-4-carboxamide)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methylenediaminetetraacetic acid (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N''' -tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazonane-1-yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraaminehexaacetic acid (TTHA), the conjugate according to claim 8, selected from.

10. The conjugate according to claim 9, wherein the chelate moiety is 1,4,7,10-tetracyclododecane-N,N',N'',N''' - tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) or 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP).

11. The chelate moiety is ４３ Sc, ４４ Sc, ４７ Sc, ６１ Cu, ６４ Cu, ６７ Cu, ６７ Ga, ６８ Ga, ９０ Y, １１１ In, １４９ Tb, １５２ Tb, １５５ Tb, １６１ Tb, １６６ Ho, １７７ Lu, １８６ Re, １８８ Re, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac, and ２２７ a chelated cation selected from the cations of Th or １８ a cationic molecule containing F, the conjugate according to claim 9.

12. The fluorine atom of SIFA is １８ F, and the conjugate according to claim 1.

13. The conjugate according to claim 1, wherein the FAP binding moiety comprises a substituted pyrrolidine ring.

14. The FAP binding moiety is of formula (2): 【Chemical Formula 5】 [wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ are independently selected from H, OH, B(OH) ２ , CO ２ H, CN, halo, C １～６ alkyl and -O-C １～６ alkyl, R ９ and R １０ each independently has a moiety having H or C １～６ alkyl], the conjugate according to claim 1

15. Formula (2a): 【Chemical Formula 6】 [wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ are independently selected from H, OH, B(OH) ２ , CO ２ H, CN, halo, C １～６ alkyl and -O-C １～６ alkyl, R ９ and R １０ are each independently H or C １～６ alkyl, n is from 0 to 3, X is a 5- to 10-membered N-containing monocyclic or bicyclic heterocyclic ring, and the heterocyclic ring optionally further contains 1, 2 or 3 heteroatoms selected from O, N and S, C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl and -NR ２０ R ２１ is optionally substituted with one to three substituents selected from, where R ２０ and R ２１ are independently selected from H and C １～６ alkyl], the conjugate according to claim 13, comprising a moiety having

16. The conjugate according to claim 15, wherein n is 0.

17. X is 【Chemical Formula 7】 selected from, the conjugate according to claim 15.

18. The conjugate according to claim 14, R ３ and R ４ is F, R ７ is CN, R １ 、R ２ 、R ５ 、R ６ 、R ８ 、R ９ and R １０ are H, conjugate.

19. The FAP binding moiety is 【Chemical Formula 8-1】 【Chemical Formula 8-2】 [wherein m is from 0 to 10] and comprises a moiety selected from the group consisting of, the conjugate according to claim 1.

20. The conjugate according to claim 1, wherein the FAP binding moiety comprises a cyclic peptide.

21. The FAP binding moiety is 【Chemical Formula 9】 selected from the group consisting of, the conjugate according to claim 1.

22. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 selected from the group consisting of, the conjugate according to claim 1.

23. A pharmaceutical composition or a diagnostic composition comprising or consisting of one or more conjugates or compounds according to any one of claims 1 to 22.

24. The composition according to claim 23, for use in medicine.

25. The composition according to claim 23, for use as a cancer diagnostic or imaging agent.

26. The composition according to claim 23, for use in the treatment of cancer.

27. The composition according to claim 23, for use in the diagnosis or treatment of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders.

28. The composition for use according to claim 27, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumor, tumor-induced osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic cancer, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer.

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