Inhibitor of fibroblast activating protein

Abstract

The present invention relates to a compound of formula I or its stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates or solvates. The present invention also relates to a pharmaceutical composition comprising said compound. The present invention also relates to said pharmaceutical composition or said compound for use as a medicament for the purpose of use in the prevention and / or treatment of diseases.

Description

Technical Field

[0001] The present invention relates to a compound of formula I or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof. The present invention further relates to pharmaceutical compositions and their use.

Background Art

[0002] Fibroblast activation protein (FAP), also known as FAPα, Seprase or α2 - antiplasmin converting enzyme, is a type II membrane - intrinsic serine protease belonging to the prolyl oligopeptidase family S9, which includes DPPIV, DPP8, DPP9 and PREP enzymes. The characteristic of this family is having exo - dipeptidyl peptidase (DPP) activity. The characteristic of this family is the ability to cleave post - proline bonds. DPPIV, DPP8 and 9 and FAP have exopeptidase activity to release dipeptides from peptides having proline at the second position. PREP has endopeptidase activity and FAP has both endo - and exo - exopeptidase activities. FAP is mainly found as a cell - surface homodimer, but it has also been reported to form heterodimers with DPPIV in vivo. The claimed physiological substrates for FAP endopeptidase activity include α2 - antiplasmin, type I collagen, gelatin and fibroblast growth factor 21 (FGF21), and the exopeptidase activities include neuropeptide Y, B - type natriuretic peptide, substance P and peptide YY.

[0003] FAP is involved in pathological processes involving proliferation, tissue remodeling, chronic inflammation and / or fibrosis, including but not limited to fibrotic diseases, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related diseases with cartilage degradation, atherosclerotic diseases and Crohn's disease. Given the numerous reports in the literature on the role of FAP in (patho)physiology, it would be reasonable to anticipate further and / or potential uses of inhibitors in disease areas characterized by: (a) invasion, metastasis and proliferation (including but not limited to cancer); (b) tissue remodeling and / or chronic inflammation (including but not limited to fibrotic diseases, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders with cartilage degradation); (c) endocrine disorders (including but not limited to glucose metabolism disorders).

[0004] One of the most potent and selective FAP inhibitors reported to date is UAMC1110 (also referred to as "cmpd.60" in the scientific literature). This is an orally bioavailable molecule with a promising biopharmaceutical profile, reported and patented by the inventors of the present application (see, for example, Jansen et al. J. Med. Chem. 2014, 3053-3074 and WO 2013107820). During the past few years, chemical derivatives of UAMC1110 with specific functionalities (e.g., radionuclides, drugs, fluorophores) have been reported. All of these derivatives rely on UAMC1110 for efficient and selective delivery of the functionality to cells or tissues expressing FAP (e.g., tumors).

[0005] WO 2020132661 discloses compounds for modulating fibroblast activation protein. Some of the compounds described include UAMC1110 derivatives in which the quinoline moiety is substituted with a phenyl or pyridine linker.

[0006] Similarly, International Publication No. 2013 / 107820 discloses inhibitors having selectivity and specificity for FAP (fibroblast activation protein). Some of the described compounds contain a quinoline ring substituted with halo or methoxy.

[0007] For various application types (e.g., therapeutic applications, PET diagnostics, etc.), it is necessary to adjust the properties of FAP inhibitors in order to improve in vivo safety and efficacy. Furthermore, good stability and the ability to penetrate different types of tissues are desired. The present invention aims to provide a solution thereto.

Summary of the Invention

Problems to be Solved by the Invention

[0008] The present invention, in a first aspect, relates to a compound of formula I according to claim 1 or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof. Said compound comprises a linker having a quaternary ammonium cation. Compounds having a quaternary ammonium cation exhibit a better in vivo pharmacokinetic profile, are less metabolized, and often have exquisite and unprecedented selectivity with respect to PREP, a protease that is very closely related to FAP. Higher metabolic stability can be associated with advantages such as a longer half-life in vivo, lower dosage requirements, or improved image quality in the context of molecular imaging tracers. Furthermore, the polarity conferred by the quaternary ammonium group promotes higher water solubility and urinary excretion, as opposed to lipophilic linker systems that generally have low water solubility and promote secretion into the hepatobiliary system and subsequent excretion via the intestine. Secretion into the hepatobiliary system can be an undesirable feature, for example, in the context of radionuclide imaging and radionuclide therapy. Specifically, significant excretion from the intestine causes a strong background signal in diagnostic imaging applications. Similarly, in radiotherapy applications, it can impose a high radiotoxicological burden on the patient. It is notable, however, that the polarity conferred by the quaternary ammonium cation is still less than that conferred by protonated primary, secondary, and tertiary amines. In primary, secondary, and tertiary amines, the electrostatic charge is generally less shielded from the environment due to the low number of N-substituents, resulting in a high polar surface area. Furthermore, the greater the number of (alkyl-type) N-substituents in the quaternary ammonium compound, the further the polarity is reduced by the inductive stabilization of the + charge by the substituents. This means that, despite the quaternary ammonium group being a polar functional group overall, it may have significantly better tissue permeability than the corresponding protonated primary, secondary, and tertiary amines. Higher permeability can be particularly important in applications where a high-density tissue type needs to be targeted by the molecule, such as fibrotic tissue, the capping tissue of atherosclerotic plaques, or certain tumor types with extensive fibrosis (e.g., pancreatic cancer).The compounds described herein are optimized to have better pharmacokinetic properties compared to overall comparable compounds lacking a quaternary ammonium group (see below). Further, the quaternary ammonium groups in the compounds according to the invention are typically part of a relatively low molecular weight short linker moiety. Further, the radioisotopes ultimately present in these compounds are typically covalently bound to the linker. This is fundamentally different from many of the UAMC1110-derived FAP-targeting compounds known in the art. These include one or several primary, secondary or tertiary amine functions which are protonated at physiological pH and are part of a large linker system which also includes a chelator complexing the radionuclide non-covalently. These linkers often have a molecular weight exceeding 500 Da. The additional electrostatic charges present in the chelators of such high molecular weight and frequently used compounds (e.g., DOTA, NOTA or DATA) are reasonably expected to cause more limited tissue penetration compared to the quaternary ammonium-based linkers of the present invention.

[0009] In a second aspect, the invention relates to a pharmaceutical composition according to claim 10.

[0010] In a third aspect, the invention relates to the use according to claims 11, 12, 13, 14 and 15. The compounds according to the invention are preferably suitable for the diagnosis and / or treatment of FAP-related diseases (including seranostics). More particularly, said compounds can preferably be used for imaging such as PET, radiodiagnosis in situations where (tumor) cells express fibroblast activation protein (FAP). BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0012] This specification describes a compound according to formula I:

Chemical Formula

[0013] During the study of UAMC1110 derivatives, the inventors found that the nature of the linker part of these molecules is an important determinant of the biological profiles (e.g., pharmacokinetic profiles and target selectivity) of these compounds. By combining 1) the UAMC1110 moiety or a structurally related FAP inhibitory moiety with 2) a quaternary ammonium-containing linker, compounds can be obtained that have more desirable pharmacokinetic profiles and superior target selectivity compared to equivalent molecules lacking a quaternary ammonium-based linker. This discovery can be utilized to obtain new FAP inhibitors with optimized or adjusted in vivo behavior. Similarly, it can be used to obtain new functionally labeled (e.g., radiolabeled or drug-labeled) UAMC1110 derivatives with more desirable pharmacokinetic profiles and / or target selectivity.

[0014] To the best of our knowledge, the optimization or preparation of UAMC1110 derivatives by introducing a specific linker moiety has not been much studied so far.

[0015] The compounds can be used to inhibit fibroblast activation protein (FAP). In certain embodiments, the compounds are used to treat a disease or disorder mediated by FAP in an individual. Such diseases or disorders can include or be characterized by proliferation, tissue remodeling, chronic inflammation, obesity, glucose intolerance and / or insulin insensitivity. In some embodiments, the present compounds are used to diagnose and / or treat diseases characterized by proliferation, tissue remodeling, chronic inflammation, obesity, glucose intolerance and / or insulin insensitivity. A non-limiting list of such diseases includes cancer, diseases characterized by fibrosis or fibrotic lesions, atherosclerosis, arthritis and diabetes.

[0016] Definitions Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention belongs. As further guidance, definitions of terms for better understanding of the teachings of the present invention are included.

[0017] As used herein, the following terms have the following meanings:

[0018] As used herein, "a", "an", and "the" refer to both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more compartments.

[0019] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range as well as the recited endpoints.

[0020] As used herein, "alkyl", unless otherwise specified, refers to a saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having the specified number of carbon atoms (i.e., C1-C 10 means 1 to 10 carbon atoms) or a combination thereof, and includes the same. Specific alkyl groups include those having 1 to 20 carbon atoms (C1-C 20 alkyl"), those having 1 to 10 carbon atoms (C1-C 10 alkyl), those having 6 to 10 carbon atoms (C6-C 10 alkyl) or those having 1 to 4 carbon atoms (C1-C4 alkyl). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

[0021] "Halo" or "halogen" refers to the Group 17 series of elements with atomic numbers 9 to 85. Preferred halogen groups include radicals of fluorine, chlorine, astatine, bromine and iodine. When the residue is substituted with two or more halogens, it can be referred to using a prefix corresponding to the number of attached halogen moieties; for example, dihaloaryl, dihaloaralkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, and these halo groups may be the same halogen, but do not necessarily have to be the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

[0022] As used herein, the term "heterocyclic ring" or "heterocyclic" refers to a saturated or unsaturated non-aromatic cyclic group having a monocyclic or polycondensed ring, and having 1 to 14 cyclic carbon atoms and 1 to 6 cyclic heteroatoms such as nitrogen, phosphorus, sulfur or oxygen. The heterocyclic ring containing two or more rings may be a condensed ring, a bridged ring, a spiro ring or any combination thereof, except for a heteroaryl group. The heterocyclic group may be independently optionally substituted with one or more substituents described herein. Particular heterocyclic groups are 3- to 14-membered rings having 1 to 13 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur, 3- to 12-membered rings having 1 to 11 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur, 3- to 10-membered rings having 1 to 9 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur, 3- to 8-membered rings having 1 to 7 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur, or 3- to 6-membered rings having 1 to 5 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur. Particular heterocyclic groups are monocyclic 3-, 4-, 5-, 6- or 7-membered rings having 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 6 cyclic carbon atoms and 1 to 2, 1 to 3 or 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur. Particularly, the heterocyclic group is a polycyclic non-aromatic ring having 1 to 12 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur.

[0023] As used herein, the term "quaternary ammonium cation" is intended to refer to a cation containing at least one nitrogen atom with a positive charge, and this nitrogen atom is bonded only to carbon. The positive electrostatic charge exists independently of pH. The nitrogen atom may be in a saturated state where it is singly bonded to four carbon atoms, or in an unsaturated state where it is singly bonded to two carbon atoms and doubly bonded to a third carbon atom. When the nitrogen atom is in an unsaturated state, it may be part of a heteroaromatic ring such as an imidazolium cation. When the nitrogen atom is in a saturated state, it may be part of an alicyclic ring such as a pyrrolidinium cation or a piperidinium cation.

[0024] "Optionally substituted" means that, unless otherwise specified, the group is unsubstituted or may be substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, and the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, or 2-5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0025] As used herein, "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result, including clinical outcomes. Beneficial or desired results include, but are not limited to, one or more of the following: reduction of one or more symptoms caused by a disease, reduction of the extent of the disease, stabilization of the disease (e.g., preventing or delaying worsening of the disease), preventing or delaying spread of the disease, delaying the onset or recurrence of the disease, delaying or retarding progression of the disease, improving the disease state, providing remission (partial or complete) of the disease, reducing the dosage of one or more oily agents required to treat the disease, enhancing the effect of another agent, delaying progression of the disease, increasing quality of life, and / or extending survival. The methods described herein contemplate any one or more of these aspects of treatment.

[0026] As used herein, the term "diagnosis" means having the ability to detect, monitor, track, and / or identify a disease or condition in an animal (including a human) or a biological sample.

[0027] As used herein, the term "theragnostic" means having the combined effect of a therapeutic composition and a diagnostic composition. This composition is suitable for delivery of identification (diagnosis) and treatment (therapeutic agent).

[0028] As used herein, the term "radionuclide" includes metallic and non-metallic radionuclides. Radionuclides are selected based on the medical use of the radiolabeled pharmaceutical composition. When the radionuclide is a metallic radionuclide, a chelator is generally employed to bind the metallic radionuclide to the remainder of the molecule. When the radionuclide is a non-metallic radionuclide, the non-metallic radionuclide is generally directly bound to the remainder of the molecule. Radionuclides are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. For example, a radiolabeled pharmaceutical contains a radionuclide that functions as a radiation source. Radionuclide therapy refers to the treatment using the said radionuclide.

[0029] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is biologically or otherwise desirable, e.g., the material can be incorporated into a pharmaceutical composition that is administered to a patient without causing significant undesirable biological effects or interacting in a harmful manner with any of the other components of the composition in which it is included. A pharmaceutically acceptable carrier or excipient preferably meets the requirements of toxicological and manufacturing tests and / or is included in the Inactive Ingredient Guide prepared by the US Food and Drug Administration and / or is approved by an administrative agency such as the EMA and / or the US Food and Drug Administration as acceptable for use in humans or livestock.

[0030] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals such as tablets containing the compounds of the present invention as active ingredients. The term "excipient" can encompass a variety of substances, including but not limited to binders, disintegrants, coatings, compression / capsule aids, creams or lotions, lubricants, parenteral solutions, materials for chewable tablets, sweeteners or flavors, suspension / gelling agents, or any substance used as a wet granulating agent. Examples of binders include, for example, carbomers, povidone, xanthan gum, etc.; examples of coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating agents, etc.; examples of compression / capsule aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; examples of disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include, for example, maltodextrin, carrageenan, etc.; examples of lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of tablet materials include, for example, glucose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; examples of suspension / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweeteners include, for example, aspartame, glucose, fructose dc, sorbitol, sucrose dc, etc.; examples of wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0031] Compound In a first aspect, the present invention relates to a compound of formula I.

[0032] [Chemistry]

[0033] In one embodiment, the compound of formula I exists as its stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates or solvates. In one embodiment, the compound of formula I exists as its pharmaceutically acceptable salts, stereoisomers or tautomers. The inventors have found that the compounds according to formula I are very effective in inhibiting fibroblast activation protein (FAP).

[0034] In one embodiment, Y1 and Y2 are independently H or F, and preferably, both Y1 and Y2 are F. In a further embodiment, the F is present in the natural proportion of the atomic isotope. The presence of said F provides improved selectivity characteristics when compared to other FAP inhibitors while maintaining a high affinity for the target enzyme. In another embodiment, both Y1 and Y2 are H. In another embodiment, Y1 is F and Y2 is H. In another embodiment, both Y1 and Y2 are 18 F.

[0035] In one embodiment, the linker (Z) contains oxygen, and said oxygen is covalently bonded to the quinoline structure of the compound at the 6-position, 7-position or 8-position.

[0036] The positions of the quinoline structure are numbered as shown in formula II (see below): [Chemistry]

[0037] In one embodiment, the linker is covalently bonded to the quinoline structure of the compound at the 6-position via oxygen. In one embodiment, the linker is covalently bonded to the quinoline structure of the compound at the 7-position via oxygen. In one embodiment, the linker is covalently bonded to the quinoline structure of the compound at the 8-position via oxygen.

[0038] In one embodiment, the linker contains a quaternary ammonium cation. In a further embodiment, the quaternary ammonium cation is bonded to 4 carbon atoms. Compounds having a quaternary ammonium cation exhibited a better in vivo pharmacokinetic profile, were less metabolized, and had exquisite and unprecedented selectivity with respect to PREP, a protease very closely related to FAP. All of these properties are advantageous in certain therapeutic, diagnostic or theranostic scenarios.

[0039] In one embodiment, the linker, optionally containing a radionuclide, has a molecular weight of at most 1000 Da, preferably at most 750 Da, preferably at most 600 Da, more preferably at most 500 Da, more preferably at most 400 Da, even more preferably at most 300 Da, and most preferably at most 200 Da. In one embodiment, the linker, optionally containing a radionuclide, has a molecular weight of at most 1000 Da, preferably at most 750 Da, preferably at most 600 Da, more preferably at most 500 Da, more preferably at most 400 Da, and a molecular weight of at least 100 Da, preferably at least 120 Da, more preferably greater than 150 Da. In one embodiment, a linker that does not contain a substituted radionuclide has a molecular weight of at most 600 Da, more preferably at most 500 Da, more preferably at most 400 Da, even more preferably at most 300 Da, and most preferably at most 200 Da. Compounds having a linker with a molecular weight higher than the above thresholds have been shown to adversely affect the pharmacokinetics of the compound. Stability in vivo, i.e., biochemical resistance in blood serum under physiological conditions, is essential for efficient functioning. Large chelating linkers can be relatively easily disrupted or degraded, and their functionality may be reduced.

[0040] In the description of this specification, all descriptions, embodiments or aspects of a certain part can be combined in the same way as if all descriptions, embodiments or aspects of other parts were specifically and individually listed in each and every combination. For example, all descriptions, embodiments or aspects provided in this specification regarding Z in formula (I) can be combined with all descriptions, embodiments or aspects of Y 1 and / or Y 2 in the same way as if each and every combination were specifically and individually listed. Also, all descriptions, embodiments or aspects of formula (I) are equally applicable to other formulas detailed in this specification where applicable, and for all formulas, it is understood that they are equally described in the same way as if each and every description, embodiment or aspect were separately and individually described.

[0041] In one embodiment, the linker is linked to a radionuclide. In one embodiment, the radionuclide is 18 F, 120 I, 122 I, 123 I, 124 I, 125 I, 131 I, 211 At, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 111 In, 152 Tb, 155 Tb, 203 Pb, 76 Br, 77 Br, 47 Sc, 67 Cu, 89 Sr, 90 Y, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb,213 Bi, 223 Ra, 225 Ac, 226 Th, 227Th , 225 Ac, 212 Bi, 213 Bi and 177 Lu are selected from the group. In one embodiment, the radionuclide is 120 I, 122 I, 123 I, 124 I, 125 I, 131 I or 211 At is selected. In one embodiment, the linker covalently binds to the radioisotope. In one embodiment, the radionuclide has a half-life of 10 minutes to 60 days, preferably 1 hour to 7 days, more preferably 2 hours to 3 days.

[0042] In one embodiment, the radionuclide is covalently bound to the linker. The covalent bond between the linker and the radionuclide is considered to be more stable compared to the radionuclide complexed in a large chelate structure

[0043] In one embodiment, the counterion is present to neutralize the positive charge of the quaternary ammonium cation. In a further embodiment, the counterion is selected from the following group: halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates, aryl sulfonates, other organic anions and combinations thereof. In a further embodiment, the counterion is a monovalent anion. In a further embodiment, the counterion is Cl or Br, or a combination thereof.

[0044] In the description herein, it is understood that the wavy line represents the point of attachment to the remainder of the compound. When the structure is not symmetric, the wavy line closer to the quinoline structure represented by Formula I is marked with an asterisk. When the structure is not symmetric, the wavy line closer to E is marked with a dot.

[0045] In one embodiment, -Z is -O-L1-A-(L2-D) 0-2 -L3-E, where: Each of L1, L2, and L3 is independently as follows

Chem.

Chem.

Chem.

[0046] In one embodiment, E is a chelating moiety, and the chelating moiety is a radical selected from the following group: DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), CB-DO2A (4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), TCMC (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), 3p-C-DEPA (2-[(carboxymethyl)]-[5-(4-nitrophenyl)-1-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)-amino]acetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NETA ({4-[2-(biscarboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonane-1-yl}-acetic acid), 3p-C-NEPA (2-{[2-(4-{2-[bis(carboxymethyl)amino]-5-(4-nitrophenyl)pentyl}-7-(carboxymethyl)-1,4,7-triazonane-1-yl)ethyl](carboxymethyl)amino}acetic acid), 3p-C-NETA-NCS ({4-[2-(bis-carboxymethylamino)-5-(4-isothiocyanatophenyl)pentyl]-7-carboxymethyl-[1,4,7]triazonane-1-yl}acetic acid), TACN-TM (N,N’,N’’,tris(2-mercaptoethyl)-1,4,7-triazacyclononane), DTPA (diethylenetriaminepentaacetic acid), CHX-A’’-DTPA (2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid), TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]), H2dedpa (1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane), H4octapa (N,N’-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N’-diacetic acid), H2azapa (N,N’-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N’-[6-(Carboxy)pyridin-2-yl]-1,2-diaminoethane), H5decapa(N,N’’-[6-(Carboxy)pyridin-2-yl]methyl)-diethylenetriamine-N,N’,N’’-triacetic acid), HBED(N,N’-bis(2-hydroxybenzyl)-ethylenediamine-N,N’-diacetic acid), SHBED(N,N’-bis(2-hydroxy-5-sulfobenzyl)-ethylenediamine-N,N’-diacetic acid), PCTA(3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid), HEHA(1,4,7,10,13,16-hexaazacyclohexadecane-N,N’,N’’,N’’’,N’’’’,N’’’’’-hexaacetic acid) and PEPA(1,4,7,10,13-pentaazacyclopentadecane-N,N’,N’’,N’’’,N’’’’’-pentaacetic acid). In a further embodiment, the radionuclide is bound to the chelating site in a stable coordination complex. In a further embodiment, the radionuclide is single photon emission computed tomography (SPECT, e.g.,, 67 Ga, 99m Tc, 111 In, 177 Lu) or positron emission tomography (PET, e.g., 68 Ga, 64 Cu, 44 Sc, 86 Y, 89 Zr, 89 Zr) or for therapeutic use (e.g., 47 Sc, 114m In, 177 Lu, 90 Y, 212 / 213 Bi, 212 Pb, 225 Ac, 186 / 188 Re).

[0047] In one embodiment, E is benzamide, where the benzamide is from the following group:

Chemical formula

[0048] In one embodiment, E is borane or carborane, where the borane or carborane is from the following group: Decaborate optionally substituted with X, dodecaborate optionally substituted with X,

Chemical formula

[0049] In one embodiment, E is a metal complex, where the metal is a metal from the platinum group. In one embodiment, E is a metal complex, where the metal complex is from the following group:

Chemical formula

[0050] In the structure according to the present invention, several classes can be identified. The first class includes compounds according to formula I, or their stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates or solvates, where Z is from the following group

Chemical formula

[0051] In one embodiment, F is 18 Present as F. In one embodiment, I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 Present as I. In one embodiment, At is 191 At, 193 At, 194 At, 195 At, 196 At, 197 At, 198 At, 199 At, 200 At, 201 At, 202 At, 203 At, 204 At, 205 At, 206 At, 207 At, 208 At, 209 At, 210 At, 211 At, 212 At, 213 At, 214 At, 215 At, 216 At, 217 At, 218 At, 219 At, 220 At, 221 At, 222 At, 223 At, and more specifically 211 Present as At. In one embodiment, one H is 2 H or 3is present as H. In one embodiment, C is, 13 C, 11 C or 14 is present as C. In one embodiment, N is, 13 is present as N. In one embodiment, O is, 15 O or 17 is present as O.

[0052] In this first class of compounds, each n is independently selected from 0 - 4. For 0 - 4, it can be selected from 0, 1, 2, 3, and 4. In one embodiment, each n is independently selected from 0 - 3. In one embodiment, n is selected from 0 or 1. In one embodiment, for all n in the compound, n is 0. In one embodiment, for all n in the compound, n is 1.

[0053] R 1 When selecting the site of, it should be noted that the compound should contain a quaternary ammonium cation. R1 bonded to the first nitrogen can be hydrogen only when there is a second nitrogen where the second nitrogen is a cation and is bonded only to carbon and / or phosphorus atoms.

[0054] Preferably, each R1 is independently from the following group: -CH3, CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2I, CH2CH2I, -CH2CH2CH2I, -CH2CH2CH2CH2At, -CH2I, CH2CH2At, -CH2CH2CH2At and -CH2CH2CH2CH2At, where F is 18 present as F, and / or I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 present as I, and / or At is 211 present as At.

[0055] In one embodiment, the linker contains 1 F and does not contain I. In one embodiment, the linker contains 1 I and does not contain F. In one embodiment, the linker contains 1 F and 1 I.

[0056] Examples of compounds according to this first class include, but are not limited to:

Chemical formula

[0057] The second class of compounds according to embodiments of the present invention includes compounds of formula I, or their stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates or solvates, where Z is the following group

Chemical formula

[0058] In one embodiment, F is 18 present as F. In one embodiment, I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 present as I. In one embodiment, At is 191 At, 193 At, 194 At, 195 At, 196 At, 197 At, 198 At, 199 At, 200 At, 201 At, 202 At, 203 At, 204 At, 205 At, 206 At, 207 At, 208 At, 209 At, 210 At, 211 At, 212 At, 213 At, 214 At, 215 At, 216 At, 217 At, 218 At, 219 At, 220 At, 221 At, 222 At, 223 At, and more particularly 211 present as At. In one embodiment, one H is 2 H or 3 present as H. In one embodiment, C is 13 C, 11 C or 14It exists as C. In one embodiment, N is, 13 It exists as N. In one embodiment, O is, 15 O or 17 It exists as O.

[0059] Each n is independently selected from 0 - 4. For 0 - 4, it can be selected from 0, 1, 2, 3, 4. In one embodiment, each n is independently selected from 0 - 3. In one embodiment, n is selected from 0 or 1. In one embodiment, for all n in the compound, n is 0. In one embodiment, for all n in the compound, n is 1.

[0060] When selecting the R1 moiety, attention should be paid to the requirement that the compound should contain a quaternary ammonium cation. R1 bonded to the first nitrogen can be hydrogen only when the second nitrogen is present and the second nitrogen is a cation and is bonded only to carbon atoms.

[0061] Preferably, each R1 is independently selected from the following group: -CH3, CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2I, CH2CH2I, -CH2CH2CH2I, -CH2CH2CH2CH2I, -CH2At, CH2CH2At, -CH2CH2CH2At, -CH2CH2CH2CH2At, COOC(CH3)3 and COC6H6-R2, where F is 18 It exists as F, and / or I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 It exists as I, and / or At is 211 It exists as At, where R2 is selected from the group consisting of I, F, At and B(OH)2.

[0062] In one embodiment, the linker contains 1 F and does not contain I. In one embodiment, the linker contains 1 I and does not contain F.

[0063] In a second class of compounds according to embodiments of the present invention, the compound is from the following group:

Chemical formula

[0064] In a third class of compounds according to embodiments of the present invention, the compound is a compound according to formula I, or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof, where Z is the following group

[0065]

Chemical formula

[0066] Each n is independently selected from 0 - 4. For 0 - 4, it can be selected from 0, 1, 2, 3, 4. In one embodiment, each n is independently selected from 0 - 3. In one embodiment, n is selected from 0 or 1. In one embodiment, for all n in the compound, n is 0. In one embodiment, for all n in the compound, n is 1.

[0067] In one embodiment, F is 18 present as F. In one embodiment, F is 18 present as F. In one embodiment, I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 present as I. In one embodiment, At is 211 present as At. In one embodiment, one H is 2 H or 3 present as H. In one embodiment, C is 13 C, 11 C or 14 present as C. In one embodiment, N is 13 present as N. In one embodiment, O is 15 O or 17 present as O.

[0068] R 1 When selecting the site of, it should be noted that the compound should contain a quaternary ammonium cation. R1 bonded to the first nitrogen can be hydrogen only when the second nitrogen is present and the second nitrogen is a cation and is bonded only to carbon atoms.

[0069] Preferably, each R1 is independently from the following group: -CH3, CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2At, CH2CH2At, -CH2CH2CH2At, -CH2CH2CH2CH2At, -CH2I, CH2CH2I, -CH2CH2CH2I and -CH2CH2CH2CH2I, where F is 18 present as F, and / or At is 211 present as At, and / or I is 120 I, 122 I, 123 I, 124 I, 125 I or 131 present as I.

[0070] In one embodiment, the linker contains one F and no I. In one embodiment, the linker contains one I and no F.

[0071] In a third class of compounds according to embodiments of the present invention, the compounds are in the following group:

Chemical formula

[0072] In one embodiment, the compound is a compound of formula I, or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof, wherein Z is an aromatic ring which is 5-membered, 6-membered or 7-membered and includes those which are optionally heterocyclic.

[0073] In one embodiment, the compound is a compound of formula I, or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof, wherein Z is a 5-membered, 6-membered or 7-membered aromatic ring including those which are optionally heterocyclic.

[0074] In one embodiment, the 5-membered, 6-membered or 7-membered aromatic ring which is optionally heterocyclic and optionally substituted with R2 and R3 is of formula III:

Chemical formula

[0075] X1, X2, X3 and X4 are independently selected from C, S, N and O and form a pharmaceutically acceptable 5-membered, 6-membered or 7-membered aromatic ring which may be substituted with R2 and R3. Preferably, X1, X2, X3 and X4 are selected from C, N and O and form a 5-membered, 6-membered or 7-membered aromatic ring. t is selected from 1, 2, 3. In one embodiment, the aromatic ring contains one heteroatom. In one embodiment, the aromatic ring contains two heteroatoms. In one embodiment, the aromatic ring contains no heteroatoms. In a further embodiment, R2 is bonded to X4 and X4 is carbon. In one embodiment, R3 is bonded to X2 and X2 is carbon. In another embodiment, R3 is bonded to X1 and X1 is carbon.

[0076] In one embodiment, the 5-membered, 6-membered or 7-membered aromatic ring, which may optionally be heterocyclic, is selected from the group consisting of furan, pyrrole, pyrazole, isoxazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, benzene, thiophene, pyridine, pyrazine, pyrimidine, pyridazine or triazine.

[0077] In one embodiment, the 5-membered, 6-membered or 7-membered aromatic ring, which may optionally be heterocyclic, is from the following group:

Chemical Formula

[0078] In one embodiment, R2 is from the following group: 18 F, 120 I, 122 I, 123 I, 124 I, 125 I, 131 Selected from I and At, preferably 211 At.

[0079] In one embodiment, R3 is selected from the following group: guanidine, aminomethyl and dialkylaminomethyl. In a further embodiment, the dialkylaminomethyl is selected from the following group: dimethylaminomethyl, diethylaminomethyl and dipropylaminoethyl. Guanidine has the general structure (R 10 R 11 N)(R 12 R 13 N)C=N-R 14を Have. Guanidine can be attached to the remainder of the compound at any position. In another embodiment, R 10 is the remainder of the compound and R 11 -R 14 is H. In another embodiment, R 10 -R 13 is H and the remainder of the compound is R 14 is.

[0080] In a fourth class of compounds according to embodiments of the present invention, the compound is a compound according to formula I, or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof, and the linker (Z) is from the following group:

Chemical formula

Chemical formula

[0081] In a further embodiment, Z is from the following group

Chemical formula

[0082] When selecting the position of X, attention should be paid to the requirements defined in other embodiments of the present invention so that a 5-, 6-, or 7-membered aromatic ring is formed.

[0083] In a fourth class of compounds according to an embodiment of the present invention, the compounds are from the following group:

Chemical formula

[0084] In a fifth class of compounds according to embodiments of the present invention, the compound is a compound according to formula I, or a stereoisomer, tautomer, racemate, metabolite, prodrug, salt, hydrate or solvate thereof, wherein Z is a linker selected from the following group

Chemical formula

Chemical formula

[0085] In a further embodiment, Z is the following group

Chemical formula

[0086] When selecting the position of X, it should be noted that a 5-, 6-, or 7-membered aromatic ring is formed.

[0087] Each n is independently selected from the range defined near the parentheses. For example, when n = 0-3, it can be selected from 0, 1, 2, 3. In one embodiment, the selected n is the minimum number suggested by the range. In one embodiment, for all n within one structure, the minimum number suggested by the range is selected. In one embodiment, the selected n is the minimum number suggested by the range +1. In one embodiment, for all n in one structure, the minimum number suggested by the range +1 is selected.

[0088] In a fifth class of compounds according to an embodiment of the present invention, the compound is selected from the following group:

Chemical formula

[0089] In one embodiment, the compound is a compound of formula I, or its stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates, or solvates shown in Table 1.

[0090]

Table 1-1

Table 1-2

Table 1-3

[0091] The compounds as detailed herein may be in a purified form in one embodiment, and compositions comprising the purified form of the compounds are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, for example, compositions of substantially pure compounds. In some embodiments, the compositions comprising a compound as detailed herein or a salt thereof are in a substantially pure form. Unless otherwise specified, "substantially pure" is intended to mean a composition that does not contain more than 35% impurities, where the impurities refer to compounds other than the compound or its salt that constitutes the majority of the composition. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, which compositions do not contain more than 25%, 20%, 15%, 10% or 5% impurities. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, which compositions do not contain more than 3%, 2%, 1% or 0.5% impurities.

[0092] The compounds depicted herein may exist as salts even when no salts are depicted, and as is well understood by those skilled in the art, the present disclosure is understood to encompass all salts and solvates of the compounds depicted herein, as well as the non-solvated forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0093] In one embodiment, the compound exists as a pharmaceutically acceptable salt. Specific examples of pharmaceutically acceptable salts include, but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clubranate, cyclopentanepropionate, digluconate salt, dihydrochloride, dodecyl sulfate, edetate, edisylic acid salt, estolate salt, esylic acid salt, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine salt, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide salt, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methyl sulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / nirophosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, theocurate, tosylate, triethiodide salt, undecanoate, and valerate, etc.

[0094] For any of the compounds described herein, if there may be tautomers, even if only one or some of the tautomers are explicitly depicted, each tautomer is intended. The specifically depicted tautomer may or may not be the dominant form in solution or when used according to the methods described herein. The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the described compounds, such as the compounds in Table 1. The structure or name is intended to encompass all possible stereoisomers of the depicted compound. All forms of the compound, such as crystalline or amorphous forms of the compound, are also encompassed by the present invention. Compositions containing the compounds of the present invention are also intended, including, for example, compositions of substantially pure compounds containing their specific stereochemical forms, or compositions containing mixtures of the compounds of the present invention in any ratio containing two or more stereochemical forms, such as racemic or non-racemic mixtures.

[0095] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. In some embodiments, the compound is isotopically labeled, such as an isotopically labeled compound of formula (I) or an embodiment thereof described herein, with some of one or more atoms replaced by isotopes of the same element. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and halogen, for example, 2 H, 3 H, 13 C, 11 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F. Certain isotopically labeled compounds (e.g., 3 H and 14 C) are useful for tissue distribution studies of compounds or substrates. Deuterium ( 2Incorporating heavy isotopes such as those of (H) results in higher metabolic stability, longer half-lives in vivo, or the ability to use lower doses, which provides therapeutic advantages and may be preferred in some instances.

[0096] The isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures similar to those described in the appended examples, substituting appropriate isotopically labeled reagents in place of the corresponding unlabeled reagents.

[0097] Pharmaceutical Compositions and Formulations In a second aspect, the present invention relates to a pharmaceutical composition or formulation comprising a compound described herein and at least one pharmaceutically acceptable carrier, diluent, excipient or adjuvant. The present invention includes a pharmaceutical composition or formulation comprising a compound or a salt thereof detailed herein and a pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutically acceptable salt is an acid addition salt.

[0098] The compounds according to the present invention can, in one embodiment, be in a purified form. In one embodiment, the composition comprises a compound or a salt thereof as detailed herein. In some embodiments, the composition comprises a compound or a salt thereof as detailed herein in a substantially pure form.

[0099] In one embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, a composition is provided that comprises a compound in substantially pure form. In another embodiment, the present invention encompasses a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another embodiment, a method of administering the compound is provided. The purified form, pharmaceutical composition and method of administering the compound are suitable for any compound or form thereof detailed herein.

[0100] The compounds or salts thereof detailed in this specification can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The pharmaceutical compositions can be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or in a form suitable for administration by inhalation. The compound or its salt can be formulated with a suitable carrier to provide a delivery form, which includes tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, pills, gums, powders, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, sprays (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs, but are not limited thereto.

[0101] One or several of the compounds or salts thereof described herein can be used in the preparation of compositions such as pharmaceutical compositions by combining the compound or compounds or its salt as the active ingredient with a pharmaceutically acceptable carrier as described above. Depending on the form of treatment of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. Further, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, coloring agents, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants. The compositions containing the present compound can also contain other substances having valuable therapeutic properties. The pharmaceutical compositions can be prepared by known pharmaceutical methods.

[0102] The compositions described herein can be administered to an individual in the form of generally acceptable oral compositions such as tablets, coated tablets and gel capsules with hard or soft shells, emulsions or suspensions. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers acceptable for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Furthermore, the pharmaceutical composition can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, regulators and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants.

[0103] In some embodiments, the composition is for use as a human or veterinary pharmaceutical. In some embodiments, the composition is for use in the methods described herein. In some embodiments, the composition is for use in the treatment of the diseases or disorders described herein.

[0104] By way of non-limiting example, such compositions can be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (including the eye), administration by inhalation, administration by skin patch, administration by implant, administration by suppository, etc. Such appropriate dosage forms - which may be solid, semi-solid or liquid depending on the mode of administration - as well as the methods and carriers, diluents and excipients used in their preparation will be apparent to those skilled in the art.

[0105] Preferred but non-limiting examples of formulations include tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (usually reconstituted before use), which may be formulated with carriers, excipients and diluents suitable for such compositions themselves, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl - and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils, or suitable mixtures thereof. The compositions may optionally contain other pharmaceutically active substances (which may or may not result in a synergistic effect with the compounds of the present invention) and other substances commonly used in pharmaceutical compositions, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preservatives, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated to provide rapid, sustained or delayed release of the active compounds contained therein, for example, using liposomes or hydrophilic polymer matrices based on natural gels or synthetic polymers. It may be advantageous to utilize α -, β - or γ - cyclodextrins or their derivatives to enhance the solubility and / or stability of the compounds of the pharmaceutical compositions according to the present invention.

[0106] Furthermore, co - solvents such as alcohol can improve the solubility and / or stability of the compounds. In the preparation of aqueous compositions, the addition of salts of the compounds of the present invention may be more suitable due to the increase in their water solubility.

[0107] The preparation can be carried out in a manner known per se and usually under aseptic conditions by mixing at least one compound according to the invention with one or more pharmaceutically acceptable carriers and, if desired and as appropriate, in combination with other pharmaceutically active compounds.

[0108] In the case of the oral administration form, the composition of the present invention can be mixed with suitable additives such as excipients, stabilizers or inert diluents and made into a suitable administration form, for example, tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions by conventional methods. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the preparation can be carried out either as dry granules or as wet granules. Suitable oily excipients or solvents are vegetable oils or animal oils, such as sunflower oil or cod liver oil. Solvents suitable for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycol and polypropylene glycol are also useful as additional adjuvants for other administration forms. As immediate-release tablets, these compositions can contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. When administered by nasal spray or inhalation, these compositions can be prepared according to techniques well known in the art of pharmaceutical compositions and can be prepared as solutions in physiological saline, and benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and / or other solubilizing or dispersing agents known in the art can be utilized. Pharmaceutical compositions suitable for administration in the form of sprays or aerosols are, for example, solutions, suspensions or emulsions of the compounds of the present invention or their physiologically acceptable salts in pharmaceutically acceptable solvents such as ethanol or water, or mixtures of such solvents. If necessary, the composition can further contain other pharmaceutical adjuvants such as surfactants, emulsifiers and stabilizers as well as propellants. In the case of subcutaneous administration, the compounds according to the present invention are made into solutions, suspensions or emulsions, if desired, together with conventional substances such as solubilizing agents, emulsifying agents or additional adjuvants. The compounds of the present invention can also be lyophilized, and the resulting lyophilizate can be used, for example, in the manufacture of injections or infusions.Suitable solvents are, for example, water, physiological saline or alcohols such as ethanol, propanol, glycerol, further sugar solutions such as glucose solution or mannitol solution, or mixtures of the various solvents described. Injectable solutions or suspensions can be formulated according to techniques using suitable non-toxic and parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or sterile fixed oils free from infection containing synthetic mono- or diglycerides, and suitable dispersing or wetting agents and suspending agents such as fatty acids containing oleic acid.

[0109] When administered rectally in the form of suppositories, these compositions can be prepared by mixing the compounds according to the invention with suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycol, which are solid at normal temperature but liquefy and / or dissolve in the rectal cavity to release the drug. In a preferred embodiment, the compounds of the invention are useful in human or veterinary medicine, particularly for use as fibroblast activation protein (FAP) inhibitors.

[0110] In one embodiment, the pharmaceutical composition may comprise a chelating agent selected from the following group: EUpypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, DOTA (dodeca-1,4,7,10-tetraamine-tetraacetate), DOTAGA (2-(l,4,7,10-tetraazacyclododecane-4,7,10) pentanedioic acid) and other DOTA derivatives, TRITA (trideca-l,4,7,10-tetraamine-tetraacetate), TETA (tetradeca-l,4,8,ll-tetraamine-tetraacetate) and its derivatives, NOTA (Nona-l,4,7-triamine-triacetate) and its derivatives, such as NOTAGA (l,4,7-triazacyclononane, l-glutaric acid, 4,7-acetate), TRAP (triazacyclononanephosphinic acid), NOPO (l,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), NETA ({4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonane-1-yl}-acetic acid), 3p-C-NEPA (2-{[2-(4-{2-[bis(carboxymethyl)amino]-5-(4-nitrophenyl)pentyl}-7-(carboxymethyl)-1,4,7-triazonane-1-yl)ethyl](carboxymethyl)amino}acetic acid), 3p-C-NETA-NCS ({4-[2-(bis-carboxymethylamino)-5-(4-isothiocyanatophenyl)pentyl]-7-carboxymethyl-[1,4,7]triazonane-1-yl}acetic acid), HEHA (hexadeca-1,4,7,10,13,16-hexaamine-hexaacetate) and its derivatives, HBED (hydroxybenzyl-ethylenediamine) and its derivatives, DEDPA and its derivatives, such as H2DEDPA (l,2-[[6-(Carboxylic acid)pyridin-2-yl]methylamine]ethane), DFO (deferoxamine) and its derivatives, tris hydroxypyridinone (THP) and its derivatives, such as YM103, TEAP (tetraazacyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepine-tetraacetate) and its derivatives, such as DATA ((6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate); SarAr (IN-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) and its salts, (Nhh SAR(1,8-diamino-B,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane) and its salts and derivatives, aminothiol and its derivatives.,

[0111] Methods of treating and using compounds or compositions Also disclosed herein are methods of treatment and / or diagnosis. More particularly, disclosed herein are compounds or pharmaceutical compositions as disclosed herein for use in the treatment and / or diagnosis of diseases.

[0112] In one embodiment, a method for treating a disease in an individual is disclosed herein, wherein said disease is an FAP-related disorder.

[0113] Said FAP-related disorders are preferably proliferative diseases selected from the group of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, and adenocarcinoma; diseases characterized by tissue remodeling and / or chronic inflammation such as fibrotic diseases, wound healing disorders, keloid formation disorders, osteoarthritis, rheumatoid arthritis, cartilage degradation disorders, atherosclerosis and Crohn's disease; disorders associated with endocrine dysfunction such as glucose metabolism disorders; and disorders selected from the list including blood coagulation disorders.

[0114] As used herein, the term "FAP-related disorder" means a disease or other adverse condition in which FAP is known to play a role. The term "FAP-related disorder" also means a disease or condition that is alleviated by treatment with an FAP inhibitor. A non-limiting list of examples of FAP-related disorders can include proliferative diseases selected from the group of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, and adenocarcinoma. Further, the list of FAP-related disorders contemplated herein includes diseases characterized by tissue remodeling and / or chronic inflammation. These include, but are not limited to, fibrotic diseases, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation, atherosclerotic diseases, type II diabetes, and Crohn's disease. Further, FAP-related disorders associated with endocrine dysfunction (including, but not limited to, disorders of glucose metabolism) and diseases associated with blood coagulation disorders are part of this list. The present invention also provides a method for the prevention and / or treatment of FAP-related disorders; said method comprising administering to a subject in need thereof a compound according to the invention, or a composition comprising said compound.

[0115] In one embodiment, the compounds or salts thereof described herein or the compositions described herein can be used in methods of treating diseases or disorders mediated by FGF21. In some embodiments, the compounds or salts thereof described herein or the compositions described herein are used in methods of treating FGF21-related disorders such as obesity, type I and type II diabetes, pancreatitis, dyslipidemia, hyperlipidemic conditions, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, impaired glucose tolerance, hyperglycemia, metabolic syndrome, acute myocardial infarction, hypertension, cardiovascular disease, atherosclerosis, peripheral arterial disease, stroke, heart failure, coronary heart disease, kidney disease, diabetic complications, neuropathy, gastric paresis, disorders associated with severe inactivating mutations of the insulin receptor, and other metabolic disorders. Provided herein is a method of increasing FGF21 expression levels in an individual, comprising administering to the individual a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein. FGF21 is thought to stimulate glucose uptake in adipocytes and to be protective against obesity and insulin insensitivity. By way of example, without wishing to be bound by theory, FAP is thought to be an enzyme responsible for the cleavage and inactivation of FGF21; thus, inhibiting FAP may increase the expression level of FGF21. Accordingly, provided herein is a method of treating diabetes, insulin insensitivity and / or obesity in which FGF21 expression is increased, in an individual in need thereof, comprising administering to the individual a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein. In some embodiments, the diabetes is type II diabetes.

[0116] Also provided herein is a method of enhancing an immune response in an individual, which comprises administering to the individual a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the individual has cancer. In some embodiments, the enhanced immune response is directed against a tumor or cancer cell. By way of example, without wishing to be bound by theory, FAP is thought to suppress the immune response, particularly in the context of cancer, and thus, inhibiting FAP may enhance the individual's immune response. Accordingly, provided herein is a method of treating cancer in an individual in need thereof, which comprises administering to the individual a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the individual's immune response is enhanced.

[0117] In one embodiment, the compound or salt thereof described herein, or the composition described herein, can be used in a method of treating a disease or disorder characterized by proliferation, tissue remodeling, fibrosis, chronic inflammation, excessive alcohol consumption, or metabolic abnormalities. In some embodiments, the compound or salt thereof described herein, or the composition described herein, can be used in a method of treating cancer such as breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, or adenocarcinoma. In some embodiments, the compound, salt, or composition can be used in a method of treating metastatic renal cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma, or non-small cell lung cancer.

[0118] The compounds and compositions described in detail herein, e.g., pharmaceutical compositions comprising a compound of any of the formulas provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells, for screening purposes and / or for performing quality control assays. Provided herein is a method of treating a disease or disorder in an individual in need thereof, comprising administering a compound described herein or a pharmaceutically acceptable salt thereof, or an embodiment or aspect thereof. In some embodiments, the compound, its pharmaceutically acceptable salt or composition is administered to an individual according to the dosages and / or methods of administration described herein.

[0119] In one embodiment, administration of the compound, salt or composition reduces tumor growth, tumor proliferation or tumorigenicity in an individual. In some embodiments, the compound, salt or composition can be used in a method of effecting a reduction in tumor growth, tumor proliferation or tumorigenicity in an individual in need thereof. In some embodiments, tumor proliferation is slowed or stopped. In some embodiments, tumor proliferation is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the tumor shrinks. In some embodiments, tumor metastasis is prevented or delayed.

[0120] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods of treating fibrotic diseases, thrombosis, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation, atherosclerotic diseases, Crohn's disease, cirrhosis, idiopathic pulmonary fibrosis, myocardial hypertrophy, diastolic dysfunction, obesity, glucose intolerance, insulin insensitivity or diabetes. In some embodiments, the cirrhosis is viral hepatitis-induced, alcohol-induced, or biliary cirrhosis. In some embodiments, the diabetes is type II diabetes. In some embodiments, the disease or disorder is fibrotic liver degeneration.

[0121] In some embodiments, provided herein is a method of inhibiting FAP. The compounds or salts thereof described herein, and the compositions described herein, are thought to be effective for inhibiting FAP. In some embodiments, the method of inhibiting FAP comprises inhibiting FAP in a cell by administering or delivering to the cell a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein. In some embodiments, the cell is a fibroblast among the cells having FAP expression, such as myofibroblast, keloid fibroblast, cancer-associated fibroblast (CAF) or reactive stromal fibroblast. In some embodiments, the method of inhibiting FAP comprises inhibiting FAP in a tumor or plasma by administering or delivering to the tumor or plasma a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein. In some embodiments, the inhibition of FAP comprises inhibiting the endopeptidase and / or exopeptidase activity of FAP. In some embodiments, FAP is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. The inhibition of FAP can be determined by methods known in the art.

[0122] In some embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an additional agent are administered sequentially, simultaneously, or concurrently. In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an additional agent are administered at intervals of about 15 minutes or less, such as about 10 minutes, 5 minutes, 1 minute, or less. In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an additional agent are administered at intervals of about 15 minutes or more, such as 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or more. Either (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, or (b) an additional agent may be administered first. In certain embodiments, (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an additional agent are administered simultaneously.

[0123] In some embodiments, the agent targets an immune checkpoint protein. In some embodiments, the agent is an antibody that targets an immune checkpoint protein. In some embodiments, the additional agent targets PD-1, PD-L1, PD-L2, CTLA4, TIMS, LAGs, CCR4, OX40, OX40L, IDO, and A2AR. In some embodiments, the agent is an anti-PD-I antibody, an anti-PD-LI antibody, or an anti-CTL4-4 antibody.

[0124] The compounds as disclosed herein exhibit high selectivity and can be used to demonstrate the presence of cancer cells or cancer-associated fibroblasts. Accordingly, the use of the compounds or compositions described herein in diagnosis is also an object of the present invention.

[0125] When administered to a patient, the compounds of the present invention can localize in specific organs or cells and can visualize the degree of disease processes in the body based on cell function and physiology, rather than depending on physical changes in the anatomical form of tissues. Since FAP is involved in many physiological or pathophysiological aspects, it offers the possibility of targeting these cells to obtain an early diagnosis by a non-invasive approach.

[0126] Also disclosed herein is a method of imaging tissues, organs, and / or cell populations with the compounds and / or compositions described herein. The present invention also relates to the compounds or pharmaceutical compositions described herein for use in imaging tissues and / or organs. The present invention also relates to the compounds or pharmaceutical compositions described herein for use as companion diagnostics. In one embodiment, methods for evaluating whole body target expression are disclosed herein. These methods can contribute to the evaluation and development of FAP targeting agents: small molecules, mAbs, ADCs, BiTEs, and radionuclide therapies.

[0127] In one embodiment, methods of measuring tumor growth, tumor proliferation, and tumorigenicity are disclosed herein, for example, by repeated imaging of an individual. In one embodiment, tumor growth, tumor proliferation, or tumorigenicity is compared to tumor growth, tumor proliferation, or tumorigenicity in an individual prior to administration of the compound, salt, or composition. In some embodiments, tumor growth, tumor proliferation, or tumorigenicity is compared to tumor growth, tumor proliferation, or tumorigenicity in a similar individual or population of individuals.

[0128] In one embodiment, the compounds described herein are radionuclides, preferably 18 F, 120 I, 122 I, 123 I, 124 I, 125 I, 131 I and 211It contains At. Compounds containing radionuclides show high affinity for tissues characterized by significant FAP expression, such as tumor tissues, and their accumulation in normal tissues is limited. Furthermore, the compounds described herein improve the contrast or signal-to-noise ratio in PET diagnosis for tumor imaging. Radiation exposure to target cells and adjacent organs is also reduced, which is a great advantage for theragnostic treatment.

[0129] In one embodiment, the above compound is used for the manufacture of radiopharmaceuticals for diagnostic imaging by positron emission tomography (PET). In one embodiment, the above compound is used for the manufacture of radiopharmaceuticals for diagnostic imaging by single photon emission computed tomography (SPECT).

[0130] In some embodiments, the individual is an animal, preferably a mammal. In some embodiments, the individual is a primate, cow, sheep, pig, horse, dog, cat or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of the tire diseases or disorders disclosed herein. In some embodiments, the individual is at risk of developing any of the diseases or disorders disclosed herein. In some embodiments, the individual is a human. In some embodiments, the human is at least about 21, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 years old, or any age in between. In some embodiments, the human is a child. In some embodiments, the human is about 21, 18, 15, 12, 10, 8, 6, 5, 4, 3, 2 years old or less than 1 year old, or any age in between.

[0131] The dosage of the compound administered to an individual (such as a human) can vary depending on the specific compound or its salt, the method of administration, and the specific disease, such as the type and stage of the cancer being treated. In some embodiments, the amount of the compound or its salt is a therapeutically effective amount.

[0132] The pharmaceutical composition of the present invention is preferably in unit dosage form and can be, for example, in a box, blister, vial, bottle, sachet, ampoule or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled); optionally, it can be appropriately packaged together with one or more leaflets containing product information and / or instructions for use. Generally, such a unit dosage contains at least one compound of the present invention in an amount of 1 to 1000 mg, usually 5 to 500 mg, for example, about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

[0133] The compound can be administered by various routes including oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the particular formulation used and the condition to be treated or prevented, and usually oral and intravenous administrations are preferred. At least one compound of the present invention is generally administered in an "effective amount", which means that any amount of the compound of formula I is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to whom it is administered upon appropriate administration. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount is usually 0.01 to 1000 mg per kg of the patient's body weight per day, more frequently 0.1 to 500 mg per kg of the patient's body weight per day, for example 1 to 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, and these can be administered once a day, once or divided into multiple times a day, or essentially continuously, for example using an intravenous drip. The dosage, route of administration and further treatment regimen can be determined by the clinician in charge of the treatment according to factors such as the patient's age, sex and general condition, as well as the nature and severity of the disease / symptom to be treated.

[0134] The effective amount of the compound can be, in one embodiment, a dosage of about 0.01 to about 100 mg / kg. The effective amount or dosage of the compounds of the present invention can be determined by routine methods such as modeling, dose escalation, or clinical trials, taking into account routine factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease being treated, and the health status, condition, and weight of the subject. Exemplary dosages are in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 g to 7 g per day.

[0135] The compounds or compositions of the present invention can be administered to an individual according to an effective dosing regimen for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, which in some embodiments can be the duration of an individual's life. In one embodiment, the compound is administered daily or on an intermittent schedule. The compound can be administered to the individual continuously (e.g., at least once a day) over a period of time. The dosing frequency can also be less than once a day, for example, about once a week. The dosing frequency can be more than once a day, for example, twice or three times a day. The dosing frequency can also be intermittent, including "drug holidays" (e.g., administering once a day for 7 days and then not administering for 7 days, repeating for any 14-day period, such as about 2 months, about 4 months, about 6 months, or more). Any dosing frequency can be used with any of the compounds described herein at any of the dosages described herein.

[0136] In one embodiment, the pharmaceutical composition can be administered separately at different times during the course of treatment, or simultaneously in a divided or single combined form.

[0137] Manufactured Articles and Kits The present disclosure further provides a manufactured article comprising a compound or a salt thereof described herein, a composition described herein, or one or more unit doses described herein in a suitable package. In certain embodiments, the manufactured article is for use in any of the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, and flexible packaging. The manufactured article may further be sterilized and / or sealed.

[0138] The present disclosure further provides a kit for performing the methods of the invention, comprising one or more compounds described herein or a composition comprising a compound described herein. The kit may employ any of the compounds disclosed herein. In one embodiment, the kit uses a compound or a salt thereof described herein. The kit can be used for any one or more of the uses described herein and, accordingly, can include instructions for the treatment of any disease or for the treatment of, for example, cancer as described herein. The kit generally comprises a suitable package. The kit can include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) can be packaged in a separate container or, where cross-reactivity and stability permit, several components can be combined in one container. The kit can be in unit dosage form, bulk package (e.g., multi-dose package) or sub-unit dosage. For example, the kit can be provided with a sufficient dosage of a compound disclosed herein and / or an additional pharmaceutically active compound useful for the diseases detailed herein to provide effective treatment to an individual for any period of time, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or more. The kit can also include multiple unit doses of the compound and instructions for use and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0139] The kit can optionally include a set of instructions, generally in written form, relating to the use of the components of the method of the invention, although an electronic storage medium (e.g., magnetic disk or optical disk) containing the instructions is also acceptable. The instructions included in the kit generally contain information regarding the components and administration to an individual.

[0140] Synthesis The compounds of formula I can be prepared as shown in the general scheme 1.

[0141] Scheme 1. General synthetic scheme of the compounds defined by formula I

Chemical formula

[0142] This can be carried out as follows.

[0143] The reaction of Boc-aminocarboxylate (A) with compound (B) can be carried out using standard techniques of peptide coupling known to those skilled in the art, and compound (C) can be obtained. This is either pyrrolidine or a pyrrolidine derivative. When pyrrolidine is pyrrolidine carboxamide, an additional dehydration step (e.g., using trifluoroacetic anhydride and pyridine, see the figure below) is required after the coupling step. The selected protecting groups of (C) containing Boc-group and Z-group can be deprotected using appropriate acids or other deprotecting agents known to those skilled in the art to produce compound (D).

[0144] The reaction of compound (D) with compound (E) can be carried out using standard peptide coupling procedures or using the corresponding acyl halide or active ester of (E) produced in situ or in another reaction using procedures known to those skilled in the art.

[0145] Alternatively, the compound of formula (I) can be obtained by substituting one or more of the groups R1, R2, R3, R4, R5, R6 or R of another compound of formula (I) obtained as described above 7をIt can also be prepared by converting to the desired substituent. The conversion method selected depends on the type of the desired substituent.

[0146] The present invention is further illustrated by the following non-limiting examples which further describe the present invention, but these are not intended to limit the scope of the present invention and should not be construed as limiting.

Examples

[0147] Synthesis approaches, procedures and property evaluations of the compounds shown in Table 1.

[0148] 1) Synthesis approaches, procedures and property evaluations of non-radioactive products (Compounds 1-14) The overall synthesis approach of the described quaternary ammonium-containing molecules is shown in Scheme 1. Using 6-hydroxyquinoline-4-carboxylic acid as a general starting material, it is first converted to the corresponding chloroethyl or chloropropyl or BoC-amine PEG derivative ether by O-alkylation followed by saponification. After amination with the required secondary amine (either dimethylamine, morpholine or N-Boc-piperazine), or after removing the Boc-group and methylating (more specifically, demethylating) the primary amine, a glycine-(2-cyano-4,4-difluoropyrrolidine) moiety is installed by COMU or HATU coupling. In the case of the N-Boc-piperazinyl derivative, deprotection of the Boc-group via trifluoroacetic acid precedes, or deprotection of the Boc-group is carried out after quaternary ammonium formation, followed by amide coupling with the corresponding benzoic acid. Alkylation requires either fluoromethyl tosylate or fluoroethyl tosylate or iodomethane.

[0149]

Chemical formula

[0150]

Chemical formula

[0151]

Chem.

[0152] Scheme 1. Reagents and Conditions: I) A) (i) Cs2CO3 (5 eq), 1-bromo-3-chloropropane or 1-bromo-2-chloroethane (4 eq), DMF, 0.3 M, 60 °C, overnight; (ii) 6 M NaOH, water, acetonitrile B) Secondary amine (6 eq), KI (6 eq), 60 °C, overnight; C) (S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethane-1-aminium 4-methylbenzenesulfonate (1.1 eq), HATU (1.1 eq), DMF, 0.15 M, rt, 2 h; or (S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethane-1-aminium 4-methylbenzenesulfonate (1.1 eq), COMU (registered trademark) (1.1 eq), DMF, 0.15 M, rt, 2 h; D) Fluoromethyl 4-methylbenzenesulfonate (5 eq), DIPEA (5 eq), 120 °C, 20’ (in the case of fluoromethylation) or E) Fluoroethyl 4-methylbenzenesulfonate (5 eq), DIPEA (5 eq), NaI, 80 °C, 120’ (in the case of fluoroethylation).

[0153] II) Reagents and Conditions: F) (i) Cs2CO3 (5 eq), 6-hydroxyquinoline-4-carboxylate (1 eq), DMF, 0 °C, 10 min; (ii) corresponding tosylate (1.1 eq), 40 °C, overnight; G) (i) LiOH (4 eq), MeOH / H2O, overnight; (ii) HATU (1.5 Eq), DIPEA (3.0 eq), (S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethane-1-aminium 4-methylbenzenesulfonate (1.1 eq), DMF, RT, overnight; H) (i) p-TsOH (2 eq), 2 h; (ii) DMF, MeI (3.3 eq), DIPEA (10 eq), RT, overnight; I) TFA (5 eq), DCM, 0 °C, overnight; (ii) formaldehyde (16 eq), NaBH4 (5 eq), 2 h.

[0154] III) Reagents and Conditions: J) DMF, MeI (3.3 eq), DIPEA (10 eq), RT, overnight; K) (i) p-TsOH (2 eq), RT, overnight; (ii) corresponding benzoic acid, (1.1 eq), HATU (2 eq), DIPEA (10 eq), DMF, RT, overnight.

[0155]

Chemical formula

[0156] 6-Hydroxyquinoline-4-carboxylic acid (1 eq) was stirred with Cs2CO3 (5 eq) in dry DMF (reaction molarity ≒ 0.3 M) at 50 °C for 20' under an argon atmosphere. Bromochloroalkane (4 eq) was added and the mixture was stirred at 60 °C overnight. The mixture was filtered under vacuum and the solid was washed with 80 mL of EtOAc. The filtrate was washed with 20 mL of water and 2 × 25 mL of brine. The aqueous phase was discarded and the organic fraction was evaporated under reduced pressure. The resulting residue was diluted with 12 mL of water and 25 mL of acetonitrile, then 5 mL of 6 M NaOH was added and the mixture was stirred until the hydrolysis of the ester was complete (about 1 h 30'). The mixture naturally separated into an upper organic layer and a lower aqueous layer. The aqueous layer was set aside and the organic layer was evaporated on a rotary evaporator. The residue was redissolved in 15 mL of DCM and extracted with 15 mL of water. The combined aqueous phases were washed with 2 × 25 mL of diethyl ether and then titrated with 6 M HCl to pH 1 to form a milky beige precipitate, which was collected on a glass filter and dried under reduced pressure.

[0157]

Chem.

[0158] 6-(3-Chloropropoxy)quinoline-4-carboxylic acid (1a) (2.289 mg, 8.62 mmol, yield 65%) was prepared according to the general procedure A using 1-bromo-3-chloropropane (5.23 mL, 52.9 mmol). MS (ESI): m / z = 266.0 [M+H]+ ( 35 Cl); 268.0 [M+H]+ ( 37 Cl). 11H NMR (400 MHz, DMSO) δ 8.87 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.52 (dd, J = 9.2, 2.7 Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.86 (t, J = 6.5 Hz, 2H), 2.27 (p, J = 6.2 Hz, 2H).

[0159]

Chem.

[0160] 6-(2-Chloroethoxy)quinoline-4-carboxylic acid (1b) (282 mg, 1.121 mmol, yield 42.4%) was prepared according to the general procedure A using 1-bromo-2-chloroethane (0.872 mL, 10.57 mmol). MS (ESI): m / z = 252.0 [M+H] + ( 35 Cl); 254.1 [M+H] + ( 37 Cl). 1 1H NMR (400 MHz, DMSO) δ 13.83 (s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.55 (dd, J = 9.2, 2.8 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H), 4.05 (t, J = 5.2 Hz, 2H).

[0161] General procedure B (nucleophilic substitution by amine)

Chem.

[0162] A suspension of 6-(chloroalkoxy)quinoline-4-carboxylic acid (1 eq), potassium iodide (6 eq) and the corresponding secondary amine (6 eq) in DMF (approx. 0.3 M reaction molarity) was stirred at 60 °C overnight. The crude mixture was filtered under vacuum and the solid was washed with ACN. After adding 2 eq of aqueous KOH 6 M to the filtrate, it was evaporated under reduced pressure. The resulting mass was triturated with 3 x 50 mL of diethyl ether and used in the following reaction without further purification.

[0163]

Chemical Structure

[0164] 6-(3-(Dimethylamino)propoxy)quinoline-4-carboxylic acid (2a) was prepared according to general procedure B using 6-(3-chloropropoxy)quinoline-4-carboxylic acid (1000 mg, 3.01 mmol) and a 2 M solution of dimethylamine in THF (8.62 mL, 17.24 mmol). MS (ESI): m / z = 275.1 [M+H] + .

[0165]

Chemical Structure

[0166] 6-(2-(Dimethylamino)ethoxy)quinoline-4-carboxylic acid (2b) was prepared according to general procedure B using 6-(2-chloroethoxy)quinoline-4-carboxylic acid (90 mg, 0.358 mmol) and a 2 M solution of dimethylamine in THF (1028 μL, 2.056 mmol). MS (ESI): m / z = 261.2 [M+H] + .

[0167]

Chemical Structure

[0168] 6-(3-Morpholinopropoxy)quinoline-4-carboxylic acid (2c) (119 mg, 0.376 mmol, yield 20%) was prepared according to General Procedure B using 6-(3-chloropropoxy)quinoline-4-carboxylic acid (500 mg, 1.882 mmol) and morpholine (0.974 mL, 11.29 mmol). MS (ESI): m / z = 317.1 [M+H] + .

[0169]

Chemical formula

[0170] 6-(2-Morpholinoethoxy)quinoline-4-carboxylic acid (2d) was prepared according to General Procedure B using 6-(2-chloroethoxy)quinoline-4-carboxylic acid (282 mg, 1.121 mmol) and morpholine (198 μL, 2.296 mmol). MS (ESI): m / z = 401.2 [M+H] + .

[0171] General Procedure C (Amide Coupling)

Chemical formula

[0172] A 10 mL round-bottom flask was charged with the corresponding carboxylic acid (1 eq), HATU (1.1 eq) or COMU (registered trademark) (3.0 eq), dry DMF (reaction molar amount ≈ 0.15 M) and dry DIPEA (5 eq). After stirring at room temperature for 5 minutes, (S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethane-1-aminium 4-methylbenzenesulfonate (1.1 eq) was added. After consumption of the starting material (UPLC monitoring), all volatiles were removed by rotary evaporator. The crude product was diluted with 5 mL of DCM, washed with saturated aqueous sodium bicarbonate solution (3 × 1 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain a residue purified by reverse-phase column chromatography eluting with a gradient of acetonitrile (ACN) in water.

[0173]

Chem.

[0174] (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-(dimethylamino)propoxy)quinoline-4-carboxamide (3a) (42.2 mg, 0.095 mmol, yield 4%) was prepared according to General Procedure C using 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid (642 mg, 2.340 mmol) and HATU. The product was further purified by RP-HPLC using a gradient of acetonitrile + 0.1% formic acid in water (5 - 50% in 20’). MS (ESI): m / z = 223.7 [M+2H] ++ ; 446.3 [M+H] + ; 468.2 [M+Na] + . 1 H NMR (400 MHz, DMSO) δ 9.13 (t, J = 6.0 Hz, 1H), 8.83 (d, J = 4.3 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 4.3 Hz, 1H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 5.15 (dd, J = 9.3, 3.0 Hz, 1H), 4.34 (m, 1H), 4.24 (d, J = 6.3 Hz, 2H), 4.21 (d, J = 6.0 Hz, 2H), 4.15 (m, 1H), 3.17 (m, 2H), 2.92 (m, 2H), 2.75 (s, 6H), 2.16 (p, J = 7.8 Hz, 2H).

[0175]

Chem.

[0176] (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(dimethylamino)ethoxy)quinoline-4-carboxamide (3b) (42.2 mg, 0.098 mmol, yield 27.4%) was prepared according to General Procedure C using 6-(2-(dimethylamino)ethoxy)quinoline-4-carboxylic acid (93 mg, 0.357 mmol) and HATU. MS (ESI): m / z = 432.3 [M+H] + ; 216.7[M+2H] 2+ .

[0177]

Chemical Structure

[0178] (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-morpholinopropoxy)quinoline-4-carboxamide (3c) (75 mg, 0.154 mmol, yield 25%) was prepared according to General Procedure C using 6-(3-morpholinopropoxy)quinoline-4-carboxylic acid (400 mg, 0.607 mmol) and COMU®. MS (ESI): m / z = 488.1 [M+H] + ; 244.6[M+2H] 2+ ; 1 1H NMR (400 MHz, MeOD) δ 8.73 (d, J = 4.5 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.44 (dd, J = 9.2, 2.7 Hz, 1H), 5.13 (dd, J = 9.4, 2.9 Hz, 1H), 4.19 (m, 6H), 3.77 (t, J = 4.7 Hz, 4H), 2.88 (m, 8H), 2.15 (dp, J = 12.2, 5.4 Hz, 2H).

[0179]

Chemical Structure

[0180] tert-Butyl (S)-4-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (3d) (42.2 mg, 0.098 mmol, yield 27%) was prepared according to General Procedure C using 6-(2-(dimethylamino)ethoxy)quinoline-4-carboxylic acid (93 mg, 0.357 mmol) and HATU. MS (ESI): m / z = 587.3 [M+H] + . 1 1H NMR (400 MHz, DMSO) δ 9.11 (t, J = 6.1 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 5.14 (dd, J = 9.2, 2.9 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.27 - 4.05 (m, 5H), 3.33 - 3.25 (m, 4H), 3.05 - 2.76 (m, 4H), 2.39 - 2.24 (m, 4H), 2.05 - 1.90 (m, 2H), 1.39 (s, 9H).

[0181] General Procedure D (Fluoromethylation, Quaternization)

[0182]

Chemical Structure

[0183] The required secondary amine-containing UAMC1110 derivative (1 eq) was dissolved in DMF (reaction molar concentration ≈ 0.4 M) in a glass vial. Fluoromethyl 4-methylbenzenesulfonate (5 eq) and DIPEA (5 eq) were added, and the reaction mixture was stirred at 120 °C for 20 minutes. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative RP-HPLC using a gradient of acetonitrile + 0.1% formic acid in water (5 - 50% in 20 min).

[0184] General procedure E (fluoroethylation, quaternization) The required secondary amine-containing UAMC1110 derivative (1 eq) was dissolved in acetonitrile (reaction molar concentration ≈ 0.4 M) in a glass vial. Fluoroethyl 4-methylbenzenesulfonate (5 eq), DIPEA (5 eq) and NaI (excess) were added, and the reaction mixture was stirred at 80 °C for 120 minutes. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative RP-HPLC using a gradient of acetonitrile + 0.1% formic acid in water (5 - 50%) in 20 min.

[0185] [Chemical formula]

[0186] (S)-3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-N-(fluoromethyl)-N,N-dimethylpropan-1-aminium benzenesulfonate (4a) (20 mg, 0.031 mmol, 47% yield) was prepared according to general procedure D using (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-(dimethylamino)propoxy)quinoline-4-carboxamide (30 mg, 0.067 mmol). MS (ESI): m / z = 239.7 [M+H] 2+ ; 478.3 [M] + . 11H NMR (400 MHz, MeOD) δ 8.77 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.99 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 4.4 Hz, 1H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.21 (d, J= 7.9 Hz, 2H), 5.46 (d, J = 13.7 Hz, 2H), 5.15 (dd, J = 9.4, 3.3 Hz, 1H), 4.37 (t, J = 5.9 Hz, 2H), 4.32 (s, 2H), 4.25 (m, 1H), 4.12 (m, 1H), 3.70 (dd, J = 10.6, 6.1 Hz, 2H), 3.22 (m, 6H), 2.89 (m, 2H), 2.41 (p, J = 5.1 Hz, 2H), 2.33 (s, 3H). 13 13C NMR (101 MHz, MeOD) δ 169.2, 168.3, 157.32, 147.9, 144.0, 142.21, 141.6, 140.3, 129.7, 128.5, 126.0, 125.8, 125.5, 123.3, 119.9, 117.2, 104.3, 97.4, 95.2, 64.9, 59.3, 51.8, 51.5, 51.2, 46.6, 44.5, 44.5, 41.5, 36.8, 36.5, 36.3, 21.9, 19.9.

[0187]

Chem.

[0188] (S)-2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-N-(fluoromethyl)-N,N-dimethylethane-1-aminium 4-methylbenzenesulfonate (4b) was prepared according to General Procedure D using (S)-2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-N-(fluoromethyl)-N,N-dimethylethane-1-aminium 4-methylbenzenesulfonate. MS (ESI): m / z = 232.7 [M+H] 2+ ; 464.2 [M] + . 1 H NMR (400 MHz, MeOD) δ 8.95 (s, 1H), 8.33 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.81 (d, J = 4.9 Hz, 1H), 7.72 - 7.67 (m, 1H), 5.16 (dd, J = 9.5, 3.3 Hz, 1H), 4.36 (s, 2H), 4.30 - 4.19 (m, 1H), 4.11 (dt, J = 20.2, 10.3 Hz, 1H), 4.02 - 3.93 (m, 2H), 3.29 (d, J = 2.1 Hz, 9H), 3.01 - 2.72 (m, 3H), 1.40 - 1.26 (m, 2H). 13 C NMR (101 MHz, MeOD) δ 160.6, 159.9, 149.5, 137.8, 137.2, 134.2, 132.4, 120.5, 118.7, 117.6, 111.6, 109.3, 100.3, 97.4, 56.9, 54.7, 45.5, 43.5 (d, J = 32.3 Hz), 43.3, 36.7 (d J = 4.2 Hz), 33.7, 28.6.

[0189]

Chemical Structure

[0190] (S)-1-(4-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-(2-fluoroethyl)-1-piperazin-1-yl)-2-fluoroethan-1-ium 4-methylbenzenesulfonate (4c) was prepared according to General Procedure E using (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperazin-1-yl)propoxy)quinoline-4-carboxamide. MS (ESI): m / z = 375.6 [M+H]; 750.3 [M] 2+ ; 750.3 [M] + .

[0191]

Chem.

[0192] (S)-4-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-4-(2-fluoroethyl)morpholin-4-ium 4-methylbenzenesulfonate (5) was prepared according to General Procedure E using (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-morpholinopropoxy)quinoline-4-carboxamide. MS (ESI): m / z = 267.6 [M+H]; 534.0 [M] 2+ ; 534.0 [M] + .

[0193]

Chem.

[0194] (S)-4-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-4-(2-fluoromethyl)morpholin-4-ium 4-methylbenzenesulfonate (6) was prepared according to General Procedure E using (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-morpholinopropoxy)quinoline-4-carboxamide. MS (ESI): m / z = 520.3 [M] + .

[0195]

Chemical formula

[0196] Methyl 6-hydroxyquinoline-4-carboxylate (200 mg, 0.98 mmol, 1.0 eq) was stirred with Cs2CO3 (639 mg, 1.96 mmol, 2.0 eq) in dry DMF (reaction molarity ≈ 0.2 M) at 0 °C for 10 min under an argon atmosphere. The alkylating agent (1.08 mmol, 1.1 eq) was added and the mixture was stirred at 40 °C overnight. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with H2O (20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The title compound was purified using column chromatography eluting with a gradient of MeOH in DCM.

[0197]

Chemical formula

[0198] Methyl 6-(2-((tert-butoxycarbonyl)amino)ethoxy)quinoline-4-carboxylate (7a) (450 mg, 1.15 mmol, 90% yield) was prepared according to General Procedure F using 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate. MS (ESI): m / z = 391.2 [M+H] + .1 1H NMR (400 MHz, DMSO) δ 8.89 (d, J = 4.5 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.93 (d, J= 4.4 Hz, 1H), 7.53 (dd, J = 9.2, 2.8 Hz, 1H), 6.84 (t, J = 5.8 Hz, 1H), 4.24 (t, J = 4.4 Hz, 2H), 3.98 (s, 3H), 3.84 - 3.79 (m, 2H), 3.48 (t, J = 6.0 Hz, 2H), 3.11 (q, J = 6.0 Hz, 2H), 1.35 (s, 9H). 13 13C NMR (101 MHz, DMSO) δ 166.3, 157.8, 155.6, 147.5, 144.8, 132.61, 131.3, 125.6, 122.6, 122.4, 104.9, 77.6, 69.3 (2C), 68.4, 67.6, 52.8, 28.2 (3C).

[0199]

Chem.

[0200] Methyl 6-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)quinoline-4-carboxylate (7b) (408 mg, 0.94 mmol, yield 96%) was prepared according to General Procedure F using 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate. MS (ESI): m / z = 435.3 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 4.5 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 5.04 (s, 1H), 4.31 (dd, J = 5.7, 3.8 Hz, 2H), 4.01 (s, 3H), 3.97 - 3.92 (m, 2H), 3.74 (dd, J = 5.8, 3.4 Hz, 2H), 3.66 (dd, J = 5.8, 3.3 Hz, 2H), 3.55 (t, J = 5.1 Hz, 2H), 3.32 (q, J = 5.4 Hz, 2H), 1.41 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.8, 158.6, 156.1, 146.9, 145.5, 132.7, 131.4, 126.8, 123.3, 122.9, 104.1, 79.3, 70.9, 70.4 (2C), 69.7, 67.8, 52.8, 40.5, 28.5 (3C).

[0201] General procedure G

[0202]

Chem.

[0203] The corresponding compound 7 (0.50 mmol, 1.0 eq) was dissolved in a MeOH / H2O mixture, and then LiOH (48 mg, 2.00 mmol, 4.0 eq) was added to the reaction mixture. After consumption of the starting material (UPLC monitoring), MeOH was evaporated in vacuo, and the reaction mixture was carefully acidified to pH = 4 - 5 by addition of 1 M HCl at 0 °C. Next, the corresponding carboxylic acid was extracted with EtOAc (3 × 20 mL), the combined organic phases were dried over Na2SO4, and the solvent was evaporated on a rotary evaporator. The carboxylic acid was dissolved in dry DMF, and HATU (285 mg, 0.75 mmol, 1.5 eq) and dry DIPEA (0.26 mL, 1.5 mmol, 3.0 eq) were added to the reaction mixture. After stirring at room temperature for 5 min, (S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethane-1-aminium 4-methylbenzenesulfonate (199 mg, 0.55 mmol, 1.1 eq) was added. After consumption of the starting material (UPLC monitoring), all volatiles were removed on a rotary evaporator. The crude product was diluted with 25 mL of EtOAc, washed with saturated aqueous sodium bicarbonate and H2O, dried over Na2SO4, filtered, and the solvent was removed in vacuo to give a residue, which was purified by reverse-phase column chromatography eluting with a gradient of ACN in water.

[0204] [Chemical Structure]

[0205] tert-Butyl (S)-(2-(2-((4-((2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)ethyl)carbamate (8a) (175 mg, 0.29 mmol, 59% yield) was prepared according to the general procedure G using 6-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)quinoline-4-carboxylic acid (206 mg, 0.49 mmol). MS (ESI): m / z = 592.3 [M+H] + ; 630.2 [M+K]+ . 1 1H NMR (400 MHz, MeOD) δ 8.70 (d, J = 4.4 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.52 (d, J = 4.5 Hz, 1H), 7.45 (dd, J = 9.3, 2.7 Hz, 1H), 5.13 (dd, J = 9.3, 3.2 Hz, 1H), 4.38 - 4.18 (m, 5H), 4.18 - 4.05 (m, 1H), 3.92 (dd, J = 5.9, 3.2 Hz, 2H), 3.76 - 3.68 (m, 2H), 3.66 - 3.59 (m, 2H), 3.50 (t, J = 5.6 Hz, 2H), 3.21 (q, J = 5.2 Hz, 2H), 2.99 - 2.75 (m, 2H), 1.40 (s, 9H). 13 13C NMR (101 MHz, MeOD) δ 170.4, 169.4, 159.1, 158.3, 148.1, 145.2, 142.5, 130.9, 127.5 (dd, J = 250.8, 247.2 Hz), 127.1, 124.7, 120.4, 118.2, 105.21, 80.0, 71.6, 71.2, 71.0, 70.5, 69.2, 52.8 (t, J = 32.3 Hz), 45.8 (d, J = 5.6 Hz), 42.9, 41.2, 38.0 (t, J = 25.1 Hz), 28.7 (3C).

[0206] General procedure H (methylation, quaternization) The corresponding Boc-amine-containing derivative (0.10 mmol, 1.0 eq) was dissolved in acetonitrile, and p-toluenesulfonic acid monohydrate (0.20 mmol, 2.0 eq) was added to the reaction mixture. After consumption of the starting material (UPLC monitoring), the solvent was removed under reduced pressure. Thereafter, the residue was dissolved in DMF in a glass vial (reaction molarity ≒ 0.4 M). MeI (21 μL, 0.33 mmol, 3.3 eq) and DIPEA (10 eq) were added, and the reaction was stirred overnight at rt. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative RP-HPLC using a gradient of ACN + 0.1% formic acid in water (5 - 50%) for 20’.

[0207] [Chemical formula]

[0208] (S)-2-(2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)-N,N,N-trimethylethane-1-aminium 4-methylbenzenesulfonate (7) (29 mg, 0.041 mmol, 41% yield) was prepared according to the general procedure H using tert-butyl (S)-(2-(2-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)ethyl)carbamate. MS (ESI): m / z = 267.6 [M+H] ++ ; 534.0 [M] + . 11H NMR (400 MHz, MeOD) δ 8.77 (d, J = 4.5 Hz, 1H), 8.04 - 7.94 (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 4.4 Hz, 1H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.24 (d, J= 8.0 Hz, 2H), 5.15 (dd, J = 9.4, 3.1 Hz, 1H), 4.41 - 4.21 (m, 5H), 4.21 - 4.06 (m, 1H), 3.93 (ddt, J = 14.1, 4.9, 2.4 Hz, 4H), 3.78 - 3.65 (m, 4H), 3.58 - 3.48 (m, 2H), 3.14 (s, 9H), 3.03 - 2.74 (m, 2H), 2.37 (s, 3H). 13 13C NMR (101 MHz, MeOD) δ 170.6, 169.6, 159.2, 148.3, 145.3, 143.7, 142.8, 141.7, 131.1, 129.9 (2C), 127.5 (dd, J = 250.9, 247.1 Hz), 127.3, 126.9 (2C), 124.5, 120.4, 118.4, 105.7, 71.5, 71.3, 70.5, 69.5, 66.9, 65.9, 54.8 (2C), 54.7, 52.9 (t, J = 31.9 Hz), 45.84 (d, J = 5.6 Hz), 42.9, 38.0 (t, J = 25.2 Hz), 21.3.

[0209] General Procedure I

Chem.

Chem.

[0210] Trifluoroacetic acid (0.34 mL, 4.50 mmol, 5.0 eq) was added to a solution of the corresponding N-Boc protected methyl ester derivative (0.90 mmol, 1.0 eq) in dry DCM at 0 °C. After stirring overnight at rt, all volatiles were removed in vacuo, and the crude was dissolved in a MeOH / H2O mixture and cooled to 0 °C. Formaldehyde (37% solution in H2O; 1.07 mL, 14.4 mmol, 16.0 eq) and NaBH4 (170 mg, 4.5 mmol, 5.0 eq) were added to the reaction mixture. After stirring at 0 °C for 2 h, the reaction mixture was alkalized to pH = 12 and left at rt. After consumption of the starting material (UPLC monitoring), all volatiles were removed with a rotary evaporator. The title compound was purified by reverse-phase column chromatography eluting with a gradient of ACN in water

[0211]

Chemical Structure

[0212] 6-(2-(2-(Dimethylamino)ethoxy)ethoxy)quinoline-4-carboxylic acid (9a) (300 mg, 0.98 mmol, 52% yield) was prepared according to General Procedure I using methyl 6-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)quinoline-4-carboxylate. MS (ESI): m / z = 377.3 [M+H] + ; 399.3 [M+Na] + . 1 H NMR (400 MHz, D2O) δ 8.65 (d, J = 4.5 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.45 (ddd, J = 12.1, 10.1, 2.6 Hz, 3H), 4.31 - 4.23 (m, 2H), 3.90 - 3.86 (m, 2H), 3.71 - 3.63 (m, 2H), 2.52 (t, J = 5.7 Hz, 2H), 2.16 (s, 6H).

[0213]

Chemical Structure

[0214] 6-(2-(2-(Dimethylamino)ethoxy)ethoxy)ethoxy)quinoline-4-carboxylic acid (9b) (207 mg, 0.59 mmol, yield 66%) was prepared according to General Procedure I using methyl 6-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)quinoline-4-carboxylate. MS (ESI): m / z = 349.2 [M+H] + ; 371.2 [M+Na] + . 1 H NMR (400 MHz, MeOD) δ 8.66 (d, J = 4.8 Hz, 1H), 7.96 - 7.83 (m, 2H), 7.57 (d, J = 4.5 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 4.25 (t, J = 4.3 Hz, 2H), 3.87 (t, J = 4.2 Hz, 2H), 3.69 (t, J = 4.5 Hz, 2H), 3.65 - 3.48 (m, 4H), 2.46 (t, J = 5.7 Hz, 2H), 2.20 (s, 6H). 13 C NMR (101 MHz, MeOD) δ 174.7, 158.4, 148.4, 147.6, 145.4, 130.6, 127.6, 123.8, 120.4, 106.5, 71.6, 71.2, 70.6, 69.6, 68.8, 59.5, 49.9, 45.8.

[0215]

Chem.

[0216] (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)quinoline-4-carboxamide (10a) (138 mg, 0.27 mmol, yield 41%) was prepared according to General Procedure C using 6-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)quinoline-4-carboxylic acid (226 mg, 0.65 mmol) and HATU. MS (ESI): m / z = 260.8 [M+2H] ++ ; 520.3 [M+H] + . 1 1H NMR (400 MHz, MeOD) δ 8.76 (d, J = 4.4 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.57 (d, J = 4.4 Hz, 1H), 7.49 (dd, J = 9.2, 2.8 Hz, 1H), 5.14 (dd, J = 9.4, 3.2 Hz, 1H), 4.42 - 4.07 (m, 6H), 3.98 - 3.88 (m, 2H), 3.77 - 3.70 (m, 2H), 3.67 - 3.58 (m, 4H), 3.02 - 2.74 (m, 2H), 2.59 (td, J = 5.7, 3.0 Hz, 2H), 2.30 (s, 6H). 13 13C NMR (101 MHz, MeOD) δ 170.7, 169.5, 159.4, 148.1, 145.4, 142.9, 130.9, 128.8 (t, J = 250.7 Hz) 127.4, 124.9, 120.4, 118.2, 105.4, 71.7, 71.4, 70.6, 69.5, 69.4, 59.4, 52.9 (t, J = 32.5 Hz), 45.8 (d, J = 5.3 Hz), 45.6 (2C), 42.9, 38.1 (t, J = 25.3 Hz).

[0217]

Chemical Structure

[0218] (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(2-(dimethylamino)ethoxy)ethoxy)quinoline-4-carboxamide (10b) (22 mg, 0.05 mmol, yield 8%) was prepared according to General Procedure C using 6-(2-(2-(dimethylamino)ethoxy)ethoxy)quinoline-4-carboxylic acid (175 mg, 0.57 mmol) and COMU®. MS (ESI): m / z = 476.3 [M+H] + . 1 1H NMR (400 MHz, MeOD) δ 9.11 (t, J = 5.8 Hz, 1H), 8.81 (d, J = 4.2 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.54 - 7.43 (m, 2H), 5.16 (d, J = 7.1 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.29 - 4.22 (m, J = 6.1 Hz, 3H), 4.20 - 4.07 (m, 1H), 3.80 (s, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.91 - 2.66 (m, 3H), 2.43 (t, J = 5.9 Hz, 2H), 2.15 (s, 6H). 13 13C NMR (101 MHz, MeOD) δ 168.07, 167.48, 156.91, 147.67, 144.13, 140.85, 130.57, 125.33, 122.57, 119.06, 117.72, 104.54, 68.76, 68.51, 67.70, 67.68, 58.26, 45.57 (2C), 44.23, 41.37.

[0219]

Chem.

[0220] (S)-2-(2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)-N-(2-fluoroethyl)-N,N-dimethylethan-1-aminium 4-methylbenzenesulfonate (8) (12 mg, 0.017 mmol, 41% yield) was prepared from Compound 10b (20 mg, 0.04 mmol) according to General Procedure E. MS (ESI): m / z = 261.8 [M+2H] ++ ; 522.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.75 (d, J = 4.4 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.46 (dd, J = 9.3, 2.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 9.4, 3.3 Hz, 1H), 4.41 (tt, J = 7.6, 4.4 Hz, 2H), 4.31 - 4.19 (m, 3H), 4.12 (dd, J = 19.5, 9.9 Hz, 1H), 4.00 (h, J = 2.5 Hz, 2H), 3.94 (t, J = 4.4 Hz, 2H), 3.88 - 3.83 (m, 1H), 3.80 - 3.76 (m, 1H), 3.74 - 3.68 (m, 2H), 3.19 (s, 6H), 3.01 - 2.72 (m, 2H). 1313C NMR (101 MHz, MeOD) δ 170.7, 169.63, 159.2, 148.4, 145.7, 143.6, 142.9, 141.6, 131.1, 129.8, 127.5 (dd, J = 251.1, 250.5 Hz), 126.9 (2C), 124.5, 120.4, 118.4, 105.8, 79.6, 77.9, 70.8, 69.0, 66.4 (d, J = 19.8 Hz), 65.8, 65.7, 53.0 (t, J = 32.2 Hz), 52.6, 45.9, 45.8, 42.9, 38.3, 37.9 (d, J = 25.3 Hz), 21.3.

[0221] [Chemical formula]

[0222] (S)-2-(2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)-N-(fluoromethyl)-N,N-dimethylethan-1-aminium 4-methylbenzenesulfonate (9) (23 mg, 0.034 mmol, yield 34%) was prepared from compound 10b (52 mg, 0.11 mmol) according to the general procedure D. MS (ESI): m / z = 254.7 [M+2H] ++ ; 508.2 [M+H] + . 1 1H NMR (400 MHz, MeOD) δ 8.77 (d, J = 4.4 Hz, 1H), 8.16 - 7.87 (m, 2H), 7.80 - 7.39 (m, 4H), 7.22 (d, J = 7.6 Hz, 2H), 5.43 (d, J = 45.5 Hz, 2H), 5.22 - 5.01 (m, 1H), 4.59 - 3.88 (m, 10H), 3.82 - 3.63 (m, 2H), 3.21 (s, 6H), 3.04 - 2.71 (m, 2H), 2.35 (s, 3H). 13¹³C NMR (101 MHz, MeOD) δ 170.7, 169.6, 159.1, 148.4, 145.4, 143.6, 142.9, 141.7, 131.1, 129.9 (2C), 127.5 (dd, J = 251.1, 250.5 Hz), 127.3, 126.9 (2C), 124.6, 120.4, 118.4, 105.8, 98.35 (d, J = 218.3 Hz), 70.8, 69.0, 65.3 (2C), 62.5 (2C), 52.92 (t, J = 32.2 Hz), 45.9 (d, J = 4.9 Hz), 42.9, 38.0 (t, J = 25.4 Hz), 21.3.

[0223]

Chem.

[0224] (S)-2-(2-(2-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)ethoxy)-N-(fluoromethyl)-N,N-dimethylethane-1-aminium hexafluorophosphate(V) (10) (12 mg, 0.017 mmol, 17% yield) was prepared from compound 10a (52 mg, 0.1 mmol) according to the general procedure D. MS (ESI): m / z = 276.7 [M+2H] ++ ; 552.3 [M+H] + . 11H NMR (400 MHz, MeOD) δ 8.77 (d, J = 4.4 Hz, 1H), 8.03 - 7.95 (m, 2H), 7.57 (d, J = 4.5 Hz, 1H), 7.50 (dd, J = 9.3, 2.8 Hz, 1H), 5.43 (d, J = 45.2 Hz, 1H), 5.16 - 5.10 (m, 1H), 4.44 - 4.20 (m, 5H), 4.13 (dt, J = 20.3, 10.3 Hz, 1H), 3.99 - 3.90 (m, 4H), 3.79 - 3.68 (m, 4H), 3.68 - 3.61 (m, 2H), 3.19 (d, J = 2.1 Hz, 6H), 3.01 - 2.74 (m, 2H). 13 13C NMR (101 MHz, MeOD) δ 170.7, 169.6, 159.3, 148.3, 145.3, 142.9, 131.1, 127.5 (dd, J = 251.1, 250.5 Hz), 127.3, 124.6, 120.4, 118.3, 105.7, 98.36 (d, J= 219.2 Hz), 71.4 (2C), 70.6, 69.5, 65.3 (2C), 62.5 (2C), 52.9 (t, J = 32.2 Hz), 45.9 (d, J = 5.6 Hz), 42.9, 38.0 (t, J = 25.2 Hz).

[0225]

Chem.

Chem.

[0226] The corresponding Boc piperazine-containing derivative (0.35 mmol, 1.0 eq) was dissolved in DMF (reaction molar concentration ≒ 0.4 M) in a glass vial. MeI (24 μL, 0.385 mmol, 1.1 eq) and DIPEA (0.12 mL, 0.70 mmol, 2.0 eq) were added, and the reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative RP-HPLC using a gradient of ACN + 0.1% formic acid in water (5 - 50%) for 20 min.

[0227] [Chemical formula]

[0228] (S)-4-(tert-Butoxycarbonyl)-1-(3-((4-((2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1-ium iodide (11) (127.5 mg, 0.175 mmol, 50% yield) was prepared from compound 3d (258 mg, 0.35 mmol) according to the general procedure J. MS (ESI): m / z = 301.3 [M+H] ++ ; 601.3 [M] + . 1 H NMR (400 MHz, MeOD) δ 8.78 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.52 - 7.48 (m, 1H), 5.14 (dd, J = 9.4, 3.3 Hz, 1H), 4.45 - 4.21 (m, 5H), 4.13 (dt, J = 20.2, 10.3 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.78 - 3.62 (m, 4H), 3.55 - 3.48 (m, 4H), 3.22 (s, 3H), 3.02 - 2.74 (m, 2H), 2.48 - 2.37 (m, 2H), 1.48 (s, 9H). 1313C NMR (101 MHz, MeOD) δ 170.8, 169.7, 158.8, 155.5, 148.5, 145.4, 143.1, 131.1, 127.6 (dd, J = 250.9, 247.1 Hz), 127.3, 124.8, 120.3, 118.6, 105.7, 82.6, 66.4, 63.0, 62.9, 60.8 (2C), 52.9 (t, J = 32.3 Hz), 47.2 (2C), 45.9 (d, J = 6.5 Hz), 42.9, 37.9 (t, J = 25.6 Hz), 28.5 (3C), 22.8.

[0229] General procedure K (removal of Boc protecting group and amide coupling) (S)-4-(tert-Butoxycarbonyl)-1-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1-ium iodide (51 mg, 0.07 mmol, 1.0 eq) was dissolved in dry MeCN, cooled to 0 °C, and p-toluenesulfonic acid monohydrate (53.2 mg, 0.28 mmol, 4.0 eq) was added to the reaction mixture. After stirring at rt for 2 days, the solvent was concentrated in vacuo. The crude product was dissolved in dry DMF and added to a 10 mL round-bottom flask precharged with the corresponding carboxylic acid (0.105 mmol, 1.5 eq), HATU (53.2 mg, 0.14 mmol, 2.0 eq), dry DIPEA (0.12 mL, 0.7 mmol, 10.0 eq), and dry DMF (reaction molar concentration ≈ 0.15 M). After consumption of the starting material (UPLC monitoring), all volatiles were removed using a rotary evaporator. The title compound was purified by RP-HPLC using a gradient of ACN + 0.1% formic acid in water (5 - 50% in 20’).

[0230]

Chem.

[0231] (S)-4-(4-Boronobenzoyl)-1-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1-ium 4-methylbenzenesulfonate (12) (32 mg, 0.039 mmol, yield 55%) was prepared according to General Procedure K using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (26 mg, 0.105 mmol, 1.5 eq). MS (ESI): m / z = 325.3 [M+H] ++ ; 649.3 [M] + . 1 1H NMR (400 MHz, MeOD) δ 8.78 (d, J = 4.4 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.87 - 7.71 (m, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 4.5 Hz, 1H), 7.50 (dd, J = 9.3, 2.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 9.3, 3.4 Hz, 1H), 4.41 (t, J = 5.8 Hz, 2H), 4.36 - 4.19 (m, 3H), 4.13 (dt, J = 20.2, 10.4 Hz, 1H), 4.04 - 3.44 (m, 10H), 3.27 (s, 3H), 3.02 - 2.75 (m, 2H), 2.48 - 2.38 (m, 2H), 2.35 (s, 3H). 1313C NMR (101 MHz, MeOD) δ 172.7, 170.7, 169.7, 158.7, 148.5, 145.4, 143.6, 143.1, 141.7 (2C), 140.6, 139.4, 135.0, 131.1, 129.8 (2C), 127.5 (dd, J = 250.9, 247.1 Hz), 127.3, 127.2 (2C), 126.9 (2C), 124.7, 120.3, 118.6, 105.8, 66.4, 63.2, 63.1, 60.8 (2C), 53.1 (t, J = 31.9 Hz), 47.5 (2C), 46.0 (d, J = 5.7 Hz), 42.9, 37.9 (t, J = 25.9 Hz), 22.9, 21.3.

[0232] [Chemical formula]

[0233] (S)-1-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-4-(4-iodobenzoyl)-1-methylpiperazin-1-ium hexafluorophosphate(V) (13) (21.5 mg, 0.025 mmol, yield 35%) was prepared according to the general procedure H using 4-iodobenzoic acid (26 mg, 0.105 mmol, 1.5 eq). MS (ESI): m / z = 366.3 [M+H] ++ ; 731.3 [M] + . 11H NMR (400 MHz, MeOD) δ 8.78 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 9.3 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 4.5 Hz, 1H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.27 (d, J= 8.4 Hz, 2H), 5.13 (dd, J = 9.4, 3.3 Hz, 1H), 4.46 - 4.19 (m, 5H), 4.12 (dt, J = 20.1, 10.2 Hz, 1H), 4.03 - 3.44 (m, 10H), 3.26 (s, 3H), 3.04 - 2.74 (m, 2H), 2.53 - 2.36 (m, 2H). 13 13C NMR (101 MHz, MeOD) δ 171.6, 170.6, 169.7, 158.8, 148.3, 145.1, 143.4, 139.2 (2C), 134.8, 130.8, 130.1 (2C), 127.5 (dd, J = 251.1, 247.4 Hz), 127.3, 124.9, 120.3, 118.6, 105.7, 97.8, 66.5, 63.2, 63.1, 60.7 (2C), 52.9 (t, J = 32.8 Hz), 47.5 (2C), 45.9 (d, J = 5.1 Hz), 42.9, 37.9 (t, J = 25.4 Hz), 22.9.

[0234]

Chem.

[0235] (S)-1-(3-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-4-(4-fluorobenzoyl)-1-methylpiperazin-1-ium (14) (10.2 mg, 0.016 mmol, 43% yield) was prepared according to General Procedure H using 4-fluorobenzoic acid (7.4 mg, 0.05 mmol). MS (ESI): m / z = 312.1 [M+H] ++ ; 623.1 [M] + . 1 H NMR (400 MHz, MeOD) δ 8.75 (d, J = 4.4 Hz, 1H), 8.39 (s, 1H), 8.03 - 7.93 (m, 2H), 7.57 - 7.43 (m, 3H), 7.25 - 7.07 (m, 3H), 5.08 (dd, J = 9.3, 3.5 Hz, 1H), 4.39 (t, J = 5.8 Hz, 2H), 4.28 (d, J = 5.2 Hz, 1H), 4.25 - 4.01 (m, 4H), 3.88 (s, 3H), 3.71 (s, 2H), 3.55 (s, 3H), 3.23 (s, 2H), 2.40 (s, 2H), 1.25 (s, 3H).

[0236] 2) Biochemical evaluation of the compound Typically, the compounds are evaluated as inhibitors of FAP, PREP, DPP4, DPP8, DPP9 and DPP2.

[0237] Enzymes used in these assays: · Purchased the gateway-entry clone of human FAP from Dharmacon (accession number DQ891423), and replaced the human secretion signal with the HoneyBee melittin secretion signal. For the transfection and expression of FAP in Sf9 insect cells, the C-terminal BaculoDirect kit from Life Technologies was used. The enzyme was purified from the supernatant of insect cells using immobilized Ni-chelate chromatography (GE healthcare, Diegem, Belgium), followed by anion exchange chromatography using a 1 mL HiTrapQ and size exclusion chromatography using a Superdex200 column (GE healthcare, Diegem, Belgium).

[0238] · Expressed human recombinant PREP in BL21(DE3) cells, purified it using immobilized Co-chelate chromatography (GE healthcare), and then performed anion exchange chromatography using a 1 mL Mono Q column (GE healthcare).

[0239] · DPP4 was purified from human seminal plasma.

[0240] · The gateway clones of human DPP8 and DPP9 were purchased from Dharmacon (accession numbers DQ891733 and DQ892325, respectively). For the transfection and expression of DPP8 and DPP9 in Sf9 insect cells, the N-terminal BaculoDirect kit from Life Technologies was used. The enzyme was purified using immobilized Ni-chelate chromatography (GE healthcare, Diegem, Belgium), followed by anion exchange chromatography using a 1 mL MonoQ (GE healthcare, Diegem, Belgium).

[0241] · Recombinant human DPP2 was purchased from R&D.

[0242] IC 50の Measurement: · For FAP: IC of the probe50 The measurement was carried out at a concentration of 50 μM using Z-Gly-Pro-7-amino-4-methylcoumarin (AMC) (Bachem) as the substrate at pH 8 (0.05 M Tris-HCl buffer, 1 mg / mL BSA, 140 mM NaCl). Eight concentrations of inhibitor / probe were tested. The final DMSO concentration was kept constant during the experiment to eliminate the influence. The inhibitor was pre-incubated with the enzyme at 37 °C for 15 min, then the substrate was added, and the release rate of AMC was measured kinetically at λex = 380 nm and λem = 465 nm at 37 °C for at least 10 min. The measurement was performed using an Infinite 200 (Tecan Group Ltd.), and Magellan software was used for data processing.

[0243] · For PREP: IC of the probe 50 The measurement was carried out at a concentration of 250 μM using N-succinyl-Gly-Pro-AMC (Bachem) as the substrate at pH 7.4 (0.1 M K-phosphate, 1 mM EDTA, 1 mM DTT and 1 mg / mL BSA). Eight concentrations of inhibitor were tested. The final DMSO concentration was kept constant during the experiment to eliminate the influence. The inhibitor was pre-incubated with the enzyme at 37 °C for 15 min, then the substrate was added, and the release rate of AMC was measured kinetically at λex = 380 nm and λem = 465 nm at 37 °C for at least 10 min. The measurement was performed using an Infinite 200 (Tecan Group Ltd.), and Magellan software was used for data processing.

[0244] · For DPP4, DPP8 & DPP9 IC 50Values were measured using Ala-Pro-p-nitroanilide (pNA) as substrate at respective final concentrations of 25 μM (DPP4), 300 μM (DPP8) or 150 μM (DPP9), at pH 7.4 (0.05 M HEPES-NaOH buffer, 0.1% Tween-20, 0.1 mg / mL BSA and 150 mM NaCl). At least eight inhibitor concentrations were used. The final DMSO concentration was kept constant during the experiment to rule out effects. The inhibitor was pre-incubated with the enzyme at 37 °C for 15 min, then the substrate was added and the pNA release rate was measured kinetically at 405 nm at 37 °C for at least 10 min. Measurements were performed on an Infinite 200 (Tecan Group Ltd.) and Magellan software was used for data processing.

[0245] · For DPP2: Initial velocity measurements were performed. Lys-Ala-pNA was used as substrate at a concentration of 1 mM at pH 5.5 (100 mM NaAc, 10 mM EDTA, 14 μg / mL aprotinin). The inhibitor was tested at one concentration, the final concentration in the well of 5 μM. The inhibitor was pre-incubated with the enzyme at 37 °C for 15 min, then the substrate was added and the pNA release rate was measured kinetically at 405 nm at 37 °C for at least 10 min. Measurements were performed on an Infinite 200 (Tecan Group Ltd.) and Magellan software was used for data processing.

[0246] IC50 results: The specificity of the reference molecule UAMC1110 was tested by comparing the inhibitory effects on FAP, PREP, DPP2, DPP4, DPP8 and DPP9 activities. UAMC1110 showed high specificity for FAP (IC50 = 0.43 ± 0.02 nM) compared to DPP2, DPP4, DPP8 and DPP9 (IC50 > 10 nM), but UAMC1110 was also shown to be an efficient inhibitor against PREP (IC50 = 1.8 ± 0.01 nM). Interestingly, when comparing UAMC1110 with UAMC-0004522 (Compound 4a) of the present invention, UAMC-0004522 had a comparable IC50 for FAP (i.e., 0.32 ± 0.02 nM), but the IC50 for PREP (i.e., > 10 nM) and the IC50 for another member S9 of the prolyl oligopeptidase family were significantly higher (Table 2). Similar results were obtained for all other test compounds of the present invention (Table 2), demonstrating that the compounds of the present invention have high specificity for FAP not currently available in the art.

[0247]

Table 2

[0248] Furthermore, the selectivity index was calculated. The selectivity index used herein is the ratio of two IC 50 values. For example: the selectivity index of FAP vs PREP is defined as (IC 50 (PREP) / IC 50 (FAP)). In Table 3, the selectivity index of FAP vs other enzymes is represented by the names of the other enzymes (PREP, DPP4, DPP8, DPP9). Therefore, the selectivity index of PREP is IC 50 (PREP) / IC 50 (FAP). Therefore, the specificity of Compound 4b for FAP is 4853 higher than that for PREP (Table 3).

[0249]

Table 3

[0250] 3) Synthetic approach, procedure and characterization of radiolabeled compound 1 Radiosynthesis was accomplished from the corresponding amine-based intermediates described in Scheme 1 (supra), the latter of which can be converted to aryl amines as shown in Scheme 2: 18 Reacted with dibromomethane-d2 in the presence of F-fluoride ion:

[0251] Scheme 2: [ka]

[0252] [ka]

[0253] Scheme 2. Reagents and conditions: A) (i) dibromomethane-d2, [18F]fluoride, Kryptofix222, ACN, 90°C; (ii) [18F]bromofluoromethane-d2, NaOH, DMF, 100°C, 10'.

[0254] Procedure: Radiation synthesis was performed using a fully automated TRASIS AllinOne module (TRASIS). 18 Aqueous solutions of [F] fluoride were prepared using an Eclipse HP cyclotron (Siemens). 18 O]H2O (Rotem Industries) by proton bombardment 18 O(p,n) 18 F reaction. After transferring to a hot cell, it was dissolved in 0.8 mL of a mixture of 0.03 M K2CO3 / 0.07 M Kryptofix222 in CH3CN / H2O (95:5 v / v) after previously conditioning with potassium bicarbonate solution (0.25 g / 5 mL) and water (10 mL) and evaporated to complete dryness in reaction vial 1. The completely dried fluoride was cooled to 40 °C and 500 μL of dibromomethane-d2 (500 μL) in ACN was added to reaction vial 1. The mixture was heated to 90 °C for 5 min. After cooling reactor 1 to 40 °C, [18 The purification of F]FCD2Br was carried out by distillation on four silica plus SepPak® cartridges using a smooth He stream (10 mL / min for 1 minute; then 40 mL / min for 10 - 15 minutes), to obtain pure 18 F]FCD2Br was trapped in reactor 2 and subsequently reacted with an amine precursor (2 mg in 200 μL of DMF) in the presence of NaOH. The alkylation was carried out at 100 °C for 10 minutes. The reaction was cooled to RT and quenched by adding 1 mL of HPLC buffer (EtOH / 0.05 M NaOAc pH 5.5 15:85 (v / v)). The crude solution was purified by semi-preparative HPLC (Phenomenex Luna C18 250×10 mm (5 μm) HPLC column, EtOH / 0.05 M NaOAc pH 5.5 15:85 (v / v); flow rate 3 mL / min -1 ). The fraction containing the desired molecule (t R = 14 minutes) was collected and loaded onto a polymer-based weak cation exchange cartridge (Oasis WCX). The purified compound 1 was obtained after sequential washing with 6% NH4OH, 6% NH4OH / EtOH (50:50 v / v), EtOH, and H2O. Compound 1 was eluted with 0.9% NaCl solution.

[0255] Characterization of the radioactive tracer: Compound 1 ( 18To evaluate the quality of [18F]UAMC-4522) and its suitability for specific applications such as medical imaging, several parameters were determined. First, the decay-corrected RCY (radiochemical yield) was calculated. This indicates the proportion of the desired radiolabeled molecules after correcting for radioactive decay. It is calculated by dividing the amount of radiolabeled molecules by the total radioactivity, taking into account the elapsed time from the radiolabeling. Next, the apparent molar activity (Am) was calculated. This represents the activity of the radioactive tracer per unit of substance (e.g., per micromole). It is calculated by dividing the activity of the radioactive tracer by the amount of labeled molecules used. Next, the radiochemical purity (RCP) was measured. This indicates the proportion of radiolabeled molecules relative to other chemical components or impurities. It is often determined using analytical techniques such as radio-HPLC (high-performance liquid chromatography) or radio-TLC (thin-layer chromatography). Finally, the partition coefficient (LogD) was calculated. This reflects the distribution of a substance between two solvents with different polarities. The LogD value represents the ratio of the concentrations of the substance in the organic solvent and the aqueous solution. This is used to understand the solubility and distribution of the radioactive tracer in biological systems.

[0256] Table 4 shows the characterization of compound 1. The data are presented as mean values and standard deviations (n = 8).

[0257]

Table 4

[0258] 4) In vivo study of compound 1 ( 18 [18F]UAMC-4522) · Experimental procedure In all in vivo studies, the following experimental procedure was used. Female CD1 nude mice (7 - 8 weeks old) received an intravenous injection of 5.1 - 7.4 MBq of compound 1 (n = 9) via the lateral tail vein. At 15, 30, and 60 minutes after the injection of the radioactive tracer (p.i.) (n = 3 for each time point), blood was collected into EDTA-coated tubes by cardiac puncture, and the mice were euthanized by cervical dislocation. - / - ​

[0259] ·In vivo stability The plasma fraction was obtained from the collected blood by centrifugation at 4000 g for 7 minutes and mixed with an equal volume of cold MeCN (200 μL) to enable protein removal from the sample. After vigorous vortexing and gamma counting, the sample was centrifuged at 4000 g for 4 minutes, and the supernatant and pellet were gamma counted separately to measure the recovered radioactivity in the organic phase. The radioactive content of the supernatant was analyzed by analytical radio-HPLC. The eluted fractions were collected every 30 seconds and the radioactivity was counted with an automatic gamma counter. Table 5 shows that the in vivo stability of Compound 1 is significantly higher than that of the control.

[0260]

Table 5

[0261] ·In vivo distribution of Compound 1 in control animals CD1 - / - The organs and tissues of nude mice (see above) were collected, weighed, and the radioactivity in the samples was measured using an automatic gamma counter (Wizard 2 2480, PerkinElmer). The uptake level of the tracer was expressed as a percentage (%) of the injected dose per gram of tissue (%ID g -1 ).

[0262] Figure 3 summarizes the tissue in vivo distribution (% injected dose / tissue gram) of [ 18 F]UAMC-4522 (Compound 1) and Compound 0 at 15, 30, and 60 minutes post-injection (p.i.) in normal CD1 nude mice (n = 3 for each time point).

[0263] ·In vivo PET imaging and in vivo distribution in tumor-bearing animals To confirm the binding specificity of Compound 1, a cohort of tumor-bearing mice (n = 4) was injected with UAMC1110 via the tail vein 30 minutes before the injection of Compound 1. Whole-body PET dynamic images were acquired over 60 minutes. The mean activity of tumors or muscles per volume was determined from the PET images, and the attenuation-corrected time-activity curve (TAC) was extracted. At the end of the scan, organs and tissues were harvested, weighed, and the radioactivity in the samples was measured using an automatic gamma counter.

[0264] The performance of this radioligand was compared with [68Ga]Ga-DOTA-FAPI-04 in U87MG xenografts (Figure 4). The tumor uptake of both radioligands represented by the TAC is shown in Figure 4. In the dynamic imaging of [18F]UAMC-4522 at 60 min p.i., it was shown that the uptake in the tumor reached a peak early and then the uptake in the tumor was maintained or slightly increased over the duration of the PET scan. The tumor uptake of [18F]UAMC-4522 was significantly higher compared to the muscle uptake (10.16 ± 2.22 vs 2.20 ± 0.33%ID / mL at 60 min p.i.). On the other hand, [68Ga]Ga-DOTA-FAPI-04 had a late peak of tumor uptake, showing a maximum uptake (5.46 ± 0.83%ID / mL) at 8.8 min p.i. and was then rapidly cleared from the tumor (Figure 4).

[0265] Importantly, the specificity of the radioligand for FAP was evaluated in a blocking test. Pretreatment of mice bearing U87MG tumors with the specific FAP inhibitor UAMC-1110 resulted in a decrease in tumor uptake, indicating the specificity of the radioligand for FAP (Figure 4). Interestingly, [18F]UAMC-4522 had lower non-specific tumor uptake compared to the 68Ga-labeled FAP ligand, which is advantageous when imaging sites with low FAP expression.

[0266] Similar to the PET results, in the biodistribution study, all FAP radioligands showed high and specific tumor uptake at 60 min post-injection (p.i.) (Table 6). The obtained tumor-to-background ratios are shown in Table 6.

[0267]

Table 6

[0268] ·Ex vivo tumor analysis Tumor sections (10 μm) were collected at regular intervals across the entire tumor volume and used for immunohistochemical analysis of FAP expression in tumor xenografts. The tumor sections were stained for FAP, and after image acquisition, FAP expression was quantified. Pearson correlation coefficients were calculated for correlation analysis.

[0269] In U87MG tumors, the FAP-positive tumor area was large (75.9 ± 11.6%). The uptake of [18F]UAMC-4522 (r = 0.967, p = 0.032) showed a high correlation with FAP expression in tumors. In contrast, in animals injected with [68Ga]Ga-DOTA-FAPI-04 (r = 0.892, p = 0.108), a poor correlation was shown between the mean radioactivity of the tumor and FAP expression in U87MG tumors. These results indicate that the uptake of [18F]UAMC-4522 in tumors is superior to that of [68Ga]Ga-DOTA-FAPI-04 as a surrogate for FAP activity and / or expression, which may be due to the lack of in vivo stability of the latter.

[0270] Description of the figures Figure 1 shows a comparison of the selectivity of compound 1 and a compound without a quaternary ammonium cation (compound 0) for FAP.

[0271] The importance of having a quaternary ammonium group in the linker part is demonstrated by comparing the selectivity of compounds 0 and 1 against FAP. Only compound 1 has a quaternary ammonium-containing linker, and this molecule has significantly higher selectivity for FAP over prolyl oligopeptidase (PREP) than compound 0. PREP is an enzyme that is closely related to FAP and is widely expressed in the human body. Therefore, the selectivity of FAP against PREP is an important parameter.

[0272] Figure 2 shows a comparison of the metabolic stability of compound 1 and a compound without a quaternary ammonium cation (compound 0).

[0273] The importance of the quaternary ammonium group in the linker part is demonstrated by comparing the metabolic stability of compounds 0 and 1. Compound 1 has significantly higher metabolic stability than compound 0. This is also important because higher metabolic stability allows for fewer administration times in in vivo applications.

[0274] Figure 3 shows a comparison of the in vivo distribution profiles of compound 1 and a compound without a quaternary ammonium cation (compound 0).

[0275] By comparing the in vivo distribution profiles of compounds 0 and 1, the importance of the quaternary ammonium group in the linker part is shown. Compound 1, which contains a quaternary ammonium, has an in vivo distribution profile that includes urinary excretion, while compound 0 is characterized by strong hepatobiliary secretion and little excretion via the intestine. The latter is an undesirable feature, for example, in the context of radiation imaging and radiotherapy. More specifically, significant excretion from the intestine causes a strong background signal in diagnostic imaging applications. Similarly, in radiotherapy applications, it can impose a radiotoxic burden on the intestine and other parts of the body.

[0276] Figure 4 shows the in vivo uptake of [18F]UAMC-4522 (black) and [68Ga]Ga-DOTA-FAPI-04 (gray) in tumor tissues at %ID / ml 60 minutes after injection, with (dotted line) or without (solid line) pre-administration of UAMC-1110.

[0277] The importance of the quaternary ammonium group in the linker moiety is demonstrated by comparing the in vivo uptake into tumor tissues. Compound 1 shows significantly higher uptake compared to FAPI-04, a reference radiotracer molecule lacking a quaternary ammonium.

Claims

1. A compound of formula I or its stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates, or solvates, wherein the compound contains a quinoline structure. 【Chemistry 1】 Equation I During the ceremony, Y １ and Y ２ is independently H or F; where the linker (Z) contains oxygen, which is covalently bonded to the quinoline structure of the compound at position 6, 7, or 8, and the linker contains a quaternary ammonium cation, the compound of formula I or its stereoisomers, tautomers, racemates, metabolites, prodrugs, salts, hydrates, or solvates.

2. The radionuclide is covalently bonded to the linker, and preferably the radionuclide is １８ F, １２０ I, １２２ I, １２３ I, １２４ I, １２５ I, １３１ I and ２１１ The compound according to claim 1, selected from the group of At.

3. The compound according to claim 1, wherein the linker has a molecular weight of up to 1000 Da.

4. The linker (Z) is one of the following groups 【Chemistry 2】 Selected from, In the formula, each R １ These are independently the following groups: -H, -CH ３ ,CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ ien-CH ２ F, CH ２ CH ２ F, -CH ２ CH ２ CH ２ F, -CH ２ CH ２ CH ２ CH ２ F, -CH ２ I, CH ２ CH ２ I, -CH ２ CH ２ CH ２ I and -CH ２ CH ２ CH ２ CH ２ Selected from I, where F is １８ It exists as F, and I is １２０ I, １２２ I, １２３ I, １２４ I, １２５ I or １３１ It exists as I, n １ , n ２ , n ３ , n ４ , n ５ , n ６ , n ７ , n ８ The compound according to claim 1, wherein is independently 0-4.

5. The linker (Z) is one of the following groups 【Transformation 3】 Selected from, In the formula, each R １ These are independently the following groups: -H, -CH ３ , CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ F, CH ２ CH ２ , -CH ２ CH ２ CH ２ , -CH ２ CH ２ CH ２ CH ２ , -CH ２ I, CH ２ CH ２ , -CH ２ CH ２ CH ２ I and -CH ２ CH ２ CH ２ CH ２ , -COOCH ３ and COC ６ H ６ selected from -R2, where R2 is selected from I, F, At or B(OH) ２ , F is １８ present as F, I is １２０ I, １２２ I, １２３ I, １２４ I, １２５ I or １３１ present as I, At is ２１１ present as At, n ９ , n １０ , n １１ , n １２ , n １３ , n １４ , n １５ , n １６ , n １７ is independently 0 - 4, the compound according to claim 1.

6. The linker (Z) is one of the following groups 【Chemistry 4】 Selected from, In the formula, each R １ These are independently the following groups: -H, -CH ３ ,CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ ien-CH ２ F, CH ２ CH ２ F, -CH ２ CH ２ CH ２ F, -CH ２ CH ２ CH ２ CH ２ F, -CH ２ I, CH ２ CH ２ I, -CH ２ CH ２ CH ２ I and -CH ２ CH ２ CH ２ CH ２ Selected from I, where F is １８ It exists as F, and I is １２０ I, １２２ I, １２３ I, １２４ I, １２５ I or １３１ It exists as I, n １８ , n １９ , n ２０ , n ２１ , n ２２ , n ２３ , n ２４ , n ２５ The compound according to claim 1, wherein is independently 0-4.

7. The compound according to claim 1, wherein the linker (Z) is an aromatic ring, optionally a heterocyclic ring, and includes five-membered, six-membered, or seven-membered rings.

8. The linker (Z) is one of the following groups 【Transformation 5】 Selected from the group, During the ceremony, Each R １ These are independently the following groups: -H, -CH ３ ,CH ２ CH ３ ien-CH ２ CH ２ CH ３ and -CH ２ CH ２ CH ２ CH ３ Selected from; n ２６ , n ２７ , n ２８ , n ２９ , n ３０ , n ３１ , n ３２ , n ３３ They are independently 0-4; E is 【Transformation 6】 And, In the formula, each １ , X ２ , X ３ , X ４ These are independently selected from the groups C, O, and N; t is independently 1, 2, or 3; Each R ２ These are independently the following groups: １８ F, １２０ I, １２２ I, １２３ I, １２４ I, １２５ I, １３１ I and ２１１ Selected from At; Each R ３ These are independently the following groups: The compound according to claim 1, selected from guanidine, aminomethyl, and dialkylaminomethyl.

9. The linker (Z) is one of the following groups 【Transformation 7】 Selected from, During the ceremony, Each R １ These are independently the following groups: -H, -CH ３ ,CH ２ CH ３ ien-CH ２ CH ２ CH ３ and -CH ２ CH ２ CH ２ CH ３ Selected from; n ３４ , n ３５ , n ３６ , n ３７ , n ３８ , n ３９ These are independently 0 to 4; E is 【Transformation 8】 And, In the formula, each １ , X ２ , X ３ , X ４ These are independently selected from the groups C, O, and N; t is independently 1, 2, or 3; Each R ２ These are independently the following groups: １８ F, １２０ I, １２２ I, １２３ I, １２４ I, １２５ I, １３１ I and ２１１ Selected from At; Each R ３ These are independently the following groups: The compound according to claim 1, selected from guanidine, aminomethyl, and dialkylaminomethyl.

10. A pharmaceutical composition comprising the compound described in claim 1 and at least one pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

11. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in the treatment and / or diagnosis of a disease.

12. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in the prevention and / or treatment of FAP-related disorders.

13. The compound according to claim 12, wherein the disorder is selected from proliferative disorders selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma; disorders characterized by tissue remodeling and / or chronic inflammation, such as fibrous diseases, impaired wound healing, impaired keloid formation, osteoarthritis, rheumatoid arthritis, cartilage degradation disorders, atherosclerosis and Crohn's disease; disorders accompanied by endocrine dysfunction, such as impaired glucose metabolism; and blood coagulation disorders.

14. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in imaging tissues and / or organs.

15. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use as a companion diagnostic agent.

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