WO2025037000A1

WO2025037000A1 - Novel fibroblast activation protein inhibitors and medical uses thereof

Info

Publication number: WO2025037000A1
Application number: PCT/EP2024/073063
Authority: WO
Inventors: Koen Augustyns; Pieter Van Der Veken; Pawel Brzeminski; Ingrid De Meester; Filipe ELVAS; Sigrid STROOBANTS; Yentl VAN RYMENANT; Emile VERHULST; Roberta PACIFICO; Adrian Fabisiak; Margarida FLORINDO ESPADINHA
Original assignee: Universiteit Antwerpen
Current assignee: Universiteit Antwerpen
Priority date: 2023-08-17
Filing date: 2024-08-16
Publication date: 2025-02-20
Anticipated expiration: 2026-02-17

Abstract

The current invention relates to a compound of Formula (I) or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, The invention also relates to a pharmaceutical composition comprising said compound. The invention also relates to said pharmaceutical composition or said compound for use as a medicine, for use in the prevention and/or treatment of diseases.

Description

NOVEL FIBROBLAST ACTIVATION PROTEIN INHIBITORS AND MEDICAL USES THEREOF FIELD OF THE INVENTION The present invention relates to a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof. The present invention further relates to a pharmaceutical composition and use thereof. BACKGROUND Fibroblast activation protein (FAP) is a type II integral membrane serine protease that belongs to the prolyl oligopeptidase family S9, which also includes DPPIV, DPP8, DPP9, and PREP enzymes. The dipeptidyl peptidases (DPPs) have an exopeptidase activity, releasing dipeptides from peptides having a proline on the second place. PREP (prolyl oligopeptidase) has strict endopeptidase activity, while FAP has both endo- and exopeptidase activity. FAP is mainly found as a cell surface homodimer but it has also been reported to form heterodimers with DPPIV in vivo. Purported physiological substrates of FAP endopeptidase activity include a2-antiplasmin, type I collagen, gelatin, and Fibroblast growth factor 21 (FGF21). For its exopeptidase activity, substrates include Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY. FAP has been implicated in pathological processes involving proliferation, tissue remodeling, chronic inflammation and/or fibrosis, including but not limited to fibrotic disease, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis, and related disorders involving cartilage degradation, atherosclerotic disease, and Crohn's disease. Based on FAP's role in (patho-)physiology, documented extensively in literature, it is reasonable to foresee further and/or potential applications of inhibitors in disease domains 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 disease, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation) and (c) endocrinological disorders (including but not limited to disorders of glucose metabolism). One of the most potent and selective FAP inhibitors in the public domain, is UAMC1110 (also referred to as ‘cmpd. 60’ in the scientific literature). This is an orally bioavailable molecule with a promising biopharmaceutical profile that was developed by inventors of this application (see, e.g., Jansen et al. J. Med. Chem. 2014, 3053-3074 and WO2013107820). During the past years, chemical derivatives of UAMC1110 have been published with specific functionalities (e.g. radionuclides, drugs, fluorophores). All these derivatives rely on UAMC1110 for efficient and selective delivery of the functionality to FAP-expressing cells or tissues (e.g. tumors). WO2020132661 discloses compounds for modulating FAP. Some of the described compounds comprise a UAMC1110 derivative in which the quinoline moiety is substituted with a phenyl or pyridine linker. Comparably, WO2013107820 discloses inhibitors having selectivity and specificity for FAP. Some of the described compounds comprise a quinoline ring substituted with a halo or methoxy. WO2021197519 relates to derivatives of UAMC1110 comprising an alternative electrophilic warhead, specifically an alpha-ketoamide group. It was shown that these molecules can have a significantly higher affinity for FAP, when compared to UAMC1110. However, these optimized FAP inhibitors inhibit PREP as efficiently as demonstrated by IC50 values in the same range as for inhibition of FAP. There is a need to tailor the properties of FAP inhibitors to improve selectivity and efficacy in vivo for different application types (e.g. therapeutic applications, PET- diagnostics, etc.). Selectivity of FAP inhibitors with respect to PREP is particularly important, as PREP is nearly ubiquitously expressed in the human body. Furthermore, good stability and an ability to penetrate different kinds of tissues is desired. The current invention aims to provide a solution thereto. SUMMARY OF THE INVENTION The present invention relates in a first aspect to a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, according to claim 1. The compound comprises an alpha-ketoamide group and one or more substitutions at the position 6, 7 and/or 8 of the quinoline structure. One of said substitutions comprises one or more amine or ammonium ion groups. Compounds comprising a quaternary ammonium cation showed exquisite selectivity with respect to PREP, a protease that is very closely related to FAP. These compounds are also less susceptible to metabolization, which has several advantages, for example, increased in vivo half-life, or reduced dosage requirements, or in the framework of molecular imaging tracers higher image quality. In addition, the polarity imparted by the quaternary ammonium group promotes higher water solubility and urinary excretion, as opposed to more lipophilic linker systems that typically cause lower water solubility and can promote hepatobiliary secretion, followed by excretion via the gut. Hepatobiliary secretion can be an undesirable feature, for example in the framework of radionuclide imaging and radionuclide therapy. More specifically, gut excretion causes a strong abdominal background signal in diagnostic imaging applications. Likewise, it can impose a higher radio-toxicological burden on the patient in radiotherapeutic applications. Interestingly, the above mentioned highly desired characteristics also apply for the compounds of Formula I comprising an alpha-ketoamide group and an amine group at the position 6, 7 and/or 8 of the quinoline structure, because these compounds become protonated at physiological pH. In a second aspect, the present invention relates to a pharmaceutical composition comprising any of the compounds of the invention herein disclosed and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. In a third aspect, the present invention relates to the medical use of the compounds and pharmaceutical compositions herein described. The compounds according to the invention are suited for diagnostics and/or therapeutics (including theragnostic), preferably of FAP related disorders. More in particular, said compounds can be used for treatment and for imaging applications such as PET and other radiological diagnosis techniques, preferably in situations wherein cells express fibroblast activation protein (FAP). DETAILED DESCRIPTION OF THE INVENTION Described herein are compounds according to Formula I: (I) or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Y3 comprises a ketoamide group and wherein Z comprises one or more amine or ammonium ion groups. During research on UAMC1110 derivatives, the inventors have found that the presence of a keto-amide electrophilic warhead improves the efficacy of UAMC1110 derivatives in inhibiting FAP. The inventors also unexpectedly found that additional substitutions at the position 6, 7 and/or 8 of the quinoline structure further increased the specificity of the compounds to FAP. One of the very successful substitutions is the introduction of an ammonium cation, more particularly a quaternary ammonium cation. Another successful substitution is the introduction of an amine, more particularly a tertiary amine. The findings herein disclosed can be exploited to obtain new FAP inhibitors with optimized or tailored in vivo behavior. Comparably, it can be exploited to obtain new, functionally labeled (e.g., radiolabeled or drug-labeled) FAP binding compounds with a more desirable pharmacokinetic profile and/or target selectivity. The compounds can be used for inhibiting FAP activity and thus to treat disorders mediated by increased FAP activity. In certain embodiments, the compound is used to treat a disease or a 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 compound is 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, fibrosis or diseases characterized by fibrotic lesions, atherosclerosis, arthritis and diabetes. Definitions Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention. As used herein, the following terms have the following meanings: “A”, “an”, and “the” as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, “a compartment” refers to one or more than one compartment. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints. “FAP” or “fibroblast activation protein” refers to the serine protease with EC code EC 3.4.2.1.B28. Alternative names for FAP are FAPa, FAP alpha subunit, seprase or a2- antiplasmin converting enzyme. “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a C1-C20 alkyl”), having 1 to 10 carbon atoms (a C1-C10 alkyl), having 6 to 10 carbon atoms (a C₆-C₁₀ alkyl), or having 1 to 4 carbon atoms (a 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, n-decyl, and the like. “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, astatine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. A “heterocycle” or “heterocyclic” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, phosphorous, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl groups. The heterocyclic group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclic groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur, or 3 to 6-nienibered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur. Particular heterocyclic groups are monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur. Particular heterocyclic groups are polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulfur. The term “keto-amide” refers to a chemical compound that contains both a carbonyl group (a carbon-oxygen double bond, C=O) and an amide group (-CONH2) within its structure. The term "alpha-ketoamide" or “a-ketoamide” refers to a specific type of keto-amide where the carbonyl group is attached to the alpha carbon atom of the amide moiety. An “amine” or “amine group” as used herein refers to a chemical structure or chemical group comprising a nitrogen atom bonded to one or more carbon atoms. It is a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced by organic substituents, typically alkyl or aryl groups. Amines can be classified into primary, secondary and tertiary amines based on the number of carbon atoms bonded to the nitrogen atom. In a primary amine, one hydrogen atom from ammonia is replaced by an organic group (alkyl or aryl). The general structure of a primary amine can be represented as R-NH₂, where R represents an alkyl or aryl group. In a secondary amine, two hydrogen atoms from ammonia are replaced by organic groups. The general structure of a secondary amine is R₂-NH, where both R groups can be the same or different. In a tertiary amine, all three hydrogen atoms from ammonia are replaced by organic groups. The general structure of a tertiary amine is R3-N, where all three R groups can be the same or different. Amines comprise a lone pair of electrons on the nitrogen atom. This lone pair of electrons can readily accept a proton (H+) from an acid, forming a positively charged ion known as an ammonium ion (e.g. NH + 4 ). The resulting ammonium ion retains the lone pair of electrons, making it capable of participating in hydrogen bonding and other interactions with negatively charged species. A “protonated amine” as used herein thus refers to an “ammonium cation” and vice versa. An “ammonium ion group” as used herein refers to a chemical structure or chemical group comprising a positively charged nitrogen atom bonded to one or more carbon atoms. Ammonium ions or more particularly ammonium cations can be categorized in primary, secondary, tertiary and quaternary ammonium ions similar to how amines are classified. A “primary ammonium cation” is formed when one alkyl or aryl group is attached to the nitrogen atom of the ammonium ion. Its general formula is R-NH₃+, where R represents the alkyl or aryl group. A “secondary ammonium cation” is formed when two alkyl or aryl groups are attached to the nitrogen atom of the ammonium ion. Its general formula is R₂-NH₂+, where both R groups can be the same or different. A “tertiary ammonium cation” is formed when three alkyl or aryl groups are attached to the nitrogen atom of the ammonium ion. Its general formula is R + 3-NH , where all three R groups can be the same or different. A “quaternary ammonium cation” is formed when four alkyl or aryl groups are attached to the nitrogen atom of the ammonium ion. It is a positively charged ion with no hydrogen atoms directly attached to the nitrogen. Its general formula is R₄N+, where all four R groups can be the same or different. Quaternary ammonium ions are often encountered in the form of salts and a positive electrostatic charge is present, independently of the pH. The nitrogen atom may be saturated, being bonded to four carbon atoms by single bonds, or may be unsaturated, being bonded to two carbon atoms by single bonds and to a third carbon atom by a double bond. Where the nitrogen atom is unsaturated, it may be part of a heteroaromatic ring, such as an imidazolium cation. Where the nitrogen atom is saturated, it may be part of an alicyclic ring, such as a pyrrolidinium or a piperidinium cation. “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of 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 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more oilier medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. The methods described herein contemplate any one or more of these aspects of treatment. The term “diagnostic” as used herein means having the ability to detect, monitor, follow, and/or identify a disease or condition in an animal (including humans) or from a biological sample. The term “theragnostic” as used herein means having the combined effects of a therapeutic and a diagnostic composition. The composition is suitable to identify (diagnose) and to deliver therapy (therapeutics). As used herein, the term “radionuclide” includes metallic and non-metallic radionuclides. The radionuclide is chosen based on the medical application of the radiolabeled pharmaceutical composition. When the radionuclide is a metallic radionuclide, a chelator is typically employed to bind the metallic radionuclide to the rest of the molecule. When the radionuclide is a non-metallic radionuclide, the non- metallic radionuclide is typically linked directly to the rest of the molecule. Radionuclides are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabeled pharmaceutical agent, for example, a radiolabeled medicament, contains a radionuclide which serves as the radiation source. Radionuclide therapy is a therapy using said radionuclides. As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration and/or have been approved by the administrations such as EMA and/or United States Food and Drug Administration as being acceptable for use in humans or domestic animals. The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc; coatings include, e.g, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.: and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. Compounds In a first aspect, the invention relates to a compound of Formula I.

In an embodiment, the compound of Formula I is present as a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof. In an embodiment, the compound of Formula I is present as a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The inventors have found that compounds according to Formula I are very effective in inhibiting fibroblast activation protein (FAP), more particularly in selectively inhibiting FAP. Hence, in one embodiment, the compound of the application is a FAP inhibitor, more particularly a specific or selective FAP inhibitor. A selective FAP inhibitor as used herein refers to a compound that specifically inhibits FAP and not or to a lesser extent closely related proteins such as PREP. In one embodiment, the selective FAP inhibitor has a FAP-to-PREP selectivity index of at least 2, 3, 4, 5, 6, 7, 8, 9 or 10. In an embodiment, Y1 and Y2 are independently H or F, preferably Y1 and Y2 are both H. In a further embodiment F is present in natural proportions of atomic isotopes. The presence of said F results in improved selectivity characteristics when compared to other FAP inhibitors, while retaining high affinity for the target enzyme. In another embodiment, Y1 and Y2 are both F. In another embodiment, Y1 is F and Y2 is H. In another embodiment, Y₁ and Y₂ are both 18F. In an embodiment, Y3 comprises a ketoamide group, more particularly an alpha- ketoamide group. In a particular embodiment, Y3 is

wherein the wavy line represents the binding position to the pyrrolidine structure. Or alternatively phrased, in one embodiment, the compound of the invention is represented by Formula II

Formula II In an embodiment, Y4 is selected from the list consisting of H, D, C1-C10 alkyl, C3- C10 cycloalkyl, adamantyl, substituted or unsubstituted aryl or C7-C20 alkylaryl, wherein the aryl is wherein the * shows the position bound to the N of the ketoamide group, and wherein R4 and R8 are independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR9, wherein R9 is selected from the group consisting of H, D, halogen, and C1-C4 alkyl or C1-C2 alkyl, and wherein R5, R6 and R7 are independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy or C1-C2 alkoxy, -CF3, -C(=O)- OR9, and -OCF₂, or Y4 comprises a 5-, 6- or 7-membered heterocyclic, optionally substituted, preferably a 5- or 6-membered heterocyclic, optionally substituted, or Y4 is

wherein the * shows the position bound to the N of the keto-amide group, and wherein R17 is selected from the group consisting of -OR9, -NHR9 , -N(-CH3)R9, pyrrolidine, and morpholine, R15 and R16 are independently selected from the group consisting of H, D, C1- C5 alkyl, phenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dimethoxybenzyl, and unsubstituted C3-C8 heteroalkylaryl, R18 and R19 are independently selected from the group consisting of H, D, C1- C6 alkyl, phenyl, benzyl, 4-hydroxybenzyl, unsubstituted C3-C8 heteroalkylaryl, -(CH2)n-C(=C))-C)R20, -(CH2)n-C(=0)-NR21R22, and -(CH2)n-NR23R24, wherein n is an integer from 1 to 4, R20 is selected from the group consisting of H, D, C1-C3 alkyl, and benzyl, R21 and R22 are independently selected from the group consisting of H, D, C1- C3 alkyl, benzyl, and 3,4-dimethoxybenzyl, and R23 and R24 are independently selected from the group consisting of H, D, and (benzyloxy)carbonyl, or Y4 is

wherein the wavy line shows the position bound to the N of the keto-amide group. In a particular embodiment, Y4 is selected from

wherein the wavy line shows the position bound to the N of the keto-amide group. In a particular embodiment, Y4 is selected from wherein the wavy line shows the position bound to the N of the keto-amide group. In an embodiment, linker (Z) is covalently bound to the quinoline structure of said compound on position 6, 7 or 8. Positions of the quinoline structures are numbered as shown in Formula III (see below):

Formula III In an embodiment the linker comprises an oxygen or a nitrogen. In another embodiment, the linker is covalently linked to the quinoline structure of said compound on position 6 via said oxygen or nitrogen. In an embodiment the linker is covalently linked via said oxygen or nitrogen to the quinoline structure of said compound on position 7. In an embodiment the linker is covalently linked via said oxygen or nitrogen to the quinoline structure of said compound on position 8. In an embodiment said linker comprises one or more amine groups and/or one or more ammonium cation groups. In a particular embodiment, the one or more ammonium cation groups is a primary, secondary, tertiary or quaternary ammonium cation. In a more particular embodiment, said linker comprises a quaternary ammonium cation. Compounds with a quaternary ammonium cation showed a better in vivo pharmacokinetic profile, were less susceptible to metabolization and had an exquisite, unprecedented selectivity with respect to PREP, a protease that is very closely related to FAP. All these properties are advantageous in certain therapeutic, diagnostic or theragnostic settings. In another embodiment, the one or more amine groups is a primary amine, secondary amine or tertiary amine. In a more particular embodiment, said linker comprises a tertiary amine. In another embodiment, said linker comprises one or more amine groups and/or one or more ammonium cation groups, wherein said linker is covalently linked via an oxygen or nitrogen to the quinoline structure of the compound on position 6, 7 or 8. In a further particular embodiment, said amine group or ammonium cation group does not comprise the nitrogen to which the linker is bound to the quinoline structure of the compound. In another or further particular embodiment, said linker further comprises an alkyl group between the amine or ammonium group and the oxygen or nitrogen linked to position 6, 7 or 8 of the compound of the invention. In a further more particular embodiment, the alkyl group is a C1-C15, C2-C12, C3-C10 or C4-C8 alkyl group. In an embodiment said linker, optionally comprising a radionuclide, has a molecular weight of maximal 1000 Da, preferably maximal 750 Da, preferably maximal 600 Da, more preferably maximal 500 Da, more preferably maximal 400 Da, even more preferably maximal 300 Da and most preferably maximal 200 Da. In an embodiment said linker, optionally comprising a radionuclide, has a molecular weight of maximal 1000 Da, preferably maximal 750 Da, preferably maximal 600 Da, more preferably maximal 500 Da, more preferably maximal 400 Da and a molecular weight of at least 100 Da, preferably at least 120 Da, more preferably more than 150 Da. In an embodiment, the linker, without the substituted radionuclide, has a molecular weight of maximal 600 Da, more preferably maximal 500 Da, more preferably maximal 400 Da, even more preferably maximal 300 Da and most preferably maximal 200 Da. It was shown that compounds having a linker with a molecular weight that is higher than the above-mentioned threshold have a negative impact on the pharmacokinetics of the compound. In vivo stability, i.e., biochemical resistance in blood serum under physiological conditions, is essential to function efficiently. Large chelating linkers can relatively easily be disturbed or degraded, and their functionality might be reduced. In the descriptions herein, it is understood that every description, embodiment or aspect of a moiety may be combined with every description, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, embodiment or aspect provided herein with respect to Z of formula (I) may be combined with every description, embodiment or aspect of Y1, Y2 and/or Y3 the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, embodiment or aspect were separately and individually listed for all formulae. In an embodiment, said linker Z is linked to a radionuclide. In an embodiment, the radionuclide is chosen from the group of 18F, 120I, 122I, 123I, 124I, 125I, 131I, 211At, 43Sc, 44Sc, 51Mn, 52Mn, 64Cu, 67Ga, 68Ga, 86Y,89Zr, 111In, 152Tb, 155Tb, 203Pb, 76Br, 77Br, 47Sc, 67Cu, 89Sr, 90Y, 153Sm, 149Tb, 161Tb, 177Lu, 186Re, 188Re, 212Pb, 213Bi, 223Ra, 225Ac, 226Th, 227Th, 225Ac, 212Bi, 213Bi, and 177Lu. In an embodiment, said radionuclide is selected from 120I, 122I, 123I, 124I, 125I, 131I or 211At. In an embodiment, the linker is bound to the radioisotope covalently. In an 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. In an embodiment, the radionuclide is covalently bound to the linker. A covalent bond between the linker and the radionuclide is considered more stable compared to complexed radionuclide in a large chelating structure. In an embodiment, a counterion is present to offset the positive charge of the quaternary ammonium cation. In a further embodiment, said counterion is selected from the group of: halide, hydroxide, carboxylate, sulphate, phosphate, nitrate, alkyl sulfonate, aryl sulfonate, other organic anions and combinations thereof. In a further embodiment, the counterion is a monovalent anion. In a further embodiment, the counterion is I, Cl or Br or a combination thereof. In the descriptions herein, it is understood that the wavy line represents the point of attachment to the rest of the compound unless otherwise specified. If a structure is not symmetrical, the wavy line closer to the quinoline structure shown in Formula I, is accompanied of a *. If a structure is not symmetrical, the wavy line closer to E, is accompanied of a •. In an embodiment, the linker -Z is -O-L1-A-(L2-D)0-2-L3-E, wherein: each L₁, L₂, L₃ is independently

,

wherein q is 0, 1, 2 or 3 and u is 0, 1, 2 or 3; D is selected from the group consisting of: wherein q is 0, 1, 2 or 3 and u is 0, 1, 2 or 3; and E is selected from the group of: R₁, a chelating moiety, a benzamide, a borane, a carborane, a metal complex and a 5-, 6- or 7- membered aromatic ring, optionally heterocyclic, optionally substituted; and wherein each R1 independently is selected from the group of: H, C1-4 alkyl and C_1-4 alkyl substituted with halo, preferably 18F, 211At, 120I, 122I, 123I, 124I, 125I or 131I. In an embodiment, R₁ is an alkyl comprising 2, 3 or 4 radionuclides. In an embodiment, R1 comprises deuterium (d) and 18F, preferably R 18 1 is fluoro- F methyl- d2. In an embodiment, E is a chelating moiety, wherein the chelating moiety is a radical selected from the group of: 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-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan- 1-yl}-acetic acid), 3p-C-NEPA (2-{[2-(4-{2-[Bis(carboxymethyl)amino]-5-(4- nitrophenyl)pentyl}-7-(carboxymethyl)-1,4,7-triazonan-1-yl)ethyl] (carboxymethyl) amino} acetic acid), 3p-C-NETA ({4-[2-(bis-carboxy- methylamino)-5-(4-nitrophenyl)-entyl]-7-carboxymethyl-[1,4,7]tri-azonan-1-yl} acetic acid), 3p-C-NETA-NCS ({4-[2-(Bis-carboxymethylamino)-5-(4- isothiocyanatophenyl) pentyl]-7-carboxymethyl-[1,4,7]triazonan-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-triazole-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’’’’,N’’’’’-pentaacetic acid). In a further embodiment, a radionuclide is bound to the chelating moiety in a stable coordination complex. In a further embodiment, the radionuclide is suitable for single photon emission computed tomography (SPECT, e.g. 67Ga, 99mTc, 111In, 177Lu), or positron emission tomography (PET, e.g. 68Ga, 64Cu, 44Sc, 86Y, 89Zr), or therapeutic applications (e.g. 47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re). In an embodiment, E is a benzamide, wherein said benzamide is selected from the group of: ,

wherein X is chosen from the group of SnBu₃, I, 125I, 211At, halo, 18F and 2H. In an embodiment, E is a borane or a carborane, wherein said borane or carborane is selected from the group of: decaborate optionally substituted with X, dodecaborate optionally substituted with X, , wherein each X is selected from the group of H, 2H, I, 125I and 211At; the open circles represent B (where substituted) or BH atoms; the filled circles represent carbon atoms. In an embodiment, a counterion is present, wherein said counterion is a cation, preferably selected from the group of Bu₄N+ and Et₃NH+. In an embodiment, E is a metal complex, wherein said metal is a metal from the platinum group. In an embodiment, E is a metal complex, wherein said metal complex is selected from the group of:

Several classes can be identified in the structures according to the current invention. A first class comprises compounds according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z is selected from the group consisting of

wherein each R1 is independently selected from the group of: -H, -CH3, CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, - CH₂CH₂CH₂CH₂F, -CH₂I, CH₂CH₂I, -CH₂CH₂CH₂I, -CH₂CH₂CH₂CH₂At, -CH₂At, CH₂CH₂At, -CH₂CH₂CH₂At, and -CH₂CH₂CH₂CH₂At wherein n₁, n₂, n₃, n₄, n₅, n₆, n₇, n8 is independently 0-4. In a more particular embodiment, Z is selected from the group consisting of

In an embodiment, F is present as 18F. In an embodiment, I is present as 120I, 122I, 123I, 124I, 125I or 131I. In an embodiment, At is present as 191At, 193At, 194At, 195At, 196At, 197At, 198At, 199At, 200At, 201At, 202At, 203At, 204At, 205At, 206At, 207At, 208At, 209At, 210At, 211At, 212At, 213At, 214At, 215At, 216At, 217At, 218At, 219At, 220At, 221At, 222At, 223At, more particularly 211At. In an embodiment, one H is present as 2H or 3H. In an embodiment, C is present as 13C, 11C or 14C. In an embodiment, N is present as 13N. In an embodiment, O is present as 15O or 17O. In said compounds of this first class, every n is independently selected from 0-4. For 0-4, a selection can be made between 0, 1, 2, 3 and 4. In an embodiment, each n is independently selected from 0-3. In an embodiment, n is selected from 0 or 1. In an embodiment, for all n in the compound n is 0. In an embodiment, for all n in the compound n is 1. In one embodiment, the compound comprises a quaternary ammonium cation and therefore the R₁ bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. Preferably each R₁ independently is selected from the group consisting of: -CH₃, CH₂CH₃, -CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, CH₂CH₂F, -CH₂CH₂CH₂F, - CH₂CH₂CH₂CH₂F, -CH₂I, CH₂CH₂I, -CH₂CH₂CH₂I, -CH₂CH₂CH₂CH₂At, -CH₂I, wherein F is present as 18F and/or

In an embodiment, the linker comprises one F and no I. In an embodiment, the linker comprises one I and no F. In an embodiment, the linker comprises one F and one I. Examples of compounds according to this first class include (but are not limited to):

A second class of compounds according to an embodiment of the current invention, comprise compounds according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z is selected from the group consisting of

wherein each R₁ is independently selected from the group of: -H, -CH3, CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, - CH2CH2CH2CH2F, -CH2I, CH2CH2I, -CH2CH2CH2I, -CH2CH2CH2CH2I, -CH2At, CH₂CH₂At, -CH₂CH₂CH₂At, -CH₂CH₂CH₂CH₂At, COOC(CH₃)₃ and COC₆H₆-R₂, wherein n₉, n₁₀, n₁₁, n₁₂, n₁₃, n₁₄, n₁₅, n₁₆, n₁₇ is independently 0-4. In a further embodiment, R2 is selected from the group consisting of I, F, At and B(OH)2. In a more particular embodiment, Z is selected from the group consisting of

In an embodiment, F is present as 18F. In an embodiment, I is present as 120I, 122I, 123I, 124I, 125I or 131I. In an embodiment, At is present as 191At, 193At, 194At, 195At, 196At, 197At, 198At, 199At, 200At, 201At, 202At, 203At, 204At, 205At, 206At, 207At, 208At, 209At, 210At, 211At, 212At, 213At, 214At, 215At, 216At, 217At, 218At, 219At, 220At, 221At, 222At, 223At, more particularly 211At. In an embodiment one H is present as 2H or 3H. In an embodiment, C is present as 13C, 11C or 14C. In an embodiment, N is present as 13N. In an embodiment, O is present as 15O or 17O. Every n is independently selected from 0-4. For 0-4, a selection can be made between 0, 1, 2, 3 and 4. In an embodiment, each n is independently selected from 0-3. In an embodiment, n is selected from 0 or 1. In an embodiment, for all n in the compound n is 0. In an embodiment, for all n in the compound n is 1. When selecting moieties for R1, one should be aware of the requirements that if the compound comprises a quaternary ammonium cation, a R1 bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. Preferably each R1 independently is selected from the group of: -CH3, CH2CH3, - CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2CH2F, - CH₂I, CH₂CH₂I, -CH₂CH₂CH₂I, -CH₂CH₂CH₂CH₂I, -CH₂At, CH₂CH₂At, -CH₂CH₂CH₂At, - CH₂CH₂CH₂CH₂At, COOC(CH₃)₃ and COC₆H₆-R₂, wherein F is present as 18F and/or I as 120I, 122I, 123I, 124I, 125I or 131I and/or At as 211At and wherein R2 is selected from the group consisting of I, F, At and B(OH)2. In an embodiment, the linker comprises one F and no I. In an embodiment, the linker comprises one I and no F. Examples of compounds according to this second class include (but are not limited to):

or wherein Y is a counterion, preferably Cl or Br; and wherein every n is independently selected from the range stipulated in proximity of the parenthesis. For example, for n=0-3, a selection can be made between 0, 1, 2 and 3. In an embodiment, the selected n is the lowest number suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range is selected. In an embodiment, the selected n is the lowest number +1 suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range +1 is selected. In a third class of compounds according to an embodiment of the current invention, the compound is a compound according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z is selected from the group consisting of

wherein each R₁ is independently selected from the group of: -H, -CH₃, CH₂CH₃, - CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, CH₂CH₂F, -CH₂CH₂CH₂F, -CH₂CH₂CH₂CH₂F, - CH2At, CH2CH2At, -CH2CH2CH2At, -CH2CH2CH2CH2At, -CH2I, CH2CH2I, -CH2CH2CH2I, and -CH2CH2CH2CH2I, and wherein n18, n19, n20, n21, n22, n23, n24, n25 is independently 0-4. Every n is independently selected from 0-4. For 0-4, a selection can be made between 0, 1, 2, 3 and 4. In an embodiment, each n is independently selected from 0-3. In an embodiment, n is selected from 0 or 1. In an embodiment, for all n in the compound n is 0. In an embodiment, for all n in the compound n is 1. In an embodiment, F is present as 18F. In an embodiment, F is present as 18F. In an embodiment, I is present as 120I, 122I, 123I, 124I, 125I or 131I. In an embodiment, At is present as 211At. In an embodiment one H is present as 2H or 3H. In an embodiment, C is present as 13C, 11C or 14C. In an embodiment, N is present as 13N. In an embodiment, O is present as 15O or 17O. When selecting moieties for R1, one should be aware of the requirements that if the compound comprises a quaternary ammonium cation, a R1 bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. Preferably each R1 independently is selected from the group of: -CH3, CH2CH3, - CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, CH₂CH₂F, -CH₂CH₂CH₂F, -CH₂CH₂CH₂CH₂F, - CH₂At, CH₂CH₂At, -CH₂CH₂CH₂At, -CH₂CH₂CH₂CH₂At, -CH₂I, CH₂CH₂I, -CH₂CH₂CH₂I, and -CH CH CH CH I, where 18 211 2 2 2 2 in F is present as F and/or At is present as At and/or I as 120I, 122I, 123I, 124I, 125I or 131I. In an embodiment, the linker comprises one F and no I. In an embodiment, the linker comprises one I and no F. Examples of compounds according to this third class include (but are not limited to): wherein Y is a counterion, preferably Cl or Br; and wherein every n is independently selected from the range stipulated in proximity of the parenthesis. For example, for n=0-3, a selection can be made between 0, 1, 2 and 3. In an embodiment, the selected n is the lowest number suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range is selected. In an embodiment, the selected n is the lowest number +1 suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range +1 is selected. In an embodiment, the compound is a compound according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z comprises an aromatic ring, optionally heterocyclic and 5-, 6- or 7-membered. In an embodiment, the compound is a compound according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z comprises a 5-, 6- or 7- membered aromatic ring, optionally heterocyclic. In an embodiment, said 5-, 6- or 7- membered aromatic ring, optionally heterocyclic, and optionally substituted with R₂ and R₃ is shown in Formula IV:

Formula IV The X₁, X₂, X₃ and X₄ are independently chosen from: C, S, N and O, to form a pharmaceutically acceptable 5-, 6- or 7-membered aromatic ring which can be substituted with R2 and R3, preferably X1, X2, X3 and X4 are chosen from: C, N and O to form a 5-, 6- or 7-membered aromatic ring. The t is chosen from 1, 2 and 3. In an embodiment, the aromatic ring comprises one heteroatom. In an embodiment, the aromatic ring comprises two heteroatoms. In an embodiment, the aromatic ring comprises no heteroatoms. In a further embodiment, R2 is bound to X4 and X4 is carbon. In an embodiment, R3 is bound to X2 and X2 is carbon. In another embodiment, R₃ is bound to X₁ and X₁ is carbon. In an embodiment, the 5-, 6- or 7-membered aromatic ring, optionally heterocyclic, is selected from the group of: furan, pyrrole, pyrazole, isoxazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, oxazole, thiazole, benzene, thiophene, pyridine, pyrazine, pyrimidine, pyridazine or triazine. In an embodiment, the 5-, 6- or 7-membered aromatic ring, optionally heterocyclic, is selected from the group consisting of:

In an embodiment, R₂ is selected from the group consisting of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and At, preferably 211At. In an embodiment, R3 is selected from the group consisting of guanidine, aminomethyl and dialkylaminomethyl. In a further embodiment, the dialkylaminomethyl is selected from the group consisting of dimethylaminomethyl, diethylaminomethyl and dipropylaminoethyl. Guanidine has a general structure (R20R21N)(R22R23N)C=N-R24. The guanidine can be bound to the rest of the compound on any position. In an embodiment, R₂₀ is the rest of the compound and R₂₁-R₂₄ are H. In another embodiment R₂₀-R₂₃ are H and the rest of the compound is R₂₄. In a fourth class of compounds according to an embodiment of the current invention, the compound is a compound according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein linker (Z) is selected from the group consisting of:

, wherein each R1 is independently selected from the group consisting of -H, -CH3, CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; and wherein n₂₆, n₂₇, n₂₈, n₂₉, n₃₀, n₃₁, n₃₂, n₃₃ is independently 0-4; E is:

wherein each X1, X2, X3, X4 is independently selected from the group of C, O and N; t is independently 1, 2 or 3; each R₂ is independently selected from the group of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At; and each R3 is independently selected from the group of: guanidine, aminomethyl and dialkylaminomethyl. In an further embodiment Z is selected from the group consisting of

wherein each X is independently selected from the group of C, O and N, each R₁ is independently selected from the group consisting of -H, -CH₃, -CH₂CH₃, - CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃, each R is independently selected from the group of: 18F, 120I 122 123 124 125 131 2 , I, I, I, I, I and 211At, preferably 211At, each R₃ is independently selected from the group of: guanidine, aminomethyl and dialkylaminomethyl, preferably the dialkylaminomethyl is selected from the group of: dimethylaminomethyl, diethylaminomethyl and dipropylaminoethyl. When selecting moieties for X, one should be aware of the requirements stipulated in the other embodiments of the current invention, so that a 5-, 6- or 7-membered aromatic ring is formed. Examples of compounds according to this fourth class include (but are not limited to):

wherein Y is a counterion, preferably Cl or Br; and wherein every n is independently selected from the range stipulated in proximity of the parenthesis. For example, for n=0-3, a selection can be made between 0, 1, 2 and 3. In an embodiment, the selected n is the lowest number suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range is selected. In an embodiment, the selected n is the lowest number +1 suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range +1 is selected. In a fifth class of compounds according to an embodiment of the current invention, the compound is a compound according to Formula I or II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein Z is selected linker from the group consisting of ,

, wherein each R₁ is independently selected from the group of: -H, -CH₃, CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; n34, n35, n36, n37, n38, n39 is independently 0-4; E is

wherein each X₁, X₂, X₃, X₄ is independently selected from the group of C, O and N; t is independently 1, 2 or 3; each R₂ is independently selected from the group of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At; and each R3 is independently selected from the group of: guanidine, aminomethyl and dialkylaminomethyl. In a further embodiment, Z is selected from the group consisting of ,

wherein each X is independently selected from the group of C, O and N, each R1 is independently selected from the group of: -H, -CH3, CH2CH3, -CH2CH2CH3, and -CH₂CH₂CH₂CH₃, each R₂ is independently selected from the group of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and At, preferably 211At, each R3 is independently selected from the group of: guanidine, aminomethyl and dialkylaminomethyl, preferably the dialkylaminomethyl is selected from the group of: dimethylaminomethyl, diethylaminomethyl and dipropylaminoethyl. When selecting moieties for X, one should be aware that a 5-, 6- or 7-membered aromatic ring is formed. Every n is independently selected from the range stipulated in proximity of the parenthesis. For example, for n=0-3, a selection can be made between 0, 1, 2 and 3. In an embodiment, the selected n is the lowest number suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range is selected. In an embodiment, the selected n is the lowest number +1 suggested by the range. In an embodiment, for all n in one structure the lowest number suggested by the range +1 is selected. In a particular embodiment of the invention, the compound herein provided is a compound of Formula II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof as presented in Table 1. Table 1: examples of structures according to an embodiment of the current invention Compound Chemical structure (1) (8b) (9b) (14a) (15a) (9a) In a particular embodiment of the invention, the compound herein provided is a compound of Formula II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof chosen from the list of: compound 8a, compound 8b, compound 8c, compound 8d, compound 8e, compound 8f, compound 8g, compound 8h, compound 8i, compound 8j, compound 9a, compound 9b, compound 9c, compound 9d, compound 9e, compound 9f, compound 9g, compound 9h, compound 9i, compound 10, compound 14a, compound 14b, compound 14c, compound 14d, compound 14e, compound 14f, compound 14g, compound 14h, compound 14i, compound 14j, compound 14k, compound 14l, compound 14m, compound 14n, compound 14o, compound 14p, compound 14q, compound 14r, compound 14s, compound 14t, compound 14u, compound 14v, compound 14w, compound 15a, compound 15b, compound 15c, compound 15d, compound 15e, compound 15f, compound 15g, compound 15h, compound 15i, compound 15j, compound 15k, compound 15l, compound 15m, compound 15n, compound 15o, compound 15p, compound 15q, compound 15r, compound 15s, compound 15t, compound 15u, compound 15v, compound 16a, and compound 16b as provided below. In a particular embodiment of the invention, the compound herein provided is a compound of Formula II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, wherein the linker comprises one or more ammonium ion groups, wherein the compound is chosen from the list of: compound 9b, compound 9c, compound 9d, compound 9e, compound 9f, compound 9g, compound 9h, compound 9i, compound 10, compound 15a, compound 15b, compound 15c, compound 15d, compound 15e, compound 15f, compound 15g, compound 15h, compound 15i, compound 15j, compound 15k, compound 15l, compound 15m, compound 15n, compound 15o, compound 15p, compound 15q, compound 15r, compound 15s, compound 15t, compound 15u, compound 15v, compound 16a, and compound 16b as provided below. In a particular embodiment of the invention, the compound herein provided is a compound of Formula II or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate, wherein the linker comprises one or more amine groups, wherein the compound is chosen from the list of: compound 8a, compound 8b, compound 8c, compound 8d, compound 8e, compound 8f, compound 8g, compound 8h, compound 8i, compound 8j, compound 9a, compound 14a, compound 14b, compound 14c, compound 14d, compound 14e, compound 14f, compound 14g, compound 14h, compound 14i, compound 14j, compound 14k, compound 14l, compound 14m, compound 14n, compound 14o, compound 14p, compound 14q, compound 14r, compound 14s, compound 14t, compound 14u, compound 14v, and compound 14w as provided below. A compound as detailed herein may in one embodiment be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity. The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. In an embodiment, the compound is present as a pharmaceutically acceptable salt. Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate and the like. Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms 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 compounds described, such as the compounds of Table 1. The structure or name is intended to embrace all possible stereoisomers of a compound depicted. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture. The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or embodiments thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, halo, such as 2H, 3H, 13C, 11C, 14C, 13N, 15O, 17O, 32P, 35S, 18F. Certain isotope labeled compounds (e.g. 3H and 14C) are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium (2H) can cause certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. 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 accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent. Pharmaceutical Compositions and Formulations In a second aspect, the invention relates to a pharmaceutical composition or formulation comprising a compound as described herein and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. The present invention includes pharmaceutical compositions or formulations comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In an embodiment, the pharmaceutically acceptable salt is an acid addition salt. A compound according to the present invention may in one embodiment be in a purified form. In an embodiment, the composition comprises a compound as detailed herein or a salt thereof. In some embodiments, the composition comprises a compound as detailed herein or a salt thereof in substantially pure form. In an embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, compositions are provided containing a compound in substantially pure form. In another embodiment, the present invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another embodiment, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. One or several compounds described herein or a salt thereof can be used in the preparation of a composition, such as a pharmaceutical composition, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g. transdermal patch versus oral tablet), the carrier may be in various forms. In addition, pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Compositions comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical compositions may be prepared by known pharmaceutical methods. Compositions as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-oils, and so on. In addition, pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein. By means of non-limiting examples, such a composition may be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person. Some preferred, but non-limiting examples of preparations include tablets, pills, powders, lozenges, 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 (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such compositions, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, 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 can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ α-, β- or γ- cyclodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility. The preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary, under aseptic conditions. For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are Arabic gum, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetal or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may 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 aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical composition and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the composition can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. When rectally administered in the form of suppositories, these compositions may be prepared by mixing the compounds according to the invention with a suitable non- irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. In a preferred embodiment, the compounds of the present invention are useful in human or veterinary medicine, in particular for use as FAP (fibroblast activation protein) inhibitors. In an embodiment, the pharmaceutical composition may comprise a chelator selected from the group of: EUpypa, EDTA (ethylenediamine tetraacetate), 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 (triazacyclononane phosphinic 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-pentaamine pentaacetate), NETA ({4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}- acetic acid), 3p-C-NEPA (2-{[2-(4-{2-[Bis(carboxymethyl)amino]-5-(4- nitrophenyl)pentyl}-7-(carboxymethyl)-1,4,7-triazonan-1-yl)ethyl] (carboxymethyl) amino} acetic acid), 3p-C-NETA ({4-[2-(bis-carboxy- methylamino)-5-(4-nitrophenyl)-entyl]-7-carboxymethyl-[1,4,7]tri-azonan-1-yl} acetic acid), 3p-C-NETA-NCS ({4-[2-(Bis-carboxymethylamino)-5-(4- isothiocyanatophenyl) pentyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), HEHA (hexadeca-1, 4,7,10,13,16-hexaamine -hexaacetate) and its derivatives, HBED (hydroxybenzyl-ethylene-di amine) and its derivatives, DEDPA and its derivatives, such as H2DEDPA (l, 2 - [[6- (carboxylate) pyridin-2-yl] methylamine] ethane), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives such as YM103, TEAP (tetraazycyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepine- tetraacetate) and derivatives such as DATA ((6 - Pentanoic acid) -6- (amino) methyl-1,4-diazepine triacetate); SarAr (IN- (4-aminobenzyl) -3,6,10,13,16,19-hexaazabicyclo [6.6.6] - eicosane-1,8-diamine) and salts thereof, (Nhh SAR (1,8-diamino-B, 6,10,13,16,19- hexaazabicyclo [6.6.6] icosane), 6-Hydrazinopyridine-3 -carboxylic acid, HYNIC (bis- (carboxymethylimidazole)glycine and salts and derivatives thereof, aminothiols and their derivatives. Methods of treatment and use of compounds or compositions Also disclosed herein are methods of treatment and/or diagnostic methods. More in particular, disclosed herein are compounds or pharmaceutical composition as disclosed herein for use for the treatment and/or the diagnosis of a disease. In an embodiment, a method for treating a disease in an individual is disclosed herein, wherein said disease is a FAP-related disorder. Said FAP-related disorder is preferably selected from the list comprising 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 sarcomas, 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, atherosclerotic disease and Crohn's disease; disorders involving endocrinological dysfunction, such as disorders of glucose metabolism, and blood clotting disorders. The term “FAP-related disorder” as used herein, means any disease or other deleterious condition in which FAP is known to play a role. The term “FAP-related disorder” also means those diseases or conditions that are alleviated by treatment with a FAP inhibitor. A non-limiting list of examples of FAP-related disorders can include proliferative diseases such as cancer or more particularly 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 sarcomas, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, and adenocarcinoma. In addition, the list of FAP-related disorders that are envisaged here, includes diseases characterized by tissue remodeling and/or chronic inflammation. These include but are not limited to fibrotic disease, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation, atherosclerotic disease, Type II diabetes and Crohn's disease. Furthermore, FAP related disorders involving endocrinological dysfunction (including but not limited to disorders of glucose metabolism) and diseases involving blood clotting disorders are part of this list. The invention also provides methods for the prevention and/or treatment of a FAP- related disorder; said method comprising administering to a subject in need thereof a compound according to this invention, or a composition comprising said compound. In an embodiment, a compound or salt thereof described herein or a composition described herein may be used in a method of treating a disease or disorder mediated by FGF21. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating a FGF21- associated disorder, such as obesity, type I-and type II diabetes, pancreatitis, dyslipidemia, hyperlipidemia conditions, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, acute myocardial infarction, hypertension, cardiovascular diseases, atherosclerosis, peripheral arterial disease, apoplexy, heart failure, coronary artery heart disease, renal disease, diabetic complications, neuropathy, gastroparesis, disorder associated with a serious inactivation mutation in insulin receptor, and other metabolic disorders. In some embodiments, the FGF21-associated disorder is diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or cardiovascular diseases. Provided herein is a method of increasing the level of FGF21 expression in an individual comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. FGF21 stimulates glucose uptake in adipocytes and is believed to protective against obesity and insulin insensitivity. By way of example and not wishing to be bound by theory, FAP is believed to be the enzyme responsible for cleavage and inactivation of FGF21; therefore, inhibiting FAP may increase levels of FGF21 expression. Accordingly, provided herein are methods of treating diabetes mellitus, insulin insensitivity, and/or obesity in an individual in need thereof comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein FGF21 expression is increased. In some embodiments, the diabetes mellitus is type II diabetes. Also provided herein is a method of enhancing an immune response in an individual comprising 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 to a tumor or cancerous cell. By way of example and not wishing to be bound by theory, FAP is believed to suppress immune responses, especially in the context of cancer, therefore inhibiting FAP may enhance the immune response of an individual. Accordingly, provided herein are methods of treating cancer in an individual in need thereof comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein an immune response of the individual is increased. In an embodiment, a compound or salt thereof described herein or a composition described herein may be used in a method of treating a disease or disorder characterized by proliferation, tissue remodeling, fibrosis, chronic inflammation, excess alcohol consumption, or abnormal metabolism. In some embodiments, a compound or salt thereof described herein or a composition described herein may 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, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, or adenocarcinoma. In some embodiments, the compound, salt, or composition may be used in a method of treating metastatic kidney cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma, or non-small cell lung cancer Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may 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 conducting quality control assays. Provided herein is a method of treating a disease or disorder in an individual in need thereof comprising administering a compound describes herein or any embodiment, or aspect thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, pharmaceutically acceptable salt thereof, or composition is administered to the individual according to a dosage and/or method of administration described herein. In an embodiment, the administration of the compound, salt, or composition reduces tumor growth, tumor proliferation, or tumorigenicity in the individual. In some embodiments, the compound, salt, or composition may be used in a method of reducing tumor growth, tumor proliferation, or tumorigenicity in an individual in need thereof. In some embodiments, tumor growth is slowed or stopped. In some embodiments, tumor growth is reduced at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the tumor is reduced in size. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in in a method of treating fibrotic disease, thrombosis, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation, atherosclerotic disease, Crohn’s disease, hepatic cirrhosis, idiopathic pulmonary fibrosis, myocardial hypertrophy, diastolic dysfunction, obesity, glucose intolerance, insulin insensitivity, or diabetes mellitus. In some embodiments, hepatic cirrhosis is viral hepatitis- induced, alcohol-induced, or biliary cirrhosis. In some embodiments, diabetes mellitus is type II diabetes. In some embodiments, the disease or disorder is fibrotic liver degeneration. In some embodiments, provided herein is a method of inhibiting FAP. The compounds or salts thereof described herein and compositions described herein are believed 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 described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the cell is a fibroblast, such as a myofibroblast, a keloid fibroblast, a cancer associated fibroblast (CAF), or a reactive stromal fibroblast, among others ceils with FAP expression. In some embodiments, the method of inhibiting FAP comprises inhibiting FAP in a tumor or in plasma by administering or delivering to the tumor or plasma a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the inhibition of FAP comprises inhibiting an endopeptidase and/or exopeptidase activity of FAP. In some embodiments, FAP is statistically significantly inhibited. In other embodiments, FAP is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Inhibition of FAP can be determined by methods known in the art and compared to a control situation in which the FAP inhibitor herein described is not administered. In some embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an additional agent are sequentially administered, concurrently administered or simultaneously administered. In certain embodiments, (a) a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an additional agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes 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 with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes. Either (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (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. 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 antibody. The compounds as disclosed herein show high selectivity and can be used to demonstrate the presence of cancer cells or cancer associated fibroblasts. Hence, use of the compounds or compositions as described herein in diagnostics is also covered by the current invention. The compounds of the current invention, once administered to the patient, can localize to specific organs or cells allowing visualizing the extent of a disease-process in the body, based on the cellular function and physiology, rather than relying on physical changes in the tissue anatomy. The involvement of FAP in many physiological or physio-pathological aspects offers the possibility of targeting these cells, to obtain an early diagnosis by a non-invasive approach. Also disclosed herein are methods of imaging tissues, organs and/or cell populations by the compounds and/or compositions described herein. The invention also relates to compounds or pharmaceutical compositions as described herein for use in tissue and/or organ imaging. The invention also relates to compounds or pharmaceutical compositions as described herein for use as a companion diagnostic. In an embodiment, methods of assessing 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 therapy. In an embodiment, methods of measuring tumor growth, tumor proliferation, and tumorigenicity are disclosed herein, for example by repeated imaging of the individual. In an embodiment, said tumor growth, tumor proliferation, or tumorigenicity is compared to the tumor growth, tumor proliferation, or tumorigenicity in the individual prior to the administration of the compound, salt, or composition. In some embodiments, the tumor growth, tumor proliferation, or tumorigenicity is compared to the tumor growth, tumor proliferation, or tumorigenicity in a similar individual or group of individuals. In an embodiment, the compounds as described herein comprise a radionuclide, preferably 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At. The compound comprising a radionuclide shows a high affinity for tissues characterized by significant FAP- expression, for example tumor tissue and limited accumulation in normal tissues. Furthermore, the compounds as described herein improve the contrast or signal-to- noise ratio in the imaging PET diagnostics of tumors. The radiation exposure to the targeted cells and neighboring organs is also reduced, which represents a considerable advantage for theragnostic treatment. In an embodiment, the compound described above is used for the production of a radiopharmaceutical for imaging diagnostics by means of positron emission tomography (PET). In an embodiment, the compound described above is used for the production of a radiopharmaceutical for imaging diagnostics by means of single- photon emission computed tomography (SPECT). In some embodiments, the individual is an animal, preferably a mammal. In some embodiments, the individual is a primate, bovine, ovine, porcine, equine, canine, feline, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of tire diseases or disorders disclosed herein. In some embodiments, the individual is a risk for developing any of the diseases or disorders disclosed herein. In some embodiments, the individual is human. In some embodiments, the human is at least about or is about any of 21, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about an age of 21, 18, 15, 12, 10, 8, 6, 5, 4, 3, 2, or 1 years old. The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount. The pharmaceutical compositions of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage. The compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred. At least one compound of the invention will generally be administered in an “effective amount”, by which is meant any amount of a compound of the Formula I or II, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. The effective amount of the compound may in one embodiment be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily. A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some embodiments may be for the duration of the individual’s life. In one embodiment, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about once-weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. In an embodiment, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Articles of Manufacture and Kits The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one embodiment, the kit employs a compound described herein or a salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment any disease or described herein, for example for the treatment of cancer. Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a 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. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual. In a particular aspect, the application also provides (1) a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof,

Formula I, wherein Y₁ and Y₂ are independently H or F, wherein Y3 comprises a ketoamide group, wherein a linker (Z) is covalently bound to the quinoline structure of said compound on position 8. Also provided is: (2) the compound of (1), wherein the linker comprises one or more ammonium ion groups and/or one or more amine groups. (3) the compound according to any of (1)-(2), wherein the linker (Z) comprises an oxygen or nitrogen by which the linker is covalently bound to the quinoline structure. (4) the compound according to any of (1)-(3), wherein at least one of the one or more ammonium ion groups is a quaternary ammonium cation. (5) the compounds according to any of (1)-(3), wherein at least one of the one or more amine groups is a tertiary amine. (6) the compound according to any of (1)-(5), wherein a radionuclide is covalently bound to the linker and wherein preferably the radionuclide is selected from the group of 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At. (7) the compound according to any of (1)-(6), wherein said linker (Z) has a molecular weight of maximal 1000 Da. (8) the compound according to any of (1)-(7), wherein said linker (Z) is selected from

wherein n1, n2, n3, n4, n5, n6, n7, n8 is independently 0-4, and wherein if the compound comprises a quaternary ammonium cation, the R1 bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. (9) the compound according to any of (1)-(7), wherein said linker (Z) is selected from

wherein each R₁ is independently selected from the group consisting of -H, - CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, -CH₂CH₂F, -CH₂CH₂CH₂F, -CH2CH2CH2CH2F, -CH2I, -CH2CH2I, -CH2CH2CH2I, -CH2CH2CH2CH2I, -COOCCH3 and COC6H6-R2, wherein R2 is selected I, F, At or B(OH)2, and wherein F is present as 18F and I as 120I, 122I, 123I, 124I, 125I or 131I, At as 211At, wherein n₉, n₁₀, n₁₁, n₁₂, n₁₃, n₁₄, n₁₅, n₁₆, n₁₇ is independently 0-4, and wherein if the compound comprises a quaternary ammonium cation, the R1 bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. (10) the compound according to any of (1)-(7), wherein said linker (Z) is selected from

wherein n₁₈, n₁₉, n₂₀, n₂₁, n₂₂, n₂₃, n₂₄, n₂₅ is independently 0-4, and wherein if the compound comprises a quaternary ammonium cation, the R₁ bound to a first nitrogen can only be hydrogen if there is a second nitrogen wherein the second nitrogen is a cation and is bound to only carbon atoms. (11) the compound according to any of (1)-(7), wherein said linker (Z) comprises an aromatic ring, optionally heterocyclic and 5-, 6- or 7-membered. (12) the compound according to any of (1)-(11), wherein Y3 is

wherein Y4 is selected from the list consisting of H, D, C1-C10 alkyl, C3-C10 cycloalkyl, adamantly, substituted or unsubstituted aryl or C7-C20 alkylaryl, wherein the aryl is wherein the * shows the position bound to the N of the keto-amide group, and wherein R4 and R8 are independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR9, wherein R9 is selected from the group consisting of H, D, halogen, and C1-C4 alkyl or C1-C2 alkyl, and wherein R5, R6 and R7 are independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy or C1-C2 alkoxy, -CF3, and - C(=O)-OR9, or wherein Y4 is

wherein the * or the wavy line shows the position bound to the N of the keto- amide group, and wherein R17 is selected from the group consisting of -OR9, -NHR9 , -N(-CH3)R9, pyrrolidine, and morpholine, R15 and R16 are independently selected from the group consisting of H, D, C1- C5 alkyl, phenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dimethoxybenzyl, and unsubstituted C3-C8 heteroalkylaryl, R18 and R19 are independently selected from the group consisting of H, D, C1- C6 alkyl, phenyl, benzyl, 4-hydroxybenzyl, unsubstituted C3-C8 heteroalkylaryl, -(CH2)n-C(=C))-C)R20, -(CH2)n-C(=0)-NR21R22, and -(CH2)n-NR23R24, wherein n is an integer from 1 to 4, R20 is selected from the group consisting of H, D, C1-C3 alkyl, and benzyl, R21 and R22 are independently selected from the group consisting of H, D, C1- C3 alkyl, benzyl, and 3,4-dimethoxybenzyl, and R23 and R24 are independently selected from the group consisting of H, D, and (benzyloxy)carbonyl. (13) a pharmaceutical composition comprising a compound according to any of (1)- (12) and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. (14) the compound according to any one of (1)-(12), or the pharmaceutical composition according to (13) for use in the treatment and/or the diagnosis of a disease. (15) the compound according to any of the (1)-(12) or the pharmaceutical composition according to (13) for use in the prevention and/or treatment of a FAP- related disorder. (16) the compound for use according to (15), wherein said disorder is selected from 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 sarcomas, 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, atherosclerotic disease and Crohn’s disease; disorders involving endocrinological dysfunction, such as disorders of glucose metabolism; and blood clotting disorders. (17) the compound according to any of (1)-(12), or pharmaceutical composition according to (13) for use in tissue and/or organ imaging. (18) the compound according to any of (1)-(12), or a pharmaceutical composition according to (13) for use as a companion diagnostic. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended to, nor should they be interpreted to, limit the scope of the invention. EXAMPLES Synthetic approach, procedures and compound characterization for compounds presented in Table 1. Example 1. Synthetic approach, procedures and compound characterization for fluorinated compounds such as 8a, 9a and 9b The overall synthetic approach to the described fluorinated compounds is shown in Scheme 1 and 2. tert-butyl (S)-4,4-difluoro-2-formylpyrrolidine-1-carboxylate was subjected to a Passerini reaction with the corresponding isocyanide and acetic acid, leading to a diastereomeric mixture of acetates. This mixture was then hydrolyzed using cesium carbonate. After the acidic removal of the tert-butyloxycarbonyl protecting group, Boc-protected glycine was introduced through propanephosphonic acid anhydride (PPAA, T3P) coupling. The resultant compound was then subjected to another coupling reaction with corresponding quinoline-4-carboxylic acid derivative. Subsequent oxidation of the secondary alcohol led to the formation of the desired ketoamide. As a final step, the tertiary amine was alkylated with methyl iodide to yield the quaternary ammonium salt. Scheme 1. a) R-NC , CH3COOH, DCM, rt; b) Cs2CO3, THF/MeOH, rt; c) 1. 4M HCl, dioxane; 2. Boc-Gly-OH, T3P, TEA, DCM, rt; d) 1.4M HCl, 1,4-dioxane; 2. quinoline-4-carboxylic acid derivative, T3P, TEA, DCM, rt; e) DMP, DCM, rt; f) MeI, DMF, rt.

Scheme 2. a) 1.4M HCl, 1,4-dioxane; 2. quinoline-4-carboxylic acid derivative, T₃P, TEA, DCM; b) DMP, DCM, rt; c) MeI, DMF, rt. The LC-MS retention time of both diastereomers is reported as R_t,1 and R_t,2. General procedure A A solution of corresponding amine 1 eq) in ethyl formate (3 eq) was heated at 60 °C until completion of the reaction (ca. 3h). Then, ethyl formate was removed in vacuo and the formed formamide was dissolved in DCM and triethylamine (5 eq) was added. The mixture was cooled down to 0 °C and POCl3 (1 eq) was added dropwise. The reaction mixture was stirred at this temperature for 10 min, then quickly purified through a silica pad with a gradient of diethyl ether and DCM. The following isocyanides were prepared according to general procedure A. Optionally the crude products were purified by column chromatography using diethyl ether to give isocyanide. ^ 4-(isocyanomethyl)-1,2-dimethoxybenzene (1a) (0.956 g, 90% yield) from (3,4-dimethoxyphenyl)methanamine (1.00 g, 6.00 mmol). ^ 2-(isocyanomethyl)thiophene (1b) (1.10 g, 92% yield) from thiophen-2- ylmethanamine (1.00 g, 9.70 mmol). ^ 5-(isocyanomethyl)benzo[d][1,3]dioxole (1c) (0.905 g, 85% yield) from benzo[d][1,3]dioxol-5-ylmethanamine (1.00 g, 6.61 mmol). ^ 1-(difluoromethoxy)-4-(isocyanomethyl)benzene (1d) (0.971 g, 92% yield) from (4-(difluoromethoxy)phenyl)methanamine (1.00 g, 5.77 mmol). ^ 5-(isocyanomethyl)oxazole (1e) (0.629 g, 92% yield) from oxazol-5- ylmethanamine hydrochloride (1.00 g, 7.26 mmol). ^ 5-(isocyanomethyl)-1,2,3-trimethoxybenzene (1f) (0.933 g, 89% yield) from (3,4,5-trimethoxyphenyl)methanamine (1.00 g, 5.06 mmol)

General procedure B To a solution of aldehyde (tert-butyl (S)-4,4-difluoro-2-formylpyrrolidine-1- carboxylate, 1eq) and corresponding isocyanide (1eq) in dry DCM under argon was added acetic acid (1eq) and the mixture was stirred overnight. The reaction was quenched by addition of NaHCO₃ and the organic phase was washed with water, dried (Na₂SO₄) and evaporated. The crude product was dissolved in the mixture of THF/MeOH (9:1) and Cs2CO3 (2 eq) was added and the mixture was stirred for 30 min. Water was added and the mixture was extracted with AcOEt (3x). The combined organic dried (Na2SO4) and evaporated. The following compounds were prepared according to general procedure B. Optionally, the crude product was purified by flash chromatography using heptane/ethyl acetate to give a mixture of diastereomeric alcohols. ^ tert-butyl (2S)-2-(2-((2,6-dimethylphenyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidine-1-carboxylate (1a) (0.586 g, 72% yield after 2 steps) from 2,6-Dimethylphenyl isocyanide (0.279 g, 2.12 mmol). ^ tert-butyl (2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidine-1-carboxylate (2b) (0.517 g, 67% yield after 2 steps) from 1a (0.366 g, 2.06 mmol). ^ tert-butyl 2(S)-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidine-1- carboxylate (2c) (0.684 g, 84% after 2 steps) from 1H-Benzotriazol-1- ylmethyl isocyanide (0.300 g, 1.90 mmol). ^ tert-butyl (2S)-4,4-difluoro-2-(1-hydroxy-2-(naphthalen-2- ylamino)-2-oxoethyl)pyrrolidine-1-carboxylate (2d) (0.406 g, 91% after 2 steps) from 2-naphthyl isocyanide (0.168 g, 1.10 mmol)

The quinoline derivatives were prepared from methyl 6-(3-chloropropoxy)quinoline- 4-carboxylate for 6-substitued derivatives or methyl 8-aminoquinoline-4- carboxylate for 8-substitued compounds (Scheme 3 and 4).

Scheme 3. a) amine, KI, CH3CN, 60 °C; b) LiOH, THF/H2O, rt; General procedure C To a solution of methyl 6-(3-chloropropoxy)quinoline-4-carboxylate (1eq) in CH3CN was added potassium iodide (6eq) followed by addition of corresponding secondary amine (6eq) and the mixture was stirred at 70 °C overnight. Then, acetonitrile was evaporated and water was added. The mixture was extracted three times with DCM. The combined organic phases were washed with water, dried (Na2SO4) and concentrated. The following compounds were prepared according to general procedure C: ^ methyl 6-(3-(piperidin-1-yl)propoxy)quinoline-4-carboxylate (3a) (0.930 g, 98% yield). ^ methyl 6-(3-morpholinopropoxy)quinoline-4-carboxylate (3b) (0.831 g, 86% yield).

Scheme 4. a) SOCl2, CH3OH, 65 °C; b) acid derivative, HATU, DIPEA, DMF, rt or acyl chloride, DIPEA, DCM, amine, KI, CH3CN, 60 °C; c) LiOH, THF/H2O, rt; methyl 8-aminoquinoline-4-carboxylate (4) To a solution of 8-aminoquinoline- 4-carboxylic acid (0.500 g, 2.66 mmol, 1eq) in MeOH (8 mL) was SOCl2 (0.482 μL, 6.64 mmol, 2.5eq) and the mixture was stirred at reflux overnight. The solvent was removed and the solid residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution and water, dried (Na2SO4) and evaporated. The formed product

General procedure D To a solution of carboxylic acid (1.1eq) and DIPEA (4eq) in dry DCM was added amine (1eq) followed by addition of HATU (1.3eq) and the mixture was stirred overnight. Then, saturated NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic layers were washed with water, dried (Na2SO4) and evaporated. General procedure E To a solution of carboxylic acid (2eq) and DMAP (2.5eq) in dry DCM was added EDC (2eq). The mixture was stirred for 15 min and, then, the amine (1eq) was added, and the stirring was continued overnight. Saturated NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic layers were washed with water, dried (Na2SO4) and concentrated. General procedure F To a solution of amine (1eq) and DIPEA (1eq) in dry DCM was added 4- bromobutanoyl chloride (1.5 eq) dropwise at 0 °C. The reaction mixture was stirred for 2h. Then, the mixture was evaporated and the crude purified by flash chromatography using a gradient mixture of heptane/ethyl acetate (from 0-100% ethyl acetate) to give methyl 8-(4-bromobutanamido)quinoline-4-carboxylate. A suspension of methyl 8-(4-bromobutanamido)quinoline-4-carboxylate (1.05eq), potassium iodide (0.03 eq), and the corresponding secondary amine (1.eq) in CH3CN was stirred at 60°C overnight. Then, CH3CN was evaporated, water was added, and the mixture was extracted with DCM. The combined organic layers were washed with water, dried (Na2SO4) and evaporated. The following compounds were prepared according to general procedure F: ^ methyl 8-(4-(dimethylamino)butanamido)quinoline-4-carboxylate (5a) (0.831 g, 86% yield). ^ methyl 8-(4-(4-(tert-butoxycarbonyl)piperazin-1- yl)butanamido)quinoline-4-carboxylate (5b) (0.745 g, 82% yield). ^ methyl 8-(3-(2-(dimethylamino)ethoxy)propanamido)quinoline-4- carboxylate (5c) (0.340 g, 75% yield). ^ methyl 8-(4-morpholinobutanamido)quinoline-4-carboxylate (5d) (0.180 g, 70% yield after 3 steps). ^ methyl 8-(4-(piperidin-1-yl)butanamido)quinoline-4-carboxylate (5e) (0.180 g, 27% yield after 3 steps).

General procedure G To a solution of the corresponding ester in THF, an aqueous solution of LiOH (2 eq) was added, and the resultant mixture was stirred for 2h. Then, THF was evaporated, and the pH of the reaction was adjusted to 3 with 1 N HCl. The mixture was freeze- dried and used without any further purification. The following compounds were prepared according to general procedure G: ^ 6-(3-(piperidin-1-yl)propoxy)quinoline-4-carboxylic acid (6a) (0.880 g, 99% yield) from methyl 6-(3-(piperidin-1-yl)propoxy)quinoline-4-carboxylate (0.921 g, 2.80 mmol). ^ 6-(3-morpholinopropoxy)quinoline-4-carboxylic acid (6b) (0.385 g, 97% yield) from methyl 6-(3-morpholinopropoxy)quinoline-4-carboxylate (0.207 g, 0.630 mmol). ^ 8-(4-(dimethylamino)butanamido)quinoline-4-carboxylic acid (6c) (0.340 g, 89% yield) from methyl 8-(4-(dimethylamino)butanamido)quinoline- 4-carboxylate (0.400 g, 1.27 mmol). ^ 8-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)butanamido)quinoline-4- carboxylic acid (6d) (0.630 g, 68% yield) from methyl 8-(4- (dimethylamino)butanamido)quinoline-4-carboxylate (1.00 g, 2.19 mmol). ^ 8-(3-(2-(Dimethylamino)ethoxy)propanamido)quinoline-4-carboxylic acid (6e) from ethyl 8-(3-(2-(dimethylamino)ethoxy)propanamido)quinoline- 4-carboxylate (0.100 g, 0.29 mmol). ^ 8-(4-Morpholinobutanamido)quinoline-4-carboxylic acid (6f) from methyl 8-(4-morpholinobutanamido)quinoline-4-carboxylate (0.180 g, 0.504 mmol). ^ 8-(4-(Piperidin-1-yl)butanamido)quinoline-4-carboxylic acid (6g) from methyl 8-(4-(piperidin-1-yl)butanamido)quinoline-4-carboxylate (0.130 g, 0.366 mmol).

General procedure H To a solution of Boc-protected compound (1eq) in dry 1,4-dioxane was added HCl (4M in 1,4-dioxane; 20eq) and the mixture was stirred for 1h. Then, the mixture was concentrated to dryness and used directly without any further purification. To a solution of carboxylic acid (1.1 eq) and triethylamine (3eq) in dry DCM was added corresponding amine followed by addition of PPAA (50% solution in AcOEt, 1.1eq) and the stirring was continued for 30 min. Then, the organic phase was washed with water, saturated NaHCO₃, brine, dried (Na₂SO₄) and concentrated. Optionally, the crude product was purified by flash chromatography using heptane/ethyl acetate or a gradient mixture of DCM/MeOH or a gradient mixture of DCM/DCM:MeOH:NH3 (7N in MeOH) to give a mixture of diastereomeric alcohols. The following compounds were prepared according to general procedure H: ^ tert-butyl (2-((2S)-2-(2-((2,6-dimethylphenyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate (7a) (0.172 g, 93% yield) from N-Boc-Glycine (0.075 g, 0.429 mmol). ^ tert-butyl (2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate (7b) (0.217 g, 76% yield) from N-Boc-Glycine (0.112 g, 0.639 mmol). ^ tert-butyl (2-((2S)-2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamate (7c) (0.065 g, 46%) from N-Boc-Glycine (0.066 g, 0.378 mmol). ^ tert-butyl (2-((2S)-4,4-difluoro-2-(1-hydroxy-2-(naphthalen-2- ylamino)-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (7d) (0.406 g, 91%) from N-Boc-Glycine (0.087 g, 0.490 mmol). ^ 6-(3-(dimethylamino)propoxy)-N-(2-((2S)-2-(2-((2,6- dimethylphenyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin- 1-yl)-2-oxoethyl)quinoline-4-carboxamide (7e) (0.160 g, 74% yield) from 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid (0.112 g, 0.399 mmol).N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (7f) (0.146 g, 70% yield) from 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid (0.103 g, 0.376 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (7g) (0.231 g, 72% yield) from 6-(3-(4-(tert- butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (0.200 g, 0.451 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (7h) (0.180 g, 85% yield) from 6-(3-(4-(tert- butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (0.127 g, 0.306 mmol). ^ N-(2-((2S)-2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-1- hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (7i) (0.037 g, 14%) from 6-(3-(piperidin-1-yl)propoxy)quinoline-4-carboxylic acid (0.181 g, 0.400 mmol). ^ N-(2-((2S)-4,4-difluoro-2-(1-hydroxy-2-(naphthalen-2-ylamino)-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (7j) (0.187 g, 94%) from tert-butyl (2-(4,4-difluoro-2-(1-hydroxy-2-(naphthalen-2-ylamino)-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (0.128 g, 0.280 mmol). ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4- (dimethylamino)butanamido)quinoline-4-carboxamide (7k) (0.130 g, 55% yield after 2 steps) from tert-butyl (2-((2S)-2-(2-((3,4- dimethoxybenzyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamate (0.173 g, 0.354 mmol) and 8-(4- (dimethylamino)butanamido)quinoline-4-carboxylic acid (0.117 g, 0.389 mmol). ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(3-(2- (dimethylamino)ethoxy)propanamido)quinoline-4-carboxamide (7l) (0.130 g, 72% yield after 2 steps) from tert-butyl (2-((2S)-2-(2-((3,4- dimethoxybenzyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamate (0.127 g, 0.260 mmol) and 8-(3-(2- (dimethylamino)ethoxy)propanamido)quinoline-4-carboxylic acid (0.095 g, 0.285 mmol). ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4- morpholinobutanamido)quinoline-4-carboxamide (7m) (0.098 g, 67% yield after 2 steps) from tert-butyl (2-((2S)-2-(2-((3,4- dimethoxybenzyl)amino)-1-hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamate (0.100 g, 0.206 mmol) and 8-(4- morpholinobutanamido)quinoline-4-carboxylic acid (0.078 g, 0.226 mmol). ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4-(piperidin-1- yl)butanamido)quinoline-4-carboxamide (7n) (0.160 g, 62% yield after 2 steps) from tert-butyl (2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate (0.179 g, 0.366 mmol) and 8-(4-(piperidin-1-yl)butanamido)quinoline-4-carboxylic acid (0.125 g, 0.366 mmol).

General procedure I To a solution of alcohols (1 eq) in dry DCM was added Dess-Martin periodinane (4 eq) and the mixture was stirring for 1h. Then Na2S2O3 was added and the mixture was left for 15 min. Water phase was extracted three times with DCM and the combined organic phases were washed with NaHCO₃, dried (Na₂SO₄) and concentrated. The following compounds were prepared according to general procedure I. Optionally, the crude product was purified by (reverse-phase) flash chromatography using DCM/MeOH or DCM/DCM:MeOH:NH₃ (7N in MeOH) or by reverse-phase flash chromatography using H₂O/CAN or by reverse-phase flash chromatography using CH3CN/H2O or by silica gel 60 PF₂₅₄ PTLC using a mixture of DCM:MeOH:NH3 (7N in MeOH) or DCM:MeOH. ^ (S)-6-(3-(dimethylamino)propoxy)-N-(2-(2-(2-((2,6- dimethylphenyl)amino)-2-oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (8a) (0.042 g, 42% yield). MS (ESI): m/z 596.3 [M+H]; 628.4 [M+H+MeOH]+; Rt,1= 1.27, Rt,2 = 1.35. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (8b) (0.022 g, 51% yield). MS (ESI): m/z 642.2 [M+H], 674.5 [M+H+MeOH]+; Rt,1= 1.24, Rt,2 = 1.29. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin- 6-yl)oxy)propyl)piperazine-1-carboxylate (8c) (0.140 g, 70% yield). MS (ESI): m/z 783.5 [M+H], 815.5 [M+H+MeOH]+; Rt,1= 1.54, Rt,2 = 1.58. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-2-oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (8d) (0.026 g, 44% yield). MS (ESI): m/z 764.5 [M+H]+, 796.5 [M+H+MeOH]+; R_t,1= 1.56, R_t,2 = 1.60. ^ (S)-N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-2- oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (8e) (0.020 g, 82%). MS (ESI): m/z 663.5 [M+H]+; R_t,1= 1.19; R_t,2= 1.25. ^ (S)-N-(2-(4,4-difluoro-2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (8f) (0.008 g, 17%). MS (ESI): m/z 658.3 [M+H]+, 690 [M+H+MeOH]+; Rt,1 = 1.46; Rt,2= 1.53. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4- (dimethylamino)butanamido)quinoline-4-carboxamide (8g) (0.028 g, 39% yield). MS (ESI): m/z 669.4 [M+H]+ (Rt,1= 1.30, Rt,2 = 1.36), 687.5 [M+H2O+H]+, 701.5 [M+H+MeOH]+. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(3-(2- (dimethylamino)ethoxy)propanamido)quinoline-4-carboxamide (8h) (0.060 g, 55% yield). MS (ESI): m/z 699.5 [M+H]+; 717.5 [M+H + 2O+H] ; 731.5 [M+CH₃OH+H]+; R_t,1= 1.32, R_t,2 = 1.37. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4- morpholinobutanamido)quinoline-4-carboxamide (8i) (0.038 g, 49% yield). MS (ESI): m/z 711.5 [M+H]+; 729.5 [M+H₂O+H]+; 743.5 [M+CH₃OH+H]+; R_t,1= 1.33, R_t,2 = 1.39. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4-(piperidin-1- yl)butanamido)quinoline-4-carboxamide (8j) (0.025 g, 17% yield). MS (ESI): m/z 709.5 [M+H]+, 727.6 [M+H₂O+H]+, 741.5 [M+CH₃OH+H]+; R_t,1= 1.40, Rt,2 = 1.44. General procedure J To a solution of tertiary amine (1 eq) in dry DMF was added CH₃I (1.5 eq) at 0 °C and the stirring was continued for 30 min at 0 °C and 30 min or overnight at rt. Then, the mixture was evaporated few times with toluene and dried on high vac pump. The following compounds were prepared according to general procedure J. Optionally, the crude product was purified by reverse-phase flash chromatography using CH₃CN/H₂O (17:83) and lyophilized or by aluminium oxide 60 F₂₅₄ PTLC using a mixture of DCM:MeOH:NH₃ (7N in MeOH). ^ (S)-3-((4-((2-(2-(2-((2,6-dimethylphenyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)- N,N,N-trimethylpropan-1-aminium iodide (9a) (0.042 g, 52% yield). MS (ESI): m/z 610.3 [M]+, 642.4 [M+MeOH]+; R_t,1= 1.39, R_t,2 = 1.45. ^ (S)-3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)- N,N,N-trimethylpropan-1-aminium iodide (9b) (0.015 g, 62% yield). MS (ESI): m/z 656.4 [M]+, 688.5 [M+H+MeOH]+; Rt,1= 1.24, Rt,2 = 1.29. ^ (S)-4-(tert-butoxycarbonyl)-1-(3-((4-((2-(2-(2-((3,4- dimethoxybenzyl)amino)-2-oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1- ium iodide (9c) (0.015 g, 58% yield). MS (ESI): m/z 797.5 [M]+; 815.5 [M+H₂O]; R_t,1= 1.46, R_t,2 = 1.51. ^ (S)-1-(3-((4-((2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-2-oxoacetyl)-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperidin-1- ium iodide (9d) (0.010 g, 24%). MS (ESI): m/z 677.4 [M+H]+; Rt,1= 1.04, Rt,2 = 1.25. ^ (S)-1-(3-((4-((2-(4,4-difluoro-2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)-1-methylpiperidin-1-ium iodide (9e) (0.005 g, 76%) was prepared according to general procedure J overnight. No further purification was needed. MS (ESI): m/z 673.4 [M]+, 704.4 [M+MeOH]+; R_t,1= 1.41, R_t,2 = 1.54. ^ (S)-4-((4-((2-(2-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)- N,N,N-trimethyl-4-oxobutan-1-aminium iodide (9f) (0.015 g, 72% yield). MS (ESI): m/z 683.5 [M]+, 701.4 [M+H₂O]+, 715.5 [M+MeOH]+; R_t,1= 1.31, R_t,2 = 1.37. ^ (S)-2-(3-((4-((2-(2-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoacetyl)- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-3-oxopropoxy)-N,N,N-trimethylethan-1-aminium iodide (9g) (0.010 g, 76% yield). MS (ESI): m/z 713.5 [M]+, 731.5 [M+H₂O]+, 745.5 [M+MeOH]+; Rt,1= 1.32, Rt,2 = 1.37. ^ (S)-4-(4-((4-((2-(2-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoacetyl)- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)-4-methylmorpholin-4-ium iodide (9h) (0.013 g, 72% yield). MS (ESI): m/z 725.5 [M]+, 743.5 [M+H + + 2O] , 757.5 [M+MeOH] ; Rt,1= 1.30, Rt,2 = 1.35. ^ (S)-1-(4-((4-((2-(2-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoacetyl)- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)-1-methylpiperidin-1-ium iodide (9i) (0.011 g, 61% yield). MS (ESI): m/z 723.5 [M]+, 741.5 [M+H2O]+, 756.5 [M+MeOH]+; Rt,1= 1.36, Rt,2 = 1.41. ^ (S)-3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-N- (fluoromethyl)-N,N-dimethylpropan-1-aminium 4- methylbenzenesulfonate (10) To a solution of 7f (0.025 mg, 0.039 mmol) in dry DMF (0.500 mL) was added DIPEA (0.034 mL, 0.194 mmol) followed by addition of fluoromethyl 4-methylbenzenesulfonate (0.031 mL, 0.194 mmol) and the resultant mixture was sitrred at 120 °C for 2h. The solvent was removed, water was added and the mixture was extracted with DCM. Water phase was liophylised. The crude product was subjected to the oxidation reaction according to the procedure J. The product was purified by reverse-phase flash chromatography using CH3CN/H2O (15:85) and lyophilized. MS (ESI): m/z 674.4 [M]+; 706.4 [M+MeOH]+; Rt,1= 1.24, Rt,2 = 1.29.

Example 2. Synthetic approach, procedures and compound characterization for non-fluorinated compounds, such as 14a and 15a The overall synthetic approach to the described non-fluorinated compounds is shown in Scheme 5 and 6. As a starting material for the preparation of non-fluorinated analogs, tert-butyl (S)- 2-formylpyrrolidine-1-carboxylate was chosen. The aldehyde was subjected to the PADAM (Passerini reaction – Amine Deprotection – Acyl Migration reaction) sequence reaction to form a diastereomeric mixture of alcohols. A primary amine was deprotected by catalytic hydrogenation, and the resultant product was coupled with 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid in the presence of PPAA, followed by oxidation with Dess-Martin periodinane. The resulting compound was methylated with methyl iodide to form the desired quaternary ammonium salt.

Scheme 5 a) 1. Z-Gly-OH, 3,4-dimethoxybenzyl isocyanide, DCM, rt; 2. TFA, DCM, rt; 3. TEA, DCM, 0 °C → rt; b) H2, Pd(OH)2, MeOH; c) quinoline-4-carboxylic acid, coupling reagent, base, DMF, rt; d) DMP, DCM, rt; e) MeI, DMF. Scheme 6. a) quinoline-4-carboxylic acid derivative, coupling reagent, base, DMF, rt; b) DMP, DCM, rt; c) MeI, DMF; General procedure K To a solution of aldehyde (1 eq), Cbz-protected glycine (1 eq) in dry DCM was added isocyanide (1 eq) and the mixture was stirred overnight. After completion of the reaction (LC-MS) trifluoroacetic acid was added and the stirring was continued for 1h. Then, the reaction mixture was evaporated to dryness, redissolved in DCM and cooled down to 0 °C. Triethylamine was added dropwise and the mixture was stirred for 1h. The organic phase was washed with water, brine, dried (Na₂SO₄) and concentrated. Optionally, the crude product was purified by flash chromatography using DCM/MeOH. The following compounds were prepared according to general procedure K: ^ benzyl (2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (6a) (0.599 g, 82% ) from 4-(Isocyanomethyl)-1,2-dimethoxybenzene (0.267 g, 1.51 mmol). ^ benzyl (2-((2S)-2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-1-hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2- oxoethyl)carbamate (11b) (0.548 g, 82% yield) from 1H-benzotriazol-1- ylmethyl isocyanide (0.254 g, 1.61 mmol). ^ benzyl (2-((2S)-2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11c) (1.20 g, 85% yield) from 1c (0.484 g, 3.01 mmol). ^ benzyl (2-((2S)-2-(2-((4-(difluoromethoxy)benzyl)amino)-1-hydroxy- 2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11d) (1.25 g, 84% yield) from 1d (0.550 g, 3.01 mmol). ^ benzyl (2-((2S)-2-(2-(((diethoxyphosphoryl)methyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11e) (0.770 g, 63% yield) from diethyl (isocyanomethyl)phosphonate (0.400 mL, 2.51 mmol). ^ benzyl (2-((2S)-2-(1-hydroxy-2-oxo-2-((((S)-tetrahydrofuran-2- yl)methyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11f) (0.897 g, 70% yield) from 2-(isocyanomethyl)tetrahydrofuran (0.340 g, 3.06 mmol). ^ benzyl (2-((2S)-2-(1-hydroxy-2-((oxazol-5-ylmethyl)amino)-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11g) (0.500 g, 76% yield) from 1e (0.170 g, 1.57 mmol). ^ benzyl (2-((2S)-2-(1-hydroxy-2-oxo-2-((3,4,5- trimethoxybenzyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11h) (1.25 g, 80% yield) from 1f (0.623 g, 3.01 mmol). ^ benzyl (2-(2-(1-hydroxy-2-(naphthalen-2-ylamino)-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11i) (1.00 g, 83%) from 2-naphthyl isocyanide (0.387 g, 2.53 mmol). ^ benzyl (2-(2-(1-hydroxy-2-oxo-2-((pyridin-3- ylmethyl)amino)ethyl)pyrrolidin-1-yl)-2 oxoethyl)carbamate (11j) (2.40 g, >99% yield) from 3-(isocyanomethyl)pyridine (0.500 g, 4.23 mmol). ^ benzyl (2-(2-(1-hydroxy-2-oxo-2-((thiophen-2- ylmethyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (11k) (2.90 g, 79% yield) from 1b (1.09 g, 8.90 mmol).

General procedure L To a solution of Cbz-protected amine (1eq) in MeOH was added Pd(OH)2/C (1eq) and the resultant suspension was stirred under hydrogen atmosphere for 2h. Then, the mixture was filtered through the short pad of Celite and concentrated. Optionally, ^ N-(3,4-dimethoxybenzyl)-2-((S)-1-glycylpyrrolidin-2-yl)-2- hydroxyacetamide (7a) (0.118 g, 90% ). ^ N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-((S)-1-glycylpyrrolidin- 2-yl)-2-hydroxyacetamide (12b) (0.085 g, 94% yield). ^ N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((S)-1-glycylpyrrolidin-2-yl)-2- hydroxyacetamide (12c) (0.789 g, 92% yield). ^ N-(4-(difluoromethoxy)benzyl)-2-((S)-1-glycylpyrrolidin-2-yl)-2- hydroxyacetamide (12d) (0.732 g, 84% yield). ^ diethyl ((2-((S)-1-glycylpyrrolidin-2-yl)-2- hydroxyacetamido)methyl)phosphonate (12e) (0.413 g, 74% yield). ^ 2-((S)-1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(((S)-tetrahydrofuran-2- yl)methyl)acetamide (12f) (0.250 g, 68% yield). ^ 2-((S)-1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(oxazol-5- ylmethyl)acetamide (12g) (0.364 g, 78% yield). ^ benzyl (2-((2S)-2-(1-hydroxy-2-oxo-2-((3,4,5- trimethoxybenzyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (12h) (0.748 g, 91% yield). ^ 2-(1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(naphthalen-2-yl)acetamide (12i) (0.591 g, 82% yield). ^ 2-(1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(pyridin-3- ylmethyl)acetamide (12j) (0.318 g, 78% yield). ^ 2-(1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(thiophen-2- ylmethyl)acetamide (12k): 11k (0.700 g, 1.62 mmol, 1eq) was treated with a hydrobromic acid solution in acetic acid (33% wt, 3.60 mL, 0.05 eq) and the stirring was continued for 2h at rt. Then, the crude was triturated with diethyl ether and the formed solid was washed with DCM/H2O. The aqueous phase containing the product was then lyophilized and purified by reverse-phase flash chromatography with H2O/ACN (96:4) to obtain 12k (0.130 g, 27% yield).

Coupling reactions: The following compounds were prepared according to general procedure D. The crude product was purified by flash chromatography using DCM/MeOH or DCM/DCM:MeOH:NH₃ (7N in MeOH) or by reverse-phase chromatography using H2O/ACN. ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (8a) (0.146 g, 70% yield) from 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid (0.103 g, 0.376 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperazine-1-carboxylate (13b) (0.116 g, 74% yield) from 6- (3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (0.152 g, 0.313 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-1-hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (13c) (0.107 g, 54% yield) from 6-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)quinoline-4-carboxylic acid (0.117 g, 0.283 mmol). ^ N-(2-((2S)-2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-1-hydroxy- 2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (13d) (0.220 g, 82% yield) from 6-(3-(dimethylamino)propoxy)quinoline-4-carboxylic acid (0.135 g, 0.429 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-((benzo[d][1,3]dioxol-5- ylmethyl)amino)-1-hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (13e) (0.161 g, 74% yield) from 6-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)quinoline-4-carboxylic acid (0.124 g, 0.298 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2-((4- (difluoromethoxy)benzyl)amino)-1-hydroxy-2-oxoethyl)pyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (13f) (0.189 g, 90% yield) from 6-(3-(4-(tert- butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (0.116 g, 0.279 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(2- (((diethoxyphosphoryl)methyl)amino)-1-hydroxy-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperazine-1-carboxylate (13g) (0.178 g, 84% yield) from 6- (3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (0.118 g, 0.284 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(1-hydroxy-2-oxo-2-((((S)- tetrahydrofuran-2-yl)methyl)amino)ethyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (13h) (0.180 g, 54% yield) from 6-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)quinoline-4-carboxylic acid (0.203 g, 0.490 mmol). ^ tert-butyl 4-(3-((4-((2-((2S)-2-(1-hydroxy-2-((oxazol-5- ylmethyl)amino)-2-oxoethyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1-carboxylate (13i) (0.212 g, 77% yield) from 6-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)quinoline-4-carboxylic acid (0.169 g, 0.407 mmol). ^ N-(2-(2-(1-hydroxy-2-(naphthalen-2-ylamino)-2-oxoethyl)pyrrolidin- 1-yl)-2-oxoethyl)-6-(3-morpholinopropoxy)quinoline-4-carboxamide (13j) (0.042 g, 13% yield) from 2-(1-glycylpyrrolidin-2-yl)-2-hydroxy-N- (naphthalen-2-yl)acetamide (0.170 g, 0.520 mmol). ^ N-(2-(2-(1-hydroxy-2-(naphthalen-2-ylamino)-2-oxoethyl)pyrrolidin- 1-yl)-2-oxoethyl)-6-(3-(piperidin-1-yl)propoxy)quinoline-4- carboxamide (13k) (0.222 g, 20% yield) from 2-(1-glycylpyrrolidin-2-yl)-2- hydroxy-N-(naphthalen-2-yl)acetamide (0.591 g, 1.81 mmol). ^ N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (13l) (0.300 g, 38% yield) was from N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-(1-glycylpyrrolidin-2-yl)-2- hydroxyacetamide (0.412 g, 1.24 mmol). ^ N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- morpholinopropoxy)quinoline-4-carboxamide (13m) (0.065 g, 46%) from N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-((R)-1-glycylpyrrolidin-2-yl)-2- hydroxyacetamide (0.074 g, 0.220 mmol). ^ N-(2-(2-(1-hydroxy-2-oxo-2-((pyridin-3- ylmethyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (13n) (0.448 g, 92% yield) from 2-(1- glycylpyrrolidin-2-yl)-2-hydroxy-N-(pyridin-3-ylmethyl)acetamide (0.244 g, 0.830 mmol). ^ N-(2-(2-(1-hydroxy-2-oxo-2-((pyridin-3- ylmethyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- morpholinopropoxy)quinoline-4-carboxamide (13o) (0.470 g, 95% yield) from 2-(1-glycylpyrrolidin-2-yl)-2-hydroxy-N-(pyridin-3-ylmethyl)acetamide (0.244 g, 0.830 mmol). ^ N-(2-(2-(1-hydroxy-2-oxo-2-((thiophen-2- ylmethyl)amino)ethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (13p) (0.128 g, 50% yield) from 2-(1- glycylpyrrolidin-2-yl)-2-hydroxy-N-(thiophen-2-ylmethyl)acetamide (0.130 g, 0.440 mmol). ^ 8-amino-N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (13q) (0.264 g, 89% yield) from 8-aminoquinoline-4-carboxylic acid (0.118 g, 0.625 mmol). ^ tert-butyl (4-((4-((2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)carbamate (13r) (0.117 g, 78% yield) from γ-(Boc- amino)butyric acid (0.086 g, 0.425 mmol). ^ N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1-hydroxy-2- oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-8-(4- (dimethylamino)butanamido)quinoline-4-carboxamide (13s) (0.162 g, 90% yield) from 8-(4-(dimethylamino)butanamido)quinoline-4-carboxylic acid (0.182 g, 0.487 mmol). ^ 8-(4-(dimethylamino)butanamido)-N-(2-((2S)-2-(1-hydroxy-2-oxo-2- ((3,4,5-trimethoxybenzyl)amino)ethyl)pyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (13t) (0.130 g, 76% yield) from 8-(4- (dimethylamino)butanamido)quinoline-4-carboxylic acid (0.195 g, 0.524 mmol). ^ tert-butyl 4-(4-((4-((2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)piperazine-1-carboxylate (13u) (0.221 g, 67% yield) from 8-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)butanamido)quinoline- 4-carboxylic acid (0.293 g, 0.640 mmol). 10

Oxidation: The following compounds were prepared according to general procedure I. Optionally, the crude product was purified by (reverse-phase) flash chromatography using DCM/MeOH or DCM/DCM:MeOH:NH₃ (7N in MeOH) or by reverse-phase flash chromatography using H₂O/ACN. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (14a) (0.024 g, 62% yield). MS (ESI): m/z 606.3 [M+H]+; 626.4 [M+H+H₂O]+ R_t,1= 1.15, R_t,2 = 1.22. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperazine-1-carboxylate (14b) (0.056 g, 70% yield). MS (ESI): m/z 747.5 [M+H], 779.5 [M+H+MeOH]+; R_t,1= 1.32, R_t,2 = 1.37. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (14c) (0.046 g, 72% yield). MS (ESI): m/z 728.5 [M+H], 760.5 [M+H+MeOH]+; R_t,1= 1.38, R_t,2 = 1.45. ^ (S)-N-(2-(2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- (dimethylamino)propoxy)quinoline-4-carboxamide (14d) (0.082 g, 64% yield). MS (ESI): m/z 590.4 [M+H], 622.4 [M+H+MeOH]+; R_t,1= 1.12, R_t,2 = 1.18. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-((benzo[d][1,3]dioxol-5- ylmethyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (14e) (0.105 g, 68% yield). MS (ESI): m/z 731.5 [M+H], 763.5 [M+H+MeOH]+; Rt,1= 1.39, Rt,2 = 1.44. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-((4- (difluoromethoxy)benzyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (14f) (0.064 g, 54% yield). MS (ESI): m/z 753.5 [M+H], 785.5 [M+H+MeOH]+; R_t,1= 1.48, R_t,2 = 1.52. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2- (((diethoxyphosphoryl)methyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazine-1- carboxylate (14g) (0.074 g, 68% yield). MS (ESI): m/z 747.5 [M+H], 779.5 [M+H+MeOH]+; Rt,1= 1.36, Rt,2 = 1.43. ^ tert-butyl 4-(3-((4-((2-oxo-2-((S)-2-(2-oxo-2-((((S)-tetrahydrofuran- 2-yl)methyl)amino)acetyl)pyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperazine-1-carboxylate (14h) (0.064 g, 58% yield). MS (ESI): m/z 681.5 [M+H]+, 699.5 [M+H+H₂O]+; R_t,1= 1.26, R_t,2 = 1.30. ^ tert-butyl (S)-4-(3-((4-((2-(2-(2-((oxazol-5-ylmethyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperazine-1-carboxylate (14i) (0.076 g, 62% yield). MS (ESI): m/z 678.5 [M+H]+, 710.6 [M+H+MeOH]+; R_t,1= 1.25, R_t,2 = 1.30. 6-(3-morpholinopropoxy)-N-(2-(2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (14j) (0.044 g, 62% yield). MS (ESI): m/z 624.4 [M+H]+; Rt,1= 1.39, Rt,2 = 1.47. ^ N-(2-(2-(2-(naphthalen-2-ylamino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)-6-(3-(piperidin-1-yl)propoxy)quinoline-4-carboxamide (14k) (0.049 g, 72% yield). MS (ESI): m/z 622.4 [M+H]+, 644.4 [M+Na]+; Rt,1= 1.38, Rt,2 = 1.45. ^ N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (14l) (0.100 g, 32% yield). MS (ESI): m/z 627.4 [M+H]+; Rt,1= 1.22, Rt,2 = 1.29. ^ N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3- morpholinopropoxy)quinoline-4-carboxamide (14m) (0.044 g, 50% yield). MS (ESI): m/z 629.4 [M+H]+, 651.5 [M+Na]+; Rt,1= 1.05, Rt,2 = 1.16. ^ N-(2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperidin-1- yl)propoxy)quinoline-4-carboxamide (14n) (0.100 g, 32% yield). MS (ESI): m/z 627.4 [M+H]+; Rt,1= 1.22, Rt,2 = 1.29. ^ 6-(3-morpholinopropoxy)-N-(2-oxo-2-(2-(2-oxo-2-((pyridin-3 ylmethyl)amino)acetyl) pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide (14o) (0.009 g, 22% yield). MS (ESI): m/z 589.3 [M+H]+; R_t,1= 0.18, R_t,2 = 0.24. ^ tert-butyl (S)-(4-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)carbamate (14p) (0.065 g, 56% yield). MS (ESI): m/z 705.1 [M+H]+, 737.4 [M+H+MeOH]+; Rt,1= 1.59, Rt,2 = 1.65. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-8-(4- (dimethylamino)butanamido)quinoline-4-carboxamide (14q) (0.072 g, 64% yield). MS (ESI): m/z 633.5 [M+H]+; 665.5 [M+H+MeOH]+; Rt,1= 1.19, R_t,2 = 1.25. ^ (S)-8-(4-(dimethylamino)butanamido)-N-(2-oxo-2-(2-(2-oxo-2- ((3,4,5-trimethoxybenzyl)amino)acetyl)pyrrolidin-1- yl)ethyl)quinoline-4-carboxamide (14r) (0.098 g, 72% yield). MS (ESI): m/z 663.5 [M+H]+; 695.5 [M+H+MeOH]+; Rt,1= 1.24, Rt,2 = 1.31. ^ tert-butyl (S)-4-(4-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutyl)piperazine-1-carboxylate (14s) (0.120 g, 69% yield). MS (ESI): m/z 774.5 [M+H]+; 806.5 [M+H+MeOH]+; Rt,1= 1.38, Rt,2 = 1.43. ^ tert-butyl (S)-4-(4-oxo-4-((4-((2-oxo-2-(2-(2-oxo-2-((3,4,5- trimethoxybenzyl)amino)acetyl)pyrrolidin-1- yl)ethyl)carbamoyl)quinolin-8-yl)amino)butyl)piperazine-1- carboxylate (14t) (0.088 g, 64% yield). MS (ESI): m/z 804.5 [M+H]+; 836.5 [M+H+MeOH]+; R_t,1= 1.48, R_t,2 = 1.54. ^ (S)-N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(4-(4- iodobenzoyl)piperazin-1-yl)propoxy)quinoline-4-carboxamide (14u) (0.074 g, 74% yield) from N-(2-((2S)-2-(2-((3,4-dimethoxybenzyl)amino)-1- hydroxy-2-oxoethyl)pyrrolidin-1-yl)-2-oxoethyl)-6-(3-(4-(4- iodobenzoyl)piperazin-1-yl)propoxy)quinoline-4-carboxamide (0.100 g, 0.114 mmol). MS (ESI): m/z 678.5 [M+H]+, 710.6 [M+H+MeOH]+; Rt,1= 1.25, Rt,2 = 1.30.

Quaternization: The following compounds were prepared according to general procedure J. Optionally, the crude product was purified by RP flash chromatography using acetonitrile/water solvent system (from 4 to 13%) and lyophilized or the crude product was purified by RP HPLC chromatography using acetonitrile + 0.1% TFA/water +0.1% TFA solvent system (from 34 to 38%) and lyophilized. ^ (S)-3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)- N,N,N-trimethylpropan-1-aminium iodide (15a) (0.013 g, 64% yield). MS (ESI): m/z 621.3 [M+H]+; Rt,1= 1.15, Rt,2 = 1.21. ^ (S)-4-(tert-butoxycarbonyl)-1-(3-((4-((2-(2-(2-((3,4- dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1- ium iodide (15b) (0.026 g, 58% yield). MS (ESI): m/z 761.5 [M]+, 779.5 [M+H₂O]+; R_t,1= 1.44, R_t,2 = 1.49. ^ (S)-1-(3-((4-((2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1- yl)methyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-4-(tert- butoxycarbonyl)-1-methylpiperazin-1-ium iodide (15c) (0.024 g, 63% yield). MS (ESI): m/z 742.5 [M]+, 774.5 [M+MeOH]+; Rt,1= 1.37, Rt,2 = 1.43. ^ (S)-3-((4-((2-(2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)- N,N,N-trimethylpropan-1-aminium iodide (15d) (0.024 g, 63% yield). MS (ESI): m/z 604.4 [M]+, 636.4 [M+MeOH]+; Rt,1= 1.15, Rt,2 = 1.22. ^ (S)-1-(3-((4-((2-(2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)-4-(tert-butoxycarbonyl)-1-methylpiperazin-1-ium iodide (15e) (0.074 g, 58% yield). MS (ESI): m/z 745.5 [M]+, 777.5 [M+MeOH]+; Rt,1= 1.37, Rt,2 = 1.43. ^ (S)-4-(tert-butoxycarbonyl)-1-(3-((4-((2-(2-(2-((4- (difluoromethoxy)benzyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1- ium iodide (15f) (0.056 g, 62% yield). MS (ESI): m/z 767.5 [M]+, 785.5 [M+H₂O]+; R_t,1= 1.47, R_t,2 = 1.52. ^ (S)-4-(tert-butoxycarbonyl)-1-(3-((4-((2-(2-(2- (((diethoxyphosphoryl)methyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1- ium iodide (15g) (0.024 g, 46% yield). MS (ESI): m/z 761.5 [M]+, 793.6 [M+MeOH]+; R_t,1= 1.26, R_t,2 = 1.31. ^ 4-(tert-butoxycarbonyl)-1-methyl-1-(3-((4-((2-oxo-2-((S)-2-(2-oxo-2- ((((S)-tetrahydrofuran-2-yl)methyl)amino)acetyl)pyrrolidin-1- yl)ethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazin-1-ium iodide (15h) (0.016 g, 42% yield). MS (ESI): m/z 695.6 [M]+, 727.6 [M+MeOH]+; R_t,1= 1.31, Rt,2 = 1.37. ^ (S)-4-(tert-butoxycarbonyl)-1-methyl-1-(3-((4-((2-(2-(2-((oxazol-5- ylmethyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)piperazin-1-ium (15i) (0.020 g, 50% yield). MS (ESI): m/z 692.5 [M]+, 724.5 [M+MeOH]+; Rt,1= 1.20, Rt,2 = 1.27. ^ (S)-1-(3-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)-4-(4-iodobenzoyl)-1-methylpiperazin-1-ium iodide (15j) (0.018 g, 54% yield). MS (ESI): m/z 891.5 [M]+, 923.5 [M+MeOH]+; R_t,1= 1.37, Rt,2 = 1.42. ^ 4-methyl-4-(3-((4-((2-(2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2 oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)morpholin-4-ium iodide (15k) (0.031 g, >99% yield). MS (ESI): m/z 638.4 [M]+, 656.5 [M+H + 2O] ; Rt,1= 1.38, Rt,2 = 1.48. ^ 1-methyl-1-(3-((4-((2-(2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperidin-1-ium iodide (15l) (0.043 g, 83% yield). MS (ESI): m/z 650.5 [M]+; Rt, = 1.25. ^ 1-(3-((4-((2-(2-(2-(((1H-benzo[d][1,2,3]triazol-1-yl)methyl)amino)- 2-oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)-1-methylpiperidin-1-ium iodide (15m) (0.030 g, 47%). MS (ESI): m/z 641.4 [M]+; Rt,1= 1.18, Rt,2 = 1.25. ^ 4-methyl-4-(3-((4-((2-(2-(2-(naphthalen-2-ylamino)-2- oxoacetyl)pyrrolidin-1-yl)-2 oxoethyl)carbamoyl)quinolin-6- yl)oxy)propyl)morpholin-4-ium iodide (15n) (0.031 g, >99% yield). MS (ESI): m/z 638.4 [M]+, 656.5 and [M+H2O]+; Rt,1= 1.38, Rt,2 = 1.48. ^ (S)-4-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)- N,N,N-trimethyl-4-oxobutan-1-aminium iodide (15o) (0.048 g, 78% yield). MS (ESI): m/z 647.5 [M]+; 679.5 [M+MeOH]+; Rt,1= 1.20, Rt,2 = 1.26. ^ (S)-N,N,N-trimethyl-4-oxo-4-((4-((2-oxo-2-(2-(2-oxo-2-((3,4,5- trimethoxybenzyl)amino)acetyl)pyrrolidin-1- yl)ethyl)carbamoyl)quinolin-8-yl)amino)butan-1-aminium iodide (15p) (0.032 g, 65% yield). MS (ESI): m/z 677.5 [M]+; 709.5 [M+MeOH]+; R_t,1= 1.25, R_t,2 = 1.32. ^ (S)-4-(tert-butoxycarbonyl)-1-(4-((4-((2-(2-(2-((3,4- dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutyl)-1- methylpiperazin-1-ium iodide (15q) (0.054 g, 68% yield). MS (ESI): m/z 788.5 [M]+; 820.5 [M+MeOH]+; R_t,1= 1.37, R_t,2 = 1.43. ^ (S)-4-(tert-butoxycarbonyl)-1-methyl-1-(4-oxo-4-((4-((2-oxo-2-(2-(2- oxo-2-((3,4,5-trimethoxybenzyl)amino)acetyl)pyrrolidin-1- yl)ethyl)carbamoyl)quinolin-8-yl)amino)butyl)piperazin-1-ium iodide (15r) (0.074 g, 74% yield). MS (ESI): m/z 818.5 [M]+; 850.5 [M+MeOH]+; R_t,1= 1.45, R_t,2 = 1.51. ^ (S)-1-methyl-1-(3-((4-((2-oxo-2-(2-(2-oxo-2-((pyridin-3- ylmethyl)amino)acetyl)pyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6- yl)oxy)propyl)piperidin-1-ium iodide (15s) (0.015 g, 83% yield). MS (ESI): m/z 601.4 [M+H]+; Rt,1= 0.17, Rt,2 = 0.20; ^ (S)-4-methyl-4-(3-((4-((2-oxo-2-(2-(2-oxo-2-((pyridin-3- ylmethyl)amino)acetyl)pyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6- yl)oxy)propyl)morpholin-4-ium iodide (15t) (0.013 g, 73% yield). MS (ESI): m/z 603.4 [M+H]+; Rt,1= 0.17, Rt,2 = 0.28.

To a solution of Boc-protected amine (1eq) in dry acetonitrile was added p-TsOH ∙ H2O (4eq) at 0 °C and the mixture was stirred at rt overnight. Then, solvent was removed and the crude product was used directly in the next step. (S)-4-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2- oxoacetyl)pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4- oxobutan-1-aminium 4-methylbenzenesulfonate (16a) (0.056 g, 84% yield) was prepared according to general procedure M. The crude product was purified by RP flash chromatography using acetonitrile/water solvent system (16:84) and lyophilized. MS (ESI): m/z 605.3 [M+H]+; R_t,1= 1.20, R_t,2 = 1.26. (S)-4-(4-boronobenzoyl)-1-(3-((4-((2-(2-(2-((3,4- dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)propyl)-1-methylpiperazin-1-ium 4-methylbenzenesulfonate (16b) (0.010 g, 44% yield). Deprotection step was performed according to the general procedure M. The crude product was dissolved in DCM (1 mL) and DIPEA (0.045 mL, 0.26 mmol, 10eq) and (4- (chlorocarbonyl)phenyl)boronic acid (0.019 g, 0.104 mmol, 4eq) and the stirring was continued for 5h. Then, water was added and the mixture was extracted with DCM. Water phase was collected and lyophilized. The crude product was purified by RP flash chromatography using acetonitrile/water solvent system (24:76) and lyophilized. MS (ESI): m/z 809.4 [M]+, 841.4 [M+MeOH]+; R_t,1= 1.17, R_t,2 = 1.23.

1H-NMR of the above synthesized products according to embodiments of the invention are shown in table 2: Table 2. Nr. 1H-NMR (400 MHz) 8a 1H NMR ((CD₃)₂SO) δ 2.12 (s, 6H), 2.33 (s, 6H), 2.64-2.72 (m, 2H), 3.73- 3.84 (m, 2H), 4.22 (dd, J = 17.1, 5.8 Hz, 1H), 4.33 (dd, J = 17.1, 5.6 Hz), 4.11 (t, J = 6.2 Hz, 2H), 5.43 (dd, J = 9.8, 5.7 Hz, 1H), 7.05-7.16 (m, 3H), 7.45 (dd, J = 9.2, 2.7 Hz, 1H), 7.50 (d, J = 4.3 Hz, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.81 (d, J = 4.3 Hz), 9.05 (t, J = 5.9 Hz, 1H) 8b 1H NMR ((CD₃)₂SO) δ 2.40 (s, 6H), 3.69 (s, 6H), 4.04-4.10 (m, 2H), 4.19- 4.37 (m, 4H), 5.43 (dd, J = 9.2, 4.8 Hz, 1H), 6.86-6.97 (m, 3H), 7.44 (dd, J = 9.2, 2.7 Hz, 1H), 7.49 (d, J = 4.3 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 8.79 (br d, J = 4.3 Hz), 9.02 (t, J = 6.0 Hz), 9.32 (t, J = 6.3 Hz, 1H); 8c 1H NMR ((CD₃)₂SO) δ 1.39 (s, 9H), 1.73-2.03 (m, 2H), 2.23-2.35 (m, 4H), 2.39 (t, J = 7.2 Hz, 2H), 2.78-2.95 (m, 2H), 3.12- 3.32 (m, 4H), 3.69 (s, 3H), 3.70 (s, 3H), 3.72-3.85 (m, 2H), 4.03-4.35 (m, 5H), 4.36-4.44 (m, 1H), 5.43 (dd, J = 9.2, 4.8 Hz, 1H), 6.78 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 7.48 (d, J = 4.4 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 8.79 (d, J = 4.4 Hz, 1H), 9.03 (t, J = 6.0 Hz, 1H), 9.32 (t, J = 6.3 Hz, 1H); d 1H NMR ((CD3)2SO) δ 1.39 (s, 9H), 2.21-2.37 (m, 4H), 3.62-3.76 (m, 3H), 3.80-3.93 (m, 3H), 3.97-4.37 (m, 4H), 5.40 (dd, J = 9.4, 4.6 Hz, 1H), 6.08 (d, J = 6.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 4.3, 1H), 7.48 (dd, J = 9.2, 2.7 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 8.00 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.99 (t, J = 5.9 Hz, 1H), 10.22 (t, J = 6.6 Hz, 1H); e 1H NMR (CDCl3) δ 1.39-1.69 (m, 4H), 1.64-1.80 (m, 2H), 1.82-1.95 (m, 2H), 2.04-2.24 (m, 3H), 2.26-2.45 (m, 3H), 2.49-2.73 (m, 2H), 3.60-3.81 (m, 2H), 3.86-4.03 (m, 2H), 4.12-4.41 (m, 3H), 4.75-4.95 (m, 2H), 6.16- 6.33 (m, 1H), 7.06 (td, J = 7.6, 1.7 Hz, 1H), 7.33 (qd, J = 8.0, 1.9 Hz, 2H), 7.47-7.58 (m, 1H), 7.66 (dd, J = 7.7, 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.2 Hz, 1H), 7.98-8.13 (m, 2H), 8.77-8.90 (m, 1H); f 1H NMR (CDCl3) δ 1.29 (d, J = 12.2 Hz, 2H), 1.46 (d, J = 8.9 Hz, 2H), 1.62 (d, J = 6.0 Hz, 4H), 2.06 (t, J = 8.1 Hz, 3H), 2.40-2.60 (m, 5H), 3.80- 3.95 (m, 1H), 4.01-4.21 (m, 3H), 4.29-4.50 (m, 2H), 5.66 (dd, J = 9.4, 6.9 Hz, 1H), 6.94-7.10 (m, 1H), 7.35-7.69 (m, 6H), 7.75-7.91 (m, 3H), 8.03 (t, J = 9.2 Hz, 1H), 8.30-8.42 (m, 1H), 8.78 (dd, J = 10.9, 4.4 Hz, 1H), 8.97 (bs, 1H); g 1H NMR ((CD₃)₂SO) δ 1.89 (p, J = 8.0, 7.2 Hz, 2H), 2.40 (s, 6H), 2.58- 2.69 (m, 4H), 2.88-3.04 (m, 2H), 3.61-3.74 (2×s, m, 8H), 4.16-4.33 (m, 4H), 5.42 (dd, J = 9.9, 5.4 Hz, 1H), 6.72-6.97 (m, 3H), 7.53-7.62 (m, 2H), 7.94 (dd, J = 8.5, 1.3 Hz, 1H), 8.65 (dd, J = 7.8, 1.2 Hz, 1H), 8.99 (d, J = 4.3 Hz, 1H), 9.10 (br t, J = 6.0 Hz, 1H), 9.35 (br t, J = 6.4 Hz, 1H), 10.20 (br s, 1H); h 1H NMR ((CD₃)₂SO) δ 2.22 (s, 6H), 2.59 (t, J = 5.9 Hz, 2H), 2.62-2.77 (m, 1H), 2.79 (t, J = 5.6 Hz, 2H), 2.88-3.01 (m, 1H), 3.60 (t, J = 5.9 Hz, 2H), 3.64 (br s, 1H), 3.68-3.72 (2×s, 6H), 3.77 (t, J = 5.9 Hz, 2H), 4.14-4.44 (m, 5H), 5.42 (dd, J = 9.9, 5.3 Hz, 1H), 6.64-7.05 (m, 3H), 7.72-7.51 (m, 2H), 7.93 (d, J = 9.5 Hz, 1H), 8.67 (d, J = 7.7 Hz, 1H), 8.97 (d, J = 4.3 Hz, 1H), 9.06 (t, J = 6.0 Hz, 1H), 9.33 (t, J = 6.3 Hz, 1H), 10.42 (br s, 1H); i 1H NMR ((CD₃)₂SO) δ 1.83 (p, J = 7.1 Hz, 2H), 2.36 (br s, 6H), 2.56-2.66 (m, 2H), 2.67-2.83 (m, 1H), 2.86-3.04 (m, 1H), 2.58-3.52 (m, 4H), 3.64 (br s, 1H), 3.67-3.81 (2×s, 6H), 4.15-4.49 (m, 5H), 5.43 (dd, J = 9.9, 5.4 Hz, 1H), 6.74-6.98 (m, 3H), 7.51-7.68 (m, 2H), 7.94 (dd, J = 8.5, 1.3 Hz, 1H), 8.68 (dd, J = 7.7, 1.2 Hz, 1H), 8.98 (d, J = 4.3 Hz, 1H), 9.10 (br t, J = 5.9 Hz, 1H), 9.35 (br t, J = 6.3 Hz, 1H), 10.11 (br s, 1H); j 1H NMR ((CD3)2SO) δ 1.53 (br s, 2H), 1.76 (br s, 4H), 2.07 (br s, 2H), 2.66-2.74 (m, 3H), 2.96 (br s, 6H), 3.07-3.23 (m, 1H), 3.63 (br s, 1H), 3.61-3.75 (2×s, m, 6H), 4.16-4.37 (m, 5H), 5.42 (dd, J = 10.0, 5.4 Hz, 1H), 6.67-6.95 (m, 3H), 7.58-7.69 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 8.67 (dd, J = 7.5 Hz, 1H), 8.99 (d, J = 4.3 Hz, 1H), 9.11 (br t, J = 5.9 Hz, 1H), 9.35 (br t, J = 6.4 Hz, 1H), 10.20 (br s, 1H); a 1H NMR ((CD₃)₂SO) δ 2.12 (s, 6H), 3.12 (s, 9H), 3.82-3.92 (m, 2H), 4.24- 4.44 (m, 2H), 5.46 (dd, J = 9.6, 6.1 Hz, 1H), 7.03-7.11 (m, 3H), 7.47 (dd, J = 9.2, 2.7 Hz, 1H), 7.52 (d, J = 4.3 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 8.83 (d, J = 4.3 Hz, 1H), 9.07 (t, J = 5.8 Hz, 1H), 9.29 (t, J = 6.2 Hz, 1H); b 1H NMR ((CD₃)₂SO) δ 3.07 (s, 6H), 3.72 (s, 9H), 4.04-4.18 (m, 2H), 4.24- 4.38 (m, 4H), 5.45 (dd, J = 9.9, 5.5 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.3, 1.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 9.2, 2.7 Hz, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.80 (d, J = 4.3 Hz, 1H), 9.06 (t, J = 5.9 Hz, 1H), 9.34 (t, J = 6.3 Hz, 1H); c 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 2.14-2.21 (m, 4H), 2.70-3.02 (m, 4H), 3.11 (s, 3H), 3.56- 3.62 (m, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 3.71-3.86 (m, 3H), 4.09-4.44 (m, 4H), 5.46 (dd, J = 9.2, 5.6 Hz, 1H), 6.78 (dd, J = 8.2, 1.7 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 8.82 (d, J = 4.4 Hz, 1H), 9.04 (t, J = 6.0 Hz, 1H), 9.33 (t, J = 6.3 Hz, 1H); d 1H NMR ((CD3)2SO) δ 1.39-1.63 (m, 4H), 1.64-1.80 (m, 2H), 1.82-1.95 (m, 2H), 2.04-2.24 (m, 3H), 2.26-2.45 (m, 3H), 2.49-2.73 (m, 2H), 3.30 (s, 3H), 3.60-3.81 (m, 2H), 3.86-4.03 (m, 2H), 4.12-4.41 (m, 3H), 4.75- 4.95 (m, 2H), 6.16-6.33 (m, 1H), 7.06 (td, J = 7.6, 1.7 Hz, 1H), 7.33 (qd, J = 8.0, 1.9 Hz, 2H), 7.47-7.58 (m, 1H), 7.66 (dd, J = 7.7, 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.2 Hz, 1H), 7.98-8.13 (m, 2H), 8.77-8.90 (m, 1H);e 1H NMR ((CD3)2SO) δ 1.64 (s, 3H), 1.81 (s, 3H), 2.06 (d, J = 22.3 Hz, 2H), 2.26 (s, 2H), 3.06 (s, 3H), 3.15 (d, J = 5.7 Hz, 2H), 3.55 (d, J = 8.2 Hz, 2H), 3.75 (d, J = 5.2 Hz, 1H), 3.84 – 4.00 (m, 1H), 4.09 – 4.38 (m, 6H), 5.59 (dd, J = 5.9, 9.8 Hz, 1H), 7.39 – 7.56 (m, 5H), 7.78 – 8.20 (m, 6H), 8.51 (d, J = 4.7 Hz, 1H), 8.80 (d, J = 4.6 Hz, 1H), 10.94 (d, J = 32.9 Hz, 1H); f 1H NMR ((CD3)2SO) δ 2.07 (p, J = 8.0, 7.2 Hz, 2H), 2.64-2.77 (m, 3H), 2.79-3.04 (m, 1H), 3.10 (s, 9H), 3.38-3.41 (m, 2H), 3.64 (br s, 1H), 3.60- 3.76 (2×s, 6H), 4.15-4.36 (m, 5H), 5.42 (dd, J = 10.0, 5.3 Hz, 1H), 6.74- 6.95 (m, 3H), 7.54-7.70 (m, 2H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 8.66 (dd, J = 7.8, 1.2 Hz, 1H), 9.00 (d, J = 4.3 Hz, 1H), 9.10 (br t, J = 6.0 Hz, 1H), 9.34 (t, J = 6.3 Hz, 1H), 10.28 (s, 1H); g 1H NMR ((CD₃)₂SO) δ 2.23-2.41 (m, 1H), 2.61-2.77 (m, 1H), 2.84-2.92 (m, 2H), 3.09 (s, 9H), 3.56-3.62 (m, 2H), 3.63 (br s, 1H), 3.66-3.74 (m, 6H), 3.83 (t, J = 5.7 Hz, 2H), 3.91 (br s, 2H), 4.14-4.36 (m, 5H), 5.42 (dd, J = 9.9, 5.3 Hz, 1H), 6.74-6.96 (m, 3H), 7.54-7.67 (m, 2H), 7.94 (dd, J = 8.5, 1.3 Hz, 1H), 8.66 (dd, J = 16.6, 8.1 Hz, 1H), 9.00 (d, J = 4.3 Hz, 1H), 9.13 (t, J = 5.9 Hz, 1H), 10.30 (br s, 1H), 10.35 (br s, 1H);h 1H NMR ((CD₃)₂SO) δ 2.09 (p, J = 8.0, 7.2 Hz, 2H), 2.56-2.52 (m, 1H), 2.70-2.77 (m, 2H), 2.89-3.00 (m, 1H), 3.19 (s, 3H), 3.46-3.52 (m, 4H), 3.53-3.58 (m, 2H), 3.63 (br s, 1H), 3.67-3.74 (2×s, 6H), 4.12-4.34 (m, 5H), 5.42 (dd, J = 10.0, 5.4 Hz, 1H), 6.76-6.92 (m, 3H), 7.60 (t, J = 8.2 Hz, 1H), 7.65 (d, J = 4.3 Hz, 1H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 8.65 (d, J = 7.5 Hz, 1H), 9.00 (d, J = 4.3 Hz, 1H), 9.09 (br t, J = 6.0 Hz, 1H), 9.33 (br t, J = 6.4 Hz, 1H), 10.27 (br s, 1H); i 1H NMR ( (CD₃)₂SO) δ 1.50-1.60 (m, 2H), 1.76-1.86 (m, 4H), 2.01-2.11 (m, 3H), 2.18-2.40 (m, 1H), 2.67-2.77 (m, 2H), 3.05 (s, 3H), 3.21-3.60 (m, 4H), 3.63 (br s, 1H), 3.67-3.73 (2×s, 6H), 4.14-4.47 (m, 5H), 5.42 (dd, J = 10.0, 5.4 Hz, 1H), 6.74-6.96 (m, 3H), 7.56-7.71 (m, 2H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 8.65 (d, J = 7.5 Hz, 1H), 9.00 (d, J = 4.3 Hz, 1H), 9.12 (t, J = 6.0 Hz, 1H), 9.35 (t, J = 6.4 Hz, 1H), 10.26 (s, 1H);0 1H NMR ((CD₃)₂SO) δ 1.95-2.24 (m, 4H), 2.83-3.01 (m, 2H), 3.12 (s, 6H), 3.68 (s, 3H), 3.69 (s, 3H), 3.69-3.74 (m, 2H), 4.09-4.44 (m, 4H), 5.45 (dd, J = 9.3, 5.6 Hz, 1H), 5.48 (d, J = 45.0 Hz, 2H), 6.78 (dd, J = 8.1, 1.9 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 4.3 Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 8.83 (d, J = 4.3 Hz, 1H), 9.04 (t, J = 6.0 Hz, 1H), 9.32 (t, J = 6.3 Hz, 1H);4a 1H NMR ((CD₃)₂SO) δ 2.36 (s, 6H), 3.69 (s, 6H), 3.70-3.75 (m, 2H), 4.07- 4.18 (m, 2H), 4.20-4.37 (m, 2H), 5.25 (dd, J = 9.0, 4.8 Hz, 1H), 6.89 (dd, J = 8.2, 2.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.55 (dd, J = 9.3, 2.7 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 8.78 (d, J = 4.3 Hz), 8.95 (t, J = 5.9 Hz), 9.19 (t, J = 6.3 Hz, 1H); b 1H NMR ((CD3)2SO) δ 1.39(s, 9H), 1.78-2.05(m, 5H), 2.19-2.28 (m, 1H), 3.61-3.64 (m, 4H), 3.69 (s, 3H), 3.70 (s, 3H), 3.71-3.74(m, 2H),4.01- 4.19(m, 4H), 4.21-4.25 (m, 2H), 4.27(t, J = 6.1 Hz, 2H), 5.25 (dd, J = 9.1, 4.8 Hz, 1H), 6.78 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 7.42(dd, J = 9.2, 2.8 Hz, 1H), 7.48(d, J = 4.3 Hz, 1H), 7.85(d, J = 2.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.78(d, J = 4.3 Hz, 1H), 8.94(t, J = 6.0 Hz, 1H), 9.18 (t, J = 6.4 Hz, 1H); c 1H NMR ((CD3)2SO) δ 1.38 (s, 9H), 1.75-1.93 (m, 3H), 1.94-2.07 (m, 2H), 2.22-2.39 (m, 4H), 3.65 (t, J = 6.6 Hz, 2H), 3.82-4.26 (m, 6H), 5.20 (dd, J = 9.0, 4.9 Hz, 1H), 6.08 (d, J = 6.4 Hz, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.45 (dd, J = 9.2, 2.6 Hz, 1H), 7.47 (d, J = 4.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.77 (d, J = 4.3 Hz, 1H), 8.91 (t, J = 5.9 Hz, 1H), 10.13 (t, J = 6.4 Hz, 1H); d 1H NMR ((CD3)2SO) δ 1.79-1.89 (m, 2H), 1.92-2.05 (m, 3H), 2.19-2.29 (m, 1H), 2.34 (s, 6H), 2.61 (t, J = 7.4 Hz, 2H), 3.67 (t, J = 7.2 Hz, 2H), 4.07-4.18 (m, 3H), 4.22-4.31 (m, 3H), 5.24 (dd, J = 9.1, 4.7 Hz, 1H), 5.96 (s, 2H), 6.74 (dd, J = 7.8, 1.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 9.3, 2.8 Hz, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 8.79(d, J = 4.3 Hz, 1H), 8.95 (t, J = 6.0 Hz, 1H), 9.22 (t, J = 6.4 Hz, 1H) e 1H NMR ((CD₃)₂SO) δ 1.39 (s, 9H), 1.79-1.96 (m, 5H), 1.98-2.05 (m, 1H), 2.31 (t, J = 5.1 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 3.67 (t, J = 6.9 Hz, 2H), 3.98-4.15 (m, 4H), 4.16-4.32 (m, 4H), 5.24 (dd, J = 9.1, 4.6 Hz, 1H), 5.96 (s, 2H), 6.74 (dd, J = 8.0, 1.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 7.42 (dd, J = 9.2, 2.7 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 8.78(d, J = 4.3 Hz, 1H), 8.94 (t, J = 6.0 Hz, 1H), 9.20 (t, J = 6.4 Hz, 1H) f 1H NMR ((CD₃)₂SO) δ 1.39 (s, 9H), 1.75-2.05 (m, 6H), 2.20-2.37 (m, 4H), 3.20-3.37 (m, 4H), 3.67 (t, J = 6.9 Hz, 2H), 4.00-4.14 (m, 4H), 4.15 (dd, J = 16.9, 6.1 Hz, 1H), 4.26 (dd, J = 16.9, 6.1 Hz, 1H), 4.33 (t, J = 7.2 Hz, 2H), 5.23 (dd, J = 9.1, 4.7 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.17 (t, J = 74.8 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.43 (dd, J = 9.3, 2.7 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.94 (t, J = 6.0 Hz, 1H), 9.29 (t, J = 6.3 Hz, 1H); g 1H NMR ((CD3)2SO) δ 1.28 (t, J = 7.2 Hz, 6H), 1.39 (s, 9H), 1.72-1.88 (m, 2H), 1.87-2.07 (m, 4H), 3.46-3.62 (m, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.98- 4.06 (m, 4H), 4.07-4.12 (m, 2H), 4.14 (t, J = 5.9 Hz, 2H), 5.22 (dd, J = 9.1, 4.7 Hz, 1H), 7.43 (dd, J = 9.2, 2.7 Hz, 1H), 7.48 (d, J = 4.4 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.94 (t, J = 6.0 Hz, 1H), 9.03 (t, J = 6.3 Hz, 1H); h 1H NMR ((CD₃)₂SO) δ 1.40 (s, 9H), 1.49-1.59 (m, 1H), 1.69-2.06 (m, 8H), 2.17-2.28 (m, 1H), 2.44 (t, J = 7.1 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 3.55- 3.62 (m, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.70-3.82 (m, 2H), 3.92 (t, J = 6.4 Hz, 2H), 4.09-4.13 (m, 2H), 4.15 (dd, J = 16.8, 6.1 Hz, 1H), 4.26 (dd, J = 16.8, 6.1 Hz, 1H), 5.24 (dd, J = 9.2, 4.5 Hz, 1H), 7.42 (dd, J = 9.2, 2.7 Hz, 1H), 7.47 (d, J = 4.3 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.94 (t, J = 5.9 Hz, 1H); i 1H NMR ((CD3)2SO) δ 1.39 (s, 9H), 1.74-2.16 (m, 4H), 2.43 (t, J = 7.1 Hz, 2H), 3.28-3.35 (m, 2H), 3.67 (t, J = 6.4 Hz, 2H), 4.00-4.21 (m, 5H), 4.26 (dd, J = 16.8, 6.1 Hz, 1H), 4.36-4.48 (m, 3H), 5.23 (dd, J = 9.2, 4.5 Hz, 1H), 7.03 (s, 1H), 7.43 (dd, J = 9.2, 2.6 Hz, 1H), 7.48 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.28 (s, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.94 (t, J = 5.8 Hz, 1H), 9.25 (t, J = 5.9 Hz, 1H); j 1H NMR (CDCl3) δ 1.96-2.19 (m, 7H), 2.48 (q, J = 5.4 Hz, 5H), 3.64-3.83 (m, 8H), 4.22-4.39 (m, 2H), 4.48 (dd, J = 17.6, 5.0 Hz, 1H), 7.36-7.48 (m, 5H), 7.54 (dd, J = 8.8, 2.2 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.70- 7.78 (m, 4H), 8.00 (d, J = 9.2 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 4.4 Hz, 1H), 9.08 (s, 1H); k 1H NMR (CDCl₃) δ 1.39-1.50 (m, 2H), 1.60 (p, J = 5.7 Hz, 4H), 2.07 (dt, J = 36.9, 6.1 Hz, 4H), 2.42-2.58 (m, 8H), 3.61-3.78 (m, 2H), 4.10 (t, J = 6.2 Hz, 2H), 4.30 (dd, J = 17.6, 4.1 Hz, 1H), 4.46 (dd, J = 17.6, 5.0 Hz, 1H), 5.49 (dd, J = 8.5, 4.6 Hz, 1H), 7.31-7.46 (m, 5H), 7.56 (dd, J = 8.8, 2.2 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.66-7.83 (m, 3H), 7.97 (d, J = 9.2 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 4.4 Hz, 1H), 9.17 (s, 1H);l 1H NMR (MeOD) δ 1.75 (p, J = 7.5 Hz, 3H), 1.97 (d, J = 5.6 Hz, 6H), 2.38- 2.50 (m, 3H), 3.52 (p, J = 5.4 Hz, 6H), 3.67-3.80 (m, 2H), 3.86 (d, J = 9.7 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 4.69-4.76 (m, 4H), 6.06-6.16 (m, 1H), 7.39-7.65 (m, 2H), 7.95-8.12 (m, 4H), 8.14 (d, J = 2.8 Hz, 1H), 8.47-8.57 (m, 1H), 8.81 (d, J = 4.4 Hz, 1H), 9.25-9.34 (m, 1H); m 1H NMR (CDCl3) δ 1.91-2.19 (m, 8H), 2.48-2.57 (m, 2H), 3.73 (dt, J = 16.9, 3.0 Hz, 6H), 3.93-4.21 (m, 4H), 4.42 (dd, J = 17.7, 5.1 Hz, 1H), 6.10 (dd, J = 32.5, 6.6 Hz, 2H), 6.17-6.24 (m, 1H), 7.34-7.62 (m, 5H), 7.81-7.93 (m, 2H), 8.00-8.08 (m, 2H), 8.75 (d, J = 4.4 Hz, 1H); n 1H NMR (MeOD) δ 1.75 (p, J = 7.5 Hz, 3H), 1.97 (d, J = 5.6 Hz, 6H), 2.38- 2.50 (m, 3H), 3.52 (p, J = 5.4 Hz, 6H), 3.67-3.80 (m, 2H), 3.86 (d, J = 9.7 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 4.69-4.76 (m, 4H), 6.06-6.16 (m, 1H), 7.39-7.65 (m, 2H), 7.95-8.12 (m, 4H), 8.14 (d, J = 2.8 Hz, 1H), 8.47-8.57 (m, 1H), 8.81 (d, J = 4.4 Hz, 1H), 9.25-9.34 (m, 1H)o 1H NMR (CDCl3) δ 2.11-2.18 (m, 2H), 2.26-2.35 (m, 2H), 2.51 (bs, 5H), 2.56-2.61 (m, 3H), 3.75 (q, J = 5.2 Hz, 5H), 4.11-4.18 (m, 3H), 4.20- 4.28 (m, 2H), 4.50 (s, 2H), 4.59 (dd, J = 15.1, 6.5 Hz, 1H), 7.40-7.46 (m, 3H), 7.48-7.54 (m, 1H), 8.05 (ddt, J = 7.5, 5.9, 3.9 Hz, 2H), 8.41 (dd, J = 8.4, 1.4 Hz, 1H), 8.55-8.57 (m, 1H), 8.76 (dd, J = 4.5, 1.4 Hz, 1H), 8.81 (td, J = 4.4, 3.6 Hz, 2H) p 1H NMR (CD3OD) δ 1.41 (s, 9H), 1.85-2.20 (m, 5H), 2.26-2.34 (m, 1H), 2.67 (t, J = 7.4 Hz, 2H), 3.14-3.20 (m, 2H), 3.65-3.74 (m, 4H), 3.75 (s, 3H), 3.76 (s, 3H), 4.23-4.35 (m, 2H), 4.35-4.44 (m, 1H), 5.34 (dd, J = 9.0, 4.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 7.51 (br t, J = 8.2 Hz, 1H), 7.59 (d, J = 4.3 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 8.63 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.3 Hz, 1H) q 1H NMR (CD₃OD) δ 1.73-1.89 (m, 4H), 1.97 (p, J = 7.4 Hz, 2H), 2.29 (s, 6H), 2.52 (br t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 3.73 (s, 6H), 3.77-3.76 (m, 2H), 4.22-4.45 (m, 2H), 5.34 (dd, J = 9.2, 4.6 Hz, 1H), 6.76-6.98 (m, 3H), 7.54 (br t, J = 8.2 Hz, 1H), 7.62 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 8.65 (d, J = 7.8 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H) r 1H NMR (CD₃OD) δ 1.74-1.93 (m, 2H), 2.00 (p, J = 7.2 Hz, 2H), 2.20-2.39 (m, 2H), 2.44 (s, 6H), 2.61-2.69 (m, 4H), 3.70 (s, 3H), 3.72-3.77 (m, 2H), 3.79 (s, 6H), 4.22-4.47 (m, 2H), 5.35 (dd, J = 8.9, 4.6 Hz, 1H), 6.62 (s, 2H), 7.53 (br t, J = 8.2 Hz, 1H), 7.62 (d, J = 4.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H)s 1H NMR (CD₃OD) δ 1.44(s, 9H), 1.78-1.91(m, 2H), 1.97(p, J = 7.2 Hz, 2H), 2.03-2.13(m, 2H), 2.41 (br t, J = 5.1 Hz, 4H), 2.47(t, J = 7.2 Hz, 2H), 2.63(t, J = 7.2 Hz, 2H), 3.26-3.56 (m, 4H), 3.77 (s, 6H), 4.23- 4.46(m, 4H), 5.34(d, J = 9.0, 4.6 Hz, 1H), 6.83-7.00 (m, 3H), 7.54(br t, J = 8.2 Hz, 1H), 7.63(d, J = 4.3 Hz, 1H), 7.98(d, J = 8.6 Hz, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H) t 1H NMR (CD₃OD) δ 1.44(s, 9H), 1.76-1.90 (m, 2H), 1.96(p, J = 7.2 Hz, 2H), 2.02-2.14 (m, 2H), 2.41(br t, J = 5.1 Hz, 4H), 2.47(t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 3.35-3.42 (m, 4H), 3.71 (s, 3H), 3.78(s, 3H), 4.20-4.48(m, 4H), 5.38(d, J = 9.0, 4.6 Hz, 1H), 6.62(s, 2H), 7.54(t, J = 8.2 Hz, 1H), 7.62 (d, J = 4.3 Hz, 1H), 7.97(d, J = 8.6 Hz, 1H), 8.67(d, J = 7.7 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H) u 1H NMR ((CD3)2SO) δ 1.39 (s, 9H), 1.74-2.16 (m, 4H), 2.43 (t, J = 7.1 Hz, 2H), 3.28-3.35 (m, 2H), 3.67 (t, J = 6.4 Hz, 2H), 4.00-4.21 (m, 5H), 4.26 (dd, J = 16.8, 6.1 Hz, 1H), 4.36-4.48 (m, 3H), 5.23 (dd, J = 9.2, 4.5 Hz, 1H), 7.03 (s, 1H), 7.43 (dd, J = 9.2, 2.6 Hz, 1H), 7.48 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 8.28 (s, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.94 (t, J = 5.8 Hz, 1H), 9.25 (t, J = 5.9 Hz, 1H)a 1H NMR ((CD3)2SO) δ 1.92-2.07 (m, 2H), 2.10-2.22 (m, 2H), 3.08 (s, 6H), 3.69 (s, 9H), 4.01-4.15 (m, 2H), 4.18-4.34 (m, 4H), 5.27 (dd, J = 9.2, 4.8 Hz, 1H), 6.77 (d, J = 8.2 Hz), 6.86 (dd, J = 8.2, 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 9.2, 2.7 Hz, 1H), 7.50 (d, J = 4.3 Hz, 1H), 7.88 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 8.81 (d, J = 4.3 Hz), 8.97 (t, J = 5.9 Hz), 9.22 (t, J = 6.3 Hz, 1H) b 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 1.78-2.08 (m, 4H), 2.13-2.29 (m, 2H), 3.11 (s, 3H), 3.53-3.62 (m, 4H), 3.69 (s, 3H), 3.70 (s, 3H), 3.72-3.74 (m, 2H), 4.05 (t, J = 7.2 Hz, 1H), 4.11-4.19 (m, 3H), 4.23-4.33 (m, 4H), 5.27 (dd, J = 9.0, 4.8 Hz, 1H), 6.77 (dd, J = 8.2, 1.8 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 9.2, 2.7 Hz, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.87 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.81 (d, J = 4.3 Hz, 1H), 8.98 (t, J = 5.9 Hz, 1H), 9.23 (t, J = 6.3 Hz, 1H)c 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 1.75-2.06 (m, 4H), 2.19-2.28 (m, 2H), 3.11 (s, 3H), 3.56-3.70 (m, 4H), 3.92 (t, J = 7.2 Hz, 1H), 3.95-4.08 (m, 3H), 4.12 (dd, J = 15.6, 6.4 Hz, 1H), 4.26 (dd, J = 16.9, 5.9 Hz, 1H), 4.33-4.58 (m, 2H), 5.23 (dd, J = 9.0, 4.9 Hz, 1H), 6.08 (d, J = 6.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.46 (dd, J = 9.3, 2.9 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.9 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.80 (d, J = 4.3 Hz, 1H), 8.93 (t, J = 5.9 Hz, 1H), 9.69 (t, J = 6.4 Hz, 1H) d 1H NMR ((CD3)2SO) δ 1.77-2.05 (m, 4H), 2.13-2.30 (m, 2H), 3.09 (s, 9H), 3.43-3.53 (m, 3H), 3.65-3.72 (m, 1H), 4.03 (t, J = 7.2 Hz, 1H), 4.12-4.19 (m, 1H), 4.23-4.34 (m, 3H), 5.27 (dd, J = 9.0, 4.7 Hz, 1H), 5.96 (s, 2H), 6.74 (dd, J = 8.1, 1.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 8.97 (d, J = 6.0 Hz, 1H), 9.24 (t, J = 6.4 Hz, 1H) e 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 1.72-1.90 (m, 2H), 1.93-2.07 (m, 2H), 2.14-2.30 (m, 2H), 3.12 (s, 3H), 3.54-3.78 (m, 6H), 4.03 (t, J =7.2 Hz, 2H), 4.09-4.18 (m, 2H), 4.23-4.34 (m, 2H), 5.27 (dd, J = 9.0, 4.7Hz, 1H), 5.96(s, 2H), 6.74 (dd, J = 8.1, 1.7Hz, 1H), 6.83(d, J = 8.1Hz, 1H), 6.84(d, J = 1.7Hz, 1H), 7.46(dd, J = 9.2, 2.8Hz, 1H), 7.51(d, J = 4.4Hz, 1H), 7.85(d, J = 2.8 Hz, 1H), 8.01(d, J = 9 Hz, 1H), 8.81(d, J = 4.4Hz, 1H), 8.97(t, J = 5.9Hz, 1H), 9.24 (t, J = 6.3Hz, 1H) f 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 1.80-2.06 (m, 2H), 2.16-2.28 (m, 4H), 3.12 (s, 3H), 3.56-3.62 (m, 3H), 3.66-3.77 (m, 3H), 3.95-4.06 (m, 4H), 4.15 (dd, J = 16.8, 6.1 Hz, 1H), 4.28 (dd, J = 16.8, 6.2 Hz, 1H), 4.34 (t, J = 7.2 Hz, 2H), 5.26 (dd, J = 9.1, 4.7 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.17 (t, J = 74.4 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.46 (dd, J = 9.3, 2.7 Hz, 1H), 7.52 (d, J = 4.3 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.82 (d, J = 4.3 Hz, 1H), 8.98 (t, J = 6.0 Hz, 1H), 9.33 (t, J = 6.3 Hz, 1H) g 1H NMR ((CD₃)₂SO) δ 1.21 (t, J = 7.1 Hz, 6H), 1.43 (s, 9H), 1.74-1.94 (m, 2H), 1.95-2.12 (m, 2H), 2.13-2.64 (m, 2H), 3.15 (s, 3H), 3.42-3.51 (m, 4H), 3.55-3.72 (m, 6H), 4.08 (q, J = 7.1 Hz, 4H), 4.19 (t, J = 6.4 Hz, 2H), 4.29 (dd, J =16.8, 6.2 Hz, 1H), 5.26 (dd, J = 9.2, 4.5 Hz, 1H), 7.49 (dd, J = 9.2, 2.8 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.91 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 8.85 (d, J = 4.4 Hz, 1H), 9.02 (t, J = 5.8 Hz, 1H), 9.03 (t, J = 6.3 Hz, 1H) h 1H NMR ((CD₃)₂SO) δ 1.43 (s, 9H), 1.73-1.95 (m, 4H), 1.98-2.06 (m, 2H), 2.15-2.37 (m, 6H), 3.14 (s, 3H), 3.16-3.24 (m, 2H), 3.56-3.65 (m, 4H), 3.70-3.82 (m, 2H), 3.84-3.97 (m, 4H), 4.08-4.13 (m, 2H), 4.15-4.22 (m, 1H), 4.28 (dd, J = 16.7, 6.1 Hz, 1H), 5.26 (dd, J = 9.1, 4.6 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 8.69 (t, J = 6.2 Hz, 1H), 8.81 (d, J = 4.3 Hz, 1H), 8.97 (t, J = 5.9 Hz, 1H) i 1H NMR ((CD3)2SO) δ 1.42 (s, 9H), 1.73-2.12 (m, 4H), 2.15-2.40 (m, 2H), 3.16 (s, 3H), 3.59-3.72 (m, 4H), 3.72-3.82 (m, 4H), 4.15 (dd, J = 16.8, 5.7 Hz, 1H), 4.28 (dd, J = 16.8, 6.0 Hz, 1H), 4.40-4.52 (m, 4H), 5.26 (dd, J = 9.1, 4.7 Hz, 1H), 7.03 (s, 1H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 8.29 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.97 (t, J = 5.9 Hz, 1H), 9.30 (t, J = 6.0 Hz, 1H) j 1H NMR ((CD3)2SO) δ 1.78-1.91 (m, 2H), 1.94-2.11 (m, 2H), 2.23-2.32 (m, 2H), 3.15 (s, 3H), 3.57-3.67 (m, 4H), 3.67 (s, 3H), 3.68 (s, 3H), 3.71- 3.74 (m, 2H), 4.04 (t, J = 7.2 Hz, 1H), 4.10-4.33 (m, 5H), 5.28 (dd, J = 9.2, 4.8 Hz, 1H), 6.76 (dd, J = 8.2, 1.9 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.46 (dd, J = 9.3, 2.8 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 9.3 Hz, 1H), 8.82 (d, J = 4.4 Hz, 1H), 8.98 (t, J = 6.0 Hz, 1H), 9.23 (t, J = 6.4 Hz, 1H) k 1H NMR ((CD3)2SO) δ 1.95-2.16 (m, 6H), 3.21 (td, J = 7.6, 4.3 Hz, 2H), 3.47-3.54 (m, 3H), 3.58 (dd, J = 7.8, 4.2 Hz, 2H), 3.75 (q, J = 6.4 Hz, 4H), 3.82 (p, J = 4.2 Hz, 3H), 3.91-3.99 (m, 2H), 4.16 (t, J = 6.0 Hz, 1H), 4.22-4.31 (m, 2H), 4.66 (d, J = 8.3 Hz, 1H), 7.44-7.54 (m, 3H), 7.82- 8.01 (m, 7H), 8.51 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 10.90 (d, J = 7.6 Hz, 1H) l 1H NMR ((CD3)2SO) δ 1.51-1.69 (m, 4H), 1.80 (d, J = 13.5 Hz, 3H), 1.94- 2.10 (m, 3H), 2.21-2.35 (m, 2H), 2.86 (s, 1H), 2.89 (s, 4H), 3.05-3.10 (m, 2H), 3.16 (dt, J = 5.3, 9.2 Hz, 2H), 3.54-3.63 (m, 2H), 3.75 (q, J = 6.2 Hz, 1H), 3.99 (s, 1H), 4.21 (ddt, J = 6.2, 11.7, 32.8 Hz, 4H), 7.39- 7.56(m, 5H), 7.82-7.92(m, 3H), 7.92(s, 3H), 8.05-8.13(m, 1H), 8.49-8.55 (m, 1H), 10.91(s, 1H) m 1H NMR (MeOD) δ 1.75 (p, J = 7.5 Hz, 3H), 1.97 (d, J = 5.6 Hz, 6H), 2.38- 2.50 (m, 3H), 3.20 (d, J = 8.3 Hz, 3H), 3.52 (p, J = 5.4 Hz, 6H), 3.67- 3.80 (m, 2H), 3.86 (d, J = 9.7 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 4.69-4.76 (m, 4H), 6.06-6.16 (m, 1H), 7.39-7.65 (m, 2H), 7.95-8.12 (m, 4H), 8.14 (d, J = 2.8 Hz, 1H), 8.47-8.57 (m, 1H), 8.81 (d, J = 4.4 Hz, 1H), 9.25- 9.34 (m, 1H) n 1H NMR (DMSO) δ 1.95-2.16 (m, 6H), 3.21 (td, J = 7.6, 4.3 Hz, 2H), 3.47- 3.54 (m, 3H), 3.58 (dd, J = 7.8, 4.2 Hz, 2H), 3.75 (q, J = 6.4 Hz, 4H), 3.82 (p, J = 4.2 Hz, 3H), 3.91-3.99 (m, 2H), 4.16 (t, J = 6.0 Hz, 1H), 4.22-4.31 (m, 2H), 4.66 (d, J = 8.3 Hz, 1H), 7.44-7.54 (m, 3H), 7.82- 8.01 (m, 7H), 8.51 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 10.90 (d, J = 7.6 Hz, 1H) o 1H NMR (CD3OD) δ 1.79-1.95 (m, 2H), 2.02-2.12 (m, 4H), 2.63 (t, J = 7.1 Hz, 2H), 3.09 (s, 9H), 3.70 (s, 3H), 3.71 (s, 3H), 3.63-3.68 (m, 3H), 3.71- 3.75 (m, 1H), 4.15 (dd, J = 16.8, 5.9 Hz, 1H), 4.22-4.34 (m, 3H), 5.24 (dd, J = 9.1, 4.6 Hz, 1H), 6.79 (dd, J = 8.2, 1.8 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.91(d, J = 1.8Hz, 1H), 7.60(br t, J = 8.2 Hz, 1H), 7.63(d, J = 4.4 Hz, 1H), 7.98(d, J = 8.6 Hz, 1H), 8.66(d, J = 7.7Hz, 1H), 9.00(d, J = 4.4 Hz, 1H), 9.20(t, J = 6.4 Hz, 1H), 10.28 (s, 1H) p 1H NMR ((CD3)2SO) δ 1.80-1.98 (m, 2H), 2.08 (p, J = 7.2 Hz, 2H), 2.19- 2.31 (m, 2H), 2.68-2.76 (m, 4H), 3.10 (s, 9H), 3.62 (s, 3H), 3.64-3.72 (m, 2H), 3.77 (s, 6H), 4.16 (dd, J = 16.8, 5.9 Hz, 1H), 4.22-4.27 (m, 2H), 4.33 (dd, J = 14.8, 6.3 Hz, 1H), 5.25 (dd, J = 9.0, 4.6 Hz, 1H), 6.61 (s, 2H), 7.59 (br t, J = 8.2 Hz, 1H), 7.63 (d, J = 4.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.98 (t, J = 5.9 Hz, 1H), 9.01 (d, J = 4.3 Hz, 1H), 9.23 (t, J = 6.3 Hz, 1H), 10.27 (s, 1H) q 1H NMR ((CD3)2SO) δ 1.43 (s, 9H), 1.78-1.97 (m, 2H), 1.99-2.14 (m, 4H), 2.68-2.79 (m, 2H), 3.13 (s, 3H), 3.41-3.52 (m, 4H), 3.60-3.68 (m, 4H), 3.70 (s, 6H), 4.15 (dd, J = 16.8, 5.8 Hz, 1H), 4.22-4.37 (m, 3H), 5.24 (d, J = 9.1, 4.5 Hz, 1H), 6.79 (dd, J = 8.2, 2.1 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 7.61 (br t, J = 8.2 Hz, 1H), 7.63(d, J = 4.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.66(d, J = 7.6Hz, 1H), 9.00(d, J = 4.3Hz, 1H), 9.20 (t, J = 6.3Hz, 1H), 10.27 (s, 1H) r 1H NMR ((CD3)2SO) δ 1.43 (s, 9H), 1.75-2.13 (m, 6H), 2.76-2.86 (m, 2H), 3.13 (s, 3H), 3.42-3.47 (m, 4H), 3.57-3.64 (m, 4H), 3.68 (s, 3H), 3.72 (s, 6H), 4.15 (dd, J = 16.8, 5.9 Hz, 1H), 4.19-4.28 (m, 2H), 4.33 (dd, J = 14.8, 6.7 Hz, 1H), 5.25 (d, J = 9.0, 4.6 Hz, 1H), 6.61 (s, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.63 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H), 9.23 (t, J = 6.4 Hz, 1H), 10.27 (s, 1H) s 1H NMR (CD3)2SO) δ 1.15-1.34 (m, 2H), 1.60 (d, J = 33.9 Hz, 3H), 1.78 (d, J = 27.6 Hz, 3H), 2.18 (d, J = 31.5 Hz, 2H), 3.03 (d, J = 30.6 Hz, 2H), 3.21-3.59 (m, 11H), 4.20 (d, J = 37.5 Hz, 5H), 4.29 – 4.42 (m, 2H), 7.23 (td, J = 1.7, 7.6 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.67 – 7.75 (m, 2H), 7.99 (dd, J = 8.0, 13.1 Hz, 3H), 8.41 – 8.53 (m, 1H), 8.66 – 8.88 (m, 1H); 15t 1H NMR (DMSO) δ 1.21-1.30 (m, 2H), 1.90-2.03 (m, 3H), 2.26 (dt, J = 9.0, 15.3 Hz, 1H), 2.56-2.68 (m, 2H), 3.50 (q, J = 3.7 Hz, 4H), 3.61 (t, J = 4.8 Hz, 4H), 3.65-3.80 (m, 4H), 3.95 (q, J = 4.8 Hz, 3H), 4.16 (ddt, J = 6.0, 11.3, 23.1 Hz, 6H), 4.29-4.42 (m, 1H), 7.03-7.10 (m, 1H), 7.44- 7.51 (m, 1H), 7.67 (dt, J = 2.0, 8.4 Hz, 1H), 7.77-7.88 (m, 1H), 7.94- 8.05 (m, 2H), 8.42-8.51 (m, 1H), 8.75-8.86 (m, 2H); 16a 1H NMR ((CD₃)₂SO) δ 1.77-1.87 (m, 1H), 1.96-2.12 (m, 5H), 2.23 (s, 3H), 2.67-2.78 (m, 2H), 2.90 (t, J = 7.5 Hz, 2H), 3.58-3.68 (m, 2H), 3.70 (s, 6H), 3.72-3.79 (m, 2H), 4.11-4.33 (m, 2H), 5.24 (dd, J = 9.0, 4.5 Hz, 1H), 6.80 (dd, J = 8.2, 2.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.50(d, J = 8.0 Hz, 2H), 7.55 (d, J = 4.4 Hz, 1H), 7.59 (br t, J = 8.2 Hz, 1H), 7.98(dd, J= 8.6 Hz, 1H), 8.67(d, J = 7.6Hz, 1H), 8.99(d, J = 4.4Hz, 1H), 9.21 (t, J = 6.3Hz, 1H), 10.2(s, 1H) 16b 1H NMR ((CD3)2SO) δ 1.77-1.89 (m, 2H), 1.88-2.06 (m, 2H), 2.15-2.25 (m, 2H), 2.29 (s, 3H), 3.15 (s, 3H), 3.44-3.56 (m, 4H), 3.69 (s, 6H), 4.04 (t, J = 7.2 Hz, 1H), 4.10-4.19 (m, 3H), 4.23-4.34 (m, 4H), 5.28 (dd, J = 9.0, 4.7 Hz, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.38-7.44 (m, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.83-7.91 (m, 3H), 8.01 (d, J = 9.2 Hz, 1H), 8.82 (d, J = 4.3 Hz, 1H), 8.99 (t, J = 5.9 Hz, 1H), 9.24 (t, J = 6.3 Hz, 1H) Example 3. Biochemical evaluation of compounds In order evaluate the specificity and selectivity of the compounds of the invention, the compounds are evaluated as inhibitors of FAP, PREP, DPP4, DPP8, DPP9 and DPP2. a) Used enzymes in these assays: • A gateway-entry clone for human FAP was purchased from Dharmacon (Accession number DQ891423) and the human secretion signal was replaced with the HoneyBee mellitin secretion signal. For transfection and expression of FAP in Sf9 insect cells the C-terminal BaculoDirect kit from LifeTechnologies was used. The enzyme was purified from the supernatant of the insect cells using immobilized Ni-chelating chromatography (GE healthcare, Diegem, Belgium), followed by anion-exchange chromatography using a 1 mL HiTrap Q and size exclusion chromatography using the Superdex 200 column (GE healthcare, Diegem, Belgium). • Human recombinant PREP was expressed in BL21(DE3) cells and purified using immobilized Co-chelating chromatography (GE healthcare), followed by anion- exchange chromatography on a 1 ml Mono Q column (GE healthcare). • DPP4 was purified from human seminal plasma. • Gateway-entry clones for human DPP8 and DPP9 were purchased from Dharmacon (Accession numbers DQ891733 and DQ892325 respectively). For transfection and expression of DPP8 and DPP9 in Sf9 insect cells the N-terminal BaculoDirect kit from LifeTechnologies was used. The enzymes were purified using immobilized Ni-chelating chromatography (GE healthcare, Diegem, Belgium), followed by anion-exchange chromatography using a 1 mL Mono Q (GE healthcare, Diegem, Belgium). b) IC50 measurements: • For FAP: IC50 measurement of the probes was performed using Z-Gly-Pro-7- amino-4-methylcoumarine (AMC) (Bachem) as the substrate at a concentration of 50 µM at pH 8 (0.05 M Tris-HCl buffer, 1 mg/mL BSA and 140 mM NaCl). Eight concentrations of inhibitors/probe were tested. The final DMSO concentration was kept constant during the experiment to exclude any effects. Inhibitors were pre- incubated with the enzyme for 15 minutes at 37 °C, afterwards the substrate was added and the velocities of AMC release were measured kinetically at λex= 380 nm, λem= 465 nm for at least 10 minutes at 37 °C. Measurements were executed on the Infinite 200 (Tecan Group Ltd.) and the Magellan software was used to process the data. • For PREP: IC₅₀ measurements of the probes were carried out using N-succinyl-Gly-Pro-AMC (Bachem) as the substrate at a concentration of 250 µM at pH 7.4 (0.1 M K- phosphate, 1 mM EDTA, 1 mM DTT and 1 mg/mL BSA). Eight concentrations of inhibitors were tested. The final DMSO concentration in kept constant during the experiment to exclude any effects. Inhibitors were pre-incubated with the enzyme for 15 minutes at 37 °C, afterwards the substrate was added and the velocities of AMC release were measured kinetically at λex= 380 nm, λem= 465 nm for at least 10 minutes at 37 °C. Measurements were done on the Infinite 200 (Tecan Group Ltd.) and the Magellan software was used to process the data. ^ For DPP4, DPP8 and DPP9 IC50-values were determined using Ala-Pro-paranitroanilide (pNA) as the substrate at the respective final concentrations of 25 µM (DPP4), 300 µM (DPP8) or 150 µM (DPP9) at pH 7.4 (0.05 M HEPES-NaOH buffer with 0.1 % Tween-20, 0.1 mg/mL BSA and 150 mM NaCl). At least eight different inhibitor concentrations were used. The final DMSO concentration is kept constant during the experiment to exclude any effects. Inhibitors were pre-incubated with the enzyme for 15 minutes at 37 °C, afterwards the substrate was added and the velocities of pNA release were measured kinetically at 405 nm for at least 10 minutes at 37 °C. Measurements were done on the Infinite 200 (Tecan Group Ltd.) and the Magellan software was used to process the data. c) IC50 results: The specificity of reference molecule 1 (WO2021197519A1) was tested by comparing its inhibitory effect on FAP, PREP, DPP4, DPP8 and DPP9 activity to that of the reference molecule UAMC1110. While reference molecule 1 showed to be a very efficient FAP inhibitor (IC₅₀ = 0.43 ± 0.02 nM) compared to DPP4, DPP8 and DPP9 (IC₅₀ >1 µM, > 1µM and >10 µM respectively), reference molecule 1was shown to be an efficient PREP inhibitor as well (IC50 = 0.6 ± 0.00 µM). Interestingly, the novel FAP inhibitors as described herein showed an increased selectivity towards FAP. While the novel FAP inhibitors have an IC₅₀ for FAP that is similar to the reference molecule 1, the IC50 for PREP was significantly higher, more particular a factor 15 to 100 times higher than that of reference molecule 1. Hence, the herein described compounds are significantly more selective for FAP (Table 3). Table 3. Selectivity of the FAP-inhibitors for FAP, PREP, DPP4, DPP8 and DPP9 as indicated by the IC50 values in nM for FAP and PREP and in µM for DPP4, DPP8, DPP9. PREP IC50 IC50 (µM) FAP IC50 Cpd (nM) (nM) DPP4 DPP8 DPP9 UAMC- 0.43± 0.02 1800 ± 0.01 >10 >10 4.70± 0.40 1110 1 1 0.41 ± 0.00 0.600 ± 0.00 >1 >1 >10 2 8b 1.85 ± 0.30 57.5 ± 4.40 >1 >10 >10 3 8c 5.40 ± 1.0 120 ± 10.0 0.624 ± >1 >10 0.030 4 8d 12.0 ± 3.0 210 ± 50.0 >1 >1 >1 5 8g 0.78 ± 0.10 - - - - 6 8h 0.83 ± 0.11 - - - - 7 8i 0.89 ± 0.14 - - - - 8 8j 0.81 ± 0.12 - - - - 9a 51.1 ± 12.1 160 ± 0.02 >10 >10 >10 9b 3.04 ± 0.45 83.1 ± 7.10 >1 >10 >10 9c 1.50 ± 0.22 107 ± 15.9 - - - 9e 4.91 ± 0.58 - - - - 9f 0.48 ± 0.07 - - - - 9g 0.77 ± 0.10 - - - - 9h 0.58 ± 0.06 - - - - 9i 0.67 ± 0.10 - - - - 10 2.44 ± 0.22 121 ± 18.7 - - - 14a 1.10 ± 0.37 13.3 ± 1.40 >1 >10 >10 14b 1.31 ± 0.04 94.0 ± 3.00 >1 >10 >10 14c 3.00 ± 0.40 170 ± 40.0 >1 >1 >10 14d 1.15 ± 0.15 - - - - 14e 3.94 ± 0.78 - - - - 14f 3.09 ± 0.64 - - - - 14g 2.25 ± 0.34 32.7 ± 4.56 - - - 14h 0.89 ± 0.13 - - - - 14i 0.74 ± 0.15 - - - - 14k 10.2 ± 1.19 - - - - 14n 5.75 ± 0.65 - - - - 14o 1.56 ± 0.15 - - - - 14q 0.79 ± 0.11 - - - - 14r 0.76 ± 0.10 - - - - 14s 2.48 ± 0.46 - - - - 14t 2.78 ± 0.43 - - - - 14u 0.78 ± 0.17 - - - - 15a 1.62 ± 0.21 15.2 ± 0.90 >1 >10 >10 15b 0.48 ± 0.14 10.0 ± 4.00 >1 >10 >10 15c 1.20 ± 0.40 61 ± 7.00 >1 >10 >10 15d 1.05 ± 0.08 - - - - 15e 0.77 ± 0.13 - - - - 40 15f 0.69 ± 0.09 - - - - 41 15g 0.78 ± 0.09 - - - - 42 15h 0.95 ± 0.13 - - - - 43 15i 0.60 ± 0.06 - - - - 44 15h 0.95 ± 0.13 - - - - 45 15j 0.48 ± 0.09 - - - - 46 15k 5.46 ± 0.52 - - - - 47 15l 5.87 ± 0.59 - - - - 48 15m 15.6 ± 3.01 102 ± 13.5 - - - 49 15n 7.25 ± 1.67 69.3 ± 9.20 - - - 50 15o 0.78 ± 0.10 - - - - 51 15p 0.54 ± 0.09 - - - - 52 15q 0.48 ± 0.06 - - - - 53 15r 0.37 ± 0.06 - - - - 54 16a 0.42 ± 0.05 - - - - 55 16b 0.97 ± 0.15 9.82 ± 1.51 - - - Additionally the selectivity index was calculated. The selectivity index as used herein is the ratio of two IC50-values. For example: the FAP-to-PREP selectivity index is defined as (IC₅₀(PREP)/IC₅₀(FAP)). In Table 3, the FAP-to-other enzyme selectivity indices are represented by the name of the other enzymes (PREP, DPP4, DPP8, DPP9). Hence, the selectivity index of PREP is IC50(PREP)/IC50(FAP). Compound 9c has thus a 71 higher specificity for FAP than for PREP (Table 4). Table 4. Selectivity indices of the FAP-inhibitors towards FAP over PREP, DPP4, DPP8 and DPP9 Selectivity indices Compound PREP DPP4 DPP8 DPP9 1 1.5 >2400 >2400 >24300 8b 31 >540 >5400 >5400 8c 21 >100 183 >1800 8d 17 >80 >80 >80 a 3 >190 >190 >190b 27 >320 >3200 >3200c 71 - - -0 50 - - - a 12 >900 >9000 >9000 b 72 >760 >7600 >7600 c 55 >330 >331 >3300 g 15 - - - a 9 >620 >6100 >6100 b 22 >2000 >20000 >20000 c 51 >800 >800 >8000m 7 - - - n 9 - - - b 10 - - -

Claims

CLAIMS 1. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof,

Formula I, wherein Y₁ and Y₂ are independently H or F, wherein Y3 comprises a ketoamide group, wherein a linker (Z) is covalently bound to the quinoline structure of said compound on position 6, 7 or 8, and characterized in that the linker comprises one or more ammonium ion groups.

2. The compound according to claim 1, wherein the linker (Z) comprises an oxygen or nitrogen by which the linker is covalently bound to the quinoline structure.

3. The compound according to any of claims 1-2, wherein the ammonium ion group is a quaternary ammonium cation.

4. The compound according to any of the preceding claims, wherein a radionuclide is covalently bound to the linker and wherein preferably the radionuclide is selected from the group of 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At.

5. The compound according to any of the preceding claims, wherein said linker has a molecular weight of maximal 1000 Da.

6. The compound according to any of the preceding claims, wherein said linker (Z) is selected from the group of

, wherein each R₁ is independently selected from the group consisting of -H, - CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2F, -CH2CH2F, -CH2CH2CH2F, -CH2CH2CH2CH2F, -CH2I, -CH2CH2I, -CH2CH2CH2I, and -CH2CH2CH2CH2I, wherein F is present as 18F and I as 120I, 122I, 123I, 124I, 125I or 131I, and wherein n₁, n₂, n₃, n₄, n₅, n₆, n₇, n₈ is independently 0-4.

7. The compound according to any of claims 1-5, wherein said linker (Z) is selected from the group consisting of

, , wherein each R₁ is independently selected from the group consisting of -H, - CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, -CH₂CH₂F, -CH₂CH₂CH₂F, -CH2CH2CH2CH2F, -CH2I, -CH2CH2I, -CH2CH2CH2I, -CH2CH2CH2CH2I, -COOCCH3 and COC6H6-R2, wherein R2 is selected I, F, At or B(OH)2, and wherein F is present as 18F and I as 120I, 122I, 123I, 124I, 125I or 131I, At as 211At and wherein n₉, n₁₀, n₁₁, n₁₂, n₁₃, n₁₄, n₁₅, n₁₆, n₁₇ is independently 0-4.

8. The compound according to any of claims 1-5, wherein said linker (Z) is selected from the group consisting of ,

, and , wherein each R1 is independently selected from the group consisting of -H, - CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH₂CH₂CH₂CH₃, -CH₂F, -CH₂CH₂F, -CH₂CH₂CH₂F, -CH₂CH₂CH₂CH₂F, -CH₂I, -CH₂CH₂I, -CH₂CH₂CH₂I, and -CH₂CH₂CH₂CH₂I, wherein F is present as 18F and I as 120I, 122I, 123I, 124I, 125I or 131I, and wherein n18, n19, n20, n21, n22, n23, n24, n25 is independently 0-4.

9. The compound according to any of claims 1-5, wherein said linker (Z) comprises an aromatic ring, optionally heterocyclic and 5-, 6- or 7-membered.

10. The compound according to any of claims 1-5 or 9, wherein said linker (Z) is selected from the group consisting of

each R₁ is independently selected from the group of: -H, -CH₃, CH₂CH₃, - CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; n₂₆, n₂₇, n₂₈, n₂₉, n₃₀, n₃₁, n₃₂, n₃₃ is independently 0-4; E is:

wherein each X₁, X₂, X₃, X₄ is independently selected from the group of C, O and N; t is independently 1, 2 or 3; each R₂ is independently selected from the group of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At; and each R3 is independently selected from the group consisting of guanidine, aminomethyl and dialkylaminomethyl.

11. The compound according to any of claims 1-5 or 9, wherein said linker (Z) is selected from the group consisting of ,

, wherein each R1 is independently selected from the group consisting of -H, -CH3, CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3; n₃₄, n₃₅, n₃₆, n₃₇, n₃₈, n₃₉ is independently 0-4; E is:

wherein each X₁, X₂, X₃, X₄ is independently selected from the group of C, O and N; t is independently 1, 2 or 3; each R₂ is independently selected from the group of: 18F, 120I, 122I, 123I, 124I, 125I, 131I and 211At; and each R3 is independently selected from the group of: guanidine, aminomethyl and dialkylaminomethyl.

12. The compound according to any of the preceding claims, wherein Y3 is

wherein Y4 is selected from the list consisting of H, D, C1-C10 alkyl, C3-C10 cycloalkyl, adamantly, substituted or unsubstituted aryl or C7-C20 alkylaryl, wherein the aryl is

wherein the * shows the position bound to the N of the keto-amide group, and wherein R4 and R8 are independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR9, wherein R9 is selected from the group consisting of H, D, halogen, and C1-C4 alkyl or C1-C2 alkyl, and wherein R5, R6 and R7 are independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy or C1-C2 alkoxy, -CF3, and - C(=O)-OR9,

wherein the * or the way line shows the position bound to the N of the keto- amide group, and wherein R17 is selected from the group consisting of -OR9, -NHR9 , -N(-CH3)R9, pyrrolidine, and morpholine, R15 and R16 are independently selected from the group consisting of H, D, C1- C5 alkyl, phenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dimethoxybenzyl, and unsubstituted C3-C8 heteroalkylaryl, R18 and R19 are independently selected from the group consisting of H, D, C1- C6 alkyl, phenyl, benzyl, 4-hydroxybenzyl, unsubstituted C3-C8 heteroalkylaryl, -(CH2)n-C(=C))-C)R20, -(CH2)n-C(=0)-NR21R22, and -(CH2)n-NR23R24, wherein n is an integer from 1 to 4, R20 is selected from the group consisting of H, D, C1-C3 alkyl, and benzyl, R21 and R22 are independently selected from the group consisting of H, D, C1- C3 alkyl, benzyl, and 3,4-dimethoxybenzyl, and R23 and R24 are independently selected from the group consisting of H, D, and (benzyloxy)carbonyl.

13. The compound according to any of the preceding claims 1-11, wherein Y3 is

wherein Y4 is selected from:

wherein the wavy line shows the position bound to the N of the keto-amide group.

14. A pharmaceutical composition comprising a compound according to any of the preceding claims and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

15. The compound according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14 for use in the treatment and/or the diagnosis of a disease.

16. The compound according to any of the claims 1 to 13 or the pharmaceutical composition according to claim 14 for use in the prevention and/or treatment of a FAP-related disorder.

17. The compound for use according to claim 16, wherein said disorder is selected from 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 sarcomas, 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, atherosclerotic disease and Crohn’s disease; disorders involving endocrinological dysfunction, such as disorders of glucose metabolism; and blood clotting disorders.

18. The compound according to any of the claims 1 to 13, or pharmaceutical composition according to claim 14 for use in tissue and/or organ imaging.

19. The compound according to any of the claims 1 to 13, or a pharmaceutical composition according to claim 14 for use as a companion diagnostic.

20. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, prodrug, salt, hydrate, or solvate thereof, Formula I, wherein Y₁ and Y₂ are independently H or F, wherein Y3 comprises a ketoamide group, wherein a linker (Z) is covalently bound to the quinoline structure of said compound on position 6, 7 or 8, and characterized in that the linker comprises one or more amine groups. The compound according claims 20, wherein at least one of the one or more amine groups is a tertiary amine.