WO2025104141A1

WO2025104141A1 - Novel reversible fluorescent probes for cb2

Info

Publication number: WO2025104141A1
Application number: PCT/EP2024/082287
Authority: WO
Inventors: Malgorzata Wasinska-Kalwa; Anahid OMRAN; Yelena MOSTINSKI; Leonard MACH; Marc Nazaré; Uwe Michael GRETHER; Wolfgang Guba
Original assignee: F Hoffmann La Roche AG; Forschungsverbund Berlin FVB eV; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Forschungsverbund Berlin FVB eV; Hoffmann La Roche Inc
Priority date: 2023-11-16
Filing date: 2024-11-14
Publication date: 2025-05-22
Anticipated expiration: 2026-05-16

Abstract

The present invention provides reversible fluorescent probes for cannabinoid receptor 2 ("CB2") having the general formula (I), wherein A, R² and R³ are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Description

Novel reversible fluorescent probes for CB2

Field of the Invention

The present invention relates to organic compounds useful as reversible fluorescent probes for the cannabinoid receptor 2 (CB2R). The probes are achieved by a novel, convergent synthetic blueprint from a central reactive motif.

Background of the Invention

Dysregulation of the endocannabinoid system, specifically of signaling pathways encompassed by CB2R, has been implicated in a range of diseases including tissue injury, neurodegenerative conditions and inflammation. Despite the evident importance of CB2R no compounds have been commercially launched so far. This feature is primarily ascribed to insufficient understanding of CB2R biology, particularly expression and localization in health and disease states. Fluorescent imaging probes have recently emerged as high- resolution tools to allow investigation of CB2R localization, expression levels and distribution in living cells and in vivo (R. C. Sarott, et. al., J. Am. Chem. Soc., 2020, 142, 16953-16964, T. Gazzi, et. al., Chem. Sci. 2022, 13, 5539-5545).

Such probes can e.g. be applied in flow cytometry fluorescence-activated cell sorting (FACS) experiments or cellular trafficking studies using confocal live cell imaging. Furthermore, fluorescent imaging probes allow for real-time monitoring of ligand-receptor interactions and protein visualization with high spatiotemporal precision (A. J. Vemall, S. J. Hill, B. Kellam, Br. J. Pharmacol. 2014, 171, 1073-1084; C. Iliopoulos- Tsoutsouvas, R. N. Kulkarni, A. Makriyannis, S. P. Nikas, Expert Opin. Drug Discov. 2018, 13, 933-947). In addition, such probes offer the potential for generating equilibrium and kinetic binding data in a high-throughput fashion, without handling radioactive material using e.g. time-resolved fluorescence resonance energy transfer (TR-FRET). Fluorescent imaging probes can also be useful to support the translation of preclinical pharmacological animal data to clinics and can be applied for dose selection in humans. They can e.g. be used as markers of target engagement via the generation of ex vivo quantitative receptor binding data in whole blood. Depending on the respective application, a fluorescent imaging probe needs to match specific criteria, including affinity, selectivity and specificity for the respective target, favorable photophysical properties, and applicability across distinct techniques and cell types.

Summary of the Invention

The Cannabinoid receptor 2 (CB2R) is predominantly expressed in cells associated with the immune system and therefore has become an attractive therapeutic target for a vast variety of pathological conditions such as immunological disorders, inflammation and neurodegenerative diseases. In spite of the therapeutic potential, no CB2R-selective drug has made its way to market to date. This is in part attributed to the complexity of CB2R signaling pathways at the cellular level and a lack of precise understanding of its function as well as its expression and localization dynamics. For example, while activation of CB2R with agonists has neuroprotective effects, its inactivation via inverse agonists/antagonists was found to have anti-inflammatory effects. A well-established tool to study receptor dynamics at the cellular level are chemical probes with various functionalities. Herein, we designed a matched agonist and inverse agonist fluoroprobe pair based on a common drug- derived chemotype to selectively address and visualize both the active and inactive states of CB2R. We have established a simple synthetic strategy to give access to a series of CB2R-selective fluoroprobes attached to various dyes (e.g. cell-permeable and cell- impermeable) suitable for diverse biological settings such as in vitro, ex vivo and in vivo. Pharmacological characterization alongside with extensive cross-validation (FACS and confocal microscopy) indicated the selectivity, specificity and imageability of our probes. The application of these diverse fluoroprobes in not limited to visualization of both the membrane and internal receptor pools, but also monitoring the expression level, dimerization, target engagement, pharmacokinetic and dynamics (e.g. receptor internalization and trafficking) in-real time. Moreover, they can be used as kinetic tracer to study the receptor-ligand engagement as an alternative for radioligand binding assay.

Detailed Description of the Invention

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The term “alkylene”, alone or in combination, denotes a linear saturated divalent hydrocarbon group of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 7 carbon atoms. Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.

The term “alkenylene”, alone or in combination, denotes a linear divalent hydrocarbon chain of 2 to 7 carbon atoms or a branched divalent hydrocarbon chain of 3 to 7 carbon atoms with at least one double bond. Exemplary alkenylene include ethenylene, 2,2- dimethylethenylene, propenylene, 2-methylpropenylene, butenylene, and pentenylene.

The term “alkynylene” alone or in combination, denotes a linear divalent hydrocarbon chain of 2-6 carbon atoms or a branched divalent hydrocarbon chain of 3-6 carbon atoms with at least one triple bond. Exemplary alkynylene include ethynylene, 2,2- dimethylethynylene, propynylene, 2-methylpropynylene, butynylene, and pentynylene.

The term “heteroalkylene”, alone or in combination, denotes an “alkylene” group comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remainder being hydrocarbon.

The term “heteroalkenylene”, alone or in combination, denotes an “alkenylene” group comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remainder being hydrocarbon.

The term “heteroalkynylene”, alone or in combination, denotes an “alkynylene” group comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remainder being hydrocarbon.

The term “alkyl”, alone or in combination, refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms (“Ci-Ce-alkyl”). In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2- dimethylpropyl. A particularly preferred, yet non-limiting example of alkyl is methyl.

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride and trifluoroacetate salts, more particularly trifluoroacetate salts.

The term “solvate” denotes crystal forms having either stoichiometric or nonstoichiometric amounts of a solvent incorporated in the crystal lattice. If the incorporated solvent is water, the solvate formed is a hydrate. When the incorporated solvent is alcohol, the solvate formed is an alcoholate.

The term “protective group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protective groups can be removed at the appropriate point. Exemplary protective groups are amino-protective groups, carb oxy-protective groups or hydroxy-protective groups. Particular protective groups are the tert-butoxy carbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxy carbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tertbutoxycarbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

The term “equilibrium and kinetic binding data” is to be understood in broad terms as generally known to the person skilled in the art. Kinetic binding describes the dynamic binding interaction between two molecules, typically expressed as k_a (the rate of association), ka (rate of disassociation) and KD (equilibrium dissociation constant, also 'affinity'). k_a (also termed k_on) describes the rate at which the studied molecules form a complex. The binding constant, or affinity constant/association constant, is a special case of the equilibrium constant K, and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and ligand (L) molecules, which is formalized as: R + L # RL.

The term “occupancy” ... is to be understood in broad term as generally known to the person skilled in the art and as described for instance in ”A Pharmacology Primer (Fourth Edition)”, Kenakin, Terry P. , ISBN 978-0-12-407663-1.

The term “agonist” denotes a compound that enhances the activity of another compound or receptor site as defined e.g. in Goodman and Gilman's “The Pharmacological Basis of Therapeutics, 7th ed.” in page 35, Macmillan Publ. Company, Canada, 1985. A “full agonist” effects a full response whereas a “partial agonist” effects less than full activation even when occupying the total receptor population. An “inverse agonist” produces an effect opposite to that of an agonist, yet binds to the same receptor binding-site.

The term “fluorescent label” or “fluorescent probe” denotes a molecule that is attached chemically to derivatives of fluorophores that selectively bind to a target protein, antibody or amino acid and aid in Its detection. The term “tautomer” refers to a constitutional isomer with the same molecular formula but different connectivity which can interconvert in a rapid equilibrium.

The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the "R" or "S" configuration.

The abbreviations “CB2” and “CB2R” refer to the cannabinoid receptor 2.

The invention thus relates to:

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is: formula (a)

or formula (b)

wherein a double line indicates the point of attachment to the rest of formula (I); and wherein

L^a and L^b are each independently selected from:

1-30 membered alkylene, 1-30 membered heteroalkylene, 2-30 membered alkenylene, 2- 30 membered heteroalkenyl ene, 2-30 membered alkynylene, and 2-30 membered heteroalkynylene; each of which is optionally substituted, wherein the optionally substituted 1-30 membered heteroalkylene, 2-30 membered heteroalkenylene, and 2-30 membered heteroalkynylene each comprise 1-15 heteroatoms selected from the group consisting of N, O, NR⁵, and C(O), wherein R⁵ is H or C1-6 alkyl

R^a and R^b are each independently a fluorescent label or one half of a biotin or biotin derivative binding pair;

R² is

R³ is:

A compound according to the invention, wherein any L^a and/or L^b is independently selected from:

wherein each n is independently an integer selected from 1, 2, 3, 4, 5, 6 and 7; a wavy line indicates the point of attachment to R^a or R^b; and an asterisk indicates the point of attachment of L^a or L^b to the remaining part of fragment

A; preferably, wherein any L^a and/or L^b are selected from:

A compound according to the invention, wherein A is formula (a) and L^a is:

wherein each n is independently an integer selected from 1, 2, 3, 4, 5, 6, and 7; a wavy line indicates the point of attachment to R^a ; and an asterisk indicates the point of attachment of L^a to rest of the fragment A;

A compound according to the invention, wherein A is formula (b) and L^b is:

wherein each n is independently an integer selected from 1, 2, 3, 4, 5, 6, and 7; a wavy line indicates the point of attachment R^b; and an asterisk indicates the point of attachment L^b to rest of the fragment A;

A compound according to the invention, wherein n is independently an integer selected from 1, 2, 3 and 4; A compound according to the invention, wherein n is independently an integer selected from 2 or 3; preferably, A is formula (a) and n is 3; or preferably, A is formula (b) and n is 2;

A compound according to the invention, wherein A is formula (a):

A compound according to the invention, wherein A is formula (

A compound according to the invention, wherein any R^a and/or R^b are independently selected from the following structures or their tautomers:

NBD SCOTfluor 510 nitrobenzo[c][1 ,2,5]thiadiazole

nitrospiro[benzo[d]imidaz 2,2-dimethyl-4-nitro-2H- 2,2-bis(methyl-d3)-4-nrtro- ole-2,1 '-cyclohexane] benzo[d]imidazole 2H-benzo[d]imidazole

Fluorescein Indocyanine green

wherein a wavy line indicates the point of attachment to the L^a or L^b;

A compound according to the invention, wherein any of R^a and/or R^b are each independently selected from the following structures or their tautomers:

NBD SCOTfluor 510 nitrobenzo[c][1 ,2,5]thiadiazole

4 2

preferably any of R^a and/or R^b are each independently selected from the following structures or their tautomers:

nitrospiro[benzo[d]imidaz

NBD ole-2, T-cyclohexane]

wherein m is 1 or 2, Silicon Rhodamine

_F|_uoreScein more preferably, any of R^a and R^b are each independently selected from the following structures or their tautomers:

A compound according to the invention, wherein R² is:

A compound according to the invention, wherein any of R^a and/or R^b are each independently selected from:

Silicon Rhodamine wherein m is 1 or 2, Fluorescein and

A compound according to the invention, wherein any of R^a and/or R^b are each independently selected from the following structures or their tautomers

Silicon Rhodamine wherein m is 1 or 2, Fluorescein , and

and n is independently an integer selected from 2 or 3; preferably n is 2;

and n is independently an integer selected from 2 or 3; preferably n is 2;

A compound according to the invention, wherein:

R² is

and

R³ is

NBD SCOTfluor 510 nitrobenzo[c][1 ,2,5]thiadiazole

NBD SCOTfluor 510 nitrobenzo[c][1 ,2,5]thiadiazole

and n is independently an integer selected from 2 or 3.

A compound according to the invention, wherein A is formula (a)

and wherein n is 3.

A compound according to the invention, wherein A is formula (b)

and wherein n is 2.

A compound according to the invention, wherein the compound is of formula (I) as described herein.

A compound according to the invention, wherein the compound is a pharmaceutically acceptable salt of the compound of formula (I) as described herein.

A compound according to the invention, wherein the compound is a solvate of the compound of formula (I) as described herein.

In one embodiment the compound of formula (I) is a compound of formula (la)

wherein L^a, R^a, R² and R³ are as described herein.

In one embodiment the compound of formula (I) is a compound of formula (lb)

wherein L^b, R^b, R² and R³ are as described herein. The invention further relates to a compound according to the invention selected from:

Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate;

Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate;

Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (7?)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (5)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (5)-l-(3’,6’-Bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-l -oxo-5, 8,1 l-trioxa-2- azapentadecan- 15 -oate;

Ethyl (S)-l-(3’,6’-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-l,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-l -oxo-5, 8,1 l-trioxa-2- azapentadecan- 15 -oate;

Ethyl 15-(5-cyclopropyl-6-(4-fhrorobenzyl)picolinamido)-15-ethyl-l-((7- nitrobenzofc] [ 1 ,2,5]oxadiazol-4-yl)amino)-3 ,6,9, 12-tetraoxahexadecan- 16-oate;

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate;

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (7?)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (5)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (5)-l-(3\6’-bis(dimethylamino)-3-oxo-3#-spiro[isobenzofuran-l,9’- xanthen]-5-yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate;

Ethyl (5)-l-(3\6’-bis(dimethylamino)-3-oxo-3#-spiro[isobenzofuran-l,9’- xanthen]-6-yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate;

Ethyl 15-ethyl-15-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-

3.6.9.12-tetraoxahexadecan- 16-oate;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-7V-(14-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo-

3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-7V-(17-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo-

3.6.9.12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,r- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2J7-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide;

7V-(3-((2-(2-(2-((2,2-bis(methyl-t/3)-7-nitro-2_JH-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-l-yl)-2_JH- benzo[d][l,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide;

7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'_JH,5_JH-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide;

3',6'-Diamino-5-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-37/-spi ro[i sobenzof iiran- l,9'-xanthene]-4',5'-disulfonic acid;

3',6'-Diamino-6-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3Z/-spiro[isobenzofuran- l,9'-xanthene]-4',5'-disulfonic acid;

5-Cyclopropyl-7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-

13 -ethyl- 1 , 12-dioxo-5,8-dioxa-2, 11 -diazapentadecan- 13 -yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-

13 -ethyl- 1 , 12-dioxo-5,8-dioxa-2, 11 -diazapentadecan- 13 -yl)-6-(4- fluorobenzyl)picolinamide;

7V-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

7V-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

3 -( 1 -(5-Cyclopropyl-6-(4-fluorobenzyl)pyri din-2 -yl)-3 ,3 -diethyl- 1 ,4, 15-trioxo-8, 11- dioxa-2,5J4-triazaicosan-20-yl)-2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3- sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-l-(3-sulfonatopropyl)- 3Z/-indol- 1 -ium-5-sulfonate;

6-(((l£,25)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3- ((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide;

6-(((l£,25)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3- ((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

7V-(14-Ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamide;

7V-(17-Ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa- 15-azanonadecan-17-yl)-6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-3//-spiro[isobenzofuran- l ,9'-xanthene]-4',5'-disiilfonic acid;

3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-3//-spiro[isobenzofiiran- l ,9'-xanthene]-4',5'-disiilfonic acid;

7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-377,5_JH-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((LS',2b')-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin- l - yl)picolinamide;

7V-(l-(3',6'-bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

7V-(l-(3',6'-bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3Z/-indol- 1 -ium-5-sulfonate;

7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13-ethyl-l,12- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13-ethyl-l,12- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide; Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate;

Ethyl 14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-2,2-dimethyl -4-oxo- 3,8,1 l-trioxa-5-azapentadecan-l 5-oate;

Ethyl 17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl -4-oxo- 3,8,11,14-tetraoxa-5 -azaoctadecan- 18-oate;

Ethyl (7?)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl-4- oxo-3 ,8,11,14-tetraoxa-5 -azaoctadecan- 18-oate;

Ethyl (5)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl-4- oxo-3 ,8,11,14-tetraoxa-5 -azaoctadecan- 18-oate;

Ethyl 20-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-20-ethyl-2,2-dimethyl -4-oxo- 3,8,11,14, 17-pentaoxa-5-azahenicosan-21 -oate;

Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-ethyl-2-(6-(((15,25)-2-

(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamido)butanoate;

Ethyl 14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azapentadecan- 15 -oate;

Ethyl 17-ethyl-17-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,l l,14-tetraoxa-5- azaoctadecan-18-oate;

Ethyl (R)- 17 -ethyl- 17-(6-((( 1 A', 2A')-2-(hydroxyrn ethyl )cycl opropyl )m ethoxy )-5 -(3 - methoxyazetidin-l-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,l l,14-tetraoxa-5- azaoctadecan-18-oate;

Ethyl (5)- 17 -ethyl- 17-(6-((( 1 \2A')-2-(hydroxyrn ethyl )cycl opropyl )m ethoxy )-5 -(3 - methoxyazetidin-l-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,l l,14-tetraoxa-5- azaoctadecan-18-oate; Ethyl 20-ethyl-20-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazeti din-l-yl)picolinamido)-2,2-dimethyl-4-oxo-3, 8,11, 14,17-pentaoxa-5- azahenicosan-21 -oate;

Tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate; Tert-butyl (l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4-dioxo-8,l l- dioxa-2,5-diazatridecan-13-yl)carbamate;

Tert-butyl (l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4-dioxo-

8,l l,14-trioxa-2,5-diazahexadecan-16-yl)carbamate;

8,l l,14,17-tetraoxa-2,5-diazanonadecan-19-yl)carbamate;

Tert-butyl (2-(2-(2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)butanamido)ethoxy)ethyl)carbamate;

Tert-butyl (3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4-dioxo-8,l l-dioxa-2,5-diazatridecan-13- yl)carbamate;

Tert-butyl (3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazeti din- l-yl)pyridin-2-yl)-l,4-di oxo-8, 1 l,14-trioxa-2,5-diazahexadecan-16- yl)carbamate; and

Tert-butyl (3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4-dioxo-8,l l,14,17-tetraoxa-2,5-diazanonadecan- 19-yl)carbamate.

The invention further relates to a compound according to the invention selected from:

Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate;

Ethyl CS')- l-(3’,6’-Bis(dirnethylarnino)-3-oxo-37/-spiro[isobenzofiiran- l,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-l -oxo-5, 8,1 l-trioxa-2- azapentadecan- 15 -oate;

Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-l-((7- nitrobenzofc] [ 1 ,2,5]oxadiazol-4-yl)amino)-3 ,6,9, 12-tetraoxahexadecan- 16-oate;

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate;

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (7?)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

3.6.9.12-tetraoxahexadecan- 16-oate;

3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide;

3.6.9.12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((4-nitrospiro[benzo[J]imidazole-2,r- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2J7-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)- 13 -ethyl- 1 , 12-dioxo-5,8-dioxa-2, 11 -diazapentadecan- 13 -yl)-6-(4- fluorobenzyl)picolinamide; 7V-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

7V-(17-Ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa- 15-azanonadecan-17-yl)-6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamide;

3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofiiran-l,9'-xanthene]-4',5'-disiilfonic acid; 3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-3//-spiro[isobenzofuran-l,9'-xanthene]-4',5'-disulfonic acid;

7V-(l-(3,7-Bis(dimethylarnino)-5,5-dimethyl-3'-oxo-37/,5J/-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((l£,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamide;

7V-(l-(3',6'-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

7V-(l-(3',6'-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3J/-indol- 1 -ium-5-sulfonate;

7V-(l-(3',6'-dihydroxy-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13-ethyl-l,12- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2-

(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

7V-(l-(3',6'-dihydroxy-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13-ethyl-l,12- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2-

(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide.

The invention further relates to a compound according to the invention selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate;

A mixture of ethyl CS')- l-(3’,6’-Bis(dirnethylarnino)-3-oxo-37/-spiro[isobenzofuran-l,9’- xanthen]-5-yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-l-oxo-

5,8, l l-trioxa-2-azapentadecan- 15-oate and ethyl (S)-l-(3’,6’-Bis(dimethylamino)-3-oxo-

3H-spiro[isobenzofuran-l,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)- 14-ethyl- 1 -oxo-5,8, 11 -trioxa-2-azapentadecan- 15-oate;

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (A)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (5)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

A mixture of ethyl (5)-l-(3’,6’-bis(dimethylamino)-3-oxo-3_JH- spiro[isobenzofuran-l,9’-xanthen]-5-yl)-14-ethyl-14-(6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3 -methoxyazetidin- 1 -yl)picolinamido)- 1 -oxo- 5,8,11 -tri oxa-2-azapentadecan- 15-oate and ethyl (5)-l-(3’,6’- bis(dimethylamino)-3-oxo-37/-spiro[isobenzofuran-l,9’-xanthen]-6-yl)-l4-ethyl-l4-(6- (((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinami do)- 1 -oxo-5, 8, 11 -tri oxa-2-azapentadecan- 15-oate;

3.6.9.12-tetraoxahexadecan- 16-oate;

5-Cyclopropyl-6-(4-fluorobenzyl)-A-(3-((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-A-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-A-(14-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-A-(17-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo-

3.6.9.12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-A-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-A-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,r- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2_JH-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide;

A mixture of 3',6'-diamino-5-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3- di ethyl- 1 ,4-dioxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3H- spiro[isobenzofuran-l,9'-xanthene]-4',5'-disulfonic acid and 3',6'-diamino-6-((l-(5- cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4-dioxo-8,l l-dioxa-2,5- diazatridecan-B-y^carbamoy^-S-oxo-S/Z-spirofisobenzofuran-l^'-xanthenel-d'^'- disulfonic acid;

A mixture of 5-cyclopropyl-A-(l-(3',6'-dihydroxy-3-oxo-3Z7-spiro[isobenzofuran-l,9'- xanthen]-5-yl)- 13 -ethyl- 1 , 12-dioxo-5, 8-dioxa-2, 11 -diazapentadecan- 13 -yl)-6-(4- fluorobenzyl)picolinamide and 5-cyclopropyl-A-(l-(3',6'-dihydroxy-3-oxo-3_JH- spiro[isobenzofuran-l, 9'-xanthen]-6-yl)-l 3-ethyl- 1,12-di oxo-5, 8-dioxa-2,l 1- diazapentadecan-13-yl)-6-(4-fluorobenzyl)picolinamide;

A-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 7V-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

3 -( 1 -(5-Cyclopropyl-6-(4-fluorobenzyl)pyri din-2 -yl)-3 ,3 -diethyl- 1 ,4, 15-tri oxo-8, 11- dioxa-2,5,14-triazaicosan-20-yl)-2-((l£',3_JE)-5-((_JE)-3,3-dimethyl-5-sulfonato-l-(3- sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-l-(3-sulfonatopropyl)- 3/7-indol- 1 -ium-5-sulfonate;

A mixture of 3',6'-diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-

(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)pyridin-2-yl)-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3Z7-spiro[isobenzofuran- l,9'-xanthene]-4',5'-disulfonic acid and 3',6'-diamino-6-((3,3-diethyl-l-(6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)pyridin-2-yl)-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3Z7-spiro[isobenzofuran- l,9'-xanthene]-4',5'-disulfonic acid; A-(l-(3,7-Bis(dimethylarnino)-5,5-dimethyl-3'-oxo-37/,5J/-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((l£,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamide;

A mixture of A-(l-(3',6'-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9'- xanthen]-5-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,ll-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide and N- (l-(3',6'-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13-ethyl- l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide; 3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3E)-5-((E)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3J/-indol- 1 -ium-5-sulfonate; A mixture of A-( l-(3',6'-dihydroxy-3-oxo-3//-spiro[isobenzofuran- l,9'-xanthen]-6-yl)- l3- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide and N- (l-(3',6'-dihydroxy-3-oxo-3//-spiro[isobenzofuran- l,9'-xanthen]-5-yl)- l3-ethyl-l, l2- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide.

The invention further relates to a compound according to the invention selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate;

Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

Ethyl (7?)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (5)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl CS')-l-(3’,6’-bis(dirnethylarnino)-3-oxo-37/-spiro[isobenzofiiran- l,9’- xanthen]-5-yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate; Ethyl CS')-l-(3’,6’-bis(dirnethylarnino)-3-oxo-37/-spiro[isobenzofiiran- l,9’- xanthen]-6-yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-7V-(14-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-7V-(17-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9, 12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitrobenzo[c][l,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,r- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2_JH-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide; 7V-(3-((2-(2-(2-((2,2-bis(methyl-t/3)-7-nitro-2_JH-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

5-Cyclopropyl-7V-(l-(3',6'-dihydroxy-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-

7V-(l-(3',6'-Bis(dimethylamino)-3-oxo-3_JH-spiro[isobenzofuran-l,9'-xanthen]-6-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 3 -( 1 -(5-Cyclopropyl-6-(4-fluorobenzyl)pyri din-2 -yl)-3 ,3 -diethyl- 1 ,4, 15-trioxo-8, 11- dioxa-2,5J4-triazaicosan-20-yl)-2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3- sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-l-(3-sulfonatopropyl)- 3Z/-indol- 1 -ium-5-sulfonate;

3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofuran-l,9'-xanthene]-4',5'-disiilfonic acid;

3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofiiran-l,9'-xanthene]-4',5'-disiilfonic acid;

_IV-(l-(3,7-Bis(dirnethylarnino)-5,5-dirnethyl-3'-oxo-3'7/,57/-spiro[dibenzo[A,c]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((LS',2A')-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamide; 7V-(l-(3',6'-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9'-xanthen]-5-yl)-13- ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3J/-indol- 1 -ium-5-sulfonate. The invention further relates to a compound according to the invention selected from:

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (5)-2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate;

3',6'-Diamino-5-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-37/-spi ro[i sobenzofuran- l,9'-xanthene]-4',5'-disulfonic acid;

3 -( 1 -(5-Cyclopropyl-6-(4-fluorobenzyl)pyri din-2 -yl)-3 ,3 -diethyl- 1 ,4, 15-tri oxo-8, 11- dioxa-2,5,14-triazaicosan-20-yl)-2-((l£',3_JE)-5-((_JE)-3,3-dimethyl-5-sulfonato-l-(3- sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-l-(3-sulfonatopropyl)- 3Z7-indol- 1 -ium-5-sulfonate;

6-(((l£,25)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3-

((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide;

3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofuran-l,9'-xanthene]-4',5'-disulfonic acid;

3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-

(3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofuran-l,9'-xanthene]-4',5'-disulfonic acid; 7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'J/,5J/-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((LS',2A')-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamide; and 3-(3,3-Diethyl-l-(6-(((lS,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3E)-5-((E)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3H-indol- 1 -ium-5-sulfonate.

Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate;

Ethyl CS')-l-(3’,6’-bis(dimethylamino)-3-oxo-37/-spiro[isobenzofiiran- l,9’-xanthen]-5- yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate;

Ethyl CS')-l-(3’,6’-bis(dimethylamino)-3-oxo-37/-spiro[isobenzofiiran- l,9’-xanthen]-6- yl)-14-ethyl-14-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamido)-l-oxo-5,8,l l-trioxa-2-azapentadecan-l 5-oate;

3 ,6, 9, 12-tetraoxahexadecan- 16-oate;

6-(((l£,25)-2-(Elydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3-

((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 7V-(14-Ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamide;

7V-(17-Ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa-

15-azanonadecan-17-yl)-6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)picolinamide;

3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofuran- l ,9'-xanthene]-4',5'-disiilfonic acid;

3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-37/-spiro[isobenzofiiran- l ,9'-xanthene]-4',5'-disiilfonic acid;

7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'_JH,5_JH-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((LS',2A')-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin- l - yl)picolinamide;

3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3 -methyl- 1 -(4-sulfonatobutyl)-3Z/-indol- 1 -ium-5-sulfonate; and A-(l-(3',6'-dihydroxy-3-oxo-3//-spiro[isobenzofuran-l,9'-xanthen]-6-yl)- l3-ethyl-l, l2- dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)-6-(((15,25)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide;

(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)picolinamide.

Ethyl (5)-l-(3’,6’-bis(dimethylamino)-3-oxo-3J/-spiro[isobenzofuran-l,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-l -oxo-5, 8,1 l-trioxa-2- azapentadecan- 15 -oate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-l-((7- nitrobenzofc] [ 1 ,2,5]oxadiazol-4-yl)amino)-3 ,6,9, 12-tetraoxahexadecan- 16-oate;

5-Cyclopropyl-7V-(14-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-7V-(17-ethyl-l-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9, 12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide;

5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2_JH-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide;

7V-(3-((2-(2-(2-((2,2-bis(methyl-d3)-7-nitro-2#-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-l-yl)-2_JH- benzo[d][l,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; and 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3-sulfonatopropyl)- 3H-indol-1-ium-5-sulfonate. The invention further relates to a compound according to the invention selected from: 5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((4-nitrospiro[benzo[J]imidazole-2,r- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

5-Cyclopropyl-7V-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2J/-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide;

7V-(3-((2-(2-(2-((2,2-bis(methyl-t/3)-7-nitro-2J/-benzo[J]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide;

5-Cyclopropyl-6-(4-fluorobenzyl)-7V-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-l-yl)-2J/- benzo[d][l,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide;

7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'J/,5J/-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3//-spi ro[i sobenzof iiran- l,9'-xanthene]-4',5'-disulfonic acid;

3',6'-Diamino-6-((l-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-l,4- di oxo-8, 11 -dioxa-2, 5-diazatridecan- 13 -yl)carbamoyl)-3 -oxo-3//-spi ro[i sobenzofuran- l,9'-xanthene]-4',5'-disulfonic acid;

3 -( 1 -(5-Cyclopropyl-6-(4-fluorobenzyl)pyri din-2 -yl)-3 ,3 -diethyl- 1 ,4, 15-tri oxo-8, 11- dioxa-2,5,14-triazaicosan-20-yl)-2-((lE,3£)-5-((£)-3,3-dimethyl-5-sulfonato-l-(3- sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-l-(3-sulfonatopropyl)- 3Z/-indol- 1 -ium-5-sulfonate;

6-(((l£,25)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3- ((2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; 6-(((15,2,S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l-yl)-7V-(3-

((2-(2-(2-((7-nitrobenzo[c][l,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide;

3',6'-Diamino-5-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-3#-spiro[isobenzofuran-l,9'-xanthene]-4',5'-disulfonic acid;

3',6'-Diamino-6-((3,3-diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3 -methoxyazetidin- 1 -yl)pyridin-2-yl)- 1 ,4-dioxo-8, 11 -dioxa-2,5-diazatridecan- 13- yl)carbamoyl)-3-oxo-3//-spiro[isobenzofiiran-l,9'-xanthene]-4',5'-disiilfonic acid;

7V-(l-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-377,5_JH-spiro[dibenzo[Z>,e]siline- 10,l'-isobenzofuran]-6'-yl)-13-ethyl-l,12-dioxo-5,8-dioxa-2,l l-diazapentadecan-13-yl)- 6-(((LS',2A')-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-l- yl)picolinamide;

3-(3,3-Diethyl-l-(6-(((15,25)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-l-yl)pyridin-2-yl)-l,4,15-trioxo-8,l l-dioxa-2,5,14-triazaicosan-20-yl)- 2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate; N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide. The invention further relates to a compound according to the invention selected from: 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; and N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide. The invention further relates to a compound according to the invention selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; and Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate. The invention further relates to a compound according to the invention selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; and Ethyl 15-ethyl-15-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)- 3,6,9,12-tetraoxahexadecan-16-oate. The invention further also relates to: A compound according to the invention, which is an inverse agonist of cannabinoid receptor type 2 (CB2); A compound according to the invention, which is an agonist of cannabinoid receptor type 2 (CB2); A compound according to the invention, for use in a cannabinoid receptor type 2 (CB2) occupancy study; A compound a according to the invention, for use in diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal; A compound according to the invention, for use in generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data; Use of a compound according to the invention in diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal; Use of a compound according to the invention, in generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data; A method of studying cannabinoid receptor type 2 (CB2) occupancy, comprising contacting CB2 with a compound according to the invention; A method of studying cannabinoid receptor type 2 (CB2) occupancy, comprising contacting CB2 in vitro with a compound according to the invention; A method of diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal, comprising contacting CB2 with a compound according to the invention; and A method of generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data, comprising contacting CB2 with a compound according to the invention. Processes of Manufacturing The invention further also relates to methods for manufacturing a compound according to the invention as described herein. A method of manufacturing a compound according to the invention, wherein the method comprises the following reaction steps:

1) Deprotonation; 2) reaction with LG-(CH2)2-L^a-PG¹; 3) 4-chlorobenzylidene group removal; Step b comprising: 1) amide coupling wi ; and Step c comprising: 1) PG¹ removal;

2) Coupling or substitution reaction to attach R^a; or Step a comprising: 1) Deprotonation; 2) reaction with LG-(CH2)2-L^a-PG¹; 3) 4-chlorobenzylidene group removal; Step d comprising: 1) Protection of amine with PG²; Step e comprising: 1) PG² removal; 2) Amide coupling with ; and Step c comprising: 3) PG¹ removal; 4) Coupling or substitution reaction to attach R^a; or Step a comprising: 1) Deprotonation; 2) reaction with LG-(CH₂)₂-L^a-PG¹; 3) 4-chlorobenzylidene group removal; Step d comprising: 2) Protection of amine with PG²; and Step c comprising: 1) PG¹ removal; Coupling or substitution reaction to attach R^a; and Step e comprising: 1) PG² removal; Amide coupling with ; wherein La, Ra, R² and R³ are as defined herein, LG is a leaving group and PG¹ and PG² are orthogonal protecting groups. The solvent in step a, sub-steps 1) and 2), can be for instance THF, diethyl ether or hexane. A preferred solvent in step a, sub-step 1), is THF. The deprotonation of step a can be performed in presence of a base. The base in step a, sub-step 1), can be for instance LDA, diisopropylhexadisilazane, n-BuLi or sodium amides. A preferred base in step a, sub-step 1), is LDA. The reaction of step a, sub-steps 1) and 2), can be for instance preformed at between around -108 °C and around 60 °C, in particular at between around -78 °C and rt. The solvent in step a, sub-step 3), can be for instance THF, water, ACN, DMF, MeOH. A preferred solvent in step a, sub-step 3), is THF. The reaction of step a, sub-step 3), can be for instance performed at between around 0 °C and around 100 °C, in particular at rt. The solvent in step b can be for instance DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane. The preferred solvents in step b were DMF or ACN. The reaction of step b can be for instance performed at between around -10 °C and around 80°C, in particular at rt. The solvent in step c, sub-step 1), can be for instance DCM or ACN. A preferred solvent in step c, sub-step 1), is DCM. The reaction of step c, sub-step 1), can be for instance performed at between around -10 °C and around 70 °C, in particular at between around 0 °C and around rt. The solvent in step c, sub-step 2), can be for instance DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane. The preferred solvents in step c, sub-step 2), were DMF or ACN. The reaction of step c, sub-step 2), can be for instance performed at between around 0 °C and around 50 °C, in particular at rt. The solvent in step d can be for instance dioxane, THF, ACN or acetone. A preferred solvent in step d is dioxane. The reaction of step d can be for instance performed at between around -10 °C and around 100 °C, in particular at between around 0 °C and around rt. The solvent in step e, sub step 1), can be for instance DCM, DMSO, ACN or DMF The preferred solvents in step e are ACN or DMF. The reaction of step e sub step 1), can be for instance performed at between around -10 °C and around 100 °C, in particular at rt. The solvent in step e, sub-step 2), can be for instance DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane. The preferred solvents in step c, sub-step 2), were DMF or ACN. The reaction of step e, sub-step 2), can be for instance performed at between around -10°C and around 80 °C, in particular at rt. In the above manufacturing method, leaving group LG can be for instance halogen, in particular iodo. In the above manufacturing method, orthogonal protecting group PG¹ can be for instance Fmoc, Boc, CBz, Trt, Ddz, Bpoc, Nps, Nsc, Bsmoc, Z, Allloc, Troc, etc. in particular Boc In the above manufacturing method, orthogonal protecting group PG² can be for instance Fmoc, Boc, CBz, Trt, Ddz, Bpoc, Nps, Nsc, Bsmoc, Z, Allloc, Troc, etc. in particular Fmoc. A method of manufacturing a compound according to the invention wherein the method comprises the following reaction steps:

i) Amide coupling with PG¹-L^b-NH2; wherein Step g comprises: i) Removal of PG² ii) Amide coupling o

wherein Step h comprises: i) Removal of PG¹ ii) Coupling or substitution reaction to attach Rb. wherein L^b, R^b, R² and R³ are as defined herein and PG¹ and PG² are orthogonal protecting groups. The solvent in step f can be for instance DMF, DMA, DCM, ACN, MeOH. The preferred solvents in step f are DMF or ACN. The reaction of step f can be for instance performed at between around -10 °C and around 80°C, in particular at rt. The solvent in step g, sub step 1), can be for instance DCM, ACN or DMF The preferred solvents in step e are ACN or DMF. The solvent in step g, sub step 1), can be for instance DCM, DMSO, ACN or DMF The preferred solvents in step e are ACN or DMF. The reaction of step g sub step 1), can be for instance performed at between around -10 °C and around 100 °C, in particular at around rt. The solvent in step g, sub-step 2), can be for instance DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane. The preferred solvents in step c, sub-step 2), were DMF or ACN. The reaction of step g, sub-step 2), can be for instance performed at between around -10 °C and around 80 °C, in particular at around rt. The solvent in step h, sub-step 1), can be for instance DCM or ACN. A preferred solvent in step c, sub-step 1), is DCM. The reaction of step h, sub-step 1), can be for instance performed at between around -10 °C and around 70 °C, in particular at between around 0 °C and around rt. The solvent in step h, sub-step 2), can be for instance DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane. The preferred solvents in step c, sub-step 2), were DMF or ACN. The reaction of step h, sub-step 2), can be for instance performed at between around 0°C and around 50 °C, in particular at around rt. In the above manufacturing method, orthogonal protecting group PG¹ can be for instance Fmoc, Boc, CBz, Trt, Ddz, Bpoc, Nps, Nsc, Bsmoc, Z, Allloc, Troc, etc. in particular Boc In the above manufacturing method, orthogonal protecting group PG² can be for instance Fmoc, Boc, CBz, Trt, Ddz, Bpoc, Nps, Nsc, Bsmoc, Z, Allloc, Troc, etc. in particular Fmoc. The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates. Using such diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically/enantiomerically enriched compounds of formula (I). The racemic mixtures were used, if not specified otherwise. A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc.1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl.1996, 35, 2056). A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity, sensitivity and nature of the intermediates. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY.1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. All reactions were performed at room temperature if not specified otherwise. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. In some instances, a mixture of stereoisomers is obtained as intermediate or final product. The isomers can be separated by, inter alia, chromatographic techniques that are common general knowledge. The isomers can further be assigned based on methods such as for instance NMR spectroscopy, X-ray crystallography or other methods known to the person skilled in the art. Alternatively, in order to avoid isomer separation, a single isomer can also be synthesized by using only one isomer of the respective dye according to methods known to the person skilled in the art. Abbreviations: ACN = acetonitrile, Alloc = Allyloxycarbonyl, Boc = tert-butyloxycarbonyl, Bpoc = 2-(4- Biphenyl)isopropoxycarbonyl, Bsmoc = (1,1-Dioxobenzo[b]thiophene-2- yl)methyloxycarbonyl, CBz = Benzyloxycarbonyl, Cu(OAc)2 = copper acetate, CAS = Chemical Abstracts Service, D₂O = deuterium oxide, DBU = 1,8- Diazabicyclo[5.4.0]undec-7-en, DCM = dichloromethane, Ddz = α,α-dimethyl-3,5- dimethoxybenzyloxycarbonyl, DMA = dimethylacetamide, DMF = N,N- dimethylformamide, DIPA = diisopropylamine, DIPEA = N,N-diisopropylethylamine, EDC.HCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, equiv. = equivalent, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOD = Ethanol-d₆, EtOH = ethanol, Fmoc = 9-Fluorenylmethoxycarbonyl, H2O = water, HATU = 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HCl = hydrogen chloride, HOAt = 1-hydroxy-7-azabenzotriazole; HPLC = high performance liquid chromatography, LC = liquid chromatography, LDA = lithium diisopropyl amide, M = molarity, MeOH = methanol, mg = milligram, min = minute(s), mL = milliliter, µL= mircoliter, µmol = mircomol(s), mmol = millimole(s), MS = mass spectrum, m/z = mass by charge ratio, N2 = nitrogen gas, NaHCO3 = sodium hydrogen carbonate, NaOH = sodium hydroxide, Na₂CO₃ = sodium carbonate, Na₂SO₄ = sodium sulfate, Na2S2O3. = sodium hyposulfite, NBD = nitrobenzoxadiazole , n-BuLi = n- butyllithium, NEt₃ = triethylamine (TEA), NH₄Cl = ammonium chloride, Nps = 2- Nitrophenylsulfenyl, Nsc = 2-(4-Nitrophenylsulfonyl)ethoxycarbonyl, OAc = acetoxy, rt = room temperature, TEA = triethylamine, TFA = trifluroacetic acid, THF = tetrahydrofuran, Troc = 2,2,2-Trichloroethyloxycarbonyl, Trt = Trityl, Z = Benzyloxycarbonyl. The synthesis of compounds with formulae Ia and Ib can, for example, be accomplished according to the following scheme 1 and scheme 2, respectively. Scheme 1:

using a suitable base and solvent and then reacted with various linkers (L^a). Bases for this type of reaction include but are not limited to LDA, diisopropylhexadisilazane, n-BuLi or sodium amides in solvents such as THF, dioxane, hexane or diethylether. Reactions of this type are typically carried out at temperatures between rt and 100 °C. Preferred linkers are polyethylene glycols including, but are not limited to, N-Boc protected iodinated polyethylene glycols of the type Boc−NH−CH2−CH2−(O−CH2−CH2)n−I, with n between 1 and 4. A person skilled in the art will acknowledge that also other protecting groups (PG¹), linkers (L^a) and leaving groups can be used instead of Boc, polyethylene glycols or iodine, respectively. Removal of benzylidene protecting group via an acidic work up gives access to the main building blocks of formula AB (step a). Compound AC can be prepared from AB and the corresponding substituted picolinic acids by suitable amide bond forming reactions (step b). These reactions are known in the art. For example, coupling reagents like N,N'-carbonyl-diimidazole (CDI), N,N'- dicyclohexylcarbodiimide (DCC), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-bis(dimethylamino)-methylene)-1H-1,2,3-triazolo[4,5- b]pyridinium-3-oxide hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HATU and a base, such as Huenig’s base or triethylamine in an inert solvent such as DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane, preferably between 0 °C and room temperature. The substituted picolinic acids are either commercially available or described in the literature, can be synthesized by a person skilled in the art (Chem. Sci., 2022, 13, 5539-5545; J. Med. Chem.2020, 63, 18, 10287–10306). Compound AC can be converted into compound Ia (step c) by: i) removal of the protecting group (PG¹) of compound AC applying methods known in the art (e.g., a Boc group using TFA in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); and ii) either coupling or substitution reactions with a suitable reporting unit (R^a) such as, but not limited to, fluorescent dyes or biotin . In case R^a possesses a carboxylic acid, compound Ia can be achieved by amide bond formation as described in step b of scheme 1. A person skilled in the art will acknowledge, that also activated carboxylic acids can be used, such as succinimidyl-ester, pentafluorophenylester or sulfodichlorophenyl ester without the need of an amide bond forming reagent. A person skilled in the art will further acknowledge, that also suitable halogenated aryls can react with the free amine or amine salt in a nucleophilic aromatic substitution manner using a suitable base and solvent such as, e.g. Huenig’s base , trimethylamine, Na₂CO₃ or Cs₂CO₃ in a suitable solvent like DMF, DMA, DCM, ACN, H2O,MeOH or 1,4-dioxane, , preferably between 0 °C and 65 °C. Suitable halogenated aryls include but are not limited to NBD-F or NBD-Cl and other such as sulfur, selenium carbon containing congeners as described by Marc Vendrell et al. (Angew.Chem.Int.Ed.2019, 58, 6911 –6915). Alternatively, compound I can also be synthesized applying the following reaction sequence: i) the amine functional group of intermediate AB can be protected with appropriate protection group (PG²) (such as Fmoc protecting group, as described e.g. in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3" edition) applying methods well-known in the art to give access to the intermediate AD (step d). The intermediate AD contains orthogonal protecting groups “PG” such as a Boc or Fmoc protective groups which can be removed selectively at a later stage of the synthesis using standard methods known in the art (“Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); ii) either coupling or substitution reactions with a suitable reporting unit (R^a) such as, but not limited to, fluorescent dyes or biotin give access to compound AD (step c). In case R^a possesses a carboxylic acid, compound Ia can be achieved by amide bond formation as described in step b of scheme 1. A person skilled in the art will acknowledge, that also activated carboxylic acids can be used, such as succinimidyl-ester, pentafluorophenylester or sulfodichlorophenyl ester without the need of an amide bond forming reagent. A person skilled in the art will further acknowledge, that also suitable halogenated aryls can react with the free amine or amine salt in a nucleophilic aromatic substitution manner using a suitable base and solvent such as, e.g. Huenig’s base , trimethylamine, Na₂CO₃ or Cs₂CO₃ in a suitable solvent like DMF, DMA, DCM, ACN, H2O, MeOH or 1,4-dioxane, , preferably between about 0 °C and about 60 °C. Suitable halogenated aryls include but are not limited to NBD-F or NBD-Cl and other sulfur or selenium containing congeners as described by Marc Vendrell et al. (Angew.Chem.Int.Ed. 2019, 58, 6911 –6915); iii) removal of the protection group (PG²) of compound AD applying methods known in the art (e.g., a Fmoc group using DBU in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); and iv) amide coupling with corresponding substituted picolinic acids using suitable coupling reagents as described in step b of scheme 1 (step e). Compounds of formula AB can contain a chiral center and may be obtained as mixtures of diastereomers or enantiomers, which can be separated if needed by methods well known in the art, e.g. (chiral) HPLC or crystallization. Racemic mixtures can e.g. be separated into their antipodes via diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Alternatively, the amine functional group in intermediate AB can be first protected by a suitable protecting group (compound AD) to facilitate separation of the enantiomers like for example a Fmoc or Cbz protecting group. Such protecting groups can be removed at a later stage of the synthesis using standard methods known in the art. Scheme 2:

amine by suitable amide bond forming reactions (step f). Preferred linkers include, but are not limited to, N-Boc protected polyethylene glycols amine of the type Boc−NH−CH2−CH2−(O−CH2−CH2)n−NH2, with n between 1 and 4. A person skilled in the art will acknowledge that also other protecting groups (PG¹) and linkers (L) can be used instead of Boc or polyethylene glycols, respectively. These reactions are known in the art. For example, coupling reagents like N,N'-carbonyldiimidazole (CDI), N,N'- dicyclohexylcarbodiimide (DCC), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-bis(dimethylamino)-methylene)-1H-1,2,3-triazolo[4,5- b]pyridinium-3-oxide hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluorophosphate (HBTU) can be employed to affect such transformation. A convenient method is to use for example HATU and a base, such as Huenig’s base or triethylamine in a solvent such as DMF, DMA, DCM, ACN, MeOH or 1,4-dioxane, preferably between 0 °C and room temperature. The intermediate BB contains orthogonal protecting groups “PG” such as a Boc or Fmoc protective groups which can be removed selectively at a later stage of the synthesis using standard methods known in the art (“Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.) Compound of formulae BA and various polyethylene glycol linkers are either commercially available or can be prepared according to literature methods. Compound BB can be converted to BC (step g).by: i) removal of the protection group (PG²) of compound AD applying methods known in the art (e.g., a Fmoc group using DBU in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); ii) amide coupling with corresponding substituted picolinic acids using suitable coupling reagents as described in step f of scheme 2. The substituted picolinic acids are either commercially available or described in the literature, can be synthesized by a person skilled in the art (Chem. Sci., 2022, 13, 5539-5545; J. Med. Chem.2020, 63, 18, 10287–10306). Compound BC can be converted into compound Ib (step h) by: i) removal of the protection group (PG¹) of compound BC applying methods known in the art (e.g., a Boc group using TFA in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); and ii) either coupling or substitution reactions with a suitable reporting unit (R^b) such as, but not limited to, fluorescent dyes or biotin . In case R^b possesses a carboxylic acid, compound Ib can be achieved by amide bond formation as described in step f of scheme 2. A person skilled in the art will acknowledge, that also activated carboxylic acids can be used, such as succinimidyl-ester, pentafluorophenylester or sulfodichlorophenyl ester without the need of an amide bond forming reagent. A person skilled in the art will further acknowledge, that also suitable halogenated aryls can react with the free amine or amine salt in a nucleophilic aromatic substitution manner using a suitable base and solvent such as, e.g. Huenig’s base , trimethylamine, Na₂CO₃ or Cs₂CO₃ in a suitable solvent like DMF, DMA, DCM, ACN, H2O, MeOH or 1,4-dioxane, , preferably between 0 °C and 65 °C. Suitable halogenated aryls include but are not limited to NBD-F or NBD-Cl and other such as sulfur, selenium or carbon containing congeners as described by Marc Vendrell et al. (Angew.Chem.Int.Ed. 2019, 58, 6911 –6915). Alternatively, compound Ib can also be synthesized applying the following reaction sequence: i) removal of the protection group (PG¹) of compound BB applying methods known in the art (e.g., a Boc group using TFA in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); ii) either coupling or substitution reactions with a suitable reporting unit (R^b) such as, but not limited to, fluorescent dyes or biotin give access to compound BD (step h). In case R^b possesses a carboxylic acid, compound Ib can be achieved by amide bond formation as described in step f of scheme 2. A person skilled in the art will acknowledge, that also activated carboxylic acids can be used, such as succinimidyl-ester, pentafluorophenylester or sulfodichlorophenyl ester without the need of an amide bond forming reagent. A person skilled in the art will further acknowledge, that also suitable halogenated aryls can react with the free amine or amine salt in a nucleophilic aromatic substitution manner using a suitable base and solvent such as, e.g. Huenig’s base , trimethylamine, Na2CO3 or Cs2CO3 in a suitable solvent like DMF, DMA, DCM, ACN, H2O, MeOH or 1,4-dioxane, , preferably between 0 °C and 60 °C. Suitable halogenated aryls include but are not limited to NBD-F or NBD-Cl and other sulfur or selenium containing congeners as described by Marc Vendrell et al. (Angew.Chem.Int.Ed. 2019, 58, 6911 –6915).; iii) removal of the protection group (PG²) of compound BD applying methods known in the art (e.g., a Fmoc group using DBU in DCM at temperatures between 0 °C and room temperature, as described for example in “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 4th Ed., 2006, Wiley N.Y.); and iv) amide coupling with corresponding substituted picolinic acids using suitable coupling reagents as in step f of scheme 2 (step g). Examples: The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization. Example 1 Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate Step a) Ethyl 2

hoxy)-2-ethylbutanoate LDA preparation: An oven-dried Schlenk tube was sealed and evacuated and backfilled with N2 three times. Then it was charged with DIPA (288 µL, 2.06 mmol, 1.10 equiv.) and anhydrous THF (11 mL) under positive N₂ pressure and placed in dry ice/acetone bath (- 78 °C). After 10 min, n-BuLi (748 µL of 2.5 ^M solution in hexane, 1.87 mmol, 1.0 equiv.) was added dropwise and the reaction mixture was allowed to stir for 15 min at -78 °C under N2 atmosphere. Then, a solution of ethyl-2-((4-chlorobenzylidene)amino)butanoate (CAS RN 126385-72-6) (237 mg, 0.94 mmol, 1.0 equiv.) in anhydrous THF (3 mL) was added to the freshly prepared LDA and the resulting mixture was stirred at -78 °C. After 15 min, tert-butyl (2-(2-iodoethoxy)ethyl)carbamate (CAS RN 629626-40-0) (325 mg, 1.03 mmol, 1.1 equiv.) solution in anhydrous THF (3 mL) was added dropwise and the mixture was stirred at -78 ^oC for an additional 15 min. Then the mixture was allowed to gradually warm and stirred overnight at rt. The reaction mixture was diluted with EtOAc and quenched with saturated NH4Cl. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated. After dissolving the residue in a mixture of THF:MeOH (3 mL, 3:1 v/v), a solution of citric acid (5 mL, 10%) was added and the mixture was stirred overnight at rt. After removal of the organic solvent under reduced pressure, the residue was extracted with Et₂O (2×). The aqueous phase was basified to pH 8 with NaOH (1 M) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude mixture was used for the next step without further purification. ESI-MS (m/z) 319.3 [M+H]⁺. Step b) Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate To a solution of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) (25 mg, 0.092 mmol, 1.0 equiv.) in anhydrous DMF (0.5 mL), DIPEA (47 µL, 0.28 mmol, 3.0 equiv.) and HATU (38 mg, 0.10 mmol, 1.1 equiv.) were added and stirred for 20 min at rt. Then a solution of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- ethylbutanoate (32 mg, 0.10 mmol, 1.1 equiv.) in DMF (0.2 mL) was added to the mixture. The reaction was stirred for 16 hours at rt. After removal of the solvent under reduced pressure, the residue was purified by preparative HPLC (30-70% ACN in H₂O) to afford the title compound as faint yellow viscous oil (18.5 mg, 35%). ESI-MS (m/z) 572.3 [M+H]⁺. Example 2 Ethyl 14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-2,2-dimethyl-4- oxo-3,8,11-trioxa-5-azapentadecan-15-oate Step a)

ioxa-5-azapentadecan-15- oate The title compound was prepared analogously to Example 1 step a) with the difference that tert-butyl (2-(2-(2-iodoethoxy)ethoxy)ethyl)carbamate (CAS RN 1820026-89-8) was used instead of tert-butyl (2-(2-iodoethoxy)ethyl)carbamate (CAS RN 629626-40-0). ESI-MS (m/z) 363.3[M+H]⁺. Step b) Ethyl 14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-2,2-dimethyl-4- oxo-3,8,11-trioxa-5-azapentadecan-15-oate The title compound was prepared analogously to Example 1 step b) with the difference that ethyl 14-amino-14-ethyl-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azapentadecan-15-oate was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-ethylbutanoate and the crude mixture was purified by automated flash chromatography on silica (10-50% EtOAc in cyclohexane). ESI-MS (m/z) 616.3[M+H]⁺. Example 3 Ethyl 17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl-4- oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate Step a) Eth aoxa-5-azaoctadecan-

18-oate The title compound was prepared analogously to Example 1 step a) with the difference that tert-butyl (2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)ethyl)carbamate (CAS RN 1801273-41- 5) was used instead of tert-butyl (2-(2-iodoethoxy)ethyl)carbamate (CAS RN 629626-40- 0). ESI-MS (m/z) 407.3[M+H]⁺. Step b) Ethyl 17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl-4- oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate The title compound was prepared analogously to Example 1 step b) with the difference that ethyl 17-amino-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- ethylbutanoate and the crude mixture was purified by automated flash chromatography on silica (10-50% EtOAc in cyclohexane). ESI-MS (m/z) 660.3[M+H]⁺. Example 4 Ethyl (R)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl- 4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate Step a) Eth

yl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl- 4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate Ethyl 17-amino-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (400 mg, 0.984 mmol, 1.0 equiv.) was suspended in a KHCO3 solution (10 mL, 1M) and stirred at 0 °C for 10 min. To the resulting mixture was added a solution of (9H-fluoren-9- yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (CAS RN 82911-69-1)(830 mg, 2.46 mmol, 2.5 equiv.) in 1,4-dioxane (10 mL) at 0 °C, allowed to warm to rt and stirred for 3 hours. The completion of the reaction was judged by LCMS. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by automated flash chromatography on silica (10-50% EtOAc in cyclohexane) to provide the racemic mixture of ethyl 17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (600 mg, 65%) as brown viscous oil. ESI-MS (m/z) 651.3[M+Na]⁺. The enantiomers were separated by chiral HPLC (Chiralpak IG from Daicel, H2O:MeOH 20% to 40% MeOH). Step b) Ethyl (R)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate Mixture A: To a solution of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (48.7 mg, 0.075 mmol, 1.0 equiv.) in anhydrous DMF (1 mL), DBU (17 µL, 0.113 mmol, 1.5 equiv.) was added. After 30 min, HOAt (16.52 mg, 0.121 mmol, 1.6 equiv.) was added and the resulting mixture was allowed to stir for another 10 min. Mixture B: To a solution of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) (20.6 mg, 0.075 mmol, 1.0 equiv.) in anhydrous DMF (1 mL) was added DIPEA (33 µL, 0.19 mmol, 2.5 equiv.) and HATU (31.5 mg, 0.083 mmol, 1.1 equiv.) and stirred for 20 min at rt. Then mixtures A and B were combined and the progress of the reaction was judged by LCMS. After removal of the solvent under reduced pressure, the residue was purified by preparative HPLC (30 to 95% ACN in H2O) to afford the title compound as faint yellow viscous oil (13.1 mg, 26%). ESI-MS (m/z) 660.3[M+H]⁺. Example 5 Ethyl (S)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl- 4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate

The

p p p g y p tep b) with the difference that ethyl (S)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4- oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from Example 4 step a) was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. ESI-MS (m/z) 660.3[M+H]⁺. Example 6 Ethyl 20-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-20-ethyl-2,2-dimethyl-4- oxo-3,8,11,14,17-pentaoxa-5-azahenicosan-21-oate

Step a) tert-buty

y To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl 4- methylbenzenesulfonate (CAS RN 1404111-69-8) (1.0 equiv.) in acetone was added potassium iodide (2.0 equiv.) in one portion and the resulting mixture was refluxed for 16 hours. After removal of solvent under the reduced pressure, the residue was partitioned between EtOAc and H2O. The organic layer was separated and washed with Na2S2O3, dried over anhydrous Na₂SO₄, filtered and concentrated to yield tert-butyl (14-iodo-3,6,9,12- tetraoxatetradecyl)carbamate. The crude was used for the next step without further purification. ESI-MS (m/z) 382.1 [M+Na]⁺. Step b) Ethyl 20-amino-20-ethyl-2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5- azahenicosan-21-oate The title compound was prepared analogously to Example 1 step a) with the difference that tert-butyl (14-iodo-3,6,9,12-tetraoxatetradecyl)carbamate was used instead of tert-butyl (2-(2-iodoethoxy)ethyl)carbamate (CAS RN 629626-40-0). ESI-MS (m/z) 451.3 [M+H]⁺. Step c) Ethyl 20-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-20-ethyl-2,2-dimethyl-4- oxo-3,8,11,14,17-pentaoxa-5-azahenicosan-21-oate The title compound was prepared analogously to Example 1 step b) with the difference that ethyl 20-amino-20-ethyl-2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azahenicosan-21- oate was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- ethylbutanoate and the crude mixture was purified by automated flash chromatography on silica (25-70% EtOAc in cyclohexane). ESI-MS (m/z) 704.4 [M+H]⁺. Example 7 Ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-ethyl-2-(6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamido)butanoate The title compou b) w

ith the difference that

6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4- fluorobenzyl)picolinic acid (CAS RN 1415899-48-7). ESI-MS (m/z) 609.3 [M+H]⁺. Example 8 Ethyl 14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5- azapentadecan-15-oate

The title com

) with the differences that 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4- fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and ethyl 14-amino-14-ethyl-2,2- dimethyl-4-oxo-3,8,11-trioxa-5-azapentadecan-15-oate (obtained from Example 2 step a) was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- ethylbutanoate. ESI-MS (m/z) 653.4 [M+H]⁺. Example 9 Ethyl 17-ethyl-17-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate

The title com b) with the differences

that 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4- fluorobenzyl)picolinic acid and ethyl 17-amino-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14- tetraoxa-5-azaoctadecan-18-oate (obtained from Example 3 step a) was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-ethylbutanoate. ESI-MS (m/z) 697.3 [M+H]⁺. Example 10 Ethyl (R)-17-ethyl-17-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate

The title compoun

) with the differences that 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4- fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 697.3 [M+H]⁺. Example 11 Ethyl (S)-17-ethyl-17-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate

The title compound was prepared analogously to Example 4 Step b) with the differences that ethyl (S)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4- oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from Example 4 step a) was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. In addition, 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 697.3 [M+H]⁺. Example 12 Ethyl 20-ethyl-20-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5- azahenicosan-21-oate The title compo

the differences that 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4- fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and ethyl 20-amino-20-ethyl-2,2- dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azahenicosan-21-oate (obtained from Example 6 step b) was used instead of ethyl 2-amino-4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- ethylbutanoate. ESI-MS (m/z) 741.3 [M+H]⁺. Example 13 Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate A solution o )-2-(5-cyclopropyl-6-(4-

fluorobenzyl)picolinamido)-2-ethylbutanoate (obtained from Example 1, step b) (18 mg, 0.032 mmol, 1.0 equiv.) in anhydrous DCM (0.9 mL) and TFA (0.1 mL) was added dropwise at 0 °C. The resulting mixture was allowed to warm to rt and stirred for 2 hours. The solvent was co-evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was placed in a brown flask and dissolved in MeOH (0.5 mL). Then, Et3N (26 µL, 0.191 mmol, 3.0 equiv.) and 4-fluoro-7- nitrobenzo[c][1,2,5]oxadiazole (CAS RN 29270-56-2) (12 mg, 064 mmol, 2.0 equiv.) were added. The resulting mixture was stirred for 16 hours at rt. After removal of the solvent under reduced pressure, the crude mixture was purified by preparative HPLC (30- 95% ACN+ 0.1% TFA in H₂O + 0.1% TFA) to afford the title compound (13.0 mg, 65%) as orange powder. ESI-MS (m/z) 635.3 [M+H]⁺. Example 14 Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate The title compou

h the difference that ethyl 14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-2,2-dimethyl-4-oxo-3,8,11- trioxa-5-azapentadecan-15-oate (obtained from Example 2, step b) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 679.3 [M+H]⁺. Example 15 Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate

The title co

e difference that ethyl 17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from Example 3, step b) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 723.3 [M+H]⁺. Example 16 Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate

Step a) Et

y ( ) (((( f y ) y) y ) ) hyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 13 with the difference that ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from example 4, step a) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 692.3 [M+H]⁺, 714.3 [M+Na]⁺. Step b) Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2- ((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 4 step b) with the difference that ethyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. ESI-MS (m/z) 723.3 [M+H]⁺. Example 17 Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate Step a) Ethyl

yl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 13 with the difference that ethyl (S)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from example 4, step a) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 692.3 [M+H]⁺, 714.3 [M+Na]⁺. Step b) Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2- ((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 4 step b) with the difference that ethyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. ESI-MS (m/z) 723.3 [M+H]⁺. Example 18 Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]- 5-yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11- trioxa-2-azapentadecan-15-oate and ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H- spiro[isobenzofuran-1,9’-xanthen]-6-yl)-14-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate

A solution of ethyl (S)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from example 4, step a); 41.2 mg, 0.062 mmol, 1.0 equiv.) in anhydrous DCM (2 mL) and TFA (0.1 mL) was added dropwise at 0 °C. The resulting mixture was allowed to warm to rt and stirred for 3 hours. The solvent was co-evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was dissolved in anhydrous DMF (1 mL) in a brown flask. To the solution were added anhydrous DIPEA (13.7 µL, 0.079 mmol, 4 equiv.), HOAt (4.3 mg, 0.031 mmol, 1.6 equiv.), EDC.HCl (6.1 mg, 0.031 mmol, 1.6 equiv.) and a mixture of 3’,6’-bis(dimethylamino)-3-oxo-3H- spiro[isobenzofuran-1,9’-xanthene]-5-carboxylic acid and 3’,6’-bis(dimethylamino)-3- oxo-3H-spiro[isobenzofuran-1,9’-xanthene]-6-carboxylic acid (TAMRA-COOH, 5/6- isomer mixture) (CAS RN 98181-63-6) (12.7 mg, 0.03 mmol, 1.5 equiv.). The solution was stirred for 18 hours at rt and the solvent removed under reduced pressure. The crude material was purified by preparative HPLC (50-95% ACN + 0.1% TFA in H₂O + 0.1% TFA). A mixture of the title compounds (6.7 mg, 35%) was obtained as dark purple powder. ESI-MS (m/z) 972.3 ([M+H]⁺). Example 19 Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate

The titl

h the difference that ethyl 20-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-20-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14,17-pentaoxa-5-azahenicosan-21-oate (obtained from Example 6, step c) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 767.3 [M+H]⁺. Example 20 Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate

The title compoun

d was prepared analogously to Example 13 with the difference that ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-ethyl-2-(6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamido)butanoate (obtained from Example 7, step b) was used instead of ethyl 4- (2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanoate was used and the crude mixture was purified by preparative HPLC (30-85% ACN in H2O). ESI-MS (m/z) 671.7 [M+H]⁺. Example 21 Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate

Step a) Ethyl 14-(((

(9 fluo en 9 yl)methoxy)ca bonyl)amino) 4 ethyl , dimethyl-4- oxo-3,8,11-trioxa-5-azapentadecan-15-oate The title compound was prepared analogously to Example 4 step a) with the difference that ethyl 14-amino-14-ethyl-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azapentadecan-15-oate (obtained from Example 2, step a) was used instead of ethyl 17-amino-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. ESI-MS (m/z) 607.3 [M+Na]⁺. Step b) Ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 13 with the difference that ethyl 14-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-14-ethyl-2,2-dimethyl-4-oxo-3,8,11- trioxa-5-azapentadecan-15-oate was used instead of ethyl 4-(2-((tert- butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanoate and the crude material was purified by automated flash chromatography on silica (15-50% EtOAc in cyclohexane). ESI-MS (m/z) 648.3 [M+H]⁺, 670.2 [M+Na]⁺. Step c) Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 4 step b) with the difference that ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 716.3 [M+H]⁺. Example 22 Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate

Step a) Ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 13 with the difference that ethyl 17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (the racemic mixture obtained from example 4, step a) was used instead of ethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(5- cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethylbutanoate. ESI-MS (m/z) 692.3 [M+H]⁺, 714.3 [M+Na]⁺. Step b) Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate The title compound was prepared analogously to Example 4 step b) with the difference that ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate was used instead of ethyl (R)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 760.3 [M+H]⁺. Example 23 Ethyl (R)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate

The title compo

difference that ethyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate (obtained from Example 16 step a) was used instead of ethyl (R)-17-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate and 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5- cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 760.4 [M+H]⁺. Example 24 Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate

The title compo

nce that ethyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate (obtained from Example 17 step a) was used instead of ethyl (R)-17-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate and 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5- cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 760.4 [M+H]⁺. Example 25 Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]- 5-yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate and ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’- xanthen]-6-yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate

Step a) Ethyl (S)-14-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(3’,6’- bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5/6-yl)-14-ethyl-1-oxo- 5,8,11-trioxa-2-azapentadecan-15-oate The title compound was synthesized analogously to Example 18 with the difference that ethyl (S)-17-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azaoctadecan-18-oate (obtained from example 4, step a) was used instead of ethyl (S)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17-ethyl-2,2- dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate. ESI-MS (m/z) 941.3 [M+H]⁺. Step b) Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’- xanthen]-5/6-yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate The title compound was prepared analogously to Example 4 step b) with the difference that ethyl (S)-14-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(3’,6’-bis(dimethylamino)- 3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5/6-yl)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate was used instead of ethyl (R)-17-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-17-ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5- azaoctadecan-18-oate. ESI-MS (m/z) 1009.3 [M+H]⁺. Example 26 Ethyl 15-ethyl-15-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)- 3,6,9,12-tetraoxahexadecan-16-oate The title compound can be synthesized analogously to Example 13 with the difference that ethyl 20-ethyl-20-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5- azahenicosan-21-oate (obtained from Example 12) was used instead of ethyl 4-(2-((tert- butoxycarbonyl)amino)ethoxy)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanoate can be used. Example 27 Tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate Step a) (9H-Fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11- diazapentadecan-13-yl)carbamate To a solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-ethylbutanoic acid (CAS RN 218926-46-6) (200 mg, 0.57 mmol, 1.0 equiv.) in anhydrous DMF (6 mL) were added anhydrous DIPEA (148.0 µL, 0.85 mmol, 1.5 eqiuv.) and HATU (215.2 mg, 0.57 mmol, 1.0 equiv.) and stirred for 20 min at rt. Then a solution of tert-butyl (2-(2- aminoethoxy)ethyl)carbamate (CAS RN 127828-22-2) (127.1 mg, 0.62 mmol, 1.1 equiv.) in anhydrous DMF (2 mL) was added. The reaction was stirred for 1 hour at rt and the solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed with NaHCO3 solution (1M) and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The title compound (255 mg, 83%) was obtained as white powder. ESI-MS (m/z) 562.3 ([M+Na]⁺). Step b) Tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate Mixture A: To a solution of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo- 3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate (20 mg, 0.037 mmol, 1.0 equiv.) in anhydrous DMF (1 mL), DBU (8.0 µL, 0.056 mmol, 1.5 equiv.) was added. After 30 min, HOAt (12 mg, 0.09 mmol, 1.6 equiv.) was added and the resulting mixture was allowed to stir for another 10 min. Mixture B: To a solution of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) (15 mg, 0.056 mmol, 1.5 equiv.) in anhydrous DMF (1 mL) was added DIPEA (9.5 µL, 0.056 mmol, 1.5 equiv.) and HATU (22 mg, 0.056 mmol, 1.5 equiv.) and stirred for 20 min at rt. Then mixtures A and B were combined and the progress of the reaction was judged by LCMS. After removal of the solvent under reduced pressure, the residue was purified by preparative HPLC (30 to 95% ACN/H₂O) to afford the title compound as faint yellow viscous oil (16 mg, 50%). ESI-MS (m/z) 571.3[M+H]⁺. Example 28 Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo- 8,11-dioxa-2,5-diazatridecan-13-yl)carbamate Step a) (9H-Fluoren-9-yl)methyl (16-ethyl-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14- diazaoctadecan-16-yl)carbamate The title compound was prepared analogously to Example 27 step a) with the difference that tert-butyl (2-(2-(2- aminoethoxy)ethoxy)ethyl)carbamate (CAS RN 153086-78-3) was used instead of tert- butyl (2-(2-aminoethoxy)ethyl)carbamate (CAS RN 127828-22-2). ESI-MS (m/z) 606.3 ([M+Na]⁺). Step b) Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that (9H-Fluoren-9-yl)methyl (16-ethyl-2,2- dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazaoctadecan-16-yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11- diazapentadecan-13-yl)carbamate. ESI-MS (m/z) 615:3 [M+H]⁺. Example 29 Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo- 8,11,14-trioxa-2,5-diazahexadecan-16-yl)carbamate Step a) (9H-Fluoren-9-yl)methyl (19-ethyl-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa- 5,17-diazahenicosan-19-yl)carbamate The title compound was prepared analogously to Example 27 step a) with the difference that tert-butyl (2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (CAS RN 101187-40-0) was used instead of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate(CAS RN 127828-22-2). ESI-MS (m/z) 650.4 ([M+Na]⁺). Step b) Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11,14-trioxa-2,5-diazahexadecan-16-yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that (9H-Fluoren-9-yl)methyl (19-ethyl-2,2- dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazahenicosan-19-yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11- diazapentadecan-13-yl)carbamate. ESI-MS (m/z) 659.4 [M+H]⁺. Example 30 Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo- 8,11,14,17-tetraoxa-2,5-diazanonadecan-19-yl)carbamate Step a) (9H-Fluoren-9-yl)methyl (22-ethyl-2,2-dimethyl-4,21-dioxo-3,8,11,14,17- pentaoxa-5,20-diazatetracosan-22-yl)carbamate The title compound was prepared analogously to Example 27 step a) with the difference that tert-butyl (14-amino-3,6,9,12- tetraoxatetradecyl)carbamate (CAS RN 811442-84-9) was used instead of tert-butyl (2-(2- aminoethoxy)ethyl)carbamate (CAS RN 127828-22-2). ESI-MS (m/z) 694.3 ([M+Na]⁺). Step b) Tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11,14,17-tetraoxa-2,5-diazanonadecan-19-yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that tert-butyl (1-(5-cyclopropyl-6-(4- fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11,14,17-tetraoxa-2,5- diazanonadecan-19-yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl- 2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate. ESI-MS (m/z) 703.4 [M+H]⁺. Example 31 Tert-butyl (2-(2-(2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)picolinamido)butanamido)ethoxy)ethyl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 608.4 [M+H]⁺. Example 32 Tert-butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that (9H-Fluoren-9-yl)methyl (16-ethyl-2,2- dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazaoctadecan-16-yl)carbamate (obtained from Example 28 step a) was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl- 4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 652.4 [M+H]⁺. Example 33 Tert-butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11,14-trioxa-2,5-diazahexadecan-16- yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that (9H-Fluoren-9-yl)methyl (19-ethyl-2,2- dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazahenicosan-19-yl)carbamate (obtained from Example 29 step a) was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2- dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 696.2 [M+H]⁺. Example 34 Tert-butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11,14,17-tetraoxa-2,5- diazanonadecan-19-yl)carbamate The title compound was prepared analogously to Example 27 step b) with the difference that tert-butyl (1-(5-cyclopropyl-6-(4- fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11,14,17-tetraoxa-2,5- diazanonadecan-19-yl)carbamate (obtained from Example 30 step a) was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11- diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) . ESI-MS (m/z) 740.4 [M+H]⁺. Example 35 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide

To a solution of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate (obtained from Example 27 step b) (28 mg, 0.05 mmol, 1.0 equiv.) in anhydrous DCM (3.5 mL) was added TFA (0.3 mL) dropwise at 0 °C and stirred for 2 hours. The solvent was co-evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was dissolved in anhydrous MeOH (1 mL) in a brown flask. To the solution were added anhydrous TEA (42 µL, 0.3 mmol, 4.0 equiv.) and 4-fluoro-7- nitrobenzo[c][1,2,5]oxadiazole (CAS RN 29270-56-2) (10 mg, 0.055 mmol, 1.1 equiv.) and the reaction mixture was allowed to stir for 16 hours. The solvent was removed under reduced pressure and the crude material was purified by preparative HPLC (40-95% ACN + 0.1% TFA in H₂O + 0.1% TFA). The title compound (21.5 mg, 68%) was obtained as orange powder. ESI-MS (m/z) 634.3 [M+H]⁺. Example 36 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11- dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate. ESI-MS (m/z) 678.3 [M+H]⁺. Example 37 5-Cyclopropyl-N-(14-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11,14- trioxa-2,5-diazahexadecan-16-yl)carbamate (obtained from Example 29 step b) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate. ESI-MS (m/z) 722.4 [M+H]⁺. Example 38 5-Cyclopropyl-N-(17-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9,12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo- 8,11,14,17-tetraoxa-2,5-diazanonadecan-19-yl)carbamate (obtained from Example 30 step b) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)- 2-ethylbutanamido)ethoxy)ethyl)carbamate. ESI-MS (m/z) 766.4 [M+H]⁺. Example 39 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]selenadiazol- 4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11- dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b)) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and 4-fluoro-7- nitrobenzo[c][1,2,5]selenadiazole (CAS RN 2351940-09-3) was used instead of 4-fluoro- 7-nitrobenzo[c][1,2,5]oxadiazole (CAS RN 29270-56-2). ESI-MS (m/z) 742.2 [M+H]⁺. Example 40 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11- dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and 4-fluoro-7-nitrobenzo[c][1,2,5]thiadiazole (CAS RN 2231233-75-1) was used instead of 4-fluoro-7-nitrobenzo[c][1,2,5]oxadiazole (CAS RN 29270-56-2). ESI-MS (m/z) 694.2 [M+H]⁺. Example 41 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole- 2,1'-cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide To a solution of tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl- 1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) (15 mg, 0.024 mmol, 1.0 equiv.) in anhydrous DCM (3.0 mL) was added TFA (0.3 mL) dropwise at 0 °C and stirred for 2 hours. The solvent was co-evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was dissolved in anhydrous ACN (1 mL) in a brown flask and a mixture of 4-fluoro-7- nitrospiro[benzo[d]imidazole-2,1'-cyclohexane] (CAS RN 2364376-63-4) (10.4 mg, 0.042 mmol, 1.7 equiv.) in ACN (0.5 mL) and NaHCO3 (5.3 mg, 0.064 mmol, 2.6 equiv) in H₂O (0.1 mL) was added. The resulting mixture was stirred at 65 ^oC for 8 hours. After removal of the solvent, the residue was purified by preparative HPLC (30 to 85% ACN in H2O) to afford the title compound as purple powder (3 mg, 16%). ESI-MS (m/z) 744.4 [M+H]⁺. Example 42 5-Cyclopropyl-N-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4- fluorobenzyl)picolinamide The title compound was prepared analogously to Example 41 with the difference that 4- fluoro-2,2-dimethyl-7-nitro-2H-benzo[d]imidazole (CAS RN 2351931-72-9) was used instead of 4-fluoro-7-nitrospiro[benzo[d]imidazole-2,1'-cyclohexane] (CAS RN 2364376- 63-4). ESI-MS (m/z) 703.8 [M+H]⁺. Example 43 N-(3-((2-(2-(2-((2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide Step a) 4-fluoro-2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazole A pressure tube was charged with a solution of 3-fluoro-6-nitrobenzene-1,2-diamine (CAS RN 1804879-89-7) (30 mg, 0.175 mmol, 1 equiv.) in EtOD (1 mL), Cu(OAc)₂ (4.7 mg, 0.026 mmol, 0.15 equiv.) and propan-2-one-d6 (128 µL, 1.27 mmol, 10 equiv.) and sealed. The reaction mixture was stirred at 90 ^oC. for 16 hours under microwave radiation. After removal of the solvent, the residue was purified using by preparative HPLC (30 to 85% ACN in H₂O) to afford 4-fluoro-2,2-bis(methyl-d₃)-7-nitro-2H-benzo[d]imidazole (23 mg, 83%). ESI-MS (m/z) 216.2 [M+H]⁺. Step b) N-(3-((2-(2-(2-((2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide The title compound was prepared analogously to Example 41 with the difference that 4- fluoro-2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazole was used instead of 4-fluoro-7- nitrospiro[benzo[d]imidazole-2,1'-cyclohexane] and D2O was used instead of H2O. ESI- MS (m/z) 710.2 [M+H]⁺. Example 44 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide Step a) 4-fluoro-7-nitro-2-(prop-2-yn-1-yl)-2H-benzo[d][1,2,3]triazole In a brown flask 4-Fluoro-7-nitro-2H-benzo[d][1,2,3]triazole (CAS RN 2351938-18-4) (50.1 mg, 0.28 mmol, 1.0 equiv.) was dissolved in DMF (1 mL) under N₂-flow. Then freshly grinded CsCO3 (273.7 mg, 0.84 mmol, 3 equiv.) and propargyl bromide (64 μL, 0.84 mmol, 3 equiv.) was added and the reaction was stirred 30 min at rt. The mixture was diluted with EtOAc (50 mL), filtered through a pad of Celite and washed with H₂O (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by automated flash chromatography on silica (0-25% EtOAc in cyclohexane) to obtain 4-fluoro-7-nitro-2- (prop-2-yn-1-yl)-2H-benzo[d][1,2,3]triazole as light brown solid (4 mg, 7%). ESI-MS (m/z) 221.0 [M+H]⁺. Step b) 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide The title compound was prepared analogously to Example 35 with the difference that tert- butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11- dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and 4-fluoro-7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazole was used instead of 4-fluoro-7-nitrobenzo[c][1,2,5]oxadiazole (CAS RN 29270-56-2). ESI-MS (m/z) 714.7 [M+H]⁺. Example 45 N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13- yl)-5-cyclopropyl-6-(4-fluorobenzyl)picolinamide

Mixture A: To a solution of tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)- 3,3-diethyl-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) (7.1 mg, 0.012 mmol, 1.1 equiv.) in anhydrous DCM (1.5 mL) was added TFA (0.1 mL) dropwise at 0 °C and stirred for 2 hours at rt. The solvent was co- evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was dissolved in anhydrous DMF (0.2 mL) in a brown flask. Mixture B: In a brown flask 3,7-bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H- spiro[dibenzo[b,e]siline-10,1'-isobenzofuran]-6'-carboxylic acid (SiR-COOH) (CAS RN 1426090-03-0) (5 mg, 0.011 mmol, 1.0 equiv.) was dissolved in anhydrous DMF (0.5 mL). Then, DIPEA (3.7 mL, 0.021 mmol, 3.0 equiv.) and HATU (4.1 mg, 0.011 mmol, 1.0 equiv.) were added and mixture was stirred for 15 min at rt. Then mixtures A and B were combined and the progress of the reaction was judged by LCMS. After removal of the solvent under reduced pressure, the residue was purified by preparative HPLC (30-95% ACN + 0.1% TFA in H2O + 0.1% TFA) to afford the title compound as blue powder (8.8 mg, 86%). ESI-MS (m/z) 970.4 [M+H]⁺. Example 46 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid and 3',6'-diamino-6-((1-(5-cyclopropyl-6-(4- fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid The title compound was prepared analogously to Example 45 with the difference that Alexa Fluor® 488 carboxylic acid, tris(triethylammonium) salt (ThermoFisher) was used instead of 3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline-10,1'- isobenzofuran]-6'-carboxylic acid (SiR-COOH) (CAS RN 1426090-03-0) to obtain the product as yellow powder. ESI-MS (m/z) 1031.3 [M+H]⁺. Example 47 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5- yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide and 5-cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H- spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11- diazapentadecan-13-yl)-6-(4-fluorobenzyl)picolinamide To a solution of tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl- 1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) (6.7 mg, 0.011 mmol, 1.1 equiv.) in anhydrous DCM (1.5 mL) was added TFA (0.1 mL) dropwise at 0 °C and stirred for 2 hours. The solvent was co-evaporated with toluene (3×) and the crude material was used for the next step without further purification. The residue was dissolved in anhydrous ACN (1 mL) in a brown flask. To the solution were added anhydrous DIPEA (3.8 µL, 0.022 mmol, 2.0 equiv.) and 2,5-dioxopyrrolidin-1-yl 3',6'- dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-6-carboxylate (Fluorescein- OSu, 5/6-isomer mixture) (CAS RN 117548-22-8) (5.9 mg, 0.012 mmol, 1.1 equiv.) and the reaction mixture was allowed to stir for 20 hours. The solvent was removed under reduced pressure and the crude material was purified by preparative HPLC (50-95% ACN + 0.1% TFA in H2O + 0.1% TFA). A mixture of the title compounds (4.7 mg, 49%) was obtained as orange powder. ESI-MS (m/z) 873.6 ([M+H]⁺). Example 48 N-(1-(3',6'-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide and N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H- spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11- diazapentadecan-13-yl)-5-cyclopropyl-6-(4-fluorobenzyl)picolinamide A mixture of the title compounds was prepared analogously to Example 18 with the difference that tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl- 1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 28 step b) was used instead of ethyl (S)-17-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-17- ethyl-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecan-18-oate and the crude was purified by preparative HPLC (30 to 95% ACN in H₂O). ESI-MS (m/z) 927.4 [M+H]⁺. Example 49 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3- sulfonatopropyl)-3H-indol-1-ium-5-sulfonate The title compound was prepared analogously to Example 45 with the difference that tris(triethylammonium) 3-(5-carboxypentyl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato- 1-(3-sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3- sulfonatopropyl)-3H-indol-1-ium-5-sulfonate (Alexa Fluor™ 647 carboxylic acid, tris(triethylammonium) salt, ThermoFisher) was used instead of 3,7-bis(dimethylamino)- 5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline-10,1'-isobenzofuran]-6'-carboxylic acid (SiR-COOH) (CAS RN 1426090-03-0). ESI-MS (m/z) 678.3 [M/2+H]⁺. Example 50 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N- (3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide Step a) (9H-fluoren-9-yl)methyl (3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)carbamate The title compound was prepared analogously to Example 35 with the difference that (9H- Fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazapentadecan- 13-yl)carbamate (obtained from Example 27 step a) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4- fluorobenzyl)picolinamido)-2-ethylbutanamido)ethoxy)ethyl)carbamate and the crude was purified by automated flash chromatography on silica (10-100% EtOAc in cyclohexane). ESI-MS (m/z) 603.2 [M+H]⁺. Step b) 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)- N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide The title compound was prepared analogously to Example 27 step b) with the difference that (9H-fluoren-9-yl)methyl (3-((2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12- dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and the crude was purified by preparative HPLC (30 to 95% ACN in H2O). ESI-MS (m/z) 671.3 [M+H]⁺. Example 51 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N- (3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide Step a) (9H-fluoren-9-yl)methyl (3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)carbamate The title compound was prepared analogously to Example 35 with the difference that (9H- Fluoren-9-yl)methyl (16-ethyl-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14- diazaoctadecan-16-yl)carbamate (obtained from Example 28 step a) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and the crude was purified by automated flash chromatography on silica (0-4% MeOH in DCM). ESI-MS (m/z) 647.3[M+H]⁺. Step b) 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)- N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide The title compound was prepared analogously to Example 27 step b) with the difference that (9H-fluoren-9-yl)methyl (3-((2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12- dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and the crude was purified by preparative HPLC (30 to 95% ACN in H2O). ESI-MS (m/z) 715.3 [M+H]⁺. Example 52 N-(14-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide Step a) (9H-fluoren-9-yl)methyl (14-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)-13-oxo-3,6,9-trioxa-12-azahexadecan-14-yl)carbamate The title compound was prepared analogously to Example 35 with the difference (9H- Fluoren-9-yl)methyl (19-ethyl-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17- diazahenicosan-19-yl)carbamate (obtained from Example 29 step a) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and and the crude was purified by automated flash chromatography on silica (0-1% MeOH in DCM). ESI-MS (m/z) 691.3 [M+H]⁺. Step b) N-(14-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9- trioxa-12-azahexadecan-14-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide The title compound was prepared analogously to Example 27 step b) with the difference that (9H-fluoren-9-yl)methyl (14-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12-azahexadecan-14- yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl-4,12- dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and the crude was purified by preparative HPLC (30 to 95% ACN in H₂O). ESI-MS (m/z) 759.4 [M+H]⁺. Example 53 N-(17-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12- tetraoxa-15-azanonadecan-17-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide Step a) (9H-fluoren-9-yl)methyl (17-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)-16-oxo-3,6,9,12-tetraoxa-15-azanonadecan-17-yl)carbamate The title compound was prepared analogously to Example 35 with the difference that (9H- Fluoren-9-yl)methyl (22-ethyl-2,2-dimethyl-4,21-dioxo-3,8,11,14,17-pentaoxa-5,20- diazatetracosan-22-yl)carbamate (obtained from Example 30 step a) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate and the crude was purified by automated flash chromatography on silica (0-1% MeOH in DCM). ESI-MS (m/z) 735.3 [M+H]⁺. Step b) N-(17-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12- tetraoxa-15-azanonadecan-17-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)picolinamide The title compound was prepared analogously to Example 27 step b) with the difference that (9H-fluoren-9-yl)methyl (17-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa-15-azanonadecan- 17-yl)carbamate was used instead of (9H-fluoren-9-yl)methyl (13-ethyl-2,2-dimethyl- 4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-13-yl)carbamate and 6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5-cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7) and the crude was purified by preparative HPLC (30 to 95% ACN in H₂O). ESI-MS (m/z) 803.3 [M+H]⁺. Example 54 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid and 3',6'-diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid

The title compound was prepared analogously to Example 45 with the difference that Alexa Fluor® 488 carboxylic acid, tris(triethylammonium) salt (ThermoFisher) was used instead of 3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline-10,1'- isobenzofuran]-6'-carboxylic acid (SiR-COOH) and tert-butyl (3,3-diethyl-1-(6-(((1S,2S)- 2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate (obtained from Example 32) was used instead of tert-butyl (1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl- 1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamate to obtain the product as purple powder) and the crude was purified by preparative HPLC (30 to 95% ACN in H₂O). ESI- MS (m/z) 1067.4 [M+H]⁺. Example 55 N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13- yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide

The title compound was prepared analogously to Example 45 with the difference that tert- butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamate (obtained from Example 32) was used instead of tert-butyl (1-(5-cyclopropyl- 6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamate to obtain the product as purple powder ) and the crude was purified by preparative HPLC (30 to 95% ACN in H₂O). ESI-MS (m/z) 503.5 [M/2+H]⁺. Example 56 N-(1-(3',6'-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide and N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide

Step a) (9H-Fluoren-9-yl)methyl (1-(3',6'-bis(dimethylamino)-3-oxo-3H- spiro[isobenzofuran-1,9'-xanthen]-5/6-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11- diazapentadecan-13-yl)carbamate The title compound was synthesized analogously to Example 18 with the difference that (9H-Fluoren-9-yl)methyl (16-ethyl-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14- diazaoctadecan-16-yl)carbamate (obtained from Example 28 step a) was used instead of tert-butyl (2-(2-(2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2- ethylbutanamido)ethoxy)ethyl)carbamate. ESI-MS (m/z) 896.4 [M+H]⁺. Step b) N-(1-(3',6'-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5/6- yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide The title compound was prepared analogously to Example 27 step b) with the difference that (9H-fluoren-9-yl)methyl (1-(3',6'- bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5/6-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)carbamate was used instead of (9H-fluoren- 9-yl)methyl (13-ethyl-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-13- yl)carbamate and 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinic acid (CAS RN 2407468-22-6) was used instead of 5- cyclopropyl-6-(4-fluorobenzyl)picolinic acid (CAS RN 1415899-48-7). ESI-MS (m/z) 964.3 [M+H]⁺. Example 57 3-(3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4,15-trioxo-8,11-dioxa-2,5,14-triazaicosan-20- yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5- sulfonate Tert-butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamate (405 mg, 0.062 mmol) was dissolved in DCM (2 mL) at 0°C and treated with TFA (800 µL) dropwise. The reaction was judged by LCMS to be completed and after removal of the solvent the residue was used for next step without further purification. The residue (2 mg, 3.3 µmol) was dissolved in a mixture of DMF/ACN (1 mL). Then 2- ((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2-ylidene)penta- 1,3-dien-1-yl)-3-(6-((2,5-dioxopyrrolidin-1-yl)oxy)-6-oxohexyl)-3-methyl-1-(4- sulfonatobutyl)-3H-indol-1-ium-5-sulfonate (AF647 NHS ester) (5 mg, 5 µmol) and DIPEA (2 µL, 6.6 µmol) was added and allowed to stir for overnight. After removal of solvent the residue was purified with preparative HPLC (5 to 95% ACN in H2O). ESI-MS (m/z) 703.3 [M/2+H]⁺. Example 58 N-(1-(3',6'-Dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl- 1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide and N-(1-(3',6'-Dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13-ethyl- 1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide The title compound can be prepared analogously to Example 47 with the difference that tert-butyl (3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamate (obtained from Example 32) can be used instead of tert-butyl (1-(5- cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4-dioxo-8,11-dioxa-2,5- diazatridecan-13-yl)carbamate. Example 59 Radioligand binding assay Cell culture and membrane preparation CHOK1hCB₁_bgal and CHOK1hCB₂_bgal cells (DiscoverRx, Fremont, CA, USA) were cultured in Dulbecco’s Modified Eagle’s Medium/Nutrient Mixture F-12 Ham supplemented with 10% fetal calf serum, 1 mM glutamine, 50 µg/mL penicillin, 50 µg/mL streptomycin, 300 mg/mL hygromycin and 800 µg/mL geneticin in a humidified atmosphere at 37°C and 5% CO2. Cells were subcultured twice a week at a ratio of 1:20 on 10-cm diameter plates by trypsinization. For membrane preparation the cells were subcultured with a ratio of 1:10 and transferred to 15-cm diameter plates. The cells were collected by scraping in 5 mL phosphate-buffered saline (PBS) and centrifuged at 1,000 g for 5 min. Pellets derived from 30 plates were combined and resuspended in 20 mL cold Tris-HCl, MgCl2 buffer (50 mM Tris-HCl (pH 7.4), 5 mM MgCl2). The cell suspension was homogenized using an UltraTurrax homogenizer (Heidolph Instruments Schwabach, Germany). Membranes and cytosolic fractions were separated by centrifugation in a Beckman Optima LE-80K ultracentrifuge (Beckman Coulter Inc., Fullerton, CA, USA) at 100,000 g for 20 min at 4°C. The supernatant was discarded. The pellet was resuspended in 10 mL cold Tris-HCl, MgCl2 buffer and homogenization and centrifugation steps were repeated. The membranes were resuspended in 10 mL cold Tris-HCl, MgCl₂ buffer. Aliquots of 100 µL were stored at -80°C until further use. The protein concentration was determined using the Pierce™ BCA Protein Assay Kit (ThermoFisher Scientific, Waltham, MA, USA). [³H]CP55940 Displacement assay [³H]CP55940 displacement assays on 96-well plates were performed in 50 mM Tris-HCl (pH 7.4), 5 mM MgCl₂, 0.1% BSA assay buffer. Membrane aliquots of either CHOK1hCB1_bgal or CHOK1CB2_bgal containing 1 or 2.5 µg membrane protein respectively, were incubated at 25°C for 2 hours in the presence of ~1.5 nM [³H]CP55940 (specific activity 106.5 Ci/mmol; PerkinElmer, Waltham, MA). At first, all compounds were tested at a final concentration of 10 µM compound. When radioligand displacement was greater than 50%, full curves were recorded to determine the affinity (pK_i) values of the compounds. To determine the total binding, a control without test compound was included. Nonspecific binding was determined in the presence of 10uM Rimonabant (CHOK1hCB1_bgal) or AM630 (CHOK1hCB2_bgal). The total assay volume was 100 µL. The final concentration of DMSO was 0.25%. The incubation was terminated by rapid vacuum filtration through GF/C 96-well filter plates (PerkinElmer, Waltham, MA), to separate the bound and free radioligand, using a PerkinElmer Filtermate-harvester (PerkinElmer, Groningen, The Netherlands). Filters were subsequently washed twenty times with ice-cold assay buffer. The filter-bound radioactivity was determined by scintillation spectrometry using a Microbeta2® 2450 microplate counter (PerkinElmer, Boston, MA), after addition of 25μl MicroScint-O (PerkinElmer, Groningen, The Netherlands) and 3 hours incubation. Data Analysis All experimental data were analyzed using GraphPad Prism 9 (GraphPad Software Inc., San Diego, CA). The data were normalized to % specific radioligand binding, where total binding is 100% and nonspecific binding is 0%. Nonlinear regression for one-site was used to determine the IC50 values from the full curve [³H]CP55940 displacement assays. The pK_i values were obtained using the Cheng-Prusoff equation¹ , where [L] is the exact concentration [³H]CP55940 determined per experime _D is the dissociation

constant of [³H]CP55940, which is 0.84 and 0.48 nM for CB1R and CB2R, respectively (data not shown). All data were obtained from at least three separate experiments performed in duplicate. TR-FRET Assay Cell Culture Cells were maintained in a humidified environment at 37 °C and 5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS) containing blasticidin (5 µg/ml; Invitrogen) and (Zeocin; 20 µg/ml; Invitrogen). For inducible expression, SNAP-tagged human CB2 receptor cDNAs, in pcDNA4/TO were introduced through transfection, using PEI into HEK293TR cells (Invitrogen, which express Tet repressor protein to allow inducible expression). A mixed population stable line was selected by resistance to blasticidin (TR vector, 5 µg/ml) and Zeocin; (receptor plasmid, 20 µg/ml). For receptor-inducible expression, cells were seeded into t175 cm² flasks, grown to 70% confluence and DMEM containing 1 µg/ml tetracycline added.24h later cells were labelled with SNAP-Lumi4-Tb (CisBio) and membranes prepared as described in detail below. Terbium labeling of SNAP-tagged CB2 HEK293-TR cells Cell culture medium was removed from the t175 cm² flasks containing confluent adherent CB2 HEK293-TR cells. Cells were washed 1× in PBS (GIBCO Carlsbad, CA) followed by 1x Tag-lite labeling medium (LABMED, CisBio) to remove the excess cell culture media, then ten millilitre of LABMED containing 100 nM of SNAP-Lumi4-Tb was added to the flask and incubated for 1 h at 37 °C under 5% CO₂. Cells were washed 1× in PBS (GIBCO Carlsbad, CA) to remove the excess of SNAP-Lumi4-Tb then detached using 5 ml of GIBCO enzyme-free Hank’s-based cell dissociation buffer (GIBCO, Carlsbad, CA) and collected in a vial containing 5 ml of DMEM (Sigma-Aldrich) supplemented with 10% fetal calf serum. Cells were pelleted by centrifugation (5 min at 1500 rpm) and the pellets were frozen to −80 °C. To prepare membranes, homogenization steps were conducted at 4 °C (to avoid receptor degradation) as described in Herenbrink et al., 2016. Fluorescent ligand-binding assays All fluorescent ligand binding experiments were conducted in white 384-well Optiplate plates, in assay binding buffer, either Hanks Balanced Salt Solution (HBSS), 5mM HEPES, 0.5% BSA, 0.02% pluronic F-127 pH 7.4, and 100 μM GppNHp or LABMED (Cisbio, Codolet, France) containing 5mM HEPES, 0.5% BSA, 0.02% pluronic acid pH 7.4, and 100 μM GppNHp. GppNHp was included to remove the G protein-coupled population of receptors that can result in two distinct populations of binding sites in membrane preparations, since the Motulsky-Mahan model is only appropriate for ligands competing at a single site. In all cases, nonspecific binding was determined by the presence of 1 μM SR144528. Determination of fluorescent ligand binding kinetics and equilibrium affinity To accurately determine association rate (kon) and dissociation rate (koff) values, the observed rate of association (kob) was calculated using at least five different concentrations fluorescent ligand. The appropriate concentration of fluorescent ligand binding was incubated with human CB2R HEK293-TR cell membranes (1 μg per well) in assay binding buffer (final assay volume, 40 μl). The degree of fluorescent ligand bound to the receptor was assessed at multiple time points by HTRF detection to allow construction of association kinetic curves. The resulting data were globally fitted to the association kinetic model (Eq.1, see signal detection and data analysis section below) to derive a single best- fit estimate for kon and koff as described under data analysis. Saturation analysis was performed at equilibrium, by simultaneously fitting total and Nonspecific (NSB) binding data (Eq.2, see signal detection and data analysis section below) allowed the determination of fluorescent ligand binding affinity. Competition binding To determine the affinity of CB₂R-specific ligands, we used a simple competition kinetic binding assay. This approach involves the simultaneous addition of both fluorescent ligand and competitor to the CB2R preparation. Compounds were added simultaneously with increasing concentrations of the unlabeled compound to CB₂R cell membranes (1 μg per well) in 40 μl of assay buffer in a 384-well plate incubated at room temperature with orbital mixing. The degree of fluorescent ligand bound to the receptor was assessed at equilibrium by HTRF detection. Nonspecific binding was determined as the amount of HTRF signal detected in the presence of SR144528 (1 μM) and was subtracted from total binding, to calculate specific binding for construction of IC₅₀ curves. Signal detection and data analysis Signal detection was performed on a Pherastar FSX (BMG Labtech, Offenburg, Germany). The terbium donor was always excited with eight laser flashes at a wavelength of 337 nm. TR-FRET signals were collected at 665 (acceptor) and 620 nm (donor) when using the red acceptor fluorescent ligand, at 520 (acceptor) and 620 nm (donor surrogate) when using the green acceptor fluorescent ligand. HTRF ratios were obtained by dividing the acceptor signal by the donor signal and multiplying this value by 10,000. All experiments were analyzed by non-regression using Prism 8.0 (GraphPad Software, San Diego, USA). Fluorescent ligand association data were fitted as follows to a global fitting model using GraphPad Prism 8.0 to simultaneously calculate k_on and k_off using the following equation, kob = [L]*kon + koff (Eq.1) Y = Y_max*(1-exp(-1*k_ob*X)) Where, kob equals the observed rate of ligand association and kon and koff are the association and dissociation-rate constants respectively of the fluorescent ligand. In this globally fitted model of tracer binding, tracer concentrations [L] are fixed, kon and koff are shared parameters whilst k_obs is allowed to vary. Here, Y is the level of receptor-bound tracer, Y_max is the level of tracer binding at equilibrium, X is in units of time (eg. min) and kobs is the rate in which equilibrium is approached (eg. min⁻¹). Saturation binding data were analysed by non-linear regression according to a one-site (Eq.2) equation by globally fitting total and NSB. Individual estimates for the fluorescent ligand dissociation constant (K_d) were calculated using the following equations where L is the fluorescent ligand concentration: Fitting the total and NSB data sets globally (simultaneously), sharing the value of slope, provides one best-fit value for both the Kd and the Bmax. Competition displacement binding data were fitted to sigmoidal (variable slope) curves using a ‘four-parameter logistic equation’: Y = Bottom + (Top-Bottom)/(1+10^{(logIC50-X).Hill coefficient}) (Eq.3) IC₅₀ values obtained from the inhibition curves were converted to K_i values using the method of Cheng and Prusoff.¹ Ki = IC50/(1+[fluorescent tracer concertation]/Kd) (Eq.4) References Table 1 provides an overview over Kd and Ki values of exemplified compounds of the invention wherein the values were obtained from the above-described assays.

30 46 1472 144

Claims

CLAIMS: 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; (I) wherein A is: formula (a) R^a L^a (a) or formula (b) _R ^{b Lb} (b) wherein a double line indicates the point of attachment to the rest of formula (I); and wherein L^a and L^b are each independently selected from: 1-30 membered alkylene, 1-30 membered heteroalkylene, 2-30 membered alkenylene, 2- 30 membered heteroalkenylene, 2-30 membered alkynylene, and 2-30 membered heteroalkynylene; each of which is optionally substituted, wherein the optionally substituted 1-30 membered heteroalkylene, 2-30 membered heteroalkenylene, and 2-30 membered heteroalkynylene each comprise 1-15 heteroatoms selected from the group consisting of N, O, NR⁵, and C(O), wherein R⁵ is H or C_1-6 alkyl R^a and R^b are each independently a fluorescent label or one half of a biotin or biotin derivative binding pair; R² is and R³ is ; or R² is: and R³ is: . 2. A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein any L^a and/or L^b is independently selected from: * * n n , , , * * n n , , * * * n n n , , , * * * n n , , n , * * * n_, n and n ; wherein each n is independently an integer selected from 1,

2, 3, 4, 5, 6 and 7; a wavy line indicates the point of attachment to R^a or R^b; and an asterisk indicates the point of attachment of L^a or L^b to the remaining part of fragment A; preferably, wherein any L^a and/or L^b are selected from: * n ; and .

3. A compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein A is formula (a) and L^a is: * n ; wherein each n is independently an integer selected from 1, 2, 3, 4, 5, 6, and 7; a wavy line indicates the point of attachment to R^a ; and an asterisk indicates the point of attachment of L^a to rest of the fragment A. 4. A compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein A is formula (b) and L^b is: wherein each n is independently an integer selected from 1, 2, 3,

4, 5, 6, and 7; a wavy line indicates the point of attachment R^b; and an asterisk indicates the point of attachment L^b to rest of the fragment A.

5. A compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt or solvate thereof, wherein n is independently an integer selected from 1, 2, 3 and 4.

6. A compound according to claim 5 or a salt or solvate thereof, wherein n is independently an integer selected from 2 or 3; preferably, A is formula (a) and n is 3; or preferably, A is formula (b) and n is 2.

7. A compound according to any one of claims 1 to 3, 5 or 6 or a pharmaceutically acceptable salt or solvate thereof, wherein A is formula (a).

8. A compound according to any one of claims 1, 2 or 4 to 6 or a pharmaceutically acceptable salt or solvate thereof, wherein A is formula (b).

9. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, wherein any R^a and/or R^b are independently selected from the following structures or their tautomers: N_{BD , , ,} , , , , , ,

Alexa647 wherein m is 1 or 2, DY480XL , Silicon Rhodamine AttoThio12 , , Cy5.5 _{, Cy5 ,}

BODIPY-FL BODIPY-630/650 , , Alexa405 Alexa546 , , Alexa633 , 150 _{Fluorescein , Indocyanine green ,} MR121 , and ; wherein a wavy line indicates the point of attachment to the L^a or L^b.

10. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, wherein any of R^a and/or R^b are each independently selected from the following structures or their tautomers: N_{BD , , ,}

nitrospiro[benzo[d]imidaz 2,2-dimethyl-4-nitro-2H- 2,2-bis(methyl-c/3)-4-nitro- ole-2,1 '-cyclohexane] benzo[d]imidazole 2H-benzo[d]imidazole

4-nitro-2-(prop-2-yn-1 -yl)- Silicon Rhodamine 2H-benzo[d][1 ,2,3]triazole 2

wherein m is 1 or 2, and ; preferably any of R^a and/or R^b are each independently selected from the following structures or their tautomers: N_{BD ,} , Alexa647

Silicon Rhodamine wherein m is 1 or 2, _{, and Fluorescein ;} more preferably, any of R^a and R^b are each independently selected from the following structures or their tautomers: N_{BD ,} Silicon Rhodamine or .

11. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, wherein R² is: and R³ is: .

12. A compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein any of R^a and/or R^b are each independently selected from:

_{NBD , ,} Alexa647 Silicon Rhodamine wherein m is 1 or 2, _{, Fluorescein , and} .

13. A compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein any of R^a and/or R^b are each independently selected from the following structures or their tautomers N_{BD , ,} Alexa647 Silicon Rhodamine wherein m is 1 or 2, , _{, Fluorescein , and ,} and n is independently an integer selected from 2 or 3; preferably n is 2.

14. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or solvate thereof, wherein: R² is and R³ is .

15. A compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, wherein any of R^a and/or R^b are each independently selected from: N_{BD , , ,} , , , Silicon Rhodamine , , ,

_{Fluorescein ,} Alexa647 wherein m is 1 or 2, and .

16. A compound according to claim 15 or a pharmaceutically acceptable salt or solvate thereof, wherein any of R^a and/or R^b are each independently selected from: N_{BD , , ,} , , , Silicon Rhodamine , , , Fluorescein , Alexa647 wherein m is 1 or 2, and , and n is independently an integer selected from 2 or 3; preferably n is 2.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or solvate thereof, selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’- xanthen]-5-yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’- xanthen]-6-yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl 15-ethyl-15-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)- 3,6,9,12-tetraoxahexadecan-16-oate; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(14-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(17-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9,12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,1'- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide; N-(3-((2-(2-(2-((2,2-bis(methyl-d₃)-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-Bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3-sulfonatopropyl)- 3H-indol-1-ium-5-sulfonate; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; N-(14-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; N-(17-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa- 15-azanonadecan-17-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; 3-(3,3-Diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4,15-trioxo-8,11-dioxa-2,5,14-triazaicosan-20-yl)- 2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate; N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; and N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide.

18. A compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,1'- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3-sulfonatopropyl)- 3H-indol-1-ium-5-sulfonate; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide; and 3-(3,3-Diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4,15-trioxo-8,11-dioxa-2,5,14-triazaicosan-20-yl)- 2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate.

19. A compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, selected from: Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl 15-ethyl-15-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)- 3,6,9,12-tetraoxahexadecan-16-oate; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; N-(14-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; N-(17-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa- 15-azanonadecan-17-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; 3-(3,3-Diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4,15-trioxo-8,11-dioxa-2,5,14-triazaicosan-20-yl)- 2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate; N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; and N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide.

20. A compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(14-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(17-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9,12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,1'- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide; N-(3-((2-(2-(2-((2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; and 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3-sulfonatopropyl)- 3H-indol-1-ium-5-sulfonate.

21. A compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, selected from: 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(14-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo- 3,6,9-trioxa-12-azahexadecan-14-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(17-ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo- 3,6,9,12-tetraoxa-15-azanonadecan-17-yl)-6-(4-fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]selenadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]thiadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((4-nitrospiro[benzo[d]imidazole-2,1'- cyclohexan]-7-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 5-Cyclopropyl-N-(3-((2-(2-(2-((2,2-dimethyl-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-6-(4-fluorobenzyl)picolinamide; N-(3-((2-(2-(2-((2,2-bis(methyl-d3)-7-nitro-2H-benzo[d]imidazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitro-2-(prop-2-yn-1-yl)-2H- benzo[d][1,2,3]triazol-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; 5-Cyclopropyl-N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)- 13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-5-cyclopropyl-6-(4- fluorobenzyl)picolinamide; 3-(1-(5-Cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4,15-trioxo-8,11- dioxa-2,5,14-triazaicosan-20-yl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3- sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(3-sulfonatopropyl)- 3H-indol-1-ium-5-sulfonate; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethyl)carbamoyl)pentan-3- yl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; N-(14-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-13-oxo-3,6,9-trioxa-12- azahexadecan-14-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; N-(17-Ethyl-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa- 15-azanonadecan-17-yl)-6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; N-(1-(3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13- ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; 3-(3,3-Diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)pyridin-2-yl)-1,4,15-trioxo-8,11-dioxa-2,5,14-triazaicosan-20-yl)- 2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfonato-1-(3-sulfonatopropyl)indolin-2- ylidene)penta-1,3-dien-1-yl)-3-methyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate; N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide; and N-(1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-13-ethyl-1,12- dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)-6-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamide.

22. A compound according to claim 17 or a salt or solvate thereof, selected from: 5-Cyclopropyl-6-(4-fluorobenzyl)-N-(3-((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 3',6'-Diamino-5-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((1-(5-cyclopropyl-6-(4-fluorobenzyl)pyridin-2-yl)-3,3-diethyl-1,4- dioxo-8,11-dioxa-2,5-diazatridecan-13-yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran- 1,9'-xanthene]-4',5'-disulfonic acid; N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 5-cyclopropyl-6-(4-fluorobenzyl)picolinamide; 6-(((1S,2S)-2-(Hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)-N-(3- ((2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)pentan-3-yl)picolinamide; 3',6'-Diamino-5-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; 3',6'-Diamino-6-((3,3-diethyl-1-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5- (3-methoxyazetidin-1-yl)pyridin-2-yl)-1,4-dioxo-8,11-dioxa-2,5-diazatridecan-13- yl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; and N-(1-(3,7-Bis(dimethylamino)-5,5-dimethyl-3'-oxo-3'H,5H-spiro[dibenzo[b,e]siline- 10,1'-isobenzofuran]-6'-yl)-13-ethyl-1,12-dioxo-5,8-dioxa-2,11-diazapentadecan-13-yl)- 6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1- yl)picolinamide.

23. A compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, selected from: Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-2-ethyl-4-(2-(2-(2-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-14-ethyl-1-oxo-5,8,11-trioxa-2- azapentadecan-15-oate; Ethyl 15-(5-cyclopropyl-6-(4-fluorobenzyl)picolinamido)-15-ethyl-1-((7- nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-3,6,9,12-tetraoxahexadecan-16-oate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)butanoate; Ethyl 2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (R)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-2-ethyl-2-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-4-(2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)ethoxy)ethoxy)ethoxy)butanoate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-5- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; Ethyl (S)-1-(3’,6’-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9’-xanthen]-6- yl)-14-ethyl-14-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-oxo-5,8,11-trioxa-2-azapentadecan-15-oate; and Ethyl 15-ethyl-15-(6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3- methoxyazetidin-1-yl)picolinamido)-1-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)- 3,6,9,12-tetraoxahexadecan-16-oate.

24. A compound according to any one of claims 1-13, 17-19 and 21-23 or a pharmaceutically acceptable salt or solvate thereof, which is an inverse agonist of cannabinoid receptor type 2 (CB2).

25. A compound according to any one of claims 1-10, 14-18 and 20-23 or a pharmaceutically acceptable salt or solvate thereof, which is an agonist of cannabinoid receptor type 2 (CB2).

26. A method of manufacturing a compound according to any one of claims 1 to 3, 5 to 7, 9 to 20, 23 to 25 or a pharmaceutically acceptable salt or solvate thereof, wherein the method comprises the following reaction steps: Step a comprising: 1) Deprotonation; 2) reaction with LG-(CH₂)₂-L^a-PG¹; 3) 4-chlorobenzylidene group removal; Step b comprising: 1) amide coupling with ; and Step c comprising: 1) PG¹ removal; 2) Coupling or substitution reaction to attach R^a; or Step a comprising: 1) Deprotonation; 2) reaction with LG-(CH2)2-L^a-PG¹; 3) 4-chlorobenzylidene group removal; Step d comprising: 1) Protection with PG²; and Step e comprising: 1) PG² removal; 2) Amide coupling with ; wherein La, Ra, R² and R³ are as defined herein, LG is a leaving group and PG¹ and PG² are orthogonal protecting groups.

27. A method of manufacturing a compound according to any one of claims 1 or 2, 4 to 6, 8 to 22, 24 to 25 or a pharmaceutically acceptable salt or solvate thereof, wherein the method comprises the following reaction steps: wherein Step f comprises: i) Amide coupling with PG¹-L^b-NH2; wherein Step g comprises: i) Removal of PG² ii) Amide coupling of ; wherein Step h comprises: i) Removal of PG¹ ii) Coupling or substitution reaction to attach Rb. wherein L^b, R^b, R² and R³ are as defined herein and PG¹ and PG² are orthogonal protecting groups.

28. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof for use in a cannabinoid receptor type 2 (CB2) occupancy study.

29. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, for use in diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal.

30. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, for use in generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data.

31. Use of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal.

32. Use of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof, in generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data.

33. A method of studying cannabinoid receptor type 2 (CB2) occupancy, comprising contacting CB2 with a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof.

34. A method of diagnostic imaging of cannabinoid receptor type 2 (CB2) in a mammal, comprising contacting CB2 with a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof.

35. A method of generating cannabinoid receptor type 2 (CB2) equilibrium and kinetic binding data, comprising contacting CB2 with a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or solvate thereof. ***