WO2019115609A1

WO2019115609A1 - Saccharide functionalised carbaborane conjugates of human peptide y

Info

Publication number: WO2019115609A1
Application number: PCT/EP2018/084553
Authority: WO
Inventors: Annette Beck-Sickinger; Sylvia ELS-HEINDL; Dennis WORM; Evamarie Hey-Hawkins; Martin KELLERT; Robert KUHNERT; Stefan SARETZ; Bernd Riedl; Donald Bierer; Johannes Koebberling; Nils Griebenow
Original assignee: Universitaet Leipzig
Current assignee: Universitaet Leipzig
Priority date: 2017-12-12
Filing date: 2018-12-12
Publication date: 2019-06-20
Anticipated expiration: 2020-06-12

Abstract

The present invention covers peptidic human Y₁ receptor agonist - saccharide functionalised carbaborane conjugate compounds of general formula (I): X⁵PSX¹PX⁶FPGX⁷X⁸X⁹PX¹⁰X¹¹X¹²X¹³X²X¹⁴YYX³X¹⁵X¹⁶X¹⁷X⁴YINLITRPRY-NH₂, in which F, G, I, L, N, P, R, S, T, Y, X¹, X², X³, X⁴, X⁵, X⁶, X^7, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷ are as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment of cancer by means of boron neutron capture therapy.

Description

SACCHARIDE FUNCTIONALISED CARBABORANE CONJUGATES OF HUMAN PEPTIDE Y

The present invention covers peptidic human Yi receptor agonist - saccharide functionalised carbaborane conjugate compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment of cancer by means of boron neutron capture therapy.

BACKGROUND

The present invention covers peptidic human Yi receptor agonist - saccharide functionalised carbaborane conjugate compounds of general formula (I) which, by selectively targeting the human Yi receptor (also referred to as NPY1 receptor), can accumulate in tumour cells and allow for the treatment of cancer by means of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a biochemically targeted radiation therapy for the treatment of cancer and was first described in 1936 [G. L. Locher, Am. J. Roentgenol. Radium Ther. 1936, 36, 1 ]. The special feature of this binary cancer therapy is its dual-targeting approach. In a first step, a drug containing the non-radioactive ¹⁰B isotope has to be accumulated inside tumor cells. In a second step, the tumor will be locally irradiated with thermal or epithermal neutrons [Barth et al., Cancer 1992, 70, 2995]. ¹⁰B has a high neutron capture cross section and occurrence of such a neutron capture event leads to the formation of excited ¹¹B, which is unstable and immediately decays into alpha particles (⁴He²⁺ nuclei) and lithium-7 nuclei. These high linear energy transfer (LET) particles have a range of approximately 5-9 pm, which corresponds to the diameter of a cell, and therefore, their lethal destructive effects are limited to boron-containing cells [Coderre et al., Radiat. Res. 1999, 151 , 1]. The success of BNCT mostly depends on the quality of the boron delivery agent: It must deliver a high amount of boron into cancer cells (at least 10^{9 10}B atoms per cell) with only low uptake of the compound in the surrounding healthy tissue (tumonnormal tissue ratio > 3:1 ) [Tolpin et al., Oncology 1975, 32, 223; Barth et al., Radiat. Oncol. 2012, 7, 146]. Additionally, the drug should reside in the tumor, while being rapidly cleared from the blood stream. Till now, only two compounds have been used in clinical trials, namely boronophenylalanine (4-dihydroxyborylphenylalanine, BPA) and sodium borocaptate (disodium undecahydro-mercapto-c/oso-dodecacarborate(12), BSH) [Soloway et al., Chem. Rev. 1998, 98, 1515]. However, both of them are lacking the desired selectivity for tumor accumulation and hence, the development of novel boron delivery agents is an important and necessary task. One approach to this issue is the use of boron-modified peptide ligands that target distinct G protein-coupled receptors (GPCRs), which are overexpressed on different cancer cell types. The specific activation of the GPCR by the modified ligand leads to cellular internalization of the peptide-receptor complex, yielding a selective uptake of boron into receptor-expressing cancer cells [Ahrens et al., ChemMedChem 2015, 10, 164]

A promising target GPCR for this purpose is the human Yi receptor, which is part of the four- membered Y receptor family in humans (hYiR, hY₂R, hY₄R and hY₅R) and is activated by the natural ligand neuropeptide Y [Larhammar et al., Neuropeptides 2004, 38, 141 ] The hYiR is physiologically mainly expressed in the central nervous system, but also in the periphery (e.g. heart, gastrointestinal tract), and is amongst others involved in the regulation of food intake, anxiety and circadian rhythm [Sheikh et al., FEBS Letters 1989, 245, 209; Widdowson, Brain Res. 1993, 631 , 27; Rettenbacher et al., Naunyn Schmiedebergs Arch. Pharmacol. 2001 , 364, 291 ; Kalra et al., Neuropeptides 2004, 38, 201 ; Heilig, Neuropeptides 2004, 38, 213]. More importantly, expression of the hYiR was found in different cancer cells, including breast carcinoma, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer [Korner and Reubi, Peptides 2007, 28, 419]. Here, the expression pattern in breast tumor is standing out, since the hYiR was found to be expressed alone in very high density in 65 % of tested breast tumors, while in non-neoplastic breast, expression of the hY₂R was predominantly observed [Reubi et al., Cancer Res. 2001 , 61 , 4636]. By using a hYiR-selective NPY analog such as [F⁷,P³⁴]-NPY [Soil et al., Eur. J. Biochem. 2001 , 268, 2828], targeting of breast tumors for cancer therapy or imaging is therefore possible. [F⁷,P³⁴]-NPY, labelled with ^99mTc or ¹⁸F, was reported to facilitate breast tumor imaging in vivo by single-photon emission computed tomography (SPECT) and positron emission tomography (PET), respectively [Khan et al., Angew. Chem. Int. Ed. 2010, 49, 1 155; Hofmann et al., Mol. Pharmaceutics 2015, 12, 1 121 ] Conjugates of [F⁷,P³⁴]-NPY with the toxic compound methotrexate could be shown to mediate cytotoxic effects selectively for hYiR-expressing breast cancer cells, while hY₂R-expressing cells were not affected [Bohme et al., ChemMedChem 2015, 10, 804]

For the purpose of modifying peptide molecules to make them suitable delivery agents for BNCT, carbaboranes have been proposed and studied as suitable synthons. These BioC₂Hi₂-clusters exhibit a high boron content, high chemical and biological stability and can be easily chemically modified to allow coupling to peptides [Scholz et al., Chem. Rev. 201 1 , 1 1 1 , 7035]. On the other hand, carbaboranes confer a high level of hydrophobicity (see e.g. J. L. Fauchere et al., Experientia 1980, 36, 1203) and are thus likely to also confer undesired properties, such as insufficient aqueous solubility. The further preparation and evaluation of stable, highly boron- loaded, potent and hYiR-selective NPY conjugates is thus an important step in the development of novel BNCT agents for breast cancer targeting.

Prior art The general idea of developing receptor-targeted, carbaborane-modified peptide ligands as potential boron delivery agents for BNCT has been reported before (Schirrmacher et al., Tetrahedron Lett. 2003, 44, 9143-9145; Mier et al., Z. anorg. allg. Chem. 2004, 630, 1258-1262; Betzel et a!., Bioconjugate Chem. 2008, 19, 1796-1802)

The concept of boron-containing [F⁷,P³⁴]-NPY conjugates for BNCT is known as well [Ahrens et al., J. Med. Chem. 201 1 , 54, 2368].

Further, it is known that a [F⁷,P³⁴]-NPY conjugate containing three orf/70-carbaboranes was able to selectively deliver sufficient amounts of boron for BNCT into hYiR-expressing cells by receptor-mediated internalization [Ahrens et al., ChemMedChem 2015, 10, 164]

Carboxylic acid derivatives (for conjugation with peptides) and sugar derivatives (for improved solubility) of carbaboranes have been disclosed in scientific publications see e.g. V. M. Ahrens et al., ChemMedChem 2015, 10, 164 (for the facilitated introduction of a carboxylate moiety), R. Frank et al., Polyhedron 2012, 39, 9-13 (for a carboxylic acid synthon featuring three carbaborane moieties per molecule), R. Frank et al., J. Organomet. Chem. 2015, 798, 46-50; for deoxygalactosyl-functionalised carbaborane synthons).

A poster presented on a scientific conference (D. J. Worm et al., 25^th American Peptide Symposium, 17 - 22 June 2017) discloses carbaborane-[F⁷,P³⁴]- peptide conjugates featuring carbaboranes modified with a hydrophilic moiety and a branching unit, with a carbaborane loading of up to six carbaboranes per [F⁷,P³⁴]-NPY peptide, which were shown to be capable of activating the Yi receptor, and of effecting internalization of the Yi receptor tagged with an eYFP fluorophore into HEK 293 cells.

It is further known that the uptake of carbaborane glycosides into tumour cells strongly depends on the specific structure of the respective carbaborane glycoside (L. F. Tietze et al., ChemBioChem 2001 , 2, 326-334). Interestingly, the same group discussed the suitability of monosaccharide carbaborane glycosides based on water solubility considerations in context of BNCT, resulting in the preparation of disaccharide carbaborane glycosides and their subjection to cancer cell toxicity studies (L. F. Tietze, U. Bothe, Chem. Eur. J. 1998, 4(7), 1 179-1 183). Therefore, ready uptake of saccharide functionalised carbaborane conjugate into tumour cells as a merit of the saccharide conjugation per se cannot be expected.

However, the state of the art does not describe the peptidic human Yi receptor agonist - saccharide functionalised carbaborane conjugates of general formula (I) of the present invention as described and defined herein.

It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.

In particular, the compounds of the present invention have surprisingly been found to effectively mediate activation of the human Yi receptor (hYiR), resulting in internalisation of the receptor, togetherwith the compounds of the present invention bonded to it, into HEK293 cells transfected with the human Yi receptor, for which data are given in biological experimental section, and can therefore be used to selectively transport boron atoms into cells expressing the human Yi receptor, such as breast cancer cells, to enable boron neutron capture therapy of cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma. Particularly surprising, high levels of receptor activation and internalisation are maintained over a wide range of carbaborane loading, up to at least eight carbaborane units per peptide unit, enabling for transferring a particularly large number of boron atoms per cell into cells expressing the human Yi receptor, and thus further enhancing the carbaborane loading known hitherto to be compatible with high levels of human Yi receptor activation and cell internalisation.

DESCRIPTION of the INVENTION

In accordance with a first aspect, the present invention covers compounds of general formula (I):

X⁵PSX¹PX⁶FPGX⁷X⁸X⁹PX¹⁰X^{1 1}X¹²X¹³X²X¹⁴YYX³X¹⁵X¹⁶X¹⁷X⁴YINLITRPRY-NH₂ (I),

in which :

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P) , X² represents a group selected from alanine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“$” indicates the point of attachment to the neighbouring amino acid X¹³, and in which“$$” indicates the point of attachment to the neighbouring amino acid X¹⁴,

X³ represents a group selected from serine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“^*” indicates the point of attachment to the neighbouring amino acid L-tyrosine

(Y), and in which“^**” indicates the point of attachment to the neighbouring amino acid X¹⁵, X⁴ represents a group selected from the amino acid histidine, being present in its natural, proteinogenic L-enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“§” indicates the point of attachment to the neighbouring amino acid X¹⁷, and in which“§§” indicates the point of attachment to the neighbouring amino acid L-tyrosine

(Y).

F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids phenylalanine (F), isoleucine (I), leucine (L), asparagine (N), proline (P), arginine (R), serine (S), threonine (T), and tyrosine (Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), leucine (X¹³, X¹⁶), arginine (X¹⁴, X¹⁷), and tyrosine (X⁵), with one instance of either X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, or X¹⁷ being present in its natural, proteinogenic L-enantiomeric form or as its D-enantiomer, or a mixture thereof, whilst all other instances of X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, or X¹⁷ being present in their natural, proteinogenic L-enantiomeric form,

q in each instance it occurs, independently from each other, represents an integer selected from 1 , 2, 3 and 4,

R¹ and R², independently from each other, represent a hydrogen atom or a group Sac,

with the proviso that at least one of R¹ and R² represents a group Sac,

Sac represents a group selected from

represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the groups X¹, X², X³, and X⁴, and

“o” represents a boron atom which is bonded to -S-CH₂-C(=0)- within the groups X¹, X², X³, and X⁴, with the proviso that the number of carbaborane moieties

per molecule of formula (I) is at least 1 but smaller than 12,

and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

DEFINITIONS

Tables 1a, 1 b, 1c, 1d and 1e: Nomenclature of amino acids, peptide sequences, and carbaboranes

Table 1a: Nomenclature of amino acids and peptide sequences

Table 1 b: Nomenclature of unnatural amino acids, building blocks and linkers:

Diaminoalkanoic acid based branching moieties of the structure shown below, in which q is as defined for the compounds of the general formula (I), are also being referred to herein as DAABM.

DAABM

Table 1c: Side chain protected amino acids:

The term“side chain protected amino acid”, as used herein, refers to an amino acid featuring a protecting group, herein also referred to as PG¹, PG², PG³, PG⁴, PG⁵, PG⁶, or PG⁷, or shown specifically, attached to a functional group on a side chain of said amino acid. Abbreviations used for said protecting groups are defined by chemical name in table 3, below, or abbreviations are used as known to the person skilled in the art. Unless specified otherwise, said side chain protected amino acids are presented as three-letter-codes, including the stereochemical terminology as discussed below. Further, the term “side chain protected amino acid” encompasses said amino acids as part of a peptide sequence, which is optionally bonded to a resin, such as an amide resin, or in free form, optionally featuring additional protecting groups at the C- and/or N-terminus, such as for additional Boc protection at the N-terminus in Boc-L- Tyr(tBu), below. Specific examples are presented in table 1c.

Carbaboranes

Carboranes (“carbaboranes” in the formal nomenclature, and as used herein) are polyhedral boron-carbon molecular clusters that are stabilised by electron-delocalised covalent bonding in the skeletal framework. In contrast to classical organoboranes such as borabenzene (C₅H₅B), the skeletal carbon atoms in carboranes typically have at least three and as many as five or six neighbours in the cluster, forming stable - in some cases, exceedingly stable - molecular structures. In late 1957, an extraordinarily stable compound characterised as BioHioC2H2 (later given the trivial name o-carborane, 1 ,2-C₂BioHi₂), has been isolated at Reation Motors, Inc. from the reaction of B1₀H14 derivatives with acetylene. The original work in the icosahedral C2B1₀H12 carboranes was published in 1963 in a series of papers from the groups at Thiokol and Olin- Mathieson. The two remaining isomers, 1 ,7- and 1 ,12-C₂BioHi₂ (m- and p-carborane, respectively) were prepared via thermal cage-rearrangement of o-carborane. Investigations of the C2B1₀H12 systems revealed that their cage C-H bonds are highly polar (especially in the 1 ,2- and 1 ,7-isomers, and to a lesser degree in the 1 ,12-isomer), imparting a positive charge on the CH hydrogens and making them acidic toward Lewis bases. (Russel N. Grimes, Carboranes, 3^rd Ed., Elsevier Inc. 2016, page 1 ). In the carbaboranes shown in the structural formulae herein, a symbol“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the respective group or formula, and a symbol“o” represents a boron atom which is bonded as shown to but not further bonded to hydrogen atoms not shown explicitly.

Table 1d: Nomenclature of the different carbaborane synthons:

Table 1e: Nomenclature of the different carbaborane moieties:

The term“resin” in general means an insoluble polymer, also called solid support, which is functionalized for solid phase peptide synthesis, wherein the C-terminal amino acid of a peptide is attached to the resin covalently and the full peptide is cleaved from the resin after completion of the synthesis. As used herein, the term“amide resin” means a resin from which upon cleavage a peptide featuring a C-terminal carboxamide is released. This is usually achieved by using a linker which is covalently attached to the resin and provides a reversible amide linkage between the synthetic peptide and the solid support. Amide resins, and said linkers contained therein, are known to the person skilled in the art and are described in the literature (see e.g. Fmoc Solid Phase Peptide Synthesis - A Practical Approach, edited by W. C. Chan and P. D. White, Oxford University Press 2000, ISBN 0-19-963724-5). Amide resins, as referred to herein, are exemplified by but not limited to a Rink amide AM resin (commercially available from Iris Biotech) or a NovaSyn® TGR R resin (commercially available from Novabiochem, Darmstadt, Germany).

The term "peptide" as used herein, refers broadly to a sequence of two or more amino acids joined together by peptide bonds. It should be understood that this term does not indicate a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring.

The term“conjugate”, as used herein, refers to a peptide as described and disclosed herein, to which at least one carbaborane moiety is attached.

The term "amino acid" or "any amino acid" as used herein refers to any and all amino acids, including naturally occurring amino acids (e.g., oL-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. Natural amino acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building- blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. Those of the 20 proteinogenic, natural amino acids of relevance for the present invention are listed in the above table 1 a. The "non- standard," natural amino acids are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). "Unnatural" or "non-natural" amino acids are non-proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 natural amino acids are known and thousands of more combinations are possible. Examples of "unnatural" amino acids include b-amino acids (3³ and b²), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present in the amino acid.

In accordance with the understanding of a person skilled in the art, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide.

Among sequences disclosed herein are sequences incorporating an "-Nhh" moiety at the carboxy terminus (C-terminus) of the sequence. An "-Nhh" moiety at the C-terminus of the sequence indicates an amino group, corresponding to the presence of an amido (-(C=0)-NH₂) group at the C-terminus.

It is further understood that the moiety at the amino terminus or carboxy terminus may be a bond, e.g., a covalent bond, particularly in situations where the amino terminus or carboxy ter minus is bonded to a linker, an amide resin, or to another chemical moiety.

In the case of non-proteinogenic or non-naturally occurring amino acids, unless they are referred to by their full name (e.g. sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including those abbreviations as indicated in the abbreviation list in table 1 b.

The terms "L-amino acid,", or,“amino acid in its natural, proteinogenic L-enantiomeric form”, or, respectively,“amino acids in their natural, proteinogenic L-enantiomeric form” as used herein, refers to the "L" isomeric form of an amino acid, and conversely the term "D-amino acid" refers to the "D" isomeric form of an amino acid. It The three-letter code in the form as indicated in the table above, i.e. Ala, Arg, Asn etc. and as generally used in the present specification, shall generally comprise the D- and L- form, and mixtures thereof, unless explicitly indicated otherwise. Likewise, the term“present in its natural, proteinogenic L-enantiomeric form or as its D-enantiomer, or a mixture thereof” shall generally comprise the D- and L- form, and mixtures thereof. The prefix“nor“ refers to a structural analogue which can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen atoms. The prefix“homo" indicates the next higher member in a homologous series. A reference to a specific isomeric form will be indicated by the capital prefix L- or D- as described above (e.g. D- Arg, L-Arg etc.). A specific reference to homo- or nor-forms will accordingly be explicitly indicated by a respective prefix (e.g. homo-Arg, h-Arg, nor-Arg, homo-Cys, h-Cys etc.). It is further a conventional manner, when using one-letter codes, to indicate the L-amino acid with a capital letter such as A, R, F, etc. and the D-amino acid with small letters such as a, r, f, and the like. Further, as used herein, nor-amino acids are being referred to with their full name, or a three- letter code as defined herein, or with the one-letter code together with“^N” or”ⁿ”, e.g. L-Nle or L^N for L-Norleucine, and D-Nle or G for D-Norleucine, as indicated to the extent used herein in the abbreviation list in table 1 b, above, and in table 3, below. As used herein, the term“protecting groups” means a group attached to an atom, preferably a oxygen or nitrogen or sulfur atom in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective hydroxyl, amino or sulfanyl group e.g. in order to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups, including methods for their introduction and removal, are well known to the person skilled in the art (see e.g. P.G.M. Wuts in Greene’s Protective Groups in Organic Synthesis, 5^th edition, Wiley 2014).

As used herein, the term“leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-fe/f-butyl- phenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

As used herein, the term“local irradiation” means the delivery of a precisely measured dose of irradiation to a defined tumor volume with as minimal damage as possible to surrounding healthy tissue (see e.g. Halperin, Edward C., Perez, Carlos A., Brady, Luther W.: Perez and Brady’s Principles and Practice of Radiation Oncology. Fifth Edition. Philadelphia: Lippincott Williams & Wilkins, a Wolters Kluwer business, 2008)

As used herein, the term“thermal neutrons” means free neutrons with a kinetic energy of 0.025 eV, and the term“epithermal neutrons” means free neutrons with a kinetic energy of 0.025-0.4 eV (see e.g. Carron, N. J.: An Introduction to the Passage of Energetic Particles through Matter. Boca Raton: Taylor & Francis Group, LLC. 2006)

It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly compounds of general formula (I) enriched in the boron isotope ¹⁰B.

The term“Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

The term“Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The expression“unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in“Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1 ), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, boron, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹⁰B, ¹¹B, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶CI, ⁸²Br, ¹²³l, ¹²⁴l, ¹²⁵l, ¹²⁹l and ¹³¹1, respectively.

With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain ¹⁰B (“¹⁰B-containing compounds of general formula (I)”). The ¹⁰B boron isotope features an effective nuclear cross section of 3835(9) barn (cf. ¹H features 0.3326(7) barn, ¹¹B 0.0055(33) barn, ¹²C 0.00353(7) barn, see e.g. Sears, Valery F., Neutron News 1992, 3, 26-37). Upon reaction with neutrons of low kinetic energy (thermal or epithermal neutrons), alpha particles (⁴He²⁺ nuclei) and lithium-7 nuclei are formed. These high linear energy transfer (LET) particles convey their lethal destructive effects only to boron-containing cells, as discussed in the background section in more detail. Since only the ¹⁰B isotope, but not the ¹¹B isotope undergoes neutron capture, ¹⁰B- enriched agents are preferred isotopic variants of the compounds of the general formula (I).

Other isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as ³H or ¹⁴C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as ¹⁸F or ¹¹C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and ¹³C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies. Replacement of hydrogen by deuterium may also alter the physicochemical properties (such as for example acidity, basicity, lipophilicity and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances.

Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, e.g. by employing ¹⁰B-enriched boric acid ¹⁰B(OH)3 as starting material for the preparation of carbaborane synthons used for the preparation of compounds of the general formula (I), according to the schemes and/or examples herein. ¹⁰B- enriched boric acid has become commercially available from a plethora of suppliers (e.g. Katchem spol. S r. o., Elisky Krasnohorske 123/6, 1 10 00 Josefov, Czech Republic; Boron Specialties LLC, Laboratory & Warehouse, 2301 Duss Avenue, Ste. 35, Ambridge, PA 15003 USA), in isotopic purities up to 99+%, and can be elaborated into ¹⁰B-enriched carbaborane synthons by multiple methods known to the person skilled in the art (see e.g. Yinghuai, Z., Widjaja, E., Lo Pei Sia, S., Zhan, W., enter, K., Maguire, J. A., Hosmane, N. S., Hawthorne, M.F., J. Am. Chem. Soc. 2007, 129, 6507-6512; Adams, L, Tomlinson, S., Wang, J., Hosmane, S. N., Maguire, J. A., Hosmane, N. S., Inorg. Chem. Commun. 2002, 5, 765-767.; Scholz, M., Hey-Hawkins, E., Chem. Rev. 201 1 , 1 1 1 , 7035-7062; Grimes, Russel N.: Carboranes. Third Edition, Academic Press (Elsevier), 2016, ISBN: 9780128018941 ) Furthermore, carbaborane synthons with high isotopic enrichment of ¹⁰B up to 99+% are also commercially available from Katchem spol. s r. o., Czech Republic (http//:www.katchem.cz/en).

Deuterium can be introduced in place of hydrogen in the course of the synthesis of compounds of the general formula (I) by many methods well known to the person skilled in the art, e.g. deuterium from D₂0 can be incorporated into said compounds directly or indirectly, or by catalytic deuteration of olefinic or acetylenic bonds using deuterium gas.

The term“¹⁰B-containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more boron atom(s) in its/their natural isotopic composition is/are replaced by one or more ¹⁰B atom(s) and in which the abundance of ¹⁰B at each respective position of the compound of general formula (I) is higher than the natural abundance of ¹⁰B, which is about 20%. Particularly, in a ¹⁰B -containing compound of general formula (I), the abundance of ¹⁰B of each boron atom of the compound of general formula (I) is higher than 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99%. It is understood that the abundance of ¹⁰B of each boron atom can be either identical with, or independent of the abundance of ¹⁰B at other boron atom(s).

In another embodiment the present invention covers a ¹⁰B-containing compound of general formula (I), in which the abundance of ¹⁰B of each boron atom of the compound of general formula (I) is higher than 90%,

In another embodiment the present invention convers a ¹⁰B-containing compound of general formula (I), in which the abundance of ¹⁰B of each boron atom of the compound of general formula (I) is higher than 98%,

and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. ln another embodiment the present invention convers a ¹⁰B-containing compound of general formula (I), in which the abundance of ¹⁰B of each boron atom of the compound of general formula (I) is higher than 99%,

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The compounds of the present invention contain stereogenic centres e.g. in the peptide backbone, in the optional diaminoalkanoic acid based branching moiety DAABM, and in the saccharide based moiety Sac. The present invention covers certain isomers of the compounds disclosed and described therein.

The peptide backbone of certain compounds of the invention, such as the Example compounds, is described by the sequence

YPSX¹PDFPGEDAPAEDLX²RYYX³ALRX⁴YINLITRPRY-NH₂

X¹, X², X³, and X⁴, respectively refer to amino acids optionally modified through conjugation to saccharide functionalised carbaborane moieties and are as described and defined herein. It is known that certain amino acids in said sequence can be present as the natural, proteinogenic L-enantiomer, its D-enantiomer, or mixtures thereof without substantially influencing the binding behaviour towards human Yi receptors, whilst other amino acids need to be present as the naturally occurring, proteinogenic L-form to maintain high affinity towards human Yi receptors (see e.g. D. A. Kirby et al., J. Med. Chem. 1993, 36, 3802-3808). Hence, within the coverage of the present invention, certain amino acids in the compounds of the present invention, namely X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷ as shown in formula (I), can be present as the natural L-enantiomer, its D-enantiomer, or mixtures thereof in one instance, whilst all other instances of said amino acids those amino acids X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷, and those amino acids which are presented in form of their one-letter codes, as defined herein and common practise to the person skilled in the art, are present as their natural, proteinogenic L-enantiomers.

In some embodiments of the present invention, only a sub-set of said amino acids X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷, namely X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, can be present as the natural L-enantiomer, its D-enantiomer, or mixtures thereof in one instance, whilst all other amino acids are present as their L-enantiomers.

In other embodiments of the present invention, all amino acids constituting the peptide backbone are present in the compounds of the invention as their natural, proteinogenic L-enantiomers. The compounds of the invention may contain one or more diaminoalkanoic acid based branching moieties of the structure

DAABM

in which q is as defined for the compounds of the general formula (I), said diaminoalkanoic acid based branching moieties being herein also referred to as DAABM. Particularly, said DAABM is derived from 2,3-diaminopropionic acid (Dap). Said DAABM allow for the attachment of two or more (if more than one DAABM is attached) carbaborane synthons per amino terminus of a given lysine side chain within the groups X¹, X², X³ and/or X⁴, which are as defined for the compounds of general formula (I). Said diaminoalkanoic acids, such as 2,3-diaminopropionic acid, featuring one stereogenic centre, can be present as (2S)-enantiomer, as (2R)-enantiomer, and mixtures thereof. The present invention covers all stereoisomeric forms of the compounds of general formula (I) resulting from the presence of (2S)-diaminoalkanoic acid (also referred to herein as (2S)-DAABM), (2R)-diaminoalkanoic acid (also referred to herein as (2R)-DAABM), and stereoisomeric mixtures thereof, particularly of (2S)-2,3-diaminopropionic acid (also referred to herein as (2S)-Dap), (2R)-2,3-diaminopropionic acid, and mixtures thereof, as branching moieties as described supra.

The compounds of the present invention feature a saccharide based unit Sac, which represents, as defined for the compounds of general formula (I), a group selected from

Scheme 1a: Sac groups as defined for the compounds of general formula (I)

The monosaccharides from which said saccharide based units Sac are derived are known to undergo isomerisation reactions referred to as to as mutarotation in the literature (see e.g. Jiff Pazourek, Monitoring of mutarotation of monosaccharides by hydrophilic interaction chromatography, J. Sep. Sci. 2010, 33, 974-981 ), inter alia in aqueous solution, as shown for D-monosaccarides below in Scheme 1 b, in which (Sac-I) represents the a-D-pyranose form, (Sac-ll) represents the open-chain D-aldose form, (Sac-Ill) represents the b-D-pyranose form, (Sac-IV) represents the b-D-furanose form, and (Sac-V) represents the a-D-furanose form. The reader is referred to the fact that the Sac units shown in Scheme 1a, above, reflect both the o and b-pyranose forms, corresponding e.g. to (Sac-I) and (Sac-Ill), already.

(Sac-v)

Scheme 1b: Mutarotation reactions of Sac units derived from D-monosaccharides

Likewise, this is shown for L-monosaccharides in Scheme 1 c, in which (Sac-VI) represents the a-L-pyranose form, (Sac-VII) represents the open-chain L-aldose form, (Sac-VIII) represents the b-L-pyranose form, (Sac-IX) represents the b-L-furanose form, and (Sac-X) represents the a-L- furanose form.

(Sac-X)

Scheme 1c: Mutarotation reactions of Sac units derived from L-monosaccharides

Specifically for 6-deoxy-D-galactose, from which Examples 1 - 6 are derived, this is shown below in Scheme 1 d, in which (Sac-XI) represents a Sac unit derived from 6-deoxy-oD- galactopyranose, (Sac-XII) represents the corresponding open-chain D-aldose form, (Sac-XIII) represents a Sac unit derived from 6-deoxy-3-D-galactopyranose, (Sac-XIV) represents a Sac unit derived from 6-deoxy-3-D-galactofuranose, and (Sac-XV) represents a Sac unit derived from 6-deoxy-oD-galactofuranose.

(Sac-XV)

Scheme 1d: Mutarotation reactions of Sac units derived from 6-deoxy-D-galactose

The isomeric forms of Sac units resulting from abovementioned mutarotation reactions, as illustrated in Schemes 1 a, 1 b, 1 c, and, as a specific example, for 6-deoxy-D-galactose in Scheme 1 d, are included within the scope of the present invention, and are collectively being referred to herein as“isomers resulting from mutarotation reactions” herein. Hence, the present invention covers compounds of formula (I), and isomers resulting from mutarotation reactions thereof, in which the Sac units as defined for the compounds of formula (I) may exist in a single isomeric form, or as a mixture of a- and b-pyranose forms, or as a mixture of two or more isomeric forms as shown in Schemes 1 b, 1c, or 1 d, as the case may be. Further, by virtue of the symmetry properties of the carbaborane core, its positions 1 and 7 in 9- monosubstituted carbaborane intermediates are not topologically identical, i.e. not interchangable by rotation as shown in the Scheme 1 e below.

1 -Gal, 9-thio 7 -Gal, 9-thio

Scheme 1e: Topological features of carbaborane core positions 1 and 7

Therefore, regioisomeric mixtures may result when substituents, such as those derived from the monosaccharide intermediates disclosed herein (e.g. Intermediate 7 in the Experimental Section; see also formula (XIII) in Scheme 5a), are attached to said position 1 or 7, as the case may be. Hence, the display of a carbaborane substituted at one of said positions 1 and 7, as exemplarily shown in Scheme 1 f, below, and also in the claims and the specification herein refers to a respective compound featuring said substitution at position 1 (but not at position 7), or a respective compound featuring said substitution at position 7 (but not at position 1 ), or a regioisomeric mixture thereof. This also applies to instances where reference is made to such substitution at a position corresponding to position 1 , such as in the Experimental section for Intermediates 8 to 10. Accordingly, and as far as compounds with one monosaccharide based substituent attached to position 1 or 7 are concerned, the present invention covers compounds of formula (I) featuring said monosubstitution at position 1 , compounds featuring said monosubstitution at position 7, and regioisomeric mixtures thereof.

Sac

Scheme 1f: Carbaborane moiety encoding for substitution at position 1 , position 7, or a regioisomeric mixture reflecting both monosubstitutions.

The purification of the compounds of the present invention can be accomplished by standard separation and purification techniques known in the art, in particular by the use of reversed- phase-HPLC, e.g., as described herein, using columns such as a C12-column (Phenomenex Jupiter® 10u Proteo 90 A: 250 mm ^c 21 .2 mm, 10 pm, 90 A), a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm x 19 mm, 10 pm, 130 A), a semi-preparative C18- column (Phenomenex Kinetex® 5u XB-C18: 250 mm x 10 mm, 5 pm, 100 A), a Biphenyl column (Phenomenex Kinetex® 5u Biphenyl: 250 mm x 21.2 mm, 5 pm, 100 A), an Aeris® C18-column (Phenomenex Aeris® Peptide 3.6u XB-C18: 250 mm x 21.2 mm, 3.6 pm, 100 A), or, preferably, a Kinetex® C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm x 21.2 mm, 5 pm, 100 A). This may, besides chemical purification, also result in separation of isomers amenable to separation on non-chiral phase, such as diastereomers. Separation of stereoisomers can be further addressed by chiral chromatography (/^'.e., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the stereoisomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.

In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).

Further, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention which contains a histidine as an amino acid for example can exist as as tautomers with regard to the imidazole ring therein, or even a mixture in any amount of the two tautomers, namely :

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.

The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.

The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono- , sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.

The term“pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et at.“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or“mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3- phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, /V-methylpiperidine, /V-methyl-glucamine, /V,/V-dimethyl-glucamine, /V-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3- propanediol, 3-amino-1 ,2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, /V-benzyl-/V,/V,/V- trimethylammonium, choline or benzalkonium.

Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF₃COOH", "x Na⁺", for example, mean a salt form, the stoichiometry of which salt form not being specified.

This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.

In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I):

X⁵PSX¹PX⁶FPGX⁷X⁸X⁹PX¹⁰X¹¹X¹²X¹³X²X¹⁴YYX³X¹⁵X¹⁶X¹⁷X⁴YINLITRPRY-NH₂

(I),

in which :

X¹ represents a group selected from L-lysine,

(Y).

G represents the amino acid glycine,

Sac represents a group selected from

“o” represents a boron atom which is bonded to -S-CH₂-C(=0)- within the groups X¹, X², X³, and X⁴,

Sac

with the proviso that the number of carbaborane moieties per molecule of formula (I) is at least 1 but smaller than 12, and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P), X² represents a group selected from alanine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

represents a group selected from serine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“^*” indicates the point of attachment to the neighbouring amino acid L-tyrosine (Y), and in which“^**” indicates the point of attachment to the neighbouring amino acid X¹⁵, X⁴ represents a group selected from the amino acid L-histidine,

(Y).

X⁵, X⁶, X⁹, X¹², X¹⁴, X¹⁵, F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁵), aspartic acid (X⁶, X¹²), phenylalanine (F), isoleucine (I), leucine (L), asparagine (N), proline (P), arginine (X¹⁴, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, respectively, represent the amino acids alanine (X¹⁰), aspartic acid (X⁸), glutamic acid (X⁷, X¹¹), leucine (X¹³, X¹⁶), and arginine (X¹⁷), with one instance of either X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, being present in its natural, proteinogenic L- enantiomeric form or as its D-enantiomer, or a mixture thereof, whilst all other instances of X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, being present in their natural, proteinogenic L- enantiomeric form,

q in each instance it occurs, independently from each other represents an integer selected from 1 and 2,

with the proviso that at least one of R¹ and R² represents a group Sac,

Sac represents a group selected from

“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the groups X¹, X², X³, and X⁴, and

per molecule of formula (I) is at least 1 but smaller than 12,

In accordance with a fourth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P),

X² represents a group selected from alanine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“$” indicates the point of attachment to the neighbouring amino acid X¹³, and in which“$$” indicates the point of attachment to the neighbouring amino acid X¹⁴, represents a group selected from serine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

in which“^*” indicates the point of attachment to the neighbouring amino acid L-tyrosine (Y), and in which“^**” indicates the point of attachment to the neighbouring amino acid X¹⁵, represents a group selected from the amino acid L-histidine,

(Y).

G represents the amino acid glycine,

Sac represents a group selected from

Sac

In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P), represents a group selected from alanine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

represents a group selected from serine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof, and

(Y).

G represents the amino acid glycine,

q represents an integer 1 ,

R² represents a hydrogen atom or a group Sac,

Sac represents a group

boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the groups X¹, X², X³, and X⁴, and

Sac

with the proviso that the number of carbaborane moieties per molecule of formula (I) is at least 1 but does not exceed 8,

In accordance with a sixth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

X¹ represents a group selected from L-lysine,

(Y).

G represents the amino acid glycine,

q represents an integer 1 ,

Sac represents a group

Sac

In accordance with an seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P), represents a group selected from L-alanine,

represents a group selected from L-serine,

in which“^*” indicates the point of attachment to the neighbouring amino acid L-tyrosine (Y), and in which“^**” indicates the point of attachment to the neighbouring amino acid X¹⁵,

X⁴ represents a group selected from the amino acid L-histidine,

(Y),

X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, X¹⁷, F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), phenylalanine (F), isoleucine (I), leucine (X¹³, X¹⁶, L), asparagine (N), proline (P), arginine (X¹⁴, X¹⁷, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

q represents an integer 1 , R² represents a hydrogen atom or a group Sac,

Sac represents a group selected from

represents a boron atom which is bonded to -S-CH₂-C(=0)- within the groups X¹, X², X³, and X⁴,

Sac

In accordance with a eigth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which :

X¹ represents a group selected from L-lysine,

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine

(S), and in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P), represents a group selected from L-alanine,

represents a group selected from L-serine,

represents a group selected from the amino acid L-histidine,

(Y),

X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, X¹⁷, F, I , L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), phenylalanine (F), isoleucine (I), leucine (X¹³, X¹⁶, L), asparagine (N), proline (P), arginine (X¹⁴, X¹⁷, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

q represents an integer 1 , Sac represents a group selected from

Sac

and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with an ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from L-lysine,

represents a group selected from L-serine,

X⁴ represents a group selected from the amino acid L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 , R² represents a hydrogen atom or a group Sac,

Sac represents a group

Sac

In accordance with a tenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from L-lysine,

represents a group selected from L-serine,

represents a group selected from the amino acid L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 , Sac represents a group

Sac

In accordance with a eleventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from:

O H"(CH₂)_q

H₍;; .^nL_Nl^⁰ N'"¾

i \·/L·7 H ^{1 1}

H N (CH₂)_q

^•¾A ^·

c i

Sac HN^O

X² represents a group selected from L-alanine,

X³ represents a group selected from L-serine,

X⁴ represents a group selected from L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 , Sac represents a group

i

Sac

with the proviso that the number of carbaborane moieties and

Sac

per molecule of formula (I) does not exceed 8,

and isomers resulting from mutarotation reactions, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a twelfth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from:

X³ represents a group selected from L-serine,

represents a group selected from L-histidine,

(Y).

G represents the amino acid glycine,

q represents an integer 1 ,

Sac represents a group

Sac

with the proviso that the number of carbaborane moieties per molecule of formula (I) does not exceed 8,

In accordance with an thirteenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from:

represents a group selected from L-serine,

represents a group selected from L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 ,

R² represents a hydrogen atom or a group Sac, Sac represents a group

Sac

with the proviso that the number of carbaborane moieties and

Sac

per molecule of formula (I) is 8,

In accordance with a fourteenth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra,

in which :

X¹ represents a group selected from:

represents a group selected from L-serine,

represents a group selected from L-histidine,

(Y).

G represents the amino acid glycine,

q represents an integer 1 ,

Sac represents a group

Sac

with the proviso that the number of carbaborane moieties per molecule of formula (I) is 8,

Further embodiments of the first aspect of the present invention:

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which

X¹ represents a group selected from:

in which“#” indicates the point of attachment to the neighbouring amino acid L-serine (S), in which“##” indicates the point of attachment to the neighbouring amino acid L-proline (P), in which“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the group X¹, and in which“o” represents a boron atom which is bonded to -S- CH₂-C(=0)- within the group X¹,

and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which

X¹ represents a group selected from:

X² represents a group selected from L-alanine,

in which“$” indicates the point of attachment to the neighbouring amino acid X¹³, in which“$$” indicates the point of attachment to the neighbouring amino acid X¹⁴, in which“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the group X², and in which“o” represents a boron atom which is bonded to -S-CH₂-C(=0)- within the group X²,

X² represents a group selected from:

X³ represents a group selected from:

in which“^*” indicates the point of attachment to the neighbouring amino acid L-tyrosine (Y), in which“^**” indicates the point of attachment to the neighbouring amino acid X¹⁵, in which“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the group X³, and in which“o” represents a boron atom which is bonded to -S-CH₂-C(=0)- within the group X³,

X⁴ represents a group selected from the amino acid L-histidine,

in which“§” indicates the point of attachment to the neighbouring amino acid X¹⁷, in which“§§” indicates the point of attachment to the neighbouring amino acid L-tyrosine (Y), in which“·” represents a boron atom which is bonded to a hydrogen atom in addition to the bonds shown within the group X⁴, and in which“o” represents a boron atom which is bonded to -S-CH₂-C(=0)- within the group X⁴,

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which X⁵, X⁶, X⁹, X¹², X¹⁴, X¹⁵, F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁵), aspartic acid (X⁶, X¹²), phenylalanine (F), isoleucine (I), leucine (L), asparagine (N), proline (P), arginine (X¹⁴, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, respectively, represent the amino acids alanine (X¹⁰), aspartic acid (X⁸), glutamic acid (X⁷, X¹¹), leucine (X¹³, X¹⁶), and arginine (X¹⁷), with one instance of either X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, being present in its natural, proteinogenic L-enantiomeric form or as its D-enantiomer, or a mixture thereof, whilst all other instances of X⁷, X⁸, X¹⁰, X¹¹, X¹³, X¹⁶, and X¹⁷, being present in their natural, proteinogenic L-enantiomeric form, and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, X¹⁷, F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), phenylalanine (F), isoleucine (I), leucine (X¹³, X¹⁶, L), asparagine (N), proline (P), arginine (X¹⁴, X¹⁷, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form, and

G represents the amino acid glycine,

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which Sac represents a group selected from:

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which Sac represents a group:

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which the number of carbaborane moieties selected from

Sac per molecule of formula (I) is at least 1 but does not exceed 8, and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is at least 1 but does not exceed 8,

Sac

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is selected from 4, 5, 6, 7 and 8,

and isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is selected from 4, 6 and 8,

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is selected from 6, 7 and 8,

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is selected from 6 and 8,

Sac

Sac per molecule of formula (I) is selected from 4, 6 and 8,

Sac

and isomers resulting from mutarotation reactions, tautomers, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula

Sac

Sac

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is 4,

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is 6,

Sac per molecule of formula (I) is 8,

Sac

(I), supra, in which the number of carbaborane moieties per molecule of formula (I) is 8,

and isomers resulting from mutarotation reactions, tautomers, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which q represents an integer selected from 1 , 2 and 3,

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which q represents an integer selected from 1 and 2,

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which q represents an integer 1 ,

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which q represents an integer 2,

In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading“further embodiments of the first aspect of the present invention”.

The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra. The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (XVII).

The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.

General Synthesis of the compounds of the present invention

The following paragraph describes the synthesis of the compounds of the present invention in general terms. For abbreviations used, the reader is referred to table 3, which immediately precedes the Experimental Section. Protecting groups, as referred to herein, including methods for their introduction and removal, are well known to the person skilled in the art (see e.g. P.G.M. Wuts in Greene’s Protective Groups in Organic Synthesis, 5^th edition, Wiley 2014).

The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in schemes 2, 4a, 4b and 5a can be modified in various ways. The usage of protecting groups, reagents, and the order the transformations exemplified is therefore not intended to be limiting.

The compounds according to the invention of general formula (I) can be prepared by Fmoc- based solid phase peptide synthesis using an automated peptide synthesizer such as a SYRO I, by MultiSynTech. As solid phase, a resin can be used, preferably an amide resin selected from a Rink amide AM resin (commercially available e.g. from Iris Biotech) and a NovaSyn® TGR R resin (commercially available e.g. from Novabiochem, Darmstadt, Germany). The solid phase peptide synthesis reaction can be performed on a 5-100 pmol scale, preferably on a 10-20 pmol scale, more preferably on a 15 pmol scale. To accomplish the reaction, the respective amino acid and the reagents Oxyma and DIC can be added in 5-10-fold, preferably 8-fold molar excess, using DMF as solvent. The used amino acids are /V-protected, preferably /V-oFmoc-protected, except for the /V-terminal amino acid of the NPY analogs (tyrosine) constituting the peptide backbone of the compounds of the invention, which can be preferably applied in a /V-a-Boc- protected form. Additional protecting groups for blocking of side chain functionalities can be advantageously used, and are herein e.g. selected from tBu, Pbf, Trt, Boc, Mtt, Mmt, TBDMS, Doc, Tos, Bom, Bum, Xan, Cpd, Mbh, Tmob, Pmc, Mtr, MIS, 2-CI-Trt, TEGBn, Mpe, 2-Ph'Pr, and Dde, (see table 3 for full names, and table 1 c for structural formulae). Protecting groups for the /V-terminal groups and for side chain functional groups are known to the person skilled in the art. Each coupling step can be performed one or more times to effect advantageous turnover, preferably two times, for a time between 30 and 60 minutes, preferably for 40 minutes. Cleavage of the /V-terminal Fmoc protecting group can be accomplished by methods known to the person skilled in the art, preferably using 40 % piperidine in DMF for 3 min and afterwards 20 % piperidine in DMF for 10 min. Upon completion of the synthesis of the resin-bonded peptide backbone, protecting groups for blocking of side chain functionalities can be removed by methods well known to the person skilled in the art, e.g. treatment with 2-3 % hydrazine in DMF (for the cleavage of Dde groups), treatment with a mixture of 2 % TFA and 5 % TIS in DCM (for the cleavage of Mmt groups). In between the reaction steps, the resin-bonded intermediates can be advantageously washed with solvents to remove excess of reagents. Specific examples are described in the Experimental Section.

Optionally, one or more diamino alkanoic acid based branching moieties DAABM as defined supra, particularly Dap (representing 2,3-diaminopropionic acid), can be introduced by coupling a bis-/V-protected DAABM building block, preferably Fmoc-(2S)-Dap(Fmoc)-OH, to the resin- bonded peptide with free side chain amino groups, such as a lysine e-amino group. Within the scope of the present invention, diamino alkanoic acid based branching moieties, featuring one stereogenic centre, can be present as (2S)-enantiomer, as (2R)-enantiomer, and mixtures thereof, which are collectively referred to herein as DAABM. Accordingly, 2,3-diaminopropionic acid, featuring one stereogenic centre, can be present as (2S)-enantiomer, as (2R)-enantiomer, and mixtures thereof, which are collectively referred to herein as Dap. In the synthesis of those example compounds featuring a DAABM, the (2S)-enantiomer of Dap ((2S)-2,3- diaminopropionic acid, or (2S)-Dap) has been used. This approach is visualised below in Scheme 2, in which“^*|^*” represents the points of attachment to the respective neighbouring amino acids in the peptide backbone of the compounds of formula (I).

Coupling of the peptides with the branching moiety can be accomplished by reacting the resin loaded with the peptide featuring /V-terminal protection, such as /V-a-Boc protection, and free side chain amino groups, as indicated in formula (II), with bis-/V-protected DAABM building blocks, preferably Fmoc-(2S)-Dap(Fmoc)-OH (III), in 3-fold molar excess per free lysine e-amino group with HOBt and DIC in 3- to 5-fold molar excess, in DMF as a solvent, to give the intermediate coupling products as indicated in formula (IV), followed by deprotection of the protecting groups attached to the DAABM amino groups, preferably by Fmoc cleavage with piperidine in DMF, particularly 30 % piperidine in DMF, to give DAABM branched peptides as indicated in formula (V). Said branching cycle can be performed once or repeated two or more times according to the desired carbaborane loading of the peptide. In between the reaction steps, the resin-bonded intermediates can be advantageously washed with solvents to remove excess of reagents. Specific examples are described in the Experimental Section.

Scheme 2: Optional introduction of a (2S)-Dap branching group to a free lysine e-amino group as present in formula (II). The respective carbaborane synthons of formula (VI), which are selected from the formulae (VI- a), (Vl-b), (Vl-c), (Vl-d), (Vl-e), (Vl-f), (Vl-g), (Vl-h), (Vl-i), (Vl-j), (Vl-k), (Vl-m), (Vl-n), (Vl-o), (VI- p), and (Vl-q) shown in Scheme 3, in which PG⁹, PG¹⁰, PG¹¹, PG¹² represent protecting groups suitable for the protection of hydroxy groups on saccharides, such as benzyl or acetyl or in which, preferably, two groups selected from PG⁹, PG¹⁰, PG¹¹, PG¹² attached to hydroxy groups on adjacent carbon atoms together form a group -C(CH3)2-, can be subsequently attached to free side chain amino groups of the resin-bonded peptide intermediate, particularly lysine e-amino groups (see formula (II)), or amino groups of one or more DAABM branching moieties, particularly (2S)-Dap (see formula (V)), by coupling in 1- to 4-fold, preferably 1.5- to 3-fold molar excess per free amino group, in the presence of HOBt and DIC in 1.5- to 5-fold, preferably 1.8- to 3.5-fold molar excess per free amino group, as illustrated in Schemes 4a and 4b, below, in which“^*|^*” represents the points of attachment to the respective neighbouring amino acids in the peptide backbone of the compounds of formula (I), to give conjugates as illustrated in formulae (VII) and (IX), in combination with Scheme 4c. Carbaborane synthons of formula (Vl-n), being derived from 6-deoxy-D-galactose, are preferred, of which the carbaborane m1J9b synthon of formula (Vl-n -a) is particularly preferred. In an analogous fashion, carbaborane synthons of formula (Vl-bis), shown in Scheme 5b (below), featuring two of the monosaccaride based groups shown in Scheme 3 attached to positions 1 and 7 of the carbaborane moiety, can be subsequently attached to free side chain amino groups of the resin-bonded peptide intermediate, particularly lysine e-amino groups (see formula (II)), or amino groups of one or more DAABM branching moieties, particularly (2S)-Dap (see formula (V)). In between the reaction steps, the resin-bonded intermediates can be advantageously washed with solvents to remove excess of reagents. Specific examples are described in the Experimental Section.

Table 2, below, shows the correlation of the carbaborane synthons of formulae (Vl-a), (Vl-b), (Vl-c), (Vl-d), (Vl-e), (Vl-f), (Vl-g), (Vl-h), (Vl-i), (Vl-j), (Vl-k), (Vl-m), (Vl-n), (Vl-o), (Vl-p), and

(Vl-q), and the names of the 6-deoxy saccharides from which they are derived.

Table 2:

Cbs

Scheme 3: Carbaborane synthons of formulae (Vl-a), (Vl-b), (Vl-c), (Vl-d), (Vl-e), (Vl-f), (Vl-g), (Vl-h), (Vl-i), (Vl-j), (Vl-k), (Vl-m), (Vl-n), (Vl-o), (Vl-p), (Vl-q), and (Vl-n-a).

Finally, the compounds of the invention can be obtained by simultaneous cleavage of the conjugates, illustrated by formulae (VII) and (IX) in combination with Scheme 4c, from the resin and removal of protecting groups still present, e.g. a /V-oterminal Boc group, and protecting groups blocking functional groups attached to the side chains and the saccharide based Sac moiety (i.e. to convert Sac’ into Sac) attached to the carbaborane, as illustrated by Schemes 4a and 4b, in which“^*|^*” represents the points of attachment to the respective neighbouring amino acids in the peptide backbone of the compounds of formula (I), using methods known to the person skilled in the art, e.g. using trifluoroacetic acid (TFA) mixed with water or mixed with thioanisole (TA) and p-thiocresole (TC), preferably using a 95:5 ( v/v ) TFA/water mixture or a 90:5:5 (v/v) TFA/TA/TC mixture, to obtain compounds of the present invention, as illustrated by formulae (VIII) and (X) in combination with Scheme 4d. This reaction may proceed with concomitant mutarotation reactions in the saccharide based Sac moiety, as discussed supra, giving rise to the respective isomers, and/or mixtures thereof. Subsequent to said cleavage reaction, the compounds of the invention can be isolated by work-up and purification using methods well known to the person skilled in the art, such as precipitation with a suitable solvent such as diethyl ether, dissolution in an aqueous solvent mixture such as aqueous acetonitrile, followed by lyophilisation and purification e.g. by preparative reversed-phase HPLC. Compounds of the present invention analogous to those of formulae (VIII) and (X), however featuring two Sac moieties at positions 1 and 7 of each respective carbaborane group, can be obtained by using carbaborane synthons of formula (Vl-bis), shown in Scheme 5b, instead of carbaborane synthons of formula (VI). Specific examples are described in the Experimental Section.

O = B atom

• = BH roup Sac'

Scheme 4a: Attachment of a carbaborane synthon of formula (VI), i.e. a synthon selected from the formulae (Vl-a) to (Vl-q), to a lysine e-amino group, followed by deprotection.

Scheme 4b: Attachment of two equivalents of a carbaborane synthon of formula (VI), i.e. a synthon selected from the formulae (Vl-a) to (Vl-q), to the free amino groups of (2S)-2,3- diaminopropionic acid, coupled to a lysine e-amino group as a branching moiety, followed by deprotection.

Scheme 4c: List of Sac’ groups referred to in Schemes 4a and 4b.

Scheme 4d: List of Sac groups referred to in Schemes 4a and 4b Availability of starting materials and carbaborane synthons

Amide resins for automated peptide synthesis, and suitably protected amino acids and protected DAABM branching moiety synthons such as Dap are well known to the person skilled in the art and are also commercially available in considerable variety. Several carbaborane synthons suitable for coupling to peptides are known to the person skilled in the art (see e.g. Ahrens, V. M., Frank, R., Stadlbauer, S., Beck-Sickinger, A. G., Hey-Hawkins, E., J. Med. Chem. 201 1 , 54, 2368-2377; Frank, R., Boehnke, S., Aliev, A., Hey-Hawkins, E., Polyhedron 2012, 39, 9-13; for a more general overview see: Grimes, Russel N.: Carboranes. Third Edition, Academic Press (Elsevier), 2016; ISBN: 9780128018941 ), some are also described in the Experimental section (see paragraph on Intermediates for Reference Examples).

Carbaborane synthons suitable for the preparation of compounds of the present invention, i.e. 9-(carboxymethylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) derivatives conjugated to a protected group Sac’ of formula (VI), as referred to in Schemes 4a and 4b, and as shown in more detail in Scheme 3, can be prepared according to Scheme 5a, below, from 9-(mercapto)- 1 ,7-dicarba-c/oso-dodecaborane(12) (formula (XI)), the preparation of which is well known (see e.g. L. I. Zakharkin, I. V. Pisareva, Phosphorus and Sulfur and Rel. Elem. 1984, 20, 357). Said 9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) can be reacted with tert- butanol in the 6-fold volume of TFA in dichloromethane as a solvent, to give 9-(fe/f-butylthio)-1 ,7-dicarba-c/oso- dodecaborane(12) (formula (XII), which in turn can be reacted with a saccharide based synthon Sac’-LG of the general formula (XIII), which is selected from the formulae (Xlll-a), (Xlll-b), (XIII- c), (Xlll-d), (Xlll-e), (Xlll-f), (Xlll-g), (Xlll-h), (Xlll-i), (Xlll-j), (Xlll-k), (Xlll-m), (Xlll-n), (Xlll-o), (Xlll-p), and (Xlll-q) shown below in Scheme 5c, in which LG represents a leaving group as defined supra, preferably [(trifluoromethyl)sulfonyl]oxy, and in which PG⁹, PG¹⁰, PG¹¹, PG¹² represent protecting groups suitable for the protection of hydroxy groups on saccharides, such as benzyl or acetyl, and in which preferably two groups selected from PG⁹, PG¹⁰, PG¹¹, PG¹² attached to hydroxy groups on adjacent carbon atoms together form the group -C(CH3)2-. Particularly, said saccharide based synthon Sac’-LG is 1 ,2:3,4-di-0-isopropylidene-6-deoxy-a- D-galactopyranosyl-6-triflate (formula (Xlll-n-a; CAS 71001 -09-7), in which PG⁹ and PG¹⁰ together form -C(CH3)2-; PG¹¹ and PG¹² together form -C(CH3)2-; LG represents [(trifluoromethyl)sulfonyl]oxy, and which can be prepared e.g. according to M. Brackhagen, H. Boye, C. Vogel, J. Carbohydrate Chem. 2001 , 20, 31 . Said reaction can yield fully protected carbaborane-saccharide conjugates of the formula (XIV). The tert- butyl group protecting the 9- mercapto group can then be removed by methods known to the person skilled in the art, e.g. using mercury(ll)acetate in a solvent such as dichloromethane, followed by treatment with a mercaptoalcohol, preferably 2-mercaptoethanol, to give the corresponding protected monosaccharide conjugates of 9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) of formula (XV). The carboxymethylene group enabling peptide coupling is subsequently established by reacting the free mercapto group thus formed with iodoacetic acid (formula (XVI), in the presence of a tertiary aliphatic amine, preferably triethylamine, in a solvent such as dichloromethane, to give carbaborane synthons of formula (VI) featuring the 9-(carboxymethylthio)-1 ,7-dicarba- c/oso-dodecaborane(12) conjugated to a protected monosaccharide. Preferably, the saccharide is 6-deoxy-D-galactose. Specific examples are described in the Experimental Section.

Scheme 5a: Synthesis of the carbaborane synthons of formula (VI) from 9-(mercapto)-1 ,7- dicarba-c/oso-dodecaborane(12) (formula (XI)).

In an analogous fashion, carbaborane synthons suitable for the preparation of further compounds of the present invention, i.e. 9-(carboxymethylthio)-1 ,7-dicarba-c/oso- dodecaborane(12) derivatives, conjugated to two protected groups Sac’, of formula (Vl-bis) can be prepared, by reacting 9-(ferf-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) (formula (XII) with an excess of saccharide based synthon Sac’-LG of the general formula (XIII), preferably in a range from 2 to 2.5 equivalents, as shown in Scheme 5b below. is )

( Vl-bis )

( XV-bis )

Scheme 5b: Synthesis of the carbaborane synthons of formula (Vl-bis) from 9-(mercapto)-1 ,7- dicarba-c/oso-dodecaborane(12) (formula (XI)).

Scheme 5c: Saccharide based synthons Sac’-LG of formula (XIII), which are selected from formulae (Xlll-a), (Xlll-b), (Xlll-c), (Xlll-d), (Xlll-e), (Xlll-f), (Xlll-g), (Xlll-h), (Xlll-i), (Xlll-j), (XIII- k), (Xlll-m), (Xlll-n), (Xlll-o), (Xlll-p), (Xlll-q), and (Xlll-n-a).

The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art. Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively mediate activation of the human Yi receptor (hYiR), said activation resulting in internalisation of the receptor together with the compounds of the present invention bonded to it, into HEK 293 cells transfected with the human Yi receptor, as shown by data given in the biological experimental section. Compounds of the present invention can therefore be used to selectively transport boron atoms into cells expressing the human Yi receptor, such as breast cancer cells, to enable boron neutron capture therapy of cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

Particularly surprising, high levels of receptor activation and internalisation are maintained over a wide range of carbaborane loading, up to at least eight carbaborane units per peptide unit, enabling for transferring a particularly large number of boron atoms per cell into cells expressing the human Yi receptor and thus further enhancing the carbaborane loading known hitherto to be compatible with high levels of human Yi receptor activation and internalisation into HEK 293 cells transfected with the human Yi receptor.

Reference examples RE3 and RE4 confirm the results from prior art [Ahrens et al., ChemMedChem 2015, 10, 164] in that conjugation of [F⁷,P³⁴]-NPY peptide to three carbaborane units in reference example RE4 (the carbaborane based moieties of which differing from those carbaborane based moieties disclosed in the prior art) results in a similar profile regarding human Yi activation and internalisation into HEK 293 cells transfected with the human Yi receptor as featured by the analogous mono-carbaborane conjugate of NPY peptide RE3.

Reference examples RE1 and RE2, featuring yet another carbaborane based moiety, do however indicate that not all carbaborane based moieties are equally suitable for multiple conjugation to [F⁷,P³⁴]-NPY peptide, as shown by the significantly reduced human Yi activation and internalisation into HEK 293 cells transfected with the human Yi receptor shown by reference example RE2 as compared to reference example RE1.

Reference examples RE5 to RE9, featuring the bis-carbaborane moiety bm9g, further demonstrate that loading of [F⁷,P³⁴]-NPY peptide with one bis-carbaborane moiety ( i.e . two carbaborane units), as present in reference examples RE5 and RE6, does not affect human Yi activation and internalisation into HEK 293 cells transfected with the human Yi receptor, which are in turn almost or completely lost upon loading [F⁷,P³⁴]-NPY peptide with two (i.e. four carbaborane units; reference examples RE7 and RE9) or three bis-carbaborane moieties (i.e. six carbaborane units; reference example RE8).

Hence, the fact that compounds of the present invention, featuring saccharide functionalised carbaborane moieties, as exemplified by examples 1 to 7, maintain high levels of human Yi receptor activation and internalisation into HEK 293 cells transfected with the human Yi receptor over a wide range of carbaborane loading, up to at least eight carbaborane units per [F⁷,P³⁴]- NPY peptide unit, could indeed not be predicted by the person skilled in the art.

Co-localisation of the TAMRA fluorescence labelled analogue of Example 4, RE11 , with the hYiR in intracellular vesicles further demonstrates that this carbaborane-containing conjugate indeed undergoes, together with the human Yi receptor, internalisation into HEK 293 cells transfected with the human Yi receptor.

It is possible therefore that said compounds can be used for the treatment or prophylaxis of diseases, preferably cancer in humans and animals.

Compounds of the present invention can be utilised to selectively transport boron atoms into cells expressing the human Yi receptor, such as breast cancer cells, to enable boron neutron capture therapy of cancer, such as breast cancer, adrenal gland and related tumours, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma. Boron neutron capture therapy of cancer comprises (i.) the step of accumulating a drug containing non-radioactive boron, preferably its ¹⁰B isotope, inside tumour cells, and (ii.). local irradiation of the tumour with thermal or epithermal neutrons. This method comprises administering to a mammal in need thereof, including a human, an amount, which is effective to treat cancer, of a compound of general formula (I) of the present invention, or an isomer resulting from a mutarotation reaction, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

Cancer includes, but is not limited to, for example: solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid cancer, adrenal gland and related tumours, and their distant metastases. Cancer also includes lymphomas, sarcomas, and leukaemias.

Examples of breast cancers include, but are not limited to, breast carcinoma, such as invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, such as renal cell carcinoma, further renal pelvis, ureter, urethral and human papillary renal cancers.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

Examples of adrenal gland and related tumours include, but are not limited to, adrenocortical adenoma, adrenocortical carcinoma, neuroblastoma and pheochromocytoma.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:

1 . yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents,

3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

4. provide for treating a broader spectrum of different cancer types in mammals, especially humans,

5. provide for a higher response rate among treated patients,

6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments,

7. provide a longer time for tumour progression, and/or

8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

In other embodiments of the present invention, the compounds of general formula (I) of the present invention can be used advantageously in combination with local irradiation of the tumour with thermal or epithermal neutrons, optionally in combination with surgical intervention.

In other embodiments of the present invention, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with irradiation with thermal or epithermal neutrons.

In other embodiments of the present invention, a cell is killed by treating the cell by irradiation with thermal or epithermal neutrons after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated by irradiation with thermal or epithermal neutrons to kill the cell.

In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the irradiation with thermal or epithermal neutrons.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

The term“treating” or“treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as cancer. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

Further, the compounds of the present invention can be used in combination with irradiation with thermal or epithermal neutrons in particular in therapy and prevention, i.e. prophylaxis, of cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma, in combination with irradiation with thermal or epithermal neutrons.

The pharmaceutical activity of the compounds according to the present invention can be explained by their affinity to, and activation of human Yi receptors, their internalisation into cells expressing human Yi receptors upon receptor activation, resulting in the selective transport of a large number of boron atoms into said cells, followed by the release of linear high energy transfer particles (alpha particles (⁴He²⁺ nuclei) and lithium-7 nuclei) upon local irradiation with thermal or epithermal neutrons.

In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers the use of a compound of general formula (I), as described supra, or an isomer resulting from a mutarotation reaction, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers the use of a compound of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma, using an effective amount of a compound of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in combination with irradiation with thermal or epithermal neutrons, for the treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers the use of a compound of formula (I), described supra, or an isomer resulting from a mutarotation reaction, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, in combination with irradiation with thermal or epithermal neutrons, for the prophylaxis or treatment of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in combination with irradiation with thermal or epithermal neutrons, in a method of treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma.

In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N- oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma, in combination with irradiation with thermal or epithermal neutrons.

In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer, such as breast cancer, adrenal gland and related tumors, renal cell carcinoma and ovarian cancer, particularly breast cancer, more particularly breast carcinoma, using an effective amount of a compound of general formula (I), as described supra, or isomers resulting from mutarotation reactions, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in combination with irradiation with thermal or epithermal neutrons.

In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or an isomer resulting from a mutarotation reaction, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.

The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel^®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos^®)),

• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette^®), sorbitan fatty acid esters (such as, for example, Span^®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween^®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor^®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic^®),

• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

• isotonicity agents (for example glucose, sodium chloride),

• adsorbents (for example highly-disperse silicas),

• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol^®); alginates, gelatine),

• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab^®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol^®)),

• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil^®)),

• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit^®)),

• capsule materials (for example gelatine, hydroxypropylmethylcellulose),

• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit^®), polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

• penetration enhancers,

• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

• flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceutical composition which comprises at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer.

Particularly, the present invention covers a pharmaceutical combination, which comprises:

• one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and

• one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer.

The term“combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit- of-parts.

A“fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a“fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

A non-fixed combination or“kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known agents for the treatment and/or prophylaxis of cancer.

Examples of agents for the treatment and/or prophylaxis of cancer include:

1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM- CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the cancer related conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

EXPERIMENTAL SECTION

Nomenclature of amino acids and peptide sequences is according to the definitions given herein, supra.

Nomenclature of Carbaboranes has been used according to:

Nomenclature of Inorganic Chemistry: Recommendations 1990. International Union of Pure and Applied Chemistry, ed. Geoffrey J Leigh. Blackwell Scientific Publications, Oxford 1990, 228- 231 ; ISBN 0-632-02494-I.

The following table 3 lists the abbreviations used herein as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

Table 3: Abbreviations

9-xanthenyl

Xan

Structures of protecting groups listed herein, such as Boc, Bom, Bpoc, Bum, Cbz, 2-CI-Trt, Cpd, Dde, Ddz, Doc, Fmoc, Mbh, MIS, Mmt, Mpe, Mtr, Mtt, Pbf, 2-Ph'Pr, Pmc, TBDMS, tBu, TEGBn, Tmob, Tos, Trt, and Xan are shown (together with amino acids to which they are bonded) in table 1 c, supra.

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

EXPERIMENTAL SECTION - GENERAL PART

All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example loose silica or silica gel in glass columns, with manual or automated fraction collecting, or using prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil^® or KP- NH^® in combination with an automated column chromatography device such as a Biotage autopurifier system (SP4^® or Isolera Four^®), and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using commercially available HPLC equipment, for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. Eluents can be removed by methods known to the person skilled in the art, such as lyophilisation.

In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

HPLC methods

Analytical methods are summarised in context of Table 6, infra. Further analytical and preparative HPLC methods are described in the protocols within the Experimental Section.

NMR spectra

NMR measurements were carried out on a Bruker AVANCE III HD spectrometer with an Ascend™ 400 magnet. Tetramethylsilane was used as internal standard, and ¹¹B-NMR spectra were referenced to the X scale (see: R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger, NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC Recommendations 2001 ). Pure Appl. Chem. 73, 1795 (2001 )). All chemical shifts are reported in ppm. Assignment of the ¹H and ¹³C signals was based on 2D NMR spectra (H,H-COSY, HMQC, HSQC, HMBC). Identification of the boron atom attached to sulfur was possible by comparison of the proton-coupled and -decoupled ¹¹B-NMR spectra.

On the following pages, some NMR signals that appear as broad overlapping signals with the shape of a multiplet in either ¹H-, ¹¹B{¹H}-, ¹¹B-, ¹⁰B{¹H}- or ¹⁰B-NMR spectra are just described as‘br’ (broad). In this case, the superscript a is added (br³).

Example of a ¹H-NMR spectrum: the rectangle marks the region of interest (Figure 1 )

O = B atom

• = BH group

Example of a ¹¹B -NMR spectrum: the rectangle marks the region of interest (Figure 2)

O = B atom

• = BH group

Example of a ¹¹B-NMR spectrum: the rectangle marks the region of interest (Figure 3)

O = B atom

• = BH group

Example of a ¹⁰B -NMR spectrum: the rectangle marks the region of interest (Figure 4)

O = B atom

• = BH group

Example of a ¹⁰B-NMR spectrum: the rectangle marks the region of interest (Figure 5)

O = B atom

• = BH group

Elemental analysis

All obtained elemental analysis data (carbon, nitrogen, hydrogen) were performed with a Heraeus VARIO EL device.

Infrared spectra

IR data were obtained with a Perkin-Elmer FT-IR spectrometer Spectrum 2000 as KBr pellets and on a Thermo Scientific Nicolet iS5 with an ATR unit in the range of 4000 to 400 cm ¹. All detected signals were interpreted as weak ( w ), medium ( m ) or strong (s).

Mass spectra

EI-LR mass spectra were obtained on a Finnigan MAT 8230 from Finnigan MAT (now: Thermo Fisher Scientific). ESI-LR mass spectra were obtained on a Bruker Daltonics Esquire 3000plus (ESI-lon Trap LC MSMS) and ESI-HR mass spectra were obtained on a Bruker Daltonics IMPACT II. Isotopic pattern simulations were performed with Bruker Compass Data Analysis 4.2 SR1 (version 4.2, copyright 2014, Bruker Daltonic GmbH). Formic acid was sometimes added for better ionisation of the carbaborane-containing compounds. Only the most intense peak of the isotopic pattern of each species is listed for the low and high resolution mass spectra.

X-Ray crystallography

The X-ray measurements were carried out on a Gemini-S CCD diffractometer (Agilent Technologies) with Mok_a radiation and w scan rotation (data reduction with CrysAlis Pro, Oxford Diffraction Ltd., Oxfordshire, UK, 2010) empirical absorption correction with SCALE3 ABSPACK (Oxford Diffraction Ltd., Oxfordshire, UK, 2010). The collected data were processed and refined by using WinGX (see L. J. Farrugia, WinGX suite for small-molecule single-crystal crystallography, J. Appl. Crystallogr. 1999, 32, 837) including the programs SIR92 (see A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, Completion and refinement of crystal structures with SIR 92, J. Appl. Crystallogr. 1993, 26, 343) and SHELX97 (see G. M. Sheldrich, SHELXL97: program for the refinement of crystal structures, Universitat Gottingen, Gottingen, Germany, 1997). All hydrogen atoms were refined independently. Images of the molecular structures were generated with ORTEP (see L. J. Farrugia, ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI), J. Appl. Crystallogr. 1997, 30, 565; Diamond Crystal and Molecular Structure Visualization; Crystal Impact, Dr. H. Putz & Dr. K. Brandenburg GbR, Kreuzherrenstr. 102, D-53227 Bonn, Germany).

EXPERIMENTAL SECTION - GENERAL PROCEDURES Peptide Synthesis

Materials

Amino acids were purchased from Orpegen (Heidelberg, Germany) and Iris Biotech (Marktredwitz, Germany). HATU, HOBt, DIC, and Oxyma were also obtained from Iris Biotech. Acetonitrile was purchased from VWR (Darmstadt, Germany) and DMF and DCM were obtained from Biosolve (Valkenswaard, The Netherlands). DIPEA, hydrazine, piperidine, TA, TIS and TFA were purchased from Sigma-Aldrich (Taufkirchen, Germany), TC was from Alfa Aesar (Ward Hill, MA, USA) and diethyl ether was from Merck (Darmstadt, Germany).

General Information

If not stated otherwise, all reactions and procedures were performed at room temperature and all ratios of solutions are given in volume distributions (v/v). In order to remove excess of reagents, resins were thoroughly washed with solvent (DMF, DCM) after each coupling and deprotection procedure. Kaiser Test and sample cleavage were carried out when deemed necessary.

The purity of the peptide conjugates was analyzed by RP-HPLC. Following eluents were thereby used for the RP-HPLC: eluent A = 0.1 % TFA in water; eluent B = 0.08 % TFA in acetonitrile. Chromatograms were recorded at l = 220 nm. Corresponding flow rates and columns are listed in the working examples.

The identity of the synthesized conjugates was confirmed by MALDI-MS (Ultraflexlll, Bruker). Due to the highly expanded isotopic pattern and the large mass of Examples 2 - 7 and Reference Examples RE10 and RE11 , ESI-MS (Orbitrap Elite, Thermo Scientific) was used to analyze the identity of these compounds. MALDI = exact mass; ESI = average mass.

General Method for Automated Peptide Synthesis

Resin-bonded peptide intermediates of the compounds of the present invention were synthesized by Fmoc-based solid phase peptide synthesis using an automated peptide synthesizer (SYRO I, MultiSynTech). As solid phase, a Rink amide AM resin (Iris Biotech) or a NovaSyn® TGR R resin (Novabiochem, Darmstadt, Germany) were used. The reaction scale was 15 pmol. Each amino acid and the reagents Oxyma and DIC were added in 8-fold molar excess (120 pmol). DMF was used as solvent for all reactions. The used amino acids were N-a- Fmoc-protected, except for the /V-terminal amino acid of the NPY analogs, which was applied in a /V-oBoc-protected form. Additional protecting groups for blocking of side chain functionalities are indicated below. Each coupling step was performed two times for 40 min. Cleavage of the /V-terminal Fmoc protecting group was accomplished by using 40 % piperidine in DMF for 3 min and afterwards 20 % piperidine in DMF for 10 min.

EXPERIMENTAL SECTION - INTERMEDIATES

The following reactions were carried out using the Schlenk technique well known to the person skilled in the art and dry nitrogen gas as an inert gas.

Intermediate 1 : 9-(Mercapto)-1 -dicarba-c/oso-dodecaborane(12) (CAS 64493-44-3)

O = B atom

• = BH group

The title compound was prepared according to L. I. Zakharkin, I. V. Pisareva, Phosphorus and Sulfur and Ret. Elem. 1984, 20, 357; see compound 3.

Yield: 8.64 g (49.0 mmol, 71 %)

¹H-NMR (400 MHz, CDCIs): d = 0.47 (m, 1 H, SH), 1.44 - 3.41 (br³, m, 9H, B_I0H₉), 2.98 (br s, 2H, CH) ppm.

¹¹B{¹H}-NMR (128 MHz, CDCIs): d = -2.6 (s, 1 B), -5.8 (s, 2B), -8.9 (s, 1 B), -12.5 (s, 2B), -13.8 (s, 2B), -17.6 (s, 1 B), -20.8 (s, 1 B) ppm. Syntheses of Intermediates for Reference Examples

Intermediate 2: 1-(Carboxy)-1 -dicarba-c/oso-dodecaborane

(Carbaborane mla synthon; CAS18581-81-2)

O = B atom

· = BH group

The title compound was prepared from m-carbaborane (CAS-Nr.: 16986-24-6; Katchem spol. s r. o., Elisky Krasnohorske 123/6, 1 10 00 Josefov, Czech Republic) according to R. A. Kasar, G. M. Knudsen, S. B. Kahl, Inorg. Chem. 1999, 38, 2936.

Yield: 0.6 g (3.1 mmol, 90%)

¹H-NMR (400 MHz, CDCIs): d = 1 .50 - 3.20 (br³, 10H, B10H10), 3.02 (s, 1 H, C¹H), 8.94 (br, s, 1 H, C³OOH) ppm.

^{1 1}B{¹H}-NMR (128 MHz, CDCI3): d = -15.7 (s, 2B), -13.2 (s, 2B), -1 1 .3 (s, 2B), -10.6 (s, 2B), -6.5 (s, 1 B), -4.9 (s, 1 B) ppm.

Intermediate 3: 9-(Carboxymethylthio)-1 -dicarba-c/oso-dodecaborane(12)

(Carbaborane m9b synthon; CAS 74555-68-3 )

O = B ato m

• = BH group

0.97 g (5.50 mmol, 1.0 eq.) 9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) (see

Intermediate 1 ) and 1 .02 g (5.50 mmol, 1.0 eq.) iodoacetic acid were dissolved in 20 ml acetonitrile. 5.74 ml (4.26 g, 33.02 mmol, 6.0 eq.) of diisopropylethylamine were added in one portion at ambient temperature. The mixture was stirred at ambient temperature for 3 days. The reaction was stopped by adding aqueous 2 N hydrochloric acid. The organic solvent was removed under reduced pressure and the aqueous phase was diluted with 75 ml distilled water and extracted three times with 150 ml DCM. The combined organic phases were dried over sodium sulfate and after filtration the solvent was removed under reduced pressure. The raw product was purified by column chromatography on silica using n- hexane/ethyl acetate (v/v) as eluent followed by recrystallisation in n-hexane yielding 0.72 g (3.07 mmol, 56%) of the title compound as a white solid.

¹H-NMR (400 MHz, CDCIs): d = 1 .30 - 3.50 (br³, 9H, BI₀H₉), 3.0 (br, s, 2H, 2xC³H), 3.40 (m, 2H, C²H₂), 10.5 (br, s, 1 H, C¹OOH) ppm

¹⁰B{¹H}-NMR (43 MHz, CDCIs): d = -0.5 (1 B), -6.4 (2B), -9.8 (1 B),—13.1 (2B), -13.7 (2B), -17.4 (1 B), -20.0 (1 B) ppm

¹³C{¹H}-NMR (100 MHz, CDCIs): d = 34.5 (C²H₂), 54.4 (2xC³H), 174.6 (C¹OOH) ppm

IR spectroscopy (KBr, v in cm ¹): 3436 (m), 3059 (s), 2916 (w), 2608 (s), 1698 (s), 1433 (s), 1390 (w), 1305 (s), 1205 (s), 1 162 (m), 1069 (w), 993 (m), 951 (m), 915 (m), 891 (m), 871 (m), 794 (w), 775 (w), 760 (w), 731 (w), 670 (w), 454 (w). Intermediate 4: 2-Chloro-4,6-bis(1 ,7-dicarba-c/oso-dodecaboran-9-ylthio)-1 ,3,5- triazine

5.00 g (28.4 mmol, 2.00 eq.) 9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) (see Intermediate 1 ) and 2.62 g (14.2 mmol, 1.00 eq.) cyanuric chloride were placed in an evacuated and nitrogen-purged 500 ml. two-neck round-bottom flask, equipped with a condenser. The starting materials were suspended in 200 ml. acetonitrile and cooled to 0 °C. 6.04 ml. (4.59 g, 35.5. mmol, 2.50 eq.) diisopropylethylamine were added slowly to this suspension. After 20 minutes stirring at 0 °C the mixture was heated to reflux. After five hours of heating the reaction mixture was cooled to room temperature and stirred overnight at ambient temperature. The reaction was stopped by adding 20 ml. water and 20 mL 2 M aqueous hydrochloric acid. Excess acetonitrile was removed under reduced pressure and the remaining aqueous phase was extracted three times with 30 mL ethyl acetate. The combined organic phases were washed with 20 mL of a saturated aqueous sodium chloride solution and 20 mL water, respectively. Both aqueous washing solutions were extracted with 50 mL diethyl ether. All combined organic phases were dried over magnesium sulfate, filtered and then the solvent was removed under reduced pressure. The purity of the obtained material proved to be sufficient (by TLC (ethyl acetate/n-hexane, 1 :2, v/v). The title compound was isolated as a slightly yellow solid (quantitative yield, 6.59 g, 14.2 mmol, R f = 0.63).

¹H-NMR (400 MHz, (CD₃)₂CO): d = 1.52 - 3.54 (br³, 18H, 2XBI₀H₉S), 3.82 (br, s, 4H, 4xC¹H) ppm.

¹¹B{¹H}-NMR (128 MHz, (CD₃)₂CO): d = -18.1 (br, s, 2B), -16.8 (s, 2B), -13.8 (s, 4B), -12.8 (br³, 4B), -10.4 (s, 2B), -5.9 (br, s, 4B), -4.0 (s, 2B, 2xBS) ppm.

¹¹B-NMR (128 MHz, (CD₃)₂CO): d = -17.5 (br³, 4B), -13.2 (br³ 8B), -10.4 (d, ¹J_BH = 152 Hz, 2B), -5.9 (d, ¹JBH = 165 Hz, 4B), -4.0 (s, 2B, 2xBS) ppm.

¹³C{¹H}-NMR (100 MHz, (CD₃)₂CO): d = 56.1 (br, s, 4xC¹H), 168.5 (s, C_q ³CI), 182.6 (s, 2xC_q ²S) ppm.

IR spectroscopy (KBr, v in cm^-1): 3446 (m), 3072 (m), 3060 (m), 3050 (m), 2962 (w), 2617 (s), 2390 (w), 2091 (w), 1988 (w), 1718 (w), 1624 (w), 1562 (w), 1501 (s), 1477 (s), 1456 (s), 1432 (m), 1312 (m), 1274 (s), 1252 (s), 1 166 (m), 1 150 (m), 1 105 (w), 1067 (m), 1036 (w), 992 (m), 954 (m), 920 (w), 863 (s), 846 (s), 806 (m), 790 (m), 773 (m), 760 (m), 732 (m), 676 (w), 624 (w), 576 (w), 507 (w), 376 (w).

Mass spectrometry (LR-ESI, positive mode, CH2CI2/CH₃CN):

calculated for C7H23B20CI1 N3S2: m/z = 465.1 ([M+H]⁺)

found: m/z = 465.4 ([M+H]⁺)

calculated for C14H46B40CI2UN6S4: m/z = 935.1 (100%, [2M+Li]⁺)

found: m/z = 935.6 (100%, [2M+Li]⁺)

Mass spectrometry (LR-ESI , negative mode, CH2CI2/CH₃CN):

calculated for C7H23B20CI2N3S2: m/z = 499.5 ([M+CI] )

found: m/z = 499.3 ([M+CI] )

Elemental analysis:

calculated (%) for C7H22B20CI1N3S2: C = 18.12, H = 4.78;

found: C = 18.1 1 , H = 4.60.

Crystallographic data

Empirical formula C7H22B20CI1 N3S2

Formula weight 464.04

Temperature 130(2) K

Wavelength 71.073 pm

Crystal system Monoclinic

Space group P2i/c

Unit cell dimensions a = 1352.87(4) pm oc = 90°

b = 141 1.68(4) pm b = 98.178(3)° c = 1249.64(5) pm g = 90°

Volume 2.3623(1 ) nm³ z 4

Density (calculated) 1.305 Mg/m³

Absorption coefficient 0.343 mm ¹

F(000) 936

Crystal size 0.5 x 0.04 x 0.04 mm³

Theta range for data collection 2.19 to 30.75°

Index ranges -19 £ h < 19, -20 < k < 19, -17 < l < 16

Reflections collected 30792

Independent reflections 6750 [R(int) = 0.0598]

Completeness to theta = 28.29 100.0%

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1 and 0.96054

Refinement method Full-matrix least-squares on F²

Data / restraints / parameters 6750 / 0 / 388

Goodness-of-fit on F² 1.045

Final R indices [l>2sigma(l)] R1 = 0.0486, wR2 = 0.0879

R indices (all data) R1 = 0.0800, wR2 = 0.0975

Extinction coefficient n/a

Largest diff. peak and hole 0.315 and -0.305 e A-³

Comments: Structure solution with SHELXS-2013 (Direct method). Anisotropic refinement of all non-hydrogen atoms with SHELXL-2014. All H atoms were located on difference Fourier maps calculated at the final stage of the structure refinement. With a displacement parameter and bond length analysis the carbaborane carbon atoms C(1 ), C(2), C(3) and C(4) could clearly be localised.

Hydrogen atoms are omitted for clarity.

Intermediate 5: 2-fr4,6-Bis(1 -dicarba-c/oso-dodecaboran-9-ylthio)-1,3,5-triazin- 2-vnthio) acetic acid (Carbaborane bm9g synthon)

2.01 g (4.33 mmol, 1 .00 eq.) 2-chloro-4,6-bis(1 ,7-dicarba-c/oso-dodecaboran-9-ylthio)-1 ,3,5- triazine (see Intermediate 4) were placed in an evacuated and nitrogen-purged 250 mL two-neck round-bottom flask, equipped with a condenser, and dissolved in 150 mL acetonitrile. 0.45 mL (0.60 g, 6.46 mmol, 1 .49 eq.) thioglycolic acid were added to this solution and the mixture was cooled to 0 °C. Then 3.00 mL (2.28 g, 17.6 mmol, 4.07 eq.) diisopropylethylamine were added to this mixture and stirred for 20 minutes. Subsequently, the mixture was warmed to room temperature and then stirred for three hours under reflux. The reaction was stopped by adding 30 mL water and 20 mL of aqueous 2 M hydrochloric acid. All volatile components were removed under reduced pressure and the remaining aqueous phase was extracted two times with 40 mL diethyl ether. The combined organic phases were washed two times with 20 mL water, dried over magnesium sulfate and filtered. The organic solvent was removed under reduced pressure. After column chromatography (ethyl acetate/n-hexane, gradient 1 :1 to 100% ethyl acetate, v/v) 600 mg (1 .15 mmol, 26.6%, R f = 0.18, 100% ethyl acetate) of the title compound were isolated as a slightly yellow solid.

¹H-NMR (400 MHz, (CD₃)₂CO): d = 1 .44 - 3.50 (br³, 18H, 2XBI₀H₉), 3.80 (br, s, 4H, 4xC¹H), 4.17 (s, 2H, C⁴H₂), 1 1 .28 (br, s, 1 H, C⁵OOH) ppm.

¹¹B{¹H}-NMR (128 MHz, (CD₃)₂CO): d = -18.2 (s, 2B), -16.9 (s, 2B), -13.9 (s, 4B), -12.7 (s, 4B), -10.4 (s, 2B), -5.9 (s, 4B), -3.8 (s, 2B, 2xBS) ppm.

¹¹B-NMR (128 MHz, (CD₃)₂CO): d = -17.6 (br³, 4B), -13.3 (br³, 8B), -10.4 (d, ¹J_BH = 150 Hz, 2B), -5.9 (d, ¹J_BH = 162 Hz, 4B), -3.8 (s, 2B, 2xBS) ppm.

¹³C{¹H}-NMR (100 MHz, (CD₃)₂CO): d = 32.6 (s, C⁴H₂), 56.1 (br, s, 4xC¹H), 169.7 (s, C_q ³S), 179.4 (s, C_q ⁵OOH), 179.6 (s, 2xC_q ²S) ppm.

Mass spectrometry (HR-ESI , positive mode, CH2CI2/CH₃CN):

calculated for C9H26B20N3O2S3: m/z = 521.31608 ([M+H]⁺) found: m/z = 521.31583 ([M+H]⁺)

Syntheses of Intermediates for Example Compounds of the present invention

Intermediate 6: 9-(terf-Butylthio)-1 -dicarba-c/oso-dodecaborane(12)

o = B atom

• = BH group

The following procedure was performed in analogy to the known synthesis of the analogous orf/70-carbaborane derivative (see R. Frank, S. Boehnke, A. Aliev, E. Hey-Hawkins, Polyhedron 2012, 39, 9.

3.00 g (17.02 mmol, 1.0 eq.) 9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) (see

Intermediate 1 ) were suspended in 140 ml fBuOH/TFA = 1/6 (v/v) and DCM was added dropwise until the mixture turned into a clear solution. The solution was kept at ambient temperature without stirring for 8 days during which a red-brown solution was formed. The reaction was stopped by the addition of an aqueous solution of sodium carbonate at 0 °C. Afterwards, the solution was diluted with 600 ml distilled water and sodium hydroxide was added until pH = 12 was reached. The aqueous phase was extracted three times with 300 ml DCM. The combined organic phases were dried over sodium sulfate, filtered and then the solvent was evaporated under reduced pressure giving 4.50 g of a yellow-brown oil, which crystallised over time. The raw product was purified by several recrystallisation steps in methanol yielding 2.93 g (12.55 mmol, 74% yield) of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CDCI₃): d = 1.45 (s, 9H, C(C³H₃)₃), 1.7 - 3.5 (br³, 9H, B_I0H₉), 2.95 (br, s, 2H, 2xC¹H) ppm.

¹¹B{¹H}-NMR (128 MHz, CDCI₃): d = -1.0 (br, 1 B, BS), -6.3 (br, 2B), -9.6 (br, 1 B), -13.0 (br, 2B), -14.0 (br, 2B), -17.7 (br, 1 B), -20.1 (br, 1 B) ppm.

¹¹B-NMR (128 MHz, CDCI₃): d = -1.0 (br, s, 1 B, BS), -6.3 (d, ¹J_BH = 165 Hz, 2B), -9.6 (d, ¹ JBH = 153 Hz, 1 B), -13.4 (m, 4B), -17.7 (d, ¹J_BH = 182 Hz, 1 B), -20.1 (d, ¹J_BH = 182 Hz, 1 B) ppm. 13 C{¹H}-NMR (100 MHz, CDCI₃): d = 32.7 (s, C(C³H₃)₃), 44.4 (s, C_q ²), 53.9 (s, 2xC¹H) ppm.

Elemental analysis:

Calculated for C H B S: C = 31 .01 % H = 8.68%;

found: C = 32.15% H = 8.41 %

Intermediate 7: 1,2:3,4-Di-0-isopropylidene-6-deoxy-a-D-qalactopyranosyl-6- triflate (CAS 71001-09-7)

The title compound was prepared according to M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1 ), 31 -43.

7.50 g (28.80 mmol, 1.0 eq.) 1 ,2:3,4-di-0-isopropylidene-a-D-galactopyranose (see M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1 ), 31 -43) were mixed with 7.6 ml (6.98 g, 57.60 mmol, 2.0 eq.) dry 2,4,6-collidine. The mixture was dissolved in 300 ml dry DCM. 7.7 ml (13.00 g, 46.08 mmol, 1.6 eq.) trifluoromethanesulfonic anhydride were added dropwise over 30 minutes at ambient temperature to this solution. The reaction mixture turned deep yellow during the addition. Over a stirring period of 4 hours at ambient temperature, the mixture turned orange. The reaction was stopped by pouring the mixture onto 300 ml of iced water. The phases were separated and the water phase was extracted two times with 100 ml chloroform. The combined organic phases were washed two times with 250 ml of an aqueous 17% solution of potassium bisulfate. The organic phase was washed two times with 200 ml of iced water, two times with 250 ml of a saturated aqueous solution of sodium bicarbonate, once with 300 ml iced water and finally once with 300 ml of a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate. The solution was concentrated by reduced pressure. TLC showed the product at an R_f-value of R_f = 0.46 (n- hexane/ethyl acetate = 3/1 v/v). The crude product was purified by column chromatography over silica using an isocratic n- hexane/ethyl acetate = 3/1 mixture (v/v) as eluent, yielding 10.54 g (26.80 mmol, 93%) of the title compound as a yellow oil, which slowly solidified in the fridge. ¹H-NMR (400 MHz, CDCI₃): d = 1 .34 (s, 3H, CH₃), 1 .34 (s, 3H, CH₃), 1 .45 (s, 3H, CH₃), 1 .53 (s, 3H, CH₃), 4.12 (ddd, ³ JHH = 7.0 Hz, ³J_HH = 4.7 Hz, ³J_HH = 2.0 Hz, 1 H, CH⁵), 4.25 (dd,

JHH = 7.8 Hz, ³J_HH = 2.0 Hz, 1 H, CH⁴), 4.36 (dd, ³ JHH = 5.0 Hz, J_HH = 2.6 Hz, 1 H, CH²), 4.55 - 4.68 (m, 3H, CH³, CH⁶ ₂), 5.54 (d, ³ JHH = 4.9 Hz, 1 H, CH¹) ppm.

¹³C{¹H}-NMR (100 MHz, CDCI₃): d = 24.4 (s, C⁹'¹¹H₃), 24.8 (s, C⁹'¹¹H₃), 25.8 (s, C⁹'¹¹H₃), 25.9 (s, C⁹'¹¹H₃), 66.1 (s, C⁵H), 70.2 (s, C²H), 70.4 (s, C⁴H), 70.6 (s, C³H), 74.6 (s, C⁶H₂), 96.1 (s, C¹H), 109.1 (s, C⁸’¹⁰(CH₃)₂), 1 10.1 (s, C⁸’¹⁰(CH₃)₂), 1 18.6 (q, ¹J_CF = 320 Hz, C⁷F₃) ppm.

Intermediate 8: 1 - 0-disopropylidene-6^,-deoxy-a-D-qalactopyranos-6^,-

yl)- 9-(te/ -butylthio)-1 -dicarba-c/oso-dodecaborane(12)

O = B atom

• = BH group

The following procedure was performed in analogy to the known synthesis of the analogous orf/70-carbaborane derivative (see R. Frank, S. Boehnke, A. Aliev, E. Hey-Hawkins, Polyhedron 2012, 39, 9).

2.97 g (12.78 mmol, 1.0 eq.) 9-(fe/f-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) (see Intermediate 6) was dissolved in 100 ml diethyl ether and cooled to 0 °C and 8.72 ml (1.45 M in n-hexane, 12.64 mmol, 0.9 eq.) n-butyllithium were added dropwise. The reaction was allowed to warm up to room temperature over 2 hours. The solution was cooled to 0 °C again and 5.00 g (12.7 mmol, 1.0 eq.) 1 ,2:3,4-di-0-isopropylidene-6-deoxy-a-D-galactopyranosyltriflate (see Intermediate 7), dissolved in 50 ml diethyl ether, were added dropwise. The reaction was allowed to warm up to ambient temperature and stirred overnight. Wet diethyl ether was added and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate/n-hexane 1 :3 v/v) yielding 3.62 g (7.67 mmol, 60% yield) of the title compound as a colourless highly viscous oil (R_f-value = 0.50, n- hexane/ethyl acetate = 3/1 v/v).

¹H-NMR (400 MHz, CDCI₃): d = 1 .30 (s, 3H, C¹²'^12'H₃), 1 .34 (s, 3H, C¹³'^13'H₃), 1 .41 (s, 3H, C¹²'^12'H₃), 1.43 (s, 9H, C(CH₃)₃), 1.50 - 3.50 (br³, 9H, BI₀H₉), 1 .59 (s, 3H, C¹³'^13'H₃), 2.15 (virtual d, ²J_HH = 15.9 Hz, 1 H, C⁴H₂), 2.34 (ddd, ²J_HH = 16.0 Hz, ³J_HH = 9.0 Hz, ³J_HH = 4.6 Hz, 1 H, C⁴H₂), 2.96 (br, s, 1 H, C¹⁴H), 3.77 (ddt, ³J_HH = 8.9 Hz, ³J_HH = 4.4 Hz, ³J_HH = 2.2 Hz, 1 H, C⁵H), 4.04 (virtual dd, ³ _HH = 7.8 Hz, J_HH = 1 .6 Hz, 1 H, C⁷H), 4.28 (virtual dd, ³J_HH = 5.1 Hz, J_HH = 2.4 Hz, 1 H, C⁸H), 4.57 (virtual dd, ³J_HH = 7.9 Hz, J_HH = 2.2 Hz, 1 H, C⁶H), 5.52 (d, ³J_HH = 5.1 Hz, 1 H, C⁹H) ppm.

¹³C{¹H}-NMR (100 MHz, CDCI₃): d = 23.3, 23.9 and 24.9 (s, 4xCH₃ of C¹²H₃, C¹² H₃, C¹³H₃ and C¹³ H₃), 31 .8 (s, C(CH₃)₃), 37.1 (s, C⁴H₂), 43.2 (C_q ²), 53.8 and 54.0 (s, C¹⁴H), 65.9 and 66.0 (s, C⁵H), 69.0 (s, C⁸H), 69.8 (s, C⁶H), 71.5 (s, C_q ³), 72.0 (s, C⁷H), 95.5 (s, C⁹H), 108.1 (s, C_q ¹¹), 108.3 (s, C_q ¹⁰) ppm.

¹¹B{¹H}-NMR (128 MHz, CDCI₃): d = -1.4 (s, 1 B, B⁹S), -2.0 to 20.0 (br³, 9B) ppm.

¹¹B-NMR (128 MHz, CDCI₃): d = -1.4 (s, 1 B, B⁹S), -2.0 to 20.0 (br³, 9B) ppm.

IR spectroscopy (KBr, v in cm ¹): 2989 (s), 2601 (s, BH), 1457 (m), 1384 (s), 1258 (s), 1213 (s), 1 166 (s), 1071 (s), 1003 (s), 899 (m), 858 (m), 738 (m), 510 (m).

Mass spectrometry (HR-ESI, positive mode):

calculated for Ci₈H₃₈BioOsSi: m/z = 475.35254 (int. 100%, [M+H]⁺) found: m/z = 475.35275 (int. 100%, [M+H]⁺)

found (Figure 6): Calculated (Figure 7):

Intermediate 9: 1 - Di-0-isopropylidene-6^,-deoxy-a-D-qalactopyranos-6^,-

yl)-9-(mercapto)-1 -dicarba-c/oso-dodecaborane(12)

12

O = B atom

• = BH group

The following procedure was performed in analogy to the known synthesis for the analogous orf/70-carbaborane derivative (see R. Frank, S. Boehnke, A. Aliev, E. Hey-Hawkins, Polyhedron 2012, 39, 9).

0.36 g (0.76 mmol, 1.0 eq.) 1-(1 ',2':3',4'-di-0-isopropylidene-6'-deoxy-a-D-galactopyranos-6'- yl)-9-(ferf-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) (see Intermediate 8) was dissolved in DCM, transferred to a Schlenk flask, dried in high vacuum, and then dissolved in 3.5 ml dry acetic acid. 0.36 g (1.14 mmol, 1.5 eq.) mercury(ll)acetate was added in one portion, resulting in a pale yellow colour of the reaction mixture. The reaction mixture was stirred at 50 °C for 3 hours, during which the colour turned intensely yellow. The reaction was stopped by the addition of 1.6 ml (1.78 g, 22.75 mmol, 20.0 eq.) 2-mercaptoethanol, resulting in a black-greyish precipitate. The suspension was diluted with 100 ml ethyl acetate. The organic phase was two times extracted with 100 ml of an aqueous 5% solution of sodium bicarbonate. The resulting aqueous phase was then four times extracted with ethyl acetate, 200 ml each. The combined organic phases were concentrated under reduced pressure and dried over sodium sulfate. After filtration, the solution was further concentrated under reduced pressure to give a suspension, which crystallised overnight. TLC showed the product with an R_f-value of R_f = 0.47 (n- hexane/ethyl acetate = 3/1 v/v) as an orange spot followed by 2-(acetylthio)ethyl acetate with an R_f-value of R_f = 0.45 as a yellow spot; both changed colour upon staining with a 10% solution of palladium(ll) chloride in methanol. The crude product was purified by column chromatography over silica using an n-hexane/ethyl acetate gradient mixture (3/1 :1/1 ) as eluent, yielding 0.30 g (0.73 mmol, 96%) product as an oily solid.

¹H-NMR (400 MHz, CDCIs): d = 2.06 (s, 3H, CH₃COO), 2.36 (s, 3H, CH₃COS), 3.13 (t, JHH = 6.5 Hz, 2H, CH₂S), 4.18 (t, JHH = 6.5 Hz, 2H, CH₂0) ppm.

for comparison see: M. Liras et al., Polym. Chem., 2013, 4, 5751 -5759.

12

O = B atom

• = BH group

¹H-NMR (400 MHz, CDCI₃): d = 0.43 (m, 1 H, SH), 1 .30 (s, 3H, 1 xCH₃, C¹¹H₃ or C^{11 '}H₃), 1 .34 (s, 3H, 1 XCH₃, C¹²H₃ or C^12'H₃), 1.42 (s, 3H, 1 xCH₃, C¹¹H₃ or C^11'H₃), 1 .50 - 3.50 (br³, 9H, B₁₀H₉),

1 .59 and 1 .60 (s, 3H, 1 xCH₃, C¹²H₃ or C^12'H₃), 2.15 (virtual dt, ²J_HH = 15.9 Hz, JHH = 2.6 Hz, 1 H, C³H₂), 2.34 (ddd, ² JHH = 15.9 Hz, ³ JHH = 8.7 Hz, JHH = 3.4 Hz, 1 H, C³H₂), 2.97 (br, s, 1 H, C¹H), 3.75 (ddt, ³ HH = 8.9 Hz, JHH = 4.4 Hz, ⁴ JHH = 2.2 Hz, 1 H, C⁴H), 4.03 (dd, ³ HH = 7.9 Hz, ⁴ JHH = 2.0 Hz, 1 H, C⁶H), 4.28 (ddd, ³JHH = 5.1 Hz, ⁴ JHH = 2.5 Hz, ⁴ JHH = 0.8 Hz, 1 H, C⁷H), 4.57 (ddd, ³ JHH = 7.8 Hz, ⁴ JHH = 2.5 Hz, ⁴ JHH = 1.0 Hz, 1 H, C⁵H), 5.52 (d, ³JHH = 5.1 Hz, 1 H, C⁸H) ppm.

¹³C{¹H}-NMR (100 MHz, CDCI₃): d = 24.4, 24.9, 25.8 and 25.9 (s, 4xCH₃: C^{1 1}H₃, C^{1 1'}H₃, C¹²H₃, C^12'H₃), 37.9 and 38.0 (s, both C³H₂), 54.8 (br, s, C¹H), 68.0 and 67.0 (s, both C⁴H), 70.0 (C⁷H), 70.8 (C⁵H), 73.05 and 73.07 (s, both C⁶H), 73.5 (br, s, C_q ²), 96.6 (s, C⁸H), 108.70 and 108.73 (s, both Cq¹⁰), 109.3 (s, both C_q ⁹) ppm. ¹¹B{¹H}-NMR (128 MHz, CDCI₃): d = -2.6 (s, 1 B, B⁹S), -5.0 to -22.0 (br³, 9B) ppm.

¹¹B-NMR (128 MHz, CDCI₃): d = -2.6 (s, 1 B, B⁹S), -5.0 to -22.0 (br³, 9B) ppm.

IR spectroscopy (KBr, v in cm^-1): 3446 (br, m), 3051 (m), 2990 (s), 2937 (m), 2600 (s, BH), 1456 (w), 1428 (w), 1384 (s), 1257 (m), 1213 (m), 1 166 (m), 1 107 (m), 1070 (s), 1003 (m), 899 (m), 856 (m), 758 (m), 668 (w), 509 (w).

Mass spectrometry (HR-ESI, positive mode):

calculated for C14H₃₀B1₀O₅S1 : m/z = 419.28960 (int. 100%, [M]+) found: m/z = 419.28976 (int. 100%, [M]⁺)

Elemental analysis:

Calculated for C14H₃₀B1₀O₅S1 : C = 40.18% H = 7.22%;

found: C = 39.35% H = 7.40%

Found (Figure 8):

Calculated (Figure 9):

Intermediate 10: l Di-O-isopropylidene-e'-deoxy-a-D-qalactopyranos-

6^,-yl)-9-(carboxymethylthio)-1 -dicarba-c/oso-dodecaborane(12) (Carbaborane m1J9b synthon)

O = B atom

• = BH group

The following procedure was performed in analogy to the known synthesis for the analogous orf/70-carbaborane derivative (see R. Frank, S. Boehnke, A. Aliev, E. Hey-Hawkins, Polyhedron 2012, 39, 9)

0.20 g (0.48 mmol, 1.0 eq.) 1-(T,2':3',4'-Di-0-isopropylidene-6'-deoxy-a-D-galactopyranos-6'- yl)-9-(mercapto)-1 ,7-dicarba-c/oso-dodecaborane(12) (see Intermediate 9) was dissolved in DCM, transferred to a Schlenk flask and dried in high vacuum. 0.27 g (1.43 mmol, 3.0 eq.) iodoacetic acid was added and both compounds were dissolved in 7 ml dry DCM. With stirring, 0.46 ml (0.34 g, 3.33 mmol, 7.0 eq.) dry triethylamine was added in one portion at ambient temperature. The mixture was stirred at ambient temperature for 3 days. The reaction mixture was cooled to 0 °C, and the reaction was stopped by the addition of ca. 10 ml of aqueous 2 N hydrochloric acid and stirred for 30 seconds. The phases were separated and the aqueous phase was first extracted two times with 10 ml ethyl acetate each and then three times with 20 ml ethyl acetate each. The combined organic phases were dried over sodium sulfate at 0 °C. After filtration, the solution was dried under reduced pressure. The raw product was purified by column chromatography on silica using an n-hexane/ethyl acetate gradient mixture (1 /1 :0/1 ) as eluent, yielding 0.1 1 g (0.24 mmol, 50%) of white oily solid.

¹ H-N MR (400 MHz, CDCI₃): d = 1 .30 (s, 3H, 1 xCH₃, C¹²H₃ or C^12'H₃), 1 .34 (s, 3H, 1 xCH₃, C¹³H₃ or C^13'H₃), 1 .42 (s, 3H, 1 xCH₃, C¹²H₃ or C^12'H₃), 1 .50 - 3.50 (br³, 9H, BI₀H₉), 1 .587 and 1 .593 (s, 3H, 1 XCH₃, C¹³H₃ or C^13'H₃), 2.14 (virtual dt, ² _HH = 15.9 Hz, JHH = 2.5 Hz, 1 H, C⁴H₂), 2.35 (ddd, ² JHH = 16.1 Hz, J_HH = 9.2 Hz, J_HH = 2.0 Hz, 1 H, C⁴H₂), 2.99 (br, s, 1 H, C¹⁴H), 3.38 (d, JHH = 5.2 Hz, 2H, C²H₂) 3.74 (m, 1 H, C⁵H), 4.03 (m, 1 H, C⁷H), 4.29 (virtual dd, ³ JHH = 5.1 Hz, ⁴ JHH = 2.5 Hz, 1 H, C⁸H), 4.58 (virtual dd, JHH = 7.9 Hz, ⁴ JHH = 2.4 Hz, 1 H, C⁶H), 5.53 (d, ³ HH = 5.1 Hz, 1 H, C⁹H), 8.45 (br, s, 1 H, COOH) ppm.

¹³C{¹ H}-N MR (100 MHz, CDCI₃): d = 24.4, 24.9, 25.85 and 25.93 (s, 4xCH₃: C¹²H₃, C^12'H₃, C¹³H₃, C^13'H₃), 34.5 (s, C²H₂), 38.0 (s, C⁴H₂), 54.4 (s, C¹⁴H), 67.0 (s, C⁵H), 70.0 (s, C⁸H), 70.9 (s, C⁶H), 73.1 (s, C⁷H), 73.2 (s, C_q ³), 96.6 (s, C⁹H), 108.7 and 108.8 (both C_q ¹¹), 109.4 (s, C_q ¹⁰), 174.2 (s, C_q ¹) ppm.

¹¹ B{¹ H}-NMR (128 MHz, CDCI₃): d = -0.8 (s, 1 B, B⁹S), -2.0 to -20.0 (br³, 9B) ppm.

¹¹ B-N MR (128 MHz, CDCI₃): d = -0.8 (s, 1 B, B⁹S), -2.0 to -20.0 (br³, 9B) ppm.

IR spectroscopy (KBr, v in cm ¹): 3053 (s), 2990 (s), 2936 (s), 2602 (s, BH), 1712 (s, COOH), 1457 (m), 1428 (m), 1385 (s), 1303 (m), 1259 (s), 1213 (s), 1 166 (s), 1 142 (m), 1 107 (s), 1069 (s), 1003 (s), 955 (m), 919 (m), 898 (m), 855 (m), 802 (m), 774 (m), 740 (m), 668 (w), 645 (w), 534 (w), 509 (m), 460 (w).

Mass spectrometry (HR-ESI , positive mode):

calculated for Ci₆H₃₂BioNai0₇Si : m/z = 499.27728 (int. 100%,[M+Na]⁺)

found: m/z = 499.27684 (int. 100%,[M+Na]⁺)

Elemental analysis:

calculated for Ci6H₃₂Bio07Si : C = 40.32% H = 6.77%;

found: C = 40.05% H = 6.67% Found (Figure 10): Calculated (Figure 11):

Intermediate 11 : 1 ,7-Bis-(1',2':3',4'-Di-0-isopropylidene-6'-deoxy-a-D- galactopyranos-6'-yl)-9-(ferf-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12)

13

• = BH group 3.00 g (12.91 mmol, I .O equiv) 9-(fe/f-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) (see

Intermediate 6) was dissolved in 100 ml tetrahydrofuran, cooled to 0 °C and 18.70 ml (1 .45 M in n-hexane, 27.1 1 mmol, 2.1 equiv) n-butyllithium were added dropwise. The reaction was warmed to room temperature over 2 h. The solution was cooled to 0 °C again and 10.66 g (27.1 1 mmol, 2.1 equiv) 1 ,2:3,4-di-0-isopropylidene-a-D-galactopyranosyltriflate (see Intermediate 7), dissolved in 50 ml tetrahydrofuran were added dropwise. The reaction was warmed to ambient temperature and stirred overnight. Wet tetrahydrofuran was added and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate/n-hexane 1 :3 v/v) yielding the title compound as colorless oily solid. Yield: 4.96 g (6.92 mmol, 54 %)

R_f-value: 0.47 (eluent: n- hexane/ethyl acetate 3: 1 , v/v)

m.p.: 64-65°C

¹ H-N MR (400 MHz, CDCI₃): d = 1 .20 - 3.50 (br³, 9H, BI₀H₉), 1 .32 (s, 6H, 1 xCH₃, C¹¹ H₃ or C^{11 '}H₃), 1 .35 (s, 6H, 1 XCH₃, C¹²H₃ or C^12'H₃), 1 .43 (s, 9H, 3xCH₃, C¹ H₃), 1 .59 and 1 .60 (s, 6H, 1 xCH₃, C¹²H₃ or C^12'H₃), 2.21 (virtual dt, ²J_HH = 1 5.8 HZ, J_HH = 3.5 HZ, 2H, C³H₂), 2.31 (ddd,

² JHH = 15.5 Hz, ³ _HH = 7.8 Hz, J_HH = 3.0 Hz, 2H, C³H₂), 3.75 (ddt, ³ JHH = 8.1 Hz, JHH = 5.8 Hz, ⁴ HH = 2.3 Hz, 2H, C⁴H), 4.12 (dt, ³ JHH = 7.8 Hz, ⁴ JHH = 2.6 Hz, 2H, C⁶H), 4.29 (dd, ³JHH = 5.2 Hz, ⁴JHH = 2.3 Hz, 2H, C⁷H), 4.57 (dd, ³JHH = 8.1 Hz, ⁴J_HH = 2.3 Hz, 2H, C⁵H), 5.52 (d, ³JHH = 5.1 Hz, 2H, C⁸H) ppm.

¹³C{¹ H}-N MR (100 MHz, CDCI3): d = 24.2, 24.8, 25.8 and 25.9 (s, 8xCH₃: C¹²H₃, C^12'H₃, C¹³H₃, C^13'H₃), 32.7 (s, C¹ H₃), 37.8 (s, C⁴H₂), 44.1 (s, C³ _q), 66.78 and 66.82 (s, both C⁸H), 70.0 (s, C⁷H), 70.7 (s, C⁵H), 71 .9 and 72.1 (s, C² _q), 72.58 and 72.60 (s, both C⁶H), 96.4 (s, C⁹H), 108.6 (s,

C_q ¹⁰), 109.1 (s, C_q ¹¹) ppm.

¹¹ B{¹ H}-NMR (128 MHz, CDCI3): d = -1 .0 (s, 1 B, B⁹S), -5.0 to -22.0 (br³, 9B) ppm.

IR spectroscopy (KBr, v in cm^-1): 3445 (s), 2964 (w), 2596 (m, BH), 1635 (m), 1382 (m), 1258 (m), 1213 (m), 1 167 (m), 1 144 (m), 1070 (s), 1031 (m), 1003 (m), 857 (w), 802 (w), 642 (w). Mass spectrometry (HR-ESI , positive mode):

calculated for C3oH₅6BioOioSNa: m/z = 740.4459 (int. 100%, [M+Na]⁺)

found (Figure 12): m/z = 740.4460 (int. 100%, [M+Na]⁺)

Elemental analysis:

Calculated for C30H56B10O10S1 : C = 50.26% H = 7.87%;

found: C = 43.46% H = 7.43%

Intermediate 12: 1,7-Bis-(1',2':3',4'-Di-0-isopropylidene-6'-deoxy-a-D- galactopyranos-6'-yl)-9-(mercapto)-1,7-dicarba-c/oso-dodecaborane(12)

O = B ato m C H ₃

• = BH group

4.92 g (6.90 mmol, I .O equiv) of 1 ,7-Bis-(1 ',2':3',4'-Di-0-isopropylidene-6'-deoxy-a-D- galactopyranos-6'-yl)-9-(fe/f-butylthio)-1 ,7-dicarba-c/oso-dodecaborane(12) (see Intermediate 1 1 ) was dissolved in 50 ml dry acetic acid. 3.30 g (10.35 mmol, 1.5 equiv) Hg(OAc)2 was added in one portion, resulting in a pale yellow color of the reaction mixture. The reaction mixture was stirred at 50 °C for 3 h, during which the color turned intensely yellow. The reaction was cooled to room temperature, 100 ml degassed ethyl acetate were added and hydrogen sulfide was bubbled through the solution over 20 min resulting in a black precipitate. The suspension was filtered, nitrogen was bubbled through the filtrate to remove hydrogen sulfide and the filtrate was washed two times with 50 ml of an aqueous 5 % sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on mercapto-propyl coated silica (see E. Svantesson, J. Pettersson, A. Olin, K. Markides, S. Sjoberg, A. Tallec, T. Shono, H. Toftlund, Acta Chem. Scand. 1999, 53, 731-736), yielding the title compound as a colorless oily solid. Yield: 4.60 g (6.72 mmol, 97 %)

R_f-value: 0.62 (eluent: n- hexane/ethyl acetate 2:1 v/v)

m.p.: 70-71 °C

¹H-NMR (400 MHz, CDCI₃): d = 0.43 (m, 1 H, SH), 1 .16 - 3.51 (br³, 9H, BI₀H₉), 1 .33 (s, 6H, 1 XCH₃, C¹¹H₃ or C¹¹ H₃), 1 .35 (s, 6H, 1 xCH₃, C¹²H₃ or C¹² H₃), 1 .43 (s, 6H, 1 xCH₃, C¹¹H₃ or C¹¹ Ή₃), 1.60 and 1 .61 (s, 6H, 1 xCH₃, C¹²H₃ or C¹² H₃), 2.22 (virtual dt, ²J_HH = 15.9 HZ,

JHH = 2.6 Hz, 2H, C³H₂), 2.32 (ddd, ²J_HH = 15.9 Hz, ³ JHH = 8.7 Hz, JHH = 3.4 Hz, 2H, C³H₂), 3.75 (ddt, ³ JHH = 8.9 Hz, JHH = 4.4 Hz, ⁴JHH = 2.2 Hz, 2H, C⁴H), 4.10 (dd, ³JHH = 7.9 Hz, ⁴J_HH = 2.0 Hz, 2H, C⁶H), 4.28 (ddd, ³JHH = 5.1 HZ, ⁴J_HH = 2.5 HZ, ⁴J_HH = 0.8 HZ, 2H, C⁷H), 4.57 (ddd,

³ HH = 7.8 Hz, ⁴ JHH = 2.5 Hz, ⁴ JHH = 1.0 Hz, 2H, C⁵H), 5.52 (d, ³JHH = 5.1 Hz, 2H, C⁸H) ppm. ¹³C{¹H}-NMR (100 MHz, CDCI₃): d = 24.3, 25.0, 25.8 and 25.9 (s, 8xCH₃: C¹¹H₃, C^11'H₃, C¹²H₃, C^12'H₃), 37.9 and 38.0 (s, both C³H₂), 60.4 (br, s, C² _q), 66.9 and 67.0 (s, both C⁴H), 70.0 (C⁷H), 70.8 (C⁶H), 72.7 and 72.8 (s, both C⁵H), 96.5 (s, C⁸H), 108.70 and 108.73 (s, both C_q ¹⁰), 109.22 and 109.24 (s, both C_q ⁹) ppm.

1¹B{¹H}-NMR (128 MHz, CDCI₃): d = -2.8 (s, 1 B, B⁹S), -4.0 to -22.0 (br³, 9B) ppm.

IR spectroscopy (KBr, v in crrf¹): 3446 (br, m), 2989 (m), 2934 (s), 2606 (m, BH), 1633 (w), 1457 (w), 1382 (s), 1257 (s), 1213 (s), 1 169 (m), 1 107 (m), 1070 (s), 918 (m), 900 (m), 884 (m), 862 (m), 804 (w), 756 (w), 648 (w), 553 (w), 51 1 (w).

Mass spectrometry (HR-ESI, positive mode):

calculated for Ci4H₃oBioOsSi: m/z = 684.3833 (int. 100%, [M+Na]⁺)

found: m/z = 684.3820 (int. 100%, [M+Na]⁺)

Elemental analysis:

Calculated for C₂₆H₄₈BI₀OI_OSI : C = 47.26% H = 7.32%;

found: C = 43.96% H = 7.21 %

Intermediate 13: 1 ,7-Bis-(1 ',2',3',4'-Di-0-isopropylidene-6'-deoxy-a-D- galactopyranos-6'-yl)-9-(carboxymethyl-thio)-1,7-dicarba -c/oso- dodecaborane(12)_(Carbaborane m1J7J9b synthon)

· = BH group

The synthesis of Intermediate 13 from Intermediate 12 was performed according to the procedure described for the preparation of Intermediate 10.

Yield: 1 .06 g (1.43 mmol, 47 %)

R_f-value: 0.38 (eluent: n- hexane/ethyl acetate 1 :1 v/v)

m.p.: 94-95 °C

¹H-NMR (400 MHz, CDCI₃): d = 1 .31 (s, 6H, C⁸H₃), 1 .33 (s, 6H, C¹²H₃), 1 .41 (s, 6H, C⁸H₃), 1.57 and 1 .58 (s, 6H, C¹²H₃), 1 .59 - 3.47 (br³, 9H, BI₀H₉), 2.22 (ddd, ²JHH = 15.8 Hz, ³ _HH = 3.0 Hz, 2H, C⁴H_2a), 2.31 (virtual dd, ²JHH = 15.8 Hz, ³J_HH = 8.5 Hz, 2H, C⁴H_2b), 3.38 (s, 2H, C²H₂), 3.70 (br d, ³JHH = 8.2 Hz, 2H, C⁵H), 4.07 and 4.09 (virtual t, ³J_HH = 8.1 Hz, 2H, C⁶H), 4.28 (dd, ³JHH = 5.1 Hz, ³J_HH = 2.3 Hz, 2H, C¹⁰H), 4.56 (virtual dd, ³JHH = 7.8 Hz, ³J_HH = 2.3 Hz, 2H, C⁹H), 5.49 (d, ³JHH = 5.1 Hz, 2H, C¹³H) ppm.

¹¹B{¹H}-NMR (128 MHz, CDCI₃): d = -1.1 (s, 1 B), -2.0 to -20.0 (br³, 9B) ppm.

¹³C{¹H}-NMR (100 MHz, CDCI₃): d = 24.3 (s, C⁸'¹²H₃), 24.9 (s, C⁸'¹²H₃), 25.8 (s, C⁸'¹²H₃), 25.9 (s, C⁸'¹²H₃), 34.5 (s, C²H), 37.8 (s, C⁴H), 66.9 (s, C⁵H), 70.0 (s, C¹⁰H), 70.8 (s, C⁹H), 72.67 and 72.69 (s, both C⁶H), 73.0 (s, C_q ³), 96.5 (s, C¹³H), 108.62 and 108.64 (s, both C_q ¹¹), 109.2 (s, C_q ⁷),

171 .2 (s, Cq¹) ppm. IR spectroscopy (KBr, v in cm ¹): 3445 (br, m), 2989 (m), 2936 (m), 2596 (m, BH), 1714 (m), 1636 (w), 1457 (w), 1426 (w), 1383 (m), 1257 (m), 1213 (s), 1 168 (m), 1 107 (m), 1070 (s), 1003 (m), 919 (w), 898 (m), 803 (w), 774 (m), 648 (w), 51 1 (w).

Mass spectrometry (HR-ESI, positive mode):

calculated for C28H₅oBioOi2SNa: m/z = 742.3888 (100 % [M+Na]⁺)

found: m/z = 742.3901 (100% [M+Na]⁺).

Elemental analysis:

Calculated for C28H50B10O12S1: C = 46.78% H = 7.01 %;

found: C = 46.51 % H = 7.14%

EXPERIMENTAL SECTION - REFERENCE EXAMPLES

Table 4: Names and Sequences of Reference Examples

Reference Examples RE1 and RE2 (NPY Conjugates with Carbaborane m1a moieties)

Synthesis of resin-bonded intermediate peptide RP1 was performed on a Rink amide AM resin, whereas the synthesis of resin-bonded intermediate peptide RP2 was performed on a NovaSyn® TGR R resin. Both compounds were prepared by automated peptide synthesis as described above.

The following coupling scheme was used:

For the removal of the Mmt protecting group in peptide RP1 , the resin-bonded peptide was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (15 x 2 min, 1 ml each). After each deprotection step, the resin-bonded peptide was washed with DCM. Finally, the resin- bonded peptide was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each).

For the cleavage of the Dde protecting groups in peptide RP2, the resin-bonded peptide was treated with 2 % hydrazine in DMF (14 x 10 min, 1 ml each).

The carbaborane m1a synthon (see Intermediate 2) was coupled manually to peptides RP1 and RP2 in 3-fold molar excess per free lysine e-amino group: For peptide RP1 , 3 eq. of the carbaborane m1 a synthon were coupled with 3 eq. HATU and 6 eq. DIPEA in DMF as solvent.

For peptide RP2, 9 eq. of the carbaborane m1 a synthon, 9 eq. HATU and 15 eq. DIPEA in DMF were used. Both couplings were performed overnight for approximately 16 h.

Cleavage of the conjugates from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/TC (90:5:5 v/v, 1 ml) for 2.5 h. The crude peptides were precipitated and washed with ice-cold diethyl ether, dissolved in ACN/H2O and subsequently lyophilized.

Purification of the crude conjugates was performed by preparative RP-HPLC using a C12-column (Phenomenex Jupiter® 10u Proteo 90 A: 250 mm x 21.2 mm, 10 pm, 90 A) and a flow rate of 10 ml/min. Linear gradients of 30 % to 80 % eluent B in A over 40 min and 40 % to 80 % eluent B in A over 40 min were applied for conjugate RE1 and RE2, respectively. Conjugate

RE2 had to be purified a second time using the same column, but with a flow rate of 15 ml/min and a linear gradient of 30 % to 70 % eluent B in A over 40 min. R .F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH₂

Chemical Formula: C198H299B10N53O56

Exact Mass: 4425.31 g/mol

Molecular Weight: 4425.99 g/mol

Reference Example RE1 was synthesized in a 15 pmol scale. The yield was 7.7 mg (12 % of theory).

Analytical RP-HPLC

Reference Example RE1 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 16.5 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 13.8 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 4426.3 [M+H]⁺, 2213.6 [M+2H]²⁺.

R ³⁴1-NPY

YPSKPDFPGEDAPAEDLKRYYKALRHYINLITRPRY-NH₂

Chemical Formula: C210H333B30N55O57

Exact Mass: 4867.76 g/mol

Molecular Weight: 4864.60 g/mol

Reference Example RE 2 was synthesized in a 15 pmol scale. The yield was 2.0 mg (3 % of theory).

Analytical RP-HPLC

Reference Example RE 2 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 21.4 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 19.3 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 4868.8 [M+H]⁺, 2434.8 [M+2H]²⁺.

Reference Examples RE3 and RE4 (NPY Conjugates with Carbaborane m9b moieties)

Synthesis of resin-bonded intermediate peptide RP3 was performed on a NovaSyn® TGR R resin, whereas the synthesis of resin-bonded intermediate peptide RP4 was performed on a Rink amide AM resin. Both compounds were prepared by automated peptide synthesis as described above.

The following coupling scheme was used:

For the removal of Dde protecting groups, the resin-bonded peptides were treated with 3 % hydrazine in DMF (12 x 10 min, 1 ml each).

The carbaborane m9b synthon (see Intermediate 3) was coupled manually to peptides RP3 and RP4 in 3-fold molar excess per free lysine e-amino group: For peptide RP3, 3 eq. of the carbaborane m9b synthon were coupled with 5 eq. HOBt and 5 eq. DIC in DMF as solvent. For peptide RP4, 9 eq. of the carbaborane m9b synthon, 15 eq. HOBt and 15 eq. DIC in DMF were used. Both couplings were performed overnight for approximately 16 h.

Cleavage of the conjugates from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/TC (90:5:5 v/v, 1 ml) for 2 h. The crude peptides were precipitated and washed with ice-cold diethyl ether, dissolved in ACN/H2O and subsequently lyophilized.

Purification of the crude conjugate RE3 was performed by preparative RP-HPLC using a Kinetex® C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm ^c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min. For the first purification of conjugate RE4, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm x 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Conjugate RE4 had to be purified a second time by using a semi-preparative C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm x 10 mm, 5 pm, 100 A) with a flow rate of 4 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 40 min. Reference Example RE3: rK⁴ .F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH₂

Chemical Formula: C₁₉₉H₃₀₁B₁₀N₅₃O₅₆S

Exact Mass: 4471.30 g/mol

Molecular Weight: 4472.07 g/mol

Reference Example RE3 was synthesized in a 15 pmol scale. The yield was 9.9 mg (15 % of theory).

Analytical RP-HPLC

Reference Example RE3 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 14.6 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 15.3 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 4472.2 [M+H]⁺, 2236.5 [M+2H]²⁺.

Reference Example RE 4: rK^{4 18 22} .F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLKRYYKALRHYINUTRPRY-NFb

A

im

H

Chemical Formula: C213H339B30N55O57S3

Exact Mass: 5005.73 g/mol

Molecular Weight: 5002.86 g/mol

Reference Example RE4 was synthesized in a 15 pmol scale. The yield was 2.7 mg (4 % of theory).

Analytical RP-HPLC

Reference Example RE4 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 19.8 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 18.7 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 5006.8 [M+H]⁺, 2504.2 [M+2H]²⁺.

Reference Examples RE5-RE9 (NPY Conjugates with Carbaborane bm9q moieties)

Resin-bonded intermediate peptides RP5-RP9 were synthesized on a NovaSyn® TGR R resin by automated peptide synthesis as described in the general section.

The following coupling scheme was used for resin-bonded intermediate peptides RP5-RP7:

The following coupling scheme was used for resin-bonded intermediate peptides RP8 and RP9:

For the removal of Dde protecting groups, the resin-bonded peptides were treated with 3 % hydrazine in DMF (10 x 10 min for peptides RP6 and RP9, 14 x 10 min for peptides RP5, RP7 and RP8).

In case of peptide RP9, the building block Fmoc-(2S)-Dap(Fmoc)-OH (45 pmol, 3-fold molar excess) was coupled manually with HOBt and DIC (75 pmol each, 5-fold molar excess) to the Lys⁴ side chain after Dde cleavage. DMF was used as solvent and the coupling time was 3.5 h. Subsequently, Fmoc deprotection was performed with 20 % piperidine in DMF (2 x 10 min, 500 pi each) to generate free amino functions.

The carbaborane bm9g synthon (see Intermediate 5) was coupled manually to resin-bonded intermediate peptides RP5 - RP9 in 3-fold molar excess per free lysine e-amino group or free amino group of (2S)-Dap. Coupling reactions were performed as follows:

Peptides RP5 and RP6: 3 eq. carbaborane bm9g synthon, 5 eq. HOBt and 5 eq. DIC in DMF as solvent.

Peptides RP7 and RP9: 6 eq. carbaborane bm9g synthon, 10 eq. HOBt and 10 eq. DIC in DMF.

Peptide RP8: 9 eq. carbaborane bm9g synthon, 15 eq. HOBt and 15 eq. DIC in DMF. All couplings were performed overnight for approximately 16 h.

Purification of the crude conjugates was performed by preparative RP-HPLC using a Kinetex® C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm x 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugates RE5 and RE6, linear gradients of 30 % to 60 % eluent B in A over 30 min and 40 % to 70 % eluent B in A over 30 min were applied, respectively. For conjugates RE7-RE9, a linear gradient of 50 % to 80 % eluent B in A over 30 min was applied.

Reference Example RE5: rK⁴(bm9q).F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH,

Chemical Formula: C204H312B20N56O56S3

Exact Mass: 4758.43 g/mol

Molecular Weight: 4757.46 g/mol

Reference Example RE5 was synthesized in a 15 pmol scale. The yield was 7.4 mg (10 % of theory).

Analytical RP-HPLC

Reference Example RE5 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 18.2 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 21.6 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 4759.3 [M+H]⁺, 2380.0 [M+2H]²⁺.

Reference Example RE6: rK¹⁸(bm9q).F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLKRYYSALRHYINLITRPRY-NH,

Chemical Formula: C207H319B20N57O56S3

Exact Mass: 4815.49 g/mol

Molecular Weight: 4814.55 g/mol

Reference Example RE6 was synthesized in a 15 pmol scale. The yield was 7.6 mg (1 1 % of theory).

Analytical RP-HPLC

Reference Example RE6 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 19.5 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 19.2 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 4816.5 [M+H]⁺, 2408.5 [M+2H]²⁺.

R PY

YPSKPDFPGEDAPAEDLKRYYSALRHYINUTRPRY-Nhi

Chemical Formula: C216H342B40N60O57S6

Exact Mass: 5320.78 g/mol

Molecular Weight: 5316.24 g/mol

Reference Example RE7 was synthesized in a 15 pmol scale. The yield was 11.4 mg (14 % of theory).

Analytical RP-HPLC

Reference Example RE7 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 22.6 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 29.0 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 5321.9 [M+H]⁺.

Chemical Formula: C228H372B60N64O57S9

Exact Mass: 5867.12 g/mol

Molecular Weight: 5859.02 g/mol

Reference Example RE8 was synthesized in a 15 pmol scale. The yield was 5.2 mg (6 % of theory).

Analytical RP-HPLC

Reference Example RE8 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 40 % to 90 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 19.9 min.

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 40 % to 90 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 26.0 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 5868.1 [M+H]⁺, 2934.6 [M+2H]²⁺. ₂).F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH-

Chemical Formula: C216H341B40N61O58S6

Exact Mass: 5349.77 g/mol

Molecular Weight: 5345.23 g/mol

Reference Example RE9 was synthesized in a 15 pmol scale. The yield was 8.3 mg (10 % of theory).

Analytical RP-HPLC

Reference Example RE9 was analyzed with two different columns; the purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 29.0 min. Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.0 ml/min, R_t = 32.6 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 5350.9 [M+H]⁺, 2675.8 [M+2H]²⁺.

Reference Example RE10 with Carbaborane m1J9b moieties

Resin-bonded intermediate peptide RP 10 was synthesized on ; NovaSyn® TGR R resin by automated peptide synthesis as described in the general section.

The following coupling scheme was used:

For the removal of Dde protecting groups, the resin-bonded peptide was treated with 3 % hydrazine in DMF (10-15 x 10 min, 1 ml each).

Subsequently, the building block Fmoc-(2S)-Dap(Fmoc)-OH was coupled manually in 3-fold molar excess per free lysine e-amino group with HOBt and DIC. The coupling reaction was performed as follows:

Peptide RP 10: 9 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 12 eq. HOBt and 12 eq. DIC in DMF. The coupling time was at least 2 h. Subsequently, removal of Fmoc protecting groups was performed with 30 % piperidine in DMF (2 x 12 min, 500 pi each).

For further branching in peptide RP10, the building block Fmoc-(2S)-Dap(Fmoc)-OH was attached to the in total six free amino groups of the previously coupled (2S)-Dap units. The coupling reaction with a 3-fold molar excess of the building block per free amino group was performed as follows:

18 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 20 eq. HOBt and 20 eq. DIC in DMF.

The coupling time was at least 6 h. Subsequent Fmoc deprotection was performed with 30 % piperidine in DMF (2 x 12 min, 500 mI each).

For the preparation of Reference Example RE10, the carbaborane m1J9b synthon (see Intermediate 10) was coupled manually to the in total 12 free amino groups of the previously coupled (2S)-Dap units in 1.5-fold molar excess per free amino group with HOBt and DIC. The coupling reactions was performed as follows:

18 eq. carbaborane ml J9b synthon, 22 eq. HOBt and 22 eq. DIC in DMF.

The coupling was performed overnight for approximately 16 h.

Cleavage of the peptide from the resin and simultaneous side chain and 6-deoxy-galactose deprotection was accomplished using a mixture of TFA/H2O (95:5 v/v, 1 ml) for 2 h. The crude conjugate was precipitated and washed with ice-cold diethyl ether, dissolved in ACN/H2O and subsequently lyophilized. For purification of RE10, a Biphenyl column (Phenomenex Kinetex® 5u Biphenyl: 250 mm x 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was used.

Reference Example RE10: rK^{4 18 22}«2S)-Dap«2S)-Dap(m1 J9b)₂)₂).F⁷.P³⁴1-NPY

Chemical Formula: C348H621B120N73O135S12

Exact Mass: 9688.18 g/mol

Molecular Weight: 9670.09 g/mol

Reference Example RE10 was synthesized in a 7.5 pmol scale. The yield was 5.6 mg (8 % of theory).

Analytical RP-HPLC

Reference Example RE10 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 15.2 min.

Column 2: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 1.55 ml/min, R_t = 1 1.9 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1612.9 [M+6H]⁶⁺, 1935.1 [M+5H]⁵⁺. Reference Example RE11 with Carbaborane m1J9b moieties and TAMRA-label

Resin-bonded intermediate peptide RP11 was synthesized on a NovaSyn® TGR R resin by automated peptide synthesis as described in the general section.

The following coupling scheme was used:

For the removal of the Dde protecting group at position 18, the resin-bonded peptide RP11 was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each).

Subsequently, the building block Fmoc-(2S)-Dap(Fmoc)-OH was coupled manually to the free lysine e-amino group in 3-fold molar excess with HOBt and DIC. The coupling reaction was performed as follows:

Peptide RP11 : 3 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 5 eq. HOBt and 5 eq. DIC in DMF. The coupling time was at least 7 h.

For the removal of the Mmt protecting group at position 4, the resulting resin-bonded peptide was treated with a mixture consisting of 2 % TFA, 5 % TIS in DCM (14 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin-bonded peptide was incubated with 5 % DIPEA in DCM (2 x 5 min, 1 ml each).

Subsequently, the building block Fmoc-(2S)-Dap(Mtt)-OH was coupled manually to the free lysine e-amino group in 3-fold molar excess with HOBt and DIC. The coupling reaction was performed as follows:

Peptide RP11 : 3 eq. Fmoc-(2S)-Dap(Mtt)-OH, 5 eq. HOBt and 5 eq. DIC in DMF. The coupling time was at least 7 h. Subsequently, removal of Fmoc protecting groups was performed with 30 % piperidine in DMF (2 x 12 min, 500 pi each).

For further branching in the resulting resin-bonded peptide, the building block Fmoc-(2S)- Dap(Fmoc)-OH was attached to the free amino groups of the previously coupled (2S)-Dap units. The coupling reaction with a 3-fold molar excess of the building block per free amino group was performed as follows:

Peptide RP11 : 9 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 12 eq. HOBt and 12 eq. DIC in DMF.

The coupling time was overnight. After the reaction, any non-coupled free amino groups were capped by acetylation with a mixture of 10 % acetic anhydride, 10 % DIPEA in DMF (15 min, 1 ml).

Removal of the Mtt protecting group at the (2S)-Dap unit at position 4 was performed as described for the Mmt protecting group before. Afterwards the last branching step at position 4 was conducted using the building block Fmoc- (2S)-Dap(Mtt)-OH. The coupling reaction with a 3-fold molar excess of the building block was performed as follows:

Peptide RP11 : 3 eq. Fmoc-(2S)-Dap(Mtt)-OH, 5 eq. HOBt and 5 eq. DIC in DMF.

The coupling time was at least 5 h. After the reaction, any non-coupled free amino groups were capped by acetylation with a mixture of 10 % acetic anhydride, 10 % DIPEA in DMF (15 min, 1 ml).

Removal of Fmoc protecting groups was then performed with 30 % piperidine in DMF (2 x 12 min, 600 pi each). Subsequently, the carbaborane m1J9b synthon (see Intermediate 10) was coupled manually in a 1 -fold molar ratio per free amino group with HOBt and DIC. The coupling reaction was performed as follows:

Peptide P11 : 7 eq. carbaborane ml J9b synthon, 15 eq. HOBt and 15 eq. DIC in DMF.

The coupling was performed overnight for approximately 16 h. After the reaction, any non- coupled free amino groups were capped by acetylation with a mixture of 10 % acetic anhydride, 10 % DIPEA in DMF (15 min, 1 ml).

Removal of the final Mtt protecting group at position 4 was performed as described for the Mmt protecting group before.

For the preparation of Reference Example RE11 , the fluorophore 6-TAMRA was coupled manually to the free (2S)-Dap 3-amino group in 2-fold molar excess with HATU and DIPEA. The coupling reaction was performed as follows:

Peptide RP11 : 2 eq. 6-TAMRA, 2 eq. HATU and 2 eq. DIPEA in DMF.

The coupling was performed overnight for approximately 16 h.

Cleavage of the conjugate from the resin and simultaneous side chain and 6-deoxy-galactose deprotection was accomplished using a mixture of TFA/H2O (95:5 v/v, 1 ml) for 2 h. The crude peptide was precipitated and washed with ice-cold diethyl ether, dissolved in ACN/H2O and subsequently lyophilized.

For purification of RE11 , an Aeris® C18-column (Phenomenex Aeris® Peptide 3.6u XB-C18: 250 mm x 21 .2 mm, 3.6 pm, 100 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was used. Reference Example RE11 : rK⁴«2S)-Dap«2S)-Dap(m1J9bM2S)- Dap(m1J9b/TAMRA)).K¹⁸ 2S)-Dap 2S)-Dap(m1J9b)₂)₂).F⁷.P³⁴1-NPY

O H

N— m1J9b

H

Chemical Formula: C311H506B70N68O107S7

Exact Mass: 7900.08 g/mol

Molecular Weight: 7890.96 g/mol

Reference Example RE11 was synthesized in a 15 pmol scale. The yield was 5.8 mg (5 % of theory).

Analytical RP-HPLC

Reference Example RE11 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 22.8 min. Column 2: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1.55 ml/min, R_t = 18.1 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1 128.3 [M+7H]⁷⁺, 1316.2 [M+6H]⁶⁺, 1579.2 [M+5H]⁵⁺. EXPERIMENTAL SECTION - EXAMPLES

Table 5: Names and Sequences of Example compounds

Examples No. 1 -5 (NPY Conjugates with Carbaborane m1J9b moieties). Example 6 (NPY Conjugate with Carbaborane ¹⁰B-m1J9b moieties) and Example 7 (NPY Conjugate with Carbaborane m1J7J9b moieties)

Resin-bonded intermediate peptides P1 -P7 were synthesized on a NovaSyn® TGR R resin by automated peptide synthesis as described in the general section.

The following coupling scheme was used:

For the removal of Dde protecting groups, the resin-bonded intermediate peptides were treated with 3 % hydrazine in DMF (10-15 x 10 min, 1 ml each).

In case of peptides P2-P7, the building block Fmoc-(2S)-Dap(Fmoc)-OH was coupled manually in 3-fold molar excess per free lysine e-amino group with HOBt and DIC. Coupling reactions were prepared as follows:

Peptide P2: 6 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 10 eq. HOBt and 10 eq. DIC in DMF as solvent. Peptides P4, P6 and P7: 6 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 6 eq. HOBt and 6 eq. DIC in DMF. Peptide P3: 9 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 12 eq. HOBt and 12 eq. DIC in DMF. Peptide P5: 12 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 12 eq. HOBt and 12 eq. DIC in DMF.

The coupling time was at least 2 h. Subsequently, removal of Fmoc protecting groups was performed with 30 % piperidine in DMF (2 x 12 min, 500 pi each).

For further branching in peptides P4, P6 and P7, the building block Fmoc-(2S)-Dap(Fmoc)-OH was attached to the free amino groups of the previously coupled (2S)-Dap units. The coupling reactions with a 3-fold molar excess of the building block per free amino group were performed as follows:

Peptides P4 and P6: 12 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 12 eq. HOBt and 12 eq. DIC in DMF as solvent.

Peptide P7: 12 eq. Fmoc-(2S)-Dap(Fmoc)-OH, 14 eq. HOBt and 14 eq. DIC in DMF.

For the preparation of Example 1 , the carbaborane ml J9b synthon (see Intermediate 10) was coupled manually to resin-bonded intermediate peptide P1 in 3-fold molar excess per free lysine e-amino group: 9 eq. of the carbaborane m1J9b synthon, 10 eq. HOBt and 10 eq. DIC were mixed in DMF as solvent and the coupling was performed overnight for approximately 16 h. For the preparation of Examples 2 - 5, the carbaborane ml J9b synthon was coupled manually to the branched resin-bonded intermediate peptides obtained from P2 - P5, respectively, in 1.5- fold molar excess per free amino group with HOBt and DIC.

For the preparation of Example 6, the carbaborane ¹⁰B-m1 J9b synthon was coupled manually to the branched resin-bonded intermediate peptide obtained from P6 in 1.5-fold molar excess per free amino group with HOBt and DIC.

For the preparation of Example 7, the carbaborane ml J7J9b synthon (see Intermedate 13) was coupled manually to the branched resin-bonded intermediate peptide obtained from P7 in 1.5- fold molar excess per free amino group with HOBt and DIC.

Coupling reactions were performed as follows:

Peptide P2: 6 eq. carbaborane ml J9b synthon, 8 eq. HOBt and 8 eq. DIC in DMF as solvent. Peptide P3: 9 eq. carbaborane m1J9b synthon, 12 eq. HOBt and 12 eq. DIC in DMF. Peptides P4, P5 and P6: 12 eq. carbaborane ml J9b or ¹⁰B-m1 J9b synthon, 15 eq. HOBt and 15 eq. DIC in DMF, Peptide P7: 12 eq. carbaborane m1J7J9b, 15 eq. HOBt and 15 eq. DIC in DMF.

All couplings were performed overnight for approximately 16 h.

Cleavage of the conjugates from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/H2O (95:5 v/v, 1 ml) for 2 h. The crude peptides were precipitated and washed with ice-cold diethyl ether, dissolved in ACN/H2O and subsequently lyophilized.

Purification of the Examples 1 - 6 was performed by preparative RP-HPLC using a Kinetex® C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm ^c 21.2 mm, 5 pm, 100 A). A flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied.

For the first purification of Example 7 by preparative RP-HPLC, an Aeris® C18-column (Phenomenex Aeris® 3.6u PEPTIDE XB-C18: 250 mm x 21.2 mm, 3.6 pm, 100 A) with a flow rate of 15 ml/min and a linear gradient of 20 % to 50 % eluent B in A over 30 min was applied. Example 7 had to be purified a second time by using a semi-preparative C18-column (Phenomenex Kinetex® 5u XB-C18: 250 mm x 10 mm, 5 pm, 100 A) with a flow rate of 5 ml/min and a linear gradient of 20 % to 50 % eluent B in A over 40 min. Example 1 : fK⁴’¹⁸’²²(m1 J9b).F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLKRYYKALRHYINLITRPRY-NK

Chemical Formula: C231 H369B30N55O72S3

Exact Mass: 5491.89 g/mol

Molecular Weight: 5489.29 g/mol

Example 1 was synthesized in a 15 pmol scale. The yield was 6.0 mg (7 % of theory).

Analytical RP-HPLC

Example 1 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 22.5 min. Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 21.3 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated monoisotopic mass. MALDI-TOF (m/z): 5492.8 [M+H]⁺, 2747.1 [M+2H]²⁺.

Example 2: rK^{4 18}«2S)-Dap(m1 J9b)₂).F⁷.P³⁴1-NPY

YPSKPDFPGEDAPAEDLKRYYSALRHYINLITRPRY-NH₂

Chemical Formula: C244H396B40N58O81S4

Exact Mass: 6003.13 g/mol

Molecular Weight: 5998.82 g/mol

Example 2 was synthesized in a 15 pmol scale. The yield was 8.4 mg (9 % of theory).

Analytical RP-HPLC

Example 2 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 22.4 min. Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 21.1 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated mass. ESI Orbitrap (m/z): 1000.9 [M+6H]⁶⁺, 1200.8 [M+5H]⁵⁺, 1500.6 [M+4H]⁴⁺; MALDI-TOF (m/z): 6003.9 [M+H]⁺, 3002.5

[M+2H]²⁺.

Example 3: rK^{4 18 22}«2S)-Dap(m1 J9b)₂).F⁷.P³⁴1-NPY

Chemical Formula: C270H453B60N61O92S6

Exact Mass: 6890.65 g/mol

Molecular Weight: 6882.89 g/mol

Example 3 was synthesized in a 15 pmol scale. The yield was 6.3 mg (6 % of theory).

Analytical RP-HPLC

Example 3 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 21 .9 min. Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 20.3 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated mass. ESI Orbitrap (m/z): 1 148.1 [M+6H]⁶⁺, 1377.6 [M+5H]⁵⁺, 1721.7 [M+4H]⁴⁺; MALDI-TOF (m/z): 6891.7 [M+H]⁺, 3445.5

[M+2H]²⁺.

Example 4: rK^{4 18}«2S)-Dap«2S)-Dap(m1 J9b)₂)₂).F⁷7. nP3³4⁴i1-NPY

Chemical Formula: C296H508B80N66O109S8

Exact Mass: 7868.14 g/mol

Molecular Weight: 7856.95 g/mol

Example 4 was synthesized in a 7.5 pmol scale. The yield was 4.5 mg (8 % of theory).

Analytical RP-HPLC

Example 4 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 14.7 min. Column 2: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .55 ml/min, R_t = 18.1 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1310.5 [M+6H]⁶⁺, 1572.5 [M+5H]⁵⁺, 1965.1 [M+4H]⁴⁺.

Example 5: rK^{4 18 22 26} 2S)-Dap(m1J9b)₂).F⁷7.P n³3⁴4i1-NPY

Chemical Formula: C293H508B80N62O106S8

Exact Mass: 7728.15 g/mol

Molecular Weight: 7716.90 g/mol

Example 5 was synthesized in a 7.5 pmol scale. The yield was 5.2 mg (9 % of theory).

Analytical RP-HPLC

Example 5 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 30 % to 80 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 15.8 min. Column 2: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .55 ml/min, R_t = 19.2 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1287.2 [M+6H]⁶⁺, 1544.5 [M+5H]⁵⁺, 1930.3 [M+4H]⁴⁺.

Example 6 with Carbaborane ¹⁰B-m1 J9b moiety

Peptide P6 was synthesized analogously to peptide P4. However, instead of the carbaborane m1 J9b synthon with a natural isotopic distribution of boron, the isotopically enriched carbaborane ¹⁰B-m1 J9b synthon, which contains ¹⁰B atoms in an isotopic purity of >99% and which was synthesized in analogy to carbaborane m1 J9b synthon (see Intermediate 10), was used for coupling with peptide P6.

Example 6: rK^{4 18}«2S)-Dap«2S)-Dapr 10Br -m1J9b)₂)₂).F :7⁷. DP3³4⁴I1-NPY

Chemical Formula: C296H₅o8¹⁰B₈oN660io9S8

Exact Mass: 7788.4 g/mol

Molecular Weight: 7793.2 g/mol Example 6 was synthesized in a 15 pmol scale. The yield was 5 mg (4 % of theory).

Analytical RP-HPLC

Example 6 was analyzed with two different columns; purity was determined to be > 95 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 23.0 min. Column 2: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1.55 ml/min, R_t = 18.8 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1299.9 [M+6H]⁶⁺, 1559.7 [M+5H]⁵⁺, 1949.4 [M+4H]⁴⁺. Example 7: rK^{4 18}«2S)-Dap«2S)-Dap(m1 J7J9b)₂)₂).F⁷.P³⁴1-NPY

N— ml J7J9b

H

Chemical Formula: C344H588B80N66O149S8

Exact Mass: 9164.57 g/mol

Molecular Weight: 9154.08 g/mol

Example 7 was synthesized in a 15 pmol scale. The yield was 2.3 mg (1.7 % of theory).

Analytical RP-HPLC

Example 7 was analyzed with two different columns; purity was determined to be > 93 %. Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 0.6 ml/min, R_t = 17.9 min. Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A), linear gradient: 20 % to 70 % eluent B in A over 40 min, flow rate: 1 .0 ml/min, R_t = 15.1 min.

Analysis by mass spectrometry

The observed mass was in correspondence to the calculated average mass. ESI Orbitrap (m/z): 1308.8 [M+7H]⁷⁺, 1526.8 [M+6H]⁶⁺, 1832.0 [M+5H]⁵⁺.

Table 6: HPLC analytics of carbaborane-NPY conjugates. The percentage of acetonitrile (ACN) needed for elution of the compounds, and the retention times of the compounds in the analytical reversed-phase HPLC, as also disclosed in the protocols regarding the preparation and purification of the individual conjugates (Reference Example RE1-RE11 , and Example 1- 6), are summarized here. Eluent A: water with 0.1 % TFA, eluent B: acetonitrile with 0.08 % TFA.

The purity of the peptide conjugates was analyzed by RP-HPLC. Following eluents were thereby used for the RP-HPLC: eluent A = 0.1 % TFA in water; eluent B = 0.08 % TFA in acetonitrile. Chromatograms were recorded at l = 220 nm. Columns and gradients were used as follows: Column 1 : Phenomenex Jupiter® 4u Proteo C12 90 A (250 mm x 4.6 mm, 4 pm, 90 A)

Flow rate: 0.6 ml/min

Gradient A: 20 % to 70 % eluent B in A over 40 min

Gradient B: 30 % to 80 % eluent B in A over 40 min

Gradient C: 40 % to 90 % eluent B in A over 40 min

Column 2: Agilent Varitide RPC 200 A (250 mm x 4.6 mm, 6 pm, 200 A)

Flow rate: 1 .0 ml/min Gradient A: 20 % to 70 % eluent B in A over 40 min

Gradient B: 30 % to 80 % eluent B in A over 40 min

Gradient C: 40 % to 90 % eluent B in A over 40 min Column 3: Phenomenex Aeris® Peptide 3.6u XB-C18 (250 mm x 4.6 mm, 3.6 pm, 100 A) Flow rate: 1 .55 ml/min

Gradient A: 20 % to 70 % eluent B in A over 40 min

Gradient B: 30 % to 80 % eluent B in A over 40 min

EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS

Examples and Reference examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein

• the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and

• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples and Reference examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

Receptor Activation and Internalization Studies

Materials

DMEM and Ham’s F12 were purchased from Lonza (Basel, Switzerland). FBS was obtained from Biochrom (Berlin, Germany), hygromycin was purchased from InvivoGen (San Diego, CA, USA) and G418 was from Merck. Opti-MEM was purchased from Life Technologies (Basel, Switzerland) and Hoechst33342 was from Sigma-Aldrich. [2-³H]-myo-inositol was obtained from PerkinElmer (Waltham, MA, USA), BSA was from Roth (Karlsruhe, Germany) and formic acid was from Grijssing (Filsum, Germany).

pNPY (Sequence: YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY-NH₂) and [F⁷,P³⁴]-NPY (Sequence: YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH₂) were prepared by automated peptide synthesis as described previously [Soil et al., Eur. J. Biochem. 2001 , 268, 2828]

Cell culture

All used cell lines were maintained under humidified atmosphere at 37 °C and 5 % carbond dioxide in 75 cm² cell culture flasks. HEK293_hYiR_eYFP and HEK293_HA_hY₂R_eYFP cells, which are expressing the hYiR or hY2R, respectively, C-terminally fused to eYFP, were cultured in DMEM/Ham’s F12 (1 :1 , v/v) supplemented with 15 % FBS and hygromycin (100 pg/ml). COS-7_hYiR-eYFP_AG_q and COS-7_hY₂R-eYFP_AG_q cells, which are co-expressing the hYiR or hY₂R, C-terminally fused to eYFP, together with the chimeric G protein Ga_A6qi4_myr, were cultured in DMEM supplemented with 10 % FBS, hygromycin (133 pg/ml) and G418 (1.5 mg/ml).

Receptor Activation: Inositol Phosphate Accumulation Assay

The effect of the carbaborane modification of the NPY conjugates on their capability to activate the hYi and hY₂ receptor was tested with an inositol phosphate accumulation assay. The measurement procedure was carried out as described previously [Bohme et al., Peptides 2007, 28, 226]. COS-7 cells, stably transfected with the hYiR or hY₂R and a chimeric G-protein, were seeded out in 48-well plates (60.000-70.000 cells/well) and grown for 24 h under humidified atmosphere at 37 °C and 5 % carbon dioxide. The following day, cells were labeled with [2-³Hj- myo-inositol (2 pCi/ml) in cell culture medium for approximately 16 h at 37 °C and 5 % carbon dioxide. On day three of the assay, cells were washed once with DMEM supplemented with 10 mM LiCI (lithium chloride) and subsequently stimulated with DMEM/LiCI containing 0.1 % ( wlv ) BSA and increasing concentrations of peptide for 1 h at 37 °C and 5 % carbon dioxide. Compounds were typically tested in a concentration range from 10 ⁵ M to 10 ¹¹ M in duplicates.

After receptor stimulation, the medium was aspirated and cells were lysed with 0.1 M NaOH (sodium hydroxide). Samples were neutralized with 0.18 M formic acid, diluted and accumulated IP species were isolated by anion-exchange chromatography using a Bio-Rad AG 1 -X8 resin. Finally, samples were measured with a Tri-Carb 2910TR b-counter. Data were analyzed with GraphPad Prism 5.0. Obtained dpm values for the compounds were normalized to NPY and EC₅₀ and pECeo values were calculated from sigmoidal concentration-response curves. Each peptide / conjugate was tested at least two times independently.

Table 7: Results for the inositol phosphate accumulation assay at hYiR and hY₂R. Values represent mean values of at least two independent experiments for each compound (Reference Examples RE1-RE11, Examples 1-7, and pNPY and [F⁷,P³⁴]-NPY for reference; n.a. : not applicable)).

RE6 4.9 8.31 ± 0.07 98 ±4 206 6.69 ± 0.07 85 ±3

RE7 > 1000 n.a. n.a. > 1000 n.a. n.a.

RE8 inactive n.a. n.a. inactive n.a. n.a.

RE9 > 1000 n.a. n.a. 1000 n.a. n.a.

RE10 50 7.30 ± 0.04 87 ± 2 1000 n.a. n.a.

RE11 4.5 8.35 ± 0.15 66 ± 5 1000 n.a. n.a.

1 3.5 8.46 ±0.07 95 ±4 416 6.38 ± 0.04 81 ±2

2.6 8.59 ±0.06 94 ±3 319 6.50 ±0.05 81 ±2

2

9.6 8.02 ±0.06 96 ±3 722 6.14 ±0.05 69 ±2

3

7.8 8.11 ±0.07 91 ±3 > 1000 n.a. n.a.

4

19 7.72 ±0.10 94 ± 5 > 1000 n.a. n.a.

5

6 6.2 8.21 ±0.15 87 ± 7 > 1000 n.a. n.a. 7 18 7.76 ±0.06 91 ±3 > 1000 n.a. n.a.

As control, the unmodified pNPY (for sequence see paragraph“Materials”) was used, which possesses a high, nanomolar activation potency at both the hYi and hY₂ receptor. In general, due to the use of [F⁷,P³⁴]-NPY (for sequence see paragraph“Materials”) as backbone sequence for carbaborane modification, all conjugates exhibited a low activity at the hY₂R with an at least 40-fold higher ECso compared to the potency at the hYiR. Conjugates RE1 and RE3, each containing one hydrophobic carbaborane moiety (m1 a and m9b, respectively), showed a nanomolar potency at the hYiR comparable to the unmodified pNPY. Incorporation of three carbaborane clusters as in conjugates RE2 and RE4 only led to a slight decrease in hYiR activation potency and here, the use of carbaborane m9b moiety in conjugate RE4 was found to be superior to carbaborane m1 a moiety in RE2. Modification of [F⁷,P³⁴]-NPY with one biscluster carbaborane bm9g moiety (RE5 and RE6) yielded conjugates with nanomolar activation potency at the hYiR. However, if two or more carbaborane bm9g moieties (corresponding to four or more carbaborane clusters) were incorporated into the peptide, the activity at the hYiR was dramatically decreased (conjugates RE7 and RE9) or even completely lost (conjugate RE8). The use of the 6-deoxy-D-galactose-carbaborane m1 J9b moiety with enhanced hydrophilicity for modification enabled a higher carbaborane loading of [F⁷,P³⁴]-NPY. Examples 1-4 and 6, which contain three, four, six or eight carbaborane m1J9b moieties, were all found to be full agonists at the hYiR with nanomolar activation potencies. A loss of activity at the hYiR could be again observed for conjugate 5 (containing eight carbaborane ml J9b moieties distributed over the peptide sequence) and conjugate RE10 (containing twelve carbaborane m1 J9b moieties). RE11 , which is structurally equivalent to conjugate 4, but with the substitution of one carbaborane ml J9b moiety by a TAMRAfluorophore, is also a highly potent agonist at the hYiR. In addition, example 7, containing eight carbaborane ml J7J9b moieties, was found to be a full agonist at the hYiR with good activation potency.

Receptor Internalization: Fluorescence Microscopy

HEK 293 cells, stably transfected with the human Yi or Y₂ receptor and C-terminally fused to eYFP, were seeded into ibiTreat 8-well m-slides (ibidi, Martinsried, Germany) at a density of 300.000 cells/well and grown for approximately 24 h under humidified atmosphere at 37 °C and 5 % carbon dioxide_. On the following day, the medium was aspirated and cells were incubated in 200 pl_ Opti-MEM®with 1 mI_ Hoechst 33342 (0.5 mg/ml) for 30 min under standard incubation conditions. Afterwards, the solution was aspirated and 200 mI_ Opti-MEM® were added. A Zeiss Axio Observer microscope with an ApoTome Imaging System and a 63x immersion oil objective was used for image acquisition. For documenting the receptor internalization of the compounds, Opti-MEM® was aspirated and 200 mI_ OptiMEM® containing 10 ⁷ M peptide / conjugate (for hYiR-expressing cells) or 10 ⁶ M peptide / conjugate (for hY₂R-expressing cells) were added. Images were taken after 60 min of stimulation at 37 °C. The nuclear stain Hoechst 33342 was visualized by a DAPI filter (excitation 335-383 nm; emission 420-470 nm), the eYFP-tag on the receptor was visualized by a YFP filter (excitation 488-512 nm; emission 520-550 nm), and the TAMRA fluorophore was visualized by a TAMRA filter (excitation 550-580 nm; emission 590- 650 nm). Image processing was performed with AxioVision 3.1 or Zeiss ZEN 2012 software.

Table 8: Internalization properties of carbaborane-NPY conjugates. Conjugates (Reference Examples RE1-RE11 , Examples 1-6), and pNPY and [F⁷,P³⁴]-NPY peptides for reference are classified as either found to be able to induce internalization of the respective receptor comparable to NPY (+), to induce slight receptor internalization (+/-) or found not to be able to stimulate receptor internalization (-). Used concentrations of the compounds for the internalization studies are 100 nM for hYiR-expressing cells and 1 mM for hY2R-expressing cells.

The ability of the carbaborane-[F⁷,P³⁴]-NPY conjugates to stimulate cellular internalization of the hYiR was investigated in internalization studies by fluorescence microscopy. Since G protein- coupled receptors internalize as complex with their bound ligand after activation, the receptor internalization can be used to prove the specific cellular uptake of the peptides / conjugates. Additionally, all compounds were checked for their internalization behavior at the hY₂R. Without peptide stimulation, both the hYiR and hY₂R are predominantly localized in the plasma membrane of the cells. Table 8 shows that the different carbaborane modifications did not change the selectivity of the [F⁷,P³⁴]-NPY backbone against the hY₂R, since none of the prepared conjugates was found to be able to stimulate internalization of this receptor. Conjugates RE1 and RE3-RE6 induced internalization of the hY-iR comparable to the unmodified pNPY, as can be seen by a nearly complete vesicular localization of the receptor inside the cell after stimulation (data not shown). Compared to that, the extent of Yi receptor internalization by conjugate RE2 was reduced and hardly visible for conjugate RE10. Conjugates RE7-RE9 were not able to stimulate hYiR internalization anymore. Importantly, with the combination of carbaborane and 6-deoxy-D-galactose in compounds Example 1-5, internalization could be recovered. Conjugates with up to eight incorporated carbaborane ml J9b moieties exhibited a high, nanomolar activation potency at the hYiR and stimulated internalization of this receptor while maintaining selectivity against the hY₂R. Additionally, example 7 with eight incorporated carbaborane m1J7J9b moieties stimulated internalization of the hYiR at a concentration of 100 nM and showed no effect on the hY₂R at a concentration of 1 mM.

In addition to the testing of the receptor internalization, the mixed carbaborane-containing and fluorophore-labeled conjugate RE11 was used to directly visualize the cellular uptake of this compound. Strong TAMRA fluorescence from RE11 could be observed inside hYiR-expressing cells after stimulation for 1 h. Furthermore, co-localisation of RE11 with the hYiR in intracellular vesicles proved the receptor-mediated internalization of this carbaborane-containing conjugate.

Claims

1. A compound of general formula (I):

(I),

in which :

X¹ represents a group selected from L-lysine,

(Y).

G represents the amino acid glycine,

X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, and X¹⁷, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), leucine (X¹³, X¹⁶), arginine (X¹⁴, X¹⁷), and tyrosine (X⁵), with one instance of either X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰,

X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, or X¹⁷ being present in its natural, proteinogenic L-enantiomeric form or as its D-enantiomer, or a mixture thereof, whilst all other instances of X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, or X¹⁷ being present in their natural, proteinogenic L-enantiomeric form,

with the proviso that at least one of R¹ and R² represents a group Sac,

Sac represents a group selected from

per molecule of formula (I) is at least 1 but smaller than 12,

or an isomer resulting from a mutarotation reaction, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound of general formula (I), according to claim 1 , in which :

X¹ represents a group selected from L-lysine,

(Y),

X⁵, X⁶, X⁹, X¹², X¹⁴, X¹⁵, F, I, L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁵), aspartic acid (X⁶, X¹²), phenylalanine (F), isoleucine (I), leucine (L), asparagine (N), proline (P), arginine (X¹⁴, R), serine (S), threonine (T), and tyrosine (X⁵,

Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

with the proviso that at least one of R¹ and R² represents a group Sac,

Sac represents a group selected from

per molecule of formula (I) is at least 1 but smaller than 12,

3. The compound of general formula (I) according to claim 1 or 2, in which

X¹ represents a group selected from L-lysine,

represents a group selected from alanine, being present in its natural, proteinogenic L- enantiomeric form or its D-enantiomer, or a mixture thereof,

(Y),

Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine,

q represents an integer 1 ,

R² represents a hydrogen atom or a group Sac,

Sac represents a group

Sac

4. The compound of general formula (I), according to Claim 1 or 2, in which :

X¹ represents a group selected from L-lysine,

represents a group selected from L-serine,

X⁴ represents a group selected from the amino acid L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 ,

R² represents a hydrogen atom or a group Sac, Sac represents a group selected from

Sac

5. The compound of general formula (I), according to any one of Claims 1 to 4, in which : X¹ represents a group selected from L-lysine,

represents a group selected from L-serine,

X⁴ represents a group selected from the amino acid L-histidine,

(Y),

G represents the amino acid glycine,

q represents an integer 1 ,

R² represents a hydrogen atom or a group Sac, Sac represents a group

i

Sac

6. The compound of general formula (I), according to any one of Claims 1 to 5, in which :

X¹ represents a group selected from:

and

X² represents a group selected from L-alanine,

represents a group selected from L-serine,

represents a group selected from L-histidine,

, and

in which“§” indicates the point of attachment to the neighbouring amino acid X¹⁷, and in which“§§” indicates the point of attachment to the neighbouring amino acid L-tyrosine X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴, X¹⁵, X¹⁶, X¹⁷, F, I , L, N, P, R, S, T, and Y, respectively, represent the amino acids alanine (X⁹, X¹⁰, X¹⁵), aspartic acid (X⁶, X⁸, X¹²), glutamic acid (X⁷, X¹¹), phenylalanine (F), isoleucine (I), leucine (X¹³, X¹⁶, L), asparagine (N), proline (P), arginine (X¹⁴, X¹⁷, R), serine (S), threonine (T), and tyrosine (X⁵, Y) in their natural, proteinogenic L-enantiomeric form,

G represents the amino acid glycine, q represents an integer 1 ,

Sac represents a group

Sac

with the proviso that the number of carbaborane moieties or

Sac

Sac

per molecule of formula (I) does not exceed 8,

or an isomer resulting from a mutarotation reaction, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The compound according to any one of claim 1 to 6, which is selected from the group consisting of:

[K^{4,i8 22}(ml J9b),F⁷,P³⁴]-NPY

YPSKPDFPGEDAPAEDLKRYYKALRHYINLITRPRY-NH

[K^{4 18}((2S)-Dap(m1 J9b)₂),F⁷,P³⁴]-NPY

YPSKPDFPGEDAPAEDLKRYYSALRHYINUTRPRY-NH

[K⁴'¹⁸'²²((2S)-Dap(m1J9b)₂) F⁷,P³⁴]-NPY

- [K⁴’¹⁸((2S)-Dap((2S)-Dap(¹⁰B-m1 J9b)₂)₂),F⁷,P³⁴]-NPY

[K⁴’¹⁸((2S)-Dap((2S)-Dap(m1 J7J9b)₂)₂),F⁷,P³⁴]-NPY

N— ml J7J9b

H or an isomer resulting from a mutarotation reaction, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

8. A compound of general formula (I) according to any one of claims 1 to 7, for use in the treatment or prophylaxis of cancer.

9. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 7, and one or more pharmaceutically acceptable excipients.

10. A pharmaceutical combination comprising:

• one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 7, and

• one or more further active ingredients, in particular agents for the treatment and/or prophylaxis of cancer.

1 1. Use of a compound of general formula (I) according to any one of claims 1 to 7, for the treatment or prophylaxis of cancer.

12. Use of a compound of general formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for the treatment or prophylaxis of cancer.

13. Use according to claim 8, 11 or 12, wherein the cancer is breast cancer.