Heterocyclic derivatives

TECHNICAL FIELD AND BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to E3 ligase binding compounds which degrade target proteins, preferably MetAP-2.

The compounds of this invention are heterocyclic derivatives and are useful in treating diseases such as of tumours, tumour metastases, proliferative dis- eases of the mesangial cells, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularisation, psoriasis, ocular neovascularisation, osteoporosis, diabetes and obesity, lymphoid leukaemia, lymphoma, malaria and prostate hypertrophy. The present invention also provides methods for preparing these compounds and pharmaceutical compositions comprising these compounds.

Small molecule degraders are increasingly utilized as tools to examine the functional roles of proteins and emerged as a novel therapeutic modality. Operating at the post-translational level, these molecules provide the potential for differentiated biological responses in comparison to classical inhibitors and expand the repertoire of methods for protein knock down beyond genetic approaches (e.g.: knock-out, siRNA).

Degrader molecules provide an example of a chemical genetic technique capable of more generally targeting the proteome. These chimeric molecules are designed to induce the degradation of their target proteins via the ubiquitin proteasome system (UPS), thereby eliminating pre-existing proteins. The UPS is the major intracellular pathway for protein degradation in which a series of enzymes known as E1s (ubiquitin activating enzymes), E2s (ubiquitin conjugating enzymes) and E3s (ubiquitin ligases) carry out covalent linkage of the 9kDa, 76 amino acid protein ubiquitin to a target protein. Subsequent enzymatic reactions result in the formation of a polyubiquitin chain, which targets the protein for degradation by the 26S proteasome.

Bifunctional degraders comprise an E3 ligase-binding motif that is linked to a target protein binding moiety. Consequently, these molecules hijack the cell’s own degradation machinery by recruiting an E3 ligase in vicinity of the target protein. The spatial proximity enables ubiquitination of the protein and subsequent recognition and depletion by the UPS through the formation of a stable ternary complex.

Specificity for a particular target protein is associated with the E3 ligase (Li W, et al. PLoS One. 2008; 3:e1487) that facilitates the final step of ubiquitin attachment to the target protein. While the first generation degraders were successfully developed using peptides as an E3 ubiquitin ligase-recognizing motif, they were either not cell-permeable or made cell-permeable by adding a cell-permeating motif such as the TAT peptide (Sakamoto KM, et al Proc Natl Acad Sci U S A. 2001 ; 98:8554-8559; Zhang D, et al. Bioorg Med Chem Lett. 2004; 14:645-648; Schneekloth JS Jr. et al. J Am Chem Soc. 2004; 126:3748-3754.). The poor cell permeability of the first generation of bifunctional degraders was significantly improved by the discovery of small molecules that bind to E3 ligases such as the Von Hippel Lindau (VHL) ligand binding to VHL ligase (Buckley et al, J. Am. Chem. Soc., 2012, 134 (10), pp 4465-4468) or thalidomide derivatives binding to the CRBN or Cereblon E3 Ligase (Winter et al, Science 19 Jun 2015: Vol. 348, Issue 6241 , pp. 1376- 1381 ). Having all small molecule degraders in hand enabled scientists to optimize those tool compounds into relevant therapeutic compounds.

Androgen receptor (AR) and estrogen receptor (ER) targeting degraders have been developed into clinical candidates, demonstrating the potential applications of these molecules in the treatment of prostate and breast cancers (Rodriguez-Gonzalez A, et al. Oncogene. 2008; 27:7201-7211 ; Cyrus K, et al. Chembiochem. 2010; 11 :1531-1534).

Next to peptidic degraders targeting methionine aminopeptidase-2 (MetAP-2) (Sakamoto KM, et al. Proc Natl Acad Sci U S A. 2001 ; 98:8554-8559; W02002020740) a range of other bifunctional degraders have been developed targeting proteins ranging from kinases, signaling proteins as well as cytosolic proteins and membrane receptors (examples in Ottis et al ACS Chem. Biol., 2017, 12 (4), pp 892-898).

The synthesis of degrader compounds that mediate the degradation of MetAP- 2 by recruiting VHL E3 ligase is reported in (W02002020740). This approach is focused on MetAP-2 ligands that bind the target protein in a covalent fashion and a peptidic sequence targetic VHL. A covalent mode of action drastically impairs the putative catalytic function of degrader molecules.

In WO 2020/152067 A1 , reversible MetAP-2 ligands conjugated to E3 ligase recruiting moieties are disclosed that degrade MetAP-2 in a human cancer cell line in a dose- and time-dependent manner.

In WO 2020/152067 A1 , thalidomide (2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro- 1 H-isoindole-1 ,3-dione) and one hydroxyproline-derivative ((2S,4R)-1 -[(2S)-2- amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1 ,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide) are used as E3 ligase recognizing moieties. In addition, nutlin (4-[(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-hydroxy-3- (propan-2-yloxy)phenyl]imidazolidine-1 -carbonyl]piperazin-2-one for MDM2) or (2S)-2-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido]-4-meth ylpentanoic acid (for clAP1 ) are described.

Nevertheless, there remains a need for compounds that can mediate efficient MetAP-2 degradation. It has surprisingly been found that the compounds according to the invention and salts thereof have particularly valuable pharma- cological properties and thereby address these and other needs in the art. Surprisingly, we found that compounds of this invention degrade MetAP-2 more efficiently than known MetAP-2 degraders. The presently disclosed compounds degrade the target protein in several relevant cancer cell lines. Compounds of the invention inhibit the MetAP-2 enzyme at nanomolar concentrations and also inhibit HLIVEC cell proliferation. This inhibition of MetAP-2 in the enzymatic as well as the cellular assays is comparable to the MetAP-2 inhibition demonstrated with compounds from the Merck applications WO 2012/048775, WO 2013/149704, WO 2016/020031. Accordingly, compounds presently claimed are useful for the treatment of diseases as decribed in WO 2012/048775, WO 2013/149704, WO 2016/020031.

The present invention specifically relates to compounds of the formula I which degrade the target protein MetAP-2, to compositions which comprise these compounds, and to processes for the use thereof for the treatment of diseases and complaints.

The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.

The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in vitro tests. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow active agents such as anti IgM to induce a cellular response such as expression of a surface marker, usually between about one hour and one week. In vitro testing can be carried out using cultivated cells from blood or from a biopsy sample. The amount of surface marker expressed is assessed by flow cytometry using specific antibodies recognising the marker.

The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.

BACKGROUND ART

Other heterocyclic amide derivatives as inhibitors of the activity of target proteins are disclosed in WO 2018/033556 A1 .

Cyclic amides are described as MetAP-2 inhibitors in WO 2012/048775 A1 , WO 2013/149704 A1 and WO 2016/020031 A1.

MetAP-2 degraders are described in WO 2020/152067 A1 .

DESCRIPTION OF THE INVENTION

The invention relates to compounds of the formula I

Q ¹ -Q ² -Q ³ in which

Q ¹ denotes

Q denotes O, NH, or CH2,

Q ² denotes unbranched alkylene having 4-25 C atoms, in which one or more single bonds between C atoms may be replaced by a triple bond, and in which 1-8 non-adjacent CH2 groups may be replaced by 0, CONH and/or NHCO, and in which one CH2 group may be replaced by

Q ³ denotes

L denotes NR ⁴ CO, CONR ⁴ , NH, 0, CO, S, SO ₂ , SO(=NH), NHCONH, SO2NH or NHSO ₂ ,

R denotes NR ² R ⁴ , Aik, C(=CH ₂ )[C(R ⁴ )2]nAr ² , Het ² , O[C(R ⁴ ) ₂ ]nAr ² or OA, X denotes CO or CH2,

Y denotes CO or CH2,

R ¹ denotes (CH ₂ )n, [C(R ⁴ ) ₂ ]nAr ¹ -, (CH ₂ ) _n Het- (CH ₂ )nCyc-,

[C(R ⁴ ) ₂ ]nCONHAr ¹ -, [C(R ⁴ ) ₂ ]nNA-, O[C(R ⁴ ) ₂ ]nAr ¹ - or [C(R ⁴ ) ₂ ]nCOO(CH ₂ )nAr ¹ -, wherein substituent L directly is connected to Ar ¹ , Het or Cyc,

R ² denotes H, [C(R ⁴ ) ₂ ]nAr ² , (CH ₂ )nCOHet ¹ , (CH ₂ )nCOAr ² , (CH ₂ )mNA ₂ , (CH ₂ )nCyc or (CH ₂ )nHet ¹ ,

R ³ denotes OH or OCOA,

R ⁴ denotes H or alkyl having 1 , 2, 3 or 4 C-atoms,

R ² and R ⁴ together also denote alkylene having 2, 3, 4 or 5 C-atoms, where a CH2 group may also be replaced by N(CH2)mOH or SO2,

R ⁵ , R ⁶ each, independently of one another H, F or A,

R ⁵ and R ⁶ together also denote alkylene having 2, 3, 4 or 5 C-atoms, where a CH2 group may also be replaced by NCOA or 0,

R ⁷ denotes H, Hal or A,

Ar ¹ denotes phenyl which is unsubstituted or mono-, di- tri-, tetra- or pentasubstituted by Hal, OH, OA, CONH ₂ , CONHA, CONA ₂ , NHSO2A, CONHCyc, NHSO ₂ Cyc, CONHAr ² , Het ¹ , COHet ¹ and/or NASO2A,

Ar ² denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A, CONH2, and/or OAr ³ ,

Ar ³ denotes phenyl which is unsubstituted or monosubstituted by NH2, Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and/or 0 and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, CN, NH2, NHA, NA ₂ , NO2, CN, COOH, COOA, (CH ₂ )nCONH ₂ , (CH ₂ )nCONHA, (CH ₂ )nCONA ₂ , NHCOA, COA, CHO, Het ¹ , SO ₂ A, SO2NH2, SO2NHA, SO2NA2, CONHNH2, CONHAr ³ , =0 and/or Ar ³ ,

Het ¹ denotes pyridazinyl, pyrazolyl, pyridyl, piperazinyl, morpholinyl, pyrimidinyl, furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazole, piperidin-1 -yl, pyrrolidin-1 -yl, tetrahydropyranyl, 1 ,2-oxazinan-2-yl, 1 ,2,5-oxadiazinan- 2-yl, 1 ,3-oxazinan-3-yl or hexahydropyrimidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A and/or OA,

Het ² denotes isoindolyl,

A denotes unbranched or branched alkyl having 1 -10 C atoms, in which 1 -7 H atoms may be replaced by F, Cl, Br, OH, CHO, COA, COOA, CN, CONA ₂ , CONHA and/or CONH ₂ , and/or in which one or two non-adjacent CH and/or CH2 groups may be replaced by 0, or Cyc,

Aik denotes alkenyl having 2, 3, 4, 5 or 6 C atoms

Cyc denotes cyclic alkyl having 3-7 C atoms which is unsubstituted or mono-, di- or trisubstituted by NHCOA, NHSO2, OH, OA, A, NH2, NHA, NA ₂ , COOA, COOH and/or CONHA,

Hal denotes F, Cl, Br or I, m denotes 1 , 2, 3 or 4, n denotes 0, 1 , 2, 3 or 4, p denotes 1 , 2 or 3, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

In compounds of the formula I above, instead of the Q ¹ moiety as defined above, alternative chemical structures can be used to recruit E3 ligases like proline- or further hydroxy-proline derivatives, halogenated Thalidominde or Lenalidomide analogs or piperidine-2, 6-dione isomers, as well as 3-(2-oxo-2,3-dihydro-1 H-1 ,3-benzodiazol-1 -y l)piperidine-2, 6-dione derivatives, N-benzyl-2-chloro-N-[4-(phenoxy-4-yl)phenyl]acetamide derivatives, 3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-4-(phenyl-4-yl)-4,5- dihydro-1 H-1 ,2,4-triazol-5-one derivatives, Idasanutlin-, bardoxolone- Indisulam-, chloroquinoxaline sulfonamide- or Nimbolide- conjugates. Alternatively, other enzymes that are known to induce target molecule degradation (including but not limited to UchL5 and RPN11 ) can be recruited by conjugation of the MetAP-2 binding moiety to respective enzyme-binding chemical structures such as 8-(benzoylsulfanyl)-3-{[2-(1 ,3- thiazol-2-yl)ethyl]carbamoyl}quinoline-6-carboxylate or (2E)-2-cyano-N-[1 - (4-hydroxyphenyl)butyl]-3-(1 ,3-thiazol-2-yl)prop-2-enamide instead of the Q ¹ moiety defined above.

The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and sol- vates of these compounds.

Moreover, the invention relates to pharmaceutically acceptable derivatives of compounds of formula I.

The term solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alkoxides.

It is understood, that the invention also relates to the solvates of the salts. The term pharmaceutically acceptable derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.

As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound of formula I that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of formula I. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of formula I that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In certain embodiments, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well- known methods.

The expression "effective amount” denotes the amount of a medicament or of a pharmaceutical active ingredient which causes in a tissue, system, animal or human a biological or medical response which is sought or de- sired, for example, by a researcher or physician.

In addition, the expression "therapeutically effective amount” denotes an amount which, compared with a corresponding subject who has not re- ceived this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syn- drome, condition, complaint, disorder or side-effects or also the reduction in the advance of a disease, complaint or disorder.

The expression "therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.

The invention also relates to the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000.

These are particularly preferably mixtures of stereoisomeric compounds.

"Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.

The invention relates to the compounds of the formula I and salts thereof and to a process for the preparation of compounds of the formula I, wherein L denotes CONR ⁴ , and pharmaceutically acceptable salts, sol- vates, tautomers and stereoisomers thereof, characterised in that a compound of formula II in which X, R, R ¹ , R ³ , R ⁵ , R ⁶ , R ⁷ and p have the meanings indicated in

Claim 1 , and L ¹ denotes Cl, Br, I or a free or reactively functionally modified OH group, is reacted with a compound of the formula III

Q ¹ -Q ² -NH ₂ in which Q ¹ and Q ² have the meanings indicated in Claim 1 , and/or a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R ¹ , R ² , R ³ have the meanings indicated for the formula I, unless explicitely stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1 , 2, 3, 4, 5, 6, 7 or 8 C atoms. A preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1- , 1 ,2- or 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1 - , 2- , 3- or 4-methylpentyl, 1 ,1 - , 1 ,2- , 1 ,3- , 2,2- , 2,3- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1 -ethyl-1 -methylpropyl, 1 -ethyl-2-methylpropyl, 1 ,1 ,2- or 1 , 2, 2-trimethy Ipropy I , furthermore preferably, for example, trifluoromethyl. A very particularly preferably denotes alkyl having 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1 ,1 ,1 -trifluoroethyl. Moreover, A denotes preferably CH2OCH3, CH2CH2OH or CH2CH2OCH3. Cyclic alkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl or cycloheptyl.

R preferably denotes NR ² R ⁴ , furthermore Aik, C(=CH2)[C(R ⁴ )2]nAr ² or Het ² . R particularly preferably denotes NR ² R ⁴ , very particularly preferably NHCH ₂ Ar ² .

X preferably denotes CO, furthermore CH2.

Y preferably denotes CO, furthermore CH2.

R ¹ preferably denotes (CH2)n, [C(R ⁴ )2]nAr ¹ -, (CH2)nHet- or (CH2)nCyc-, furthermore [C(R ⁴ ) ₂ ]nCONHAr ¹ or [C(R ⁴ ) ₂ ]nNA-.

Substituent L is directly connected to Ar ¹ , Het or Cyc and not to the (CH2)n or [C(R ⁴ )2]n moiety.

R ¹ particularly preferably denotes o-, m- or p-phenylen, indole-diyl or benzimidazole-diyl.

R ² preferably denotes [C(R ⁴ )2]nAr ² , (CH2)nCyc or (CH2)nHet ¹ .

R ³ preferably denotes OH.

R ⁴ preferably denotes H, methyl, ethyl or propyl, very particularly preferably H or methyl.

R ⁵ , R ⁶ preferably denote H.

R ⁷ preferably denotes H, F or CH3.

Ar ¹ preferably denotes phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromo- phenyl, o-, m- or p-chlorophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p- methoxyphenyl, o-, m- or p-aminocarbonylphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodophenyl, 4-fluoro-3- chlorophenyl, 2-fluoro-4-bromophenyl or 2,5-difluoro-4-bromophenyl.

Ar ¹ preferably denotes phenyl.

Ar ² preferably denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butyl- phenyl, o- m- or p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o- m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-aminocarbonylphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5- difluoro-4-bromophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar ² preferably denotes phenyl which is unsubstituted or mono-, di-, tri- or tetra-substituted by Hal.

Ar ² furthermore particularly preferably denotes phenyl which is mono- or disubstituted by Hal.

Irrespective of further substitutions, Het preferably denotes 2- or 3-furyl, 2- or

3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1 -, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazoly 1 , 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1 ,2,3-triazol-1 -, -4- or -5-yl, 1 ,2,4-triazol-1 -, -3- or 5-yl, 1 - or

5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,3,4-thia- diazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 3- or

4-pyridazinyl, pyrazinyl, 1 -, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1 -, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1 -, 3-, 4-, 5-,

6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or

7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benz- isothiazolyl, 4-, 5-, 6- or 7-benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or

8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4-oxazinyl, further preferably 1 ,3-benzodioxol-5-yl, 1 ,4- benzodioxan-6-yl, 2,1 ,3-benzothiadiazol-4- or -5-yl or 2,1 ,3-benzoxadiazol-5- yi.

The heterocyclic radicals may also be partially or fully hydrogenated. Unsubstituted Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-di- oxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyr- rolyl, 2,5-dihydro-1 -, -2- -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetra- hydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetra- hydro-1-, -3- or -4-pyrazolyl, 1 ,4-dihydro-1- -2-, -3- or -4-pyridyl, 1 ,2,3,4- tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1 ,4-dioxanyl, 1 ,3-dioxan-2-, -4- or -5-yl, hexahydro-1 -, -3- or -4-pyridazinyl, hexahydro-1 -, -2-, -4- or -5-pyri- midinyl, 1-, 2- or 3-piperazinyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1 ,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy- phenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3- dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or also 3,4- dihydro-2H-1 ,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydro- benzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het furthermore preferably denotes pyrazinyl, pyrazolyl, benzimidazolyl, pyridyl, indolyl, dihydroindolyl, benzofuranyl, tetrahydropyranyl, dihydro- quinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydro- isoquinolinyl, indazolyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, benzothiazolyl, piperidin-1 -yl, pyrrolidin-1 -yl, 3,4-dihydro-2H- pyrido[3,2-b]-1 ,4-oxazinyl, 3,4-dihydro-2H-benzo-1 ,4-oxazinyl, benzofuranyl, azetidinyl, 3-azabicylo[3.2.0]hexyl, pyrrolo[2,3-b]pyridinyl, tetrahydrofuranyl, tetrahydro-1 ,8-naphthyridinyl, 2,3- dihydrobenzoisothiazolyl, 1 ,2,3,4-tetrahydrobenzothiazinyl or hexahydro- benzo-1 ,3-dioxolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CN, COOH, COOA, (CH ₂ )nCONH ₂ , (CH ₂ ) _n CONHA, (CH ₂ ) _n CONA ₂ , NHCOA, COA, CHO, Het ¹ , SO ₂ A, SO ₂ NH _2I SO ₂ NHA, SO ₂ NA _2I CONHNH _2I CONHAr ³ , =0 and/or Ar ³ .

Het furthermore preferably denotes benzimidazolyl or indolyl, each of which is unsubstituted or monosubstituted by Hal. Het ¹ preferably denotes pyridazinyl, pyrazolyl, pyridyl, piperazinyl, morpholinyl, pyrimidinyl, furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazole, piperidin-1 -yl, pyrrolidin-1 -yl, tetrahydropyranyl, 1 ,2-oxazinan-2-yl, 1 ,2,5-oxadiazinan-2-yl, 1 ,3-oxazinan-3-yl or hexahydropyrimidinyl, each of which is unsubstituted or monosubstituted by A and/or OA.

Het ¹ furthermore preferably denotes pyridyl, pyrimidinyl, furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl or tetrazolyl. Het ¹ furthermore particularly preferably denotes pyridyl, furyl, thienyl, imidazolyl or pyrrolyl.

Q ² preferably denotes CH2OCH2CH2OCH2CH2O,

(CH ₂ )2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH ₂ )2,

OCH2CH2CH2OCH2 CH2CH2, (CH ₂ ) ₅ , (CH ₂ ) ₆ , (CH ₂ ) ₇ , (CH ₂ ) _8I (CH ₂ ) ₃ O(CH ₂ )4,

(CH ₂ )2O(CH ₂ )4O, (CH ₂ )2O(CH2)2O(CH2)2O(CH ₂ )3, or

(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)3, wherein one CH2 group may be replaced by a group such as

Throughout the invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres and can therefore occur in various stereoisomeric forms. The formula I encom- passes all these forms.

Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae la to le, which conform to the for- mula I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which in la Het denotes pyrazinyl, pyrazolyl, benzimidazolyl, pyridyl, thienyl, furanyl, indolyl, dihydroindolyl, benzofuranyl, tetrahydropyranyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetra- hydroisoquinolinyl, indazolyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, benzothiazolyl, piperidin-1 -yl, pyrrolidin-1 -yl, 3,4-dihydro-2H-pyrido[3,2- b]-1 ,4-oxazinyl, 3,4-dihydro-2H-benzo-1 ,4-oxazinyl, benzofuranyl, azetidinyl, 1 H-pyrrolo[2,3-b ]pyridinyl, 2H- chromenyl, 3-azabicylo[3.2.0]hexyl, pyrrolo[2,3- b]pyridinyl, tetrahydrofuranyl, tetrahydro-1 ,8- naphthyridinyl 2,3-dihydro-benzoisothiazolyl, 1 ,2,3,4- tetrahydrobenzothiazinyl or hexahydrobenzo-1 ,3- dioxolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CN, COOH, COOA, (CH ₂ )nCONH ₂ , (CH ₂ ) _n CONHA, (CH ₂ ) _n CONA ₂ , NHCOA, COA, CHO, Het ¹ , SO ₂ A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NA ₂ , CONHNH _2I CONHAr ³ , =0 and/or Ar ³ ; in lb Het denotes benzimidazolyl or indolyl, each of which is unsubstituted or monosubstituted by Hal; in Ic Q ¹ denotes in Id R denotes NR ² R ⁴ ; in le R ¹ denotes (CH ₂ ) _n , [C(R ⁴ ) ₂ ] _n Ar ¹ - or (CH ₂ ) _n Het-; in If Ar ² denotes phenyl which is unsubstituted or mono-, di-, tri- or tetra-substituted by Hal; in Ig R ² denotes [C(R ⁴ ) ₂ ] _n Ar ² , (CH ₂ ) _n Cyc or (CH ₂ ) _n Het ¹ ; in Ih A denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F, Cl and/or OH; in li Q ¹ denotes

Q denotes 0, NH, or CH2,

Q ² denotes unbranched alkylene having 4-25 C atoms, in which one or more single bonds between C atoms may be replaced by a triple bond, and in which 1-8 non-adjacent CH2 groups may be replaced by O, CONH and/or NHCO, and in which one CH2 group may be replaced by

L denotes NR ⁴ CO, CONR ⁴ , NH, 0, CO, S, SO ₂ , SO(=NH), NHCONH, SO2NH or NHSO2,

R denotes NR ² R ⁴ ,

X denotes CO or CH2,

Y denotes CO or CH2,

R ¹ denotes (CH ₂ )n, [C(R ⁴ ) ₂ ]nAr ¹ - or (CH ₂ ) _n Het- wherein substituent L directly is connected to Ar ¹ , Het or Cyc,

R ² denotes [C(R ⁴ ) ₂ ]nAr ² , (CH ₂ )nCyc or (CH ₂ )nHet ¹ ,

R ³ denotes OH,

R ⁴ denotes H or alkyl having 1 , 2, 3 or 4 C-atoms,

R ⁵ , R ⁶ denote H,

R ⁷ denotes H, Hal or A,

Ar ¹ denotes phenyl,

Ar ² denotes phenyl which is unsubstituted or mono-, di-, tri- or tetra-substituted by Hal, Het denotes pyrazinyl, pyrazolyl, benzimidazolyl, pyridyl, thienyl, furanyl, indolyl, dihydroindolyl, benzofuranyl, tetrahydropyranyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indazolyl, imidazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, benzothiazolyl, piperidin-1 -yl, pyrrolidin-1 -yl, 3,4-dihydro- 2H-pyrido[3,2-b]-1 ,4-oxazinyl, 3,4-dihydro-2H-benzo-1 ,4- oxazinyl, benzofuranyl, azetidinyl, 1 H-pyrrolo[2,3-b ]- pyridinyl, 2H-chromenyl, 3-azabicylo[3.2.0]hexyl, pyrrolo[2,3-b]pyridinyl, tetrahydrofuranyl, tetrahydro-1 ,8- naphthyridinyl 2,3-dihydro-benzoisothiazolyl, 1 , 2,3,4- tetrahydrobenzothiazinyl or hexahydrobenzo-1 ,3-dioxolyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, CN, NH ₂ , NHA, NA ₂ , NO ₂ , CN, COOH, COOA, (CH ₂ )nCONH ₂ , (CH ₂ ) _n CONHA, (CH ₂ ) _n CONA ₂ , NHCOA, COA, CHO, Het ¹ , SO ₂ A, SO ₂ NH ₂ , SO ₂ NHA, SO ₂ NA ₂ , CONHNH _2I CONHAr ³ , =0 and/or Ar ³ ,

Het ¹ denotes pyridyl, furyl, thienyl, imidazolyl or pyrrolyl,

A denotes unbranched or branched alkyl having 1 -6 C atoms, in which 1 -5 H atoms may be replaced by F, Cl and/or OH,

Cyc denotes cyclic alkyl having 3-7 C atoms, Hal denotes F, Cl, Br or I, n denotes 0, 1 , 2, 3 or 4, p denotes 1 , 2 or 3; and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

In preferred embodiments, Q ³ is

wherein L denotes NR ⁴ CO, CONR ⁴ , NH, 0, CO, S, SO ₂ , SO(=NH), NHCONH, SO2NH or NHSO2, and preferably L denotes CO. Alternative MetAP-2 binding chemical structures that can be used instead of this Q ³ moiety are described in

WO 2012/048775, WO 2013/149704 and WO 2016/020031.

Stereochemical mixtures work, but preferred are enantiomerical pure MetAP-2 binding substructures where the descriptor at the chiral carbon is

Also disclosed are the preferred compounds B1 and B2 depicted in the following table

and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Also disclosed are alternative compounds that are identical to B1 or B2 above apart from the Q ¹ moiety of B1 or B2 being replaced by an alternative chemical structure suitable to recruit (a) E3 ligases (e.g. proline- or further hydroxy-proline derivatives, halogenated Thalidominde or Lenalidomide analogs or piperidine-2, 6-dione isomers, as well as 3-(2-oxo- 2, 3-dihydro-1 H-1 ,3-benzodiazol-1 -yl)piperidine-2, 6-dione derivatives, , N- benzyl-2-chloro-N-[4-(phenoxy-4-yl)phenyl]acetamide derivatives, 3-[2,4- dihydroxy-5-(propan-2-yl)phenyl]-4-(phenyl-4-yl)-4,5-dihydro -1 H-1 ,2,4- triazol-5-one derivatives, Idasanutlin-, bardoxolone-, Indisulam-, chloroquinoxaline sulfonamide- or Nimbolide- conjugates) or (b) other enzymes that are known to induce target molecule degradation such as UchL5 and RPN11 (e.g. 8-(benzoylsulfanyl)-3-{[2-(1 ,3-thiazol-2- yl)ethyl]carbamoyl}quinoline-6-carboxylate or (2E)-2-cyano-N-[1 -(4- hydroxyphenyl)butyl]-3-(1 ,3-thiazol-2-yl)prop-2-enamide).

The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, as des- cribed in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se which are not mentioned here in greater detail.

Compounds of the formula I can preferably be obtained by reacting com- pounds of the formula II with a compound of the formula III.

The compounds of the formula II and of the formula III are generally known or can be prepared by methods known per se.

In the compounds of the formula II, L preferably denotes Cl, Br, I or a free or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction preferably succeeds in the presence of a dehydrating agent, such as, for example, a carbodiimide, such as N,N'-dicyclohexyl- carbodiimide ("DCCI"), 1 ,1'-carbonyldiimidazole or N-3-dimethylamino- propyl-N'-ethylcarbodiimide ("DAPECI"), furthermore propanephosphonic anhydride T3P (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1 ,2-dihydroquinoline, optionally in the presence of N-hydroxybenzotriaole;

Moreover, preferably preferred is HATU [O-(7-Azabenzotriazol-1-yl)- A/,A/,A/',A/'-tetramethyluronium-hexafluorphosphat]

The reaction is carried out in an inert solvent and is generally carried out in the presence of an acid-binding agent, preferably an organic base, such as DIPEA, 4-methylmorpholine, triethylamine, dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline-earth metal hydroxide, carbonate or bi- carbonate or another salt of a weak acid of the alkali or alkaline-earth metals, preferably of potassium, sodium, calcium or caesium, may also be favourable.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -15° and 150°, normally between 0° and 120°, particularly preferably between 20° and 40°C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2-dichloroethane, carbon tetrachloride, chloro- form or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon di- sulfide; carboxylic acids, such as formic acid or acetic acid; nitro com- pounds, such as nitromethane or nitrobenzene; esters, such as ethyl ace- tate, or mixtures of the said solvents. Particular preference is given to glycol ethers, such as ethylene glycol monomethyl ether, THF, dichloromethane and/or DMF.

Pharmaceutical salts and other forms

The said compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically accept- able salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I contains a car- boxyl group, one of its suitable salts can be formed by reacting the com- pound with a suitable base to give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methyl- glutamine. The aluminium salts of the compounds of the formula I are like- wise included. In the case of certain compounds of the formula I, acid-addi- tion salts can be formed by treating these compounds with pharmaceuti- cally acceptable organic and inorganic acids, for example hydrogen hal- ides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro- acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascor- bate and the like. Accordingly, pharmaceutically acceptable acid-addition salts of the compounds of the formula I include the following: acetate, adi- pate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, diglu- conate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane- sulfonate, fumarate, formate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydro- bromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso- butyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphos- phate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmo- ate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the invention include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magnesium, manganese(lll), manganese(ll), potassium, sodium and zinc salts, but this is not intended to represent a restriction. Of the above-men- tioned salts, preference is given to ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion ex- changer resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl- piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl- amine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl)methylamine (tromethamine), but this is not intended to represent a restriction. Compounds of the present invention which contain basic nitrogen-contain- ing groups can be quaternised using agents such as (C1-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C ₁ -C ₄ )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10-C18)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C1-C4)alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-solu- ble compounds according to the invention can be prepared using such salts. The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisucci- nate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, me- glumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stea- rate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and trometh- amine, but this is not intended to represent a restriction. Particular preference is given to hydrochloride, dihydrochloride, hydro- bromide, maleate, mesylate, phosphate, sulfate and succinate. The acid-addition salts of basic compounds of the formula I are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner. The free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner. The free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other- wise correspond to the respective free base forms thereof. As mentioned, the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanol- amine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conven- tional manner. The free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional man- ner. The free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solu- bility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof.

If a compound according to the invention contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di- phosphate, disodium and trihydrochloride, but this is not intended to repre- sent a restriction.

With regard to that stated above, it can be seen that the expression "phar- maceutically acceptable salt” in the present connection is taken to mean an active ingredient which comprises a compound of the formula I in the form of one of its salts, in particular if this salt form imparts improved pharma- cokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.

There is furthermore intended that a compound of the formula I includes isotope-labelled forms thereof. An isotope-labelled form of a compound of the formula I is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of the formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ CI, respectively. A compound of the formula I, a prodrug, thereof or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other iso-topes of other atoms is intended to be part of the present invention. An isotope-labelled compound of the formula I can be used in a number of beneficial ways. For example, an isotope-labelled compound of the formula I into which, for example, a radioisotope, such as ³ H or ¹⁴ C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred owing to simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium ( ² H), into a compound of the formula I has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of the formula I can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope- labelled reactant.

Deuterium ( ² H) can also be incorporated into a compound of the formula I for the purpose in order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus cause a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kM/ko = 2-7 are typical. If this rate difference is successfully applied to a compound of the formula I that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of the formula I with improved stability through resistance to such oxidative meta-bolism. Significant improvements in the pharmacokinetic profiles of compounds of the formula I are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t1/2), concen-tra-tion at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and materi-als costs.

The following is intended to illustrate the above: a compound of the formula I which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent of the extent to which the improve-ment in resistance to oxidative metabolism has improved. In this way, it is deter-mined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate- determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326- 3334, 1987, Foster, Adv. Drug Res. 14, 1 -40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993. The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, prefer- ably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a com- pound according to the invention, depending on the condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process which is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublin- gual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).

Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, cal- cium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica- ment after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants and disin- tegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disinteg- rant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl- pyrrolidone, a dissolution retardant, such as, for example, paraffin, an ab- sorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, giving lumps of non-uniform shape, which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The compounds according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can be pre- pared in the form of dosage units so that a given quantity comprises a pre- specified amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for- mulated by dispersion of the compound in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added. The dosage unit formulations for oral administration can, if desired, be en- capsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.

The compounds of the formula I and pharmaceutically salts, tautomers and stereoisomers thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, tautomers and stereoisomers thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted medicament carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxy- ethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-capro- lactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihy- droxypyrans, polycyanoacrylates and crosslinked or amphipathic block co- polymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis. Pharmaceutical compounds adapted for topical administration can be for- mulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can be ad- ministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation en- compass finely particulate dusts or mists, which can be generated by vari- ous types of pressurised dispensers with aerosols, nebulisers or insuffla- tors.

Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxi- dants, buffers, bacteriostatics and solutes, by means of which the formula- tion is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise sus- pension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, imme- diately before use is necessary. Injection solutions and suspensions pre- pared in accordance with the recipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, for- mulations which are suitable for oral administration may comprise flavours.

A therapeutically effective amount of a compound of the formula I depends on a number of factors, including, for example, the age and weight of the animal, the precise condition that requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimate- ly determined by the treating doctor or vet. However, an effective amount of a compound according to the invention is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particu- larly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as a single dose per day or usually in a series of part-doses (such as, for exam- ple, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically func- tional derivative thereof can be determined as the fraction of the effective amount of the compound according to the invention perse. It can be assumed that similar doses are suitable for the treatment of other condi- tions mentioned above.

A combined treatment of this type can be achieved with the aid of simulta- neous, consecutive or separate dispensing of the individual components of the treatment. Combination products of this type employ the compounds according to the invention.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packs of

(a) an effective amount of a compound of the formula I and/or pharma- ceutically acceptable salts, tautomers and stereoisomers thereof, in- cluding mixtures thereof in all ratios, and

(b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The set may, for example, comprise separate am- poules, each containing an effective amount of a compound of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient in dis- solved or lyophilised form.

"Treating" as used herein, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder.

The term "effective amount" in connection with a compound of formula (I) can mean an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing or providing prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein, such as inflammatory conditions, immunological conditions, cancer or metabolic conditions.

USE

The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment of diseases in which the degradation and/or modulation of MetAP-2 plays a role.

The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the degradation and/or modulation of MetAP-2. The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use for the treatment and control of diseases.

These diseases include the proliferation of tumour cells, pathological neovascularisation (or angiogenesis), which promotes the growth of solid tumours, neovascularisation in the eye (diabetic retinopathy, age-induced macular degeneration and the like) and inflammation (psoriasis, rheumatoid arthritis and the like), and proliferative diseases of the mesangial cells.

The invention relates to compounds for use of the formula I according to claim 1 and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the treatment and/or prevention of tumours, tumour metastases, proliferative diseases of the mesangial cells, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularisation, psoriasis, ocular neovascularisation, osteoporosis, diabetes and obesity, lymphoid leu- kaemia, lymphoma, malaria and prostate hypertrophy.

The invention relates to compounds for use where the tumour disease is selected from the group of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the stomach, of the larynx, of the lung, of the skin, monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinoma, pancreatic cancer, glioblastoma, breast carcinoma, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma.

The present invention encompasses the use of the compounds of the for- mula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of tumours, tumour diseases and/or tumour metastases.

The tumour disease is preferably selected from the group tumour of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the urogenital tract, the lymphatic system, the stomach, the larynx, the lung, the skin, monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinoma, pancreatic cancer, glioblastoma, breast carcinoma, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma.

Likewise encompassed is the use of the compounds according to Claim 1 according to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment of osteoporosis, diabetes and obesity.

Likewise encompassed is the use of the compounds according to Claim 1 according to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of a disease in which angiogenesis is involved.

A disease of this type in which angiogenesis is involved is an eye disease, such as retina vascularisation, diabetic retinopathy, age-induced macular degeneration and the like.

The angiogenic disease is preferably selected from the group diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, haeman- gioma, myocardial angiogenesis, atherosclerotic plaque neovascularisation, angiogenic eye diseases, choroidal neovascularisation, retrolental fibroplasia, macular degeneration, corneal transplant rejection, rubeosis iridis, neuroscular glaucoma, Oster Webber syndrome.

The proliferative disease of the mesangial cells is preferably selected from the group glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, throm- botic microangiopathy syndrome, transplant rejection, glomerulopathy.

The use of compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of inflammatory diseases likewise falls within the scope of the present invention. Examples of such inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed hyper- sensitivity reaction and the like.

The inflammatory disease is preferably selected from the group inflammatory bowel disease, arthritis, atherosclersosis, asthma, allergies, inflammatory kidney diseases, multiple sclerosis, chronic obstructive pulmo- nary disease, inflammatory skin diseases, pardontai diseases, psoriasis, T-cell-promoted immune disease.

The inflammatory bowel disease is preferably selected from the group ulcerative colitis, Crohn’s disease, non-specific colitis.

The T-cell-promoted immune disease is preferably selected from the group allergic encephalomyelitis, allergic neuritis, transplant rejection, graft-versus- host reaction, myocarditis, thyroiditis, nephritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus.

The arthritis disease is preferably selected from the group rheumatoid arthritis, osteoarthritis, Caplan's syndrome, Felty's syndrome, Sjogren's syndrome, spondylitis ankylosans, Still’s disease, chondrocalcinosis, metabolic arthritis, rheumatic fever, Reiter’s disease, Wissler's syndrome.

The inflammatory kidney disease is preferably selected from the group glomerulonephritis, glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture’s syndrome, Wegener’s granulomatosis, renal vasculitis, IgA nephropathy, idiopatic glomerular disease. The inflammatory skin disease is preferably selected from the group psoriasis, atopic dermatitis, contact sensitivity, acne.

Likewise encompassed is the use of the compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of a disease or condition in a mammal, in which to this method a therapeutically effective amount of a compound according to the invention is administered to a sick mammal in need of such treatment. The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without undue effort.

The present invention also encompasses the use compounds of the for- mula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of retinal vas- cularisation.

Likewise encompassed is the use of the compounds of the formula I and/or physiologically acceptable salts thereof for the preparation of a medicament for the treatment and/or combating of a tumour-induced disease in a mammal, in which to this method a therapeutically effective amount of a compound according to the invention is administered to a sick mammal in need of such treatment. The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without undue effort.

The disclosed compounds of the formula I can be administered in combi- nation with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the can- cer. The anti-cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the herein disclosed compounds of formula I, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents:

Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboguone; apaziguone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 ⁴ , VAL-083 ⁴ ;

Platinum Compounds such as carboplatin, cisplatin, eptaplatin, m iriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA altering agents such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine ^{1 3} ;

Topoisomerase Inhibitors such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule modifiers such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;

Antimetabolites such as asparaginase ³ , azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur ^{2 3} , trimetrexate; Anticancer antibiotics such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide ^{1 3} ;

Aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

Small molecule kinase inhibitors such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib ⁴ , cabozantinib S-malate ^{1 3} , ibrutinib ^{1 3} , icotinib ⁴ , buparlisib ² , cipatinib ⁴ , cobimetinib ¹ ’ ³ , idelalisib ^{1 3} , fedratinib ¹ , XL-647 ⁴ ;

Photosensitizers such as methoxsalen ³ ; porfimer sodium, talaporfin, temoporfin; Antibodies such as avelumab, alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab ^{2 3} ; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab ¹ ’ ^{2 3} , onartuzumab ^{1 3} , racotumomab ¹ , tabalumab ¹ ’ ³ , EMD-525797 ⁴ , nivolumab ^{1 3} ;

Cytokines such as aldesleukin, interferon alfa ² , interferon alfa2a ³ , interferon alfa2b ^{2 3} ; celmoleukin, tasonermin, teceleukin, oprelvekin ^{1 3} , recombinant interferon beta-1 a ⁴ ;

Drug Conjugates such as denileukin diftitox, ibritumomab tiuxetan, iobenguane 1123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab ¹ ’ ³ , vintafolide ^{1 3} ;

Vaccines such as sipuleucel ³ ; vitespen ³ , emepepimut-S ³ , oncoVAX ⁴ , rindopepimut ³ , troVax ⁴ , MGN-1601 ⁴ , MGN-1703 ⁴ ;

Miscellaneous alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiguimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel ³ , sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasguinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine ⁴ , picibanil ⁴ , reolysin ⁴ , retaspimycin hydrochloride ^{1 3} , trebananib ^{2 3} , virulizin ⁴ , carfilzomib ¹ ’ ³ , endostatin ⁴ , immucothel ⁴ , belinostat ³ , MGN-1703 ⁴ ;

¹ Prop. INN (Proposed International Nonproprietary Name)

² Rec. INN (Recommended International Nonproprietary Names)

³ LISAN (United States Adopted Name)

⁴ no INN.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : MetAP2 expression levels (in %, normalized to y-Tubulin) in A549 or HT1080 cells at various concentrations of compounds and at time points 24 hours (black bars, filled or dotted pattern) and 48 hours (white bars filled or dotted pattern) after treatment. Cell lysates were analyzed via Simple Western and DMSO-treated samples were set to 100% MetAP2 protein expression. Mean values of n=2 experiments are shown in panels B and C, error bars illustrate the standard deviation. (A) Treatment with compound A2 of WO 2020/152067 A1 (filled bars) or compound A1 of WO 2020/152067 A1 (bars with dotted pattern). (B) Treatment with compound A56 of WO 2020/152067 A1 (filled bars) or compound B2 of the present invention (bars with dotted pattern). (C) Treatment with compound C1 as defined herein (filled bars) or compound C2 as defined herein (bars with dotted pattern).

Figure 2: MetAPI expression levels (in %, normalized to y-Tubulin) in A549 or HT1080 cells at various concentrations of compound B2 of the present invention (filled bars) or compound A56 of WO 2020/152067 A1 (bars with dotted pattern) and at time points 24 hours (black bars, filled or dotted pattern) and 48 hours (white bars filled or dotted pattern). Cell lysates were analyzed via Simple Western and DMSO treated samples were set to 100% MetAPI protein expression. EXAMPLES The preferred exemplary compounds B1 and B2 shown below were synthesized as described in the following Examples 1 and 2, respectively. The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl3 (deuterated chloroform), CD3OD (deuterated methanol), CH ₃ CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d6 (deuterated dimethylsulfoxide), EDC (1-(3- dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-spray ionization), EtOAc (ethyl acetate), Et2O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methy lene]-dimethyl- ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), K2CO3 (potassium carbonate), LC (Liquid Chromatography), MeOH (methanol), MgSO4 (magnesium sulfate), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), NaHCO ₃ (sodium bicarbonate), NaBH ₄ (sodium borohydride), NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), PyBOP (benzotriazole-1-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazole-1- yl)-1,1,3,3-tetramethyluromium tetrafluoro borate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet). ¹ H NMR was recorded on a spectrometer with the frequece specified in the context of the results below, using residual signal of deuterated solvent as internal reference. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 2.49 ppm for ¹ H NMR in DMSO-d6). ¹ H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). LC-MS methods: Method 1: Instrument type: Agilent 1260 Infinity II Column: SunFire C185.0 μm 100-3 mm; T: 40°C | Flow: 1.4 ml/min | MS: 61-1000 amu positive | UV detection: 220 & 254 nm A: H2O + 0.05% HCOOH | B: MeCN + 0,04% HCOOH + 1% H2O Gradient: 1% → 99% B: 0 → 2,0 min | 99% B: 2,0 → 2,7 min Method 2: Instrument type: Agilent 1260 Infinity II Column: Chromolith HR RP-18e 50-4.6 mm; T: 40°C | Flow: 3.3 ml/min | MS: 61-800 amu positive | UV detection: 220 & 254 nm A: H2O + 0.05% HCOOH | B: MeCN + 0,04% HCOOH + 1% H2O Gradient: 0% → 100% B: 0 → 2,0 min | 100% B: 2,0 → 2,5 min Example 1: Synthesis of compound B1: 1-phenyl-2,5,8,11-tetraoxatridecan-13-yl methanesulfonate To a solution of 1-phenyl-2,5,8,11-tetraoxatridecan-13-ol (6.00 g; 21.1 mmol; 1.00 eq) and triethylamine (4.39 ml; 31.7 mmol; 1.50 eq) in DCM (30.0 ml) was added methanesulfonyl chloride (2.13 ml; 27.4 mmol; 1.30 eq) and the reaction was stirred at 0°C for 2 h. A solution of saturated NaHCO3-solution (30 mL) was added, the phases were seperated and it was extracted with DCM (2 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ and all volatile incredients were removed under reduced pressure to provide 1-phenyl- 2,5,8,11-tetraoxatridecan-13-yl methanesulfonate (7.73 g; 21.3 mmol; 101% yield) as a colourless oil. Area: 100% (crude) LCMS: (Method 1), RT = 1.44 min, 362.9 [M+H] ⁺ 13-iodo-1-phenyl-2,5,8,11-tetraoxatridecane To a solution of 1-phenyl-2,5,8,11-tetraoxatridecan-13-yl methanesulfonate (7.65 g; 21.1 mmol; 1.00 eq) in propan-2-one (30.0 ml) was added sodium iodide (31.6 g; 211 mmol; 10.0 eq) and the reaction was stirred at 60°C for 14 h. A solution of saturated NaHCO ₃ -solution (30 mL) and DCM (30 mL) were added, the phases were seperated and it was extracted with DCM (2 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ and all volatile incredients were removed under reduced pressure to provide 13-iodo-1-phenyl- 2,5,8,11-tetraoxatridecane (8.39 g; 21.3 mmol; 100% yield) as a colourless oil. Area: 100% (crude) LCMS: (Method 2), RT = 1.66 min, 394.8 [M+H] ⁺ 3-[1-oxo-4-(14-phenyl-4,7,10,13-tetraoxa-1-azatetradecan-1-y l)-2,3- dihydro-1H-isoindol-2-yl]piperidine-2,6-dione To a solution of Lenalidomide (1.00 g; 3.86 mmol; 1.00 eq) and 13-iodo-1- phenyl-2,5,8,11-tetraoxatridecane (1.82 g; 4.63 mmol; 1.20 eq) in 1-methyl-2- pyrrolidinone (4.0 ml) was added N-ethyldiisopropylamine (1.97 ml; 11.6 mmol; 3.00 eq) and the reaction was stirred at 80°C for 36 h. A solution of saturated NaHCO ₃ -solution (30 mL) and EtOAc (30 mL) were added, the phases were seperated and it was extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over Na2SO4 and all volatile incredients were removed under reduced pressure. The crude product was purified by column chromatography to provide 3-[1-oxo-4-(14-phenyl-4,7,10,13-tetraoxa-1-azatetradecan-1-y l)-2,3- dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (2.05 g; 3.73 mmol; 97% yield) as a yellow oil. Area: 95% LCMS: (Method 1), RT = 2.23 min, 525.9 [M+H] ⁺ 3-[4-(12-hydroxy-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]piperidine-2,6-dione A suspension of tert-butyl 9-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (1.98 g, 3.58 mmol, 1.00 eq) and Pd/C (5%, 1.00 g) in THF (12 mL) were stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was than filtered over through Celite, all volatile incredients were removed under reduced pressure and the crude product was purified by column chromatography to provide 3-[4-(12-hydroxy- 4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-2,3-dihydro-1H-isoind ol-2- yl]piperidine-2,6-dione (920 mg, 2.11 mmol, 57% yield) as a colourless oil. 1H NMR: 700 MHz, DMSO-d6 δ 11.0 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.58 (t, J = 5.7 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (q, J = 5.7 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.62 – 3.45 (m, 13H), 3.44 – 3.39 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H), 2.92 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.62 (ddd, J = 17.4, 4.5, 2.3 Hz, 1H), 2.31 (qd, J = 13.2, 4.4 Hz, 1H), 2.03 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H) Area: 100% LCMS: (Method 1), RT = 1.77 min, 435.9 [M+H] ⁺ 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H-isoindol-4- yl]amino}ethoxy)ethoxy]ethoxy}ethyl methanesulfonate To a solution of 3-[4-(12-hydroxy-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-2,3- dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (920 mg; 2.11 mmol; 1.00 eq) and triethylamine for synthesis (585 µl; 4.23 mmol; 2.00 eq) in dichloromethane (5.0 ml) was added methanesulfonyl chloride (245 µl; 3.17 mmol; 1.50 eq) and the reaction was stirred at 0°C for 2 h. A solution of saturated NaHCO3-solution (30 mL) was added, the phases were seperated and it was extracted with DCM (2 x 30 mL). The combined organic phases were dried over Na2SO4 and all volatile incredients were removed under reduced pressure to provide crude 2- {2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4- yl]amino}ethoxy)ethoxy]ethoxy}ethyl methanesulfonate (1.13 g; 2.20 mmol; 104% yield) as a colourless oil. Area: 100% LCMS: (Method 1), RT = 1.96 min, 513.8 [M+H] ⁺ tert-butyl 9-(2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydr o-1H- isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}ethyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H- isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}ethyl methanesulfonate (1.00 g; 1.95 mmol; 1.00 eq) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (544 mg; 2.14 mmol; 1.10 eq) in 1-methyl-2-pyrrolidinone (993 µl; 5.84 mmol; 3.00 eq) and the reaction was stirred at 100°C for 24h. The solids were filtered off, all volatile incredients were removed under reduced pressure and the crude product was purified by column chromatography to provide tert-butyl 9-(2-{2-[2- (2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoind ol-4- yl]amino}ethoxy)ethoxy]ethoxy}ethyl)-3,9-diazaspiro[5.5]unde cane-3- carboxylate (685 mg; 1.01 mmol; 52% yield) as a colourless oil. 1H NMR: 700 MHz, DMSO-d6 δ 11.01 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.56 (t, J = 5.7 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.57 – 3.45 (m, 10H), 3.26 (d, J = 5.8 Hz, 4H), 2.96 – 2.89 (m, 1H), 2.61 (ddd, J = 17.4, 4.4, 2.4 Hz, 1H), 2.45 - 2.40 (m, 2H), 2.37 – 2.27 (m, 5H), 2.03 (dtd, J = 12.9, 5.4, 2.4 Hz, 1H), 1.38 (s, 13H), 1.32 – 1.26 (m, 4H). Area: 99% (crude) LCMS: (Method 1), RT = 1.68 min, 671.9 [M+H] ⁺ 3-[4-(12-{3,9-diazaspiro[5.5]undecan-3-yl}-4,7,10-trioxa-1-a zadodecan-1- yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione dihydrochloride To a solution of tert-butyl 9-(2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}ethyl)-3 ,9- diazaspiro[5.5]undecane-3-carboxylate (675 mg; 1.00 mmol; 1.00 eq) in dichloromethane (5.0 ml) was added hydrogen chloride (4.0 M in dioxane; 366 mg; 10.1mmol; 10.0 eq) and the reaction mixture was stirred at room temperature for 24 h. Evapuration of all volatile incredients under reduced pressure afforded the crude product 3-[4-(12-{3,9-diazaspiro[5.5]undecan-3-yl}- 4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-2,3-dihydro-1H-isoind ol-2- yl]piperidine-2,6-dione dihydrochloride (640 mg; 0.99 mmol; 99% yield) as beige solid. Area: 99% (crude) LCMS: (Method 1), RT = 1.35 min, 603.9 [M+Na] ⁺ (3S)-N-[(3,5-difluorophenyl)methyl]-1-{2-[9-(2-{2-[2-(2-{[2- (2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]amino}ethoxy)ethoxy]ethoxy}ethyl)-3,9-diazaspiro[5.5]unde cane-3- carbonyl]-1H-indol-5-yl}-3-hydroxy-2-oxopyrrolidine-3-carbox amide To a solution of 3-[4-(12-{3,9-diazaspiro[5.5]undecan-3-yl}-4,7,10-trioxa-1- azadodecan-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidi ne-2,6-dione dihydrochloride (60.0 mg; 0.09 mmol; 1.00 eq) and 5-[(3S)-3-{[(3,5- difluorophenyl)methyl]carbamoyl}-3-hydroxy-2-oxopyrrolidin-1 -yl]-1H-indole-2- carboxylic acid (40.0 mg; 0.09 mmol; 1.00 eq) in N,N-dimethylformamide (1.00 ml) was added 4-methylmorpholine (81.8 µl; 0.74 mmol; 8.00 eq) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]py ridin-3- yl})oxidanium; hexafluoro-phosphanuide (42.5 mg; 0.11 mmol; 1.20 eq) and the reaction mixture was stirred at room temperature for 12 h. It was than directly purified by pre-HPLC (column: SunFire Prep OBD C18; 30 mm x 150 mm 5 μm; mobile phase: [water (0.1% formic acid)-MeCN]; B%: 10%, 2.5 min; 10% - 60%, 20 min). Tubes containing clean product were combined and diluted with EtOAc (50 mL) and saturated NaHCO3-solution (50 mL). Phases were separated and evaporation of the solvent furnished (3S)-N-[(3,5-difluorophenyl)methyl]-1-{2-[9- (2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4- yl]amino}ethoxy)ethoxy]ethoxy}ethyl)-3,9-diazaspiro[5.5]unde cane-3- carbonyl]-1H-indol-5-yl}-3-hydroxy-2-oxopyrrolidine-3-carbox amide (63.0 mg; 0.06 mmol; 69% yield) as colourless solid. 1H NMR: 700 MHz, DMSO-d6 δ 11.58 (s, 1H), 11.01 (s, 1H), 8.69 (s, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.9, 2.1 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.07 (tt, J = 9.4, 2.4 Hz, 1H), 7.02 – 6.98 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.71 (s, 1H), 5.57 (t, J = 5.7 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.42 (dd, J = 15.8, 6.8 Hz, 1H), 4.27 (dd, J = 15.9, 6.0 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.92 – 3.86 (m, 2H), 3.69 (b), 3.60 (t, J = 6.0 Hz, 2H), 3.56 – 3.46 (m, 10H), 3.31 (m), 2.92 (ddd, J = 17.4, 13.7, 5.4 Hz, 1H), 2.65 – 2.59 (m, 2H), 2.44 (b, 2 H), 2.37 (b, 4H), 2.30 (qd, J = 13.2, 4.5 Hz, 1H), 2.14 (ddd, J = 12.8, 8.3, 6.8 Hz, 1H), 2.02 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H), 1.51 – 1.42 (m, 8H). Area: 99% (crude) LCMS: (Method 1), RT = 1.70 min, 492.0 [M+2H] ²⁺ Example 2: Synthesis of compound B2: 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzene-1- sulfonate To a solution of 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (5.00 g; 15.2 mmol; 1.00 eq) and triethylamine (6.33 ml; 45.7 mmol; 3.00 eq) in DCM (45 mL) was added 4-methylbenzene-1-sulfonyl chloride (3.48 g; 18.3 mmol; 1.20 eq) at 0°C. The reaction mixture was warmed to room temperature and was stirred over night. The reaction was quenched by the addition of water (100 mL) and the phases were separated. The water phase was washed with DCM (3 x 40 mL) and the combined organic extracts were dried over Na2SO4. The solvents were removed under reduced pressure and the crude product was purified by column chromatography to provide 1-phenyl-2,5,8,11,14- pentaoxahexadecan-16-yl 4-methylbenzene-1-sulfonate (6.44 g, 13.3 mmol, 88% yield) as a colourless oil. 1H NMR: 500 MHz, DMSO-d6 δ 7.82 – 7.74 (m, 2H), 7.50 – 7.44 (m, 2H), 7.38 – 7.24 (m, 5H), 4.48 (s, 2H), 4.12 – 4.09 (m, 2H), 3.598 – 3.42 (m, 18H), 2.41 (s, 3H). Area: 100% LCMS: (Method 2), RT = 1.2 min, 482.8 [M+H] ⁺ tert-butyl 4-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)piperazine-1 - carboxylate To a solution of 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl 4- methylbenzene-1-sulfonate (6.35 g; 13.2 mmol; 1.00 eq) and tert-butyl 1- piperazinecarboxylate (2.94 g; 15.8 mmol; 1.20 eq) in N,N-dimethylformamide (50.0 ml) was added potassium carbonate (1.50 ml; 26.3 mmol; 2.00 eq) and reaction mixture was stirred two days at 60°C. The solvent was removed under reduced pressure and the residue was partioned between EtOAc (100 mL) and water (100 mL). The phases were separated und the water phase was washed with EtOAc (2 x 60 mL). The combined organic phases were dried over Na2SO4, the solvents were removed under reduced pressure and the crude product was purified by column chromatography to provide tert-butyl 4-(1-phenyl- 2,5,8,11,14-pentaoxahexadecan-16-yl)piperazine-1-carboxylate (5.77 g, 11.6 mmol, 88% yield) as a colourless oil. 1H NMR: 500 MHz, DMSO-d6 δ 7.38 – 7.23 (m, 5H), 4.49 (s, 2H), 3.61 – 3.46 (m, 18H), 3.27 – 3.24 (m, 4H), 2.46 (t, J = 5.9 Hz, 2H), 2.37 – 2.31 (m, 4H), 1.39 (s, J = 7.4 Hz, 9H). LCMS: (Method 2), RT = 1.44 min, 497.0 [M+H] ⁺ tert-butyl 4-(14-hydroxy-3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1- carboxylate A suspension of tert-butyl 4-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16- yl)piperazine-1-carboxylate (6.53 g, 13.1 mmol, 1.00 eq) and Pd/C (5%, 15.8 g) in THF (60 mL) were stirred under hydrogen atmosphere at room temperature for 19 h. The reaction mixture was than filtered over through Celite, all volatile incredients were removed under reduced pressure and the crude product was purified by column chromatography to provide tert-butyl 4-(14-hydroxy-3,6,9,12- tetraoxatetradecan-1-yl)piperazine-1-carboxylate (3.78 g, 9.30 mmol, 71% yield) as a colourless oil. 1H NMR: 700 MHz, DMSO-d6 δ 4.56 (t, J = 5.5 Hz, 1H), 3.53 – 3.46 (m, 14H), 3.41 (t, J = 5.3 Hz, 2H), 3.28 (t, J = 6.6 Hz, 4H), 2.47 (t, J = 5.9 Hz, 2H), 2.35 (t, J = 5.1 Hz, 4H), 1.39 (s, 9H). LCMS: (Method 2), RT = 1.09 min, 407.0 [M+H] ⁺ tert-butyl 4-[14-(methanesulfonyloxy)-3,6,9,12-tetraoxatetradecan-1- yl]piperazine-1-carboxylate To a solution of tert-butyl 4-(14-hydroxy-3,6,9,12-tetraoxatetradecan-1- yl)piperazine-1-carboxylate (400 mg; 0.98 mmol; 1.00 eq) and triethylamine (205 µl; 1.48 mmol; 1.50 eq) in DCM (5.0 ml) at 0°C was added methansulfonyl chloride (107 µl; 1.38 mmol; 1.40 eq) and the reaction mixture was stirred at the same temperature over night. The reaction was quenched by the addition of saturated NaHCO3-Lösung (20 mL), the phases were seperated and the water phase was extracted with DCM (3 x 20 mL). The combinded organic layers were dried over Na ₂ SO ₄ , the solvents were removed under reduced pressure and the crude product was used directly in the next step. LCMS: (Method 2), RT = 1.20 min, 484.9 [M+H] ⁺ tert-butyl 4-(14-iodo-3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1- carboxylate To a solution of tert-butyl 4-[14-(methanesulfonyloxy)-3,6,9,12- tetraoxatetradecan-1-yl]piperazine-1-carboxylate (476 mg; 0.98 mmol; 1.00 eq) in propan-2-one (5.0 ml) was added sodium iodide (2.95 g; 19.7 mmol; 20.0 eq) and the reaction mixture was stirred at 60°C for 3 h. The reaction was quenched by the addition of saturated NaHCO ₃ -Lösung (20 mL) and EtOAc (20 mL), the phases were seperated and the water phase was extracted with EtOAc (3 x 20 mL). The combinded organic layers were dried over Na2SO4, the solvents were removed under reduced pressure and the crude product was used directly in the next step. LCMS: (Method 2), RT = 1.36 min, 516.9 [M+H] ⁺ tert-butyl 4-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]amino}-3,6,9,12-tetraoxatetradecan-1-yl)pipera zine-1- carboxylate To a solution of tert-butyl 4-(14-iodo-3,6,9,12-tetraoxatetradecan-1- yl)piperazine-1-carboxylate (478 mg; 0.93 mmol; 1.00 eq) and 3-(4-amino-1- oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (240 mg; 0.93 mmol; 1.00 eq) in 1-methyl-2-pyrrolidinone was added N-ethyldiisopropylamine (472 µl; 2.78 mmol; 3.00 eq) and the reaction mixture was stirred at 110°C for 16 h. The reaction was quenched by the addition of saturated NaHCO3-Lösung (20 mL) and EtOAc (20 mL), the phases were seperated and the water phase was extracted with EtOAc (3 x 20 mL). The combinded organic layers were dried over Na2SO4, the solvents were removed under reduced pressure and the crude product was purified by flash chromatography to furnish tert-butyl 4-(14- {[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol- 4-yl]amino}- 3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carboxylate (128 mg; 0.20 mmol; 21% yield) as colourless solid. 1H NMR: 700 MHz, DMSO-d6 δ 11.00 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.96 – 6.92 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 5.58 (t, J = 5.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.56 – 3.44 (m, 14H), 3.27 (b, 4H), 2.92 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.65 – 2.59 (m, 1H), 2.45 (t, J = 5.9 Hz, 2H), 2.36 – 2.26 (m, 5H), 2.03 (dtd, J = 12.8, 5.4, 2.4 Hz, 1H), 1.38 (s, 9H). Area: 99% LCMS: (Method 2), RT = 1.26 min, 647.9 [M+H] ⁺ 3-{1-oxo-4-[15-(piperazin-1-yl)-4,7,10,13-tetraoxa-1-azapent adecan-1-yl]- 2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione dihydrochloride To a solution of tert-butyl 4-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]amino}-3,6,9,12-tetraoxatetradecan-1-yl)pip erazine-1- carboxylate (120 mg; 0.19 mmol; 1.00 eq) in DCM (4.0 ml) was added hydrogen chloride (4 m in dioxane, 0.92 mL; 3.71 mmol; 20.0 eq) and the reaction mixture was stirred at RT for 14 h. The reaction mixture was concentrated under educed pressure and the crude product was dried over night (50°C, ~ 3 mbar) and used without further purification in the next step (125 mg; 0.20 mmol; 106% yield). Area: 97% (crude) LCMS: (Method 1), RT = 1.03 min, 547.0 [M+H] ⁺ (3S)-N-[(3,5-difluorophenyl)methyl]-1-{2-[4-(14-{[2-(2,6-dio xopiperidin-3- yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-3,6,9,12- tetraoxatetradecan-1-yl)piperazine-1-carbonyl]-1H-indol-5-yl }-3-hydroxy- 2-oxopyrrolidine-3-carboxamide To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[15-(piperazin-1-yl)-4,7,10,13 - tetraoxa-1-azapentadecan-1-yl]-2,3-dihydro-1H-isoindole-1,3- dione dihydrochloride (52.0 mg; 0.08 mmol; 1.00 eq) and 5-[(3S)-3-{[(3,5- difluorophenyl)methyl]carbamoyl}-3-hydroxy-2-oxopyrrolidin-1 -yl]-1H-indole-2- carboxylic acid (37.0 mg; 0.09 mmol; 1.05 eq) in N,N-dimethylformamide (2.0 ml) was added 4-methylmorpholine (72 µl; 0.66 mmol; 8.00 eq) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]py ridin-3- yl})oxidanium; hexafluoro-phosphanuide (37.4 mg; 0,10 mmol; 1.20 eq) and the reaction mixture was stirred at RT for 14 h. The mixture was partioned between EtOAc (10 mL) and saturated NaHCO3-solution (10 mL). The phases were separated and the water phase was washed with EtOAc (3 x 15 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by chromatography to furnish (3S)-N-[(3,5-difluorophenyl)methyl]-1-{2-[4-(14-{[2- (2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol- 4-yl]amino}- 3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carbonyl]-1H-i ndol-5-yl}-3- hydroxy-2-oxopyrrolidine-3-carboxamide (57.9 mg; 0.06 mmol; 71% yield) as colourless solid. 1H NMR: 700 MHz, DMSO-d6 δ 11.62 (s, 1H), 11.00 (s, 1H), 8.69 (t, J = 6.5 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.8, 2.1 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.06 (tt, J = 9.3, 2.4 Hz, 1H), 7.00 (h, J = 4.2 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.81 – 6.77 (m, 2H), 6.71 (s, 1H), 5.56 (t, J = 5.7 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.41 (dd, J = 15.8, 6.9 Hz, 1H), 4.29 – 4.20 (m, 2H), 4.12 (d, J = 17.0 Hz, 1H), 3.89 (qd, J = 9.2, 5.8 Hz, 2H), 3.58 (t, J = 5.9 Hz, 2H), 3.55 – 3.46 (m, 14H), 3.33 – 3.28 (m), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.64 – 2.59 (m, 2H), 2.52 – 2.45 (m, 5H), 2.29 (qd, J = 13.4, 4.6 Hz, 1H), 2.14 (ddd, J = 12.8, 8.3, 6.8 Hz, 1H), 2.04 – 2.00 (m, 1H). Area: 98% LCMS: (Method 1), RT = 1.75 min, 972.05 [M+H] ⁺ Reference Example 3: Synthesis of compound C1 (negative control no.1): In compound C1 as depicted below, the thalidomide nitrogen is methylated. This alkylation prevents binding to the E3 ligase cereblon so that this ligase cannot be recruited by compound C1. 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H -isoindole-1,3- dione To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindol e- 1,3-dione (500 mg; 1.81 mmol; 1.00 eq.) in N,N-dimethylformamide (5.0 ml) was added sodium hydride (60% in mineral oil; 109 mg; 2.72 mmol; 1.50 eq.) at 0°C and the reaction mixture was stirred for 30 min at the same temperature. Iodomethane (0.17 ml; 2.72 mmol; 1.50 eq.) was added and it was stirred for 45 min at 0°C. The reaction mixture was partioned between EtOAc (30 mL) and saturated NaHCO3 solution (30 mL). The phases were separated und the water phase was washed with EtOAc (2 x 60 mL). The combined organic phases were dried over Na2SO4, the solvents were removed under reduced pressure and the crude product was purified by column chromatography to furnish 4-fluoro-2-(1-methyl- 2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione as a colourless solid (245 mg; 0.84 mmol; 47% yield). 1H NMR: 500 MHz, DMSO-d6 δ 7.95 (ddd, J = 8.4, 7.4, 4.6 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.74 (ddd, J = 9.3, 8.4, 0.7 Hz, 1H), 5.22 (dd, J = 13.1, 5.4 Hz, 1H), 3.03 (s, 3H), 2.96 (ddd, J = 17.3, 13.9, 5.5 Hz, 1H), 2.78 (ddd, J = 17.3, 4.6, 2.6 Hz, 1H), 2.58 – 2.49 (m, 1H), 2.08 (dtd, J = 13.1, 5.5, 2.6 Hz, 1H). Area: 100% LCMS: (Method 2), RT = 1.30 min, 290.9 [M+H] ⁺ tert-butyl 4-(14-{[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3- dihydro-1H-isoindol-4-yl]amino}-3,6,9,12-tetraoxatetradecan- 1- yl)piperazine-1-carboxylate To a solution of 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H - isoindole-1,3-dione (64.4 mg; 0.22 mmol; 0.90 eq.) and tert-butyl 4-(14-amino- 3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carboxylate (100.0 mg; 0.25 mmol; 1.00 eq.) in dimethyl sulfoxide (1.50 ml) was added N- ethyldiisopropylamine for synthesis (210 µl; 1.23 mmol; 5.00 eq.) and reaction mixture has been stirred for four hours at 80°C. The reaction mixture was partioned between EtOAc (25 mL) and saturated NaHCO3-solution (25 mL). The phases were separated und the water phase was washed with EtOAc (2 x 60 mL). The combined organic phases were dried over Na2SO4, the solvents were removed under reduced pressure and the crude product was purified by column chromatography to furnish tert-butyl 4-(14-{[2- (1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-4- yl]amino}-3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carb oxylate as a colourless solid (61.8 mg; 0.09 mmol; 37% yield). 1H NMR: 700 MHz, DMSO-d6 δ 7.59 (dd, J = 8.6, 7.0 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 5.12 (dd, J = 13.0, 5.4 Hz, 1H), 3.62 (t, J = 5.5 Hz, 2H), 3.58 – 3.43 (m, 12H), 3.30 – 3.25 (m, 4H), 3.02 (s, 3H), 2.95 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.76 (ddd, J = 17.2, 4.4, 2.5 Hz, 1H), 2.54 – 2.50 (m, 1H), 2.45 (t, J = 5.9 Hz, 2H), 2.34 (q, J = 5.0 Hz, 4H), 2.04 (dtd, J = 13.0, 5.5, 2.6 Hz, 1H), 1.38 (s, 9H). Area: 100% LCMS: (Method 2), RT = 1.48 min, 675.8 [M+H] ⁺ 2-(1-methyl-2,6-dioxopiperidin-3-yl)-4-[15-(piperazin-1-yl)- 4,7,10,13- tetraoxa-1-azapentadecan-1-yl]-2,3-dihydro-1H-isoindole-1,3- dione hydrochloride To a solution of tert-butyl 4-(14-{[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo- 2,3-dihydro-1H-isoindol-4-yl]amino}-3,6,9,12-tetraoxatetrade can-1- yl)piperazine-1-carboxylate (60.0 mg; 0.09 mmol; 1.00 eq.) in dichloromethane (2.00 ml) was added hydrogen chloride (4 ^M in dioxane; 64.8 mg; 1,78 mmol; 20.0 eq.) and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the crude product was directly used in the next step. LCMS: (Method 2), RT = 1.29 min, 575.9 [M+H] ⁺ (3S)-N-[(3,5-difluorophenyl)methyl]-3-hydroxy-1-{2-[4-(14-{[ 2-(1-methyl- 2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4 -yl]amino}- 3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carbonyl]-1H-i ndol-5-yl}-2- oxopyrrolidine-3-carboxamide To a solution of 5-[(3S)-3-{[(3,5-difluorophenyl)methyl]carbamoyl}-3-hydroxy- 2- oxopyrrolidin-1-yl]-1H-indole-2-carboxylic acid (42.4 mg; 0.10 mmol; 1.10 eq.) and 2-(1-methyl-2,6-dioxopiperidin-3-yl)-4-[15-(piperazin-1-yl)- 4,7,10,13- tetraoxa-1-azapentadecan-1-yl]-2,3-dihydro-1H-isoindole-1,3- dione hydrochloride (55.0 mg; 0.09 mmol; 1.00 eq.) in N,N-dimethylformamide (1.00 ml) was added 4-methylmorpholine (98.8 µl; 0.90 mmol; 10.0 eq.) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]py ridin-3- yl})oxidanium; hexafluoro-lambda5-phosphanuide (44.4 mg; 0.12 mmol; 1.30 eq.) and the reaction mixture was stirred at RT for 14 h. It was than directly purified by pre-HPLC (column: SunFire Prep OBD C18; 30 mm x 150 mm 5 μm; mobile phase: [water (0.1% formic acid)-MeCN]; B%: 10%, 2.5 min; 10% - 60%, 20 min). Tubes containing clean product were combined and diluted with EtOAc (50 mL) and saturated NaHCO3-solution (50 mL). Phases were separated and evaporation of the solvent furnished (3S)- N-[(3,5-difluorophenyl)methyl]-3-hydroxy-1-{2-[4-(14-{[2-(1- methyl-2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] amino}-3,6,9,12- tetraoxatetradecan-1-yl)piperazine-1-carbonyl]-1H-indol-5-yl }-2-oxopyrrolidine- 3-carboxamide as a colourless solid (36.6 mg; 0.094 mmol; 41% yield). 1H NMR: 700 MHz, DMSO-d6 δ 11.61 (s, 1H), 8.69 (t, J = 6.4 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.09 – 6.97 (m, 4H), 6.78 (d, J = 2.1 Hz, 1H), 6.72 (s, 1H), 6.59 (t, J = 5.9 Hz, 1H), 5.12 (dd, J = 13.1, 5.4 Hz, 1H), 4.41 (dd, J = 15.8, 6.8 Hz, 1H), 4.27 (dd, J = 15.8, 6.0 Hz, 1H), 3.91 – 3.86 (m, 2H), 3.60 (t, J = 5.5 Hz, 2H), 3.56 – 3.47 (m, 12H), 3.45 (q, J = 5.6 Hz, 2H), 3.01 (s, 3H), 2.94 (ddd, J = 17.2, 14.0, 5.4 Hz, 1H), 2.75 (ddd, J = 17.3, 4.4, 2.6 Hz, 1H), 2.6 – 2.59 (m, 1H), 2.54 – 2.46 (m, 7H), 2.14 (ddd, J = 12.8, 8.3, 6.8 Hz, 1H), 2.03 (dtd, J = 13.0, 5.4, 2.5 Hz, 1H). Area: 100% LCMS: (Method 1), RT = 1.79 min, 986.5 [M+H] ⁺ Reference Example 4: Synthesis of compound C2 (negative control no.2): Compound C2, as depicted below, can be used as a negative control because it includes a Q3 moiety that is an R-enantiomer which does not bind to MetAP2. The target protein MetAP2 therefore cannot be recruited by compound C2. (3R)-N-[(3,5-difluorophenyl)methyl]-1-{2-[4-(14-{[2-(2,6-dio xopiperidin-3- yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}-3,6,9,12- tetraoxatetradecan-1-yl)piperazine-1-carbonyl]-1H-indol-5-yl }-3-hydroxy- 2-oxopyrrolidine-3-carboxamide To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[15-(piperazin-1-yl)-4,7,10,13 - tetraoxa-1-azapentadecan-1-yl]-2,3-dihydro-1H-isoindole-1,3- dione hydrochloride (50.0 mg; 0.08 mmol; 1.00 eq.) and 5-[(3R)-3-{[(3,5- difluorophenyl)methyl]carbamoyl}-3-hydroxy-2-oxopyrrolidin-1 -yl]-1H-indole-2- carboxylic acid (39.5 mg; 0.09 mmol; 1.10 eq.) in N,N-dimethylformamide (1.00 ml) was added 4-methylmorpholine (84.6 mg; 0.84 mmol; 10.0 eq.) and [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]py ridin-3- yl})oxidanium; hexafluoro-lambda5-phosphanuide (41.3 mg; 0.11 mmol; 1.30 eq.) and the reaction mixture was stirred at RT for 14 h. The mixture was partioned between EtOAc (10 mL) and saturated NaHCO3- solution (10 mL). The phases were separated and the water phase was washed with EtOAc (3 x 15 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by chromatography to furnish (3R)-N-[(3,5-difluorophenyl)methyl]-1-{2- [4-(14-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H-isoindol-4- yl]amino}-3,6,9,12-tetraoxatetradecan-1-yl)piperazine-1-carb onyl]-1H-indol-5- yl}-3-hydroxy-2-oxopyrrolidine-3-carboxamide (47.6 mg; 0.05 mmol; 59% yield) as colourless solid. 1H NMR: 700 MHz, DMSO-d6 δ 11.61 (s, 1H), 11.10 (s, 1H), 8.70 (t, J = 6.5 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.10 – 6.98 (m, 4H), 6.79 (s, 1H), 6.71 (s, 1H), 6.59 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.9, 5.5 Hz, 1H), 4.42 (dd, J = 15.8, 6.8 Hz, 1H), 4.27 (dd, J = 15.8, 6.0 Hz, 1H), 3.92 – 3.85 (m, 2H), 3.72 (b), 3.60 (t, J = 5.5 Hz, 2H), 3.57 – 3.43 (m, 14H), 2.88 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.65 – 2.56 (m, 2H), 2.55 – 2.44 (m, 7H), 2.14 (ddd, J = 12.8, 8.3, 6.8 Hz, 1H), 2.02 (dtd, J = 13.0, 5.3, 2.4 Hz, 1H). Area: 100% LCMS: (Method 2), RT = 1.47 min, 486.9 [M+2H] ²⁺ Example 5: Functional characterization of compound B2: Analysis of degradation of MetAP2 and MetAP1 upon treatment of A549 and HT1080 cells with compound – Simple Western Blot Compounds B2, C1 and C2 (as defined herein and as synthesized in Examples 2, 3 and 4, respectively) and, for further comparison, the compounds A1, A2 and A56 of WO 2020/152067 A1 were analyzed by Simple Western for their MetAP2 degradation potential in A549 (ATCC CCL185) and HT1080 (ATCC CCL-121) cells. Similarly, compound B2 was analyzed concerning its MetAP1 degradation potential in both cell lines. The experiment was performed as follows: A549 and HT1080 cells were cultured in DMEM + 10% FBS. Cells were seeded in 6-well plates and incubated at 37°C and 10% CO2. After a 24 h or 48 h treatment with 0.1µM, 1µM, 10µM of compound or DMSO (as control), the cells were lysed using HGNT lysis buffer (20mM HEPES pH7.4, 10% (v/v) Glycerin, 150mM NaCl, 1% (v/v) Triton X-100, 2mM EDTA pH8, 25mM NaF + Protease inhibitors (Roche, 04693124001) + Phosphatase inhibitors (Roche, 04906837001). Bicinchoninic acid (Thermo Scientific, 23225) was used for protein determination. The final protein concentration for Jess loading was 0.2 mg/ml per sample. Simple Western analysis was performed on a Jess system (ProteinSimple, 004-650) using a 12-230 kDa Separation Module (ProteinSimple, SM-W004) according to the manufacturer’s instructions. Based on primary antibodies against ^-Tubulin (4µg/ml; Sigma, T6557) and MetAP2 (1µg/ml; CST, 12547) the anti-mouse NIR and the anti- rabbit detection module were used (ProteinSimple, DM-009 and DM-001). Accordingly, for the primary antibodies against ^-Tubulin (20µg/ml; Invitrogen, MA5-32514) and MetAP1 (1µg/ml; Santa Cruz, SC-514653), the anti-rabbit NIR and the anti-mouse detection module were used (ProteinSimple, DM-007 and DM-002). Data analysis was accomplished using Compass Software Version 5.0.0 (ProteinSimple). The amount of MetAP2 or MetAP1 degradation was determined by quantifying the peak area of MetAP2 or MetAP1 and normalization to the respective ^-Tubulin peak area. Subsequently, DMSO control was set to 100% MetAP2 or MetAP1 protein expression and the MetAP2 or MetAP1 expression of each treatment condition was calculated accordingly. Results were plotted in bar graphs against compound concentration using GraphPad Prism Version 8.2.1 (Fig.1 and Fig.2). Results: Treatment with the compounds A1 and A2 of WO 2020/152067 A1 led to a dose-dependent MetAP2 degradation in two cell lines, A549 and HT1080 (Fig. 1A). Compound A56 of WO 2020/152067 A1 was found to have a stronger dose-dependent effect on MetAP2 degradation in these cell lines than compounds A1 and A2 of WO 2020/152067 A1 (Fig.1B). Compound B2 of the present invention was found to have an even stronger effect on MetAP2 degradation than compound A56 of WO 2020/152067 A1 (Fig.1B). No MetAP2 degradation was seen for control compounds C1 and C2 (Fig.1C). As shown in the same two cell lines (A549 and HT1080), MetAP1 was not degraded upon treatment with compound B2 (Fig.2).

The following examples relate to medicaments: Example A: Injection vials A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient. Example B: Suppositories A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient. Example C: Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH2PO4 ∙ 2 H2O, 28.48 g of Na2HPO4 ∙ 12 H2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops. Example D: Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. Example E: Tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient. Example F: Dragees Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga- canth and dye. Example G: Capsules 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule con- tains 20 mg of the active ingredient. Example H: Ampoules A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.