Chimeric radiopharmaceuticals targeting the proton sensing receptor gpr4

Abstract

The present invention relates to a compound of formula (0-a) or a pharmaceutically acceptable salt thereof. The compounds of the invention bind to proton sensing G-protein coupled receptor type 4 (GPR4) and include a linker and a chelating agent that can comprise a radioligand. These compounds of the invention are particularly useful in imaging and in the treatment of solid tumors.

Description

[0001] Chimeric radiopharmaceuticals targeting the proton sensing receptor GPR4

[0002] Field of the invention

[0003] The present invention relates to a compound of formula (0) or a pharmaceutically acceptable salt thereof. The compounds of the invention bind to proton sensing G-protein coupled receptor type 4 (GPR4) and include a linker and a chelating agent that can comprise a radioligand. These compounds of the invention are particularly useful in imaging and in the treatment of tumors, in particular solid tumors.

[0004] Background

[0005] Radioligand therapy (RLT), i.e. , a therapy using radiopharmaceuticals, has gained significant momentum in the last few years as oncology treatment continues to become more specific and personalized. RLT delivers radiation therapy (typically emitted helium nucleus or electron particles) at the cellular level to specifically target cancer cells and the surrounding microenvironment while sparing normal cells, in contrast to traditional external beam radiation therapy (EBRT) (Jang et al. Ther Adv Med Oncol 2023, Vol. 15: 1-12). Both small molecules and antibody radionuclide conjugates have been used to target cancer cells, however, RLT is currently used in a small number of cancers including prostate and neuroendocrine tumors.

[0006] GPR4 is a GPCR on the plasma membrane that is sensitive to changing acidity changes in the extracellular environment and proliferating blood vessels of cancers (Seuwen et al. J Receptors and Signal Transduction 2006, 26:5-6, 599). Many tumors, in particular solid tumors, including Colorectal Cancers are overexpressing GPR4 and this correlates with poor prognosis of patient survival (Xue et al. Oncology Lett 2020 19: 2609). The GPR4 receptor is also expressed on the new blood vessels vascularising the tumors (Miltz Bioorganic & Medicinal Chemistry 2017, 25: 4512). Therfore a GPR4 based RLT can emit radiation along the blood vessels in the tumor microenvironment as well as from the target expressed on the cancer cells - a 2-pronged attack.

[0007] Furthermore, radiolabeled compounds targeting GPR4 are envisaged for use in diagnostic applications.

[0008] GPR4 ligands have been designed for systemic treatments in different indications and are disclosed in: US 20150216867, WO 2014049514, WO 2012131633, US 20090291942, WO 2005082905, WO 2005082904, WO 2004017995, WO 2004017994. Summary of the invention

[0009] It was therefore an object of the present invention to provide highly efficient radiotherapeutics, in particular for the treatment of cancer.

[0010] The present invention provides new GPR4 targeting radioligands, which comprise portion of the compound for binding or colocalization with GPR4, and a portion of the compound capable of bearing radioligand. Said compounds are particularly useful in the treatment or diagnosis of diseases associated with GPR4, in particular of cancers characterized by overexpression of GPR4.

[0011] The present inventors have demonstrated that exemplary compounds of formula (0) (including formula (0-a)), loaded with a radioligand (in a specific example with177Lu, as demonstrated in the Examples section) not only maintain low nanomolar affinity for the target receptor, GPR4, despite the introduction of the chelator moiety, but are capable of tumor uptake. Said colocalization of the compounds of the present invention with the GPR4- expressing tumor has been shown to be due to the interactions of the compounds with said GPR4, as demonstrated in the competition experiments. Furthermore, the compounds of formula (0) exhibit outstanding stability in plasma, which supports their use not only as radiopharmaceuticals, but - depending on the choice of the radioligand, as diagnostic agents specific for accumulation of GPR4.

[0012] The invention will be summarized in the following embodiments.

[0013] In a first embodiment, the present invention relates to a compound of formula (0) (in the following, depicted using formula (0-a)): or a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3are independently selected from C and N;

[0014] R1, R2, and R3are independently selected from H, and C1-6 alkyl;

[0015] R4is selected from H, and C1-6 alkyl;

[0016] R5is selected from H, C alkyl, and C3-6 cycloalkyl, wherein R5is optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2;

[0017] R6and R7are independently selected from -H, halogen, and C1-6 alkyl; n is 1 or 2; m is 0 or 1

[0018] Y is -CH2CH2- or -CH2O-;

[0019] L is C2-20 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1-6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH2, -(CM alkylene)-NHCO(Ci-5 alkyl), -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-S04H, -(C1-6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -0(Ci-6 alkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, - CONH2 and -COOH, preferably from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -0-, -NR’-, -CO-, Ce-w arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl;

[0020] Q is selected from a covalent bond, -CH2-, -CHOG2-, -C(=0) -, Ce- arylene, C5-10 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -0-, - CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl; and

[0021] Z is a chelator adapted to bind a radionuclide.

[0022] It is to be understood that the compound according to first embodiment of the present invention may also exists in a form of a kit of parts, comprising the compound wherein Z is a chelator adapted to bind a radionuclide, and a radionuclide. Accordingly, the compounds according to first embodiment of the invention may be obtained by contacting the parts of the kit of parts of the invention with each other, i.e., by contacting the compound wherein Z is a chelator adapted to bind a radionuclide, and a radionuclide. It will be understood that the present invention further provides a kit of parts, comprising the following parts: i. the compound of formula (0) (preferably of formula (I)) wherein Z is a chelator adapted to bind a radionuclide, and ii. a radionuclide.

[0023] In a second embodiment, the present invention relates to a pharmaceutical composition comprising the compound of formula (0) and a pharmaceutically acceptable carrier. It is to be understood that the pharmaceutical composition of the present invention may also be referred to as a radiopharmaceutical composition.

[0024] In a third embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition of the present invention for use as a medicament.

[0025] In a fourth embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention for use in the treatment of solid tumors. It is to be understood that, preferably, the solid tumor is characterized by expression (or overexpression) of GPR4.

[0026] In a fifth embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention for use in the treatment or prevention of a disease associated with, mediated by or caused by GPR4.

[0027] In a sixth embodiment, the present invention relates to use of the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention in a manufacture of a medicament, in particular for use in the treatment of solid tumors. It is to be understood that, preferably, the solid tumor is characterized by expression (or overexpression) of GPR4.

[0028] In a seventh embodiment, the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in a manufacture of a medicament for use in the treatment of the treatment or prevention of a disease associated with, mediated by or caused by GPR4.

[0029] In an eight embodiment, the present invention relates to a method of treatment of a subject suffering from a solid tumor characterized by expression (or overexpression) of GPR4, the method comprising the step of administering the compound of the present invention or the pharmaceutical (radiopharmaceutical) composition of the present invention to a subject in need thereof. It is to be understood that a therapeutically effective amount is to be administered. In a ninth embodiment, the present invention relates to a method of treatment of a subject suffering from a disease associated with or caused by GPR4, the method comprising the step of administering the compound of the present invention or the pharmaceutical composition of the present invention to a subject in need thereof.

[0030] In a tenth embodiment, the present invention relates to the compound of the present invention for use in diagnostic application.

[0031] In an eleventh embodiment, the present invention relates to the compound of the present invention for use in diagnosing a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4.

[0032] In a twelfth embodiment, the present invention relates to use of the compound of the present invention in the manufacture of a reagent for diagnosing a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4.

[0033] In a thirteenth specific embodiment, the present invention relates to a method of determining whether a subject is suffering from a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4, the method comprising the steps of (a) administering the subject with the compound of the present invention and (b) determining if the subject is suffering from a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4.

[0034] Brief description of figures

[0035] The invention is illustrated in the following Figures. These are not meant to be limiting to the scope of the invention in any way, and merely serve to illustrate the invention.

[0036] Fig. 1 presents labeling experiments: 2 A: Ratio of 1:17 with a yield of 83.84 % and low free Lu. Side products are present at a high percentage. B: Ratio of 1 :50 with yield of 79.28 % and a low free Lu. Side products are present at a high percentage. C: The 1 : 100 ratio shows low free lutetium and low presence of side products with a yield of the labelled AMX-0053 of 95.31%. D: A ratio of 1 :150 with 96.61% shows a slightly higher yield with a same profile as 1 :100.

[0037] Fig. 2 presents E: HPLC profile of AMX-0055 labelled in a ratio of 1 :100 with177Lu showing a yield of 82.89%. F: The Dimer AMX-0056 shows a yield of 84.99% when labelled at a ratio of 1 :100.

[0038] Fig. 3 presents mass spectrometry measurements of the monomer and dimers labelled with stable lutetium 175.

[0039] A The analysis shows that there is no free lutetium, and it has all bonded to AMX-0053. It shows a similar binding affinity as the radioactive isotope177Lu. B: The mass spectrum of the stable lutetium of the dimers AMX-0055 and AMX-0056also show no free lutetium. The labelling with stable lutetium was successful.

[0040] Fig. 4 presents the graph showing that AMX-0053 shows a specific binding of around 15% to the GPR4 expressing cells. The wild type cells do not show a specific binding of the AMX-0053. 1 x10-6M of AMX-0053were used for the blocking.

[0041] Fig. 5 presents IC50 measurements. Each panel shows three independent experiments. Each point of each graph is the mean value of triplicates. A: The IC50 of AMX-0053 ranges between 8 nM and 15 nM. B: The Dimer AMX-0055 shows an IC50 range of 13 nM to 14 nM. C: AMX-0056 shows the highest difference in between the single experiments ranging from 2.5 nM to nine nM. D: A comparison of all the data points of each compound showing the mean IC50 values.

[0042] Fig. 6 presents biodistribution of [177Lu]Lu-AMX-0053 in mice transplanted with HEK293 cells bearing the GRP4 receptor. [,77Lu]Lu-AMX-0053 was given alone or with an excess of unlabeled AMX-053 which competes for the GPR4 receptor. In the HEK293 tumor the uptake of [,77Lu]Lu-AMX-0053 is significantly reduced by co-administering unlabeled AMX-0053 whereas in other tissues and organs there is no reduction. This suggests that the uptake of [177Lu]Lu-AMX-0053 into the HEK293 tumor was due to binding to GPR4 receptors.

[0043] Fig. 7 presents pooled plasma stability data from 3 individual experiments. The radiolabeled compound remained stable over time up to 4 hours. After 24 hours, the amount of free177Lu-AMX-0053 was still at 60%.

[0044] Fig. 8 shows radio-HPLC chromatograms for compounds according to preparative examples 5 to 7 loaded with 177Lu. The chromatograms indicate both high loading and high purity of the obtained compounds.

[0045] Detailed description of the invention

[0046] As mentioned above, in one embodiment the present invention relates to a compound of formula (0):

[0047] or a pharmaceutically acceptable salt thereof.

[0048] In formula (0), X1, X2, X3are independently selected from C and N. Preferably, one of X1, X2, X3is N and the other two are C. More preferably, X1is N and X2and X3are C.

[0049] To this end, the skilled person immediately understands that, depending on whether particular X1, X2or X3is C or N, the valence of particular bonds in the ring system shown in formula (0), as depicted in the following: may change. For example, in a preferred embodiment wherein X1is N and X2and X3are C, said ring system will have the following structure, including valence of the bonds in the ring system: which corresponds to the following structures, wherein X1is N and X2and X3are C:

[0050] In turn, in an embodiment wherein X1and X2are C and X3is N, said ring system will have the following structure:

[0051] As mentioned before, it is preferred in formula (0) that Accordingly, the compound of formula (0) may also be depicted with formula (0-a), as shown in the following: (0-a)

[0052] It is to be understood that reference to formula (0) also specifically includes individual and specific reference to formula (0-a). In formula (0-a), X1, X2, X3, R1, R2, R3, R4, R5, R6, R7, L, Q, Z, m and n are as defined for formula (0).

[0053] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (0) is preferably a compound of formula (0-b):

[0054] (0-b)

[0055] It is to be understood that reference to formula (0) also specifically includes individual and specific reference to formula (0-b). In formula (0-b), R1, R2, R3, R4, R5, R6, R7, L, Q, Z, m and n are as defined for formula (0).

[0056] In formula (0), R1, R2, and R3are independently selected from H, and C1-6 alkyl. Preferably, R1, R2, and R3are independently C1-6 alkyl. More preferably, R1and R2are each methyl, and R3is ethyl.

[0057] In formula (0), R4is selected from H, and C1-6 alkyl. Preferably, R4is H.

[0058] In formula (0), R5is selected from H, C alkyl, and C3-6 cycloalkyl, wherein R5is optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2. Preferably, R5is H.

[0059] In formula (0), R6and R7are independently selected from -H, halogen, and C1-6 alkyl.

[0060] In formula (0), n is 1 or 2. It is preferred that n is equal to 1 . However, n can also be 2. In formula (0), m is 0 or 1. The skilled person understands that if m is 0, R7is bound to the same carbon atom to which Y is bound if m is 1. It follows that if m is 0, Ra is bound to the carbon atom which is bound to N if m is 1 . Preferably, m is 0.

[0061] In formula (0), Y is -CH2CH2- or -CH2O-. Preferably, Y is -CH2CH2-.

[0062] In formula (0), L is C2-20 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1-6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH2, -(C1-6 alkylene)-NHCO(Ci-5 alkyl), -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6 alkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH- C(=NH)NH2, -SO3H, -CONH2 and -COOH, preferably from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce-w arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0063] Preferably, L is C2-20 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1.6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkylene)- SO3H, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)- aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6alkyl), -SH, -S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and -COOH, preferably from - CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by - CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce-w arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, - CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0064] It is to be understood that L may comprise amino acid residues, forming part of the linker, for example if one -CH2- group is optionally substituted with a group selected from C1-6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-COOH, - (C1-6 alkylene)-SO4H, -(Ci -6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6 alkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, - CONH2 and -COOH.

[0065] Preferably, L is C2-20 alkylene, wherein one or more -CH2- groups may independently be replaced by one or more of -CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, - CO-O-, -CO-NR’-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, C5-11 bicyclo[n’.n”.n’”]alkylene, wherein the sum of n’, n” and n’” is at least 3 and does not exceed 9, wherein R’ is H or Ci-Ce alkyl. L may also be as defined in any one of specific embodiments of the compound of formula (0).

[0066] In formula (0), Q is selected from a covalent bond, -CH2-, -CHOG2-, -C(=O) CMO arylene, C5-10 heteroarylene, C3- 11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -O-, -CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl.

[0067] Preferably, Q is selected from a covalent bond, -CH2-, -CHOG2-, -C(=O) -, Ce arylene, C5-6 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkylene)-G1-, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH- or -CH2NH-, and wherein G2is H or C1-C4 alkyl.

[0068] More preferably, Q is selected from a covalent bond, -CH2-, -CHOH-, -C(=O), C3-11 cycloalkylene, -(4-11 membered heterocycloalkylene)-G1-, >CH-, and N, wherein G1is a covalent bond, -NH- or -CH2NH-.

[0069] Even more preferably, Q is a covalent bond.

[0070] Q may also be as in any one of specific embodiments of the compound of formula (0).

[0071] In formula (0), Z is a radionuclide moiety, or a chelator adapted to bind a radionuclide. As it is to be understood herein, the radionuclide moiety may be a chelator adapted to bind a radionuclide, with a radionuclide bound to it. The radionuclide moiety is not to be particularly limited and any moiety comprising a radionuclide is encompassed as Z in formula (0). It is to be preferably understood that Z comprises a metal chelator, also referred to as chelator, that can be charged with a radionuclide, and a radionuclide. However, the skilled person appreciates that a radionuclide may also be covalently included in said radionuclide moiety, without the need for a chelator moiety. For example, the skilled person knows compounds comprising covalently attached iodine isotope1311, as for example in m-iodobenzylguanidine, a known radiopharmaceutical.

[0072] Preferably, the chelator to be charged with the radionuclide (in other words, the chelator adapted to bind a radionuclide) is selected from 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic (DTPA), desferrioxamine (DFO) and triethylenetetramine (TETA), 1 ,4,8,11- tetraazabicyclo[6.6.2]hexadecane-4, 11 -diacetic acid (CB-TE2A); ethylenediaminetetraacetic acid (EDTA); ethylene glycolbis(2-aminoethyl)-N,N,N’,N’-tetraacetic acid (EGTA); 1 ,4, 8, 11-tetraazacyclotetradecane-1 , 4, 8, 11 -tetraacetic acid (TETA); ethylenebis-(2 hydroxy-phenylglycine) (EHPG); 5-CI-EHPG; 5BrEHPG; 5-Me-EHPG; 5t-Bu-EHPG; 5-sec-Bu-EHPG; benzodiethylenetriamine pentaacetic acid (benzo-DTPA); dibenzo-DTPA; phenyl-DTPA, diphenyl-DTPA; benzyl-DTPA; dibenzyl-DTPA; bis-2(hydroxybenzyl)-ethylene-diaminediacetic acid (HBED) and derivatives thereof; Ac-DOTA; benzo-DOTA; dibenzo-DOTA; 1 ,4,7-triazacyclononane N,N’,N”-triacetic acid(NOTA); benzo-NOTA; 1 ,4,7-triazacyclononane N,N’-diacetic acid N”-glutaminic acid(NODAGA), benzo-TETA, benzo-DOTMA, where DOTMA is 1 ,4,7,10-tetraazacyclotetradecane-1 ,4,7, 10-tetra(methyl tetraacetic acid), benzo- TETMA, where TETMA is 1 ,4,8,11-tetraazacyclotetradecane-1 ,4,8,11 -(methyl tetraacetic acid); derivatives of 1 ,3- propylenediaminetetraacetic acid (PDTA); triethylenetetraaminehexaacetic acid (TTHA); derivatives of 1 ,5,10- N,N’,N”-tris(2,3- dihydroxybenzoyl)-tricatecholate (LICAM); and 1 ,3,5-N,N’,N”-tris(2,3- dihydroxybenzoyl)aminomethylbenzene (MECAM),. As encompassed by the present invention, the payload may comprise more than one chelator. Other preferred chelators can be selected from the group consisting of cyclic DPT A (diethylene triaminepentaacetic acid ) anhydride, ethylenediaminetetraacetic acid (EDTA), DOTA (1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10- tetraacetic acid), and OTA (1 ,4,7-triazonane-l,4,7-triacetic acid). Accordingly, it is to be understood that the present invention refers to a compound of the present invention wherein Z comprises a chelator (preferably is a chelator), preferably a chelator as described herein.

[0073] The skilled person will understand that in certain cases additional chemical moiety or moieties may have to be added to the chelator in order to attach it (conjugate it) with the Q moiety. For example, certain chelator moieties include one or more -COOH group. It is conceivable to the skilled person that said -COOH group can be modified to become an amide group -CONH- for the attachment of the chelator group to the Q moiety. For example, commonly used, and hence preferred chelator DOTA can be modified in such a way:

[0074] Alternatively, the skilled person can envisage modifying a -CH2- group by the means of substitution for engineering an attachment point of the chelator for attachment with the Q moiety. An example wherein such a modification is done to a commonly used DOTA moiety is shown in the following:

[0075] It is conceivable to the skilled person that such a modification can also be done in the context of other common metal chelators, for example NOTA:

[0076] The attachment of the chelator moiety and the Q moiety may also involve a linker moiety. The skilled person is capable of selecting a suitable linker for such an attachment A suitable linker moiety is, for example, a C1-10 alkylene, wherein one or more -CH2- groups may each independently be replaced by -O-, -NR’-, -CO-, -(CH2-O- CH2)-, -(CH2-CH2-O)-, -CO-O-, or -CO-NR’-, wherein R’ is H or Ci-Ce alkyl. Preferred linkers include -COCH2NH-, i.e. C3 alkylene wherein one -CH2- group is replaced with a -CO- moiety, thus being attached to Q, and one -CH2- group is replaced with -NH- moiety, thus being attached to the metal chelator (for example through an amide bond, as discussed hereinabove). It is further preferred that said linker includes not more than 12 non-hydrogen atoms, preferably not more than 8 non-hydrogen atoms.

[0077] Any radionuclide can be used in Z in formula (0).

[0078] The radionuclide present in Z is preferably selected from225Ac,213Bi,67Cu, "Y,1111n,131l,161Tb,169Er, and177Lu. An especially preferred radionuclide for use in the present invention is177Lu or225Ac. Alternatively, the radionuclide can be selected from the group consisting of161Tb and213Bi. Further suitable radionuclides include those emitting 0+(62QUI64QUJ68Gai76Br,82Rb,124l,44Sc,43Sc,89Sr or any other 0+emitting isotope), 0 (e.g. "Y,177Lu,161Tb, “Cu,67Cu,47Sc or any other 0 emitting isotope), a (225Ac,213Bi,211At,223 / 25Ra,212Pb or any other a emitting isotope), or Auger electron emitter (161Tb,169Er,111ln or any other Auger electron emitting isotope), or any combination of therapeutic applicable radio-emissions.

[0079] As further encompassed by the present invention, the radionuclide used in Z can be radioisotope or radionuclide useful in a diagnostic application, such as, but not limited to,18F,43Sc,44Sc,61Cu, “Cu, ^Ga,89Zr,1111n,123l,153Tb,155Tb (preferably43Sc,44Sc,61Cu, “Cu, ^Ga,89Zr,111ln,153Tb,155Tb). The radionuclide used in Z can also be a radionuclide applicable therapeutically, for example selected from, but not limited to47Sc,67Cu,89Sr, "Y,131l,149Tb,153Sm,161Tb,177Lu,223Ra and225Ac.

[0080] Particularly preferred radionuclide used in Z is177Lu.

[0081] In the present invention, Z may be a chelator adapted to bind a radionuclide. Accordingly, the present invention also encompasses the compound of formula (0) not charged with radionuclide, which can be charged with radionuclide upon contacting said compound of formula (0) wherein Z is a chelator adapted to bind a radionuclide, with said radionuclide. Such an operation is well known to the skilled person. It is preferred that, if Z is a chelator adapted to bind a radionuclide, then the radionuclide is not F or I isotope. Accordingly, it is apparent to the skilled person that such radionuclides as for example F or I isotopes are preferably covalently incorporated into Z.

[0082] The present invention further specifically refers to a compound wherein Z comprises a radionuclide, as described herein.

[0083] In a particularly preferred embodiment of the present invention, Z is according to formula: wherein preferably Z further comprises a radionuclide, as referred to herein.

[0084] In the following, specific embodiments of the compound of formula (0) are discussed. While the compound of formula (0) is to be defined using the variables (including variable substituents) X1, X2, X3, R1, R2, R3, R4, R5, R6R7, n, m, Y, L and Q, the specific embodiments discussed in the following may stay silent about some of these variables. In such case, it is to be understood that said specific embodiments include the definition of any of not discussed variables as in formula (0), including any preferred definition of said variable or any definition of said variable which is discussed in any of the following specific embodiments.

[0085] In a first specific embodiment of the compound of formula (0), X2is N and X1and X3are C.

[0086] In a second specific embodiment, X3is N and X1and X2are C.

[0087] In a third specific embodiment, wherein Q is C3-11 cycloalkylene or -(4-11 membered heterocycloalkyl)— G1—, Q is preferably selected from: fragment a fragment b fragment c fragment d fragment e fragment f fragment g fragment h fragment i fragment j fragment k fragment I fragment m fragment n fragment 0 fragment p fragment q wherein for each fragment independently,

[0088] X4 is selected from -CH2-, -0-, -SO-, and -SO2-, preferably from -CH2-, and -O-;

[0089] X5 is selected from -CH2-, -O-, -SO-, -SO2-, preferably from -CH2-, -O-, and -SO2-; X6is selected from C, and N; n1is selected from 0, 1, 2, and 3; n2is selected from 1, 2, 3, 4, and 5; n3is selected from 1, 2, 3, 4, and 5, preferably from 1, 2, 3, and 4; n5is selected from 0, 1 , and 2; n4is selected from 1 , and 2; n6and n7are independently selected from 1 , 2, and 3; n8is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, preferably selected from 0, 1, 2, and 3; with the proviso that the total number of ring atoms of each fragment a-q does not exceed 11. In a fourth specific embodiment of the compound of formula (0), n is 1 and Q is C3-11 cycloalkylene or -(4-11 membered heterocycloalkylene)-G1-. In this specific embodiment, Q is preferably selected from:

[0090] I a fifth specific embodiment of the compound of formula (0), n is 2 and Q is selected from Ce arylene, C5-6 heteroarylene, C3-11 cycloalkylene, 4-11 membered heterocycloalkylene, >CH-, >N-, and -C(=O)N<, wherein G2is H or C1-C4 alkyl. Preferably, in this specific embodiment, Q is selected from Ce arylene, >CH-, >N-, and -C(=O)N<.

[0091] In a sixth specific embodiment of the compound of formula (0), L is a C2-20 alkyl, wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO- O-, -CO-NR’-, or any one of the following fragments a, g, r, s fragment a fragment r fragment s fragment g wherein for each fragment independently and for each occurrence of each fragment independently,

[0092] X6, X7are independently selected from C and N;

[0093] X8is selected from C, and -0- with the proviso that two of X6, X7, X8are C; n1is selected from 0, 1 , 2, and 3; n2is selected from 1 , 2, 3, 4, and 5; n3is selected from 1 , 2, 3, 4, and 5, preferably from 1 , 2, 3, and 4; n5is selected from 0, 1 , and 2; with the proviso that the sum of n1, n2and n3does not exceed 9 and wherein R’ is H or Ci-Ce alkyl.

[0094] In a seventh specific embodiment of the compound of formula (0), L is a C2-10 alkyl, wherein one or more -degroups may each independently be replaced by -CH=CH-, -O-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -NR’-, -CO-, -CO- O-, -CO-NR’-, or any one of the following

[0095] In an eighth specific embodiment of the compound of formula (0), L is -La-Lb-

[0096] In this eighth specific embodiment of the compound of formula (0), Lais C a alkylene, which is optionally substituted with one or more optional substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by a group selected from -CH=CH-,-CHC-, -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, and 5-6 membered heterocycloalkylene, wherein R’ is H or C1-6 alkyl.

[0097] Preferably, Lais C1.7 alkylene, wherein one or more -CH2- groups may each independently be replaced by a group selected from -CH=CH-,-CHC-, -O-, -NR’-, -CO-, phenylene, 5-6 membered heteroarylene, and 5-6 membered heterocycloalkylene, wherein R’ is H or C1-6 alkyl;

[0098] In this eighth specific embodiment of the compound of formula (0), Lbis C1-12 alkylene, which is optionally substituted with one or more optional substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(O-CH2-CH2)- , -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0099] Preferably, Lbis C1-7 alkylene, wherein one or more -CH2- groups may each independently be replaced by a group selected from -CH=CH-, -CEC-, -O-,-NR’-, -CO-, -(CH2-O-CH2)-, -(O-CH2-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’- , C3-C11 cycloalkylene, and 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl

[0100] It is understood that Lbis attached to Q. Consequently, Lais not directly attached to Q. As an example, in formula 0, Lais attached to the carbon atom that is directly adjacent to the carbon atom substituted with R7, and Lbis attached to Q. In a ninth specific embodiment of the compound of formula (0), L is a moiety according to the formula:

[0101] In this ninth specific embodiment, it is to be understood that Lcis bound to Q.

[0102] In this ninth specific embodiment, the bond indicated with a dashed line is to be understood as a single bond or a double bond, preferably wherein the double bond has a trans configuration. Preferably, the dashed bond is a double bond. More preferably, the dashed bond is a double bond in trans configuration.

[0103] In this ninth specific embodiment, Lcis C2-18 alkyl, which is optionally substituted with one or more optional substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -O-, -NR’-, -CO-, CMO arylene, 5-6 membered heteroarylene, - (CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl;

[0104] Preferably, Lcis a C2-18 alkyl, wherein one or more -CH2- groups may each independently be replaced by a group selected from -CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2- CH2-O)-, -CO-O-, -CO-NR’-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and C5-11 bicyclo[n’.n”.n’”]alkylene, wherein the sum of n’, n” and n’” is at least 3 and does not exceed 9, wherein R’ is H or Ci-Ce alkyl.

[0105] In one particular embodiment of the ninth embodiment of the compound of formula (0), Lcis a C2-18 alkyl, wherein one or more CH2groups may each independently be replaced by a group selected from -CH=CH-, -C=C-, -O-, - NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, or any one of the following fragments a, g, r, s fragment a fragment r fragment s fragment g wherein for each fragment independently and for each occurrence of each fragment independently,

[0106] X6, X7are independently selected from C and N;

[0107] X8is selected from C, and -0- with the proviso that two of X6, X7, X8are C; n1is selected from 0, 1 , 2, and 3; n2is selected from 1 , 2, 3, 4, and 5; n3is selected from 1 , 2, 3, 4, and 5, preferably from 1 , 2, 3, and 4; n5is selected from 0, 1 , and 2; with the proviso that the sum of n1, n2and n3does not exceed 9 and wherein R’ is H or Ci-Ce alkyl.

[0108] In an alternative specific embodiment of the ninth embodiment of the compound of formula (0), Lcis a C2-10 alkyl, wherein one or more CH2groups may each independently be replaced by -CH=CH-, -O-, -(CH2-O-CH2)-, -(CH2- CH2-O)-, -NR’-, -CO-, -CO-O-, -CO-NR’-, or any one of the following wherein R’ is H or Ci-Ce alkyl.

[0109] In a tenth specific embodiment of the compound of formula (0), L is a moiety according to the formula:

[0110] In this tenth specific embodiment, it is to be understood that Lcis bound to Q.

[0111] In this tenth specific embodiment of the compound of formula (0), Lcis as defined for the ninth specific embodiment of the compound of formula (0), as defined hereinabove.

[0112] In this tenth specific embodiment of the compound of formula (0), X6, X7are independently selected from C and N, and X8is selected from C, and -O- with the proviso that two of X6, X7, X8are C.

[0113] Preferably, X6, X7are C. Thus preferably, X6, X7are C and X8is -O-.

[0114] However, in an alternative specific embodiment of the tenth specific embodiment of the compound of formula (0) one of X6, X7is C and the other of X6, X7is N. Preferably, in this specific embodiment of the compound of formula III, IV or V, one of X6, X7is C and the other of X6, X7is N, and X8is C.

[0115] In an eleventh specific embodiment of the compound of formula (0), L is a moiety according to the formula:

[0116] In this eleventh specific embodiment of the compound of formula (0), it is to be understood that Lcis bound to Q.

[0117] In this eleventh specific embodiment of the compound of formula (0), Lcis as defined for the ninth specific embodiment of the compound of formula (0), as defined hereinabove.

[0118] In this eleventh specific embodiment of the compound of formula (0), X9is selected from -O-, and -NR’-, wherein R’ is H or Ci-Ce alkyl. Preferably, X9is O. However, in one specific embodiment of the eleventh embodiment of the compound of formula (0), X9is NR’ wherein R’ is H or Ci-Ce alkyl.

[0119] In a twelfth specific embodiment, L is a moiety according to formula:

[0120] In this twelfth specific embodiment, the bond indicated with a dashed line is to be understood as a single bond or a double bond, preferably wherein the double bond has a trans configuration. Preferably, the dashed bond is a double bond. More preferably, the dashed bond is a double bond in trans configuration.

[0121] In this twelfth specific embodiment of the compound of formula (0), it is to be understood that Leis bound to Q.

[0122] In this twelfth specific embodiment of the compound of formula (0), Ldis a covalent bond, C alkylene, -C=O-, - G2-(5-6 membered heterocycloalkylene)- or Ce arylene, wherein G2is a covalent bond, CH2, CH2NH or CH2O.

[0123] Preferably, Ldis a covalent bond, C alkylene, -C(=O)- ,— G2— (piperidinylene)— , -G2-(piperazinylene)- or phenylene, wherein G2is a covalent bond, -CH2-, -CH2NH- or -CH2O-.

[0124] More preferably, Ldis a covalent bond, CM alkylene, —G2— (piperidinylene)— , -G2-(piperazinylene)- or phenylene, wherein G2is a covalent bond or -CH2-.

[0125] Even more preferably, Ldis a covalent bond, piperidinylene, -CH2-(piperazinylene)- or phenylene.

[0126] In this twelfth specific embodiment of the compound of formula (0), Leis a covalent bond or C 2 alkylene, which is optionally substituted with one or more optional substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -CHC-, -0-, -NR’-, -CO-, C&. 10 arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0127] Preferably, Leis a covalent bond or C1-12 alkylene, wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, -0-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2- CH2-O)-, -C0-0-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci- Ce alkyl.

[0128] More preferably, Leis a covalent bond or C1-10 alkylene, wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -CEC-, -0-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, or -CO-NR’-, wherein R’ is H or Ci-Ce alkyl, and wherein one -CH2- group may be replaced by C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene.

[0129] Even more preferably Leis a covalent bond or C1-10 alkylene, wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -CEC-, -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO- NR’-, or C3-8 cycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0130] Still more preferably, Leis a covalent bond or C1-10 alkylene, wherein one or more CH2 groups may each independently be replaced by -CH=CH-, -CEC-, -0-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, -CO- NR’-, or bicyclo[1.1 .1 ]pentyl, wherein R’ is H or Ci-Ce alkyl.

[0131] Again more preferably, Leis preferably a covalent bond or C1-10 alkylene, wherein one or more -CH2- groups may each independently be replaced by -0-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, -CO-NR’-, or bicyclo[1.1.1]pentyl, wherein R’ is H or Ci-Ce alkyl.

[0132] In a thirteenth specific embodiment of the compound of formula (0), L is a moiety according to the formula:

[0133] In this thirteenth specific embodiment of the compound of formula (0), it is to be understood that Leis bound to Q.

[0134] In this thirteenth specific embodiment of the compound of formula (0), Ldand Leare defined as in twelfth specific embodiment of the compound of formula (0), hereinabove. In this thirteenth specific embodiment of the compound of formula (0), X6, X7are independently selected from C and N, and X8is selected from C, and -0- with the proviso that two of X6, X7, X8are C.

[0135] Preferably, X6, X7are C. Thus preferably, X6, X7are C and X8is -0-.

[0136] However, in an alternative specific embodiment of the thirteenth specific embodiment of the compound of formula (0) one of X6, X7is C and the other of X6, X7is N. Preferably, in this specific embodiment of the compound of formula III, IV or V, one of X6, X7is C and the other of X6, X7is N, and X8is C.

[0137] In a fourteenth specific embodiment of the compound of formula (0), L is a moiety according to formula:

[0138] |— X9— Ld— Le— |

[0139] In this fourteenth specific embodiment of the compound of formula (0), it is to be understood that Leis bound to Q.

[0140] In this fourteenth specific embodiment of the compound of formula (0), Ldand Leare defined as in twelfth specific embodiment of the compound of formula (0), hereinabove.

[0141] In this fourteenth specific embodiment of the compound of formula (0), X9is selected from -O-, and -NR’-, wherein R’ is H or Ci-Ce alkyl. Preferably, X9is O. However, in one specific embodiment of the eleventh embodiment of the compound of formula (0), X9is NR’ wherein R’ is H or Ci-Ce alkyl.

[0142] A fifteenth, sixteenth and seventeenth specific embodiment of the compound of formula (0) are each defined as in twelfth, thirteenth or fourteenth specific embodiment of the compound of formula (0), respectively, wherein Leis a covalent bond or a group of formula (i), (ii), (iii), (iv) or (v): wherein:

[0143] Y1, Y2, Y3, Y4, Y5are each independently C1-10 alkylene, wherein one or more -CH2- groups may independently of each other be replaced by -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2- O)-,-(O-CH2-CH2)-, -CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl; p, q are independently of each other 0, 1 , 2.

[0144] Preferably, Y1, Y2, Y3are each independently C a alkylene, wherein one or more -CH2- groups may independently of each other be replaced by -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-,-(O-CH2-CH2)-, -CO-O-, -CO-NR’-, or bicyclo[1.1.1]pentyl, wherein R’ is H or Ci-Ce alkyl. Preferably, Y4, Y5are independently C1-10 alkylene, wherein one or more -CH2- groups may independently of each other be replaced by -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2- CH2-O)-,-(O-CH2-CH2)-, -CO-O-, -CO-NR’-, or bicyclo[1.1.1 ]pentyl, wherein R’ is H or Ci-Ce alkyl.

[0145] In an eighteenth specific embodiment of the compound of formula (0), L is a moiety according to formula: wherein Lfis C1-12 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1.6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkylene)- SO3H, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)- aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6alkyl), -SH, -S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and -COOH, preferably from - CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by - CH=CH-, -C=C-, -O-, -NR’-, -CO-, Co-io arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, - CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl. It is to be understood that Lfis connected to Q.

[0146] In a nineteenth specific embodiment of the compound of formula (0), L is a moiety according to formula: wherein Lfis according to formula -CO-NH-CH(Rf)-CO-NH-CH2-(CH2CH2-O)f-CH2CH2CH2- wherein f is 2, 3, or 4, preferably wherein f is 3 and wherein Rfis selected from H, C1-6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH2, - (C1-6 alkylene)-NHCO(Ci-5 alkyl), -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, - O(Ci-6alkyl), -SH, -S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and -COOH. Particularly preferred Rfinclude -CH2OH and -CH2NHCOCH3. It is to be understood that Lfis connected to Q, preferably through -CH2- group of Lf.

[0147] In a twentieth specific embodiment of the compound of formula (0), L is a moiety according to formula: wherein Lfis according to formula -CO-NH-(heterocycloalkylene)-CO-NH-CH2-(CH2CH2-O)f-CH2CH2CH2- wherein f is 2, 3, or 4, preferably wherein f is 3. Particularly preferred heterocycloalkylene is 3,3-oxetanylene. It is to be understood that Lfis connected to Q, preferably through -CH2- group of Lf.

[0148] In a twenty-first specific embodiment of the compound of formula (0), L is a moiety according to formula: wherein Lfis according to formula -CO-(heterocycloalkylene)-CO-NH-CH2-(CH2CH2-O)t-CH2CH2CH2- wherein f is

[0149] 2, 3, or 4, preferably wherein f is 3. Particularly preferred heterocycloalkylene is selected from and wherein the N atom is connected to CO moiety on the left side of the foregoing formula. Preferably, heterocycloalkylene wherein the N atom is connected to CO moiety on the left side of the foregoing formula. It is to be understood that Lfis connected to Q, preferably through -CH2- group of Lf.

[0150] In a twenty second specific embodiment of the compound of formula (0), L is a moiety according to formula: wherein Lffis according to formula -NH-CO-CHRff-NH-CO-(CH2CH2-O)ff-CH2CH2-NH-CO-CHRff- wherein ff is 1 , 2, or 3, preferably wherein ff is 2, and wherein each Rffis independently selected from H, C1-6 alkyl, -(C1-6 alkylene)- OH, -(C1-6 alkylene)-NH2, -(C1-6 alkylene)-NHCO(Ci-5 alkyl), -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6alkyl), -SH, -S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and -COOH. Particularly preferred Rffinclude H and -CH2OH and -CH2NHCOCH3. It is to be understood that Lffis connected to Q, preferably through -CHRff- group of Lff.

[0151] Preferably, m = 0 and the compound of formula (0) is preferably a compound of formula (I): or a pharmaceutically acceptable salt thereof. X1, X2, X3, R1, R2, R3, R4, R7, n, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove.

[0152] As discussed in the foregoing, the compound of formula (I), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (l-a):

[0153] (l-a)

[0154] In formula (l-a), X1, X2, X3, R1, R2, R3, R4, R7, n, L, Q and Z are as defined for the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (I) also specifically includes individual and specific reference to formula (l-a).

[0155] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (I) is preferably a compound of formula (l-b):

[0156] If n is 1 , then the compound of formula (I) is a compound of formula (la):

[0157] or a pharmaceutically acceptable salt thereof. X1, X2, X3, R1, R2, R3, R4, R7, n, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove.

[0158] As discussed in the foregoing, the compound of formula (la), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (la-a):

[0159] (la-a)

[0160] In formula (la-a), X1, X2, X3, R1, R2, R3, R4, R7, L, Q and Z are as defined for the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (la) also specifically includes individual and specific reference to formula (la-a).

[0161] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (la) is preferably a compound of formula (la-b):

[0162]

[0163] (la-b)

[0164] In formula (la-b), R1, R2, R3, R4, R7, L, Q and Z are as defined for the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (la) also specifically includes individual and specific reference to formula (la-b).

[0165] If n is 2, then the compound of formula (I) is a compound of formula (lb): or a pharmaceutically acceptable salt thereof. Each X1, X2, X3, R1, R2, R3, R4, R7, n, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. As discussed in the foregoing, the compound of formula (lb), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (Ib-a):

[0166]

[0167] (Ib-a)

[0168] In formula (Ib-a), each X1, X2, X3, R1, R2, R3, R4, R7, L, Q and Z are as defined for the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (lb) also specifically includes individual and specific reference to formula (Ib-a).

[0169] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (lb) is preferably a compound of formula (Ib-b):

[0170] (Ib-b)

[0171] In formula (Ib-b), each X1, X2, X3, R1, R2, R3, R4, R7, L, Q and Z are as defined for the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (lb) also specifically includes individual and specific reference to formula (Ib-b). Alternatively, m can also be equal to 1 and the compound of formula (0) can also be a compound of formula (II): or a pharmaceutically acceptable salt thereof. X1, X2, X3, R1, R2, R3, R4, R5, R6R7, n, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove.

[0172] As discussed in the foregoing, the compound of formula (II), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (ll-a): In formula (ll-a), X1, X2, X3, R1, R2, R3, R4, R5, R6R7, n, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (II) also specifically includes individual and specific reference to formula (ll-a). As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (II) is preferably a compound of formula (ll-b):

[0173] (ll-b)

[0174] In formula (ll-b), R1, R2, R3, R4, R5, R6R7, n, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (II) also specifically includes individual and specific reference to formula (ll-b).

[0175] If n is 1 , then the compound of formula (II) is a compound of formula (Ila): or a pharmaceutically acceptable salt thereof. X1, X2, X3, R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. As discussed in the foregoing, the compound of formula (Ila), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (lla-a):

[0176] In formula (lla-a), X1, X2, X3, R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (Ila) also specifically includes individual and specific reference to formula (lla-a).

[0177] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (Ila) is preferably a compound of formula (lla-b):

[0178] (lla-b) In formula (lla-b), R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (Ila) also specifically includes individual and specific reference to formula (lla-b).

[0179] If n is 2, then the compound of formula (II) is a compound of formula (lib): or a pharmaceutically acceptable salt thereof. Each X1, X2, X3, R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove.

[0180] As discussed in the foregoing, the compound of formula (lib), depending on specific X1, X2, and X3, may also be depicted as a compound of formula (llb-a):

[0181] (llb-a)

[0182] In formula (lla-a), X1, X2, X3, R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (lib) also specifically includes individual and specific reference to formula (llb-a).

[0183] As mentioned before, preferably, X1is N and X2and X3are C. Thus, preferably, the compound of formula (Ila) is preferably a compound of formula (llb-b):

[0184] (llb-b)

[0185] In formula (llb-b), R1, R2, R3, R4, R5, R6R7, Y, L, Q and Z are as defined in the compound of formula (0) or any of its specific embodiments, as discussed hereinabove. Any reference to formula (lib) also specifically includes individual and specific reference to formula (llb-b).

[0186] It is to be preferably understood that, unless indicated to the contrary, any reference to formula (0) includes an individual and specific reference to each of formulae (0-a), (0-b), (I), (l-a), (l-b), (la), (la-a), (la-b), (lb), (Ib-a), (Ib-b), (II), (ll-a), (ll-b), (Ila), (lla-a), (lla-b), (lib), (llb-a), and (llb-b).

[0187] Particularly preferred compounds of formula (0) are selected from (E)-2,2’,2”-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- y I) methyl) b icyclo[1 .1.1 ]pentan-1 -yl)-1 , 17-d ioxo-6 , 9 , 12-trioxa-2, 16-diazaoctadecan-18-yl)- 1 ,4,7, 10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0188] (E)-2,2’,2”-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1 ,30-dioxo-5,8,11 ,14,17,20,23,26-octaoxa-2,29-diazahentriacontan-31-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0189] 2,2’,2”-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan- 16-yl)-1 ,18,21-trioxo-5,8,11 ,14-tetraoxa-2,17,20-triazadocosan-22-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7- triyl)triacetic acid; and 2,2’,2”-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan-

[0190] 16-yl)- 1 , 18-dioxo-5,8, 11 ,14-tetraoxa-2, 17-diazanonadecan-19-y I)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7- triyl)triacetic acid or their pharmaceutically acceptable salts. It is to be understood that the present invention encompasses both forms of these compounds that are free of radionuclide, as well as radionuclide of any of these compounds, or their salts, as demonstrated in the preparative examples 1 to 4.

[0191] Further particularly preferred compounds of formula (0) are selected from (S,E)-2,2',2"-(10-(4-(2-carboxyethyl)-18-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)amino)-2,5, 15,18-tetraoxo-9, 12-dioxa- 3,6,16-triazaoctadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0192] (S,E)-2,2',2"-(10-(19-carboxy-17-((3-((4-(3-(4-((2-ethy l-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)carbamoyl)-2,5, 15-trioxo-9, 12-d ioxa-3 , 6 , 16- triazanonadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; and

[0193] (4S, 17S)-4-((3-((4-((E)-3-(4-((2-ethy I-5 , 7-d imethy I py razolo[1 ,5-a] pyri mid in-3-y I) methyl ) pheny l)al ly I) pi perazi n- 1 - yl)methyl)bicyclo[1 .1.1]pentan-1-yl)carbamoyl)-6,16-dioxo-17-(2-(4,7,10-tris(carboxymethyl)-1 ,4,7,10- tetraazacyclododecan-1 -yl)acetamido)-9, 12-dioxa-5, 15-diazaicosanedioic acid or their pharmaceutically acceptable salts. It is to be understood that the present invention encompasses both forms of these compounds that are free of radionuclide, as well as radionuclide of any of these compounds, or their salts, as demonstrated in the preparative examples 5 to 7.

[0194] Further particularly preferred compounds of formula (0) are selected from (S,E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(hydroxymethyl)-1 ,4,20-trioxo-9,12,15-trioxa-2,5,19-triazahenicosan-21-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0195] (E)-2,2',2"-(10-(1-(3-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin- 1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamido)oxetan-3-yl)-1 ,17-dioxo-6,9,12-trioxa-2,16-diazaoctadecan-18- yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0196] 2,2',2"-(10-(1-((2S)-1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1 ,1]pentane-1-carbonyl)octahydro-1H-indol-2-yl)-1 ,17-dioxo- 6,9, 12-trioxa-2, 16-diazaoctadecan-18-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; and (S,E)-2,2',2"-(10-(19-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-

[0197] 1 -yl)methy l)b icyclo[ 1 .1.1 ]pentane-1 -carboxamido)-2, 18 ,22-trioxo-7, 10,13-trioxa-3, 17,21 -triazatricosyl)- 1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid or their pharmaceutically acceptable salts. It is to be understood that the present invention encompasses both forms of these compounds that are free of radionuclide, as well as radionuclide of any of these compounds, or their salts, as demonstrated in the preparative examples 8 to 11 . The compounds of the present invention are obtainable according to the methods demonstrated in the preparative examples, or per analogy to these methods. Skilled person is capable of obtaining the compounds according to the present invention by relying on the methods disclosed herein or per analogy to said methods.

[0198] The following definitions apply throughout the present description, unless explicitly indicated to the contrary.

[0199] It is understood that “independently of each other” means that when a group is occurring more than one time in any compound, its definition on each occurrence is independent from any other occurrence.

[0200] It is further understood that a dashed line or a wave being transverse to a bond or a solid line without attachment, such as - C alkyl, depicts the site of attachment of a residue (i.e. a partial formula). A dashed line that runs parallel to a bond is understood as an optional double bond instead of a single bond.

[0201] It is further understood that the abbreviations “C” and “N” are representative for all possible degrees of saturation, which typically do not result in radicals, nitrenes or carbenes, i.e. N includes -NH-, -N= and , C includes - =c /

[0202] CH2-, =CH- and \ . In addition, “C” as an atom in an aromatic or heteroaromatic ring which has a substituent Rxat any suitable position, includes =CH- as well as =CRX-. In addition, "C” as an atom in an aromatic or =c / heteroaromatic ring which does not have substituents Rxat any suitable position, includes =CH- and \ , as the case may be. It is understood and known to the skilled person that the general rules of valency must be abided by.

[0203] As referred to herein, >N- is to be understood as referring to . Similar provision applies to >CH-, which is to

[0204] CH be understood as a moiety of formula / \.

[0205] As further understood herein, a moiety of formula -C(=O)N< is to be understood as a moiety of formula

[0206] The term “saturated” in reference to ring systems refers to a ring having no double or triple bonds. The term “partially unsaturated” in reference to ring systems refers to a ring that includes at least one double or triple bond but does not include aromatic systems.

[0207] It is understood that whenever, in any formula, more than one -CH2- group of a straight-chain or branched alkyl chain, e.g. straight-chain or branched C2-25 alkylene, is replaced by a heteroatom or a heteroatom-containing 31 groups, the two or more -CH2- groups are replaced such that directly adjacent heteroatoms, e.g. -0-0- or -NH-NH-, are avoided. In particular, the two or more -CH2- groups shall be replaced such that the alkyl chain does not contain peroxide groups.

[0208] The term "aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl,9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0209] The term “arylene” refers to an aryl group, as defined herein above, but having two or three points of attachment, preferably two points of attachment i.e. a divalent or trivalent aromatic hydrocarbon ring group, preferably a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 ,3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5- diyl, naphthalen-1 , 6-diyl, naphthalen-1 , 7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2,7-diyl, or naphthalen-2,8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene,9H-fluorenylene, or azulenylene. Unless defined otherwise, an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen-1 ,4-diyl).

[0210] The arylene, as defined herein, may be a bivalent group, for example: trivalent group, for example:

[0211] The term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,

[0212] 1 .2.4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl,

[0213] 1 .2.5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3- yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H- 1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5- triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzod ioxolyl , benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl.

[0214] The term “5-6 membered heteroaryl” refers to a ring system in form of monocycles having 5, or 6 ring atoms selected from C, N, S and 0, provided that at least one atom is N, S or 0, with the number of N atoms being 0, 1 , 2 or 3, and the number of 0 atoms each being 0, 1 or 2 and the number of S atoms being 0 or 1 . In some embodiments a 5-6 membered heteroaryl refers to a ring system having 5 or 6, e.g.5 ring atoms selected from C, N,S and 0, with the number of N atoms being 1 , 2, such as 2 and the number of 0 atoms being 1 , 2, such as 1 .In some embodiments, examples of “5-6 membered heteroaryl” include furyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, oxazolinyl, isoxazolinyl, thiazolyl and the like. In some embodiments, examples of “5-6 membered heteroaryl” include 5-membered heteroaryl, such as oxadiazolyl, triazolyl, oxazolyl, thiazolyl. The term “5-10 membered heteroaryl” refers to a ring system (monocyclic ring or fused ring system) which may have 5, 6, 7, 8, 9 or 10 ring atoms selected from C, N, and 0, with the number of N atoms being e.g. 0, 1 , 2 or 3, and the number of 0 atoms each being 0, 1 or 2. The term "heteroarylene” refers to a heteroaryl group with 2 or 3 points of attachment, preferably with 2 points of attachment. Thus, heteroarylene may bea divalent aromatic ring group (a monocyclic ring or a fused ring system), for example:

[0215] “Heteroarylene” may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5- diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, -carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g., 1 ,2,4-oxadiazol-3,5-diyl, 1 ,2,5-oxadiazol-3,4-diyl, or 1 ,3,4-oxadiazol-2,5- diyl), thiadiazolylene (e.g., 1 ,2,4-thiadiazol-3,5-diyl, 1 ,2,5-thiadiazol-3,4-diyl, or 1 ,3,4-thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidinylene, 1 ,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1 ,2,3-triazolylene, 2H-1 ,2, 3-triazolylene, 1 H-1 ,2,4-triazolylene, or 4H-1 ,2,4- triazolylene), benzotriazolylene, 1 H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1 ,2,3-triazinylene, 1 ,2,4- triazinylene, or 1 ,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3- c]pyridinylene or 1 ,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4, 5,6,7- tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene, 1 ,3-benzodioxolylene, benzodioxanylene (e.g., 1 ,3-benzodioxanylene or 1 ,4-benzodioxanylene), or coumarinylene.

[0216] Heteroarylene may also be a trivalent aromatic ring group (a monocyclic ring or a fused ring system), for example:

[0217] It is understood and known to the skilled person that the exact position of the double bond(s) in a partially or fully aromatic heteroaryl are positioned such that the rules of valency are fulfilled. The term "cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl.

[0218] The term “C3.11 cycloalkyl”refers to saturated or partially unsaturated alkyl ring systems containing 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms and comprises monocycles, fused bicycles, bridged bicycles or spirobicycles.Examples of “C3-11 cycloalkyl” include monocycles, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; bridged bicycles, such as bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.1]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane; fused bicycles, such asbicyclo[2.1.0]pentane, bicyclo[2.2.0]hexane, bicyclo[3.1.0]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[4.2.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, spirocycles, such as spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.4]octane, spiro[4.4]nonane, spiro[3.5]nonane, spiro[4.5]decane, spiro[5.5]undecane.

[0219] The C3-11 cycloalkyl group can bea monocycle, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The C3-11 cycloalkyl group can be a bridged bicycle, such as bicyclo[1.1.1 ]pentane, bicyclo[2.2.2]octane.

[0220] The term “cycloalkylene” refers to a cycloalkyl group, as defined herein above, but having two or three, preferably two points of attachment, i.e. a divalent or trivalent, preferably a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkylene” may, e.g., refer to cyclopropylene (e.g., cyclopropan-1, 1-diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1 ,1-diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan- 1 , 1-diyl, cyclopentan-1 ,2-diyl, or cyclopentan-1 ,3-diyl), cyclohexylene (e.g., cyclohexan-1 , 1-diyl, cyclohexan-1 ,2-diyl, cyclohexan-1 ,3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene.

[0221] A “Cs-ncycloalkylene” group may have 2 or 3 points of attachment. A point of attachment is an atom which forms a covalent bond with another atom to which the group is attached. The two or three points of attachment may be located at the same or different atoms. In the case of three points of attachment, all three or only two points of attachment may be located at the same atom.

[0222] Accordingly, the term “C3.11 cycloalkyl” refers to a group which has two points of attachment, such as a bicyclo[1.1.1]pentane ring which is connected to two other groups via its bridgehead carbon atoms. In some embodiments, the term “C3-11 cycloalkyl” refers to a group which has three points of attachment, for example: Spirocycles:

[0223] 5 Fused bicycles:

[0224]

[0225] The term "heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e. , to form an oxo group). “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1-dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yL The term “4-11 membered heterocycloal kyl” refers to non-aromatic, i.e. saturated or partially unsaturated ring systems, such as monocycles, fused bicycles, bridged bicycles or spirobicycles, having 4, 5, 6, 7, 8, 9, 10 or 11 ring atoms, which ring atoms areselected from C, N, S and 0, provided that at least one atom is N, S or 0, the number of N atoms being 0, 1 , or 2, the number of S atoms being 0, 1 , or 2 and the number of 0 atoms being 0, 1 , or 2. Examples of 4-11 membered heterocycloalkyl groups include monocycles, such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, 1 ,3- dithianyl, piperazinyl, piperidinyl, morpholinyl.

[0226] The term "5-6 membered heterocycloalkyl” refers to non-aromatic, i.e. saturated or partially unsaturated monocyclic ring systems having 5 or 6 ring atoms, which ring atoms are selected from C, N,S and 0, provided that at least one atom is N, S or 0, the number of N atoms being 0, 1 , or 2 and the number of 0 atoms being 0, 1 , or 2 and the number of S atoms being 0 or 1. Examples of 5-6 membered heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, 1 ,4- oxathianyl 1 ,4-dithianyl, 1 ,3-dioxane, 1 ,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, and the like. In some embodiments the 5-6 membered heterocycloalkyl group is a 6-membered heterocycloalkyl group, such as piperazinyl or piperidinyl.

[0227] The term “heterocycloalkylene” refers to a heterocycloalkyl group, as defined herein above, but having two or three points of attachment, i.e. a divalent or trivalent saturated ring group, preferably having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).

[0228] Heterocycloalkylene include bivalent groups, e.g. bicyclic bivalent groups, such as

[0229]

[0230] The term “halogen” or “hal” as used herein may be fluoro, chloro, bromo or iodo, such as fluoro, chloro or bromo, e.g. fluoro or chloro. The term “alkyl” (for example “C1-24 alkyl” and “C1.6 alkyl”) refers to a fully saturated branched or unbranched (linear) hydrocarbon moiety having the indicated number of carbon atoms. Representative examples of C1-24 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. Representative examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl or neohexyl. The term “alkylene” relates to an alkyl group, as defined herein, which has 2 or 3 points of attachment, preferably 2 points of attachment. Accordingly, alkylene group is preferably an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group, which may be linear or branched.

[0231] Based on the definitions given throughout the application the skilled person knows which combinations are synthetically feasible and realistic, e.g. typically combinations of groups leading to some heteroatoms directly linked to each other, e.g. -O-O-, are not contemplated, however synthetically feasible combinations, such as -S-N= in isothiazole are contemplated.

[0232] The compounds of the invention may contain one or more asymmetric centers in the molecule. A compound without designation of the stereochemistry is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods).

[0233] The compounds may be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, sulfur or chlorine.

[0234] The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

[0235] The compounds of the present invention include the free form as well as the pharmaceutically acceptable salts and stereoisomers thereof. The pharmaceutically acceptable salts include all the typical pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of this inventionwhich contain a basic or acidic moiety by conventional chemical methods, see e.g. Berge et al, “Pharmaceutical Salts,” J. Pharm. Sci, 1977, 66, 1-19. Furthermore, the compounds of the inventionalso include lyophilized form and polymorphs of the free form.

[0236] For example, conventional pharmaceutically acceptable salts for a basic compound include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Conventional pharmaceutically acceptable salts for an acidic compound include those derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2 -dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

[0237] The compounds of the invention may exist in solid, i.e., crystalline (e.g., polymorphs, i.e., different crystalline structures that have the same chemical composition but differ in packing, geometrical arrangement) or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. The formation of solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or EtOAc, or aqueous solvents such as water (also called “hydrates”). Different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents.

[0238] In yet another embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention (accordingly, one or more of the compounds of the invention or pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier is meant to also encompass one or more pharmaceutically acceptable carriers and / or excipients (also referred to as diluents). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient). It is to be understood that said compounds or their salts are preferably present in a therapeutically-effective amount. The term “therapeutically- effective amount” as used herein refers to the amount of a compound (as such or in form of a pharmaceutical composition) of the present invention which is effective for producing some desired therapeutic effect.

[0239] Pharmaceutical compositions may be in unit dose form containing a predetermined amount of a compound of the invention per unit dose. Such a unit may contain a therapeutically effective dose of a compound of the invention or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the invention or salt thereof.

[0240] The compounds of the invention may be administered by any acceptable means in form of a solid, liquid, gel or other form, by any administration route including oral, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral, for example, by subcutaneous, intramuscular, intraarticular, intravenous, intraarterial, intracavitary, intraperitoneal, intrapleural, intralesional, intratumoral or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical, for example, as a cream, ointment, eye-drop or a controlled-release patch or spray applied to a body part, such as the skin or the eye; intravaginal or intrarectal, for example, as a pessary, cream or foam; sublingual; ocular; intraocular, intravitreal; transdermal; nasal; pulmonary; intrathecal, intraarticular, by inhalation; or direct contact with the nasal, genitourinary, reproductive or oral mucosa. It is to be understood that, preferably, the compounds wherein Z includes a radionuclide are to be administered by parenteral administration route, including subcutaneous, intramuscular, intraarticular, intravenous, intraarterial, intracavitary, intraperitoneal, intrapleural, intralesional, intratumoral and epidural route of administration. More preferably, the compounds wherein Z includes a radionuclide are to be administered by intravenous, intraarterial, intracavitary, intralesional or intratumoral route of administration. Even more preferably, the compounds wherein Z includes a radionuclide are to be administered by intravenous route of administration.

[0241] The phrase "pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical compositions.

[0242] Such compositions may contain further components conventional in pharmaceutical preparations, e.g. wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, gentesic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), DTPA, sorbitol, tartaric acid, phosphoric acid, and the like. Such compositions may be prepared by any method known in the art, for example, by bringing into association the active ingredient with one or more carriers and / or excipients. Different compositions and examples of carriers and / or excipients are well known to the skilled person and are described in detail in, e.g., Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 2009. Excipients that may be used in the preparation of the pharmaceutical compositions may include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents, and other known additives to provide a composition suitable for an administration of choice.

[0243] As indicated above, the compounds of the present invention may be in solid or liquid form and may be administered by various routes in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Preferably, the compounds wherein Z includes a radionuclide are to be administered by parenteral administration route.

[0244] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), a compound is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0245] It is to be understood that, preferably, the solid administration forms intended for oral administration route, as described hereinabove, are intended for the compounds wherein Z does not include any radionuclide.

[0246] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. An oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0247] It is to be understood that, preferably, the liquid administration forms intended for oral administration route, as described hereinabove, are intended for the compounds wherein Z does not include any radionuclide.

[0248] In form of suspensions, a compound may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0249] Dosage forms for rectal or vaginal administration of a compound of the invention include a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at RT, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Preferably, dosage forms for rectal or vaginal administrations, as described herein, are suitable for the compounds of the invention wherein Z does not include any radionuclide.

[0250] Dosage forms for the topical ortransdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. Such ointments, pastes, creams and gels may contain, in addition to a compound of the invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0251] Dosage forms such as powders and sprays for administration of a compound of the invention, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0252] Dosage forms such as transdermal patches for administration of a compound of the invention may include absorption enhancers or retarders to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0253] Preferably, topical and / or transdermal administration of the compound of the invention is particularly suitable in the case wherein Z does not include any radionuclide.

[0254] Other dosage forms contemplated include ophthalmic formulations including intraocular and extraocular delivery, eye ointments, powders, solutions, and the like. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0255] The dosage levels of a compound of the invention in the pharmaceutical compositions of the invention may be adjusted in order to obtain an amount of a compound of the invention which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being deleterious to the patient. The dosage of choice will depend upon a variety of factors including the nature of the particular compound of the present invention used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A medical practitioner having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

[0256] Typically, a suitable daily dose of a compound of the invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.00001 to about 100 mg / kg, more usual 0.1 to 100 mg / kg per kilogram of body weight of recipient (patient, mammal) per day. Acceptable daily dosages may be from about 1 to about 1000 mg / day, and for example, from about 1 to about 100 mg / day. An typical dose of a radiopharmaceutical to be administered to a patient in a single administration session can range from 1 to 20 pg in total.

[0257] For the compounds of the present invention comprising a radionuclide, in particular a radionuclide useful in therapy, the dose of radionuclide may also be described in the units of radioactivity, preferably in MBq / kg body weight. The total daily dose of the compound comprising a radionuclide, wherein said radionuclide is a P-emitter administered to a human subject or patient in single dose or in divided doses preferably is between 3 and 300 MBq / kg body weight. In case of radionuclide being a-emitter, typical doses are lower, for example less than 30 MBq in total (e.g., in a typical administration of a radiopharmaceutical including225Ac, it can be 18.5 MBq / patient). As it is known to the skilled person, the further preferred dosing regimens depend on the used radionuclide. For the compounds of the present invention comprising yttrium-90 the total daily dose administered to a human subject or patient in single dose or in divided doses preferably is between 5 and 35 MBq / kg body weight, even more preferably between 7 and 25 MBq / kg body weight, most preferably between 10 and 15 MBq / kg body weight. For the compounds of the present invention comprising177Lu the total daily dose administered to a human subject or patient in single dose or in divided doses preferably is between 5 and 150 MBq / kg body weight, even more preferably between 10 and 80 MBq / kg body weight, most preferably between 10 and 60 MBq / kg body weight. Accordingly, a typical dose of177Lu administrated to a patient can be, e.g., 7.4 GBq per session. As it is to be understood herein, a daily dose is preferably understood as a dose administered in a single session, to be concluded in a single day, which according to the therapy schedule may be administered with intervals of several days, for example every two weeks, every four weeks, or every eight weeks. As understood herein, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. As understood herein, the skilled person will be able to determine the preferred dosage, depending on the radionuclide and on the desired application (for example treatment of a solid tumor).

[0258] A compound of the invention, or a pharmaceutically acceptable salt, or stereoisomer, thereof, may be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID) or may be administered in regular intervals of more than one day, such as every two days (Q2D). Administration may be continuous (i.e., daily for consecutive days or every day) or intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt, or stereoisomer thereof, is administered every day for at least 21 days. In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered every two days for at least 21 days. The compound of the invention or its pharmaceutically acceptable salt, or a stereoisomer thereof, may also be administered less often, for example in weekly intervals, biweekly intervals, monthly intervals or every six weeks.

[0259] The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound of the invention, or a pharmaceutically acceptable salt, or stereoisomer, thereof, is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest (or holiday) period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a compound of the Invention, or a pharmaceutically acceptable salt or stereoisomer, thereof, is administered daily or continuously but with a rest period. In some embodiments, the rest period is the same length as the treatment period. In other embodiments, the rest period has different length from the treatment period. In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt, or stereoisomer, thereof, is administered intermittently once per day for 5 days followed by a rest of 3 days (i.e. 5 days on / 3 days off). This intermittent administration is repeated for 3 to 4 cycles. In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt, or stereoisomer thereof, is administered intermittently once per day for 5 days followed by a rest of 9 days (i.e. 5 days on / 9 days off). This intermittent administration is repeated for 2 cycles. It is understood that dosing regimen also depend on factors as indicated above, e.g. on the administration, and can be readily arrived at by one skilled in medicine or the pharmacy art.

[0260] For the compounds of the present invention wherein Z comprises a radionuclide, or their pharmaceutically acceptable salts or stereoisomers, which are preferably to be administered parenterally, e.g. intravenously, preferably the compound is administered in weekly intervals, biweekly intervals or monthly intervals.

[0261] The compounds and compositions of the present invention are particularly useful in medical applications. Thus, in one embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition of the present invention for use as a medicament. It follows that the compounds of the present invention can be used in the manufacture of a medicament, and that the present invention relates in one embodiment to such a use.

[0262] Without being bound to the theory, the present inventors postulate that the compounds of formula (0) bind to GPR4 and modulate the function of GPR4. In other words, the compounds of formula (0) can preferably inhibit the function of GPR4 in the signaling pathways. Thus, the compounds of the present invention as well as pharmaceutical (or radiopharmaceutical) compositions of the present invention are useful in the treatment or prevention of a disease associated with, mediated by or caused by GPR4.

[0263] As understood herein, the term "disease associated with, mediated by or caused by GPR4” preferably refers to a pathological condition wherein the GPR4 is expressed in an amount significantly higher than in a healthy tissue, for example at least 2 times higher, preferably 3 times higher, more preferably 4 times higher, even more preferably 5 times higher, still more preferably 10 times higher, again more preferably 50 times higher, or more. The level of GPR4 can be measured in the cell using the methods known to the skilled person, including transcriptomics methods, proteomics methods, real-time PCR or ELISA assay. The healthy tissue as understood herein is a corresponding healthy tissue. For example, if the disease considered is cancer, then the corresponding healthy tissue is the same tissue that is not cancer, i.e. is not neoplastic. It is further preferably understood herein that when a disease is associated with, mediated by or caused by GPR4, the increased expression level (which may herein also be referred to as expression of GPR4, or overexpression of GPR4) is associated with the onset of the disease (preferably is associated with the disease), and that modulating the protein expression level back to its normal level, by using the techniques known to the skilled person, like treatment with miRNA or CRISPR / CAS technology, the disease state can be, at least to a certain extent, reversed or attenuated. Similarly, by modulating the function of GPR4, by attenuating the function, for example by using small molecule that inhibit its function, the disease state can be, at least to a certain extent, reversed or attenuated. Accordingly, the disease associated with, mediated by or caused by GPR4 is herein preferably considered to be a disease which can be treated by inhibiting the function of GPR4, as described herein. Specific diseases that fall under the category of diseases associated with, mediated by or caused by GPR4, are provided herein.

[0264] According to the present invention, the term "disease associated with, mediated by or caused by GPR4” may be understood as a disease wherein the affected tissue is characterized by the presence of GPR4 (or, in other words, characterized by expression of GPR4), preferably wherein the GPR4 is expressed in an amount significantly higher than in a healthy tissue, for example at least 2 times higher, 3 times higher, 4 times higher, 5 times higher, or 10 times higher (when compared to healthy corresponding tissue). In such a case, the presence of GPR4 in the cell (in particular exposed on the outer cell surface) allows for binding, localization or colocalization of the compound of the present invention, which binds and inhibits GPR4, to said GPR4 present in the tissue. In case of the compounds of the invention wherein Z comprises a radionuclide, in particular a therapeutically-relevant radionuclide, the binding, localization or colocalization of the compound of the invention to said GPR4 and accordingly to tissue characterized by the presence of GPR4, which is not a healthy tissue, would translate to binding, localization or colocalization of said radionuclide to said tissue, allowing for a therapeutic effect of said radionuclide.

[0265] As understood herein, preferably the term “overexpression of GPR4” refers to a situation wherein in tumour tissue the GPR4 is expressed in an amount significantly higher than in a healthy tissue, for example at least 2 times higher, 3 times higher, 4 times higher, 5 times higher, or 10 times higher (when compared to healthy corresponding tissue). As referred to herein, the tissue may be solid tumour tissue. Accordingly, as preferably understood herein, solid tumor characterized by overexpression of GPR4 is a tumour wherein the GPR4 is expressed in an amount significantly higher than in a healthy tissue or corresponding tumour not characterized by overexpression of GPR4, for example at least 2 times higher, 3 times higher, 4 times higher, 5 times higher, or 10 times higher (when compared to healthy corresponding tissue or to corresponding tumour). More preferably, solid tumor characterized by overexpression of GPR4 is a tumour wherein the GPR4 is present on average on the cell surface in an amount significantly higher than in a healthy tissue or corresponding tumour not characterized by overexpression of GPR4, for example at least 2 times higher, 3 times higher, 4 times higher, 5 times higher, or 10 times higher (when compared to healthy corresponding tissue or to corresponding tumour).

[0266] Accordingly, in one embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention for use in the treatment or prevention of a disease associated with or caused by GPR4. It is to be understood that, consequently, in one embodiment the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in a manufacture of a medicament for use in the treatment or prevention of a disease associated with, mediated by, or caused by GPR4. The disease associated with, mediated by or caused by GPR4 may in one embodiment be a disease characterized by expression of GPR4. In this embodiment, preferably the radiopharmaceutical composition of the invention or the compound wherein Z comprises a radionuclide, is used.

[0267] Further accordingly, in one embodiment, the present invention relates to a method of treatment of a subject suffering from a disease associated with or caused by GPR4, the method comprising the step of administering the compound of the present invention or the pharmaceutical composition of the present invention to a subject in need thereof. It is to be understood that preferably a therapeutically effective amount of the compound or the composition of the present invention is to be administered.

[0268] Preferably, a disease associated with, mediated by, or caused by GPR4 can be selected from osteoporosis (juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or corticosteroid therapy or inactivity), gingivitis, periodontitis, pain, dental pain, Paget's disease, hypercalcemia of malignancy, tumor induced hypercalcemia, metabolic bone disease, cancers of tissues and organs of the body including but limited to, blood, lung, mouth, esophagus, stomach, gastrointestinal tract, colon, rectum, bone, pancreatic, CNS, eye, skin, kidneys, liver, gall bladder, ovaries, uterus, vagina, testes, prostate, and breast, cardiovascular disorders, atherosclerose, myocardial infarction, ischemic diseases, arrhythmias (e.g. atrial and ventricular tachyarrhythmias, atrial tachycardia, atrial flutter, atrial fibrillation, atrio-ventricular reentrant tachycardia, preexcitation syndrome, ventricular tachycardia, ventricular flutter, ventricular fibrillation), hypertensive vascular diseases, peripheral vascular diseases ( e.g. chronic peripheral arterial occlusive disease (PAOD), acute arterial thrombosis and embolism, inflammatory vascular disorders, Raynaud's phenomenon and venous disorders), atherosclerosis (and atherosclerotic lesions), limb diseases, post thrombotic syndrome (PTS), peripheral arterial occlusive disease, eye diseases, retinopathies, e.g. diabetic retinopathy, macular degeneration, diabetic macular edema uveitis, arthritis, rheumatoid arthritis, osteoarthritis wound healing, skin diseases (including hypertrophic and Keloid scarring), inflammatory and obstructive airway diseases, asthma, intrinsic and extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise induced asthma, occupational asthma, asthma induced following bacterial infection, acute lung injury, acute / adult respiratory distress syndrome, chronic obstructive pulmonary airways or lung disease, chronic bronchitis, dyspnea associated with chronic bronchitis, emphysema, exacerbation of airways hyperactivity consequent to other drug therapy, bronchitis (including acute arachidic, catarrhal, croupus, chronic or phthinoid bronchitis), pneumoconiosis, aluminosis, anthracosis, asbestosis, chlicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis, eosinophilia, bronchopulmonar aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug reaction, infectious diseases cause by organisms such as Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei, Crithidia fusculata, parasitic diseases such as schistosomiasis and malaria, angiogenesis related diseases, tumor invasion and metastasis, metachromatic leukodystrophy, muscular dystrophy, amythrophy, autoimmune disease, including inflammatory bowel disease, e.g. Crohn's disease, ulcerative colitis, intestinal fibrosis, ischaemic colitis, immunologically mediated disease, transplant rejection, liver diseases including primary or secondary, acute or chronic diseases or injury of the liver, disorders of the bilirubin metabolism, jaundice, syndroms of Gilbert's, Crigler- Najjar, Dubin-Johnson and Rotor; intrahepatic cholestasis, hepatomegaly, portal hypertension, ascites, Budd-Chiari syndrome, portal-systemic encephalopathy, fatty liver, steatosis, Reye's syndrome, liver diseases due to alcohol, alcoholic hepatitis or cirrhosis, fibrosis and cirrhosis, fibrosis and cirrhosis of the liver due to inborn errors of metabolism or exogenous substances, storage diseases, syndromes of Gaucher's, Zellweger's, Wilson's disease, acute or chronic hepatitis, viral hepatitis and its variants, inflammatory conditions of the liver due to viruses, bacteria, fungi, protozoa, helminths; drug induced disorders of the liver, chronic liver diseases like primary sclerosing cholangitis, alpha-antitrypsin-deficiency, primary biliary cirrhosis, postoperative liver disorders like postoperative intrahepatic cholestasis, hepatic granulomas, vascular liver disorders associated with systemic disease, benign or malignant neoplasms of the liver, disturbance of liver metabolism in the new-born or prematurely born, genitourinary disorders including disorders of the organs constituting the genitourinary system of female and male, renal diseases like acute or chronic renal failure, immunologically mediated renal diseases like renal transplant rejection, lupus nephritis, immune complex renal diseases, glomerulopathies, nephritis, toxic nephropathy, obstructive uropathies like benign prostatic hyperplasia (BPH), neurogenic bladder syndrome, urinary incontinence like urge-, stress-, or overflow incontinence, pelvic pain, erectile dysfunction, CNS (and CNS-related) psychiatric and neurological disorders, such as brain injuries, brain ischemia, cerebrovascular diseases, neurodegenerative diseases e.g. Parkinson's disease, Alzheimer’s Disease, corticobasal degeneration, motor neuron disease, multiple sclerosis, spinal cord injury (including vascular lesions in the brain and spinal cord, e.g., infarct, hemorrhage, vascular malformation), sciatica, failed back surgery syndrome, traumatic and post-traumatic brain injury, stroke and poststroke, epilepsy, and small-vessel cerebrovascular disease; dementias, such as ALS, vascular dementia, dementia with Lewy bodies, Parkinsonism linked to chromosome 17, frontotemporal dementias, including Pick's disease, progressive nuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, Creutzfeld- Jakob dementia, HIV dementia, schizophrenia with dementia, and Korsakoffs psychosis; cognitive-related disorders, such as mild cognitive impairment, age-associated memory impairment, age-related cognitive decline, vascular cognitive impairment, attention deficit disorders, attention deficit hyperactivity disorders, autism, and memory disturbances in children with learning disabilities. CNS disorders may also include psychiatric diseases including anxiety disorders, depression disorders, obsessive-compulsive disorder, drug abuse, CNS disorders may also include pain associated with such disorders, including non-central neuropathic pain, such as pain associated with post mastectomy pain, phantom feeling, reflex sympathetic dystrophy (RSD), trigeminal neuralgia radiculopathy, post-surgical pain, HIV / AIDS related pain, metabolic neuropathies (e.g., diabetic neuropathy, vasculitic neuropathy secondary to connective tissue disease), paraneoplastic polyneuropathy trigeminal neuralgia, cranial neuralgias, and post-herpetic neuralgia; pain associated with peripheral nerve damage, central pain (i.e. due to cerebral ischemia) and various chronic pain i.e., lumbago, back pain (low back pain), inflammatory and or rheumaic pain; headache pain (e.g., migraine disorders), episodic and chronic tension-type headache, tension-type like headache, cluster headache, and chronic paroxysmal hemicranias; visceral pain such as pain associated with pancreatitis, intestinal cystitis, dysmenorrhea, irritable Bowel syndrome, inflammatory bowel disease, e.g. Crohn's disease and ulcerative colitis, ischemic colitis, fibrosis, fibrotic diseases of the body, e.g. intestinal, skin, kidey, lung, cardiac, skin, biliary colic, ureteral colic, myocardial infarction, and pain syndromes of the pelvic cavity, e.g., vulvodynia, orchialgia, urethral syndrome and protatodyni, as well as postoperative pain, and pain after trauma. CNS disorders may also include psychiatric or neurological disorders mediated or affected by changes in other organs e.g. dietary and intestinal changes.

[0269] The disease associated with, mediated by, or caused by GPR4 can also be selected from osteoporosis (juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or corticosteroid therapy or inactivity), gingivitis, periodontitis, Paget’s disease, hypercalcemia of malignancy, tumor induced hypercalcemia, metabolic bone disease, cancer, solid tumors including those of the intestine, colon, lung, ovary, skin, testes, prostate, breast, bone, brain and spinal cord, kidney, and blood cells, cardiovascular disorders, atherosclerose, myocardial infarction, limb diseases, peripheral arterial occlusive disease, eye diseases, diabetic retinopathy, macular degeneration, uveitis, arthritis, rheumatoid arthritis, osteoarthritis, wound healing, skin diseases, inflammatory and obstructive airway diseases, asthma, intrinsic and extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury, acute / adult respiratory distress syndrome, chronic obstructive pulmonary airways or lung diseases, chronic bronchitis, dyspnea associated herewith, emphysema, exacerbation of airways hyperactivity consequent to other drug therapy, bronchitis, acute arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chlicosis, ptilosis, siderosis, silicosis, tabacosis byssinosis, eosinophilia, bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug reaction, infectious diseases caused by organisms such as Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei, Crithidia fusculata, parasitic diseases such as schistosomiasis and malaria, sarcoidosis and other granulomatous inflammation, tumor invasion and metastasis, metachromatic leukodystrophy, muscular dystrophy, amythrophy, autoimmune disease, respiratory disease, immunologically mediated disease, transplant rejection, inflammatory pain, visceral pain, acute and chronic pain, tumor pain, neuropathic pain, kidney diseases, renal tubular acidosis and other disorders of acid-base and metabolism, Crohn's disease, inflammatory bowel disease, intestinal fibrosis, hypersensitivity reactions, reflux disease (GERD) including erosive disease and / or non erosive reflux disease (NERD), diseases associated with pregnancy (e.g. preeclampsia, eclampsia, gestational hypertension, chronic hypertension, and chronic hypertension with superimposed pre-eclampsia) and after birth (e.g. post-partum preeclampsia), lung injury caused by X-ray irradiation.

[0270] It is preferred that the compound of the present invention comprises a radionuclide, and accordingly the pharmaceutical composition of the present invention is preferably a radiopharmaceutical composition. The accordingly preferred compounds of the present invention are useful in treatment of a solid tumor, and in the treatment of a hematological tumor. Particularly preferred is the treatment of solid tumors using the compounds or the radiopharmaceutical composition of the present invention. Accordingly, as encompassed by the present invention, the disease characterized by expression of GPR4 may be a solid tumor.

[0271] Solid tumor, as referred to herein, may be a tumour of every organ or tissue of the body. Preferably, the solid tumor is selected from bladder cancer, breast cancer, cervical cancer, mouth cancer, esophagus cancer, stomach cancer, intestinal cancer, colon and rectal cancer, eye cancer, endometrial cancer, kidney cancer, lip cancer, oral cancer, hepatocellular cancer, melanoma, mesothelioma, liver cancer, lung cancer (in particular non-small cell lung-cancer, but also including small cell lung cancer), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and thyroid cancer, more preferably from bladder cancer, breast cancer, cervical cancer, mouth cancer, aesophagus cancer, stomach cancer, intestinal cancer, colon and rectal cancer, eye cancer, endometrial cancer, kidney cancer, lip cancer, oral cancer, melanoma, mesothelioma, liver cancer, lung cancer (in particular non-small cell lung-cancer, but also including small cell lung cancer), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, or thyroid cancer. Particularly preferred is the treatment of tumors with significant overexpression of GPR4, for example breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer or kidney cancer. Herein, significant overexpression of GPR4 is preferably understood as the expression level, as measured by using transcriptomics techniques, of said GPR4 at least 5 times higher than in the corresponding healthy tissue.

[0272] Hematological tumors, as referred to herein, include leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma.

[0273] Thus, in one embodiment, the present invention relates to the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention for use in the treatment of solid tumors. It is to be understood that, preferably, the solid tumor is characterized by expression (or overexpression) of GPR4. Thus, preferably, the present invention relates to the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention for use in the treatment of breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer or kidney cancer. It will accordingly be understood that in one embodiment the present invention relates to use of the compound of the present invention or the pharmaceutical composition (i.e., the radiopharmaceutical composition) of the present invention in a manufacture of a medicament for use in the treatment of solid tumors, preferably the solid tumor characterized by expression (or overexpression) of GPR4, in particular breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer or kidney cancer.

[0274] In one embodiment, the present invention relates to a method of treatment of a subject suffering from a solid tumor characterized by expression (or overexpression) of GPR4, the method comprising the step of administering the compound of the present invention or the pharmaceutical (radiopharmaceutical) composition of the present invention to a subject in need thereof. It is to be understood that a therapeutically effective amount is to be administered. The solid tumor is preferably selected from breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer and kidney cancer.

[0275] However, the invention is not limited to the treatment of solid tumors and, as recognizable to the skilled person, a tumor in every tissue and organ of the body characterized by expression (or overexpression) of GPR4 can be treated using the compounds of the present invention. Accordingly, said cancer is preferably selected from bladder cancer, breast cancer, cervical cancer, mouth cancer, esophagus cancer, stomach cancer, intestinal cancer, colon and rectal cancer, eye cancer, endometrial cancer, kidney cancer, lip cancer, oral cancer, hepatocellular cancer, melanoma, mesothelioma, liver cancer, lung cancer (in particular non-small cell lung-cancer, but also including small cell lung cancer), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and thyroid cancer, more preferably from bladder cancer, breast cancer, cervical cancer, mouth cancer, esophagus cancer, stomach cancer, intestinal cancer, colon and rectal cancer, eye cancer, endometrial cancer, kidney cancer, lip cancer, oral cancer, melanoma, mesothelioma, liver cancer, lung cancer (in particular non-small cell lung-cancer, but also including small cell lung cancer), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and thyroid cancer. Said cancer can also be cancer of blood, lung, mouth, esophagus, stomach, gastrointestinal tract, colon, rectum, bone, pancreatic, CNS, eye, skin, kidneys, liver, gall bladder, ovaries, uterus, vagina, testes, prostate, or breast.

[0276] According to the present invention, the cancer characterized by expression (or overexpression) of GPR4 may be a cancer associated with known mutation(s). These include, but are not limited to, mutation(s) in BRAF, KRAS, KIT, NRAS, GNAQ, GNA11 Monosomy 3, AKT, BRCA1 , BRCA2, ErBB2, ESR, PI3KCA, EML4 / ALK, HRAS, MTOR, RET, APC, TP53, ATM, RB1 , FGFR3, GN11 , EGFR, MET, ROS1 , NTRK1 fusion, NTRK2 fusion, and NTRK3 fusion. In one embodiment of the invention, cancer characterized by expression (or overexpression) of GPR4 is a cancer characterized by the presence of BRAF V600E mutation. Accordingly, the compounds of the present invention are particularly suitable for the treatment of cancer characterized by the presence of BRAF V600E mutation. In one embodiment of the invention, cancer characterized by expression (or overexpression) of GPR4 is a cancer associated with KRAS. Accordingly, the compounds of the present invention are particularly suitable for the treatment of cancer associated with KRAS.

[0277] In particularly preferred compounds comprising a radionuclide, or corresponding radiopharmaceutical compositions, that are envisaged for therapeutic applications, as provided herein, the radionuclide is selected from67Cu,89Sr, "Y,131l,153Sm,177Lu,223Ra,225Ac,47Sc,149Tb,161Tb, and212Pb, preferably from67Cu,89Sr, "Y,153Sm,177Lu,223Ra,225Ac,47Sc,149Tb,161Tb, and212Pb.

[0278] In one embodiment, the present invention relates to the compound of the present invention for use in diagnostic application. Particularly preferred in the diagnostic applications are compounds of the present invention wherein Z includes a radionuclide that is suitable for a diagnostic application, preferably selected from radioisotopes such as, but not limited to,111ln,152Tb, and1

[0279] As encompassed by the present invention, certain radionuclides as disclosed herein, can be monitored, for example161Tb due to its y-emission can be visualized with gamma camera and hence used for detection of cancer tissue or cell-type, as targeted to by the compound of formula (0) to e.g. appropriate solid tumor characterized by (over)expression of GPR4. Terbium-149 which can be used for targeted alpha therapy, has visibility in PET scans and thus can be monitored. According to the present disclosure,18F,43Sc, ^Sc,61Cu, “Cu, “Ga,89Zr,111ln,123l,152Tb, and155Tb (preferably43Sc,44Sc, “Cu, ^Ga,89Zr,111In,152Tb, and155Tb) are particularly useful in diagnostic application as described herein and may be referred to as radionuclides useful in diagnosis. As known to the skilled person, the radionuclides useful in diagnosis can be monitored by using a suitable method, for example Scintigraphy, Single Photon Emission Computed Tomography (SPE-CT); or Positron emission tomography Computed Tomography (PET-CT). Furthermore, the skilled person will appreciate that the compound of the present invention which comprises a radionuclide useful for therapeutic application, for example selected from67Cu,89Sr, "Y,131l,153Sm,177Lu,223Ra, and225Ac (these radionuclides may be referred to as radionuclides useful in therapy) will have substantially the same biodistribution as the compound wherein the radionuclide is useful for diagnostic application. Therefore, according to the present invention, the compounds of the present invention can preferably be used for monitoring of biodistribution of therapeutic compounds of the present invention during therapy. For example, a compound comprising an active agent being a radionuclide useful in therapy can be supplemented for this purpose preferably with less than 10 weight% of a compound of the invention which comprises a radionuclide useful in diagnosis, as referred to herein. For example, changes in biodistribution of the compound comprising a radionuclide useful in diagnosis, may indicate progress of a therapy targeting said cancer tissue. In particular, this approach may be useful in cancer monitoring, preferably in monitoring therapy of cancerthat has metastasized. As disclosed herein, the compounds of the present invention may be useful in cancer monitoring, herein defined as distribution of cancer tissue in the body of a subject, preferably of a patient.

[0280] Thus accordingly, in one embodiment, the present invention relates to the compound of the present invention for use in diagnosing a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4. Preferably, said tumor or said disease is as referred to hereinabove.

[0281] In one embodiment, the present invention relates to use of the compound of the present invention in the manufacture of a reagent for diagnosing a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4. Preferably, said tumor or said disease is as referred to hereinabove.

[0282] As encompassed by the present invention, the compound of the present invention comprising a radionuclide suitable for diagnostic application can be used in therapeutic drug monitoring. In particular, such compound can be used to monitor the progress of therapy using the compound of the present invention wherein Z comprises a radionuclide suitable for therapy.

[0283] In one embodiment, the present invention relates to a method of determining whether a subject is suffering from a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4, the method comprising the steps of (a) administering the subject with the compound of the present invention and (b) determining if the subject is suffering from a solid tumor characterized by expression (overexpression) of GPR4 or a disease associated with or caused by GPR4. Preferably, said tumor or said disease is as referred to hereinabove.

[0284] Further embodiments of the present inventions are disclosed in the following numbered items.

[0285] 1 . A compound of formula (0): (0) or a pharmaceutically acceptable salt thereof, wherein:

[0286] X1, X2, X3are independently selected from C and N;

[0287] R1, R2, and R3are independently selected from H, and C1-6 alkyl;

[0288] R4is selected from H, and C1-6 alkyl;

[0289] R5is selected from H, C alkyl, and C3-6 cycloalkyl, wherein R5is optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2;

[0290] R6and R7are independently selected from -H, halogen, and C1-6 alkyl; n is 1 or 2; m is 0 or 1 ;

[0291] Y is -CH2CH2- or -CH2O-;

[0292] L is C2-20 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1-6 alkyl, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-SO4H, -(C1-6 alkylene)- SO3H, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -O(Ci-6alkyl), -SH, -S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and - COOH, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -CHC-, -O-, -NR’-, -CO-, C6-10 arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO- NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl;

[0293] Q is selected from a covalent bond, -CH2-, -CHOG2-, -C(=O) -, CMO arylene, C5-10 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -O-, -CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl; and

[0294] Z is a radionuclide moiety or a chelator adapted to bind a radionuclide. The compound of item 1 , wherein X1is N and X2and X3are C. 3. The compound of item 1 or 2, wherein R1and R2are each methyl, and R3is ethyl.

[0295] 4. The compound of any one of items 1 to 3, wherein R4is H and / or R5is H.

[0296] 5. The compound of any one of items 1 to 4, wherein Y is -CH2CH2-.

[0297] 6. The compound of any one of items 1 to 4, wherein m is 0.

[0298] 7. The compound of any one of items 1 to 6, wherein n=1.

[0299] 8. The compound of any one of items 1 to 7, wherein L is C2-20 alkylene, wherein one or more -CH2- groups may independently be replaced by one or more of -CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, C5-11 bicyclo[n’.n”.n”’]alkylene, wherein the sum of n’, n” and n’” is at least 3 and does not exceed 9, wherein R’ is H or Ci-Ce alkyl.

[0300] 9. The compound of any one of items 1 to 8, wherein Q is selected from a covalent bond, -CH2-, -CHOG2-, - C(=O) -, C6-10 arylene, C5-10 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -O-, -CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl.

[0301] 10. The compound of any one of items 1 to 9, wherein Z comprises a chelator selected from DOTA (1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10- tetraacetic acid), 1 ,4,7-triazacyclononane N,N',N"-triacetic acid(NOTA) and OTA (1 ,4,7-triazonane-l ,4, 7-triacetic acid).

[0302] 11 . The compound of any one of items 1 to 10, wherein the compound is a compound of formula (la): or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, R1, R2, R3, R4, R7, L, Q and Z are as defined in any one of claims 1 to 10.

[0303] 12. The compound of item 1 , selected from the following compounds:

[0304] (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)- 1 , 17-d ioxo-6 ,9 , 12-trioxa-2, 16- diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0305] (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)- 1 ,30-d ioxo-5,8 , 11 ,14,17,20,23,26- octaoxa-2,29-diazahentriacontan-31 -yl)-1 ,4,7, 10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;

[0306] 2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentan-1-yl)-

[0307] 1 -oxo-5, 8, 11 , 14-tetraoxa-2-azahexadecan-16-yl)- 1 , 18,21 -trioxo-5 , 8 , 11 ,14-tetraoxa-2, 17,20-triazadocosan- 22-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; and 2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentan-1-yl)- 1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)-1 ,18-dioxo-5,8,11 ,14-tetraoxa-2,17-diazanonadecan-19- yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; or their pharmaceutically acceptable salts and / or radionuclide complexes.

[0308] 13. A pharmaceutical composition comprising the compound of any one of items 1 to 12 and at least one pharmaceutically acceptable carrier.

[0309] 14. The compound of any one of items 1 to 12 or the pharmaceutical composition of item 13 for use as a medicament.

[0310] 15. The compound of any one of items 1 to 12 for use in diagnosis.

[0311] 16. The compound of any one of items 1 to 12 or the pharmaceutical composition of item 13 for use in the treatment or prevention of solid tumor characterized by overexpression of GPR4 or a disease associated with, mediated by or caused by GPR4.

[0312] 17. The compound of any one of items 1 to 12 for use in diagnosis of solid tumor characterized by overexpression of GPR4 or a disease associated with, mediated by or caused by GPR4. 18. The compound for use of item 16 or 17, or the pharmaceutical composition for use of item 16, wherein the solid tumor characterized by overexpression of GPR4 is selected from breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer and kidney cancer, and / or wherein the disease associated with, mediated by or caused by GPR4 is selected from osteoporosis (juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or corticosteroid therapy or inactivity), gingivitis, periodontitis, Paget’s disease, hypercalcemia of malignancy, tumor induced hypercalcemia, metabolic bone disease, cancer, solid tumors including those of the intestine, colon, lung, ovary, skin, testes, prostate, breast, bone, brain and spinal cord, kidney, and blood cells, cardiovascular disorders, atherosclerose, myocardial infarction, limb diseases, peripheral arterial occlusive disease, eye diseases, diabetic retinopathy, macular degeneration, uveitis, arthritis, rheumatoid arthritis, osteoarthritis, wound healing, skin diseases, inflammatory and obstructive airway diseases, asthma, intrinsic and extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury, acute / adult respiratory distress syndrome, chronic obstructive pulmonary airways or lung diseases, chronic bronchitis, dyspnea associated herewith, emphysema, exacerbation of airways hyperactivity consequent to other drug therapy, bronchitis, acute arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chlicosis, ptilosis, siderosis, silicosis, tabacosis byssinosis, eosinophilia, bronchopulmonar aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil- related disorders affecting the airways occasioned by drug reaction, infectious diseases caused by organisms such as Pneumocystis carinii, Trypanosomacruzi, Trypanosoma brucei, Crithidia fusculata, parasitic diseases such as schistosomiasis and malaria, sarcoidosis and other granulomatous inflammation, tumor invasion and metastasis, metachromatic leukodystrophy, muscular dystrophy, amythrophy, autoimmune disease, respiratory disease, immunologically mediated disease, transplant rejection, inflammatory pain, visceral pain, acute and chronic pain, tumor pain, neuropathic pain, kidney diseases, renal tubular acidosis and other disorders of acid-base and metabolism, Crohn's disease, inflammatory bowel disease, intestinal fibrosis, hypersensitivity reactions, reflux disease (GERD) including erosive disease and / or non erosive reflux disease (NERD), diseases associated with pregnancy (e.g. preeclampsia, eclampsia, gestational hypertension, chronic hypertension, and chronic hypertension with superimposed pre-eclampsia) and after birth (e.g. post-partum preeclampsia), lung injury caused by X-ray irradiation.

[0313] The invention is further illustrated by the following examples, which should not be construed as limiting. Demonstration of efficacy in these assays is predictive of efficacy in subjects.

[0314] Examples

[0315] Methods General conditions:

[0316] Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical and electron impact ionization methods from a range of instruments of the following configurations: Waters ACQUITY UPLC system and equipped with a ZQ 2000 or SQD MS system where (M+1) refers to the protonated molecular ion of the chemical species, (M+) refers to the unprotonated quaternary ammonium cation and (M-1) refers to the deprotonated molecular ion of the chemical species.

[0317] NMR spectra were run on a Bruker BioSpin 600MHz, Bruker AVANCE 500MHz or Varian 400MHz NMR spectrometers using ICON-NMR, under TopSpin program control. Spectra were measured at 298K, unless indicated otherwise, and were referenced relative to the solvent resonance.

[0318] Abbreviations:

[0319] DMF : Dimethylformamide

[0320] NMP : N-Methyl-2-pyrrolidone

[0321] NMR : Nuclear Magnetic Resonance

[0322] RT: Room temperature

[0323] TFA : Trifluoroacetic Acid

[0324] HATU : 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0325] General Procedure A: Saponification.

[0326] The ester (1.0 eq) was dissolved in a 3:1 mixture of THF:water. LiOH monohydrate (5 eq) was added, and the reaction mixture was stirred at RT. After complete consumption of the starting material, THF was evaporated under vacuum and the aqueous slayer was extracted with CH2CI2. The aqueous layer was acidified to pH 1 using 1 M HCI and extracted with CH2CI2. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford the carboxylic acid. In some cases, the aqueous layer was basified to pH 2-4 and extracted with a mixture of CH2CI2 and isopropanol.

[0327] General Procedure B: Amide formation

[0328] Carboxylic acid (2.0 eq), amine (1.0 eq), HATU (1.2 eq) and triethylamine (4 eq) were dissolved in NMP. The reaction mixture was purged with N2 and stirred at 100°C under N2 (16h). The reaction mixture was directly purified by reverse phase chromatography to afford the product.

[0329] Preparation of intermediates:

[0330] (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1 .1 ]pentane-1 -carboxylic acid

[0331] Step 1 : 2-(4-bromobenzyl)-3-oxopentanenitrile

[0332] To a solution of 3-(4-bromophenyl)propanenitrile (5.00 g, 23.8 mmol) in THF (30 mL) in toluene (24.6 mL, 231.0 mmol) potassium fert-butoxide (71.4 mL, 1 M, 71.4 mmol) was added slowly at RT followed by ethyl propionate (11.0 mL, 95.2 mmol). The reaction mixture was stirred at RT. After complete consumption (ca 16h) of the starting material, the mixture was quenched with 1 M HCI and extracted with ethylacetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to yield 2-(4-bromobenzyl)-3-oxopentanenitrile (4.2 g, 16 mmol, 66%).

[0333] 1H NMR (400 MHz, CDCI3) 5 1.09 (t, J = 7.2 Hz, 3H), 2.56 - 2.77 (m, 2H), 3.07 (dd, J = 14.0, 8.3 Hz, 1 H), 3.18 (dd, J = 13.9, 5.5 Hz, 1 H), 3.59 (dd, J = 8.3, 5.5 Hz, 1 H), 7.08 - 7.17 (m, 2H), 7.44 - 7.50 (m, 2H).

[0334] Step 2: 4-(4-bromobenzyl)-3-ethyl-1 H-pyrazol-5-amine

[0335] A solution of 2-(4-bromobenzyl)-3-oxopentanenitrile (3.0 g, 11.27 mmol), hydrazinehydrate (855 L, 64%, 11.27 mmol) in a 1 :1 mixturec of ethanol and acetic cacid (10 mL) was heated in a microwave vial to 140°C for 2 hours. After cooling, the reaction mixture was diluted with ethylacetate and washed with a saturated NaHCCh solution, followed by brine. The organic layer was dried over Na2SO4 and evaporated. The crude product was taken up in a 1 M aqueous solution of NaOH and heated to 140°C under microwave for 1 hour. The reaction mixture was extracted with EtOAc and the organic layer was washed with brine, dried over NazSO4 and concentrated under vacuum to yield 4-(4-bromobenzyl)-3-ethyl-1 H-pyrazol-5-amine (2.7 g, 9.637 mmol, 85.49 %).

[0336] 1H NMR (400 MHz, CDCI3) 5 1.21 (tt, J = 18.0, 7.4 Hz, 3H), 2.54 (dq, J = 22.4, 7.6 Hz, 2H), 3.63 (s, 2H), 6.99 - 7.10 (m, 2H), 7.36 - 7.45 (m, 2H).

[0337] Step 3: 3-(4-bromobenzyl)-2-ethyl-5, 7-dimethyl pyrazolo[1 ,5-a]pyrimidine

[0338] To a solution of 4-(4-bromobenzyl)-3-ethyl-1 H-pyrazol-5-amine (2.7 g, 9.64 mmol) in a 1 :1 mixture of dioxane and TFA (40 mL) was added pentane-2, 4-dione (9.98 mL, 9.637 mmol) at RT. The reaction mixture was stirred at 100°C (16 h) and neutralized with saturated aqueous NaHCOs solution. The mixture was extracted with ethylacetate, dried &7 over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to yield 3-(4- bromobenzyl)-2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidine (1.85 g, 5.37 mmol, 56 %).

[0339] 1H NMR (400 MHz, CDCI3) 5 1.21 (t, J = 7.6 Hz, 3H), 2.66 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.79 (s, 3H), 4.13 (s, 2H), 6.58 (s 1 H), 7.01 - 7.09 (m, 2H), 7.31 - 7.39 (m, 2H).

[0340] Step 4: methyl (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)acrylate

[0341] To an oven dried microwave reactor were added 3-(4-bromobenzyl)-2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidine (1 .3 g ,3.77 mmol), N-cyclohexyl-N-methylcyclohexanamine (1 .62 mL, 7.55 mmol), methylacrylate (0.68 mL, 2 Eq, 7.55 mmol) and Pd(t-Bu3P)2 (48.25 mg, 0.094 mmol) and 1 ,4-dioxane (15 mL). The reactor was degassed with argon and stirred at 130°C for 20 minutes under microwave heating. After cooling to RT, the mixture was concentrated under vacuum. The residue was diluted in ethylacetate, washed with saturated aqueous NaHCCh solution and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to yield: methyl (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)acrylate (1.26g, 3.60 mmol, 95 %) as a solid.

[0342] 1H NMR (400 MHz, CDCI3) 5 1.20 (t, J = 7.6 Hz, 3H), 2.59 (s, 3H), 2.68 - 2.79 (m, 5H), 3.79 (s, 3H), 4.19 (s, 2H), 6.37 (d, J = 16.0 Hz, 1 H), 6.48 (s, 1 H), 7.23-7.28 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1 H).

[0343] Step 5: (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)prop-2-en- 1 -ol

[0344] To a solution of methyl (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)acrylate (1.35 g, 3.863 mmol) in CH2CI2 (40 mL) at -78°C was added a DIBAL-H solution in CH2CI2 (11.59 mL, 1 M, 3 Eq, 11.59 mmol). The reaction mixture was stirred at -78°C (16 h). The mixture was quenched with MeOH and concentrated under vacuum. The residue was diluted with ethylacetate, washed with brine, dried over Na2SO4 and concentrated under vacuum to yield (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)prop-2-en-1-ol (1.240 g, 3.858 mmol, 99%).

[0345] 1H NMR (400 MHz, CDCI3) 5 1.19 (td, J = 7.6, 1.7 Hz, 3H), 2.54 (d, J = 1.3 Hz, 3H), 2.67 - 2.74 (m, 5H), 4.10 - 4.15 (m, 3H), 4.29 (s, 2H), 6.29 (dt, J = 15.8, 5.9 Hz, 1 H), 6.45 (dd, J = 4.0, 1.0 Hz, 1 H), 6.51 - 6.60 (m, 1 H), 7.12 - 7.21 (m, 2H), 7.25 (d, J = 5.6 Hz, 2H). Step 6: (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)acrylaldehyde

[0346] To a solution of (E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)prop-2-en-1-ol (920 mg, 2.86 mmol) in MeCN (25 mL) was added manganese (IV) oxide (2.49 g, 28.6 mmol) at RT. The reaction mixture was stirred for 16h. The mixture was filtered over a pad of celite and washed with MeCN. The filtrate was concentrated under vacuum and purified by flash chromatography to afford the aldehyde (680 mg, 74 %).

[0347] 1H NMR (400 MHz, CDCI3) 6 1.21 (t, J = 7.6 Hz, 3H), 2.58 (s, 3H), 2.68 - 2.79 (m, 5H), 4.20 (s, 2H), 6.49 (s, 1 H), 6.66 (dd, J = 15.9, 7.7 Hz , 1 H), 7.26 - 7.34 (m, 2H), 7.39 - 7.48 (m, 2H), 9.67 (d, J = 7.7 Hz, 1 H).

[0348] Step 7: tert-butyl (E)-4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazine-1 - carboxylate

[0349] Sodium triacetoxyhydroborate (677 mg, 3.19 mmol), DIPEA (389 L, 2.24 mmol), (E)-3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)acrylaldehyde (680 mg, 2.13 mmol) and tert-butyl piperazine- 1-carboxylate (397 mg, 2.13 mmol) were dissolved in 1 ,2 dichloroethane (15 mL) at RT. The reaction mixture was stirred at for 16h, then diluted with CH2CI2, washed with a saturated aqueous NaHCOs and the organic layer was dried over Na2SO4. The reaction nmixture was concentrated under vacuum and purified by column chromatography to afford tert-butyl (E)-4-(3-(4-((2-ethyl-5,7-d imethylpyrazolo[1 , 5-a]pyrimidin-yl)methyl)phenyl)allyl)pi perazine- 1 - carboxylate (700 mg, 67 %).

[0350] 1H NMR (400 MHz, CDCI3) 6 1.20 (t, J = 7.61 Hz, 3H), 1 .45 (s, 9H), 2.43 (s, 4H), 2.54 (s, 3H), 2.66 - 2.77 (m, 5H), 3.45 (s, 4H), 4.11 (s, 2H), 6.18 (d, J = 15.9 Hz, 1 H), 6.43 - 6.51 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H).

[0351] Step 8 : (E)-2-ethyl-5,7-dimethyl-3-(4-(3-(piperazin-1 -yl)prop-1 -en-1 -yl)benzyl)pyrazolo[1 ,5-a]pyrimidine

[0352] To a solution of tert-butyl (E)-4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazine-1-carboxylate (700 mg, 1.43 mmol) in CH2CI2 (20 mL) was added 2 mL of TFA. The reaction was stirred overnight and concentrated under reduced pressure. The residue was dissolved in CH2CI2 and washed with a saturated aqueous NaHCO ssolution. The aqueous layer was extracted with CH2CI2 and the combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford the title compound (530 mg, 95 %).

[0353] 1H NMR (400 MHz, CDCI3) 5 1 .19 (t, J = 7.6 Hz, 3H), 2.54 (br s, 7H), 2.67 - 2.76 (m, 5H), 3.00 (d, J = 27.2 Hz, 4H), 3.14 (t, J= 8.1 Hz, 2H), 4.12 (s, 2H), 6.17 (dt, J = 15.5, 7.1 Hz, 1 H), 6.43 - 6.51 (m, 2H), 7.13 - 7.21 (m, 2H), 7.24 (d, J = 8.2 Hz, 2H).

[0354] Step 9: methyl (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1 - yl)methyl)bicyclo[1.1 .1 ]pentane-1 -carboxylate

[0355] A solution of K2CO3 (229 mg, 1.66 mmol), (E)-2-ethyl-5,7-dimethyl-3-(4-(3-(piperazin-1-yl)prop-1-en-1- yl)benzyl)pyrazolo[1 ,5-a]pyrimidine (430 mg, 1.10 mmol) and methyl 3-(bromomethyl)bicyclo[1.1.1]pentane-1- carboxylate (242 mg, 1.10 mmol) was stirred overnight at 70°C in DMF. Then, the DMF was evaporated in vacuo. The residue was diluted with CH2CI2. The organic layer was washed with brine and dried over Na2SO4. The reaction mixture was concentrated under vacuum and purified by column chromatography to afford methyl (E)-3-((4-(3-(4- ((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentane-1 -carboxylate (330 mg, 56 %).

[0356] 1H NMR (400 MHz, CDCI3) 5 1 .18 (t, J = 7.6 Hz, 3H), 2.00 (s, 6H), 2.47 (s, 3H),2.51 - 2.60 (m, 9H), 2.66 - 2.76 (m, 5H), 3.19 (d, J = 6.9 Hz, 2H), 3.65 (s, 3H), 4.11 (s, 2H), 6.19 (dt, J = 15.7, 7.0 Hz, 1 H), 6.43 - 6.51 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H).

[0357] Step 10: (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1 .1 ]pentane-1 -carboxylic acid

[0358] Following general procedure A, methyl (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate (330 mg, 625 mol) and LiOH monohydrate (131 mg, 3.13 mmol) were used to afford the title compound (250 mg, 78 %)

[0359] 1H NMR (400 MHz, CDCI3) 5 1.15 - 1.22 (m, 3H), 2.04 (s, 6H), 2.54 (s, 3H), 2.66 - 2.78 (m, 7H), 2.92 (br s, 6H), 3.42 (s, 2H), 3.63 (s, 2H)4.12 (s, 2H), 6.22 (dt, J = 14.7, 6.9 Hz, 1 H), 6.45 (s, 1 H), 6.56 (dd, J = 15.8, 11.4 Hz, 1 H),

[0360] 7.14 - 7.22 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H). tert-butyl bis(14-amino-3,6,9,12-tetraoxatetradecyl)carbamate

[0361] Step 1 : 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate

[0362] To a solution of 3,6,9, 12-tetraoxatetradecane-1 , 14-diol (10.0 g, 42.0 mmol, 1 eq.) in CH2CI2 (84 mL, 0.5 molar) at 0°C were added KI (1.39 g, 8.39 mmol, 0.2 eq.) and Ag2O (14.6 g, 63.0 mmol, 1.5 eq.). p-Touenesulfonyl chloride (8.80 g, 46.2 mmol, 1.1 eq.) was then added portion wise and the reaction mixture was stirred at 0°C (1h). The mixture was filtered through a pad of Celite and the pad was washed with CH2CI2. The filtrates were combined and evaporated. The crude material was purified by silica gel chromatography to provide the title compound (11.412 g, 29.078 mmol, 69.3 %).

[0363] 1H NMR (400 MHz, CDCI3) 5 7.79 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.17 - 4.14 (m, 2H), 3.73 - 3.58 (m, 18H), 2.51 - 2.45 (m, 1 H), 2.44 (s, 3H).

[0364] Step 2: N,N-bis(14-hydroxy-3,6,9,12-tetraoxatetradecyl)-2-nitrobenzenesulfonamide

[0365] A mixture of 2-nitrobenzenesulfonamide (1 .70 g, 8.38 mmol, 0.4 eq.) and cesium carbonate (6.00 g, 18.44 mmol, 0.88 eq.) in DMF (16.8 mL, 1.25 molar) was heated at 80 °C for 1h. Then, 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (8.22 g, 20.95 mmol, 1 eq.) was added dropwise and the reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to RT, quenched with sat. aqueous NH4CI solution and diluted with CH2CI2. The two layers were separated, and the aqueous layer was washed with CH2CI2. The combined organic layers were washed with brine (3x), dried over Na2SO4, filtrated, and concentrated under vacuum. The crude material was then purified by silica gel chromatography to give N,N-bis(14-hydroxy-3,6,9,12- tetraoxatetradecyl)-2-nitrobenzenesulfonamide (3.92 g, 6.11 mmol, 73%).

[0366] 1H NMR (400 MHz, CDCI3) 5 8.11 - 8.04 (m, 1 H), 7.73 - 7.59 (m, 3H), 3.72 - 3.70 (m, 4H), 3.67 - 3.58 (m, 28H), 3.58 - 3.52 (m, 8H), 2.49 - 2.43 (m, 2H).

[0367] Step 3: tert-butyl bis(14-hydroxy-3,6,9,12-tetraoxatetradecyl)carbamate

[0368] To a solution of N,N-bis(14-hydroxy-3,6,9,12-tetraoxatetradecyl)-2-nitrobenzenesulfonamide (3.65 g, 5.68 mmol, 1 eq.) in acetonitrile (57 mL, 0.1 molar) was added K2CO3 (1.570 g, 11.36 mmol, 2 eq.) and thiophenol (643 pL, 6.25 mmol, 1 .1 eq.). The reaction mixture was stirred at room temperature overnight. Triethylamine (2.4 mL, 17.04 mmol, 3 eq.) and BOC2O (1.4 mL, 6.25 mmol, 1.1 eq.) was then added and the reaction mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under vacuum and the crude product was purified by silica gel chromatography to give tert-butyl bis(14-hydroxy-3,6,9,12-tetraoxatetradecyl)carbamate (2.50 g, 4.47 mmol, 79%).

[0369] 1H NMR (400 MHz, CDCI3) 6 3.72 (t, J = 4.4 Hz, 4H), 3.68 - 3.56 (m, 32H), 3.47 - 3.37 (m, 4H), 2.84 - 2.57 (m, 2H), 1.44 (s, 9H).

[0370] Step 4 :15-(tert-butoxycarbonyl)-3,6,9,12,18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29-diyl bis(4- methylbenzenesulfonate)

[0371] To a solution of tert-butyl bis(14-hydroxy-3,6,9,12-tetraoxatetradecyl)carbamate (2.39 g, 4.28 mmol, 1 eq.) in CH2CI2 (42.8 mL, 0.1 molar) at 0°C was added KI (284 mg, 1.71 mmol, 0.4 eq.) and Ag2O (2.97 g, 12.84 mmol, 3 eq.). 4-Methylbenzenesulfonyl chloride (2.04 g, 10.70 mmol, 2.5 eq.) was then added portion-wise and the reaction mixture was stirred at RT overnight. The mixture was filtered through a pad of Celite and the pad was washed with CH2CI2. The filtrate was evaporated and the crude material was purified by silica gel chromatography to give 15- (tert-butoxycarbonyl)-3,6,9,12,18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29-diyl bis(4-methyl benzenesulfonate) (2.827 g, 3.264 mmol, 76 %).

[0372] 1H NMR (400 MHz, CDCI3) 6 7.87 - 7.72 (m, 4H), 7.36 - 7.31 (m, 4H), 4.17 - 4.14 (m, 4H), 3.70 - 3.67 (m, 4H), 3.63 - 3.53 (m, 28H), 3.45 - 3.38 (m, 4H), 2.44 (s, 6H), 1 .44 (s, 9H). Step 5 tert-butyl bis(14-azido-3,6,9,12-tetraoxatetradecyl)carbamate

[0373] To a solution of 15-(tert-butoxycarbonyl)-3,6,9,12,18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29-diyl bis(4- methylbenzenesulfonate) (2.80 g, 3.23 mmol, 1 eq.) in DMF (16.2 mL, 0.2 molar) was added sodium azide (841 mg, 12.94 mmol, 4 eq.) and the mixture was stirred at 60°C overnight. After concentration, CFhCbwas added, and the mixture was filtered through a pad of Celite and the pad was washed with CH2CI2. The solvent was evaporated under vacuum and the crude material was purified by silica gel chromatography to give tert-butyl bis(14-azido- 3,6,9,12-tetraoxatetradecyl)carbamate (1.77 g, 2.9 mmol, 90 %).

[0374] 1H NMR (400 MHz, CDCI3) 5 3.69 - 3.54 (m, 32H), 3.45 - 3.35 (m, 8H), 1.44 (s, 9H).

[0375] Step 6: tert-butyl bis(14-amino-3,6,9,12-tetraoxatetradecyl)carbamate

[0376] Tert-butyl bis(14-azido-3,6,9,12-tetraoxatetradecyl)carbamate (1.76 g, 2.90 mmol, 1 eq.) was dissolved in EtOH (29.0 mL, 0.1 molar). Three cycles of N2 / vacuum were performed before addition of Pd / C (176 mg, 10 wt.%). Three cycles of H2 / vacuum were performed again. Then, the reaction mixture was kept under a H2 atmosphere (1 atm) overnight. The reaction mixture was filtrated through a pad of celite and concentrated under vacuum. The crude product was purified by reverse phase chromatography giving tert-butyl bis(14-amino-3,6,9,12- tetraoxatetradecyl)carbamate (129 mg, 232 pmol, 8.0 %) as a transparent oil.

[0377] 1H NMR (400 MHz, CDCI3) 5 6.32 - 6.15 (m, 4H), 3.80 - 3.72 (m, 4H), 3.68 - 3.58 (m, 28H), 3.49 - 3.39 (m, 4H), 3.17 - 3.08 (m, 4H), 1.43 (s, 9H).

[0378] 2 ,5-dioxopyrrolidin-1 -yl (tert-butoxycarbonyl)glycinate

[0379] To a mixture of (tert-butoxycarbonyl)glycine (1.00 g, 5.71 mmol, 1 eq.) in EtOAc (28.5 mL, 0.2 molar) at 0°C was added N-Hydroxysuccinimide (723 mg, 6.28 mmol, 1.1 eq.) followed by dicyclohexyl carbodiimide (1.41 g, 6.85 mmol, 1 .2 eq.). The mixture was stirred for 30 min at 0°C and then at room temperature for 72h. The reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc. The solvent was removed under vacuum. The resulting residue was dissolved in 100 mL of ethyl acetate and the organic layer was washed with 5% 13 aqueous NaHCOs aqueous and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 2,5-dioxopyrrolidin-1 -yl (tert-butoxycarbonyl)glycinate as a white solid.

[0380] 1H NMR (400 MHz, DMSO) 5 7.47 (t, J = 6.1 Hz, 1 H), 4.08 (d, J = 6.2 Hz, 2H), 2.80 (s, 4H), 1.38 (s, 9H).

[0381] Preparative examples

[0382] Preparative Example 1 :

[0383] (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- y I) methyl) b icyclo[1 .1.1 ]pentan-1 -yl)-1 , 17-d ioxo-6 , 9 , 12-trioxa-2, 16-diazaoctadecan-18-yl)- 1 ,4,7, 10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0384] Step 1 : tert-butyl (E)-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 1 -oxo-6, 9, 12-trioxa-2-azapentadecan-15- yl)carbamate

[0385] Following general procedure B, intermediate (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (100 mg, 195 pmol, 1 eq.) in NMP (390 pL, 0.5 molar), HATU (88.8 mg, 234 pmol, 1.2 eq.), 6,9,12-trioxa-2-azapentadecanoic acid, 15-amino-, 1 ,1 -dimethylethyl ester (60.3 pL, 195 pmol, 1 eq.) and triethylamine (59.7 pL, 428 pmol, 2.2 eq.) were used. The product was purified by reverse phase chromatography. 76.7 mg (94.0 pmol, 48.3 %) of the title compound was obtained.

[0386] 1H NMR (400 MHz, CDCI3) 5 7.28 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 15.3 Hz, 1 H), 6.46 (d, J = 1.0 Hz, 1 H), 6.31 (s, 1 H), 6.26 - 6.14 (m, 1 H), 4.97 (s, 1 H), 4.12 (s, 2H), 3.66 - 3.50 (m, 16H), 3.33 (q, J = 6.0 Hz, 2H), 3.21 (q, J = 6.5 Hz, 3H), 3.01 - 2.78 (m, 5H), 2.74 - 2.68 (m, 6H), 2.54 (s, 3H), 1 .99 (s, 6H), 1.80 - 1.70 (m, 5H), 1.43 (s, 9H), 1.19 (t, J = 7.6 Hz, 3H).

[0387] Step 2: (E)-N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5- a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

[0388] To a solution of tert-butyl (E)-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 1 -oxo-6, 9, 12-trioxa-2-azapentadecan-15- yl)carbamate (76.7 mg, 94.0 pmol, 1 eq.) in 1 ,4-dioxane (310 pL) was added dropwise HCI (235 pL, 4 molar in 1 ,4-dioxane, 940 pmol, 10 eq.). The reaction mixture was stirred at RT for 16h. The reaction mixture was then evaporated under vacuum to yield the product as a solid. The crude was directly used in the next step.

[0389] 1H NMR (400 MHz, CDC13) 5 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (s, 1 H), 6.67 (d, J = 16.2 Hz, 1 H), 6.47 (d, J = 1.0 Hz, 1 H), 6.35 - 6.23 (m, 1 H), 4.13 (s, 2H), 3.83 (t, J = 5.0 Hz, 2H), 3.76 - 3.52 (m, 39H), 3.44 - 3.39 (m, 4H), 3.18 (s, 2H), 2.79 - 2.65 (m, 6H), 2.55 (s, 3H), 2.16 (s, 6H), 1.19 (t, J = 7.6 Hz, 3H), 0.84 (s, 2H).

[0390] Step 3: tri-tert-butyl 2,2', 2"-(10-(1 -(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)- 1 , 17-d ioxo-6 ,9 , 12-trioxa-2, 16- diazaoctadecan-18-y I)- 1 ,4,7,10-tetraazacyclododecane-1 ,4 , 7-triyl)( E)-triacetate

[0391] To a solution of crude intermediate from step 2 (70.7 mg, 94.0 pmol, 1 eq.) in anhydrous DMF (940 pL, 0.1 molar) was added triethylamine (39.3 pL, 282 pmol, 3 eq.) followed by tri-tert-butyl 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1- yl)oxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetate (63 mg, 94.0 pmol, 1 eq.). The reaction mixture was stirred at RT for 16h. The reaction mixture was then purified directly by reverse phase and the product was freeze dried to afford the title compound (12 mg, 9.4 pmol, 10 %).

[0392] 1H NMR (400 MHz, CDCh) 5 7.30 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 6.83 - 6.61 (m, 3H), 6.49 - 6.44 (m, 1 H), 6.25 (m, 1 H), 4.12 (s, 2H), 4.10 - 2.81 (m, 52H), 2.75 - 2.64 (m, 5H), 2.55 (s, 3H), 2.20 (s, 6H), 5 1.76 (m, 4H), 1.49 (s, 9H), 1.41 (s, 18H), 1.18 (t, J = 7.6 Hz, 3H).

[0393] Step 4 (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 1 , 17-d ioxo-6 ,9 , 12-trioxa-2 , 16- diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid IS

[0394] To a solution of tri-tert-butyl 2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)- 1 , 17-d ioxo-6 ,9 , 12-trioxa-2, 16- diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(E)-triacetate (12 mg, 9.4 mol, 1 eq.) in CH2CI2 (0.15 mL, 0.065 molar) at 0°C, was added TFA (0.15 mL, 0.065 molar). The reaction mixture was stirred at 0°C for 1 h and then at RT for 16h. The solvent was then evaporated under vacuum and the residue was freeze dried to give the desired product (3.4 mg, 3.1 mol, 33 %).

[0395] 1H NMR (400 MHz, DMSO-d6) 58.15 - 8.06 (m, 1 H), 7.65 - 7.55 (m, 1 H), 7.35 - 7.29 (d, J = 7.8 Hz, 2H), 7.18 - 7.12 (d, J = 7.8 Hz, 2H), 6.76 (s, 1 H), 6.59 - 6.51 (m, 1 H), 6.26 - 6.15 (m, 1 H), 4.02 (s, 2H), 3.58 - 2.92 (m, 48H), 2.79 - 2.58 (m, 15H), 1.87 (s, 6H), 1.71 - 1.56 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H).

[0396] Preparative Example 2

[0397] (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1 ,30-dioxo-5,8,11 ,14,17,20,23,26-octaoxa-2,29-diazahentriacontan-31-yl)-

[0398] 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0399] Step 1 : (E)-N-(26-azido-3, 6,9, 12,15, 18,21 ,24-octaoxahexacosyl)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5- a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentane-1-carboxamide

[0400] Following general procedure B, intermediate (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (200 mg, 389 mol, 1 eq.) in NMP (780 L, 0.5 molar), HATU (178 mg, 467 pmol, 1.2 eq.), 26-azido-3,6,9,12,15,18,21 ,24-octaoxahexacosan- 1-amine (171 mg, 389 mol, 1 eq.) and triethylamine (120 L, 857 pmol, 2.2 eq.) were used. The reaction mixture was purified by reverse phase and the product was freeze dried to afford the title compound (141 mg, 151 pmol, 38.8 %).

[0401] 1H NMR (400 MHz, CDCI3) 6 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 15.6 Hz, 1 H), 6.47 (s, 1 H), 6.34 - 6.12 (m, 2H), 4.13 (s, 2H), 3.72 - 3.59 (m, 39H), 3.54 (t, J = 5.1 Hz, 3H), 3.44 - 3.33 (m, 5H), 2.74 - 2.65 (m, 6H), 2.55 (s, 3H), 2.04 (s, 6H), 1.19 (t, J = 7.6 Hz, 3H).

[0402] Step 2: (E)-N-(26-amino-3,6,9, 12,15, 18,21 ,24-octaoxahexacosyl)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5- a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1 ,1]pentane-1-carboxamide

[0403] To a solution of (E)-N-(26-azido-3,6,9,12,15,18,21 ,24-octaoxahexacosyl)-3-((4-(3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentane-1- carboxamide (70 mg, 75 mol, 1 eq) in THF (1.1 mL, 0.07 molar) and H2O (1.1 mL, 0.07 molar) was added triphenylphosphine (59 mg, 0.22 mmol, 3 eq.). The resulting mixture was stirred at RT for 16h and additional 72 hours. LC-MS still showed intermediate so HCI (0.1 mL, 2 molar in water, 0.2 mmol, 5 eq.) was added and the reaction mixture was stirred at RT for 16h. LC-MS finally showed complete conversion. The mixture was evaporated under vacuum and diluted in 1 mL of DMF before being purified by reverse phase chromatography. The fractions were combined and freeze dried to afford the desired product (36 mg, 40 pmol, 53 %).

[0404] 1H NMR (400 MHz, CDCI3) 5 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (s, 1 H), 6.67 (d, J = 16.2 Hz, 1 H), 6.47 (d, J = 1.0 Hz, 1 H), 6.35 - 6.23 (m, 1 H), 4.13 (s, 2H), 3.83 (t, J = 5.0 Hz, 2H), 3.76 - 3.52 (m, 39H), 3.44 - 3.39 (m, 4H), 3.18 (s, 2H), 2.79 - 2.65 (m, 6H), 2.55 (s, 3H), 2.16 (s, 6H), 1.19 (t, J = 7.6 Hz, 3H), 0.84 (s, 2H).

[0405] Step 3 tri-tert-butyl 2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y l)methy I) bicyclo[ 1.1.1 ] pentan- 1 -yl)-1 ,30-d ioxo-5,8 , 11 ,14,17,20,23,26-octaoxa- 2,29-diazahentriacontan-31-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(E)-triacetate To a solution of (E)-N-(26-amino-3,6,9,12,15,18,21 ,24-octaoxahexacosyl)-3-((4-(3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentane-1- carboxamide (36 mg, 40 pmol, 1 eq.) in anhydrous DMF (1.3 mL, 0.03 molar) was added tri-tert-butyl 2,2',2"-(10- (2-((2,5-dioxopyrrolidin- 1 -yl)oxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetate (27 mg, 40 pmol, 1 eq.) followed by triethylamine (22 pL, 0.16 mmol, 4 eq.). The reaction mixture was stirred at room temperature for 4h and purified by reverse phase chromatography to afford the title compound (38.8 mg, 26.5 pmol, 67 %).

[0406] 1H NMR (400 MHz, CDCI3) 5 8.40 (s, 1 H), 7.24 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.53 (d, J = 16.0 Hz, 1 H), 6.45 (d, J = 0.8 Hz, 1 H), 6.30 - 6.17 (m, 1 H), 6.16 - 6.07 (m, 1 H), 4.12 (s, 2H), 3.68 - 3.58 (m, 38H), 3.54 (t, J = 4.9 Hz, 2H), 3.46 - 3.41 (m, 4H), 3.38 - 3.27 (m, 9H), 3.09 - 2.91 (m, 10H), 2.84 (s, 6H), 2.74 - 2.67 (m, 8H), 2.54 (s, 3H), 1.98 (s, 6H), 1.45 (s, 27H), 1.19 (t, J = 7.6 Hz, 3H).

[0407] Step 4 (E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 1 ,30-d ioxo-5,8 , 11 ,14,17,20,23,26-octaoxa- 2,29-diazahentriacontan-31 -yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0408] To a solution of : tri-tert-butyl 2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 1 ,30-d ioxo-5,8 , 11 ,14,17,20,23,26-octaoxa- 2,29-diazahentriacontan-31-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(E)-triacetate

[0409] (36.8 mg, 25.2 pmol, 1 eq.) in CH2CI2 (390 pL, 0.065 molar) was added TFA (390 pL, 5.03 mmol, 200 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then at room temperature for 24h. LC-MS showed remaining monoprotected product so additional TFA (390 pL, 5.03 mmol, 200 eq.) was added and the reaction mixture was stirred at room temperature for 48h. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford the desired product (18 mg, 14 pmol, 55 %) as a white solid.

[0410] 1H NMR (400 MHz, CDCI3) 5 7.65 (s, 1 H), 7.24 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 6.66 (s, 1 H), 6.56 (d, J = 15.8 Hz, 1 H), 6.46 (d, J = 1.1 Hz, 1 H), 6.20 - 6.09 (m, 1H), 4.12 (s, 2H), 3.70 - 3.36 (m, 48H), 2.34 - 2.77 (d, J = 81 .4 Hz, 24H), 2.75 - 2.67 (m, 8H), 2.54 (s, 3H), 2.03 (s, 6H), 1 .19 (t, J = 7.6 Hz, 3H).

[0411] Preparative Example 3

[0412] 2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan- 16-yl)-1 ,18,21-trioxo-5,8,11 ,14-tetraoxa-2,17,20-triazadocosan-22-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7- triyl)triacetic acid

[0413] Step 1 : tert-butyl bis(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan- 16-yl)carbamate

[0414] To a solution of intermediate (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (238 mg, 464 mol, 2 eq.) in NMP (1.16 mL, 0.2 molar) was added HATU (106 mg, 279 mol, 1.2 eq.), tert-butyl bis(14-amino-3,6,9,12- tetraoxatetradecyl)carbamate (129 mg, 232 mol, 1 eq.) and triethylamine (130 L, 929 pmol, 4 eq.). The reaction mixture was purged with N2 and stirred at 100°C overnight. Purification on reverse phase chromatography provided the target compound (130 mg, 84.0 pmol, 36 %) as a white solid.

[0415] 1H NMR (400 MHz, CDCI3) 6 7.25 (d, J = 8.3 Hz, 4H), 7.18 (d, J = 8.3 Hz, 4H), 6.58 (d, J = 15.7, 2H), 6.45 (d, J = 0.9 Hz, 2H), 6.35 - 6.20 (br m, 2H), 6.19 - 6.06 (m, 2H), 4.11 (s, 4H), 3.68 - 3.50 (m, 40H), 3.47 - 3.38 (m, 12H), 2.99 - 2.78 (m, 8H), 2.74 - 2.61 (m, 14H), 2.53 (s, 6H), 2.03 (s, 12H), 1 .43 (s, 9H), 1 .18 (t, J = 7.6 Hz, 6H).

[0416] Step 2: N,N'-(3,6,9, 12, 18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29-diyl)bis(3-((4-((E)-3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1- carboxamide)

[0417] To a solution of tert-butyl bis(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan- 16-yl)carbamate (50 mg, 32 pmol, 1 eq.) in CH2CI2 (0.11 mL, 0.3 molar) was added dropwise trifluoroacetic acid (0.10 mL, 1.3 mmol, 40 eq.) at 0°C. The reaction mixture was stirred at 0°C for 30 min and then at room temperature until complete conversion (2h). The solvent was removed under vacuum to give the title compound, which was used in the next step without purification.

[0418] Step 3: tert-butyl (1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo- 5,8,11 ,14-tetraoxa-2-azahexadecan-16-yl)-1 ,18-dioxo-5,8,11 ,14-tetraoxa-2,17-diazanonadecan-19-yl)carbamate

[0419] Following general procedure B, intermediate N,N'-(3,6,9,12,18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29- diyl)bis(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentane-1 -carboxamide) (47 mg, 32 pmol, 1 eq.) in DMF (0.32 mL, 0.1 molar), triethylamine (23 pL, 0.16 mmol, 5 eq.) and 2,5-dioxopyrrolidin-1 -yl (tert-butoxycarbonyl)glycinate (8.8 mg, 32 pmol, 1 eq.) were used to give the title compound (28.6 mg, 17.8 pmol, 55 %).

[0420] 1H NMR (400 MHz, CDCI3) 5 7.24 (d, J = 8.3 Hz, 4H), 7.17 (d, J = 8.2 Hz, 4H), 6.51 (d, J = 15.8 Hz, 2H), 6.45 (d, J = 1.0 Hz, 2H), 6.23 - 6.03 (m, 4H), 5.57 (t, J = 4.5 Hz, 1 H), 4.11 (s, 4H), 4.05 (d, J = 4.6 Hz, 2H), 3.64 - 3.52 (m, 40H), 3.42 (q, J = 5.3 Hz, 4H), 3.30 (d, J = 7.0 Hz, 4H), 2.78 - 2.64 (m, 22H), 2.56 (s, 4H), 2.53 (s, 6H), 1.97 (s, 12H), 1.43 (s, 9H), 1.18 (t, J = 7.6 Hz, 6H).

[0421] Step 4: 3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)-N-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-glycyl-1-oxo-5,8,11,14,20,23,26,29-octaoxa-2,17-diazahentriacontan-31- yl)bicyclo[1 .1 .1 ]pentane-1 -carboxamide

[0422] To a solution of the product from step 3 (28.6 mg, 17.8 pmol, 1 eq.) in CH2CI2 (180 pL, 0.1 molar) was added trifluoroacetic acid (110 pL, 1 .43 mmol, 80 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then at RT for 3 h. The mixture was concentrated under vacuum to give the title compound which was used in the next step without purification.

[0423] Step 5: tri-tert-butyl 2,2'J2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1J5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-oxo- 5,8, 11 , 14-tetraoxa-2-azahexadecan-16-y I)- 1 , 18,21 -trioxo-5,8, 11 , 14-tetraoxa-2, 17,20-triazadocosan-22-yl)-

[0424] 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetate

[0425] To a solution of 3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)-N-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-glycyl-1-oxo-5,8,11,14,20,23,26,29-octaoxa-2,17-diazahentriacontan-31- yl)bicyclo[1 .1 .1 ]pentane-1 -carboxamide

[0426] (26.8 mg, 17.8 pmol, 1 eq.) in DMF (180 pL, 0.1 molar) was added triethylamine (9.9 pL, 71.3 pmol, 4 eq.) followed by tri-tert-butyl 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7- triyl)triacetate (13.1 mg, 19.6 pmol, 1.1 eq.). The reaction was stirred at room temperature overnight. The reaction mixture was purified by reverse phase and the product was freeze-dried to give the title compound (20.7 mg, 10.1 pmol, 56.4 % over 2 steps) as a white solid.

[0427] 1H NMR (400 MHz, CDCI3) 5 7.17 (d, J = 7.9 Hz, 4H), 7.11 (d, J = 7.9 Hz, 4H), 6.47 - 6.41 (m, 2H), 6.39 (d, J = 1.0 Hz, 2H), 6.17 - 6.07 (m, 4H), 4.11 (d, J = 5.3 Hz, 2H), 4.05 (s, 4H), 3.59 - 3.45 (m, 40H), 3.35 (t, J = 6.0 Hz, 8H), 3.02 - 2.77 (m, 16H), 2.68 - 2.60 (m, 12H), 2.47 (s, 6H), 1.91 (s, 12H), 1.75- 1.50 (m, 22H), 1.37 (s, 27H), 1.12 (t, J = 7.6 Hz, 6H).

[0428] Step 6: 2,2',2"-( 10-(1 -(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1 ,1]pentan-1-yl)-1-oxo- 5,8, 11 , 14-tetraoxa-2-azahexadecan-16-y I)- 1 , 18,21 -trioxo-5,8, 11 , 14-tetraoxa-2, 17,20-triazadocosan-22-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0429] To the product from step 5 (20.7 mg, 10.1 pmol, 1 eq.) was added trifluoroacetic acid (200 pL, 0.05 molar) at 0°C. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the residue was diluted with DMF before being purified by reverse phase chromatography to afford the title compound (13mg, 6.98 pmol, 69.4 %) as a white solid after lyophilisation.1H NMR (400 MHz, CDCI3) 5 7.28 (d, J = 7.9 Hz, 4H), 7.19 (d, J = 7.9 Hz, 4H), 6.63 (d, J = 15.9 Hz, 2H), 6.46 (s, 2H), 6.32 - 6.12 (m, 4H), 4.12 (s, 4H), 3.81 - 3.44 (m, 50H), 3.41 - 3.36 (m, 4H), 3.19 - 2.81 (m, 12H), 2.74 - 2.66 (m, 10H), 2.54 (s, 6H), 2.28 - 1.79 (m, 37H), 1.19 (t, J = 7.6 Hz, 6H).

[0430] Preparative Example 4

[0431] 2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1 .1]pentan-1-yl)-1-oxo-5,8,11 ,14-tetraoxa-2-azahexadecan- 16-yl)- 1 , 18-dioxo-5, 8, 11 , 14-tetraoxa-2, 17-diazanonadecan-19-yl)-1 ,4,7, 10-tetraazacyclododecane-1 ,4,7- triyl)triacetic acid

[0432] Step 1 : tri-tert-butyl 2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1 ,1]pentan-1-yl)-1-oxo- 5,8, 11 , 14-tetraoxa-2-azahexadecan-16-y I)- 1 , 18-dioxo-5,8, 11 ,14-tetraoxa-2, 17-diazanonadecan-19-y I)- 1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triyl)triacetate

[0433] To a solution of N,N'-(3,6,9,12,18,21 ,24,27-octaoxa-15-azanonacosane-1 ,29-diyl)bis(3-((4-((E)-3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentane-1- carboxamide (93 mg, 64 mol, 1 eq.) in anhydrous DMF (0.64 mL, 0.1 molar) was added tri-tert-butyl 2,2',2"-(10- (2-((2,5-dioxopyrrolidin-1 -yl)oxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetate (47 mg, 71 mol, 1.1 eq.) followed by triethylamine (36 L, 0.26 mmol, 4 eq.) at room temperature. The reaction mixture was stirred at RT (72 h). The solution was purified by reverse phase chromatography to give the target compound (28 mg, 14.1 pmol, 22 %) as a white solid.

[0434] 1H NMR (400 MHz, CDCI3) 5 7.25 (d, J = 7.9 Hz, 4H), 7.19 (d, J = 7.9 Hz, 4H), 6.59 (d, J = 15.8 Hz, 2H), 6.46 (s, 2H), 6.27 - 6.10 (m, 4H), 4.12 (s, 4H), 3.62 (t, J = 6.5 Hz, 36H), 3.55 - 3.52 (m, 8H), 3.44 - 3.38 (m, 8H), 3.05 - 2.82 (m, 22H), 2.74 - 2.68 (m, 16H), 2.54 (s, 6H), 2.02 (s, 12H), 1.47 - 1.41 (m, 35H), 1.19 (t, J = 7.6 Hz, 6H).

[0435] Step 2: 2,2',2"-(10-(1 -(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-17-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1 ,1]pentan-1-yl)-1-oxo- 5,8,11 ,14-tetraoxa-2-azahexadecan-16-yl)-1 ,18-dioxo-5,8,11 ,14-tetraoxa-2,17-diazanonadecan-19-yl)-1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0436] To a solution of 24 (10 mg, 5.0 mol, 1 eq.) in CH2CI2 (0.10 mL, 0.05 molar) was added dropwise TFA (0.10 mL, 0.05 molar) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by reverse phase chromatography to afford the desired product (5.4 mg, 2.9 mol, 59 %) as a white solid.

[0437] 1H NMR (400 MHz, CDCI3) 5 7.28 (d, J = 8.0 Hz, 4H), 7.19 (d, J = 8.0 Hz, 4H), 7.71 - 6.56 (m, 3H), 6.46 (d, J = 1 .0 Hz, 2H), 6.30 - 6.16 (m, 3H), 4.12 (s, 4H), 3.70 - 3.46 (m, 34H), 3.44 - 3.33 (m, 8H), 3.27 - 2.83 (m, 22H), 2.74 - 2.64 (m, 10H), 2.54 (s, 6H), 2.38 - 1.82 (m, 36H), 1.19 (t, J = 7.6 Hz, 6H).

[0438] General tic scheme for SPPS 5-7: a) Fmoc-AA-OH (1.2 eq.), DIPEA (8.0 eq.), DCM, 16 h (ON); b) DCM:MeOH:DIPEA (17 / 2 / 1 , v / v / v), 1 h; c) DMFPiperidine (1 :1 , v / v), 2x 15 s + 2x 5 min; d) Fmoc-AA-OH (4.00 eq.), HBTU (3.97 eq.), DIPEA (8.00 eq.), DMF, 1 h; e) Fmoc-PEG2-OH (4.00 eq.), HBTU (3.97 eq.), DIPEA (8.00 eq.), DMF, 1 h; f) DOTA-tris(tBu)ester (2.00 eq.), HBTU (1 .98 eq.), DIPEA (4.00 eq.), DMF, 2 h; g) DCM:HFIP (3:1 , v / v), 2x 1.5 h.

[0439] Fragments F5-7 were synthesized by conventional fluorenylmethoxycarbonyl (Fmoc)-protected solid-phase peptide synthesis (SPPS) using orthogonal building blocks and a 2-chlorotrityl chloride (2-CITrt-CI) resin as a solid support, according to the above scheme.

[0440] General procedures for SPPS production of linker-chelator-fraqments (F5-7) of preparative examples 5-7:

[0441] I. Swelling of the Resin: Before performing any reaction, the dry resin was swollen in dichloromethane (DCM, 3 mL) for 30 minutes and then washed with the solvent used in the next reaction step (6x 3 mL).

[0442] I I . Standard Washing Procedures and Drying of the Resin: Residual reactants were removed after every reaction step by washing the resin with dimethylformamide (DMF) or DCM, depending on the utilized solvent (6x 3 mL). Before exposing the resin to vacuum for drying, additional washing steps with DCM and diethyl ether (Et20) were performed (6x 3 mL each).

[0443] III. Removal ofFmoc Protecting Groups: The resin-immobilized compounds were exposed to piperidine in DMF (1 :1 , v / v, 2x 3 mL for 15 s and 2x 3 mL for 5 min). After completion of the last repetition, the liquid content of the syringe was discarded into water, and the absence of white precipitate indicated complete removal of the Fmoc protecting groups.

[0444] IV. Quantitative Removal of the Fmoc Protecting Group & Extinction Measurement: The first Fmoc deprotection of each synthesis was performed quantitatively to estimate the amount of amino acid loaded onto the resin. The Fmoc deprotection was performed in accordance with the procedure reported above; however, in this case, the deprotection solution and resulting DMF washes were collected and diluted to a known concentration. The extinction of the diluted sample was measured at the maximum absorption wavelength of Fmoc (Amax,Fmoc = 301 nm) using a UV-VIS spectrophotometer (SPECORD 40, Analytik Jena GmbH). The resulting molar absorption was used to determine the Fmoc concentration using the coefficient of Fmoc EFmoc = 7800 mol-1cm-1and the value for the applied dilution. This data represents a direct estimation of the amount of compound attached to the solid support and was used for the calculation of the loading capacity of the resin. Yields reported for SPPS fragments F5-7 are indicated relative to the initially determined achieved resin loading.

[0445] V. HBTU-catalyzed Amide Coupling Reactions: For each amide coupling step, a solution containing the appropriate building block (e.g. protected amino acid, Fmoc-AA-OH, 4.00 equiv.), the coupling reagent O-(benzotriazol-1-yl)-N, / V,N,N-tetramethyluronium-hexafluorophosphate (HBTU, 3.97 equiv.) and DIPEA (8.00 equiv.) in dry DMF (3-4 mL), was prepared. The resulting solution was vortexed for two minutes to allow the formation of the activated ester. The activated solution was then added to the resin-immobilized compound and agitated for 1 .5 h (+ 0.5 h).

[0446] Note: Coupling of the DOTA-tris(fBu)-esters (DOTA) was performed using 2.00 equiv. DOTA, 1 .98 equiv. HBTU and 4.00 equiv. DIPEA. After activation, the resulting solution was added to the resin and agitated for 2 h.

[0447] VI. Cleavage from the resin: For cleavage of the SPPS fragments F5-7 from the dried 2-CITrt-CI resin, the resin-immobilized compounds were exposed to a cleavage solution of 1 ,1 , 1,3,3, 3-hexafluor-2- propanol (HFIP) in DCM (1 :3, v / v) for 1.5 h. An additional washing step with cleavage solution for 1.5 h ensured complete cleavage from the resin. The combined filtrates were concentrated under reduced pressure. VII. Sample Preparation and Purification using UV-HPLC:Tne concentrated compounds were redissolved in ACN and Milli-Q H2O (1 :1, v / v, 1-2 ml), and the resultant solutions were filtered (0.2 pm PTFE filters) prior to HPLC injection. UV-HPLC purification was performed using a Merck-Hitachi LaChrom HPLC system equipped with a D-7000 interface, an L-7200 autosampler, an L-7400 UV detector, an L-7100 pump and a semipreparative reversed-phase (RP) column (C18, Phenomenex, 10x250 mm, 5 pm, 110 A). SPPS fragments F^ were eluted using linear gradients of Milli-Q water containing 0.1 % TFA and ACN at a flow-rate of 2 ml / min. At a later stage, purification was further optimized and conducted with a preparative RP column (C18, CLIPEUS, 20x250 mm, 10 pm), operating a flow-rate of 15 ml / min.

[0448] Summarized Results for SPPS synthesized fragments F5-7:

[0449] SPPS fragment F5:

[0450] (S)-(2,2-dimethyl-4,8-dioxo-7-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1- yl)acetamido)-3, 12,15-trioxa-9-azaoctadecan-18-oy l)g lyci ne

[0451] (S)-(2,2-dimethyl-4,8-dioxo-7-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1- yl)acetamido)-3,12,15-trioxa-9-azaoctadecan-18-oyl)glycine was synthesized by SPPS according to the scheme and general procedures (l-VII) mentioned above. Determined resin loading: 0.380 mmol; Yield: 200 mg (0.205 mmol, 54%).

[0452] LC-MS (ETH, Agilent-G6135C-1 , PN_100-1000, UV 220 nm): tR: 3.8 min, m / z calculated for C46H84N7OI5+[M + H]+: 974.6, found: 974.8.

[0453] HR-MS: Partial fragmentation of fBu groups is observed: m / z calculated for [M + 2H]2+: 487.8047; found: 487.8046 m / z calculated for [M + 2H - tBu]2+: 459.7734; found: 459.7741 m / z calculated for [M + 2H - 2tBu]2+: 431.7421 ; found: 431.7431 SPPS fragment Fe:

[0454] (S)-17-(3-(tert-butoxy)-3-oxopropyl)-2,5, 15-trioxo- 1 -(4,7, 10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1-yl)-9,12-dioxa-3,6,16-triazaoctadecan-18-oic acid

[0455] (S)-17-(3-(tert-butoxy)-3-oxopropyl)-2,5, 15-trioxo- 1 -(4,7, 10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1-yl)-9,12-dioxa-3,6,16-triazaoctadecan-18-oic acid was synthesized by SPPS according to the scheme and general procedures (l-VII) mentioned above. Determined resin loading: 0.346 mmol; Yield: 150 mg (0.154 mmol, 45%).

[0456] LC-MS (ETH, Agilent-G6135C-1 , PN_100-1000, UV 220 nm): tR: 3.5 min, m / z calculated for C46H84N7OI5+[M + H]+: 974.6, found: 974.2.

[0457] HR-MS: Partial fragmentation of fBu groups is observed: m / z calculated for [M + 2H]2+: 487.8047; found: 487.8046 m / z calculated for [M + 2H - tBu]2+: 459.7734; found: 459.7737 m / z calculated for [M + 2H - 2tBu]2+: 431.7421 ; found: 431.7425

[0458] SPPS fragment F?:

[0459] (2S, 15S)-2-(3-(tert-butoxy)-3-oxopropy l)-20 , 20-d i methyl-4 , 14, 18-trioxo- 15-(2-(4 , 7 , 10-tris(2-(tert-butoxy)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecan-1 -yl)acetamido)-7, 10,19-trioxa-3, 13-diazahenicosanoic acid (2S, 15S)-2-(3-(tert-butoxy)-3-oxopropy l)-20 , 20-d i methyl-4 , 14, 18-trioxo- 15-(2-(4 , 7 , 10-tris(2-(tert-butoxy)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecan-1 -yl)acetamido)-7, 10,19-trioxa-3, 13-diazahenicosanoic acid was synthesized by SPPS according to the scheme and general procedures (l-VII) mentioned above. Determined resin loading: 0.204 mmol; Yield: 132 mg (0.120 mmol, 59%).

[0460] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000, UV 220 nm): Retention time: 3.9 min, m / z calculated for CssHgeNzOlz" [M + H]+: 1102.7, found: 1102.2.

[0461] HR-MS: Partial fragmentation of fBu groups is observed: m / z calculated for [M + 2H]2+: 551.8465; found: 551.8476 m / z calculated for [M + 2H - tBu]2+: 523.8152; found: 523.8162 m / z calculated for [M + 2H - 2tBu]2+: 495.7839; found: 495.7851

[0462] Synthesis of GPR4 Ligand with terminal amine:

[0463] Starting material obtained from SpiroChem AG: tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (SPC-a749)

[0464] 1H-NMR (400 MHz, CDCI3): 5 / ppm = 3.70 (s, 2H), 1.94 (s, 6H), 1 .44 (s, 9H).

[0465] (3-((tert-butoxycarbonyl)amino)bicyclo[1.1 .1 ]pentan- 1 -yl)methyl 4-methylbenzenesulfonate

[0466] Tert-butyl (3-(hydroxymethyl)bicyclo[1.1 .1]pentan-1-yl)carbamate (180 mg, 844 mol, 1 .0 equiv.) and pyridine (136 ul, 1.69 mmol, 2.0 equiv.) were dissolved in DCM (4 ml). The reaction was cooled to 0 °C and then 4- methylbenzenesulfonyl chloride (241 mg, 1 .27 mmol, 1 .5 equiv.) was added. The reaction was allowed to reach room temperature (rt) and stirred for 16 h (ON). After completion, water was added to the reaction and stirred for 10 min. The mixture was diluted with DCM and washed with 1 M HCI and saturated NaHCOs. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography afforded the title compound (200 mg, 65%). LC-MS (Agilent-G6135C-1 , PN_100-1000, UV 254 nm): tR: 5.56 min, m / z calculated for C19H26NO7S- [M + HCOO] : 412.1 , found: 412.2.

[0467] 1H-NMR (400 MHz, CDCI3): 6 / ppm = 7.81-7.73 (m, 2H), 7.38-7.30 (m, 2H), 4.10 (s, 2H), 2.47-2.42 (m, 3H), 1.92 (s, 6H), 1.42 (s, 9H). tert-butyl (E)-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1 .1.1]pentan-1-yl)carbamate

[0468] (E)-2-ethyl-5,7-dimethyl-3-(4-(3-(piperazin-1-yl)prop-1-en-1-yl)benzyl)pyrazolo[1 ,5-a]pyrimidine (131 mg, 336 mol, 1.0 equiv.) and K2CO3 (70 mg, 504 mol, 1.5 equiv.) were dissolved acetonitrile (2.5 ml). Then, (3-((tert- butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate (124 mg, 336 mol, 1.0 equiv.) in acetonitrile (1.5 ml) was added. The resulting mixture was stirred for 16 h at 70 °C. After completion of the reaction the solvent was removed under reduced pressure. The residue was diluted with CH2CI2. The organic layer was washed with brine, dried over water-free sodium sulfate (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography afforded the title compound (102 mg, 52%).

[0469] LC-MS (Agilent-G6135C-1 , PN_100-1000, UV 254 nm): tR: 4.20 min; m / z calculated for Css^gNeCV [M + H]+: 585.4, found: 585.2.

[0470] 1H-NMR (400 MHz, CDCI3): 6 / ppm = 7.24 (dd, J = 8.2, 2.0 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.50-6.42 (m, 2H), 6.19 (dt, J = 14.8, 6.7 Hz, 1 H), 5.30 (d, J = 0.6 Hz, 2H), 4.12 (s, 2H), 3.14 (bs, 2H), 2.78-2.66 (m, 5H), 2.60-2.46 (bs, 11 H), 1.95 (s, 6H), 1.43 (s, 9H), 1.19 (t, J = 7.6 Hz, 3H).

[0471] (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- y I) methyl) b icyclo[1 .1.1 ]pentan-1 -amine tert-butyl (E)-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1 .1]pentan-1-yl)carbamate was dissolved in 20% TFA in DCM and reacted at rt for 16 h (ON).

[0472] After completion, the reaction was concentrated under reduced pressure and the crude (E)-3-((4-(3-(4-((2-ethyl- 5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-amine (81 mg, 96%) was directly used for the production of preparative examples 5-7. LC-MS: tp: 3.05 min; m / z calculated for C30H41 N6+[M + H]+: 485.3; found: 485.0.

[0473] 1H-NMR (400 MHz, CD3CN): 5 / ppm = 7.18-7.14 (m, 2H), 7.07-7.02 (m, 2H), 6.57 (d, J= 15.9 Hz, 1H), 6.45 (q, J = 1.0 Hz, 1H), 6.10-5.98 (m, 1H), 3.91 (s, 2H), 3.53 (dd, J = 7.4, 1.2 Hz, 2H), 3.14-2.99 (bs, 4H), 2.98-2.84 (bs, 4H), 2.78 (s, 2H), 2.54 (q, J= 7.6 Hz, 2H), 2.47 (d, J = 0.9 Hz, 3H), 1.78 (p, J = 2.5 Hz, 6H), 1.00 (t, J= 7.6 Hz, 1H).

[0474] Amide coupling of GPR4 ligand with fragments Fsjto access preparative Examples 5-7:

[0475] F5: R1= H, R2= CH2CH2COOtBu Preparative example 5: R1' = H, R2' = CH2CH2COOtBu F6: R1= CH2CH2COOtBu, R2= H Preparative example 6: R1' = CH2CH2COOtBu, R2' = H F7: R1= R2= CH2CH2COOtBu Preparative example 7: R1' = R2' = CH2CH2COOtBu

[0476] In-solution peptide coupling procedure followed to produce preparative examples 5-7. Preparative Example 5 (AMX-0057) tri-tert-butyl 2,2',2"-(10-(4-(3-(tert-butoxy)-3-oxopropyl)-18-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5- a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)amino)-2,5,15,18-tetraoxo-

[0477] 9,12-dioxa-3,6,16-triazaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S,E)-triacetate

[0478] (S)-(2,2-dimethyl-4,8-dioxo-7-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1- yl)acetamido)-3,12,15-trioxa-9-azaoctadecan-18-oyl)glycine (F5, 60 mg, 61.9 mol, 1.00 equiv.) and coupling reagent 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 23 mg, 60.7 mol, 0.98 equiv.) were dissolved in DMF (dry, 1 ml). Triethylamine (35 ul, 247.6 mol, 4.00 equiv.) was added and the resulting mixture was activated for 10 min at 45 °C. After activation, (E)-3-((4-(3-(4-((2-ethyl- 5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-amine (30 mg, 61.9 mol, 1.00 equiv.) was added and the reaction was stirred for 1.5 h at 45 °C. After completion, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in a mixture of H2O and MeCN (1 :1, v / v, 2 mL). RP-HPLC purification afforded the title compound (36 mg, 40%).

[0479] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 4.21 min, 100% (UV, 254 nm); m / z calculated for C6oH9oNi3Oi4+[M + H]+: 1440.9, found: 1440.2.

[0480] 1H-NMR (400 MHz, CD3CI): 5 / ppm = 7.92 (s, 1 H), 7.80 (s, 1 H), 7.69 (s, 1 H), 7.30-7.26 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 15.7 Hz, 1 H), 6.50 (d, J = 1.0 Hz, 1 H), 6.12 (dt, J = 15.1 , 7.2 Hz, 1 H), 4.35-4.27 (bs, 1 H), 4.24- 4.16 (bs, 1 H), 4.15 (s, 2H), 4.12-4.00 (bs, 1 H), 3.90-2.81 (series of broad overlapping signals, ~40H), 2.78-2.68 (m, 5H), 2.58 (s, 3H), 2.55-2.46 (m, 2H), 2.37-2.29 (m, 2H), 2.17 (s, 6H), 2.06-1.94 (m, 1 H), 1.51 (s, 9H), 1.44 (s, 18H), 1.41 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H).

[0481] (S,E)-2,2',2"-(10-(4-(2-carboxyethyl)-18-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y l)methy I) bicyclo[ 1.1.1 ] pentan- 1 -y l)am i no)-2 , 5, 15,18-tetraoxo-9, 12-dioxa- 3,6, 16-triazaoctadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid tri-tert-butyl 2 ,2’,2"-( 10-(4-(3-(tert-butoxy)-3-oxopropyl)-18-((3-((4-(3-(4-((2-ethy l-5,7-dimethy lpyrazolo[1 ,5- a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentan-1-yl)amino)-2,5,15,18-tetraoxo- 9,12-dioxa-3,6,16-triazaoctadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(S,E)-triacetate (26 mg, 18 pmol, 1 equiv.) was dissolved in a mixture of TFA and DCM (1 :2, v / v, 600 uL). After stirring for 24 h at rt, the reaction was concentrated under reduced pressure and the residue redissolved in a mixture of H2O and MeCN (1 :1 , v / v, 2 mL). RP-HPLC purification afforded the title compound (AMX-0057, 4.42 mg, 20%).

[0482] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 3.23 min, 100% (UV, 254 nm); m / z calculated for C?6Hi22Ni30i4+[M + H]+: 1216.7, found: 1217.0.

[0483] HR-MS: m / z calculated for [M + 2H]2+: 608.8399; found: 608.8409. m / z calculated for [M + 3H]3+: 406.2290; found: 406.2297.

[0484] 1H-NMR (400 MHz, CD3OD): 5 / ppm = 7.35 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 15.7 Hz, 1 H), 6.72 (d, J = 1.0 Hz, 1 H), 6.22 (dt, J = 15.2, 7.3 Hz, 1 H), 4.404.31 (m, 1 H), 4.13 (s, 2H), 4.01-3.70 (m, 14H), 3.61 (s, 4H), 3.58-3.53 (m, 2H), 3.51-3.43 (m, 1 H), 3.41-3.13 (broad signal covered by solvent peak, -12H), 3.19 (s, 3H), 3.07 (s, 2H), 2.75-2.65 (m, 5H), 2.54 (s, 3H), 2.51 (td, J = 5.9, 2.6 Hz), 2.41 (t, J = 7.7 Hz, 2H), 2.20-2.09 (m, 1 H), 2.12 (s, 6H), 1.93 (dq, J = 15.1 , 8.1 Hz, 1 H), 1.13 (t, J = 7.6 Hz, 3H).

[0485] Prepartive Example 6 (AMX-0058) tri-tert-butyl 2,2',2"-(10-(17-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)-22,22-dimethyl-2,5,15,20- tetraoxo-9,12,21-trioxa-3,6,16-triazatricosyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(S,E)-triacetate

[0486] (S)-17-(3-(tert-butoxy)-3-oxopropyl)-2,5, 15-trioxo- 1 -(4,7, 10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1-yl)-9,12-dioxa-3,6,16-triazaoctadecan-18-oic acid (F6, 48 mg, 49.5 mol, 1.00 equiv.) and coupling reagent HATU (18 mg, 48.5 mol, 0.98 equiv.) were dissolved in DMF (dry, 1 ml). Triethylamine (28 ul, 198.0 mol, 4.00 equiv.) was added and the resulting mixture was activated for 10 min at 45 °C. After activation, (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1 .1.1 ]pentan-1 -amine (24 mg, 49.5 mol, 1.00 equiv.) was added and the reaction was stirred for 1 .5 h at 45 °C. After completion, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in a mixture of H2O and MeCN (1 :1 , v / v, 2 mL). RP-HPLC purification afforded the title compound (27 mg, 38%).

[0487] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 4.04 min, 100% (UV, 254 nm); m / z calculated for C76Hi22Ni3Oi4+[M + H]+: 1440.9, found: 1440.0.

[0488] 1H-NMR (400 MHz, CD3CI): 5 / ppm = 7.82 (s, 1 H), 7.76-7.66 (m, 2H), 7.28-7.24 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 15.7 Hz, 1 H), 6.48 (d, J = 1.0 Hz, 1 H), 6.10 (dt, J = 15.4, 7.3 Hz, 1 H), 4.374.28 (m, 1 H), 4.23-4.15 (bs, 1 H), 4.13 (s, 2H), 4.02-3.84 (bs, 3H), 3.82-2.78 (series of broad overlapping signals, ~40H), 2.76-2.66 (m, 5H), 2.56 (s, 3H), 2.53-2.40 (m, 2H), 2.27 (t, J = 7.4 Hz, 2H), 2.16 (s, 6H), 2.06-1.95 (m, 1 H), 1.91-1.79 (m, 1 H), 1 .50 (s, 9H), 1 .40 (s, 27H), 1 .18 (t, J = 7.6 Hz, 3H).

[0489] (S,E)-2,2',2"-(10-(19-carboxy-17-((3-((4-(3-(4-((2-ethy l-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)carbamoyl)-2,5, 15-trioxo-9, 12-d ioxa-3 , 6 , 16- triazanonadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0490] Tri-tert-butyl 2,2',2"-(10-(17-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)-22,22-dimethyl-2,5,15,20- tetraoxo-9,12,21-trioxa-3,6,16-triazatricosyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)(S,E)-triacetate (16 mg, 11.1 mol, 1 equiv.) was dissolved in a mixture of TFA and DCM (1 :2, v / v, 600 uL). After stirring for 24 h at rt, the reaction was concentrated under reduced pressure and the residue redissolved in a mixture of H2O and MeCN (1 :1, v / v, 2 mL). RP-HPLC purification afforded the title compound (AMX-0058, 4.69 mg, 35%).

[0491] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 3.27 min, 100% (UV, 254 nm); m / z calculated for CeoH9oNi30i4+[M + H]+: 1216.7, found: 1216.0.

[0492] HR-MS: m / z calculated for [M + 2H]2+: 608.8399; found: 608.8402. m / z calculated for [M + 3H]3+: 406.2290; found: 406.2295. m / z calculated for [M + 4H]4+: 304.9236; found: 304.9244.

[0493] 1H-NMR (400 MHz, CD3OD): 5 / ppm = 7.39-7.32 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 15.8 Hz, 1 H), 6.73 (d, J = 1.0 Hz, 1 H), 6.23 (dt, J = 15.2, 7.3 Hz, 1 H), 4.29 (dd, J = 9.1 , 5.1 Hz, 1 H), 4.14 (s, 2H), 3.93-3.70 (m, 14H), 3.61 (s, 3H), 3.57 (t, J = 5.5 Hz, 2H), 3.41 (t, J = 5.5 Hz, 2H), 3.37-3.121 (bs covered by solvent peak, ~12H), 3.15 (s, 4H), 3.05 (s, 2H), 2.76-2.66 (m, 5H), 2.55 (s, 3H), 2.53-2.47 (m, 2H), 2.41-2.32 (m, 2H), 2.13 (s, 6H), 2.11-1.98 (m, 1 H), 1.93-1.79 (m, 1 H), 1.15 (t, J = 7.6 Hz, 3H).

[0494] Preparative Example 7 (AMX-0059) di-tert-butyl (4S,17S)-4-((3-((4-((E)-3-(4-((2-ethyl-5,7-dimethyl pyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)carbamoyl)-6, 16-dioxo- 17-(2-(4 , 7 , 10-tris(2- (tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1-yl)acetamido)-9, 12-dioxa-5, 15-diazaicosanedioate (2S, 15S)-2-(3-(tert-butoxy)-3-oxopropy l)-20 , 20-d i methyl-4 , 14, 18-trioxo- 15-(2-(4 , 7 , 10-tris(2-(tert-butoxy)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecan-1 -yl)acetamido)-7, 10,19-trioxa-3, 13-diazahenicosanoic acid (F7, 50, 45.4 mol, 1.00 equiv.) and coupling reagent HATU (17 mg, 44.5 mol, 0.98 equiv.) were dissolved in DMF (dry, 1 ml). Triethylamine (25 ul, 181.6 mol, 4.00 equiv.) was added and the resulting mixture was activated for 10 min at 45 °C. After activation, (E)-3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1 -amine (22 mg, 45.4 mol, 1.00 equiv.) was added and the reaction was stirred for 1 .5 h at 45 °C. After completion, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in a mixture of H2O and MeCN (1 :1 , v / v, 2 mL). RP- HPLC purification afforded the title compound (30 mg, 42%).

[0495] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 4.49 min; m / z calculated for CBSHWN OW* [M + H]+: 1569.0, found: 1568.2.

[0496] 1H-NMR (400 MHz, CD3CI): 5 / ppm = 7.95-7.63 (m, 4H), 7.29-7.24 (m, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.71 (d, J = 15.8 Hz, 1 H), 6.47 (d, J = 1.0 Hz, 1 H), 6.11 (dt, J = 15.5, 7.4 Hz, 1 H), 4.42-4.24 (m, 3H), 4.13 (s, 2H), 4.06-2.81 (series of broad overlapping signals, ~42H), 2.76-2.66 (m, 5H), 2.55 (s, 3H), 2.51-2.42 (m, 2H), 2.38-2.24 (m, 5H), 2.17 (d, J = 2.5, 6H), 2.14-1.94 (m, 4H), 1.91-1.80 (m, 2H), 1.50 (s, 9H), 1.43 (s, 18H), 1.41 (s, 9H), 1.40 (s, 9H), 1.19 (t, J = 7.6 Hz, 3H).

[0497] (4S, 17S)-4-((3-((4-((E)-3-(4-((2-ethy I-5 , 7-d imethy I py razolo[1 ,5-a] pyri mid in-3-y I) methy I ) pheny I )al ly I) pi perazi n- 1 - yl)methyl)bicyclo[1 .1.1]pentan-1-yl)carbamoyl)-6,16-dioxo-17-(2-(4,7,10-tris(carboxymethyl)-1 ,4,7,10- tetraazacyclododecan-1 -yl)acetamido)-9, 12-dioxa-5, 15-diazaicosanedioic acid di-tert-butyl (4S, 17S)-4-((3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methy I) bicyclof 1.1.1 ]pentan-1 -yl)carbamoyl)-6, 16-dioxo- 17-(2-(4 , 7 , 10-tris(2- (tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1-yl)acetamido)-9, 12-dioxa-5, 15-diazaicosanedioate (8 mg, 5.1 pmol, 1 equiv.) was dissolved in a mixture of TFA and DCM (1 :2, v / v, 600 uL). After stirring for 24 h at rt, the reaction was concentrated under reduced pressure and the residue redissolved in a mixture of H2O and MeCN (1 :1 , v / v, 2 mL). RP-HPLC purification afforded the title compound (AMX-0059, 2.66 mg, 40%).

[0498] LC-MS (ETH, Agilent-G6135C-1 , PN_800-2000): tR: 3.27 min, 100% (UV, 254 nm); m / z calculated for C63H94Ni3Oi6+[M + H]+: 1288.7, found: 1288.0.

[0499] HR-MS: m / z calculated for [M + H]+: 1288.6936; found: 1288.6973. m / z calculated for [M + Na]+: 1310.6756; found: 1310.6780. m / z calculated for [M + 2H]2+: 644.8505; found: 644.8520.1H-NMR (400 MHz, CD3OD): 6 / ppm = 7.36 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.81 (d, J= 15.7 Hz, 1H), 6.73 (d, J = 1.1 Hz, 1H), 6.23 (dt, J = 15.1, 7.3 Hz, 1H), 4.424.27 (m, 2H), 4.14 (s, 2H), 4.01-3.05 (series of broad overlapping signals, -42H), 2.76-2.66 (m, 5H), 2.56 (s, 3H), 2.54-2.46 (m, 2H) ,2.45-2.33 (m, 4H), 2.15 (d, J= 2.2 Hz, 6H), 2.12-1.82 (m, 4H), 1.14 (t, J= 7.6 Hz, 3H).

[0500] 5

[0501] Radiolabeling of preparative examples 5-7 with lutetium-177:

[0502] Preparative examples 5-7 were dissolved in MilliQ water to obtain stock solutions of 0.5 mM concentrations.

[0503] 10

[0504] Selected volumes of the stock solutions of preparative examples 5-7 were mixed with [177Lu]LuC and aqueous ammonium acetate buffer (pH = 5.5), according to the table above. The mixtures were incubated on a shaker for 10 min at 90 °C with slow agitation. Diluted samples of these mixtures were injected for HPLC quality control to 15 assess the radiochemical purity of the lutetium-177-labeled compounds. The respective radio-HPLC chromatograms are depicted in Figure 8 and they show high (>95%) radiochemical purities for all the three labelled compounds.

[0505] General synthetic scheme for the preparation of Examples 8-11

[0506] 20

[0507] Preparative Examples 8 to 11 were synthesized via the aforementioned synthetic route, employing conventional organic chemistry reaction conditions. After deprotection, the following procedures have been employed to isolate the targeted compounds.

[0508] General procedure for the DOTA Amide Coupling step:

[0509] In a Vial, each compound was dissolved in 1 mL of amine free DMF and DOTA-tris(tert-butyl ester) (1.5 Eq), HATU (1 .5 Eq), and DIPEA (3 Eq) were added. The vial was capped, and agitated for 0.5 hrs. Once deemed complete by UPLC-MS, ammonia in methanol (7M, 5 Eq) was added and the vial was capped and shaken for 0.5 hrs. The resulting solution was then dried for 64 hrs under a stream of N2. The residue was purified by Si-Carbonate functionalized gel (40-63 pm, 60 A, SiliCycle). The Si-carbonate was preconditioned with CH2CI2 and 12% MeOH / CH2Cl2 before adding the residue dissolved in 10% MeOH / CH2Cl2. The compound was eluted with 10% MeOH / CH2CI2 (3X). The eluents were dried under N2 overnight.

[0510] General procedure for the tBu Deprotection:

[0511] In a vial, the Dota -tBu derivative was dissolved in a 2 mL solution containing 75% TFA / 3% TIPS / 22% CH2CI2 . The reaction solution was shaken for 2 hrs at room temperature. The volatiles were evaporated under a stream of N2 and retreated, overnight, using 2 mL of a solution containing 50% TFA / 3% TIPS / 47% CH2CI2. Once complete, the volatiles were evaporated under a stream of N2. The compound was then dissolved in 1.5 mL of 95% DMSO / water for preparative HPLC purification.

[0512] Preparative Example 8 (S,E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-(hydroxymethyl)-1 ,4,20-trioxo-9,12,15-trioxa-2,5,19-triazahenicosan-21-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0513] UPLC-MS: tR: 3.09 min, 97% (UV, 220 nm), [(M+H)+] 1190.1 m / z

[0514] Yield: 11.1 mg, 12.5%

[0515] 1H NMR (CD3OD, 500 MHz): 5 7.33 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 1.0 Hz, 1 H), 6.68 (d, J = 15.5 Hz, 1 H), 6.26-6.20 (m, 1 H), 4.36 (t, J = 5.5 Hz, 1 H), 4.13 (s, 2H), 3.78-3.75 (m, 2H), 3.71 (br s, 4H), 3.65- 3.56 (m, 10H), 3.55-3.49 (m, 9H), 3.40 (br s, 2H), 3.37 (br s, 1 H), 3.36 (br s, 1 H), 3.35 (s, 2H), 3.27-3.24 (m, 2H), 3.16-2.88 (series of br s, 16H), 2.82 (s, 2H), 2.74-2.69 (m, 5H), 2.55 (s, 3H), 2.10 (s, 6H), 2.03 (s, 1 H), 1.81-1.73 (m, 4H), 1.52 (s, 2H), 1.15 (t, J = 7.5, 3H).

[0516] Preparative Example 9

[0517] (E)-2,2',2"-(10-(1-(3-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin- 1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamido)oxetan-3-yl)-1 ,17-dioxo-6,9,12-trioxa-2,16-diazaoctadecan-18- yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0518] UPLC-MS: tR: 3.07 min, 94% (UV, 220 nm), [(M+H2O)+] 1220.0 m / z

[0519] Yield: 9.5 mg, 10.6%

[0520] 1H NMR (CD3OD, 500 MHz): 5 7.33 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.73 (br d, J = 0.5 Hz, 1 H), 6.69 (d, J = 15.5 Hz, 1 H), 6.27-6.19 (m, 1 H), 4.13 (s, 2H), 3.95 (d, J = 11 .0 Hz, 2H), 3.87 (d, J = 11.0 Hz, 2H), 3.70 (br s, 4H), 3.65-3.62 (m, 6H), 3.60-3.57 (m, 5H), 3.56-3.48 (series of m, 9H), 3.47 (br s, 1 H), 3.40 (br s, 1 H) 3.38 (br s, 1 H), 3.36 (br s, 2H), 3.35 (s, 1 H), 3.27 (t, J = 7.0 Hz, 2H), 3.14-2.85 (series of br s, 16H), 2.80 (s, 2H), 2.74- 2.69 (m, 5H), 2.55 (s, 3H), 2.09 (s, 5H), 2.03 (s, 2H), 1.82-1.73 (m, 4H), 1.52 (s, 1 H), 1 .17-1 .13 (m, 3H).

[0521] Preparative Example 10

[0522] 2,2',2"-(10-(1-((2S)-1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1 .1]pentane-1-carbonyl)octahydro-1 / 7-indol-2-yl)-1 ,17-dioxo-

[0523] 6,9, 12-trioxa-2, 16-diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0524] UPLC-MS: tR: 3.29 min, 93% (UV, 220 nm), [(M+H)+] 1254.2 m / z

[0525] Yield: 19.8 mg, 21.0%

[0526] 1H NMR (CD3OD, 500 MHz): 5 7.34 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.76-6.69 (m, 2H), 6.29-6.21 (m, 1 H), 4.33-4.29 (m, 1 H), 4.13 (s, 3H), 4.04-4.00 (m, 1 H), 3.70 (br s, 4H), 3.64-3.57 (m, 10H), 3.55-3.48 (m, 8H), 3.45 (m, 3H), 3.38 (br s, 4H), 3.35 (s, 3H), 3.28-3.25 (m, 3H), 3.11-2.89 (series of br s, 16H), 2.78 (s, 2H), 2.74- 2.69 (m, 5H), 2.55 (s, 3H), 2.38-2.32 (m, 1 H), 2.19 (dd, J = 9.5, 1.5 Hz, 2H), 2.11 (dd, J = 9.5, 1.5 Hz, 2H), 2.06- 1.99 (m, 4H), 1.86 (br s, 1 H), 1.80-1.67 (m, 8H), 1.53-1.46 (m, 1 H), 1.17-1.13 (m, 3H).

[0527] Preparative Example 11 (S,E)-2,2',2"-(10-(19-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin- 1 -yl)methy l)b icyclo[ 1 .1.1 ]pentane-1 -carboxamido)-2, 18 ,22-trioxo-7, 10,13-trioxa-3, 17,21 -triazatricosyl)- 1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid

[0528] UPLC-MS: tR: 3.06 min, 98% (UV, 220 nm), [(M+H)+] 1231.1 m / z

[0529] Yield: 14.3 mg, 15.5%

[0530] 1H NMR (CD3OD, 500 MHz): 5 7.34 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 1 Hz, 1 H), 6.70 (d, J = 16 Hz, 1 H), 6.27-6.20 (m, 1 H), 4.39-4.37 (m, 1 H), 4.13 (s, 2H), 3.72 (br s, 4H), 3.64-3.61 (m, 4H), 3.59-3.56 (m, 6H), 3.53-3.48 (m, 10H), 3.47 (br s, 1 H), 3.43 (br s, 1 H), 3.39 (br s, 3H), 3.35 (s, 2H), 3.29-3.21 (m, 5H), 3.11- 2.94 (series of br s, 16H), 2.83 (s, 2H), 2.74-2.69 (m, 5H), 2.55 (s, 3H), 2.08 (s, 5H), 1.94 (s, 3H), 1.80-1.72 (m, 4H), 1.52 (s, 1 H), 1.15 (t, J = 7.5 Hz, 3H.

[0531] Example 1

[0532] Summary

[0533] Radiopharmaceuticals represent a new therapeutic approach to treating cancer. They consist of molecules bearing radioactive isotopes that bind to cancer cells and selectively irradiate the tumor. This is advantageous over whole body irradiation (‘radiotherapy’) which also irradiates healthy tissue and organs. Cancer cells express GPR4, a G- protein-coupled receptor (GPCR) that is sensitive to changes in acidity in the extracellular environment of the cell helping the cells adapt to adverse conditions. Clinical and non-clinical research has revealed that GPR4 are overexpressed in a range of solid tumors many of which have poor treatment options and represent unmet medical need. This project investigated the potential for GPR4 ligands synthesized by Amphilix AG to be used as radiopharmaceuticals for the treatment of solid tumors. 4 compounds were assessed: AMX-0053 (monomeric ligand, corresponding to Preparative Example 1), AMX-0054 (monomeric ligand corresponding to Preparative Example 2), AMX-0055 (dimer, corresponding to Preparative Example 4), AMX-0056 (dimer, corresponding to Preparative Example 3).

[0534] In a first step, the labelling capacity of the monomer AMX-0053 and the dimers AMX-0055 and AMX-0056 had to be determined to go on with further in vitro and in vivo binding studies. For AMX-0053 a binding assay, experiment was performed showing a binding to human GPR4 (hGPR4) expressing HEK293 cells without any significant binding to 293 HEK wild type cells. The amount of monomer and dimer with a binding of 50 percent (IC50) was measured by incubating the cells with177Lu labelled AMX-0053 and increasing concentrations of AMX-0053, AMX- 0055 or AMX-0056 (Figure 1).

[0535] To further see the uptake into GPR4 expressing tumors and background organs an in vivo biodistribution study was performed with AMX-0053 and AMX-0055. GPR4-positive tumor bearing mice were injected with either radioactive labelled AMX-0053 or AMX-0055 and euthanized 4h post injections, the tumors and organ were harvested, and the remaining activity was measured showing a good uptake into the tumor. A repetition of the biodistribution of the monomer AMX-0053 was performed in GPR4-expressing tumor bearing mice with and without additional administration of 1000x unlabelled AMX-0053 which would compete for the GPR4 binding sites with labelled compound. Compared to injection of labelled compound only, this would show the specificity of binding to the tumor compared to other organs due to over-expression of GPR4.

[0536] Material Table 1. Materials and equipment.

[0537] Labelling For the determination of nuclide to compound ratio the monomer AMX-0053 was labelled with 4 different molar ratios, 1 :17, 1 :50, 1 :100 and 1 :150 and the yield of each labelling solution was measured with HPLC with a C18 affinity column.

[0538] 5 AMX-0053 was mixed with177Lu, ammonium acetate and water, according to Table 2. The mixture was incubated on a shaker for 15 min at 90° C and 300 rpm.

[0539] After the incubation, the radiolabelling was analysed by HPLC and the activity of the solution was measured. 1 l of each solution was added to 50 pl of PBS and 1 pl DTPA (chelator for free Lu) for quality control in the HPLC 10 (Figure 1).

[0540] Table 2. Labelling of AMX-0053 with177Lu at different ratios. The amount of nuclide remained the same for each ratio.

[0541] 15 Results

[0542] For all further experiments, a ratio of 1 :100 was used for the labelling of AMX-0053. For the labelling of the dimers AMX-0055 and AMX-0056 the same ratio was used showing similar yields as can be seen in Figure 2. Mass spectrometry data is shown in Figure 3.

[0543] 20

[0544] Binding experiments

[0545] The binding capacity of AMX-0053 was determined with a cell binding assay. One day prior to the experiment 1 x106HEK GPR4+ or 293 HEK wt cells were seeded into six- well plates. The plates were incubated over night at 37° C 25 and 5 % CO2. The next day the medium was removed, and each well was washed twice with ice cold PBS. The cells were put on ice and assay medium containing 100'000 cpm of177Lu-AMX-0053 were added to all wells. To three wells per plate 100 ul of assay medium (DMEM BSA 0.1 %) with 1x10-® M AMX-0053 were added. The plates were incubated at 4°C for one hour. The supernatant was aspirated, and the wells were washed twice with ice cold PBS. The cells were then incubated twice for 12 min at room temperature with 1 M NaOH. The dislodged and lysed cells were measured with a gamma counter. The remaining radioactivity was calculated as a fraction of the total binding activity. The data is shown in Figure 4.

[0546] IC50 determination

[0547] Experimental data are summarized in Figure 5.

[0548] AMX-0053

[0549] For the ICsodetermination, different concentrations of AMX-0053 labelled with stable175Lu were added to the cells as well as 100'000 cpm of177Lu-AMX-0053.

[0550] One day prior to the experiment 1x106HEK GPR4+ cells were seeded into six- well plates. The plates were incubated over night at 37° C and 5 % CO2. The next day the medium was removed, and each well was washed twice with ice cold PBS before adding the compound. The plates were incubated at 4°C for one hour. After that the supernatant was aspirated and the wells were washed twice with ice cold PBS. The cells were then incubated twice for 12 min at room temperature with 1 M NaOH. The dislodged and lysed cells were measured with a gamma counter. The remaining radioactivity as a fraction of the total binding activity was calculated and plotted against the different concentrations to evaluate the relative IC50 values (One site - Fit logICso function of the software Graph Pad Prism8).

[0551] AMX-0055 and AMX-0056

[0552] For the IC50 determination, different concentrations of AMX-0055 or AMX-0056 labelled with stable175Lu were added to the cells as well as 100'000 cpm of [177Lu]-AMX-0053. The experimental set up was done according to the setup for AMX-0053.

[0553] Biodistribution measurements

[0554] Blocked vs unblocked

[0555] To confirm the uptake of AMX-0053 into GPR4 expressing tumors and background organs in vivo, 10 SCID mice (SCID CB17 / lcr-Prkdcscid / lcrlcoCrl, Charles River, Germany) were subcutaneously injected with 5x106GPR4 positive cells on their left side and 5x106293 HEK cells on their right side (150 kBq in100 ul). The tumor bearing mice were injected with radioactive labelled AMX-0053 (0.02nmol / mouse) or a combination of radioactive labelled AMX-0053 (0.02 nmol / mouse) and non-radioactive labelled AMX-0053 (60 nmol / mouse blocking agent) and euthanized 4h post injections, the tumors and organ were harvested, and the remaining activity was measured with a gamma counter. The percentage i.A. / g was calculated. The results are shown in Figure 6.

[0556] Plasma stability

[0557] The plasma stability of the monomer AMX-0053 was determined by measuring the binding of the AMX-0053 to proteins. Therefore, human blood plasma was incubated at 37°C 5% CO2 with 100 kBq of177Lu labelled AMX-0053. The total activity of the radiolabelled compound was measured and compared to the activity of the free177Lu -AMX- 0053 at different time points. The activity of the free compound was shown as the percentage of the total activity (for the results see Figure 7).

[0558] Conclusions

[0559] The following conclusions can be made:

[0560] 1 . Successful radiolabelling of the 4 molecules was achieved with a good yield and high specific activity of the labelled compounds and with little unbound lutetium remaining and low presence of side products.

[0561] 2. All 4 compounds bound to the hGPR4 in vitro with low nanomolar affinity. The affinity for the target was therefore maintained despite the use of monomeric or dimeric structures or addition of a chelator.

[0562] 3. Administration of AMX-0053 and AMX-0055 to tumor-bearing mice, wherein the tumor expresses GPR4, showed uptake in the tumors. Higher uptake was observed with AMX-0053 than AMX-0055. The reasons for this are uncertain. AMX-0053 is monomeric for the GPR4 pharmacophore and is a much smaller molecule than the dimer AMX-0055. AMX-0053 may potentially achieve better tumor penetration.

[0563] 4. The tumor uptake of AMX-0053 is specific due to the presence of GPR4 because the gamma radio signal could be reduced by co-administration of ‘cold’ AMX-0053 which competes for the receptors against 'hot' AMX-0053. Importantly this profile of displacement was not observed in other tissues or organs suggesting that the signal detected simply reflects compound in the blood that is perfusing the body.

[0564] 5. AMX-0053 was stable in plasma over 24 hours. The uptake into the tumors 4 hours post-administration in the in vivo experiments likely represents the binding of the parent molecule.

[0565] 6. These experiments demonstrate the potential of the compounds of formula (0) as radiopharmaceuticals.

Claims

Claims1 . A compound of formula (0-a):(0-a) or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3are independently selected from C and N;R1, R2, and R3are independently selected from H, and C1-6 alkyl;R4is selected from H, and C1-6 alkyl;R5is selected from H, C alkyl, and C3-6 cycloalkyl, wherein R5is optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2;R6and R7are independently selected from -H, halogen, and C1-6 alkyl; n is 1 or 2; m is 0 or 1 ;Y is -CH2CH2- or -CH2O-;L is C2-20 alkylene, which is optionally substituted with one or more substituents selected from -CN, halogen, -OH, -NH2, C1-6 alkyl, -(Ci-6alkylene)-OH, -(Ci-6alkylene)-NH2, -(Ci-6alkylene)-NHCO(Ci-5alkyl), -(Ci-6alkylene)-COOH, -(C1-6 alkylene)-S04H, -(C1-6 alkyleneJ-SOsH, -(C0-3 alkylene)-aryl and -(C0-3 alkylene)- heteroaryl, wherein said alkyl, said aryl moiety in -(C0-3 alkylene)-aryl and said heteroaryl moiety in -(C0-3 alkylene)-heteroaryl are each optionally substituted with a group selected from -OH, -0(Ci-6 alkyl), -SH, - S(Ci-6alkyl), -NH2, -NH-C(=NH)NH2, -SO3H, -CONH2and -COOH, preferably from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may each independently be replaced by -CH=CH-, -C=C-, - 0-, -NR’-, -CO-, Ce-io arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -C0-0-, -CO- NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl;Q is selected from a covalent bond, -CH2-, -CHOG2-, -C(=0) -, CMO arylene, C5-10 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—, >CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -0-, -CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl; andZ is a chelator adapted to bind a radionuclide.

2. The compound of claim 1 , wherein X1is N and X2and X3are C,3. The compound of claim 1 or 2, wherein R1and R2are each methyl, and R3is ethyl.

4. The compound of any one of claims 1 to 3, wherein R4is H and / or R5is H.

5. The compound of any one of claims 1 to 4, wherein Y is -CH2CH2-.

6. The compound of any one of claims 1 to 4, wherein m is 0.

7. The compound of any one of claims 1 to 6, wherein n=1 .

8. The compound of any one of claims 1 to 7, wherein L is C2-20 alkylene, wherein one or more -CH2- groups may independently be replaced by one or more of -CH=CH-, -C=C-, -O-, -NR’-, -CO-, Ce arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, C5-11 bicyclo[n’.n”.n’”]alkylene, wherein the sum of n’, n” and n’” is at least 3 and does not exceed 9, wherein R’ is H or Ci-Ce alkyl.

9. The compound of any one of claims 1 to 8, wherein Q is selected from a covalent bond, -CH2-, -CHOG2-, - C(=O) -, Ce-io arylene, C5-10 heteroarylene, C3-11 cycloalkylene, -(4-11 membered heterocycloalkyl)— G1—,>CH-, N, and -C(=O)N<, wherein G1is a covalent bond, -NH-, -O-, -CH2NH- or -CH2O-, and wherein G2is H or Ci-Ce alkyl.

10. The compound of any one of claims 1 to 9, wherein Z comprises a chelator selected from DOTA (1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10- tetraacetic acid), 1 ,4,7-triazacyclononane N,N',N"-triacetic acid(NOTA) and OTA (1 ,4,7-triazonane-l ,4,7-triacetic acid).11 . The compound of any one of claims 1 to 10, wherein the compound is a compound of formula (la-a):(la-a) or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, R1, R2, R3, R4, R7, L, Q and Z are as defined in any one of claims 1 to 10.

12. The compound of claim 1 , selected from the following compounds:(E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1 ,17-dioxo-6,9,12-trioxa-2,16- diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;(E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)- 1 ,30-d ioxo-5 , 8 , 11 , 14, 17,20,23,26- octaoxa-2,29-diazahentriacontan-31-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentan-1-yl)-1 -oxo-5, 8, 11 , 14-tetraoxa-2-azahexadecan-16-yl)- 1 , 18,21 -trioxo-5 , 8, 11 ,14-tetraoxa-2, 17,20-triazadocosan- 22-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;2,2',2"-(10-(1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny I )al ly I) pi perazi n- 1 -y I) methyl) bicyclo[1.1.1 ] pentan- 1 -yl)- 17-( 1 -(3-((4-((E) -3-(4-((2-et hy I-5, 7- dimethylpyrazolo[1 ,5-a]pyrimidin-3-yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1 .1.1]pentan-1-yl)-1 -oxo-5, 8,11,14-tetraoxa-2-azahexadecan-16-yl)-1 ,18-dioxo-5,8,11 ,14-tetraoxa-2,17-diazanonadecan-19- yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;(S,E)-2,2',2"-(10-(4-(2-carboxyethyl)-18-((3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)amino)-2,5, 15,18-tetraoxo-9, 12- dioxa-3,6,16-triazaoctadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;(S,E)-2,2',2"-(10-(19-carboxy-17-((3-((4-(3-(4-((2-ethy l-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[ 1.1.1 ]pentan-1 -yl)carbamoyl)-2,5, 15-trioxo-9, 12-dioxa- 3,6,16-triazanonadecyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;(4S, 17S)-4-((3-((4-((E)-3-(4-((2-ethy l-5,7-dimethy lpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[1.1.1 ]pentan-1 -yl)carbamoyl)-6, 16-dioxo-17-(2-(4 , 7 , 10- tris(carboxymethyl)- 1 ,4,7, 10-tetraazacyclododecan-1 -yl)acetamido)-9, 12-dioxa-5, 15-diazaicosanedioic acid;(S,E)-2,2',2"-(10-(1-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[1.1.1 ]pentan-1 -yl)-3-( hyd roxy methyl)- 1 ,4 ,20-trioxo- 9,12,15-trioxa-2,5,19-triazahenicosan-21-yl)-1 ,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; (E)-2,2',2"-(10-(1-(3-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1 .1]pentane-1-carboxamido)oxetan-3-yl)-1 ,17-dioxo- 6,9, 12-trioxa-2, 16-diazaoctadecan-18-yl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid;2,2',2"-(10-(1-((2S)-1-(3-((4-((E)-3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- yl)methyl)phenyl)allyl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonyl)octahydro-1H-indol-2-yl)- 1 ,17-dioxo-6,9, 12-trioxa-2, 16-diazaoctadecan-18-yl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; and(S,E)-2,2',2"-(10-(19-(3-((4-(3-(4-((2-ethyl-5,7-dimethylpyrazolo[1 ,5-a]pyrimidin-3- y I) methyl)pheny l)al ly I) pi perazi n- 1 -y I) methyl) bicyclo[1.1.1 ]pentane-1 -carboxamido)-2, 18,22-trioxo-7, 10,13- trioxa-3, 17,21 -triazatricosyl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid; or their pharmaceutically acceptable salts and / or radionuclide complexes.

13. The compound of any one of claims 1 to 12, wherein Z comprises a radionuclide selected from67Cu,89Sr, "Y,153Sm,177Lu,223Ra,225Ac,47Sc,149Tb,161Tb, and212Pb.

14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 and at least one pharmaceutically acceptable carrier.

15. The compound of any one of claims 1 to 13 or the pharmaceutical composition of claim 14 for use as a medicament.

16. The compound of any one of claims 1 to 12 for use in diagnosis.

17. The compound of any one of claims 1 to 13 or the pharmaceutical composition of claim 14 for use in the treatment or prevention of solid tumor characterized by overexpression of GPR4 or a disease associated with, mediated by or caused by GPR4.

18. The compound of any one of claims 1 to 12 for use in diagnosis of solid tumor characterized by overexpression of GPR4 or a disease associated with, mediated by or caused by GPR4.

19. The compound for use of claim 17 or 18, or the pharmaceutical composition for use of claim 17, wherein the solid tumor characterized by overexpression of GPR4 is selected from bladder cancer, breast cancer, cervical cancer, mouth cancer, aesophagus cancer, stomach cancer, intestinal cancer, colon and rectal cancer, eye cancer, endometrial cancer, kidney cancer, lip cancer, oral cancer, hepatocellular cancer, melanoma, mesothelioma, liver cancer, lung cancer, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and thyroid cancer20. The compound for use of claim 17 or 18, or the pharmaceutical composition for use of claim 17, wherein the solid tumor characterized by overexpression of GPR4 is selected from breast cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer and kidney cancer.21 . The compound for use of claim 17 or 18, or the pharmaceutical composition for use of claim 17, wherein the disease associated with, mediated by or caused by GPR4 is selected from osteoporosis (juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or corticosteroid therapy or inactivity), gingivitis, periodontitis, Paget’s disease, hypercalcemia of malignancy, tumor induced hypercalcemia, metabolic bone disease, cancer, solid tumors including those of the intestine, colon, lung, ovary, skin, testes, prostate, breast, bone, brain and spinal cord, kidney, and blood cells, cardiovascular disorders, atherosclerose, myocardial infarction, limb diseases, peripheral arterial occlusive disease, eye diseases, diabetic retinopathy, macular degeneration, uveitis, arthritis, rheumatoid arthritis, osteoarthritis, wound healing, skin diseases, inflammatory and obstructive airway diseases, asthma, intrinsic and extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury, acute / adult respiratory distress syndrome, chronic obstructive pulmonary airways or lung diseases, chronic bronchitis, dyspnea associated herewith, emphysema, exacerbation of airways hyperactivity consequent to other drug therapy, bronchitis, acute arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chlicosis, ptilosis, siderosis, silicosis, tabacosis byssinosis, eosinophilia, bronchopulmonar aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil- related disorders affecting the airways occasioned by drug reaction, infectious diseases caused by organisms such as Pneumocystis carinii, Trypanosomacruzi, Trypanosoma brucei, Crithidia fusculata, parasitic diseases such as schistosomiasis and malaria, sarcoidosis and other granulomatous inflammation,tumor invasion and metastasis, metachromatic leukodystrophy, muscular dystrophy, amythrophy, autoimmune disease, respiratory disease, immunologically mediated disease, transplant rejection, inflammatory pain, visceral pain, acute and chronic pain, tumor pain, neuropathic pain, kidney diseases, renal tubular acidosis and other disorders of acid-base and metabolism, Crohn's disease, inflammatory bowel disease, intestinal fibrosis, hypersensitivity reactions, reflux disease (GERD) including erosive disease and / or non erosive reflux disease (NERD), diseases associated with pregnancy (e.g. preeclampsia, eclampsia, gestational hypertension, chronic hypertension, and chronic hypertension with superimposed pre-eclampsia) and after birth (e.g. post-partum preeclampsia), lung injury caused by X-ray irradiation.

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