Anticancer compounds

Abstract

The present invention relates to compounds of formula (I) and compositions comprising a compound of formula (I). The compounds and compositions of the invention find utility as medicaments, in particular medicaments for the treatment or prevention of cancer.

Description

[0001] COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compounds of formula (I) and compositions comprising a compound of formula (I). The compounds and compositions of the invention find utility as medicaments, in particular medicaments for the treatment or prevention of cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0006] Alkylating agents, such as those with nitrogen mustard reactive groups (e.g. bis(2- chloroethyl)amine and its derivatives), are widely used as chemotherapeutic drugs for treating various cancers. A particular example is melphalan. However, many alkylating agents, including melphalan, exhibit limited efficacy, dose-limiting toxicities, and the potential for resistance development.

[0007] Thus, there is a need in the art for additional and / or improved alkylating agents, in particular additional and / or improved alkylating agents that may be used in the treatment or prevention of cancers, such as haematological cancers.

[0008] SUMMARY OF THE INVENTION

[0009] The present invention provides compounds according to formula (I): wherein,

[0010] X is Ci-6alkylene,

[0011] 1

[0012] 55645095-2 R1is selected from the group consisting of H; Ci-ealkyl optionally substituted by 1 , 2 or 3 halogens; and halogen;

[0013] R2is -N(Ra)(Rb) and R3is according to formula (II):

[0014] ; or

[0015] (II)

[0016] R2is according to formula (III): R3is according to formula (IV):

[0017] ; or

[0018] R2is according to formula (V):

[0019] , and

[0020] 55645095-2 R3is selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce-waryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms; wherein, Raand Rbare each independently selected from the group consisting of H, Ci-ealkyl, and C(O)Ci-6alkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens;

[0021] Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; -CH2- phenyl; and -CH2-3 to 12-membered heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected from N, O and S; wherein said alkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of OH, -OCi-ealkyl, NH2, NHC(=NH)NH2, - NHC(O)NH2, -C(O)OH, -C(O)NH2, SH, SCH3, and halogen; and said phenyl or heterocyclyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2.OH, and OCi-ealkyl;

[0022] Reis selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms; and

[0023] Rfand Rgare each independently selected from the group consisting of H and Ci-ealkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens, or Rfand R9together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered heterocycle which is optionally substituted by 1 , 2 or 3 halogens; or a pharmaceutically acceptable salt or solvate thereof.

[0024] The present invention further provides a pharmaceutical composition comprising a compound of the present invention and at least one pharmaceutically acceptable binder, carrier or excipient.

[0025] The present invention further provides a compound of formula (I), or a pharmaceutical composition of the invention, for use as a medicament. For example, the compound of formula (I), or pharmaceutical composition of the invention, may find utility in the treatment or prevention of a cancer.

[0026] The present invention further provides a method of treating or preventing a disease or disorder, said method comprising a step of administering a compound or pharmaceutical composition

[0027] 3

[0028] 55645095-2 of the present invention to a subject in need thereof, for example, the disease or disorder may be a cancer. The present invention also provides a use of a compound of formula (I) in the manufacture of a medicament, for example use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of a cancer.

[0029] Preferred but optional features are set out in the dependent claims. Additional aspects and embodiments of the compounds, compositions, uses, and methods of the present invention will be apparent from the following description, drawings and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment.

[0030] BRIEF DESCRIPTION OF FIGURES

[0031] FIG. 1 shows the cytotoxicity of Example compound 1 (i.e. Mel-Ala-Ala-OEt), Example compound 2 (i.e. Mel-Val-Cit-OEt), and comparator compounds (melphalan and melphalan flufenamide (i.e. J1)) against a human myeloma cell line.

[0032] FIG. 2 shows the NMR spectrum for Example compound 1 (i.e. Mel-Ala-Ala-OEt).

[0033] FIG. 3 shows the NMR spectrum for Example compound 2 (i.e. Mel-Val-Cit-OEt).

[0034] FIG. 4 shows the cytotoxicity of a) Example compound 5 (i.e. Mel-Ala-Phe-OEt TFA salt), b) Example compound 6 (i.e. Mel-Ala-Leu-OEt TFA salt), c) Example compound 7 (i.e. Mel-Phe- Ala-OEt TFA salt), d) Example compound 8 (i.e. Mel-Phe-Leu-OEt TFA salt), e) Example compound 3 (i.e. Mel-Ala-GIn-OEt TFA salt), f) Example compound 4 (i.e. Mel-Phe-GIn-OEt TFA salt), g) melphalan flufenamide (i.e. J 1 ), and h) melphalan against a human myeloma cell line.

[0035] FIG. 5 shows the cytotoxicity of a) Example compound 5 (i.e. Mel-Ala-Phe-OEt TFA salt), b) Example compound 6 (i.e. Mel-Ala-Leu-OEt TFA salt), c) Example compound 7 (i.e. Mel-Phe- Ala-OEt TFA salt), d) Example compound 8 (i.e. Mel-Phe-Leu-OEt TFA salt), e) Example compound 3 (i.e. Mel-Ala-GIn-OEt TFA salt), f) Example compound 4 (i.e. Mel-Phe-GIn-OEt TFA salt), g) melphalan flufenamide (i.e. J 1), and h) melphalan against a colorectal cancer cell line.

[0036] 4

[0037] 55645095-2 DETAILED DESCRIPTION OF THE INVENTION

[0038] The present inventors have found a new class of alkylating compounds that are surprisingly cytotoxic towards human cancer cells. As described in the Examples section herein, the present inventors have demonstrated that compounds according to formula (I) display surprising cytotoxicity towards human myeloma cells in an in vitro cytotoxicity assay. It has also been demonstrated that compounds according to formula (I) display surprising cytotoxicity towards colorectal cancer cells in an in vitro cytotoxicity assay. Thus, the present invention provides compounds according to formula (I):

[0039] In certain preferred embodiments, formula (I) is according to formula (la):

[0040] 5

[0041] 55645095-2 For the avoidance of doubt, when a compound structure is depicted or named herein, the compound structure or name is considered to encompass all stereoisomers of the compound, unless stated otherwise. For example, if the stereochemistry of the compound is not indicated in the compound structure or name, the compound structure or name encompasses all stereoisomers of the compound.

[0042] Thus, in certain embodiments, formula (I) may be according to formula (lb):

[0043] In certain preferred embodiments, formula (I) is according to formula (Ic):

[0044] 6

[0045] 55645095-2 In the compounds of formula (I), X is Ci-6alkylene. For example, X may be Ci-salkylene, Ci- 4alkylene, Ci-3alkylene, C2alkylene, or Cialkylene. In certain embodiments, X is Cialkylene.

[0046] In the compounds of formula (I), R1is selected from the group consisting of H; Ci-ealkyl optionally substituted by 1 , 2 or 3 halogens; and halogen. For example, R1may be selected from the group consisting of H, Ci-4alkyl, and halogen. For example, R1may be selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, Br and I (e.g. F or Cl). In certain preferred embodiments, R1is H.

[0047] In certain embodiments, in the compounds of formula (I), R2is -N(Ra)(Rb) and R3is according to formula (II):

[0048] In such embodiments, R2is -N(Ra)(Rb) and R3may be according to formula (Ila):

[0049] In certain other embodiments, in the compounds of formula (I), R2is according to formula (III):

[0050] , and

[0051] R3is according to formula (IV):

[0052] 55645095-2

[0053] In such embodiments, R2may be according to formula (Illa):

[0054] , and

[0055] R3may be according to formula (IVa):

[0056] In certain other embodiments, R2is according to formula (V):

[0057] , and

[0058] R3is selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12

[0059] 8

[0060] 55645095-2 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms.

[0061] In such embodiments, R2may be according to formula (Va):

[0062] , and

[0063] R3is selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12 membered heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms. For example, R3may be selected from the group consisting of OH and -OCi-ealkyl, for example, R3may be -OCi-ealkyl, for example, R3may be -OC2alkyl.

[0064] In certain exemplary embodiments, R2is -N(Ra)(Rb) and R3is according to formula (II) (for example, formula (Ila)).

[0065] For the avoidance of doubt, / VW* in formulas (II), (III), (IV), (V), (Ila), (Illa), (IVa), and (Va) denotes the point of attachment of formulas (II), (III), (IV), (V), (Ila), (Illa), (IVa) or (Va) to formula (I).

[0066] In compounds of formula (I), Raand Rbare each independently selected from the group consisting of H, Ci-ealkyl, and -C(O)Ci-6alkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens. For example, Rais H and Rbmay be selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C(O)methyl, C(O)ethyl, C(O)propyl, C(O)isopropyl, C(O)n-butyl, C(O)isobutyl and C(O)sec-butyl, C(O)tert-butyl. In certain embodiments, Rais H and Rbis H.

[0067] In compounds of formula (I), Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; -CH2-phenyl; and -CH2-3 to 12-membered heterocyclyl comprising

[0068] 9

[0069] 55645095-2 1 , 2, 3 or 4 heteroatoms selected from N, O and S; wherein said Ci-ealkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of OH, -OCi-ealkyl, NH2, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)OH, -C(O)NH2, SH, SCH3, and halogen; and said phenyl or heterocyclyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2, OH, and OCi-ealkyl.

[0070] For example, in compounds of formula (I), Rcand Rdmay each be independently selected from the group consisting of H; Ci-4alkyl; -CH2-indolyl; -CH2-phenyl; and -CH2-5-membered heteroaryl comprising two N atoms; wherein Ci-4alkyl is optionally substituted by OH;

[0071] NH2, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)OH, -C(O)NH2, SH, SCH3, or halogen (e.g. F or Cl); and phenyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2, OH, and OCi-ealkyl.

[0072] For example, in compounds of formula (I), Rcand Rdmay each be independently selected from the group consisting of H; Ci-4alkyl; and -CH2-phenyl.

[0073] For example, Rcand Rdmay each be independently selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, -CH2CH2SCH3, benzyl, hydroxy benzyl, -CH2.indol-3-yl, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(=NH)NH2, -CH2CH2CH2NHC(O)NH2,-CH2-imidazol-4-yl, -CH2CH2CH2CH2NH2, -CH2C(O)OH, and -CH2CH2C(O)OH.

[0074] For example, Rcand Rdmay each be independently selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, benzyl, and hydroxy benzyl.

[0075] In certain embodiments, Rcand Rdmay each be independently selected from the group consisting of Ci-ealkyl or -CH2-phenyl; wherein said Ci-ealkyl is optionally substituted by -C(O)NH2or -NHC(=NH)NH2. For example, Rcand Rdmay each be independently selected from the group consisting of methyl, isopropyl, isobutyl, sec-butyl, benzyl, -CH2C(O)NH2, and -CH2CH2CH2NHC(=NH)NH2(e.g. methyl, isobutyl, benzyl, and -CH2C(O)NH2).

[0076] In certain embodiments, Rcand Rdmay each be independently selected from the group consisting of Ci-ealkyl or -CH2-phenyl. For example, Rcand Rdmay each be independently selected from the group consisting of methyl, isopropyl, isobutyl, sec-butyl, and benzyl (e.g. methyl, isobutyl, and benzyl).

[0077] 10

[0078] 55645095-2 In one exemplary embodiment, Rcis Ci-ealkyl (e.g. isopropyl), and Rdis Ci-ealkyl substituted by -NHC(O)NH2 (e.g. Rdmay be -CH2CH2CH2NHC(O)NH2). In another exemplary embodiment, Rcand Rdmay each be a Ci-ealkyl (e.g. Rcand Rdmay each be methyl, or Rcmay be methyl and Rdmay be isobutyl). In another embodiment, one of Rcand Rdis benzyl and the other is Ci-ealkyl (e.g. Rcmay be methyl and Rdmay be benzyl, Rcmay be benzyl and Rdmay be methyl, Rcmay be isobutyl and Rdmay be benzyl, or Rcmay be benzyl and Rdmay be isobutyl). In another embodiment, one of Rcand Rdis -CH2CH2C(O)NH2 and the other is benzyl or Ci-ealkyl (e.g. Rcmay be methyl and Rdmay be -CH2CH2C(O)NH2 or Rcmay be benzyl and Rdmay be -CH2CH2C(O)NH2).

[0079] In other exemplary embodiments, (i) Rcand Rdmay each be a Ci-ealkyl (e.g. Rcand Rdmay each be methyl, or Rcmay be methyl and Rdmay be isobutyl); or (ii) one of Rcand Rdis benzyl and the other is Ci-ealkyl (e.g. Rcmay be methyl and Rdmay be benzyl, Rcmay be benzyl and Rdmay be methyl, Rcmay be isobutyl and Rdmay be benzyl, or Rcmay be benzyl and Rdmay be isobutyl).

[0080] For the avoidance of doubt, when Rcand / or Rdare -CH2-imidazol-4-yl, Rcand / or Rdeach have the following structure (i.e. the structure of the side chain of histidine): wherein, A AT denotes the point of attachment of the Rcor Rdgroup to formula (II), (III), (IV), (V), (Ila), (Illa), (IVa), or (Va).

[0081] Also for the avoidance of doubt, when Rcand / or Rdare -CH2-indol-3-yl, Rcand / or Rdeach have the following structure (i.e. the structure of the side chain of tryptophan): wherein, / VW* denotes the point of attachment of the Rcor Rdgroup to formula (II), (III), (IV), (V), (Ila), (Illa), (IVa), or (Va).

[0082] 11

[0083] 55645095-2 In certain embodiments, when Rcand / or Rdare -CH2-phenyl, the phenyl may be substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen and OH. For example, Rcand / or Rdmay be hydroxybenzyl (e.g. 4-hydroxybenzyl) or fluorobenzyl (e.g. 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl).

[0084] In certain embodiments, in the compound of formula (I), R2is N(Ra)(Rb), R3is according to formula (II), and Rcand Rdmay each be independently selected from the group consisting of H, methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2, for example, methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2.

[0085] In certain embodiments, in the compound of formula (I), R2is N(Ra)(Rb), R3is according to formula (II), and Rcand Rdmay each be independently selected from the group consisting of

[0086] H, methyl, benzyl, and isobutyl, for example, methyl, benzyl, and isobutyl.

[0087] In compounds of formula (I), Reis selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by

[0088] I , 2 or 3 O, N or S atoms.

[0089] According to particular embodiments of formula (I), Reis selected from the group consisting of -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, CN, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms.

[0090] According to still further particular embodiments of formula (I), Reis -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, CN, Ce-waryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms.

[0091] According to yet further particular embodiments of formula (I), Reis -OCi-ealkyl, for example ethoxy.

[0092] In compounds of formula (I), Rfand Rgare each independently selected from the group consisting of H and Ci-ealkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens,

[0093] 12

[0094] 55645095-2 or Rfand R9together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6- membered heterocycle which is optionally substituted by 1, 2 or 3 halogens.

[0095] In certain embodiments, Reis selected from the group consisting of OH and -OCi-ealkyl, for example, Remay be -OCi-ealkyl. In certain exemplary embodiments, Reis -OC2alkyl.

[0096] In one preferred embodiment, in the compound of formula (I), X is Cialkylene, Ri is H, R2is NH2; R3is according to formula (II); Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; -CH2-phenyl; and -CH2-3 to 12-membered heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected from N, O and S; wherein said Ci-ealkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of OH, -OCi-ealkyl, NH2, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)OH, -C(O)NH2, SH, SCH3, and halogen; and said phenyl or heterocyclyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2, OH, and OCi-ealkyl, for example, Rcand Rdmay each be independently selected from the group consisting of H, methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2.

[0097] In one preferred embodiment, in the compound of formula (I), X is Cialkylene, R1 is H, R2is NH2; R3is according to formula (II); Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; and -CH2-phenyl, for example, Rcand Rdmay each be independently selected from the group consisting of H, methyl, benzyl, and isobutyl.

[0098] For example, the compound of formula (I) may be according to formula (Ic), X may be Cialkylene, R1 may be H, R2may be NH2; R3may be according to formula (Ila); and Rcand Rdmay be each independently selected from the group consisting of H; Ci-ealkyl; -CH2-phenyl; and -CH2-3 to 12-membered heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected from N, O and S; wherein said Ci-ealkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of OH, -OCi-ealkyl, NH2, -NHC(=NH)NH2, - C(O)OH, -C(O)NH2, SH, SCH3, and halogen; and said phenyl or heterocyclyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2, OH, and -OCi-ealkyl, for example, Rcand Rdmay each be independently selected from the group consisting of methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2 (e.g. Rcand Rdmay each be methyl); or, for example, Rcmay be Ci-ealkyl (e.g. Rcmay be isopropyl), and Rdmay be Ci-ealkyl substituted by -NHC(O)NH2 (e.g. Rdmay be -CH2CH2CH2NHC(O)NH2); or Rcand Rdmay each be a Ci-ealkyl (e.g. Rcand Rdmay each be methyl, or, for example, Rcmay be methyl and Rdmay be isobutyl); or, for example, one of Rcand Rdmay be benzyl and the other may be Ci-ealkyl (e.g. Rcmay be methyl and Rdmay

[0099] 13

[0100] 55645095-2 be benzyl, Rcmay be benzyl and Rdmay be methyl, Rcmay be isobutyl and Rdmay be benzyl, or Rcmay be benzyl and Rdmay be isobutyl); or, for example, one of Rcand Rdmay be - CH2CH2C(O)NH2 and the other may be benzyl or Ci-ealkyl (e.g. Rcmay be methyl and Rdmay be -CH2CH2C(O)NH2, or Rcmay be benzyl and Rdmay be -CH2CH2C(O)NH2).

[0101] For example, the compound of formula (I) may be according to formula (Ic), X may be Cialkylene, Ri may be H, R2may be NH2; R3may be according to formula (Ila); and Rcand Rdmay be each independently selected from the group consisting of H; Ci-ealkyl; and -CH2- phenyl, for example, Rcand Rdmay each be independently selected from the group consisting of methyl, benzyl, and isobutyl (e.g. Rcand Rdmay each be methyl); or, for example, Rcand Rdmay each be a Ci-ealkyl (e.g. Rcand Rdmay each be methyl, or, for example, Rcmay be methyl and Rdmay be isobutyl); or, for example, one of Rcand Rdmay be benzyl and the other may be Ci-ealkyl (e.g. Rcmay be methyl and Rdmay be benzyl, Rcmay be benzyl and Rdmay be methyl, Rcmay be isobutyl and Rdmay be benzyl, or Rcmay be benzyl and Rdmay be isobutyl).

[0102] In certain embodiments, formula (I) is according to formula (Ic), X is Cialkylene, R1 is H, R2is N(Ra)(Rb), R3is according to formula (II), Rcand Rdare each independently selected from the group consisting of H, methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2 (e.g. methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2), and Reis -OCi-ealkyl. For example, R2may be NH2, R3may be according to formula (II) (e.g. R3may be according to formula (Ila)), Rcand Rdmay each be independently selected from the group consisting of H, methyl, benzyl, and isobutyl, and Remay be -OC2alkyl.

[0103] In certain embodiments, formula (I) is according to formula (Ic), X is Cialkylene, R1 is H, R2is N(Ra)(Rb), R3is according to formula (II), Rcand Rdare each independently selected from the group consisting of H, methyl, benzyl, and isobutyl (e.g. methyl, benzyl, and isobutyl), and Reis -OCi-ealkyl. For example, R2may be NH2, R3may be according to formula (II) (e.g. R3may be according to formula (Ila)), Rcand Rdmay each be independently selected from the group consisting of H, methyl, benzyl, and isobutyl, and Remay be -OC2alkyl.

[0104] In a certain preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0105] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester (also referred to herein as Mel-Ala-Ala-OEt or Example compound 1);

[0106] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylvalinylcitrulline ethyl ester (also referred to herein as Mel-Val-Cit-OEt or Example compound 2);

[0107] 14

[0108] 55645095-2 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylglutamine ethyl ester (also referred to herein as Mel-Ala-GIn-OEt or Example compound 3);

[0109] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylglutamine ethyl ester (also referred to herein as Mel-Phe-GIn-OEt or Example compound 4);

[0110] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylphenylalanine ethyl ester (also referred to herein as Mel-Ala-Phe-OEt or Example compound 5);

[0111] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylleucine ethyl ester (also referred to herein as Mel-Ala-Leu-OEt or Example compound 6);

[0112] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester (also referred to herein as Mel-Phe-Ala-OEt or Example compound 7); and 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylleucine ethyl ester (also referred to herein as Mel-Phe-Leu-OEt or Example compound 8), for example, the compound of formula (I) may be 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester (i.e. Example compound 1).

[0113] According to particular embodiments the compound of formula (I) is 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester (also referred to herein as Mel-Phe-Ala-OEt or Example compound 7); or 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester (i.e. Example compound 1).

[0114] Thus, the compound of formula (I) may be selected from the group consisting of:

[0115] 55645095-2

[0116]

[0117] 55645095-2

[0118]

[0119] 55645095-2

[0120] Or, in certain preferred embodiments, the compound of formula (I) may be selected from the group consisting of:

[0121] 55645095-2

[0122]

[0123] 55645095-2

[0124]

[0125] ; and

[0126] 55645095-2

[0127]

[0128] In certain exemplary embodiments, the compound of formula (I) is 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester. Thus, the compound of formula (I) may be:

[0129] 55645095-2 For example, the compound of formula (I) may be:

[0130] In certain exemplary embodiments, the compound of formula (I) is 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester. Thus, the compound of formula (I) may be:

[0131] For example, the compound of formula (I) may be:

[0132] 55645095-2 The compounds of the present invention may be prepared using methods known to those skilled in the art of organic chemistry. Exemplary procedures for the preparation of compounds of formula (I) are described in the Examples section.

[0133] As used herein, the term “alkyl” encompasses both linear and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, isobutyl, sec-butyl, pentyl and hexyl groups. Examples of linear alkyl groups include methyl, ethyl, n-propyl, isopropyl and n-butyl groups. Examples of branched alkyl groups include tert-butyl, sec-butyl, isobutyl, 1-ethylpropyl and 1-ethylbutyl groups.

[0134] As used herein, the term “halogen” refers to fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are particularly preferred.

[0135] As used herein, the term “heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected from N, O and S” encompasses aromatic and non-aromatic cyclic or bicyclic groups of carbon atoms wherein one, two, three or four of the carbon atoms is / are replaced by one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur (preferably nitrogen and sulfur). Examples of 5-membered heterocyclyl groups comprising 1 , 2 or 3 nitrogen and / or sulfur atoms include thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, and thiadiazolyl. An example of a 9-membered heterocyclyl group comprising one nitrogen atom is indolyl.

[0136] The compound of formula (I) may comprise an isotope atom. As defined herein, an isotope atom is an atom of an element that is not the most common naturally occurring isotope. Deuterium is a stable isotope of hydrogen. In certain embodiments, the compound of formula (I) has a deuterium abundance level greater than the naturally occurring abundance of deuterium. The naturally occurring abundance of deuterium is about 0.0156 mol%, wherein mol% is the percentage of the total moles of a sample’s hydrogen that is deuterium. Therefore, in 1 mole of naturally occurring hydrogen, about 0.156 mmol is deuterium, or in a sample of about 6.022 x 1023naturally occurring hydrogen atoms there are about 9.39 x1019atoms of deuterium, or in a sample of about 6413 naturally occurring hydrogen atoms there is about one atom of deuterium. A deuterium abundance level greater than the naturally occurring abundance of deuterium may be at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol% or 98 mol% deuterium. In certain embodiments, the compound of formula (I) has a deuterium abundance level of at least 1 mol%, 5 mol%, 10 mol%, 50 mol%, 90 mol% or 98 mol% deuterium. Procedures for preparing deuterated compounds are known in the art. See for example Sajiki, New Horizons of Process Chemistry (2017), Springer, pg 29-40, and Hanson, The Organic Chemistry of Isotopic Labelling (2011), Chapter 3, RSC Publishing.

[0137] 23

[0138] 55645095-2 The compound of formula (I) may form salts or solvates. Salts of the compound of formula (I) which are suitable for use in the present invention are those wherein a counterion is pharmaceutically acceptable. However, the use of salts having non-pharmaceutically acceptable counter-ions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compound of formula (I) and their pharmaceutically acceptable salts and solvates, and physiologically functional derivatives thereof. Suitable salts for use according to the invention include those formed with organic or inorganic acids. In particular, suitable salts formed with acids for use according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Ci-4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Suitable cations which may be present in salts include alkali metal cations, especially sodium, potassium and calcium, and ammonium or amino cations. In certain embodiments, the compound of the present invention is in the form of an acetate salt or a hydrochloride salt, for example an acetate salt.

[0139] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a "hydrate". The complex may incorporate a solvent in stoichiometric or non- stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation, 2nded R. Lui CRC Press, page 553 and Byrn et al., Pharm Res 12(7), 1995, 945-954. Before it is made up in solution, the compound of formula (I) may be in the form of a solvate. Solvates of the compound of formula (I) which are suitable for use as a medicament according to the invention are those wherein the associated solvent is pharmaceutically acceptable. For example, a hydrate is a pharmaceutically acceptable solvate.

[0140] The present invention provides a composition comprising a compound of the present invention and at least one binder, carrier or excipient. Preferably, the composition of the invention is a pharmaceutical composition. For example, the composition may be a pharmaceutical

[0141] 24

[0142] 55645095-2 composition comprising a compound of the present invention and at least one pharmaceutically acceptable binder, carrier or excipient.

[0143] In embodiments herein, the word “comprising” may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word “comprising” may also relate to the situation where only the components / features listed are intended to be present (e.g. the word “comprising” may be replaced by the phrases “consists of’ or “consists essentially of’). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word “comprising” and synonyms thereof may be replaced by the phrase “consisting of’ or the phrase “consists essentially of’ or synonyms thereof and vice versa.

[0144] The pharmaceutical composition of the invention may be suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous infusion, intramuscular, intravascular (bolus or infusion), and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend upon the characteristics of the subject under treatment, for example the species, age, weight, sex, medical conditions, the particular type of disease or disorder, its severity, and other relevant medical and physical factors.

[0145] Pharmaceutically acceptable binders, carriers or excipients suitable for including in the pharmaceutical composition of the invention may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable binders, carriers or excipients may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical composition may be found in, for example, Remington The Science and Practice of Pharmacy, 19thed., Mack Printing Company, Easton, Pennsylvania (1995). Otherwise, the preparation of suitable formulations may be achieved routinely by the skilled person using routine techniques and / or in accordance with standard and / or accepted pharmaceutical practice.

[0146] Compositions of the present invention suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats (e.g. benzyl alcohol, chlorobutanol, and cresol) and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The Compositions may be presented in unit-dose or multi-dose containers, for example sealed

[0147] 25

[0148] 55645095-2 ampoules and vials, and may be stored in a freeze- dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described herein. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or a polyoxyl-ethylated castor oil (e.g. Cremophor EL).

[0149] Compositions suitable for rectal administration may be presented as a suppository with carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug.

[0150] Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A compound of the invention may also be presented as a bolus, electuary or paste. Various pharmaceutically acceptable carriers and their formulation are described, for example, by Remington The Science and Practice of Pharmacy, 19thed., Mack Printing Company, Easton, Pennsylvania (1995). See also Wang, Y. J. and Hanson, M. A., Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.

[0151] Compositions suitable for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0152] In certain embodiments, the pharmaceutical composition is suitable for administration by injection and / or infusion, for example, the pharmaceutical composition may comprise the compound of formula (I) together with one or more of water for injection, polyvinylpyrrolidone (e.g. Povidone K12), sodium citrate, propylene glycol and ethanol. In certain other embodiments, the pharmaceutical composition is a suitable for oral administration, for example the pharmaceutical composition may be a tablet comprising a compound of formula (I) together with one or more of the group consisting of colloidal silicon dioxide,

[0153] 26

[0154] 55645095-2 polyvinylpyrrolidone (e.g. Povidone K12), PEG 400, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

[0155] Preferred unit dosage compositions are those containing an exploratory dose or therapeutic dose, or an appropriate fraction thereof, of the compound of formula (I). In preferred embodiments, a composition for use according to the present invention consists essentially of a compound according to formula (I), and at least one pharmaceutically acceptable binder, carrier or excipient. Preferred unit dosage compositions are those containing an exploratory dose or therapeutic dose, or an appropriate fraction thereof, of a compound of the invention.

[0156] It should be understood that in addition to the ingredients mentioned above, the compositions for use in the present invention may also include other agents having regard to the type of composition in question.

[0157] For example, the compositions of the invention may comprise one or more further therapeutic agents. Examples of further therapeutic agents that may be present in a composition of the present invention include, but are not limited, to steroids (e.g. dexamethasone, prednisone, methylprednisolone, hydrocortisone, betamethasone, triamcinolone, fludrocortisone, and budesonide), checkpoint inhibitors (e.g. CTLA-4 inhibitors, PD-1 / PD-L1 inhibitors, LAG-3 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, and IDO inhibitors), nuclear transport inhibitors (e.g. selinexor, verdinexor, mitoxantrone, and tasquinimod), anti-apoptotic inhibitors (e.g. venetoclax, navitoclax, obatoclax, and sabutoclax), adoptive cell therapy (e.g., tumorinfiltrating lymphocyte (TIL) therapy, Natural Killer (NK) cell therapy, chimeric antigen receptor (CAR) T-cell therapy, and engineered T-cell receptor therapy), bi-specific T-cell engagers (BiTEs), immunomodulatory imide drugs (IMiDs) (e.g. thalidomide, lenalidomide and pomalidomide), proteasome inhibitors (Pls) (e.g. bortezomib, carfilzomib, ixazomib and marizomib), histone deacetylase (HDAC) inhibitors (e.g. panobinostat), alkylators (e.g. melflufen, melphalan, cyclophosphamide, busulfan, carmustine, temozolomide, dacarbazine, ifosfamide, mechlorethamine, and thiotepa), and DNA intercalators (e.g. doxorubicin, daunorubicin, actinomycin D, and mitoxantrone). For example, the composition of the invention of the invention may comprise a compound of formula (I) and a steroid, such as dexamethasone or prednisone.

[0158] The present invention also provides a compound according to formula (I), or a composition comprising a compound according to formula (I) together with at least one pharmaceutically acceptable binder, carrier or excipient, for use as a medicament.

[0159] 27

[0160] 55645095-2 In particular, compounds and compositions of the present invention find use in the treatment and / or prevention of a cancer. Particular examples of cancers that may be treated or prevented by administering a compound or composition of the invention include carcinoma, a sarcoma, a myeloma, a leukemia, a lymphoma or a mixed type of cancer. For example, cancers that may be treated or prevented by administering a compound or composition of the present invention include, but are not limited to, hematologic / blood cell cancers such as a leukemia (for example, acute lymphoblastic leukemia including adult and childhood acute lymphoblastic leukemia; acute myeloid leukemia including adult and childhood acute myeloid leukemia; chronic lymphocytic leukemia such as B Cell chronic lymphocytic leukemia; chronic myelogenous leukemia; and hairy cell leukemia); lymphoma (e.g., AIDS-related lymphoma; cutaneous T-cell lymphoma; Hodgkin's lymphoma including adult and childhood Hodgkin's lymphoma and Hodgkin's lymphoma during pregnancy; non-Hodgkin's lymphoma including adult and childhood non-Hodgkin's lymphoma and non-Hodgkin's lymphoma during pregnancy; mycosis fungoides; Sezary syndrome; Waldenstrom's macroglobulinemia; primary mediastinal large B cell lymphoma; mantle cell lymphoma; diffuse large B cell lymphoma; and primary central nervous system lymphoma); and other hematologic cancers (for example, chronic myeloproliferative disorders; multiple myeloma / plasma cell neoplasm; myelodysplastic syndromes; and myelodysplastic / myeloproliferative disorders); osteosarcoma, ovarian cancer, breast cancer; lung cancer; glioblastoma; retinoblastoma and metastases of the aforementioned cancers.

[0161] The compounds of the present invention may be used for the treatment or prevention of one or more hematological cancers. The compounds may also be used in the treatment of solid tumors. Compounds and compositions of the invention may also find utility in a method of treating or preventing a disease or disorder, said method comprising a step of administering a compound of the invention, or a composition of the invention, to a subject in need thereof. As such, a compound or composition of the invention may be administered to a patient suffering, or at risk of developing, a cancer, particularly a haematological cancer. The step of administering a compound of the invention, or a composition of the invention, to a subject in need thereof may comprises administering a pharmaceutically effective amount of the compound of the invention, or a composition of the invention.

[0162] Compounds of the invention also find use in the manufacture of a medicament, particularly use in the manufacture of a medicament for the treatment or prevention of a cancer, for example, a haematological cancer.

[0163] 28

[0164] 55645095-2 For example, the compounds of the present invention (and pharmaceutical compositions of the present invention) may be used for the treatment or prevention of one or more cancer selected from the group consisting of multiple myeloma, osteosarcoma, breast cancer, lung cancer, ovarian cancer, leukemia and lymphoma, for example, the cancer is multiple myeloma, acute myeloid leukemia or lymphoma.

[0165] The compounds of the present invention may be used for the treatment or prevention of one or more ophthalmological cancers (also known as eye cancers). Such cancers are characterised by occurring in or around the eye. Examples include ocular melanoma, lymphoma, retinoblastoma and squamous cell carcinoma.

[0166] The most common type of primary eye cancer (cancer that begins in the eye) in adults is uveal melanoma. Uveal melanoma develops in the uvea, a pigmented layer of tissue in the eye. A common example of uveal melanoma is choroidal melanoma, which originates in the choroid part of the uvea. Other examples are iris and ciliary body melanomas. Uveal melanomas can metastasise, primarily to the liver.

[0167] The use of melphalan in the treatment of ophthalmological cancers has been described previously, for example via intra-arterial administration via selective catheterisation of the ophthalmic artery. This can minimises systemic side effects, for example associated with general brachtherapy (although brachtherapy may be and commonly is used in conjunction with chemotherapy with melphalan) or more irreversible intervention such as enucleation. It well-established, for example for the treatment of retinoblastoma and other ophthalmologic cancers (for a recent example see R Jorge et al. (Int J Retin Vitr 8, 55 (2022). https: / / doi . org / 10.1186 / s40942-022-00404- 1 ) .

[0168] Accordingly, the compounds of the present invention may be used for the treatment or prevention of one or more ophthalmologic cancers, including but not limited to uveal melanomas. As such, a compound or composition of the invention may be administered to a patient suffering, or at risk of developing, such a cancer. The step of administering a compound of the invention, or a composition of the invention, to a subject in need thereof may comprises administering a pharmaceutically effective amount of the compound of the invention, or a composition of the invention.

[0169] As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the

[0170] 29

[0171] 55645095-2 subject is a subject in need of treatment or a subject with a disease or disorder, for example cancer (e.g. a haematological cancer). The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

[0172] The amount of a compound of the invention which is required to achieve a therapeutic effect will vary with particular route of administration and the characteristics of the subject under treatment, for example the species, age, weight, sex, medical conditions, the particular disease or condition and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer an effective amount of the compound of the invention required for treatment or prophylaxis of a disease or condition.

[0173] The term “pharmaceutically effective amount” as used herein refers to an amount of the compound of the invention or pharmaceutical composition of the invention that confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease, such as cancer). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

[0174] The compound of the invention, or salt and / or solvate thereof, may be administered daily (including several times daily), every second or third day, weekly, every second, third or fourth week or even as a high single dose depending on the subject and disease or disorder to be treated.

[0175] Typically, a compound of the invention, or salt and / or solvate thereof (excluding the mass of any counterion or solvent), may be administered in an amount of about 0.1 mg to about 150 mg per administration. For example, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg or about 150 mg. Alternatively, a compound of the invention, or salt and / or solvate thereof (excluding the mass of any counterion or solvent), may be administered in a single high dose. A single high dose may be, for example, about 50 mg to about 800 mg. For example, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg. Whilst a compound of the invention may be used as the sole active ingredient, it may also be used in combination with one or more further therapeutic agent(s). Such further therapeutic agents may be agents useful in the treatment or prevention of a cancer, or other pharmaceutically active materials. Such agents are known in the art. Examples of further therapeutic agents suitable for use in the present invention are described herein.

[0176] 30

[0177] 55645095-2 The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, within 1 %, within 0.5%, within 0.1%, within 0.05%, within 15 0.01%, within 0.005%, or within 0.001% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0178] The one or more further therapeutic agent(s) may be used simultaneously, sequentially or separately with / from the administration of a compound of the invention. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. For example, the one or more further therapeutic agent(s) that may be used simultaneously, sequentially or separately with / from the administration of a compound of the invention, may be a steroid, such as dexamethasone or prednisone.

[0179] The present invention also provides a kit comprising a compound of formula (I), one or more pharmaceutically acceptable binder, carrier or excipient, and optionally one or more further therapeutic agents. Examples of such further therapeutic agents include those described herein as being suitable for use in the present invention, and being optionally present in a pharmaceutical composition of the invention as a further therapeutic agent. Kits of the present invention may find use in the treatment and / or prevention of a cancer, for example, a haematological cancer.

[0180] In certain embodiments, the kit comprises one or more containers and may also include sampling equipment, for example, bottles, bags, vials, syringes, and test tubes. Other components may include needles, wash reagents and buffers. The kit may include at least one container comprising a binder, carrier (e.g. a physiologically acceptable solvent or diluent), and / or excipient. For example, the container may comprise a physiologically acceptable aqueous solvent or diluent, such as a phosphate-buffered saline, Ringer's solution, a glucose solution, or a dextrose solution.

[0181] Typically, the kit comprises instructions, for example instructions that instruct a user to admix a stated amount of compound or composition of the present invention with a stated amount pharmaceutically acceptable binder, carrier and / or excipient, and / or optional one or more further therapeutic agents.

[0182] For the avoidance of doubt, the compound or composition of the present invention, optional pharmaceutically acceptable binder, carrier and / or excipient, and optional one or more further

[0183] 31

[0184] 55645095-2 therapeutic agents, are present in a kit according to the present invention in a form and quantity suitable for the preparation of a pharmaceutical preparation suitable for use according to the present invention. The person skilled in the art can readily determine a suitable quantity of a compound or composition of the present invention, pharmaceutically acceptable binder, carrier and / or excipient, and optional one or more further therapeutic agents, for use according the present invention.

[0185] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The applicant reserves the right physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[0186] Further aspects and embodiments of the invention will now be discussed by reference to the following non-limiting examples. Examples 2 to 4 do not fall within the scope of certain embodiments of the invention disclosed herein.

[0187] EXAMPLES

[0188] Materials and Methods:

[0189] Reagents and solvents were purchased from commercial suppliers and used as received.

[0190] Abbreviations used herein include:

[0191] ACN - acetonitrile

[0192] TEA - trimethylamine

[0193] DCM - dichloromethane

[0194] DMF - N,N-Dimethylformamide

[0195] TEA - triethylamine

[0196] TFA - trifluoroacetic acid

[0197] PyBOP - benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

[0198] DIPEA - N,N-Diisopropylethylamine

[0199] TLC - thin layer chromatography pTLC - preparative thin layer chromatography

[0200] RT - room temperature o / n - overnight

[0201] Mel - melphalan

[0202] 32

[0203] 55645095-2 Rt - retention time

[0204] Trt - Trityl

[0205] MeOH - methanol

[0206] HPLC - High Performance Liquid Chromatography

[0207] LIPLC - Ultra Performance Liquid Chromatography

[0208] LC / MS - Liquid Chromatography Mass Spectrometry

[0209] EtOAc - ethyl acetate

[0210] SM - starting material.

[0211] 1H spectra were acquired on a Bruker 400 MHz Spectrometer. Deuterated dimethyl sulfoxide (d6-DMSO) was used as a solvent.

[0212] LC / MS was performed using a Dionex UHPLC Ultimate 3000 with Diode Array Detector (DAD) detector coupled with a Thermo Scientific ISQ EC - Mass Spectrometer. A Kinetex® 2.6 pm XB-C18 (4.6 x 50mm), 110A column was used. The following method was used with a mobile phase A of 0.1 % v / v water solution of formic acid, and mobile phase B of 0.1 % v / v acetonitrile solution of formic acid:

[0213] Table 1 : HPLC method

[0214] A wavelength range of from 190 - 350 nm ± 4 nm was used, unless stated otherwise. The column temperature was maintained at 25 °C and the autosampler temperature maintained at 20 °C.

[0215] 55645095-2 Example 1 - Mel-Ala-Ala-OEt (2-amino-3-f4-fbis(2- chloroethyl)aminolphenyl}propanoylalanylalanine ethyl ester):

[0216] Preparation of Boc-Me 1-0 H:

[0217] Molecular Weight: 405,32

[0218] Melphalan (250 mg, 0.8 mmol, 1.0 eq.) was dissolved in 2.0 ml of 1 ,4-dioxane. The solution was then cooled to 10 °C and TEA (0.91 ml, 0.9 mmol, 1.1 eq.) was added followed by addition of BOC2O (197 mg, 0.9 mmol, 1.1 eq.) in one portion. The resulting reaction mixture was stirred at room temperature for 3.5 hours. Solvent was evaporated under reduced pressure and the residue was re-dissolved in 2 ml of ethyl acetate. 2 ml of water was added and the mixture was acidified to pH 3 with 1 M HCI. The organic layer was separated, washed with water and brine, dried over MgSC>4 and concentrated under reduced pressure to give 291 mg of title product as a foam.

[0219] Preparation of Boc-Ala-Ala-OEt:

[0220] Boc-Ala-Ala-OH (0.5 g, 1.9 mmol, 1.0 eq.) was dissolved in DMF (5 ml) and NaHCOs (484 mg, 5.8 mmol, 3.0 eq.) was added followed by addition of iodoethane (0.89 g, 5.8 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature overnight. Subsequently, the mixture

[0221] 34

[0222] 55645095-2 was poured into cold water (50 ml) and extracted with ethyl acetate (2 x 20 ml). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to colorless oil.

[0223] Preparation of Ala-Ala-OEt:

[0224] Boc-Ala-Ala-OEt (417 mg, 1.4 mmol, 1.0 eq.) was dissolved in DCM (2 ml) and TFA (2 ml, 26 mmol, 18 eq.) was added. The resulting mixture was stirred at RT for 45 minutes. The reaction mixture was then concentrated under reduced pressure and co-evaporated twice with DCM, and then dried under vacuum overnight.

[0225] Preparation of Boc-Mel-Ala-Ala-OEt:

[0226] Boc-Mel-OH (52 mg, 0.13 mmol, 1.0 eq.) was dissolved in DMF (1 ml). PyBOP (73 mg, 0.14 mmol, 1.1 eq.) and were added. After stirring at room temperature for 30 minutes, DIPEA (18 mg, 0.14 mmol, 1.1 eq.) was added to the reaction mixture followed by mixture of Ala-Ala-OEt (P86%, 52 mg, 0.15 mmol, 1.15 eq.) in 1 ml of DMF. The reaction mixture was stirred at room

[0227] 35

[0228] 55645095-2 temperature overnight. Subsequently, reaction mixture was poured into cold water and extracted with ethyl acetate (5 x 3 ml). Combined organic layers were washed with brine, dried over MgSC>4 and concentrated. The resulting crude material was purified twice by preparative TLC (5% MeOH in DCM). n.d. - not determined.

[0229] Preparation of title compound (Example compound 1 - Mel-Ala-Ala-OEt):

[0230] Molecular Weight: 535,46

[0231] Boc-Mel-Ala-Ala-OEt (43 mg, 0.11 mmol, 1.0 eq.) and TFA (840 mg, 63.7 mmol, 60 eq.) were dissolved in 1 ml of DCM and stirred for 30 min at RT. The solvent was evaporated and then co-evaporated 3 times with DCM. The residue was dissolved in DCM, alkalized to pH 8 with cone. NaHCOs. The organic phase was evaporated and the residue was purified by pTLC (8% MeOH in DCM). The obtained product was dissolved in ACN and water and then was treated with acetic acid, stirred for 30 min and freeze dried.

[0232] 55645095-2 Example 2 - Mel-Val-CIt-OEt (2-amlno-3-{4-[bls(2- chloroethyl)aminolphenyl}propanoylvalinylcitrulline ethyl ester)

[0233] Preparation of Boc-Val-Cit-OEt:

[0234] Boc-Val-Cit-OH (0.5 g, 1.3 mmol, 1.0 eq.) was dissolved in DMF (4 ml) and KHCO3 (401 mg, 4 mmol, 3.0 eq.) was added followed by addition of lodoethane (0.41 g, 2.7 mmol, 3.0 eq.). Incomplete conversion was observed by LIPLC. Additional portions of iodoethane (0.41 g, 2.7 mmol, 2.0 eq.) and KHCO3 (267 mg, 2.7 mmol, 2.0 eq.) were added and the reaction mixture was stirred for 2 hours. Subsequently, the mixture was poured into cold water (50 ml) and extracted with ethyl acetate (7 x 15 ml). Combined organic layers were washed with brine, dried over Na2SC>4 and concentrated to white foam.

[0235] Preparation of Val-Cit-OEt:

[0236] Boc-Val-Cit-OEt (441 mg, 1.1 mmol, 1.0 eq.), was dissolved in DCM (2 ml) and TFA (1.5 ml, 26 mmol, 18 eq.) was added. The resulting mixture was stirred at RT for 60 minutes. The reaction mixture was then concentrated under reduced pressure and co-evaporated twice with DCM, and then dried under vacuum overnight.

[0237] 37

[0238] 55645095-2

[0239] Preparation of Boc-Mel-Val-Cit-OEt: Boc-Mel-OH (85 mg, 0.21 mmol, 1.0 eq.), prepared according to Example 1 above, was dissolved in DMF (1 ml). DIPEA (32 mg, 0.25 mmol, 1.2 eq.) and PyBOP (142 mg, 0.27 mmol, 1.1 eq.), were added. After stirring at room temperature for 30 minutes, DIPEA (32 mg, 0.25 mmol, 1.2 eq.) was added to the reaction mixture followed by mixture of Val-Cit-OEt (P79%, 127 mg, 0.24 mmol, 1.15 eq.) in 1 ml of DMF. The reaction mixture was stirred at room temperature overnight. Subsequently, reaction mixture was poured into cold water and extracted with ethyl acetate (2x5ml). Combined organic layers were washed with brine, dried over MgSC>4 and concentrated. The resulting crude material was purified twice by preparative TLC (5% MeOH in DCM). n.d. - not determined.

[0240] 55645095-2 Preparation of title compound (Example compound 2 - Mel-Val-Cit-OEt):

[0241] Molecular Weight: 649,61

[0242] Boc-Mel-Val-Cit-OEt (65 mg, 0.11 mmol, 1.0 eq.) and TFA (591 mg, 52 mmol, 55 eq.) were dissolved in 1 ml of DCM and stirred for 30 min at RT. The solvent was evaporated and then co-evaporated 3 times with DCM. The residue was dissolved in DCM, alkalized to pH 8 with cone. NaHCOs. The organic phase was evaporated and the residue was purified by pTLC (10% MeOH in DCM). The obtained product was dissolved in ACN and water and then was treated with acetic acid, stirred for 30 min and freeze dried.

[0243] 55645095-2 Examples 3 and 4 - Synthesis of Mel-Ala-GIn-OEt (Example compound 3) and Mel- Phe-GIn-OEt (Example compound 4):

[0244] Example compounds 3 and 4 were prepared following the general synthesis route set out in Scheme 1.

[0245] Scheme 1: General synthesis route for Example compounds 3 and 4: a) Dipeptide synthesis - Steps 1 to 4 of Scheme 1:

[0246] 55645095-2 n.d. - not determined.

[0247] 1. Coupling Fmoc-Gln(Trt)-OH to 2-chlorotrityl chloride (2-CTC) resin:

[0248] 2-CTC resin was washed three times with DCM (20 ml). A solution of Fmoc-Gln(Trt)-OH in DCM was added, followed by DI PEA. The reagents were mixed on an orbital shaker over 2 h. The solvent was removed and the resin was quenched with 20 ml of a solution of DCM, MeOH and DIPEA (volume ratio of 27:2:1). The resin was then washed with DCM (3 x 20 ml), DMF (3 x 20 ml) and DCM (3 x 20 ml) and dried in vacuo.

[0249] 2. Fmoc deprotection: The resin was mixed on an orbital shaker with 20 ml of 20% piperidine in DMF over 20 min. The solution was removed and a portion of fresh 20% piperidine in DMF was added. After mixing over 20 min, the solution was removed and the resin washed with DCM (3 x 20 ml), MeOH (3 x 20 ml) and DCM (3 x 20 ml).

[0250] 41

[0251] 55645095-2 3. Coupling of a Boc-protected amino acid to Gln(Trt)-2CTC resin:

[0252] A solution of a Boc-protected amino acid in DMF was added to the resin, followed by a mixture of COMII (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), Oxyma (ethyl cyanohydroxyiminoacetate) and DI PEA. The reagents were mixed over 2 h, until negative Kaiser test was observed. Liquids were removed and the resin was washed with DCM, MeOH and DCM (3 x 20 ml each).

[0253] 4. Cleavage of the dipeptide from the 2-CTC resin:

[0254] The resin was shaken with 20 ml of 1% TFA in DCM over 1 min. The solution was removed and collected. This operation was repeated four times. Solution fractions containing product (checked by TLC) were combined and evaporated to give desired product as a white foams.

[0255] A solution of SM, potassium carbonate (K2CO3) and ethyl iodide (Etl) was stirred at ambient temperature over 24 h. The resulting mixture was filtered and evaporated. Residue was taken into DMF and additional portions of potassium carbonate and ethyl iodide were added. The reaction mixture was stirred at RT over 2 h and poured into 20 ml of cold water and 10 ml of ethyl acetate. Layers were separated and aqueous phase was extracted with ethyl acetate (2 x 10ml). Combined extracts were washed with water and brine, dried and evaporated to give the desired product as a foam.

[0256] 42

[0257] 55645095-2 Boc-Ala-Gln(Trt)-OEt (Example 3, R = H): LC / MS: Rt = 2.62 min, [M+H]+= 588.

[0258] Boc-Phe-Gln(Trt)-OEt (Example 4, R = Ph): LC / MS: Rt = 2.82 min, [M+ H]+= 664. b) Removal of trityl (Trt) and Boc protecting group - Step 6 of Scheme 1:

[0259] To a stirred solution of SM in DCM, TFA was added and the resulting mixture was stirred over 2 h. Volatiles were evaporated and the residue was taken into DCM. Resulting solution was evaporated. Obtained material was used without purification. LCMS purity is low mainly due to ratio of absorption coefficient of the desired and side products.

[0260] Ala-GIn-OEt TFA salt (Example 3, R = H): LC / MS: Rt = 0.60 min, [M+ H]+= 246.

[0261] Phe-GIn-OEt TFA salt (Example 4, R = Ph): LC / MS: Rt = 0.55 min, [M+H]+= 322. c) Coupling of Boc-Mel-OH to the dipeptide - Step 7 of Scheme 1:

[0262] 43

[0263] 55645095-2

[0264] A solution of Boc-Mel-OH, PyBOP and DI PEA in DMF was stirred at RT over 30 min. Ala-GIn- OEt TFA salt or Phe-GIn-OEt TFA salt was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 5 ml of cold water and the product was extracted with ethyl acetate (3 x 5 ml).

[0265] Expt. Nos. 1 and 2 (Boc-Mel-Ala-GIn-OEt, Example 3, R = H): Combined organic extracts were washed with water and brine, dried and evaporated. Crude material was purified twice by pTLC (SiC>2 / 3% MeOH in DCM). Both products were combined and used in the next step. Experiment No. 1 : LC / MS: Rt = 2.25 min, [M+H]+= 632; Experiment No. 2: Rt = 2.25 min, [M+H]+= 632.

[0266] Expt. No. 3 (Boc-Mel-Phe-GIn-OEt, Example 4, R = Ph): Precipitate was filtered off, washed with ethyl acetate, dried and purified by pTLC (3% MeOH in DCM) to give the product as a white solid. LC / MS: Rt = 2.45 min, [M+H]+= 708. d) Boc removal to provide example compounds - Step 8 of Scheme 1:

[0267] 55645095-2

[0268] *NMR spectrum not measured due to low amount of the final product

[0269] To a solution of SM in DCM, TFA was added and the resulting mixture was stirred over 2 h at ambient temperature. Volatiles were evaporated under reduced pressure. Residue was taken into DCM and evaporated. Crude material was purified by preparative HPLC.

[0270] Example compound 3 (Mel-Ala-GIn-OEt; 2-amino-3-{4-fbis(2- chloroethyl)aminolphenyl}propanoylalanylqlutamine ethyl ester): The example compound was purified by preparative HPLC, dissolved in a saturated NaHCO3 solution and extracted with EtOAc. The combined extracts were dried and evaporated, and further purified by pTLC (SiC>2 / 10% MeOH in DCM). LC / MS: Rt = 2.45 min, m / z calcd. [M]+532.21 found 532.

[0271] 45

[0272] 55645095-2 Example compound 4 (Mel-Phe-GIn-OEt; 2-amino-3-{4-[bis(2- chloroethyl)aminolphenyl}propanoylphenylalanylqlutamine ethyl ester):

[0273] The example compound was purified by preparative HPLC and lyophilized, followed by further purification by pTLC (SiC>2 / 10% MeOH in DCM). LC / MS: Rt = 2.77 min, m / z calcd. [M]+608.24, found 608.

[0274] Examples 5 to 8 - Synthesis of Mel-Ala-Phe-OEt (Example compound 5), Mel-Ala-Leu-

[0275] OEt (Example compound 6), Mel-Phe-Ala-OEt (Example compound 7), and Mel-Phe-Leu- OEt (Example compound 8):

[0276] Example compounds 5 to 8 were prepared following the general synthesis route set out in Scheme 2.

[0277] Scheme 2: General synthesis route for Example compounds 5 to 8:

[0278] 55645095-2

[0279] To a stirred solution of Boc protected amino acid (Boc-AA-OH: Boc-Ala-OH or Boc-Phe-OH), amino acid ester hydrochloride (H-AA-OEt*HCI: Boc-Phe-OEt, Boc-Leu-OEt or Boc-Ala-OEt), Oxyma and DIPEA in DMF, COMII was added and the resulting solution was stirred at RT overnight. The mixture was dilluted with EtOAc to 75 ml and extracted with 1 M HCI (2 x 25 ml), saturated NaHCCh (2 x 25 ml) and brine (2 x 25 ml). Organic solution was dried over anhydrous MgSO4 and evaporated to give crude product which was purified by pTLC.

[0280] 55645095-2

[0281] SM was dissolved in 50% TFA. The resulting solution was stirred over 2 h and evaporated. The residue was taken into DCM and evaporated. Crude materials were used without further purification.

[0282] Ala-Phe-OEt TFA salt (Example 5, R = Ph, R’ = H): LC / MS: Rt = 0.46 min, [M+H]+= 265. Ala-Leu-OEt TFA salt (Example 6, R = IPr, R’ = H): LC / MS: Rt = 1.11 min, [M+H]+= 344.6.

[0283] Phe-Ala-OEt TFA salt (Example 7, R = H, R’ = Ph): LC / MS: Rt = 0.73 min, [M+H]+= 265.5.

[0284] Phe-Leu-OEt TFA salt (Example 8, R = IPr, R’ = Ph): LC / MS: Rt = 1.08 min, 1.10 min, [M+H]+= 307.6. c) Coupling of Boc-Mel-OH to the dipeptide - Step 3 of Scheme 2:

[0285] 55645095-2

[0286] A solution of Boc-Mel-OH and PyBOP in DMF was stirred at RT over 30 min. H-AA-OEt TFA salt (Ala-Phe-OEt, Ala-Leu-OEt, Phe-Ala-OEt or Phe-Leu-OEt) and DI PEA were added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 10 ml of cold water and the product was extracted with ethyl acetate (3 x 15 ml).

[0287] Combined extracts were washed with brine, dried and evaporated. Crude material was purified by pTLC (SiC>2 / 50% EtOAc in cyclohexane).

[0288] Boc-Mel-Ala-Phe-OEt: LC / MS: Rt = 2.21 min, [M+H]+= 651.6. Boc-Mel-Ala-Leu-OEt: LC / MS: Rt = 2.22 min, [M+H]+= 617.7.

[0289] Boc-Mel-Phe-Ala-OEt: LC / MS: Rt = 2.16 min, [M+H]+= 651.1.

[0290] Boc-Mel-Phe-Leu-OEt: LC / MS: Rt = 2.29 min, [M+H]+= 693.1 d) Boc removal from tripeptide to provide the example compound - Step 4 of Scheme 2:

[0291] 55645095-2 SM was dissolved in 50% TFA. The resulting solution was stirred over 2 h and evaporated. The residue was taken into DCM and evaporated. Crude materials were purified by preparative HPLC.

[0292] Example compound 5 (Mel-Ala-Phe-OEt; 2-amino-3-{4-fbis(2- chloroethyl)aminolphenyl}propanoylalanylphenylalanine ethyl ester):

[0293] LC / MS: Rt = 3.11 min, m / z calcd. [M + H]+551.22 found 551.

[0294] Example compound 6 (Mel-Ala-Leu-OEt; 2-amino-3- 4-rbis(2- chloroethyl)aminolphenyl}propanoylalanylleucine ethyl ester):

[0295] LC / MS: Rt = 3.12 min, m / z calcd. [M+H]+517.23 found 516.9.

[0296] Example compound 7 (Mel-Phe-Ala-OEt; 2-amino-3-{4-fbis(2- chloroethyl)aminolphenyl}propanoylphenylalanylalanine ethyl ester):

[0297] 55645095-2 LC / MS: Rt = 3.07, m / z calcd. [M+H]+551.22 found 551.

[0298] Example compound 8 (Mel-Phe-Leu-OEt; 2-amino-3-{4-[bis(2- chloroethyl)aminolphenyl}propanoylphenylalanylleucine ethyl ester):

[0299] LC / MS: Rt = 3.07, m / z calcd. [M+H]+593.27 found 593.

[0300] Biological example 1 - Assessment of in vitro cytotoxicity:

[0301] The cytotoxicity of Example compounds 1 to 8, and comparator compounds melphalan and melphalan flufenamide (i.e. J1) were tested in a fluorometric microculture cytotoxicity assay (FMCA) using RPMI 8226 cells (a human myeloma cell line). The FMCA is based on measurement of fluorescence generated from hydrolysis of fluorescein diacetate (FDA) to fluorescein by cells with intact plasma membranes. The assay was performed according to the method described by Byrgazov et al., (Bone Rep. 2021 ; 15:101098). In brief, 5000 cells per well were seeded in 384-well plates and cultured overnight before the test compound (Example compound 1-8, melphalan or J1) were added. For each plate, four columns without test compound were included to serve as controls and one column with medium only served as blank. Each compound was tested in duplicate three times (n=3). Cell survival, expressed as survival index (Sl%) is defined as fluorescence in test wells divided by fluorescence of control wells, with blank values subtracted, multiplied by 100. The results of the assay are shown in Figures 1 and 4. The IC50S indicated (2.483 pM, 2.468 pM, 2.763 pM, 4.969 pM, 121.9 pM, 9.573 pM, 2.427 pM and 19.26 pM for Figures 4a) to h) respectively refer to the concentration of compound in the assay giving rise to 50% SI.

[0302] Biological example 2 - Assessment of in vitro cytotoxicity:

[0303] The cytotoxicity of Example compounds 3 to 8, and comparator compounds melphalan and melphalan flufenamide (i.e. J1) were tested in a fluorometric microculture cytotoxicity assay (FMCA) using HCT-116 cells (a colorectal cancer cell line). The FMCA is based on measurement of fluorescence generated from hydrolysis of fluorescein diacetate (FDA) to fluorescein by cells with intact plasma membranes. The assay was performed as described in

[0304] 51

[0305] 55645095-2 Biological example 1 (72 hour incubation). The IC50S indicated (2.456 pM, 2.016 pM, 2.783 pM, 5.955 pM, unstable, 16.09 pM, 2.535 pM and 64.46 pM for Figures 5a) to h) respectively refer to the concentration of compound in the assay giving rise to 50% SI.

[0306] The invention may be further understood with reference to the following non-limiing clauses:

[0307] 1 . A compound according to formula (I): wherein,

[0308] X is Ci-6alkylene,

[0309] R1is selected from the group consisting of H; Ci-ealkyl optionally substituted by 1 , 2 or 3 halogens; and halogen;

[0310] R2is -N(Ra)(Rb) and R3is according to formula (II):

[0311] R2is according to formula (III):

[0312] 52

[0313] 55645095-2 and

[0314] R3is according to formula (IV):

[0315] ; or

[0316] R2is according to formula (V):

[0317] , and

[0318] R3is selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms; wherein, Raand Rbare each independently selected from the group consisting of H, Ci-ealkyl, and C(O)Ci-6alkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens;

[0319] Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; -CH2- phenyl; and -CH2-3 to 12-membered heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms selected

[0320] 55645095-2 from N, O and S; wherein said alkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of OH, -OCi-ealkyl, NH2,

[0321] -NHC(=NH)NH2, -NHC(O)NH2, -C(O)OH, -C(O)NH2, SH, SCH3, and halogen; and said phenyl or heterocyclyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen, NH2, OH, and -OCi-ealkyl;

[0322] Reis selected from the group consisting of OH; -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, ON, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms; and

[0323] Rfand Rgare each independently selected from the group consisting of H and Ci-ealkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens, or Rfand R9together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered heterocycle which is optionally substituted by 1 , 2 or 3 halogen groups; or a pharmaceutically acceptable salt or solvate thereof.

[0324] 2. The compound of clause 1 , wherein the compound is according to formula (la):

[0325] 3. The compound of clause 1 or clause 2, wherein X is Cialkylene.

[0326] 4. The compound of any one of the preceding clauses, wherein R1is H.

[0327] 55645095-2 5. The compound of any one of the preceding clauses, wherein Raand Rbare each H.

[0328] 6. The compound of any one of the preceding clauses, wherein Rcand Rdare each independently selected from the group consisting of consisting of H; Ci-4alkyl; -CH2- indolyl; -CH2-phenyl; and -CH2-5-membered heteroaryl comprising two N atoms; wherein said alkyl is optionally substituted by OH; NH2; -NHC(=NH)NH2; -NHC(O)NH2, -C(O)OH;

[0329] -C(O)NH2; SH; SCH3; or halogen (e.g. F or Cl); and said phenyl is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of halogen; NH2; OH; and -OCi-6alkyl.

[0330] 7. The compound of clause 6, wherein Rcand Rdare each independently selected from the group consisting of Ci-ealkyl or -CH2-phenyl; wherein said alkyl is optionally substituted by -C(O)NH2, for example, Rcand Rdmay each independently be selected from the group consisting of methyl, benzyl, isobutyl, and -CH2CH2C(O)NH2.

[0331] 8. The compound of any one of the preceding clauses, wherein R2is -N(Ra)(Rb) and R3is according to formula (II).

[0332] 9. The compound of clause 8, wherein R3is according to formula (Ila):

[0333] 10. The compound of any one of the preceding clauses, wherein the compound of formula (I) is according to formula (Ic):

[0334] 55645095-2

[0335]

[0336] 11 . The compound of clause 10, wherein R2is NH2; R3is according to formula (Ila); Rcand Rdare each independently selected from the group consisting of methyl, benzyl, isobutyl, and - CH2CH2C(O)NH2; and Reis -OCi-6alkyl.

[0337] 12. The compound of clause 11 , wherein Rcand Rdare each independently selected from the group consisting of methyl, benzyl, and isobutyl; and Reis -OC2alkyl.

[0338] 13. The compound of clause 11 , wherein Rcand Rdare each methyl.

[0339] 14. The compound of clause 1 , wherein the compound of formula (I) is selected from the group consisting of:

[0340] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylleucine ethyl ester;

[0341] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylleucine ethyl ester;

[0342] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylglutamine ethyl ester; and

[0343] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylvalinylcitrulline ethyl ester.

[0344] 15. The compound of clause 14, wherein the compound of formula (I) is selected from the group consisting of:

[0345] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylleucine ethyl ester;

[0346] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylleucine ethyl ester;

[0347] 56

[0348] 55645095-2 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylglutamine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylglutamine ethyl ester;

[0349] 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylphenylalanine ethyl ester; and 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylvalinylcitrulline ethyl ester.

[0350] 16. The compound of clause 1 , wherein the compound of formula (I) is 2-amino-3-{4-[bis(2- chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester.

[0351] 17. A pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 16 and at least one pharmaceutically acceptable binder, carrier or excipient.

[0352] 18. A compound as defined in any one of clauses 1 to 16, or a pharmaceutical composition as defined in clause 17, for use as a medicament.

[0353] 19. A compound as defined in any one of clauses 1 to 16, or a pharmaceutical composition as defined in clause 17, for use in the treatment or prevention of a cancer.

[0354] 20. A compound or pharmaceutical composition for the use of clause 18 or 19, wherein the compound or pharmaceutical composition is administered with one or more additional therapeutic agent(s).

[0355] 21. A method for the treatment or prevention of a disease or disorder, said method comprising a step of administering a compound as defined in any one of clauses 1 to 16, or a pharmaceutical composition as defined in clause 17, to a subject in need thereof.

[0356] 22. The method according to clause 21 , wherein the disease or disorder is a cancer.

[0357] 23. Use of a compound as defined in any one of clauses 1 to 16 in the manufacture of a medicament for the treatment or prevention of a cancer.

[0358] 24. The compound for use according to clause 19, the method of clause 22, or the use of clause 22, wherein the cancer is a haematological cancer.

[0359] 25. The compound for use according to clause 19, the method of clause 22, or the use of clause 23, wherein the cancer is selected from the group consisting of multiple myeloma, osteosarcoma, breast cancer, lung cancer, ovarian cancer, leukemia and lymphoma, for example, the cancer is multiple myeloma, acute myeloid leukemia or lymphoma.

[0360] 57

[0361] 55645095-2

Claims

CLAIMS1. A pharmaceutical composition comprising:(i) a compound according to formula (I):wherein,X is Ci-6alkylene,R1is selected from the group consisting of H; Ci-ealkyl optionally substituted by 1 , 2 or 3 halogens; and halogen;R2is -N(Ra)(Rb) and R3is according to formula (II):wherein, Raand Rbare each independently selected from the group consisting of H, Ci-ealkyl, and C(O)Ci-ealkyl, wherein said alkyl is optionally substituted by 1 , 2 or 3 halogens;Rcand Rdare each independently selected from the group consisting of H; Ci-ealkyl; and - CH2-phenyl;Reis selected from the group consisting of -N(Rf)(Rg); and -OCi-ealkyl optionally substituted by one or more groups selected from halogen, OH, CN, Ce- aryl, or 3 to 12 membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of N, O and S, and / or wherein said alkyl is optionally interrupted by 1 , 2 or 3 O, N or S atoms; and5855645095-2Rfand Rgare each independently selected from the group consisting of H and Ci-ealkyl, wherein said alkyl is optionally substituted by 1, 2 or 3 halogens, or Rfand R9together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered heterocycle which is optionally substituted by 1, 2 or 3 halogen groups; or a pharmaceutically acceptable salt or solvate thereof; and(ii) at least one pharmaceutically acceptable binder, carrier or excipient.

2. The pharmaceutical composition of claim 1, wherein the compound is according to formula (la):

3. The pharmaceutical composition of claim 1 or claim 2, wherein X is Cialkylene.

4. The pharmaceutical composition of any one of the preceding claims, wherein R1is H.

5. The pharmaceutical composition of any one of the preceding claims, wherein RaandRbare each H.

6. The pharmaceutical composition of any one of the preceding claims, wherein RcandRdare each independently selected from the group consisting of consisting of H; Ci-4alkyl; and ; -CH2-phenyl.55645095-27. The pharmaceutical composition of claim 6, wherein Rcand Rdare each independently selected from the group consisting of Ci-ealkyl or -CH2-phenyl, for example, Rcand Rdmay each independently be selected from the group consisting of methyl, benzyl, and isobutyl.

8. The pharmaceutical composition of any one preceding claim, wherein R3is according to formula (Ila):

9. The pharmaceutical composition of any one of the preceding claims, wherein the compound of formula (I) is according to formula (Ic):

10. The pharmaceutical composition of any one preceding claim, wherein Reis -OCi-ealkyl.

11. The pharmaceutical composition of claim 9, wherein R2is NH2; R3is according to formula (Ila); Rcand Rdare each independently selected from the group consisting of methyl, benzyl, and isobutyl; and Reis -OCi-ealkyl.6055645095-212. The pharmaceutical composition of claim 10 or claim 11, wherein Rcand Rdare each independently selected from the group consisting of methyl, benzyl, and isobutyl; and Reis - OC2alkyl.

13. The pharmaceutical composition of any one of claims 10 to 12, wherein Rcis benzyl and Rdis methyl.

14. The pharmaceutical composition of any one of claims 10 to 12, wherein Rcand Rdare each methyl.

15. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is selected from the group consisting of: 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester;2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylleucine ethyl ester; 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester;2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylleucine ethyl ester; and 2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylphenylalanine ethyl ester.

16. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is 2- amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylphenylalanylalanine ethyl ester.

17. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is 2- amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoylalanylalanine ethyl ester.

18. A compound as defined in any one of claims 10 to 17.

19. A compound as defined in any one of claims 1 to 18, or a pharmaceutical composition as claimed in any one of claims 1 to 17, for use as a medicament.

20. A compound as defined in any one of claims 1 to 18, or a pharmaceutical composition as claimed in any one of claims 1 to 17, for use in the treatment or prevention of a cancer.

21. The compound or pharmaceutical composition for use as claimed in claim 19 or claim 20, wherein the compound or pharmaceutical composition is administered with one or more additional therapeutic agent(s).6155645095-222. A method for the treatment or prevention of a disease or disorder, said method comprising a step of administering a compound as defined in any one of claims 1 to 18, or a pharmaceutical composition as claimed in any one of claims 1 to 17, to a subject in need thereof.

23. The method according to claim 21, wherein the disease or disorder is a cancer.

24. Use of a compound as defined in any one of claims 1 to 18 in the manufacture of a medicament for the treatment or prevention of a cancer.

25. The compound for use according to claim 20, the method of claim 23, or the use of claim 24, wherein the cancer is a haematological cancer or an ophthalmological cancer.

26. The compound for use according to claim 20, the method of claim 23, or the use of claim 24, wherein the cancer is an uveal melanoma.

27. The compound for use according to claim 20, the method of claim 23, or the use of claim 24, wherein the cancer is selected from the group consisting of multiple myeloma, osteosarcoma, breast cancer, lung cancer, ovarian cancer, leukemia and lymphoma, for example, the cancer is multiple myeloma, acute myeloid leukemia or lymphoma.6255645095-2

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