Anti-cancer compounds

Abstract

The present invention relates to novel medicaments and their use in the treatment of proliferative diseases such as cancer, in particular brain cancer.

Description

[0001] This application is a divisional application of the invention patent application with application number 201980011536.4, filing date February 1, 2019, and invention name “Anticancer Compounds”. Field of the Invention

[0002] The present invention relates to medicaments and their use in the treatment of proliferative diseases, such as cancer, in particular brain cancer. Background of the Invention

[0003] Current treatments for solid brain cancers (i.e., brain tumors) include one or more surgical procedures, radiation therapy, and chemotherapy. For example, glioblastoma (the most common brain cancer in humans) is treated with the Stupp regimen. This includes concomitant radiation therapy / temozolomide-based chemotherapy, followed by adjuvant chemotherapy with temozolomide alone, and after maximal surgical resection of the tumor. Temozolomide extends survival by approximately three months (compared to radiation therapy alone), and the median survival of glioblastoma patients is 15 months. Avastin has been approved for recurrent glioblastoma, but has shown little improvement in survival.

[0004] Furthermore, even though 50% of glioblastomas are dependent on epidermal growth factor receptor (EGFR) signaling, clinically available EGFR inhibitors have failed in glioblastoma clinical trials. Some inhibitors do not have adequate blood-brain barrier (BBB) ​​permeability. Recent studies have also shown that glioblastomas respond only to type II EGFR inhibitors, while type I inhibitors have been tried. The extreme heterogeneity and aggressiveness of glioblastomas have also led to the failure of molecular targeted therapies as an effective treatment for brain cancer.

[0005] Another class of compounds that have been shown to be effective in many non-brain cancers is tubulin-targeted chemotherapies. However, clinically used tubulin inhibitors (such as paclitaxel) are very large molecules that cannot penetrate the BBB. In addition, paclitaxel and other tubulin-targeted chemotherapies (such as vinblastine and vincristine) have serious side effects (such as chemotherapy-induced peripheral neuropathy).

[0006] Therefore, there is a need to find new treatments for proliferative diseases such as cancer, and in particular to find effective treatments for brain cancer.

[0007] The reference to any prior art in the specification is not an acknowledgement or implication that the prior art forms part of the common general knowledge in any jurisdiction, or that the prior art could reasonably be expected to be understood by a person skilled in the art, to be relevant, and / or to be combined with other prior art. Summary of the invention

[0008] The present invention seeks to solve one or more of the above problems and / or provide improvements in cancer treatment, and in a first aspect, provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

[0009]

[0010] in:

[0011] X is a C1-C6 alkyl group or a C2-C6 alkenyl group;

[0012] Y is

[0013] W is O or S;

[0014] R2 is H, alkyl or alkenyl;

[0015] Z is aryl, heterocycloalkyl or heteroaryl, wherein the aryl, heterocycloalkyl or heteroaryl is optionally substituted;

[0016] R1 is halogen, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted;

[0017] Ar is aryl or heteroaryl.

[0018] X may be a C3 alkyl or C3 alkenyl group.

[0019] W can be O.

[0020] R1 can be an aryl group. The aryl group can be monocyclic or bicyclic. The aryl group can be phenyl or naphthyl. The aryl group can be substituted. The substituent can be selected from a halogen group and a heteroalkyl group. The halogen group can be F, and the heteroalkyl group can be an O-alkyl group (e.g., -OCH3) or an aminoalkyl group (e.g., -CH2NH2).

[0021] R1 can be a heteroaryl. The heteroaryl can be monocyclic or bicyclic. The heteroaryl can include one or more nitrogen atoms. For example, the heteroaryl can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole. The heteroaryl can be substituted. For example, the substituent can be a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, such as -OCH3, or aminoalkyl, such as -CH2NH2).

[0022] R1 can be heterocycloalkyl.Heterocycloalkyl can include one or more nitrogen atoms.Heterocycloalkyl can be piperazine.Heterocycloalkyl can contain (except one or more nitrogen atoms or as its replacement) one or more oxygen atoms.Heterocycloalkyl can be morpholine.Heterocycloalkyl can be replaced by, for example, halogen groups (for example F) or assorted alkyl groups (for example O-alkyl, for example-OCH3, or aminoalkyl, for example-CH2NH2).

[0023] Ar may be an aryl group. An aryl group may be a phenyl group. Ar may be a heteroaryl group. A heteroaryl group may include one or more nitrogen atoms and / or NH groups. A heteroaryl group may have 4 or 5 ring carbon atoms. A heteroaryl group may be pyridine or pyrimidine.

[0024] Z can be an aryl group. The aryl group can be monocyclic or bicyclic. For example, the aryl group can be a phenyl group. The aryl group can be substituted. The substituent can be a heteroalkyl group. The heteroalkyl group can include one or more oxygen atoms. The heteroalkyl group can form a ring with the aryl group.

[0025] Z can be a heteroaryl. The heteroaryl can be monocyclic or bicyclic. The heteroaryl can include one or more nitrogen atoms. For example, the heteroaryl can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, benzimidazole or indole. The heteroaryl can contain one or more oxygen atoms (in addition to or as a substitute for one or more nitrogen atoms). For example, the heteroaryl can be furan. The heteroatom can be at one or more positions on one or more rings. For example, when Z is pyridyl, the nitrogen can be at one or more positions on the ring. For example, the nitrogen can be at the meta position. The nitrogen can be at one or more of the ortho and / or meta and / or para positions. The heteroaryl can be substituted. For example, the substituent can be a hydroxyl, a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, e.g., -OCH3, or an aminoalkyl, e.g., -CH2NH2).

[0026] Z can be heterocycloalkyl.Heterocycloalkyl can include one or more nitrogen atoms.Heterocycloalkyl can be piperazine.Heterocycloalkyl can contain (in addition to one or more nitrogen atoms or as its replacement) one or more oxygen atoms.Heterocycloalkyl can be morpholine.Heterocycloalkyl can be partially unsaturated.Heterocycloalkyl can be substituted by, for example, hydroxyl, halogen group (for example F) or assorted alkyl group (for example O-alkyl, for example-OCH , or aminoalkyl, for example-CH NH ).

[0027] R2 may be H, alkyl or alkenyl. R2 may be H.

[0028] The compound of formula (I) may be selected from:

[0029]

[0030]

[0031] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) (according to the first aspect of the invention) and a pharmaceutically acceptable excipient.

[0032] The compounds and pharmaceutical compositions according to the present invention may be suitable for treating or preventing proliferative diseases. Therefore, on the other hand, the present invention relates to a method for treating or preventing a proliferative disease in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as described in the first aspect of the present invention or a pharmaceutical composition as described in the second aspect of the present invention.

[0033] In another aspect, the present invention relates to the use of the compound of formula (I) described in the first aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for treating or preventing a proliferative disease. In another aspect, the present invention relates to the use of the compound of formula (I) described in the first aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention in treating or preventing a proliferative disease in a subject.

[0034] In another aspect, the present invention relates to a compound of formula (I) as described in the first aspect of the present invention or a pharmaceutical composition as described in the second aspect of the present invention for use in treating or preventing a proliferative disease in a subject.

[0035] In one embodiment, the proliferative disease is cancer. The cancer may be selected from the group consisting of brain cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer, skin cancer, colon cancer and bladder cancer.

[0036] Cancer can be primary. Cancer can be metastatic. Cancer can be benign. Cancer can be malignant.

[0037] The cancer may be a brain cancer (e.g., anaplastic astrocytoma, astrocytoma, central neurocytoma, choroid plexus carcinoma, choroid plexus papilloma, choroid plexus tumor, diffuse pontine glioma, embryonic proliferative neuroepithelioma, ependymoma, fibrillary astrocytoma, giant cell glioblastoma, multiforme glioma, glioma cerebri, gliosarcoma, hemangiopericytoma, medulloblastoma, medullary epithelioma, meningeal carcinomatosis, neuroblastoma, neurocytoma, oligoastrocytoma, oligodendroglioma, optic nerve sheath meningioma, pediatric ependymoma, pilocytic astrocytoma, pineoblastoma, pineocytoma, anaplastic neuroblastoma pleomorphic, pleomorphic xanthoastrocytoma, primary central nervous system lymphoma, sphenoid meningioma, subependymal giant cell astrocytoma, subependymoma, trilateral retinoblastoma). Brain cancer can be a primary cancer (e.g., a glioma, meningioma, pituitary adenoma, or schwannoma). Brain cancer can be a metastatic cancer (e.g., a result of melanoma or lung cancer).

[0038] In another aspect, the present invention relates to a method for completely or partially preventing the recurrence of a solid tumor in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) as described in the first aspect of the present invention or a pharmaceutical composition as described in the second aspect of the present invention.

[0039] In another aspect, the present invention relates to use of the compound described in the first aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for completely or partially preventing the recurrence of solid tumors.

[0040] In another aspect, the present invention relates to use of the compound of formula (I) according to the first aspect of the present invention or the pharmaceutical composition according to the second aspect of the present invention for completely or partially preventing the recurrence of a solid tumor in a subject.

[0041] In another aspect, the present invention relates to a compound of formula (I) according to the first aspect of the present invention or a pharmaceutical composition according to the second aspect of the present invention for complete or partial prevention of recurrence of a solid tumor in a subject.

[0042] The solid tumor may be a brain cancer (eg, a glioblastoma, an astrocytoma, or a glioma). The brain cancer may be a primary cancer. The brain cancer may be a metastatic cancer.

[0043] The compounds of formula (I) may be used in therapy alone or in combination with one or more other therapeutic agents, for example as part of a combination therapy.

[0044] Further aspects of the invention and further implementations of the aspects described in the preceding paragraphs will become apparent from the following description given by way of example with reference to the accompanying drawings.

[0045] BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 . Results of in vitro tubulin polymerization assay using WJA69b.

[0047] Figure 2 . Results of in vitro tubulin polymerization assay using WJA88.

[0048] Figure 3 Metabolic stability testing of CMPD1, WJA69b and WJA88.

[0049] Figure 4 . Cellular potency of WJA88 in clonogenic assays.

[0050] Figure 5 .Cellular efficacy of compounds in 3D spheroid assays.

[0051] Detailed description of embodiments

[0052] Reference will now be made in detail to certain embodiments of the present invention. Although the present invention will be described in conjunction with the embodiments, it should be understood that it is not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all substitutions, improvements and equivalents included within the scope of the present invention defined by the claims.

[0053] Those skilled in the art will recognize many methods and materials that can be used in the practice of the present invention, which are similar or equivalent to the methods and materials described herein. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more individual features mentioned or apparent in the text or drawings. All of these different combinations constitute various alternative aspects of the present invention.

[0054] Throughout the specification, references to individual steps, compositions of matter, groups of steps, or groups of compositions of matter shall be deemed to include one or more (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter, unless expressly stated otherwise or the context requires otherwise. Thus, as used herein, the singular forms "a," "an," and "the" include plural aspects, and vice versa, unless the context clearly dictates otherwise. For example, reference to "a" includes one as well as two or more; reference to "an" includes the singular as well as two or more; reference to "the" includes the singular as well as two or more, and so forth.

[0055] The present invention is based on the surprising discovery that compounds of formula (I) provide unexpected improvements in the treatment of proliferative diseases such as cancer, especially brain cancer.

[0056] Compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it is understood that all optical isomers and mixtures thereof are included unless otherwise specified. Compounds with two or more asymmetric elements may also exist as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may exist in Z and E forms, and all isomeric forms of the compounds are included in the present invention unless otherwise specified. When compounds exist in various tautomeric forms, the compounds listed are not limited to any one specific tautomer, but are intended to cover all tautomeric forms. The listed compounds are further intended to cover compounds in which one or more atoms are isotopically substituted, i.e., atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C, 13 C and 14 C.

[0057] The compounds with one or more stereogenic centers according to the formula provided herein have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95% or 98%. Some embodiments of the compound have an enantiomeric excess of at least 99%. It is apparent that a single enantiomer (optically active form) can be synthesized asymmetric, from an optically pure precursor, biosynthesized or by the resolution of a racemate, such as enzymatic resolution or by conventional methods, such as crystallization in the presence of a resolving agent, or, for example, by chromatography using a chiral HPLC column.

[0058] Certain compounds are described herein using general formulas including variables such as R1, R2, Ar, W, X, Y, and Z. Unless otherwise specified, each variable within the general formula is defined independently of any other variable, and any variable that appears multiple times within a general formula is defined separately at each occurrence. Thus, for example, if a group is shown to be substituted with 0, 1, or 2 R*, the group may be unsubstituted or substituted with up to two R* groups, and each time R* appears, it is independently selected from the definition of R*. Moreover, combinations of substituents and / or variables are permitted only when the combination produces a stable compound, such as one that can be isolated, characterized, and tested for biological activity.

[0059] "Pharmaceutically acceptable salts" of the compounds disclosed herein are acidic or basic salts generally considered in the art to be suitable for contact with human or animal tissues without excessive toxicity or carcinogenicity, and preferably without irritation, allergic reactions or other problems and complications. In particular, pharmaceutically acceptable salts according to the present invention are those that do not adversely affect the ability of the compound to cross the BBB. Such salts include inorganic and organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids.

[0060] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of various acids, such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, p-aminobenzenesulfonic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids (such as acetic acid, HOOC-(CH2) n-COOH, wherein n is any integer from 0 to 6, i.e., 0, 1, 2, 3, 4, 5 or 6) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize other pharmaceutically acceptable salts of the compounds provided herein. In general, pharmaceutically acceptable acid or basic salts can be synthesized from a parent compound containing a basic or acidic moiety by any conventional chemical method. In short, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol or acetonitrile) or a mixture of the two.

[0061] It is obvious that each compound of formula (I) may, but need not, exist in the form of a hydrate, solvate or non-covalent complex. In addition, various crystal forms and polymorphs are within the scope of the present invention, as are the prodrugs of the compounds of formula (I) provided herein.

[0062] A prodrug is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxyl, carboxyl, amine or sulfhydryl group is bonded to any group that, when administered to a mammalian subject, cleaves to form free hydroxyl, carboxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of compounds provided herein can be prepared by modifying functional groups present in the compound in a manner that allows the modifier to be cleaved in vivo to produce the parent compound.

[0063] As used herein, "substituent" refers to the molecular part of the covalently bonded atom in the target molecule. For example, a "ring substituent" can be a part covalently bonded to an atom (preferably a carbon or nitrogen atom) as a ring member, such as a halogen, an alkyl, a heteroalkyl, a haloalkyl or other substituent described herein. As used herein, the term "substituted" refers to any one or more hydrogens on the designated atom being replaced by a substituent selected from the substituent shown, provided that the normal valence of the designated atom is not exceeded, and the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When the substituent is an oxo, i.e., =O, then two hydrogens on the atom are replaced. The oxo group as a substituent of an aromatic carbon atom results in the conversion of -CH- to -C(=O)- and the loss of aromatic properties. For example, a pyridyl substituted by oxo is a pyridone. Examples of suitable substituents are alkyl (including haloalkyl, such as CF3), heteroalkyl (e.g., -OCH3, -CH2NHCH 3，-CH2NH2), a halogen (e.g., a fluorine, chlorine, bromine or iodine atom), OH, =O, SH, SO3H, NH2, =NH, N3 and NO2 groups.

[0064] The term "alkyl" refers to a saturated, straight or branched hydrocarbon group. Specific examples of alkyl are methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and 2,2-dimethylbutyl.

[0065] The term "heteroalkyl" refers to an alkyl group as defined above containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Specific examples of heteroalkyl groups are O-alkyl groups such as methoxy, trifluoromethoxy, ethoxy, n-propoxy, iso-propoxy, butoxy and tert-butoxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, aminoalkyl groups (e.g. -CH2NH2, -CH2CH2NH2, etc.), methylamino, ethylamino, propylamino, Iso-propylamino, dimethylamino, diethylamino, iso-propylethylamino, methylaminomethyl, ethylaminomethyl, diiso-propylaminoethyl, methylthio, ethylthio, iso-propylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetamido, propionamido, carboxymethyl, carboxyethyl, carboxypropyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Other examples of heteroalkyl are nitrile, iso-nitrile, cyanate, thiocyanate, iso-cyanate, iso-thiocyanate and alkylnitrile.

[0066] The term "alkenyl" refers to an at least partially unsaturated straight or branched hydrocarbon group containing at least two carbon atoms (e.g., C2 alkenyl). Specific examples of alkenyl are ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethynyl, propynyl, butynyl, ethynyl, propargyl, isopentenyl and hex-2-enyl. Preferably, the alkenyl has one or two double bonds.

[0067] The term "cycloalkyl" refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group containing one or more rings (preferably 1 or 2) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. Specific examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornene, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetracyclo, adamantane (e.g., tricyclo[3.3.1.13,7]decane), cyclopentylcyclohexyl and cyclohex-2-enyl.

[0068] The term "heterocycloalkyl" refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are each independently replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms). This includes groups containing such atoms as NH. Heterocycloalkyl preferably has 1 or 2 rings containing 3 to 10 (particularly 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Specific examples are piperidinyl, prolyl, imidazolidinyl, piperazinyl, morpholinyl, uracilyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl and 2-pyrazolinyl, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0069] The term "aryl" refers to an aromatic group containing one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl.

[0070] The term "heteroaryl" refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6) ring atoms, and containing one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). This includes O, S or N containing groups, such as NH. Examples are pyridinyl (e.g. 4-pyridinyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, iso-thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazole, benzoxazole, benzisoxazolyl, benzothiazolyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3′-difuranyl and pyrazolyl (e.g. 3-pyrazolyl).

[0071] The expression "halogen" or "halogen atom" as used herein refers to fluorine, chlorine, bromine or iodine.

[0072] The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms are independently halogenated (e.g., fluorine, chlorine, bromine or iodine atoms) and / or substituted by, for example, OH, =O, SH, SO3H, NH2, N-alkyl, NH-alkyl, N3 or NO2 groups. The expression also refers to a group that is substituted by one, two, three or more alkyl, alkenyl or heteroalkyl (e.g., -OCH3, -OCH2CH3, -CH2NHCH3 and -CH2NH2). These groups themselves can be substituted. For example, an alkyl substituent can be substituted by one or more halogen atoms (e.g., can be a haloalkyl). The term "haloalkyl" refers to an alkyl group (as defined above) substituted by one or more halogen atoms (as defined above). Specific examples of haloalkyl are trifluoromethyl, dichloroethyl, dichloromethyl and iodoethyl.

[0073] As used herein, words defining the limits of a length range, such as "from 1 to 5" refer to any integer from 1 to 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by two explicitly mentioned integers is intended to include and disclose any integers defining the limits as well as any integer included in the range.

[0074] Preferred compounds of formula (I) are those wherein X is C1, C2 or C3 alkyl, or C2 or C3 alkenyl (eg C3 alkyl or C3 alkenyl).

[0075] R1 can be an aryl group. The aryl group can be monocyclic or bicyclic. The aryl group can be phenyl or naphthyl. The aryl group can be substituted. The substituent can be selected from a halogen group and a heteroalkyl group. The halogen group can be F, and the heteroalkyl group can be an O-alkyl group (e.g., OCH3 or OCH2CH3) or an aminoalkyl group (e.g., -CH2NH2 or -CH2CH2NH2).

[0076] R1 can be a heteroaryl. The heteroaryl can be monocyclic or bicyclic. The heteroaryl can include one or more nitrogen atoms. For example, the heteroaryl can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole. The heteroaryl can be substituted. For example, the substituent can be a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, such as -OCH3 or OCH2CH3, or aminoalkyl, such as -CH2NH2 or -CH2CH2NH2).

[0077] R1 can be a heterocycloalkyl. The heterocycloalkyl may include one or more nitrogen atoms. The heterocycloalkyl may be piperazine. The heterocycloalkyl may include one or more oxygen atoms. The heterocycloalkyl may be morpholine. The heterocycloalkyl may be substituted by, for example, a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, such as -OCH3 or OCH2CH3, or an aminoalkyl, such as -CH2NH2 or -CH2CH2NH2).

[0078] Ar can be an aryl group. The aryl group can be a phenyl group. Ar can be a heteroaryl group. The heteroaryl group can include one or more nitrogen atoms. The heteroaryl group can have 4 or 5 ring carbon atoms. The heteroaryl group can be pyridine or pyrimidine.

[0079] Z can be an aryl group. The aryl group can be monocyclic or bicyclic. For example, the aryl group can be a phenyl group. The aryl group can be substituted. The substituent can be an alkyl, alkenyl or heteroalkyl group. The heteroalkyl group can include one or more oxygen atoms, one or more amino groups and / or one or more N-alkyl groups. The heteroalkyl group can form a ring with the aryl group.

[0080] Z can be a heteroaryl. The heteroaryl can be monocyclic or bicyclic. The heteroaryl can include one or more nitrogen atoms. For example, the heteroaryl can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, benzimidazole or indole. The heteroaryl can contain one or more oxygen atoms (in addition to or as a substitute for one or more nitrogen atoms). For example, the heteroaryl can be furan. The heteroatom can be at one or more positions on one or more rings. For example, when Z is pyridyl, nitrogen can be at the meta position. Nitrogen can be at the ortho position and / or at one or more meta and / or para positions. The heteroaryl can be substituted. For example, the substituent can be a hydroxyl, a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, e.g., -OCH3, or an aminoalkyl, e.g., -CH2NH2).

[0081] Z can be heterocycloalkyl.Heterocycloalkyl can include one or more nitrogen atoms.Heterocycloalkyl can be piperazine.Heterocycloalkyl can contain (in addition to one or more nitrogen atoms or as its replacement) one or more oxygen atoms.Heterocycloalkyl can be morpholine.Heterocycloalkyl can be partially unsaturated.Heterocycloalkyl can be replaced by, for example, hydroxyl, halogen group (for example F) or assorted alkyl group (for example O-alkyl, for example-OCH3, or aminoalkyl, for example-CH2NH2).

[0082] R2 may be H, alkyl or alkenyl. R2 may be H.

[0083] Specific examples of compounds of the present invention are given in Table 1 below.

[0084] Table 1 Examples of compounds of the present invention

[0085]

[0086]

[0087] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds WJA69b, WJA88, WJA69c, 1, 2, 3, 4 and 5 from Table 1 above.

[0088] The compounds of the present invention can be synthesized by any suitable method known to those skilled in the art. The general synthesis is given in Scheme 1 below.

[0089]

[0090]

[0091] Scheme 1 General Synthesis Example of Compounds of the Invention

[0092] The compounds of the present invention may exhibit high antiproliferative activity, and particularly high efficacy against brain cancer. Specifically, in the examples herein, specific compounds were shown to induce apoptosis and also be able to cross the BBB.

[0093] The therapeutic use of the compound of formula (I), its pharmaceutically acceptable salt, solvate, hydrate, prodrug and preparation and pharmaceutical composition (including mixture of the compound of formula (I)) is also within the scope of the present invention. Therefore, the present invention also relates to a pharmaceutical composition, which comprises a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate or prodrug, and one or more pharmaceutically acceptable excipients.

[0094] "Pharmaceutical carriers, diluents or excipients" include, but are not limited to, any physiological buffer (e.g., pH 7.0 to 7.4) including suitable water-soluble carriers, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Suitable water-soluble carriers include, but are not limited to, saline, dextrose, corn oil, dimethyl sulfoxide and gelatin capsules. Other conventional additives include lactose, mannitol, corn starch, potato starch, binders (such as crystalline cellulose), cellulose derivatives, gum arabic, gelatin, disintegrants (such as sodium carboxymethyl cellulose) and lubricants (such as talc or magnesium stearate).

[0095] The pharmaceutical composition can be formulated for any suitable route of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injections, and any similar injection or infusion techniques. In certain embodiments, the composition is preferably suitable for oral or parenteral use. Suitable oral forms include, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. For intravenous, intramuscular, subcutaneous or intraperitoneal administration, one or more compounds can be mixed with a sterile aqueous solution, which is preferably isotonic with the recipient's blood. Such preparations can be prepared by dissolving the solid active ingredient in water containing a physiologically compatible substance such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to prepare an aqueous solution, and sterilizing the solution. The preparation can be present in a unit or multi-dose container, such as a sealed ampoule or bottle. Examples of suitable components are described in Martindale's Pharmacopoeia (Pharmaceutical Press, London, 1993) and Martin (et al.), Remington Pharmaceutical Science.

[0096] In order to treat proliferative diseases, the dosage of the bioactive compound of the present invention can vary in a wide range and can be adjusted according to individual needs. The active compound of the present invention is usually applied in a therapeutically effective amount. The preferred dosage is about 0.1 mg to about 140 mg per kg of body weight per day (e.g., about 0.5 mg to about 7 g per patient per day). The daily dose can be applied in a single dose or in multiple doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the treated host and a specific mode of administration. The dosage unit form will usually contain about 1 mg to about 500 mg of active ingredient.

[0097] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, administration time, route of administration, excretion rate, drug combination (e.g., other drugs for treating the patient), the severity of the specific disease being treated, and the location of the unwanted proliferating cells. If the compound is administered locally rather than systemically, and is for prevention rather than treatment, the dosage will usually be lower. Such treatment can be carried out within the required time and at the time determined by the attending physician. It will be understood by those skilled in the art that it may be necessary to optimize the dosage regimen or therapeutically effective amount of the compound of formula (I) to be administered for each individual.

[0098] It should be understood that different doses may be required to treat different diseases. An effective amount of an agent is that amount that causes a statistically significant decrease in tumor cell count, growth or size. Neoplastic diseases that respond to the agents of the invention include, but are not limited to, brain cancer.

[0099] The term "therapeutically effective amount" or "effective amount" refers to the amount of the compound of formula (I) that results in prevention, improvement or remediation of proliferative disease symptoms. The dosage form and amount of the compound or pharmaceutical composition of the present invention can be easily determined by reference to known treatment or prevention regimens.

[0100] Preferred compounds of the present invention will possess certain pharmacological properties. Such properties include, but are not limited to, oral bioavailability and BBB permeability, such that the preferred oral dosage forms described above can provide therapeutically effective levels of the compounds in vivo.

[0101] The compounds of the invention are preferably administered orally or parenterally to a patient (eg, a human) and are present in at least one body fluid or tissue of the patient. Thus, the invention further provides methods for treating a patient suffering from a proliferative disease (including cancer, such as brain cancer).

[0102] The terms "treat", "treatment" and "therapy" are used herein to refer to curative therapy. Therefore, in the context of the present disclosure, the term "treatment" encompasses both curing and ameliorating the severity of cancer or its associated symptoms.

[0103] "Inhibit" or "prevent" refers to preventing the occurrence of cancer or, if it develops following administration of the compounds or pharmaceutical compositions of the invention, lessening the severity of the cancer. This can be preventing the occurrence of clinically apparent unwanted cell proliferation altogether, as well as preventing the preclinically apparent stage of unwanted rapid cell proliferation in individuals at risk.

[0104] Patients may include, but are not limited to, primates, particularly humans, domesticated companion animals (eg, dogs, cats, horses), and livestock (eg, cattle, pigs, sheep), with dosages as described herein.

[0105] The compounds of the present invention can be used to treat and / or prevent diseases and conditions associated with cell proliferation (including cancer, such as brain cancer). Therefore, the present invention also relates to a method for treating or preventing a proliferative disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof in the treatment or prevention of a proliferative disease. In any embodiment described in the specification, the present invention also provides a pharmaceutical composition for the treatment or prevention of a proliferative disease. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof in the preparation of a medicament for the treatment or prevention of a proliferative disease.

[0106] When used in a method for treating or preventing a proliferative disease, the present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The present invention further relates to a composition containing an active ingredient for treating or preventing a proliferative disease, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The present invention further relates to the use of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof in treating or preventing a proliferative disease as described above. In one embodiment, the compound of formula (I) is substantially the only active ingredient of the composition. In one embodiment, the proliferative disease is cancer. In one embodiment, the cancer is brain cancer (e.g., a solid tumor).

[0107] The compounds of formula (I) and pharmaceutical compositions thereof of the present invention can be used to treat or prevent proliferative diseases, preferably cancer. The compounds and compositions of the present invention can be used to treat a variety of cancers (tumors), including but not limited to solid tumors, such as brain cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer, brain cancer, skin cancer, colon cancer and bladder cancer.

[0108] The types of cancer or tumor cells that may be suitable for treatment by the present invention include, for example, breast cancer, colon cancer, lung cancer and prostate cancer, gastrointestinal cancer, including esophageal cancer, gastric cancer, colorectal cancer, polyps associated with colorectal tumors, pancreatic cancer and gallbladder cancer, adrenocortical carcinoma, ACTH-producing tumors, bladder cancer, brain cancer (including those discussed below), Ewing's sarcoma, head and neck cancer (including oral cancer and laryngeal cancer), kidney cancer (including renal cell carcinoma), liver cancer, lung cancer (including small cell and non-small cell lung cancer), malignant peritoneal effusion, malignant pleural effusion, skin cancer In one embodiment, the cancer is primary. In one embodiment, the cancer is metastatic. In one embodiment, the cancer is benign. In one embodiment, the cancer is malignant.

[0109] In one embodiment, the proliferative disease to be treated and / or prevented is brain cancer. The brain cancer may be selected from the group consisting of anaplastic astrocytoma, astrocytoma, central neurocytoma, choroid plexus carcinoma, choroid plexus papilloma, choroid plexus tumor, diffuse pontine glioma, embryonic proliferative neuroepithelioma, ependymoma, fibrillary astrocytoma, giant cell glioblastoma, multiform cell glioma, glioma cerebri, gliosarcoma, hemangiopericytoma, medulloblastoma, medullary epithelioma, meningeal carcinoma, neuroblastoma, neurocytoma, oligoastrocytoma, oligodendroglioma, optic nerve sheath meningioma, pediatric ependymoma, pilocytic astrocytoma, pinealoblastoma, pineocytoma, pleomorphic anaplastic neuroblastoma, pleomorphic xanthoastrocytoma, primary central nervous system lymphoma, sphenoid meningioma, subependymal giant cell astrocytoma, subependymoma, trilateral retinoblastoma. Thus, preferably, the brain cancer is a tumor (preferably a solid tumor). The brain cancer may be a primary cancer (e.g. a glioma, meningioma, pituitary adenoma or schwannoma) or a metastatic cancer (e.g. a brain cancer arising from a cancer elsewhere in the body (e.g. a melanoma or lung cancer)).

[0110] Alternatively or additionally, the compounds may be administered in combination with other agents, such as chemotherapeutic or immunostimulatory drugs or therapeutic agents.

[0111] The terms "combination therapy" or "adjuvant therapy" in defining the use of a compound of the invention and one or more other drugs are intended to include the administration of each drug in a sequential manner in a regimen that provides a beneficial effect of the drug combination, and are also intended to include co-administration of these agents in a substantially simultaneous manner (e.g., in a single formulation having a fixed ratio of these active agents, or multiple separate formulations of each agent).

[0112] According to various embodiments of the present invention, one or more compounds of formula (I) can be formulated or administered together with one or more other therapeutic agents. Therefore, according to various embodiments of the present invention, one or more compounds of formula (I) can be included in a combined treatment regimen together with surgery and / or other known treatments or therapeutic agents, such as other anticancer agents, particularly chemotherapeutic agents, radiotherapeutic agents and / or adjuvants or preventive agents.

[0113] There are a large number of antineoplastic drugs available for commercial use, clinical evaluation and preclinical development, which are selected for the treatment of cancer or other tumors through combination drug chemotherapy. Such antineoplastic agents are divided into several major categories, namely antibiotics, antimetabolites, hormones, immunology drugs, interferons and miscellaneous drugs. Alternatively, other antineoplastic agents, such as metal matrix proteinase inhibitors, can be used. Reagents that are considered suitable by those skilled in the art can be used in combination therapy. Suitable agents are listed in, for example, the Merck Index, Encyclopedia of Chemistry, Drugs and Biology, 12th edition, 1996.

[0114] The combination regimen may include administering the active agents together, sequentially or intermittently, as appropriate in each case.The combination of active agents including the compounds of the invention may be synergistic.

[0115] Co-administration of a compound of formula (I) may be by a compound of formula (I) in the same unit dose as a chemotherapeutic or other anticancer agent, or a compound of formula (I) and a chemotherapeutic or chemical formula or compound. Other anticancer agents may be present in separate and discrete unit doses at the same or similar times. Sequential administration may be performed in any order desired, and may require that the continued physiological effects of the first or initial compound be present when a second or subsequent compound is administered, particularly where cumulative or synergistic effects are desired.

[0116] For various applications, the compounds of the present invention can be labeled with isotopes, fluorescent or luminescent labels, antibodies or antibody fragments, any other affinity markers (such as nanobodies, aptamers, peptides, etc.), enzymes or enzyme substrates. These labeled compounds of the present invention can be used in vivo, in vitro, in vitro and in situ, such as mapping receptor locations in tissue sections by autoradiography, and used as radioactive tracers for positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT), etc., to characterize those receptors in living or other materials. The labeled compounds described in the present invention can be used for treatment, diagnosis and other applications, such as in vivo and in vitro research tools, particularly the applications disclosed herein.

[0117] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0118] Experimentation of the present invention will now be discussed in more detail with reference to the Examples, which are provided for illustrative purposes only and should not be construed in any way as limiting the scope of the present invention. Example

[0119] synthesis

[0120] General synthetic route of heterocycle A&B

[0121]

[0122] 4-(2'-Fluoro-[1,1'-biphenyl]-4-yl)butanoic acid

[0123]

[0124] Tetrakis(triphenylphosphine)palladium(0) (590 mg, 0.51 mmol) was added to a stirred suspension of 2-fluorophenylboric acid (1.7 g, 12.3 mmol), Cs2CO3 (9.9 g, 30.6 mmol) and 4-bromophenylbutyric acid (2.50 g, 10.2 mmol) in dry, degassed THF / water (100 mL, 9.1 v / v mixture) and the resulting mixture was stirred at reflux for 8 hours. The resulting solution was diluted with HCl (100 mL, 1 M (aq)) and extracted with EtOAc (3×50 mL), and the combined organic phases were subsequently washed with brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting acid was purified by flash column chromatography (silica, 1:1 v / v EtOAc:Hex) to give the title compound as a white crystalline solid (1.6 g, 61%).

[0125] 1H NMR (300MHz, DMSO-d6) δ12.06(br s,1H),7.57–7.23(m,8H),2.64(t,J=7.4Hz,2H),2.25(t,J=7.4Hz,2H),1.88–1.80(m,2H). 13 C NMR (75MHz, DMSO-d6) δ174.2, 159.1 (d, J = 245.8Hz), 141.3, 132.6, 130.7 (d, J = 3.7Hz), 129.3 (d, J = 8.5Hz), 128.7 (d, J = 3.0Hz), 128.6, 128.2 (d, J = 13.9Hz), 124.9 (d, J = 3.7Hz), 116.0 (d, J = 22.6Hz), 34.1, 33.1, 26.2. 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3026,2902,1696,1480,1435,1250,1202,939,799,756,563cm –1 .LRMS(-ESI)m / z:257[(MH) - ,100%]

[0126] 4-(2'-Fluoro-[1,1'-biphenyl]-4-yl)-N-(pyridin-3-yl)butanamide (WJA69b)

[0127]

[0128] 4-(2'-Fluoro-[1,1'-biphenyl]-4-yl)butanoic acid (200 mg, 0.77 mmol), 3-aminopyridine (80 mg, 0.85 mmol) and i A solution of Pr2NEt (268 μL, 1.54 mmol) was used (400 mg, 0.77 mmol), heated to room temperature, and continued stirring for 12 hours. The reaction mass was diluted with CH2Cl2 (50 mL) and water (50 mL), then the separated organic phase was washed with NaHCO3 (25 mL saturated aqueous solution) and brine (100 mL), then dried (MgSO4), filtered and purified by flash column chromatography (silica gel, 1:1 v / v EtOAc:Hex) to give the title compound as a white solid (169 mg, 64%)

[0129] 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.73(d,J=2.6Hz,1H),8.23(dd,J=4.7,1.5Hz,1H),8.03(ddd,J=8.3,2.5,1.6Hz,1H), 7.56–7.45(m,3H),7.44–7.36(m,1H),7.36–7.25(m,5H),2.69(t,J=7.5Hz,2H),2.39(t,J=7.5Hz,2H),1.95(p,J=7.5Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ171.5,159.1(d,J=245.6Hz),144.0,141.4,140.7,135.9,132.7,130.7(d,J=3.5Hz),129.3(d,J=8.4H z), 128.8 (d, J = 2.9Hz), 128.7, 128.2 (d, J = 13.2Hz), 126.0, 124.9 (d, J = 3.6Hz), 123.6, 116.1 (d, J = 22.6Hz), 35.6, 34.3, 26.4. 19 FNMR (282MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3252,1688,1582,1545,1481,1420,1277,1169,1026,798,753,701,561cm –1 .LRMS(+ESI)m / z:335[(M+H) + ,25%],357[(M+Na) + ,100%].

[0130] 4-(2'-Fluoro-[1,1'-biphenyl]-4-yl)-N-(pyridin-4-yl)butanamide (WJA69c)

[0131]

[0132] 4-(2'-Fluoro-[1,1'-biphenyl]-4-yl)butanoic acid (200 mg, 0.77 mmol), 4-aminopyridine (80 mg, 0.85 mmol) and i A solution of Pr2NEt (268 μL, 1.54 mmol) in DMF (5 mL) was added with The mixture was stirred for 12 h at 4 °C for 1 hr at 4 °C for 2 h. The mixture was stirred for 12 h at 4 °C for 3 hrs. The mixture was stirred for 12 h at 4 °C for 2 hrs ...

[0133] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.67(d,J=7.2Hz,2H),8.16(d,J=7.3Hz,2H),7.53–7 .42(m,3H),7.37–7.23(m,5H),2.73–2.64(m,2H),2.58(t,J=7.3Hz,2H),2.02–1.92(m,2H). 13 C NMR (101MHz, DMSO-d6) δ173.8,159.1(d,J=245.6Hz),153.0,142.0,141.2,132.7,131.1,130.6(d,J=3.4Hz),129.3(d, J=8.4Hz),128.7(d,J=2.9Hz),128.1(d,J=13.2Hz),124.9(d,J=3.6Hz),116.1(d,J=22.5Hz),114.2,36.2,34.1,25.9. 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :2926,1716,1561,1500,1483,1313,1135,823,754,514cm –1 .LRMS(+ESI)m / z:335[(M+H) + ,100%],357[(M+Na) + ,40%].

[0134] General synthetic route of heterocyclic C&D

[0135]

[0136] Summary of WJA88 synthesis route

[0137]

[0138] 3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)propanoic acid

[0139]

[0140] Tetrakis(triphenylphosphine)palladium(0) (554.7 mg, 0.48 mmol) was added to a stirred suspension of 2-fluorophenylboric acid (1.61 g, 11.5 mmol), Cs2CO3 (11.2 g, 34.5 mmol) and 4-bromophenylpropionic acid (2.2 g, 9.6 mmol) in dry, degassed THF / water (100 mL, 9:1 v / v mixture) and the resulting mixture was stirred at reflux for 8 hours. The resulting solution was diluted with HCl (100 mL, 1 M (aq)) and extracted with EtOAc (3×50 mL) and the combined organic phases were subsequently washed with brine and then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting acid was purified by flash column chromatography (silica, 1:1 v / v EtOAc:Hex) to give the title compound as a white crystalline solid (1.3 g, 54%).

[0141] 1 H NMR (300MHz, DMSO-d6) δ12.16(br s,1H),7.58–7.16(m,8H),2.88(t,J=7.8Hz,2H),2.67–2.54(m,2H). 13 C NMR (75MHz, DMSO-d6) δ173.7,159.1(d,J=245.7Hz),140.6,132.8,130.6(d,J=6.0Hz),129.3(d,J =7.9Hz), 128.7, 128.5, 128.1 (d, J = 12.3Hz), 124.9 (d, J = 3.6Hz), 116.0 (d, J = 22.6Hz), 35.0, 30.0. 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3187,1696,1483,1410,1216,1009,940,814,755,666,566,cm –1 .LRMS(-ESI)m / z:243[(MH) - ,100%]

[0142] 3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)propanamide

[0143]

[0144] 3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)propanoic acid (1.0 g, 4.1 mmol) and 1,1'-carbonyldiimidazole (854 mg, 5.2 mmol) were stirred in THF (4 mL) at room temperature for 1 hour under N2 atmosphere. The reactants were cooled on ice and then aqueous ammonia (28%, 2.25 mL) was added. The reaction was stirred for 4 hours and the solution was allowed to warm to room temperature. The solvent was removed by rotary evaporation and the residue dissolved in dichloromethane (15 mL) was washed with aqueous sodium hydroxide solution (1 M, 5 mL), then aqueous hydrochloric acid solution (1 M, 5 mL), and then with water (5 mL). The organic layer was dried (MgSO4), filtered and evaporated to dryness to give the title compound as a white powder (607 mg, 61%).

[0145] 1 H NMR (300MHz, DMSO-d6) δ7.57–7.17(m,8H),6.79(s,2H),2.86(t,J=7.9Hz,2H),2.41(t,J=7.9Hz,2H). 13 C NMR (75MHz, DMSO-d6) δ173.3, 157.4 (d, J = 246.3Hz), 141.2, 132.6, 130.5 (d, J = 7.9Hz), 129. 2(d,J=8.3Hz),128.6,128.4,128.1(d,J=12.1Hz),124.8,116.0(d,J=22.7Hz),36.4,30.5. 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3400,3180,1650,1482,1412,1009,806,754,624cm –1 .LRMS(+ESI)m / z:266[(M+Na) + ,100%].

[0146] 3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)propan-1-amine

[0147]

[0148] A solution of amide (500 mg, 2.1 mmol) in THF (8 mL) was treated with LiAlH (312 mg, 8.2 mmol) at 0 ° C and stirred under N atmosphere while warming to room temperature. After 2 hours, the reaction was heated to reflux for 16 hours and then cooled on ice. Cooled H2O (300 μL) was added dropwise under vigorous stirring, followed by aqueous sodium hydroxide solution (15% w / v, 300 μL) and additional water (1 mL). The solution was stirred at room temperature until bubbling stopped and the gray powder turned white (30 minutes). The solution was dried (MgSO4) and then filtered. The precipitate was washed with additional dichloromethane (2×10 mL). The filtrate in each case was combined and the solvent was removed under reduced pressure. The crude oil thus obtained was purified by flash column chromatography (silica, 0.5:9.5 v / v MeOH (saturated with NH3): CH2Cl2) to give the title compound as a colorless wax (375 mg, 78%).

[0149] 1 H NMR (400MHz, DMSO-d6) δ7.60–7.12(m,8H),4.17(br s,2H),3.05–2.88(m,2H),2.75–2.52(m,2H),1.77–1.64(m,2H). 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3334,2923,1611,1481,1314,814,751,551cm –1 .LRMS(+ESI)m / z:230[(M+Na) + ,100%].

[0150] N-(3-(2'-Fluoro-[1,1'-biphenyl]-4-yl)propyl)nicotinamide (WJA88)

[0151]

[0152] 3-(2'-fluoro-[1,1'-biphenyl]-4-yl)propan-1-amine (200 mg, 0.87 mmol), nicotinic acid (129 mg, 1.04 mmol) and i A solution of Pr2NEt (303 μL, 1.74 mmol) in DMF (5 mL) was added with The mixture was stirred for 12 hours at 4 ℃ for 2 hours at 4 ℃ for 30 minutes.Then the mixture was stirred for 12 hours at 4 ℃ for 2 hours at 4 ℃ for 30 minutes.Then the mixture was stirred for 12 hours at 4 ℃ for 20 minutes ...

[0153] 1 H NMR(400MHz, DMSO-d6)δ9.03(d,J=1.5Hz,1H),8.73–8.66(m,1H),8.19(dt,J=7.9,2.0Hz,1H),7. 73–7.42(m,4H),7.40–7.15(m,5H),3.42–3.30(m,2H),2.70(t,J=7.6Hz,2H),1.95–1.85(m,2H).

[0154] 13 C NMR (101MHz, DMSO-d6) δ164.8,159.1(d,J=245.6Hz),151.7,148.3,141.4,134.86,132.6,130.6(d,J=3.5Hz),130.1,1 29.2(d,J=8.2Hz),128.7(d,J=2.9Hz),128.6,128.2,126.5(d,J=11.6Hz),124.8(d,J=3.4Hz),123.4,32.6,32.3,30.6. 19 F NMR (282 MHz, DMSO) δ-118.4. IR (diamond cell, pure) ν max :3302,3027,2948,2465,1626,1588,1544,1481,1448,1431,1406,1362,1317,1211,820,757,742,708,697,622,535cm –1 .LRMS(+ESI)m / z 357[(M+Na) + ,100%].

[0155] Biological Assessment

[0156] Tubulin polymerization assay

[0157] Fluorescence-based tubulin polymerization assays were performed using a Tubulin Polymerization Assay Kit (Cytoskeleton, Colorado, USA) according to the manufacturer's instructions in a final volume of 55 μL. Briefly, porcine brain tubulin was incubated with test compounds at 37°C and fluorescence was measured using a Tecan M200 PRO+ microplate reader (Tecan, Switzerland) at 355 nm excitation and 460 nm emission.

[0158] Compared with the control (DMSO), paclitaxel (PTX) enhanced tubulin polymerization, whereas vinblastine (VIN), WJA69b, and WJA88 inhibited tubulin polymerization (see Figure 1 and Figure 2 ).

[0159] Metabolic stability assay

[0160] All reactions were performed in duplicate with a reaction volume of 200 μl. 10 μM WJA85 was incubated with human microsomes (0.4 mg / ml) in potassium phosphate buffer (0.1 M, pH 7.4) at 37°C with slow shaking for 5 minutes. The assay was started by adding 12 μl of NADPH regeneration system (containing a final concentration of 1 mM NADP, 3.0 mM 6-phosphoglucose, 3.3 mM MgCl2 and 0.4 u / ml 6-phosphoglucose dehydrogenase). 130 μl of ice-cold methanol was added, vortexed vigorously, and centrifuged at 15000g, 4°C for 10 minutes to quench the reaction. The supernatant was collected for analysis, and 5 μl was analyzed using LC / MS / MS (see below). The results are shown in Figure 3 Negative controls included reaction mixtures without the addition of the NADPH regeneration system and reaction mixtures with inactive microsomes (inactivated by heating at 80°C for 30 min).

[0161] LC-MS analysis was performed on an Agilent 1260 liquid chromatography system coupled to a QTRAP 6500 mass spectrometer. For LC, a zorbax Extend-C18 (2.1 x 50 mm 1.8 um) column was used in reverse phase mode with a flow rate of 200 μl / min, and a gradient elution started with 10% of phase B (0.1% formic acid in water) and 90% of phase A (0.1% formic acid in acetonitrile). The amount of phase B was linearly increased from 10% to 90% in 5 minutes, then at 90% B for 2 minutes, and then returned to the initial state after 8 minutes.

[0162] The MS detector was operated in ESI positive ionization mode. The source temperature and capillary voltage were set to 300 °C and 4000 V, respectively. Analyst software was used to control the instrument and data acquisition. The determination of mitotic inhibitors was performed using the multiple reaction monitoring (MRM) mode with the following conditions for each compound. The ion transitions for CMPD1 were from 350.3 to 241, for WJA88 from 335 to 106, and for WJA69b from 335 to 185. The fragmentor voltage was set to 145 V and the collision energy was 30 for all compounds.

[0163] Clonal analysis

[0164] WK1(2x10 4 Cells / well) were plated on 6-well plates coated with Matrigel matrix (1:50; Corning, USA). The next day, cells were treated with different concentrations of WJA88 in duplicate and incubated at 37°C, 5% CO2 for 14 days. The cells were then washed with phosphate-buffered saline and stained with toluidine blue solution (50% w / v in 50% v / v methanol) for 45 minutes at 4°C. The stain was removed, and the cells were washed with water and dried, then imaged with a Gel-Doc XR Imager (Biorad Laboratories, USA). Images were analyzed using ImageJ software (NIH, USA) using the colony area plug-in to reflect the percentage of cell fusion in each well. Cell fusion was then normalized to control wells, and EC was determined using nonlinear regression (GraphpadPRISM, USA). 50 Data are mean ± SEM values ​​from two independent experiments. Figure 4 shown.

[0165] 3D spheroid assay

[0166] PB1 cells (8x10 4 Cells / well) were plated on a 0.8% v / v agarose-coated flat-bottom 96-well plate and left to stand for 48-72 h to form spheres. After spheroid formation, individual spheroids were imaged using a Zeiss AXIO Vert.A1 (Carl Zeiss, Germany) in bright field with a 5x or 10x objective, and these images were taken as day 0. The spheroids were then treated in duplicate with various concentrations of the test compound and imaged on day 14. The spheroid area (μm) of individual spheroid images on day 0 and day 14 was analyzed using ImageJ software (NIH, USA). 2 The fold change of spheroid area over time was calculated as a measure of spheroid growth. Data are mean ± SEM values ​​from two independent experiments. Figure 5 shown.

[0167] CMPD1 has the following structure:

[0168]

[0169] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All these different combinations constitute various alternative aspects of the invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof: in: X is a C1-C6 alkyl group or a C2-C6 alkenyl group; Y is W is O or S; R2 is H, alkyl or alkenyl; Z is heterocycloalkyl or heteroaryl, which is optionally substituted; R1 is halogen, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted; Ar is aryl or heteroaryl.

2. The compound of claim 1, wherein X is a C3 alkyl or C3 alkenyl group.

3. A compound as claimed in claim 1 or claim 2, wherein R2 is H.

4. The compound of any one of claims 1 to 3, wherein R1 is aryl.

5. The compound of claim 4, wherein the aryl group is monocyclic or bicyclic.

6. The compound according to claim 4 or 5, wherein The aryl group is phenyl or naphthyl.

7. The compound of any one of claims 4 to 7, wherein the aryl group is substituted.

8. The compound of claim 7, wherein the substituent is selected from a halogen group and a heteroalkyl group.

9. The compound according to claim 8, wherein The halogen group is F.

10. The compound of claim 8, wherein the heteroalkyl group is O-alkyl.

11. The compound of claim 10, wherein O-alkyl is -OCH3.

12. The compound of claim 8, wherein the heteroalkyl group is an aminoalkyl group.

13. The compound of claim 12, wherein the aminoalkyl group is -CH2NH2.

14. The compound of any one of claims 1 to 3, wherein R1 is heteroaryl.

15. The compound of claim 14, wherein the heteroaryl group is monocyclic or bicyclic.

16. The compound according to claim 14 or 15, wherein The heteroaryl group includes one or more nitrogen atoms.

17. The compound of claim 15, wherein the heteroaryl group is pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole.

18. A compound as described in any one of claims 14 to 17, wherein the heteroaryl is substituted.

19. The compound of claim 18, wherein the substituent is selected from a halogen group and a heteroalkyl group.

20. The compound of claim 19, wherein the halogen group is F.

21. The compound of claim 19, wherein the heteroalkyl group is O-alkyl.

22. The compound of claim 21, wherein O-alkyl is -OCH3.

23. The compound of claim 19, wherein the heteroalkyl group is an aminoalkyl group.

24. The compound of claim 23, wherein the aminoalkyl group is -CH2NH2.

25. The compound of any one of claims 1 to 3, wherein R1 is heterocycloalkyl.

26. The compound of claim 25, wherein the heterocycloalkyl group comprises one or more nitrogen atoms.

27. The compound of claim 26, wherein the heterocycloalkyl group is piperazine.

28. The compound of claim 25 or 26, wherein the heterocycloalkyl group includes one or more oxygen atoms.

29. The compound of claim 28, wherein the heterocycloalkyl group is morpholine.

30. The compound of any one of claims 25 to 29, wherein the heterocycloalkyl is substituted.

31. The compound of claim 30, wherein the substituent is selected from a halogen group and a heteroalkyl group.

32. The compound of claim 31, wherein the halogen group is F.

33. The compound of claim 31, wherein the heteroalkyl group is O-alkyl.

34. The compound of claim 35, wherein O-alkyl is -OCH3.

35. The compound of claim 31, wherein the heteroalkyl group is an aminoalkyl group.

36. The compound of claim 35, wherein the aminoalkyl group is -CH2NH2.

37. A compound as claimed in any one of the preceding claims, wherein Ar is aryl.

38. The compound of claim 37, wherein aryl is phenyl.

39. A compound as described in any one of claims 1 to 36, wherein Ar is heteroaryl.

40. The compound of claim 39, wherein the heteroaryl group comprises one or more nitrogen atoms.

41. The compound of claim 39 or 40, wherein the heteroaryl group has 4 or 5 ring carbon atoms.

42. The compound of any one of claims 39 to 41, wherein the heteroaryl is pyridine or pyrimidine.

43. A compound as claimed in any one of the preceding claims, wherein Z is aryl.

44. The compound of claim 43, wherein the aryl group is monocyclic.

45. The compound of claim 44, wherein aryl is phenyl.

46. ​​A compound as described in any one of claims 43 to 45, wherein the aryl is substituted.

47. The compound of claim 46, wherein the substituent is a heteroalkyl group.

48. The compound of claim 47, wherein the heteroalkyl group comprises one or more oxygen atoms.

49. The compound of claim 47 or claim 48, wherein the heteroalkyl group and the aryl group form a ring.

50. The compound of any one of claims 1-42, wherein Z is a monocyclic or bicyclic heteroaryl.

51. The compound of claim 50, wherein the heteroaryl group comprises one or more nitrogen atoms.

52. The compound of claim 50 or 51 , wherein heteroaryl is substituted.

53. The compound of claim 52, wherein the substituents are selected from hydroxy, halogen and heteroalkyl.

54. The compound of claim 53, wherein the halogen group is F.

55. The compound of claim 53, wherein heteroalkyl is O-alkyl.

56. The compound of claim 55, wherein O-alkyl is -OCH3.

57. The compound of claim 53, wherein the heteroalkyl group is an aminoalkyl group.

58. The compound of claim 57, wherein the aminoalkyl group is -CH2NH2.

59. A compound as claimed in any one of claims 50 to 58, wherein Z is pyridine.

60. The compound of claim 59, wherein the nitrogen of the pyridine is in the meta position.

61. The compound of any one of claims 1-42, wherein Z is heterocycloalkyl.

62. The compound of claim 61, wherein the heterocycloalkyl group comprises at least one nitrogen atom.

63. A compound as described in claim 61 or 62, wherein the heterocycloalkyl group includes at least one oxygen atom.

64. The compound of any one of claims 61 to 63, wherein the Heterocycloalkyl is substituted.

65. The compound of claim 64, wherein the substituent is selected from a halogen group and a heteroalkyl group.

66. The compound of claim 65, wherein the halogen group is F.

67. The compound of claim 65, wherein heteroalkyl is O-alkyl.

68. The compound of claim 67, wherein O-alkyl is -OCH3.

69. The compound of claim 65, wherein the heteroalkyl group is an aminoalkyl group.

70. The compound of claim 69, wherein the aminoalkyl group is -CH2NH2.

71. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of the preceding claims and a pharmaceutically acceptable excipient.

72. A method of treating or preventing a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 70.

73. A method of treating or preventing a proliferative disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 71.

74. The method of claim 72 or 73, wherein the proliferative disease is cancer.

75. The method of claim 74, wherein the cancer is brain cancer.

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