阅读说明：本技术 抗癌化合物 (Anticancer compounds ) 是由 M·卡修 W·约尔根森 L·穆诺茨 于 2019-02-01 设计创作，主要内容包括：本发明涉及新的药物,及其在例如癌症(特别是脑癌)等增生性疾病的治疗中的用途。(The present invention relates to novel medicaments and their use in the treatment of proliferative diseases such as cancer, particularly brain cancer.)

1. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:

wherein:

x is C₁-C₆Alkyl or C₂-C₆An alkenyl group;

y is

W is O or S;

R₂is H, alkyl or alkenyl;

z is heterocycloalkyl or heteroaryl, which heterocycloalkyl or heteroaryl is optionally substituted;

R₁is halogen, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, which cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted;

ar is aryl or heteroaryl.

2. The compound of claim 1, wherein X is C₃Alkyl or C₃An alkenyl group.

3. A compound as claimed in claim 1 or claim 2 wherein R is₂Is H.

4. The compound of any one of claims 1 to 3, wherein R₁Is an aryl group.

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

6. The compound of 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 substituents are selected from the group consisting of halogen groups and heteroalkyl groups.

9. The compound of claim 8, wherein the halogen group is F.

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

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

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

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

14. The compound of any one of claims 1 to 3, wherein R₁Is a heteroaryl group.

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

16. The compound of claim 14 or 15, wherein the heteroaryl group comprises one or more nitrogen atoms.

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

18. The compound of any one of claims 14 to 17, wherein the heteroaryl is substituted.

19. The compound of claim 18, wherein the substituents are selected from the group consisting of halogen groups and heteroalkyl groups.

20. The compound of claim 19, wherein halo is F.

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

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

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

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

25. The compound of any one of claims 1 to 3, wherein R₁Is a heterocycloalkyl group.

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

27. The compound of claim 26, wherein heterocycloalkyl 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 heterocycloalkyl 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 substituents are selected from the group consisting of halogen groups and heteroalkyl groups.

32. The compound of claim 31, wherein halo is F.

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

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

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

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

37. The compound of any one of the preceding claims, wherein Ar is aryl.

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

39. The compound of any one of claims 1 to 36, wherein Ar is heteroaryl.

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

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

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

43. The compound of any one of the preceding claims, wherein Z is aryl.

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

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

46. The compound of any one of claims 43-45, wherein the aryl is substituted.

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

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

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

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

51. The compound of claim 50, wherein heteroaryl 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 the group consisting of hydroxy, halogen, and heteroalkyl.

54. The compound of claim 53, wherein halo 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 heteroalkyl is aminoalkyl.

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

59. The compound of any one of claims 50-58, 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 heterocycloalkyl includes at least one nitrogen atom.

63. The compound of claim 61 or 62, wherein heterocycloalkyl comprises at least one oxygen atom.

64. The compound of any one of claims 61-63, wherein the heterocycloalkyl is substituted.

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

66. The compound of claim 65, wherein halo 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 heteroalkyl is aminoalkyl.

70. The compound of claim 69, wherein aminoalkyl 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 claimed 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.

Technical Field

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

Background

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

Furthermore, even though 50% of glioblastomas are dependent on Epidermal Growth Factor Receptor (EGFR) signaling, clinically available EGFR inhibitors have failed in clinical trials of glioblastomas. Some inhibitors do not have sufficient Blood Brain Barrier (BBB) permeability. Recent studies have also shown that glioblastoma responds only to type II EGFR inhibitors, whereas type I inhibitors have been tested. The extreme heterogeneity and invasiveness of glioblastoma has also led to the failure of molecularly targeted therapies as an effective treatment for brain cancer.

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

Therefore, there is a need to find new therapies for proliferative diseases such as cancer, in particular to find effective therapies for brain cancer.

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

Disclosure of Invention

The present invention seeks to address one or more of the above problems, and/or to provide improvements in the treatment of cancer, and in a first aspect, provides a compound of formula (I):

wherein:

x is C₁-C₆Alkyl or C₂-C₆An alkenyl group;

y is

W is O or S;

R₂is H, alkyl or alkenyl;

z is aryl, heterocycloalkyl or heteroaryl, wherein aryl, heterocycloalkyl or heteroaryl is optionally substituted;

R₁is halogen, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted;

ar is aryl or heteroaryl.

X may be C₃Alkyl or C₃An alkenyl group.

W may be O.

R₁May be an aryl group. The aryl group may be monocyclic or bicyclic. Aryl may be phenyl or naphthyl. The aryl group may be substituted. The substituents may be selected from halogen groups and heteroalkyl groups.The halogen group can be F and the heteroalkyl group can be O-alkyl (e.g., -OCH)₃) Or aminoalkyl (e.g. -CH)₂NH₂)。

R₁May be a heteroaryl group. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups may include one or more nitrogen atoms. For example, the heteroaryl group can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole. Heteroaryl groups may be substituted. For example, the substituent may be a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, e.g., -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂)。

R₁May be a heterocycloalkyl group. The heterocycloalkyl group may include one or more nitrogen atoms. The heterocycloalkyl group can be piperazine. The heterocycloalkyl group may contain (in addition to or as an alternative to one or more nitrogen atoms) one or more oxygen atoms. The heterocycloalkyl group may be morpholine. The heterocycloalkyl radical may be substituted, for example, by a halogen radical (e.g. F) or a heteroalkyl radical (e.g. O-alkyl, e.g. -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂) And (4) substitution.

Ar may be an aryl group. The aryl group may be phenyl. Ar may be heteroaryl. Heteroaryl groups may include one or more nitrogen atoms and/or NH groups. Heteroaryl groups can have 4 or 5 ring carbon atoms. The heteroaryl group may be pyridine or pyrimidine.

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

Z may be heteroaryl. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups may include one or more nitrogen atoms. For example, the heteroaryl group can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, benzimidazole or indole. Heteroaryl groups may contain one or more oxygen atoms (in addition to or as an alternative to one or more nitrogen atoms). For example, the heteroaryl group can be furan. The heteroatoms may be in one or more positions on one or more rings. For example, when Z is a pyridyl group,the nitrogen may be at one or more positions on the ring. For example, the nitrogen may be in the meta position. The nitrogen may be in one or more of the ortho and/or meta and/or para positions. Heteroaryl groups may be substituted. For example, the substituent may be a hydroxyl group, a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, e.g., -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂)。

Z may be heterocycloalkyl. The heterocycloalkyl group may include one or more nitrogen atoms. The heterocycloalkyl group can be piperazine. The heterocycloalkyl group may contain (in addition to or as an alternative to one or more nitrogen atoms) one or more oxygen atoms. The heterocycloalkyl group may be morpholine. The heterocycloalkyl group may be partially unsaturated. The heterocycloalkyl radical may be substituted, for example, by hydroxy, halogen radicals (e.g. F) or heteroalkyl radicals (e.g. O-alkyl, e.g. -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂) And (4) substitution.

R₂May be H, alkyl or alkenyl. R₂May be H.

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

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.

The compounds and pharmaceutical compositions according to the invention may be suitable for the treatment or prevention of proliferative diseases. Thus, in another aspect, the present invention relates to a method of 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) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

In another aspect, the invention relates to the use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the manufacture of a medicament for the treatment or prevention of a proliferative disease. In another aspect, the invention relates to the use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the treatment or prevention of a proliferative disease in a subject.

In another aspect, the present invention relates to a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for use in the treatment or prevention of a proliferative disease in a subject.

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.

The cancer may be primary. The cancer may be metastatic. The cancer may be benign. The cancer may be malignant.

The cancer may be a brain cancer (e.g., anaplastic astrocytoma, central neuroblastoma, choroid plexus cancer, choroid plexus papilloma, choroid plexus tumor, diffuse pontocerebral glioma, embryonal neuroepithelioma, ependymoma, fibroastrocytoma, giant cell glioblastoma, glioblastoma multiforme, glioma, gliosarcoma, hemangiothecoma, medulloblastoma, meningioma, neuroblastoma, oligoastrocytoma, oligodendroglioma, optic nerve sheath meningioma, pediatric ependymoma, hairy cell astrocytoma, pinealoblastoma, loose cell tumor, anaplastic neuroblastoma, yellow astrocytoma, primary central nervous system lymphoma, pterocarcinoma, giant cell astrocytoma under ependymoma, ependymal tumor, tripartite retinoblastoma). The brain cancer may be a primary cancer (e.g., glioma, meningioma, pituitary adenoma, or schwannoma). Brain cancer can be a metastatic cancer (e.g., as a result of melanoma or lung cancer).

In another aspect, the present invention relates to a method of 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) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

In another aspect, the present invention relates to the use of a compound according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for the manufacture of a medicament for the complete or partial prevention of recurrence of a solid tumor.

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

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

The solid tumor can be a brain cancer (e.g., glioblastoma, astrocytoma, or glioma). Brain cancer may be a primary cancer. The brain cancer may be a metastatic cancer.

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

Other aspects of the invention and other embodiments 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.

Brief description of the drawings

FIG. 1 results of in vitro tubulin polymerization assay using WJA69 b.

Figure 2 results of in vitro tubulin polymerization assay using WJA 88.

FIG. 3 Metabolic stability testing of CMPD1, WJA69b and WJA 88.

FIG. 4. cellular potency of WJA88 in the clonogenic assay.

Figure 5 cellular efficacy of compounds in 3D sphere assay.

Detailed description of the embodiments

Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims.

Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention. 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 of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the present invention.

Throughout this specification, unless expressly stated otherwise or the context requires otherwise, reference to an individual step, composition of matter, group of steps or group of matter shall be taken to include one or more (i.e., one or more) of those steps, compositions of matter, groups of steps or groups of matter. 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 and two or more; references to "a" or "an" include both individually and in two or more; reference to "the" includes a single as well as two or more, and so forth.

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, particularly brain cancer.

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it is understood that all optical isomers and mixtures thereof are included unless otherwise indicated. Compounds having two or more asymmetric elements may also exist as mixtures of diastereomers. In addition, compounds having carbon-carbon double bonds may exist in the Z and E forms, and all isomeric forms of the compounds are included in the present invention unless otherwise specified.When a compound exists in various tautomeric forms, the recited compounds are not limited to any one particular tautomer, but are intended to encompass all tautomeric forms. The enumerated compounds are further intended to encompass compounds in which one or more atoms are isotopically substituted, i.e., atoms having the same atomic number but different mass numbers. By way of general example, but not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include¹¹C，¹³C and¹⁴C。

compounds having 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 compounds have an enantiomeric excess of at least 99%. It will be apparent that the single enantiomers (optically active forms) may be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis or by resolution of the racemate, for example by enzymatic resolution or by conventional methods, for example by crystallization in the presence of a resolving agent, or by chromatography, for example using a chiral HPLC column.

As used herein includes such things as R₁，R₂The general formulae for the variables Ar, W, X, Y and Z describe certain compounds. Unless otherwise specified, each variable within the formula is defined independently of any other variable, and any variable occurring multiple times within a formula is defined individually at each occurrence. Thus, for example, if a group is shown to be substituted by 0, 1 or 2R^＊Substituted, the radical may be unsubstituted or substituted by up to two R^＊Is substituted by radicals, and each time R^＊When present, are each independently from R^＊Is selected from the definitions of (1). Moreover, combinations of substituents and/or variables are permissible only if the combination results in a stable compound, e.g., a compound can be isolated, characterized, and tested for biological activity.

"pharmaceutically acceptable salts" of the compounds disclosed herein are acid or base salts generally recognized in the art as suitable for contact with human or animal tissue without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problems and complications. In particular, pharmaceutically acceptable salts according to the 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.

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, sulfanilic 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 (e.g., acetic acid, HOOC- (CH-H-C-H-₂)_n-COOH, wherein n is any integer from 0 to 6, i.e. 0, 1,2,3, 4,5 or 6), etc. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. One skilled in the art will recognize other pharmaceutically acceptable salts of the compounds provided herein. In general, pharmaceutically acceptable acid or base salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by any conventional chemical method. In short, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent (e.g., diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) or a mixture of the two.

It will be apparent that each compound of formula (I) may, but need not, be present 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 prodrugs of the compounds of formula (I) provided herein.

A prodrug is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo following 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 wherein a hydroxyl, carboxyl, amine or sulfhydryl group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, carboxyl, amino or sulfhydryl group, 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 the compounds provided herein may be prepared by modifying functional groups present in the compounds in a manner such that the modifications are cleaved, in vivo, to yield the parent compound.

As used herein, "substituent" refers to a molecular moiety that covalently bonds atoms within a target molecule. For example, a "ring substituent" may be a moiety such as a halogen, alkyl, heteroalkyl, haloalkyl or other substituent described herein covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of the ring. As used herein, the term "substituted" means that any one or more hydrogens on the designated atom is replaced with a substituent selected from the indicated substituents, provided that the designated atom's normal valency is not exceeded, and that 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 oxo, i.e., ═ O, then two hydrogens on the atom are substituted. The oxo group as a substituent of an aromatic carbon atom results in the conversion of-CH-to-C (═ O) -and loss of aromatic character. For example, pyridyl substituted with oxo is pyridone. Examples of suitable substituents are alkyl (including haloalkyl, e.g. CF)₃) Heteroalkyl groups (e.g., -OCH)₃，-CH₂NHCH₃，-CH₂NH₂) Halogen (e.g. fluorine, chlorine, bromine or iodine atom), OH, ═ O, SH, SO₃H，NH₂，＝NH，N₃And NO₂A group.

The term "alkyl" refers to a saturated, straight or branched chain hydrocarbon group. Specific examples of alkyl groups are methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl and 2, 2-dimethylbutyl.

The term "heteroalkyl" refers to an alkyl group as defined above containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (particularly oxygen and nitrogen). Specific examples of heteroalkyl groups are O-alkyl groups, such as methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, butoxy and t-butoxy, methoxymethyl, ethoxymethyl, -CH₂CH₂OH，-CH₂OH, methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, aminoalkyl (e.g. -CH)₂NH₂，–CH₂CH₂NH₂Etc.), methylamino, ethylamino, propylamino, i-propylamino, dimethylamino, diethylamino, i-propylethylamino, methylaminomethyl, ethylaminomethyl, diiso-propylaminoethyl, methylthio, ethylthio, i-propylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino, propionylamino, carboxymethyl, carboxyethyl, carboxypropyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Other examples of heteroalkyl groups are nitrile, iso-nitrile, cyanate, thiocyanate, iso-cyanate, iso-thiocyanate and alkyl nitrile groups.

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

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 from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4,5, 6, or 7) ring carbon atoms. Specific examples of cycloalkyl groups 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.

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 substituted by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably an oxygen, sulfur or nitrogen atom). This includes groups containing atoms such as NH. Heterocycloalkyl preferably has 1 or 2 rings comprising 3 to 10 (in particular 3, 4,5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Specific examples are piperidinyl, prolyl, imidazolidinyl, piperazinyl, morpholinyl, uracil, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl and 2-pyrazolinyl, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

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

The term "heteroaryl" refers to an aryl group comprising one or more rings comprising 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6) ring atoms, and comprising one or more (preferably 1,2,3 or 4) ring atoms of oxygen, nitrogen, phosphorus or sulfur (preferably O, S or N). This includes O, S or N containing groups such as NH. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 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, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3' -difuranyl and pyrazolyl (e.g. 3-pyrazolyl).

The expression "halogen" or "halogen atom" as used herein means fluorine, chlorine, bromine or iodine.

The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms are independently from each other replaced by halogen (e.g., fluorine, chlorine, bromine or iodine atoms) and/or replaced by, for example, OH, ═ O, SH, SO₃H，NH₂N-alkyl, NH-alkyl, N₃Or NO₂And (4) substituting the group. The expression also refers to a group which is substituted by one, two, three or more alkyl, alkenyl or heteroalkyl groups (e.g. -OCH)₃，-OCH₂CH₃，-CH₂NHCH₃and-CH₂NH₂) And (4) substitution. These groups may themselves be substituted. For example, an alkyl substituent may be substituted with one or more halogen atoms (e.g., may be a haloalkyl). The term "haloalkyl" refers to an alkyl (as defined above) substituted with one or more halogen atoms (as defined above). Specific examples of haloalkyl groups are trifluoromethyl, dichloroethyl, dichloromethyl and iodoethyl.

As used herein, a phrase defining a limit of a length range, such as "from 1 to 5," refers to any integer from 1 to 5, i.e., 1,2,3, 4, and 5. In other words, any range defined by two integers specifically mentioned is intended to include and disclose any integer which defines the stated limit as well as any integer which is included within the stated range.

Preferred compounds of formula (I) are those wherein X is C₁，C₂Or C₃Alkyl, or C₂Or C₃Alkenyl (e.g. C)₃Alkyl or C₃Alkenyl) groups.

R₁May be an aryl group. The aryl group may be monocyclic or bicyclic. Aryl may be phenyl or naphthyl. The aryl group may be substituted. The substituents may be selected from halogen groups and heteroalkyl groups. The halogen group can be F and the heteroalkyl group can be O-alkyl (e.g., OCH)₃Or OCH₂CH₃) Or aminoalkyl (e.g. -CH)₂NH₂or-CH₂CH₂NH₂)。

R₁May be a heteroaryl group. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups may include one or more nitrogen atoms. For example, heteroAryl may be pyrazole, isoxazole, triazole, pyridine, pyrimidine, quinoline, benzimidazole or indole. Heteroaryl groups may be substituted. For example, the substituent may be a halogen group (e.g., F) or a heteroalkyl group (e.g., O-alkyl, e.g., -OCH)₃Or OCH₂CH₃Or aminoalkyl radicals, e.g. -CH₂NH₂or-CH₂CH₂NH₂)。

R₁May be a heterocycloalkyl group. The heterocycloalkyl group may include one or more nitrogen atoms. The heterocycloalkyl group can be piperazine. The heterocycloalkyl group may contain one or more oxygen atoms. The heterocycloalkyl group may be morpholine. The heterocycloalkyl radical may be substituted, for example, by a halogen radical (e.g. F) or a heteroalkyl radical (e.g. O-alkyl, e.g. -OCH)₃Or OCH₂CH₃Or aminoalkyl radicals, e.g. -CH₂NH₂or-CH₂CH₂NH₂) And (4) substitution.

Ar may be an aryl group. The aryl group may be phenyl. Ar may be heteroaryl. Heteroaryl groups may include one or more nitrogen atoms. Heteroaryl groups can have 4 or 5 ring carbon atoms. The heteroaryl group may be pyridine or pyrimidine.

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

Z may be heteroaryl. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups may include one or more nitrogen atoms. For example, the heteroaryl group can be pyrazole, isoxazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, benzimidazole or indole. Heteroaryl groups may contain one or more oxygen atoms (in addition to or as an alternative to one or more nitrogen atoms). For example, the heteroaryl group can be furan. The heteroatoms may be in one or more positions on one or more rings. For example, when Z is pyridyl, the nitrogen may be in the meta position. The nitrogen may be in the ortho and/or one or more meta and/or para positions. Heteroaryl groups may be substituted. For example, the substituent may be a hydroxyl group,halogen radicals (e.g. F) or heteroalkyl radicals (e.g. O-alkyl, e.g. -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂)。

Z may be heterocycloalkyl. The heterocycloalkyl group may include one or more nitrogen atoms. The heterocycloalkyl group can be piperazine. The heterocycloalkyl group may contain (in addition to or as an alternative to one or more nitrogen atoms) one or more oxygen atoms. The heterocycloalkyl group may be morpholine. The heterocycloalkyl group may be partially unsaturated. The heterocycloalkyl radical may be substituted, for example, by hydroxy, halogen radicals (e.g. F) or heteroalkyl radicals (e.g. O-alkyl, e.g. -OCH)₃Or aminoalkyl radicals, e.g. -CH₂NH₂) And (4) substitution.

R₂May be H, alkyl or alkenyl. R₂Possibly H.

Specific examples of the compounds of the present invention are given in table 1 below.

Table 1 examples of compounds of the invention

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.

The compounds of the invention may be synthesized by any suitable method known to those skilled in the art. The general synthesis is given in scheme 1 below.

Scheme 1 general synthetic examples of the compounds of the present invention

The compounds of the present invention can exhibit high antiproliferative activity, and particularly high efficacy against brain cancer. In particular, in the examples herein, particular compounds are shown to induce apoptosis and are also able to cross the BBB.

Therapeutic uses of the compounds of formula (I), pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and formulations and pharmaceutical compositions thereof, including mixtures of the compounds of formula (I), are also within the scope of the invention. Accordingly, the present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and one or more pharmaceutically acceptable excipients.

"pharmaceutical carrier, diluent or excipient" includes, but is 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 (e.g., crystalline cellulose), cellulose derivatives, acacia, gelatin, disintegrants (e.g., sodium carboxymethylcellulose) and lubricants (e.g., talc or magnesium stearate).

The pharmaceutical compositions may 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, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral or parenteral use are preferred. Suitable oral forms include, for example, tablets, troches, 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 may be mixed with a sterile aqueous solution, which is preferably isotonic with the blood of the recipient. Such formulations may 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 formulations may be presented in unit or multi-dose containers, for example sealed ampoules or vials. Examples of suitable components are described in the martindale pharmacopoeia (pharmaceutical Press, London, 1993) and Martin (et al), Remington pharmaceutical sciences.

For the treatment of proliferative diseases, the dosage of the biologically active compounds of the invention can vary over a wide range and can be adjusted to the individual needs. The active compounds of the present invention are generally administered in a therapeutically effective amount. A preferred dosage is from about 0.1mg to about 140mg per kilogram of body weight per day (e.g., from about 0.5mg to about 7g per patient per day). The daily dose may be administered in a single dose or in multiple doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will typically contain from about 1mg to about 500mg of the active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (e.g., other drugs used to treat the patient), the severity of the particular disease undergoing therapy, and the location of unwanted proliferating cells. If the compound is administered locally rather than systemically, and is intended for prophylaxis rather than therapy, the dosage will generally be lower. Such treatment may be carried out for as long as desired and as determined by the attending physician. One skilled in the art will appreciate that the dosage regimen or therapeutically effective amount of the compound of formula (I) to be administered may need to be optimized for each individual.

It will be appreciated that different dosages may be required to treat different diseases. An effective amount of an agent is that amount which causes a statistically significant reduction in tumor cell count, growth, or size. Neoplastic diseases responsive to the agents of the invention include, but are not limited to, brain cancer.

The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound of formula (I) that results in the prevention, amelioration or remediation of the symptoms of a proliferative disease. Dosage forms and amounts of the compounds or pharmaceutical compositions of the invention can be readily determined by reference to known therapeutic or prophylactic regimens.

Preferred compounds of the 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 compound in vivo.

The compounds of the invention are preferably administered to a patient (e.g., a human) orally or parenterally and are present in at least one body fluid or tissue of the patient. Accordingly, the invention further provides methods for treating patients suffering from proliferative diseases, including cancer, such as brain cancer.

The terms "treatment," "treating," and "therapy" are used herein to refer to curative therapy. Thus, in the context of the present disclosure, the term "treating" encompasses curing and ameliorating the severity of cancer or its associated symptoms.

"preventing" or "prevention" refers to preventing the occurrence of cancer or, if it develops after administration of a compound or pharmaceutical composition of the invention, to lessening the severity of cancer. This can completely prevent the onset of clinically significant unwanted cell proliferation and prevent the onset of an undesirably rapid preclinically significant phase of cell proliferation in individuals at risk.

Patients may include, but are not limited to, primates, particularly humans, domesticated companion animals (e.g., dogs, cats, horses) and livestock (e.g., cattle, pigs, sheep), at dosages as described herein.

The compounds of the invention are useful for the treatment and/or prevention of diseases and disorders associated with cell proliferation (including cancer, e.g., brain cancer). Accordingly, the present invention also relates to a method of 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 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 of the embodiments described in the specification, the invention also provides a pharmaceutical composition for treating or preventing a proliferative disease. The 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 manufacture of a medicament for the treatment or prevention of a proliferative disease.

The invention also relates to compounds of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, when used in a method of treatment or prevention of a proliferative disease. The present invention also relates to a composition for treating or preventing a proliferative disease comprising an active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The invention also relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in the treatment or prevention of a proliferative disease as described above. In one embodiment, the compound of formula (I) is essentially the only active ingredient of the composition. In one embodiment, the proliferative disease is cancer. In one embodiment, the cancer is a brain cancer (e.g., a solid tumor).

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

Types of cancers or neoplastic cells that may be suitable for treatment in the present invention include, for example, breast, colon, lung and prostate cancers, gastrointestinal cancers including esophageal, gastric, colorectal, polyps associated with colorectal tumors, pancreatic and gall bladder cancers, adrenocortical cancers, ACTH producing tumors, bladder cancers, brain cancers including those discussed below, ewing's sarcoma, head and neck cancers including oral and throat cancers, kidney cancers including renal cell carcinoma, liver cancers, lung cancers including small and non-small cell lung cancers, malignant ascites, malignant pleural effusions, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal and vascular skin tumors, mesothelioma, kaposi's disease sarcoma, bone cancers including osteomas and fibrosarcoma such as fibrosarcoma and osteosarcoma, female genital tract including uterine cancer, endometrial cancer, ovarian (germ cell) cancer and ovarian follicular solid tumors, vaginal cancer, vulvar and cervical cancer, breast cancer (small cell and ductal carcinoma), penile cancer, retinoblastoma, testicular cancer, thyroid cancer, trophoblastic tumors and wilms tumors. 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.

In one embodiment, the proliferative disease to be treated and/or prevented is brain cancer. The brain cancer may be selected from: anaplastic astrocytoma, central neuroblastoma, choroid plexus cancer, choroid plexus papilloma, choroid plexus tumor, diffuse pontocerebral glioma, embryonal neuroepithelial tumor, ependymoma, fibrillary astrocytoma, giant cell glioblastoma, glioblastoma multiforme, brain glioma disease, gliosarcoma, vascular endothelial cell tumor, medulloblastoma, meningiocarcinoma, neuroblastoma, oligoastrocytoma, oligodendroglioma, optic nerve sheath meningioma, pediatric ependymoma, hairy cell astrocytoma, pinealoblastoma, loose cell tumor, anaplastic neuroblastoma, yellow astrocytoma, primary central nervous system lymphoma, pterocarcinoma, giant cell astrocytoma under ependymoma, subintimal tumor, three-sided retinoblastoma. Thus, preferably, the brain cancer is a tumor (preferably, a solid tumor). The brain cancer may be a primary cancer (e.g., glioma, meningioma, pituitary adenoma, or schwannoma) or a metastatic cancer (e.g., brain cancer due to a cancer in other parts of the body (e.g., melanoma or lung cancer)).

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

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

According to various embodiments of the invention, one or more compounds of formula (I) may be formulated or administered with one or more other therapeutic agents. Thus, according to various embodiments of the invention, one or more compounds of formula (I) may be included in a combination treatment regimen with surgery and/or other known therapeutic or therapeutic agents, such as other anti-cancer agents, particularly chemotherapeutic radiotherapeutic agents and/or adjuvants or prophylactic agents.

A large number of antineoplastic agents are available for commercial, clinical evaluation and preclinical development, and are selected for the treatment of cancer or other tumors by combination drug chemotherapy. Such antineoplastic agents fall into several broad classes, namely antibiotic drugs, antimetabolite drugs, hormonal drugs, immunological drugs, interferon drugs and miscellaneous drugs. Alternatively, other antineoplastic agents, such as metallo-matrix protease inhibitors, may be used. Agents deemed suitable by those skilled in the art may be used in combination therapy. Suitable reagents are listed, for example, in the Merck index, encyclopedia of chemistry, medicine and biology, 12 th edition, 1996.

The combination regimen may comprise the administration of the active agents in each case together, sequentially or intermittently. Combinations of active agents comprising the compounds of the present invention may be synergistic.

Co-administration of a compound of formula (I) may be carried out by co-administering a compound of formula (I) with a chemotherapeutic agent or other anti-cancer agent, or a compound of formula (I) with a chemotherapeutic agent or a compound of formula (la). Other anti-cancer agents may be present in separate and discrete unit doses for the same or similar time. Sequential administration may be in any order desired, and where a second or subsequent compound is administered, particularly where cumulative or synergistic effects are desired, it may be desirable that the sustained physiological effect of the first or initial compound is current.

For various applications, the compounds of the invention may be labeled with an isotope, fluorescent or luminescent label, antibody or antibody fragment, any other affinity label (e.g., nanobody, aptamer, peptide, etc.), enzyme or enzyme substrate. These labeled compounds of the invention are useful for mapping receptor locations in vivo, ex vivo, in vitro, and in situ, for example, by autoradiography in tissue sections, and as radiotracers for Positron Emission Tomography (PET) imaging, Single Photon Emission Computed Tomography (SPECT), and the like, to characterize those receptors in living organisms or other materials. The labeled compounds of the present invention may be used in therapeutic, diagnostic and other applications, such as research tools in vivo and in vitro, particularly the applications disclosed herein.

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 of these different combinations constitute various alternative aspects of the present invention.

The experiments of the present invention will now be discussed in more detail with reference to examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.