BCR-ABL degradation agent and application thereof

Abstract

The invention provides a compound with a BCR-ABL protein degradation effect as shown in a formula I and application of the compound to preparation of a medicine for treating diseases related to BCR-ABL activity. X-Y-Z is represented by formula I.

Description

Technical Field

[0001] The present invention relates to a compound with BCR-ABL protein degradation function and use thereof in preparing medicines for diseases related to BCR-ABL activity. Background Art

[0002] The BCR-ABL fusion gene is the pathogenic gene that causes all chronic myeloid leukemia (CML) and some Philadelphia chromosome-positive (PH+) acute lymphoblastic leukemia (ALL). The Philadelphia chromosome refers to a new chromosome formed by the translocation of the long arm of chromosome 22 and chromosome 9. This translocation causes the proto-oncogene ABL on chromosome 9 to recombine with the BCR gene on chromosome 22, forming the BCR-ABL fusion gene and expressing it as a fusion oncoprotein [2] The ABL tyrosine kinase in the BCR-ABL fusion protein is continuously activated, activating a series of downstream signaling pathways, causing cancer cells to proliferate uncontrollably, leading to the onset of CML.

[0003] As the first tyrosine kinase inhibitor (TKI) and the first generation of ABL inhibitors, imatinib has significantly improved clinical efficacy and is used as a first-line treatment for CML patients. It has increased the ten-year survival rate of CML from less than 50% to about 90%. Although imatinib has become a model for targeted cancer therapy, its drug resistance problem has become increasingly prominent in clinical medication. Due to the continuous mutation of the BCR-ABL gene, the BCR-ABL kinase domain has changed, interfering with the binding of the drug to the target, making imatinib ineffective for about 40% of patients, or relapse during medication. Therefore, the second-generation (nilotinib, dasatinib and bosutinib) and third-generation (ponatinib) ABL inhibitors have emerged one after another, providing patients with a variety of options.

[0004] Dasatinib is an oral ABL kinase inhibitor that, unlike imatinib, binds to both active and inactive conformations of the ABL kinase domain and also inhibits a range of kinases that overlap with those inhibited by imatinib. Because it has less stringent binding requirements than imatinib, dasatinib is active against many imatinib-resistant kinase domain mutations of BCR-ABL. In cell line models, dasatinib inhibited 18 of 19 imatinib-resistant BCR-ABL mutations over a narrow concentration range, similar to the concentrations required to block wild-type BCR-ABL. The only exception is a single mutation deep in the ATP-binding pocket of the ABL tyrosine kinase (T315I mutation), which is highly resistant to imatinib and dasatinib, as well as the imatinib analog AMN-107, likely due to steric hindrance caused by the replacement of threonine with a larger isoleucine residue.

[0005] Although the second and third generation TKIs can supplement the shortcomings of imatinib in clinical application, the new TKIs cannot inhibit all drug-resistant mutants, especially the T315I mutation; in addition, adverse reactions such as vascular disease of ponatinib and pulmonary hypertension of dasatinib severely limit their application. Ponatinib was temporarily withdrawn from the market in 2013 due to its serious vascular adverse events, but was later re-approved for marketing as the only targeted drug for the BCR-ABL T315I mutant.

[0006] Based on the above problems, we look forward to the emergence of new treatments to address the problems of drug resistance, intolerance, and serious adverse reactions of existing drugs. PROTAC technology is gradually becoming a new favorite in the field of innovative drugs and has the potential to solve the challenges faced in current drug development. Unlike small molecule inhibitors that can only interfere with a single function of a protein, PROTAC induces protein degradation and interferes with all protein functions. In addition, PROTAC may provide opportunities for selective degradation of homologous proteins and avoid off-target effects. At the same time, PROTAC technology may also reduce some serious adverse reactions caused by traditional small molecule inhibitors and has the potential to solve drug resistance problems.

[0007] Ubiquitin is a small molecule protein that exists in eukaryotic cells and consists of 76 amino acids with a highly conserved sequence. The main function of ubiquitin is to mark target proteins, which can be recognized and degraded by proteasomes. This process is called the ubiquitin / proteasome system. Among them, E3 ubiquitin-protein ligase directly binds to proteins, determining the specificity of degradation. The degradation process of the ubiquitin / proteasome system mainly includes the following four steps: 1) Ubiquitin activation: the carboxyl residue of ubiquitin combines with the thiol group of the ubiquitin activating enzyme E1; 2) Ubiquitin cross-linking: E1 transfers the activated ubiquitin to the ubiquitin-binding enzyme E2 through the transesterification process; 3) E3 binds the ubiquitin complex to the target protein: the ubiquitin-protein ligase E3 connects the ubiquitin bound to E2 to the target protein. If ubiquitin already exists on the target protein, the ubiquitin bound to E2 can be directly connected to the target protein; 4) Proteasome degradation: the proteasome recognizes the marked target protein, thereby hydrolyzing the target protein into a peptide chain of 7-8 amino acids in length, completing the degradation of the target protein.

[0008] The proteolysis targeting chimeric molecule is a bifunctional molecule that can bind to E3 ubiquitin ligase and target protein at the same time, ubiquitinating the target protein that cannot bind to E3, and selectively degrading it through the ubiquitin / proteasome system, thereby controlling the target protein level in the cell. The current E3 ubiquitin ligases mainly include CRBN, VHL, MDM2 and cIAP1. Summary of the invention

[0009] The present invention provides a compound having a BCR-ABL protein degradation function and use thereof in preparing medicines for diseases related to BCR-ABL activity.

[0010] The technical solution of the present invention is as follows:

[0011] The present invention provides a compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0012] XYZ

[0013] Formula I

[0014] in,

[0015] X is a group that binds to the BCR-ABL protein;

[0016] Y is a linking group;

[0017] Z is a group that binds to E3 ubiquitin ligase.

[0018] According to some embodiments of the present invention, X is selected from

[0019] Wherein, the A ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R A1 replace;

[0020] Each R A1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0021] W2 is selected from -C0～6 Alkylene-, -C 0～6 Alkylene-O-, -OC 0～6 Alkylene-, -C 2～6 Alkenylene-, -C 2～6 Alkenylene-O-, -OC 2～6 Alkenylene-, -C 2～6 Alkynylidene-, -C 2～6 Alkynylidene-O- or -OC 2～6 Alkynylidene-;

[0022] Ring B is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R B1 replace;

[0023] Each R B1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0024] W1 is selected from -NHC(O)-, -C(O)NH-, -C 0～6 Alkylene-, -C 0～6 Alkylene-O-, -OC 0～6 Alkylene-, -C 2～6 Alkenylene-, -C 2～6 Alkenylene-O-, -OC 2～6 Alkenylene-, -C 2～6 Alkynylidene-, -C 2～6 Alkynylidene-O- or -OC 2～6 Alkynylidene-;

[0025] The C ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R C1 replace;

[0026] Each R C1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5- to 10-membered aromatic heterocycle).

[0027] According to some embodiments of the invention, ring A is selected from a 9-membered aromatic heterocycle.

[0028] Further: the A ring is selected from

[0029] According to some embodiments of the present invention, the B ring is selected from a benzene ring; wherein the benzene ring may be further separated by one, two or three R B1 Replace; each R B1 Selected from hydrogen, halogen, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0030] As a preference: the B ring is selected from

[0031] According to some embodiments of the present invention, the C ring is selected from a benzene ring; wherein the benzene ring may be further separated by one, two or three R C1 Replace; each R C1 Selected from hydrogen, halogen, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0032] As a preference: the C ring is selected from

[0033] As a preference: W2 is selected from -C 2～4 Alkynylene-; W1 is selected from -NHC(O)-, -C(O)NH-.

[0034] According to some embodiments of the present invention, the A ring is selected from Ring B is selected from The C ring is selected from W2 is selected from -C2 alkynylene-; W1 is selected from -NHC(O)-, -C(O)NH-.

[0035] Further: the X is selected from

[0036] According to some embodiments of the present invention, said Y is selected from -(L Y ) q -;

[0037] q is an integer from 1 to 30;

[0038] Each L Y are independently selected from C(R)2, C(O), O, S, S(O), S(O)2, NR, -CR=CR-, -C≡C-, 3-10-membered cycloalkane, 3-10-membered heterocycloalkane, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro ring, 5-12-membered spiro heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R YL replace;

[0039] Each R YL are independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR, -N(R)2;

[0040] Each R is independently selected from hydrogen, halogen, C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered carbocyclic group), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl).

[0041] According to some embodiments of the present invention, Y is selected from Wherein, n is selected from an integer of 0 to 10; preferably, n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0042] According to some embodiments of the present invention, Y is selected from

[0043] In some embodiments of the invention, the E3 ubiquitin ligase is selected from the group consisting of CRBN, von Hippel-Lindau (VHL), XIAP, MDM2, cIAP-1.

[0044] According to some embodiments of the present invention, Z is selected from

[0045] In some specific embodiments of the present invention, the compound described in formula I is specifically:

[0046]

[0047] The present invention also provides a pharmaceutical composition comprising a preparation prepared from any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0048] The above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0049] The present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing and / or treating diseases associated with BCR-ABL activity.

[0050] The present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions in the preparation of drugs for preventing and / or treating cancer.

[0051] The present invention also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in preventing and / or treating diseases associated with BCR-ABL activity.

[0052] The present invention also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in preventing and / or treating cancer.

[0053] A method for preventing and / or treating a disease associated with BCR-ABL activity, comprising administering an effective amount of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions to a subject in need thereof.

[0054] A method for preventing and / or treating cancer, comprising administering an effective amount of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions to a subject in need thereof.

[0055] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0056] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0057] "Substitution" means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0058] “Can be further substituted” means that “substitution” can but does not have to occur, and the description includes situations where it occurs or does not occur.

[0059] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0060] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups may also be part of other groups, such as -O(C 1～6 alkyl).

[0061] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a ~ b Alkylene refers to an alkylene group having from a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0062] The C0-4 alkylene group of the present invention can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-, etc.), a C3 alkylene group or a C4 alkylene group; the C0 alkylene group means that the group here does not exist and is connected in the form of a chemical bond, such as A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0063] "Carbocyclyl" described in the present invention refers to a partially saturated cyclic group with multiple carbon atoms and no ring heteroatoms having a single ring or multiple rings (fused, bridged, spiro) saturated or non-aromatic. The term "carbocyclyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of monocarbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups of condensed carbocyclyl systems include dicyclohexyl, dicyclopentyl, dicyclooctyl, etc., and two such dicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Examples of carbocyclyl groups of the bridged carbocyclyl system include adamantyl, etc. Examples of the carbocyclyl group of the spirocarbocyclyl system include The term "carbocyclic group" also includes the case where an aromatic ring is fused with a non-aromatic ring to form a partially saturated cyclic group, and the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0064] The "cycloalkane" described in the present invention refers to a partially saturated divalent cyclic alkane having multiple carbon atoms and no ring heteroatoms, having a single ring or multiple rings (fused), saturated or non-aromatic. The term "cycloalkane" includes cycloolefins, such as cyclohexene. Examples of monocarbocyclic groups include, for example, cyclopropane, cyclobutane, cyclohexane, cyclopentane, cyclooctane, cyclopentene and cyclohexene. Examples of fused cycloalkane systems include dicyclohexane, dicyclopentane, dicyclooctane, etc. The "cycloalkane" described in the present invention includes but is not limited to wait.

[0065] The "heterocycloalkane" described in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring having a single ring or multiple rings (fused) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of heterocycloalkane of a monoheterocycloalkane system are oxetane, azetidine, pyrrolidine, 2-oxo-pyrrolidine, tetrahydrofuran, tetrahydro-thiophene, pyrazolidine, imidazolidine, thiazolidine, piperidine, tetrahydropyran, tetrahydrothiopyran, piperazine, morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, azepane, diazepane, etc. Examples of fused heterocycloalkane systems include 8-aza-bicyclo[3.2.1]octane, quinuclidine, 8-oxa-3-aza-bicyclo[3.2.1]octane, 9-aza-bicyclo[3.3.1]nonane, etc. The term "heterocycloalkane" also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated ring, and the connection point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. The "heterocycloalkane" described in the present invention includes but is not limited to wait.

[0066] The term "spiro ring" as used herein refers to a saturated or non-aromatic partially saturated divalent ring formed by two or more rings having multiple carbon atoms and no ring heteroatoms. Examples of spiro ring systems include wait.

[0067] The "spiro heterocycle" described in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by two or more rings containing at least one heteroatom. Examples of spiro heterocyclic systems include wait.

[0068] The "bridged ring" described in the present invention is a saturated or non-aromatic partially saturated divalent ring formed by bridging multiple rings having multiple carbon atoms and no ring heteroatoms. Examples of bridged ring systems include wait.

[0069] The "bridged heterocycle" in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by bridging multiple rings containing at least one heteroatom; examples of bridged heterocyclic ring systems include wait.

[0070] The unsaturated mentioned in the present invention refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the groups or molecules.

[0071] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon group having at least one vinyl unsaturated site (>C=C<). a-b Alkenyl refers to an alkenyl group having from a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0072] The "alkenylene" mentioned in the present invention refers to a straight or branched divalent carbon chain having at least one carbon-carbon double bond. a-b Alkenylene refers to an alkenylene group having a to b carbon atoms.

[0073] The term "alkynyl" as used herein refers to a linear monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0074] The "alkynylene group" described in the present invention refers to a straight-chain divalent hydrocarbon group or a branched divalent hydrocarbon group containing at least one triple bond. a-b Alkyne refers to an alkynylene group having a to b carbon atoms.

[0075] The "heterocycloalkyl" described in the present invention refers to a saturated ring or a non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heterocycloalkyl groups of monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, etc. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems include etc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system include Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl, etc. The term "heterocycloalkyl" also includes a partially saturated cyclic group formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, and the attachment point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples include

[0076] The "aromatic ring" described in the present invention refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is generally a monocyclic, bicyclic or tricyclic aromatic group having multiple carbon atoms. In addition, the term "aryl" used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

[0077] The "aromatic heterocycle" described in the present invention refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, and S heteroatoms. Preferably there are one to three heteroatoms. Heterocyclic aromatic groups, for example, represent: pyridyl, indolyl, quinoxalyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

[0078] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0079] The term "halogen-substituted alkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are substituted by halogen. 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which the hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluoromethyl, difluoromethyl and trifluoromethyl.

[0080] The term "halogen-substituted alkenyl" as used herein means that one or more hydrogen atoms in the alkenyl group are substituted by halogen. 2-6 The alkenyl group refers to an alkenyl group containing 2 to 6 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluorovinyl, bisfluorovinyl and trifluoropropenyl.

[0081] The term "halogen-substituted alkynyl" as used herein means that one or more hydrogen atoms in the alkynyl group are substituted by halogen. 2-6 The alkynyl group refers to an alkynyl group containing 2 to 6 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluoroethynyl, bisfluoroethynyl and trifluoropropynyl.

[0082] The "-OR", "-N(R)2" and the like described in the present invention refer to that the R group is connected to the oxygen atom or the nitrogen atom by a single bond.

[0083] The "=O" mentioned in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0084] In the "-C(O)R", "-S(O)2R" and the like described in the present invention, the oxygen atom is connected to the carbon atom or the sulfur atom by a double bond, and the R group is connected to the oxygen atom or the sulfur atom by a single bond. For another example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0085] The group description of the present invention It is used to describe the position of group substitution.

[0086] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0087] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0088] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compounds. They can also be obtained by mixing the above compounds, or their stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0089] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0090] The terms "treat," ...

[0091] In certain embodiments, one or more compounds of the present invention may be used in combination with each other. It is also possible to select the compounds of the present invention and any other active agent for use in combination to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately or sequentially.

[0092] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0093] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0094] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0095] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0096] The reagents described in the examples are abbreviated as follows: DIPEA: N,N-diisopropylethylamine; DCM: dichloromethane; EDCI: 1-ethyl-3-(3-dimethylammoniumpropyl)carbonammonium; HOBT: 1-hydroxybenzotriazole; DMF: N,N-dimethylformamide; TFA: trifluoroacetic acid.

[0097] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0098] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shift (δ) is given in units of 10-6 (ppm). NMR was measured using a (Bruker AvanceIII 400 and Bruker Avance 600) nuclear magnetic spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS was measured using a Shimadzu LC-MS2020 (ESI)). HPLC was measured using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

[0099] Example 1. Preparation of Compound A1

[0100]

[0101] Step 1. Synthesis of compound 3

[0102]

[0103] Compound 1 (51.80 mg, 99.90 μmol), compound 2 (23.79 mg, 99.90 μmol), NaHCO3 (41.96 mg, 499.49 μmol), water (0.5 mL) and acetonitrile (15 mL) were added to a 50 mL reaction bottle, heated to 80 ° C and stirred vigorously for 10 hours, and water was added to quench the reaction after the reaction was complete (LC-MS monitoring). The crude product was extracted with saturated saline solution (50 mL) and ethyl acetate (3X 50 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was evaporated, and the solvent was removed by concentration under reduced pressure to obtain compound 3 as a yellow solid (crude product).

[0104] Step 2: Preparation of Compound 4

[0105]

[0106] Compound 3 (crude product) and HCl (5 mL) were added to a 50 mL reaction bottle and stirred at room temperature for 1 hour. After the reaction was complete (LC-MS monitoring), the solvent was removed by concentration under reduced pressure, and then purified by MPLC and concentrated under reduced pressure to obtain compound 4 (40.00 mg, 69.49 μmol, 78.26% yield) as a white solid.

[0107] Step 3: Preparation of Compound A1

[0108]

[0109] Compound 5 (22.74 mg, 69.49 μmol), N,N-dimethylformamide (2 mL), DIPEA (4.91 mg, 347.45 μmol, 60.52 μL), EDCI (19.91 mg, 104.23 μmol) and HOBT (14.08 mg, 104.23 μmol) were added to a 50 mL reaction bottle in sequence. After stirring for 20 minutes under ice bath, compound 4 (40.00 mg, 69.49 μmol) was added to the reaction system and stirred at room temperature for 1 hour. After the reaction was complete (LC-MS monitoring), it was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound A1 (16.20 mg, 18.23 μmol, 26.24% yield, purity 99.6%) as a white solid. LC-MS: C 47 H 43 F3N 10 O5, [M+H] + 885.3; found 885.4. 1H NMR(600MHz, Methanol-d4)δ8.68(dd,J=4.5,1.5Hz,1H),8.18(d,J=2.1Hz,1H),8.17-8.11(m,3H),8.01(dd,J=8.4,2.4Hz ,1H),7.91(dd,J=8.1,2.1Hz,1H),7.77(d,J=8.4Hz,1H),7.72(d,J=8.1Hz,1H),7.56-7.53(m,1H),7.50(d,J=8.1Hz,1H), 7.43(dd,J=9.0,4.4Hz,1H),7.33(ddd,J=8.1,6.9,1.2Hz,1H),7.28(ddd,J=8.0,6.9,1.2Hz,1H),4.58(s,1H),4.25(d,J= 9.9Hz,2H),4.16(s,1H),3.80(s,2H),3.81-3.38(m,5H),3.33(s,1H),3.24-2.74(m,6H),2.66-2.52(m,5H),2.12(s,2H).

[0110] Referring to the synthesis method of compound A1, the raw materials in the following table 1 are used to replace compound 2, and other raw materials and operation methods remain unchanged to obtain compounds A2-A3

[0111] Table 1. Compounds A2-A3

[0112]

[0113] Example 2, Preparation of Compound B1

[0114] Step 1. Synthesis of compound 9

[0115]

[0116] Compound 1 (370.00 mg, 713.55 μmol), compound 8 (202.93 mg, 713.55 μmol), DIPEA (461.11 mg, 3.57 mmol, 621.44 μL), and DCM (10 mL) were added to a 50 mL reaction bottle. NaBH(OAc)3 (302.55 mg, 1.43 mmol) was then added to the reaction system and stirred at room temperature for 2 hours. After the reaction was complete (LC-MS monitoring), water was added to quench the reaction. The crude product was extracted with water (50 mL) and DCM (3X 50 mL), the organic phases were combined, the organic phases were backwashed with saturated NaCl solution, and then dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain a crude product. After MPLC purification and concentration under reduced pressure to remove the solvent, compound 9 (230.00 mg, 292.28 μmol, 40.96% yield) was obtained as a white solid.

[0117] Step 2: Synthesis of Compound 10

[0118]

[0119] Compound 9 (230.00 mg, 292.28 μmol), DCM (20 mL) and TFA (5 mL) were added to a 100 mL reaction bottle in sequence and stirred at room temperature for 1 hour. After the reaction was complete (LC-MS monitoring), it was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 10 (80.00 mg, 262.08 μmol, 89.67% yield) as a white solid.

[0120] Step 3. Synthesis of Compound B1

[0121]

[0122] Compound 11 (42.89 mg, 131.04 μmol), N,N-dimethylformamide (3 mL), DIPEA (56.45 mg, 436.80 μmol, 76.08 μL), EDCI (25.03 mg, 131.04 μmol) and HOBT (14.17 mg, 104.83 μmol) were added to a 50 mL reaction bottle in sequence. After stirring for 20 minutes under ice bath, compound 10 (60.00 mg, 87.36 μmol) was added to the reaction system and stirred at room temperature for 1 hour. After the reaction was complete (LC-MS monitoring), it was purified by MPLC to obtain compound B1 (3.30 mg, 3.31 μmol, 3.79% yield, purity 98.8%) as a white solid. LC-MS: C 54 H 56 F3N 11 O5, [M+H] +996.4; found996.3. 1 H NMR (400MHz, Methanol-d4) δ8.70 (d, J = 4.4Hz, 1H), 8.18-8.16 (m, 4H), 8.01 (dd, J = 8. 4,2.2Hz,1H),7.91(dd,J=8.0,2.0Hz,1H),7.84-7.65(m,2H),7.54-7.44(m,3H),7.33 -7.23(m,2H),4.38(s,2H),4.24(d,J=9.6Hz,2H),3.79(s,2H),3.77-3.33(m,7H),3.3 1-3.06(m,9H),3.03(s,2H),2.91-2.46(m,7H),1.88-1.71(m,4H),1.55-1.37(m,4H).

[0123] By referring to the synthesis method of compound B1, compound 12 is used to replace compound 8, and other raw materials and operation methods remain unchanged, compound B2 can be obtained.

[0124] Table 2. Compound B2

[0125]

[0126] The following test examples illustrate the technical effects of the compounds of the present invention.

[0127] Experimental Example 1: Evaluation of PROTAC degradation of BCR-ABL T315I protein in Ba / F3 BCR-ABL T315I cells by Western blot

[0128] 1. Experimental instruments and reagents:

[0129] SDS-PAGE gel (4-12%) (Genscript), PMSF 100mM (Biyotime), Cocktail 100× (Biyotime), P / S (Hyclone), FBS (Corning), 4× loading buffer (Thermo), c-ABL Antibody (CST), Tween-20, Anti-rabbit IgG-HRP (CST), Anti-β-actin (Abcam), RIPA (Biyotime), skim milk powder (Sangong Biotechnology), BCA Protein Assay Kit (TIANGEN), 6-well plate (Costar), PVDF membrane equilibration liquid (Genscript), MOPS Running Buffer liquid (20x) (Genscript), gel imager (ThermoFisher), -PSQPVDF membrane (Millipore), 1.5 mL centrifuge tube (AXYGEN), CriterionTM Blotter transfer tank (BIO-RAD), Roswell Park Memorial Institute (RPMI) 1640 (Gibco), Immobilon Western Chemiluminescent HRP Substrate (Millipore).

[0130] 2. Experimental methods:

[0131] 1) Compound incubation with cells: 1 mL of 2×10 6 Ba / F3 BCR-ABL T315I cells (medium 89% 1640, 10%

[0132] FBS, 1% P / S) were seeded in a 6-well cell culture plate. The compound was diluted with DMSO to eight concentration points, and then the compound diluted in DMSO was diluted again into the cell culture medium, and 1 mL of the diluted compound was directly added to the 6-well cell culture plate and incubated for 30 h.

[0133] 2) Sample collection: After the compound and cells were incubated for 30 hours, the cells were collected in a 1.5 mL centrifuge tube, washed twice with ice PBS, and 70 μL RIPA lysis buffer was added to the supernatant and lysed on ice for 60 minutes; the cell lysate was then centrifuged in a low-temperature centrifuge for 10 minutes at 15,000 rpm, and the supernatant was collected; the protein in the obtained cell lysate supernatant was quantified using the BCA Protein Assay Kit. 4× loading buffer was added to the cell lysate supernatant and incubated at 95°C for 10 minutes to obtain the sample. The obtained sample was stored in a -80°C refrigerator.

[0134] 3) Western blot: Take 20 μg of sample for SDS-PAGE running and transfer. Use 5% skim milk to block the membrane at room temperature for 1 hour, then incubate with c-ABL and Anti-β-actin antibodies at 4°C overnight, wash three times with TBST and then incubate with Anti-

[0135] Rabbit IgG-HRP secondary antibody was incubated at room temperature for 1 hour, and then washed three times with TBST. Immobilon Western Chemiluminescent HRP Substrate was used for color development and analyzed using a gel imaging instrument.

[0136] 3. Data Analysis:

[0137] Grayscale analysis software was used for analysis. After correcting the amount of BCR-ABL T315I protein by the amount of β-actin, the degradation of BCR-ABL T315I protein was analyzed.

[0138] The above experimental results of the compounds of the present invention are shown in Table 1.

[0139] Table 1. Effects of compounds on BCR-ABL T315I protein degradation

[0140] serial number <![CDATA[DC 50 ]]> A1 +++ A2 +++ A3 +++ B1 ++ B2 ++++

[0141] Among them, ++ represents 100μM>DC 50 >10μM, +++ represents 10μM>DC 50 >1μM, ++++ represents DC 50 <1 μM.

[0142] The above experiments show that the compounds of the present invention can effectively degrade BCR-ABL protein, providing a new medicinal possibility for the development of new BCR-ABL protein degradation drugs.

Claims

1. A compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: in, X is a group that binds to the BCR-ABL protein; Y is a linking group; Z is a group that binds to E3 ubiquitin ligase.

2. The compound according to claim 1, characterized in that: The X is selected from Wherein, the A ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R A1 replace; Each R A1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); W2 is selected from -C 0～6 Alkylene-, -C 0～6 Alkylene-O-, -OC 0～6 Alkylene-, -C 2～6 Alkenylene-, -C 2～6 Alkenylene-O-, -OC 2～6 Alkenylene-, -C 2～6 Alkynylidene-, -C 2～6 Alkynylidene-O- or -OC 2～6 Alkynylidene-; Ring B is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R B1 replace; Each R B1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); W1 is selected from -NHC(O)-, -C(O)NH-, -C 0～6 Alkylene-, -C 0～6 Alkylene-O-, -OC 0～6 Alkylene-, -C 2～6 Alkenylene-, -C 2～6 Alkenylene-O-, -OC 2～6 Alkenylene-, -C 2～6 Alkynylidene-, -C 2～6 Alkynylidene-O- or -OC 2～6 Alkynylidene-; The C ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R C1 replace; Each R C1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5- to 10-membered aromatic heterocycle).

3. The compound according to claim 2, characterized in that: The A ring is selected from a 9-membered aromatic heterocycle.

4. The compound according to claim 3, characterized in that: The A ring is selected from 5. The compound according to claim 2, characterized in that: The B ring is selected from a benzene ring; wherein the benzene ring can be further replaced by one, two or three R B1 replace; Each R B1 Selected from hydrogen, halogen, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

6. The compound according to claim 5, characterized in that: The B ring is selected from 7. The compound according to claim 2, characterized in that: The C ring is selected from a benzene ring; wherein the benzene ring can be further replaced by one, two or three R C1 replace; Each R C1 Selected from hydrogen, halogen, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

8. The compound according to claim 7, characterized in that: The C ring is selected from 9. The compound according to claim 2, characterized in that: W2 is selected from -C 2～4 Alkynylene-; W1 is selected from -NHC(O)-, -C(O)NH-.

10. The compound according to claim 2, characterized in that: Ring A is selected from Ring B is selected from The C ring is selected from W2 is selected from -C2 alkynylene-; W1 is selected from -NHC(O)-, -C(O)NH-.

11. The compound according to any one of claims 1 to 2, characterized in that: The X is selected from 12. The compound according to claim 1, characterized in that: The Y is selected from -(L Y ) q -; q is an integer from 1 to 30; Each L Y are independently selected from C(R)2, C(O), O, S, S(O), S(O)2, NR, -CR=CR-, -C≡C-, 3-10-membered cycloalkane, 3-10-membered heterocycloalkane, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro ring, 5-12-membered spiro heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R YL replace; Each R YL are independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR, -N(R)2; Each R is independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered carbocyclic group), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl).

13. The compound according to claim 12, characterized in that: The Y is selected from Wherein, n is selected from an integer of 0 to 10; preferably, n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

14. The compound according to claim 13, characterized in that: The Y is selected from 15. The compound according to claim 1, characterized in that: The E3 ubiquitin ligase is selected from CRBN, vonHippel-Lindau (VHL), XIAP, MDM2, and cIAP-1.

16. The compound according to claim 15, characterized in that: The Z is selected from 17. The compound according to any one of claims 1 to 16, characterized in that: The compound is specifically:

18. A pharmaceutical composition comprising a preparation prepared from the compound according to any one of claims 1 to 17, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 18, characterized in that: It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

20. Use of the compound according to any one of claims 1 to 17, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 18 to 19 in the preparation of a medicament for preventing and / or treating a disease associated with BCR-ABL activity.

21. Use of the compound according to any one of claims 1 to 17, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 18 to 19 in the preparation of a medicament for preventing and / or treating cancer.

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