CN111217815B - Compound containing pteridinone skeleton and preparation method and application thereof - Google Patents
Compound containing pteridinone skeleton and preparation method and application thereof Download PDFInfo
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- CN111217815B CN111217815B CN201811425468.XA CN201811425468A CN111217815B CN 111217815 B CN111217815 B CN 111217815B CN 201811425468 A CN201811425468 A CN 201811425468A CN 111217815 B CN111217815 B CN 111217815B
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- amino
- cyclopentyl
- phenyl
- pteridine
- ketones
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
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- 238000002372 labelling Methods 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
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- 230000036961 partial effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 101150073897 plk1 gene Proteins 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to pteridinone skeleton compounds shown as a general formula I, a preparation method thereof and a pharmaceutical composition taking the compounds shown as the general formula I as active ingredients, wherein a substituent R1、R2、R3、R4、A1、A2、A3Have the meanings given in the description. The invention also relates to the use of the compounds of the general formula I and the optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof and the pharmaceutical compositions thereof in the preparation of medicaments for the treatment and/or prevention of cancer and other proliferative diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a compound containing a pteridinone skeleton, a preparation method and application thereof, in particular to a compound containing the pteridinone skeleton, a geometric isomer thereof, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to application of the compounds in preparing and/or preventing medicaments for cancers and other proliferative diseases.
Background
Cancer (cancer), a malignant tumor, is a fatal disease that seriously harms human health. Around the world, there are 1400 new cancer cases and 820 ten thousand cancer deaths worldwide. 180 ten thousand cases of lung cancer and 159 ten thousand deaths are seen. Thus, malignancies have become second-class killers in humans after cardiovascular disease.
Polo-like kinases (PLKs) are a class of serine/threonine protein kinases with highly conserved structures and functions, and play a crucial role in the mitotic stage of cells. PLKs family contains 5 subtypes in human body, including PLK1, PLK2(SNK), PLK3(FNK or PRK), PLK4(SAK) and PLK5, which play important roles in regulating and controlling cell cycle at each stage. The PLKs structure contains two conserved regions: highly conserved N-and C-terminal components, wherein the N-terminal has a highly homologous serine/threonine kinase domain and the C-terminal has a characteristic domain (PBD) that regulates PLKs activity and subcellular dynamic localization. The subtypes PLK1, PLK2 and PLK3 are expressed in all tissues of human body, however, the distribution of PLK4m RNA in adults is limited to tissues such as testis and thymus, and has unique physiological action. The PLK1 gene was reported in 1994 to be located at 16p12, the mRNA was about 2.3kb long, and the encoded protein mass was about 6.6X 104, which is the most well studied PLK family member.
The human PLK1 kinase structure comprises two regions: a highly conserved N-terminal region consisting of 252 amino acids; the C-terminus consists of 2 polo box structures, called PBD regions (polo box domains), each of which is a special region consisting of 1. beta.6-. alpha.sequence. Although the overall crystal structure of PLK1 has not been reported, the crystal structures of both the N-terminal kinase domain and the C-terminal PBD domain have been successfully determined.
Currently, many compounds targeting PLK1 have entered clinical research phase, such as: BI6727, BI2536, Rigoserinib (ON-01910), GSK461364, MLN0905, TAK-960, and the like. BI6727 reported in literature was developed by Boehringer Ingelheim, belongs to pteridinone compounds, is a selective Paul-like kinase 1 (PLKs) inhibitor virtually screened from compounds, and inhibits IC of PLK1 in vitro50It was 0.87 nM. It can be seen that inhibition of PLK1 activity, both in vitro and in vivo, has an anti-tumor effect. Research on the small-molecule inhibitor taking PLK1 as a target opens up a new direction for research and development of antitumor drugs, and has good development prospect. Many research institutes and commercial pharmaceutical companies have therefore initiated corresponding development programs.
The inventor designs and synthesizes [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -ketone, 1-methyl- [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -ketone and tetrazolo [4,3-f ] pteridine-4 (5H) -ketone trite pteridinone derivatives on the basis of a reference document, and carries out antitumor activity screening on various tumor cell strains in vitro, and the result shows that the derivatives have antitumor activity.
Disclosure of Invention
The invention relates to pteridinone compounds shown in a general formula (I) and geometrical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
A1is N or CR1，A2Is N or CR1a，A3Is N, C or CR1b，
Wherein R is1，R1a,R1bIndependently selected from hydrogen, halogen, (C), if present1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkoxy group;
R2is (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
R3is (C)1-C6) Alkyl, a 3-12 membered saturated or partially unsaturated carbocyclic ring, or a 4-7 membered heterocyclic ring containing N, O and/or S; or NHnR4R5、NHnCOR4R5、NHnCONHnR4R5、SO2(CH2)nNR4R5、SO2(CH2)nCONR4R5(ii) a They may be substituted by 0 to 3 identical or different R6Substitution;
n is an integer of 0 to 2;
R4and R5The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C4) Alkoxy group, (C)2-C10) Alkenyl, (C)2-C10) An alkynyl group;
or R4And R5Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, other than R4And R5Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, other than R4And R5Said heterocyclyl optionally including 0-2 carbon-carbon double or carbon-carbon triple bonds in addition to the attached nitrogen atom, said heterocyclyl or heteroaryl optionally being substituted with 0-3R, which may be the same or different6Substitution;
R6is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C6) Alkoxy, hydroxy, halogen, halo (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy and nitro.
The invention preferably relates to pteridinones of the general formula (I) and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
A1is N, A2Is N, A3Is N, C or CR1b，
R1bIndependently selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkoxy group;
R2is (C)3-C8) A cycloalkyl group;
R3is (C)1-C6) Alkyl, a 3-6 membered saturated or partially unsaturated carbocyclic ring, or a 4-7 membered heterocyclic ring containing N, O and/or S; or NHnR4R5、NHnCOR4R5、NHnCONHnR4R5、SO2(CH2)nNR4R5、SO2(CH2)nCONR4R5(ii) a They may be substituted by 0 to 3 identical or different R6Substitution;
n is an integer of 0 to 2;
R4and R5The same or different, are respectively and independently selected from hydrogen and (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C4) Alkoxy group, (C)2-C6) Alkenyl, (C)2-C6) An alkynyl group;
or R4、R5Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl group, other than R4And R5Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclyl or heteroaryl group optionally being substituted with 0 to 3R, which may be the same or different6Substitution;
R6is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C6) Alkoxy, hydroxy, halogen, halo (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy and nitro.
The invention preferably relates to pteridinones of the general formula (I) and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
A1is N, A2Is N, A3Is N, C or CR1b，
R1bIndependently selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkoxy group;
R2is (C)3-C6) A cycloalkyl group;
R3is R3Is composed of
The present invention preferably relates to pteridinones of the general formula (I) and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, preferably the following compounds, which are not intended to limit the invention in any way:
5-cyclopentyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (piperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (cyclopentylamino) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((2-methoxy-4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((2-methoxy-4- (piperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((2-methoxy-4- (morpholin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (piperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-1-methyl-7- ((4- (cyclopentylamino) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (piperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (cyclopentylamino) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
5-cyclopentyl-7- ((4- (4- (4-methylpiperazin-1-yl) -piperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one.
Furthermore, the pteridinone skeleton-containing compounds of the formula I according to the invention may be combined with an acid to form a pharmaceutically acceptable salt according to methods customary in the art to which the invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to phenyl with no substituents or with substituents; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring systems containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The pteridinone skeleton-containing compound of the formula I, pharmaceutically acceptable salts and solvates thereof are used as active ingredients, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the pteridinone skeleton-containing compounds of the invention of the formula I above for administration to a patient can be determined according to: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10-500mg, preferably 50-300 mg. Thus, when the pharmaceutical composition according to the invention is formulated in unit dosage form, the pteridinone skeleton-containing compound of the above formula I should be present in an amount of 10 to 500mg, preferably 50 to 300mg, per unit formulation, taking into account the effective dose mentioned above. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binders, lubricants, disintegrants, solubilizing agents, diluents, stabilizers, suspending agents, flavoring agents, preservatives, solubilizers, bases and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
Through in vitro inhibition activity tests of human prostate cancer cell PC-3, human breast cancer cell MCF-7, human breast cancer cell MDA-MB-231, human colon cancer cell HCT116 and human lung adenocarcinoma cell A549, the compounds have remarkable antitumor activity, so that the compounds can be used for preparing medicaments for treating and/or preventing various cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophageal cancer, leukemia, neuroblastoma and the like. In particular to the preparation of the medicine for treating and/or preventing lung cancer and liver cancer.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca base medicament novinova, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
Route one:
and a second route:
and a third route:
and a fourth route:
the specific implementation mode is as follows:
the following examples are intended to illustrate, but not limit, the scope of the invention. NMR of the compounds was measured using Bruker ARX-400 or-600, and Mass Spectroscopy was measured using Agilent 1100LC/M (S) D; all reagents used were analytically or chemically pure.
Example 15-cyclopentyl-7- ((4- (4-morpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
1.12-chloro-4-cyclopentylamino-5-nitropyrimidine (2)
50g (259mmol) of 2, 4-dichloro-5-nitropyrimidine and 43.5g (518mmol) of NaHCO are introduced3Then, 200mL of DCM was added to the three-necked flask, and a solution of 26.4g (311mmol) of cyclopentylamine in DCM was added dropwise to the above reaction solution, followed by reaction at room temperature for 10 hours. After the reaction, the reaction mixture was poured into 200mL of water, the organic layer was separated, the aqueous layer was extracted twice with 100mL of DCM, and the organic layers were combined withoutDrying with sodium sulfate, evaporating solvent, adding diethyl ether into the residue, precipitating to obtain light yellow solid, vacuum filtering, and drying to obtain light yellow solid 53.27g with yield of 85.0%, MS (ESI) M/z 243.3[ M + H ]]+。
1.22 Synthesis of chloro-4-cyclopentylamino-5-aminopyrimidine (3)
Iron powder (57.8g,1033mmol) was added to 95% ethanol (200mL) with stirring at room temperature, and the reaction was activated for 30min by warming to 70 ℃. 2-chloro-4-cyclopentylamino-5-nitropyrimidine 2(50g,207mmol) is added to the reaction solution, and the temperature is raised to 80 ℃ for reaction for 2h. After the reaction, the diatomite is filtered while it is hot, the solvent is distilled off, 32.0g of white solid is obtained after column chromatography purification, the yield is 73 percent, and MS (ESI) M/z is 213.2[ M + H ]]+。
Synthesis of 32-chloro-8-cyclopentyl-5, 8-dihydropteridine-6, 7-dione (4)
2-chloro-4-cyclopentylamino-5-aminopyrimidine 3(30g,124mmol), K at room temperature2CO3(34.2g,248mmol) was dissolved in 150mL of acetone, and oxalyl chloride monoethyl ester (28.9g,136.4mmol) was slowly added dropwise to the reaction solution, followed by reaction at room temperature for 2 hours. Suction filtration, filtrate concentration, residue, 200mL EtOH, TEA (15.1g,148.8mmol) into 500mL pressure bottle, heating to 120 deg.C and stirring for 4H, after reaction, cooling reaction liquid to room temperature, suction filtration, drying to obtain white solid 27.4g, yield 83%, MS (ESI) M/z:264.9[ M-H ]]-。
Synthesis of 42, 6-dichloro-8-cyclopentylpteridin-7 (8H) -one (5)
2-chloro-8-cyclopentyl-5, 8-dihydropteridine-6, 7-dione 4(25g,94mmol) was dissolved in 80mL SOCl2Heating to 80 deg.C, reacting for 3H, concentrating the reaction solution, adding the residue into ice water, vacuum filtering, and drying to obtain white solid 24.3g with yield of 91%, MS (ESI) M/z 285.26[ M + H ])]+。
Synthesis of 1.52-chloro-8-cyclopentyl-6-hydrazinopteridin-7 (8H) -one (6)
Dissolving 2, 6-dichloro-8-cyclopentyl pteridine-7 (8H) -ketone 5(18g,63.4mmol) and 80% hydrazine hydrate (9.5g,190mmol) in 200mL EtOH, heating to 40 ℃ to react for 2H, cooling the reaction liquid to room temperature, performing suction filtration, and drying to obtain white solid 15.6g, wherein the yield is 88%, and MS (ESI)m/z:279.0[M-H]-。
1.67-chloro-5-cyclopentyl- [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -one (7)
2-chloro-8-cyclopentyl-6-hydrazinopteridin-7 (8H) -one 6(6g,21.4mmol) was added to 20mL triethyl orthoformate and stirred at 80 ℃ for 2H. After the reaction, the reaction solution was cooled to room temperature, filtered and dried to obtain 5.3g of a white solid with a yield of 86%, MS (ESI) M/z 313.1[ M + Na ]]+。
1.74 Synthesis of (4-nitrophenyl) morpholine (11)
P-fluoronitrobenzene, morpholine and K2CO3Adding into DMF, heating to 80 deg.C, and stirring for 2h. After the reaction is finished, cooling the reaction liquid to room temperature, adding the reaction liquid into ice water, performing suction filtration, and drying to obtain a yellow solid.
Synthesis of 1.84-morpholinylaniline (12)
4- (4-nitrophenyl) morpholine and palladium on carbon (Pd/C) were added to 50mL of ethanol, hydrogen was introduced, the mixture was evacuated, and the reaction was carried out at room temperature for 6 hours. The filter cake was washed with suction, ethanol (30 mL. times.3), the filter cake was discarded, and the filtrate was retained. The filtrate solvent was removed.
1.95-cyclopentyl-7- ((4- (4-morpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
Adding 7-chloro-5-cyclopentyl- [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -ketone 7(1equiv), 12(1.1equiv), p-toluenesulfonic acid (1equiv) and isopropanol into a 50mL pressure-resistant bottle, and heating to 100 ℃ for reaction for 12H. After the reaction, the reaction solution is cooled to room temperature, a saturated sodium carbonate solution is added, dichloromethane of 3X 30mL is used for extraction, organic phases are combined, drying is carried out, an organic solvent is removed by evaporation, and light yellow powder is obtained after column chromatography purification.
The compounds of examples 1-13 were prepared according to the procedure for example 1 starting from intermediate 7 and various substituted anilines (see Table 1).
TABLE 1
Example 25-cyclopentyl-1-methyl-7- ((4- (4-morpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
Synthesis of 2.17-chloro-5-cyclopentyl-1-methyl- [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one (9)
Intermediate 9 was prepared by the method of example 1 starting from intermediate 6 and triethyl orthoacetate.
Synthesis of 25-cyclopentyl-1-methyl-7- ((4- (4-morpholinyl) phenyl) amino) - [1,2,4] triazolo [4,3-f ] pteridin-4 (5H) -one
Adding 7-chloro-5-cyclopentyl-1-methyl- [1,2,4] triazolo [4,3-f ] pteridine-4 (5H) -ketone 7(1equiv), 12(1.1equiv), p-toluenesulfonic acid (1equiv) and isopropanol into a 50mL pressure-resistant bottle, and heating to 100 ℃ for reaction for 12H. After the reaction, the reaction solution is cooled to room temperature, a saturated sodium carbonate solution is added, dichloromethane of 3X 30mL is used for extraction, organic phases are combined, drying is carried out, an organic solvent is removed by evaporation, and light yellow powder is obtained after column chromatography purification.
The compounds of examples 14-23 were prepared by the procedure of example 2 starting from intermediate 9 and reacting with various substituted anilines (see Table 2).
TABLE 2
Example 35-cyclopentyl-7- ((4- (4-morpholinyl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
Synthesis (8) of 2.17-chloro-5-cyclopentyl-tetrazolo [4,3-f ] pteridine-4 (5H) -one
Intermediate 8 was prepared by reacting intermediate 5 with sodium azide as the starting material in accordance with the procedure of example 1.
2.25 Synthesis of cyclopentyl-7- ((4- (4-morpholinyl) phenyl) amino) -tetrazolo [4,3-f ] pteridin-4 (5H) -one
Adding 7-chloro-5-cyclopentyl-tetrazolo [4,3-f ] pteridine-4 (5H) -ketone 8(1equiv), 12(1.1equiv), p-toluenesulfonic acid (1equiv) and isopropanol into a 50mL pressure-resistant bottle, and heating to 100 ℃ for reaction for 12H. After the reaction, the reaction solution is cooled to room temperature, a saturated sodium carbonate solution is added, dichloromethane of 3X 30mL is used for extraction, organic phases are combined, drying is carried out, an organic solvent is removed by evaporation, and light yellow powder is obtained after column chromatography purification.
The compounds of examples 24-34 were prepared according to the procedure for example 3 starting from intermediate 8 and various substituted anilines (see Table 3).
TABLE 3
In vitro anti-tumor cell activity of the product of the invention
The pteridinone scaffold compounds of formula I above according to the invention were tested for their activity in inhibiting human prostate cancer cell PC-3, human breast cancer cell MCF-7, human breast cancer cell MDA-MB-231, human colon cancer cell HCT116 and human lung adenocarcinoma cell A549 in vitro. Control BI6727 was prepared as described in the literature (WO 2015180552).
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate.
The culture medium in the 96-well plate is discarded, 3 wells are added for each concentration, wherein two rows and two columns of cells around the culture medium are greatly influenced by the environment and are only used as blank cell wells. The 96-well plate was placed in an incubator for 72 h.
(3) After 10. mu.L of MTT (0.5mg/mL) was added to each well and placed in an incubator for 4 hours, the MTT solution was discarded, and 100. mu.L of dimethyl sulfoxide was added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the activity tests of partial compounds on human prostate cancer cell PC-3, human breast cancer cell MCF-7, human breast cancer cell MDA-MB-231, human colon cancer cell HCT116 and human lung adenocarcinoma cell A549 are shown in Table 4.
TABLE 4
From the above experimental results, it is clear that the compound of formula I to be protected in the present invention has good in vitro anti-tumor activity, comparable to or superior to BI6727 as a positive control drug.
Claims (10)
1. A compound of general formula (I) and geometric isomers, pharmaceutically acceptable salts and solvates thereof,
wherein,
A1is N, A2Is N, A3Is N, C or CR1b，
Wherein R is1bIndependently selected from hydrogen, halogen, (C), if present1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkoxy group;
R2is (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
R3is a 4-7 membered heterocyclic ring containing N, O and/or S; or NHnR4R5、NHnCONHnR4R5、SO2(CH2)nNR4R5、SO2(CH2)nCONR4R5(ii) a They may be substituted by 0 to 3 identical or different R6Substitution;
n is an integer of 0 to 2;
R4and R5The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C4) An alkoxy group;
or R4And R5Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, other than R4And R5Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, other than R4And R5Said heterocyclyl optionally including 0-2 carbon-carbon double or carbon-carbon triple bonds in addition to the attached nitrogen atom, said heterocyclyl or heteroaryl optionally being substituted with 0-3R, which may be the same or different6Substitution;
R6is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C6) Alkoxy, hydroxy, halogen, halo (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy and nitro.
2. A compound of general formula (I) according to claim 1, and geometric isomers, pharmaceutically acceptable salts, solvates thereof,
wherein,
A1is N, A2Is N, A3Is N, C or CR1b，
R1bIndependently selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkoxy group.
3. A compound of general formula (I) according to claim 1 or 2, and geometric isomers, pharmaceutically acceptable salts, solvates thereof,
wherein,
R3is a 4-7 membered heterocyclic ring containing N, O and/or S; or NHnR4R5、NHnCONHnR4R5、SO2(CH2)nNR4R5、SO2(CH2)nCONR4R5(ii) a They can be divided into 0-3Identical or different R6Substitution;
n is an integer of 0 to 2;
R4and R5The same or different, are respectively and independently selected from hydrogen and (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C4) An alkoxy group;
or R4、R5Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl group, other than R4And R5Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclyl or heteroaryl group optionally being substituted with 0 to 3R, which may be the same or different6And (4) substitution.
4. A compound of general formula (I) according to any one of claims 1 to 3, and geometric isomers, pharmaceutically acceptable salts, solvates thereof,
wherein,
R3is composed of
5. The following compounds and optical isomers, pharmaceutically acceptable salts and solvates thereof:
5-cyclopentyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (piperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (cyclopentylamino) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((2-methoxy-4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-7- ((2-methoxy-4- (piperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-7- ((2-methoxy-4- (morpholin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (piperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H)-
Ketones
5-cyclopentyl-1-methyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Butterfly
Pyridine-4 (5)H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]
Pteridine-4 (5)H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine
-4(5H) -ketones
5-cyclopentyl-1-methyl-7- ((4- (cyclopentylamino) phenyl) amino) - [1,2,4]Triazolo [4,3-f]Pteridine-4 (5)H)-
Ketones
5-cyclopentyl-7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (piperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-methylpiperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (pyrrolidin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (3, 5-dimethylpiperazin-1-yl) phenyl) amino) tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-thiomorpholinyl) phenyl) amino) tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) amino) tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (cyclopentylamino) phenyl) amino) -tetrazolo [4,3-f]Pteridine-4 (5)H) -ketones
5-cyclopentyl-7- ((4- (4- (4-methylpiperazin-1-yl) -piperidin-1-yl) phenyl) amino) -tetrazolo [4,3-f]Pteridine
-4(5H) -a ketone.
6. A pharmaceutical composition comprising a compound of any one of claims 1-5 and pharmaceutically acceptable salts, solvates thereof as an active ingredient and a pharmaceutically acceptable excipient.
7. A process for the preparation of the compound of claim 1, wherein the intermediate is prepared as follows:
route one:
and a second route:
and a third route:
and a fourth route:
8. the use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts, solvates thereof, or pharmaceutical compositions according to claim 6, for the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases.
9. Use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts, solvates thereof, or pharmaceutical compositions according to claim 6, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
10. Use of a compound of any one of claims 1-5 and pharmaceutically acceptable salts, solvates thereof, or pharmaceutical composition of claim 6 for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
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