VEGFR inhibitor and preparation method and application thereof
阅读说明：本技术 Vegfr抑制剂及其制备方法和应用 (VEGFR inhibitor and preparation method and application thereof ) 是由 吴勇 彭宇然 龚彦春 史谦 邓洁 吴小东 刘永强 于 2019-05-31 设计创作，主要内容包括：VEGFR抑制剂及其制备方法和应用。本发明涉及具有式(I)结构的喹啉或喹唑啉衍生物、含有式(I)化合物的药物组合物及所述化合物在制备预防或治疗血管生成相关疾病的药物的用途,特别是用于预防或治疗与蛋白质酪氨酸激酶相关的肿瘤。其中式(I)中的各取代基与说明书中的定义相同。<Image he="409" wi="521" file="DDA0002080307790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(VEGFR inhibitors, methods of making, and uses thereof. The invention relates to a quinoline or quinazoline derivative with a structure shown in a formula (I), a pharmaceutical composition containing the compound shown in the formula (I) and application of the compound in preparing a medicament for preventing or treating angiogenesis-related diseases, in particular to application in preventing or treating tumors related to protein tyrosine kinase. Wherein each substituent in the formula (I) is defined as the specification.)
1. A compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvate thereof:
R1Is selected from C1-C8Alkyl or C3-C8Cycloalkyl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, -NR8R9、-NR8COR7、-COR7、-SO2R7、-SOR7、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C8Alkoxy or 4-to 10-membered heterocyclic group, said C3-C6Cycloalkyl or 4-to 10-membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4Alkyl or C1-C4Alkoxy groups.
n is selected from 0, 1,2 or 3;
R2Selected from H, deuterium or halogen;
X is selected from N or CH;
Y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R7selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, -NR8R9Or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl substituted;
R8And R9Each independently selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group.
2. The compound of claim 1, wherein:
R1Is C1-C4Alkyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, methyl, ethyl, cyclopropyl or 4-6 membered heterocyclyl, said cyclopropyl or 4-6 membered heterocyclyl may further be substituted with amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Alkoxy, and the 4-6 membered heterocyclic group is selected from pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
R2Selected from H, deuterium or halogen;
X is CH;
Y is CH2；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group.
3. The compound of claim 1, a stereoisomer, a pharmaceutically acceptable salt, or ester, or a solvate thereof, of formula (I), which is a compound of formula (II), a stereoisomer, a pharmaceutically acceptable salt, or ester, or a solvate thereof:
R1Is C1-C8Alkyl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, -COR7、C1-C6Alkyl radical, C3-C6cycloalkyl or 4-6 membered heterocyclyl, said C3-C6Cycloalkyl or 4-6 membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4Alkyl or C1-C4Alkoxy substituted;
n is selected from 0, 1,2 or 3;
R7Selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl groups are substituted.
4. A compound according to claim 3, characterized in that:
R1Is C1-C4Alkyl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C1-C2Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl, said C3-C6Cycloalkyl or 4-6 membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN、carboxy, C1-C4Alkyl or C1-C4Alkoxy substituted;
n is selected from 0, 1 or 2.
5. The compound of claim 4, wherein:
R1Is C1-C4Alkyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, methyl, ethyl, cyclopropyl or 4-6 membered heterocyclyl, said cyclopropyl or 4-6 membered heterocyclyl may further be substituted with amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Alkoxy, and the 4-6 membered heterocyclic group is selected from pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
6. A compound, a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvent, wherein the compound is selected from the group consisting of:
7. A pharmaceutical composition comprising a compound of any one of claims 1-6, a stereoisomer, pharmaceutically acceptable salt or ester thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository, or patch.
9. use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 in the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by angiogenesis.
10. use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 for the manufacture of a medicament for the prophylaxis or treatment of a malignant tumour.
Technical Field
the application belongs to the technical field of medicines, and particularly relates to a quinoline or quinazoline derivative and application thereof in preparing a medicine for treating malignant tumor diseases.
The present application claims priority from chinese patent CN201810597224.3 (application date 2018, 6/8, title VEGFR inhibitors, methods of preparation and uses thereof).
Background
receptor tyrosine kinases are a class of enzymes that span the cell membrane and have an extracellular binding domain that binds growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residues in proteins and to influence cell proliferation.
Vascular Endothelial Growth Factor (VEGF), also known as Vascular Permeability Factor (VPF), is a highly specific vascular endothelial cell growth factor, specifically binds to vascular endothelial growth factor receptors (including VEGFR-1, VEGFR-2, VEGFR-3) and activates receptor tyrosine kinases to exert a vascular regulating effect, promoting vascular permeability increase, extracellular matrix degeneration, vascular endothelial cell migration, proliferation and vascularization.
Normal angiogenesis plays an important role in a variety of processes, including embryonic development, wound healing, and the like; undesirable or pathological angiogenesis is associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability are mainly regulated by Vascular Endothelial Growth Factor (VEGF) (of tumor origin), which acts through at least two different receptors: VEGFR-1 and VEGFR-2, receptors are highly specific for vascular endothelial cells (Endocr. Rev.1992,13, 18; FASEB J.1999,13, 9). VEGFR-1 and VEGFR-2 are mainly distributed on the surface of tumor vascular endothelium and regulate the generation of tumor blood vessels; VEGFR-3 is distributed mainly on the surface of lymphatic endothelium and regulates the generation of tumor lymphatic vessels. The high level expression of VEGF and its receptors by most human tumors has led to the hypothesis that VEGF released by tumor cells stimulates capillary growth and tumor endothelial proliferation in a paracrine manner and promotes tumor growth by increasing blood supply.
The effect of VEGF as a tumor angiogenesis factor in vivo is shown in that the inhibition of VEGF expression or VEGF activity by VEGF antibodies, VEGFR-2 negative mutants, VEGF antisense RNA can slow down the growth of glioma cell lines or other tumor cell lines in vivo. Several major mechanisms play important roles in the anti-tumor angiogenesis inhibitory activity: inhibition of blood vessel growth, particularly capillaries, a balance is achieved between cell death and proliferation such that there is no net growth of the tumor; inhibition of tumor cell metastasis due to lack of blood influx and efflux from the tumor; inhibiting the proliferation of endothelial cells and avoiding the paracrine growth-stimulation effect of the endothelial cells of the arranged blood vessels on the surrounding tissues.
A series of VEGFR inhibitors and patent applications for their use in vascular related diseases have been published, including WO 2016091165, WO 2017177962, CN103382206, etc., but there is still a need to develop new VEGFR inhibitors with better potency.
Disclosure of Invention
The invention aims to provide quinoline or quinazoline VEGFR inhibitors with excellent activity.
The invention also aims to provide application of the quinoline or quinazoline VEGFR inhibitor in preparing medicines for preventing or treating angiogenesis-related diseases, in particular tumor diseases related to protein tyrosine kinases.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention relates to a compound shown as the following formula (I), a stereoisomer, a pharmaceutically acceptable salt or ester thereof or a solvate thereof:
R1Is selected from C1-C8alkyl or C3-C8Cycloalkyl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, -NR8R9、-NR8COR7、-COR7、-SO2R7、-SOR7、C1-C6alkyl radical, C3-C6Cycloalkyl radical, C1-C8Alkoxy or 4-to 10-membered heterocyclic group, said C3-C6Cycloalkyl or 4-to 10-membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4Alkyl or C1-C4Alkoxy groups.
n is selected from 0, 1,2 or 3;
R2Selected from H, deuterium or halogen;
X is selected from N or CH;
Y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5Selected from H, C1-C8Alkyl or C3-C8a cycloalkyl group;
R6Selected from H, C1-C8alkyl or C3-C8A cycloalkyl group;
R7selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, -NR8R9Or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl substituted;
R8And R9Each independently selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group.
The implementation scheme of the invention is characterized in that:
R1Is C1-C4Alkyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, methyl, ethyl, cyclopropyl or 4-6 membered heterocyclyl, said cyclopropyl or 4-6 membered heterocyclyl may further be substituted with amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Alkoxy, and the 4-6 membered heterocyclic group is selected from pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
R2Selected from H, deuterium or halogen;
X is CH;
Y is CH2；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6Selected from H, C1-C8alkyl or C3-C8A cycloalkyl group.
An embodiment of the present invention is a compound described by general formula (II), a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvate thereof:
R1is C1-C8Alkyl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, -COR7、C1-C6alkyl radical, C3-C6cycloalkyl or 4-6 membered heterocyclyl, said C3-C6Cycloalkyl or 4-6 membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4alkyl or C1-C4Alkoxy substituted;
n is selected from 0, 1,2 or 3;
R7selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl groups are substituted.
the implementation scheme of the invention is characterized in that:
R1Is C1-C4Alkyl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C1-C2Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl, said C3-C6Cycloalkyl or 4-6 membered heterocyclyl may be further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4alkyl or C1-C4Alkoxy substituted; preferably, R1Is methyl, ethyl, further substituted by hydroxy, methyl, cyclopropyl or pyrrolidinyl, said cyclopropyl or pyrrolidinyl being further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, methyl or methoxy;
n is selected from 0, 1 or 2, preferably n is 0 or 1.
The implementation scheme of the invention is characterized in that:
R1Is C1-C4Alkyl, optionally further substituted with one or more substituents selected from deuterium, hydroxy, methyl, ethyl, cyclopropyl or 4-6 membered heterocyclyl, said cyclopropyl or 4-6 membered heterocyclyl may further be substituted with amino, hydroxy, carboxy, C1-C4alkyl or C1-C4Alkoxy, and the 4-6 membered heterocyclic group is selected from pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
In a preferred embodiment of the invention, the compound is selected from:
In another aspect, the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof, comprising the steps of:
Wherein R is1、R2、R3、R4、R5、R6X, Y are as defined for the compounds of formula (I).
The compound of formula (I) or the pharmaceutically acceptable salt, ester or solvate thereof is a novel VEGFR inhibitor, so that the compound can be used for preparing a medicament for preventing or treating angiogenesis related diseases, in particular for preventing or treating malignant tumor diseases related to protein tyrosine kinases.
As a further preferred embodiment, the tumor is selected from the group consisting of: ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma or mesothelioma, soft tissue sarcoma.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or ester or solvate thereof, as an active ingredient and a pharmaceutically acceptable carrier.
The invention also provides application of the pharmaceutical composition in preparing a medicament for preventing or treating malignant tumors.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"C" in the invention1-C8alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylTert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2-dimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2, 4-dimethylpentyl group, 2-dimethylpentyl group, 3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, or various branched isomers thereof.
as used herein, "cycloalkyl" refers to a saturated monocyclic hydrocarbon substituent, "C3-C8Cycloalkyl "refers to monocyclic cycloalkyl groups comprising 3 to 8 carbon atoms, for example: non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
"Heterocyclyl" as used herein refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) r (where r is an integer 0, 1, 2), but does not include the ring portion of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. "4-10 membered heterocyclyl" refers to a cyclic group containing from 4 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
"alkoxy" in the context of the present invention means-O- (alkyl) wherein alkyl is as defined above. "C1-C8Alkoxy "means an alkyloxy group having 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
In the preparation steps of the present invention, abbreviations for reagents used respectively represent:
DCM dichloromethane
DIEA N, N-diisopropylethylamine
MTBE methyl tert-butyl ether
EA Ethyl acetate
PE Petroleum Ether
THF tetrahydrofuran
TFAA trifluoroacetic anhydride
EtOH ethanol
BnBr benzyl bromide
DMAP 4-dimethylaminopyridine
TFA trifluoroacetic acid
MsCl-p-methylbenzenesulfonyl chloride
DMAC Dimethylacetamide
TBDPSCl tert-butyldiphenylchlorosilane
TBAB tetrabutylammonium bromide
Drawings
FIG. 1 NMR spectra of the compound of example 1;
FIG. 2 NMR spectra of the compound of example 2;
FIG. 3 NMR spectra of the compound of example 3;
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
the experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified.
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