Receptor tyrosine kinase inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound shown in a formula (I), a preparation method thereof and application of the compound in treatment and / or prevention of PDGFR beta biological activity related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a novel compound of receptor tyrosine kinase inhibitor, a preparation method thereof, and an application thereof in the treatment and / or prevention of diseases related to the biological activity of receptor tyrosine kinase PDGFRβ. Background Art

[0002] Platelet-derived growth factor receptor (PDGFR) is a member of the receptor tyrosine protein kinase family, and has two family members, PDGFRα and PDGFRβ, which can form homodimers or heterodimers, namely PDGFRαα, PDGFRαβ, PDGFRββ. After PDGFR binds to its ligand PDGF, the tyrosine residues thereof will undergo autophosphorylation, and at the same time activate multiple signal pathways such as downstream PI3K-Akt, PLCγ, Src, Ras-MEK-ERK, Rho-ROCK, etc., and regulate various biological functions such as cell survival, proliferation, migration and transdifferentiation. The PDGF family has four members, PDGF-A, PDGF-B, PDGF-C, PDGF-D, which can form five homodimers or heterodimers: PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, PDGF-DD; among them, PDGF-AA has the highest selectivity and can only activate PDGFRαα; PDGF-BB has the lowest selectivity and can activate three receptor types (Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev 2004; 15(4): 205-213).

[0003] PDGFRβ is highly expressed in fibroblasts, pericytes, myofibroblasts, vascular smooth muscle cells, brain glial cells, hematopoietic stem cells, vascular endothelial progenitor cells, etc., and is a key molecule for the survival, proliferation, migration and interaction of these cells with other cells. PDGFRα is highly expressed in mesenchymal cells, such as chondrocytes, oligodendrocytes, neural crest cells, and interstitial cells in the intestine, kidney and skin. PDGFRβ and PDGFRα have differential effects on a series of diseases such as fibrosis, tumors, and inflammation after adulthood. For example, in the study of pulmonary fibrosis, it was found that PDGFRβ promotes the process of fibrosis, while PDGFRα does not have this effect. (Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev 2004;15(4):205-213; Hideto S, Tetsuo S. Functional Blockade of Platelet-Derived Growth Factor Receptor-b but Not of Receptor-a Prevents Vascular Smooth Muscle Cell Accumulation in Fibrous Cap Lesions in Apolipoprotein E-Deficient Mice. Circulation, 2001(103):2955-2960).

[0004] Under pathophysiological conditions such as tumors, fibrosis, and inflammation, the PDGF-PDGFRβ signaling pathway can maintain the survival, proliferation, and extracellular matrix secretion functions of mesenchymal cells such as fibroblasts and mesangial cells, and promote mesenchymal cells to secrete a series of cytokines (TGF-β, IL-6, etc.) and chemokines (CCL2, CXCL16, etc.), attracting immune cells such as macrophages to infiltrate into damaged tissues and organs. There is a close interaction between fibroblasts and macrophages. Macrophages secrete cytokines such as PDGF and EGF to maintain the survival of mesenchymal cells and promote the differentiation of fibroblasts into myofibroblasts, secrete extracellular matrix, attract macrophages to continuously migrate, survive, and polarize, resulting in the continuous amplification of fibrosis and inflammatory responses. Therefore, inhibiting the PDGFRβ signal is beneficial to improving pathophysiological abnormalities caused by excessive proliferation, activation, and transdifferentiation of mesenchymal cells (Matthew B, Wenxian F, Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer, Immunity, 2021(54):903-915). Based on this, the development of novel and effective PDGFRβ inhibitors will have important clinical value and market demand. Summary of the Invention

[0005] Problems to be Solved by the Invention:

[0006] Although there are currently small molecule PDGFRβ inhibitors on the market, however, based on the prospects shown by PDGFRβ inhibitors in the treatment of various diseases, new compounds still need to be further developed.

[0007] To solve the above problems, the present invention has conducted in-depth research. After continuous efforts, the present invention designs compounds with the structure shown in general formula (I), and finds that compounds with such structures exhibit excellent PDGFRβ inhibitory effects and functions, and can achieve the desired purpose, thus completing the present invention.

[0008] Specifically, the present invention relates to the following technical solutions:

[0009] A compound of formula (I), or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt:

[0010]

[0011] Wherein, X is selected from CH or N;

[0012] R 1 is selected from C 1-6 alkyl, C 1-6Halogenated alkyl, 4- to 10-membered heterocyclic group; the 4- to 10-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S; the C 1-6 alkyl is unsubstituted or substituted with one or more substituents selected from R 1A ; the 4- to 10-membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from R 1B ;

[0013] Each R 1A is independently selected from hydroxy, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 4- to 10-membered heterocyclic group; the 4- to 10-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S; the 4- to 10-membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from R 1B ;

[0014] R 2 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy;

[0015] Or R 1 and R 2 together with the carbon atom and oxygen atom to which they are attached form a 5- to 10-membered heterocyclic group; the 5- to 10-membered heterocyclic group contains 0 to 3 heteroatoms selected from N, O, and S other than the oxygen atom; the 5- to 10-membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from R 1B ;

[0016] Each R 1B is independently selected from C 1-6 alkyl, halogen, C 1-6 halogenated alkyl substitution;

[0017] R 3 , R 6 are independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 halogenated alkyl;

[0018] R 4 , R 5 , R 8 , R 9 are independently selected from hydrogen, deuterium, halogen;

[0019] Ring A is selected from C 3-10 cycloalkyl, C 6-10 aryl, 4- to 12-membered heterocyclic group; the 4- to 12-membered heterocyclic group contains 1 to 4 heteroatoms selected from N, O, and S;

[0020] R 7 selected from halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl;

[0021] m is selected from 0, 1, 2, 3, 4, 5, 6.

[0022] In one embodiment, in the above compound, or its deuterated compound, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt, R 1 is selected from C 1-3 alkyl, C 4-6 alkyl, C 1-3 haloalkyl, C 4-6 haloalkyl, 4- to 6-membered heterocyclic group, 7- to 8-membered heterocyclic group, 9- to 10-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S; the alkyl is unsubstituted or substituted by one or more substituents selected from R 1A ; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0023] In a preferred embodiment, R 1 is selected from C 1-3 alkyl, C 1-3 haloalkyl, 4- to 6-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S; the alkyl is unsubstituted or substituted by one or more substituents selected from R 1A ; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0024] Or in a preferred embodiment, R 1 is selected from C 4 alkyl, C 5 alkyl, C 6 alkyl, C 4 haloalkyl, C 5 haloalkyl, C 6 haloalkyl, 4- to 6-membered heterocyclic group, 7- to 8-membered heterocyclic group, 9- to 10-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S; the alkyl is unsubstituted or substituted by one or more substituents selected from R 1A ; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0025] In a more preferred embodiment, R 1 is selected from methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, 4-6 membered heterocycloalkyl; the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the methyl, ethyl, propyl, isopropyl are unsubstituted or substituted with one or more substituents selected from R 1A ; the heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from R 1B .

[0026] In an even more preferred embodiment, R 1 is selected from methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, cyclobutane, cyclopentane, cyclohexane; the cyclobutane, cyclopentane, cyclohexane contain 1-2 heteroatoms selected from N, O, S; the methyl, ethyl, propyl, isopropyl are unsubstituted or substituted with one or more substituents selected from R 1A ; the cyclobutane, cyclopentane, cyclohexane are unsubstituted or substituted with one or more substituents selected from R 1B .

[0027] In an even more preferred embodiment, R 1 is selected from methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CH 2 CH2 CH 2 Cl, -CH 2 CH 2 CHCl 2 、-CH 2 CH 2 CCl 3 、 epoxybutane, oxolane, tetrahydropyran, pyrrolidine, morpholine, piperidine; the methyl, ethyl, propyl, isopropyl are unsubstituted or substituted by one or more substituents selected from R 1A ; the epoxybutane, oxolane, tetrahydropyran, pyrrolidine, morpholine, piperidine are unsubstituted or substituted by one or more substituents selected from R 1B .

[0028] In a further preferred embodiment, R 1 is selected from methyl, ethyl, propyl, isopropyl, -CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, oxolane; the methyl, ethyl, propyl, isopropyl are unsubstituted or substituted by one or more substituents selected from R 1A .

[0029] In a preferred embodiment, each R 1A is independently selected from hydroxyl, C 1-3 alkoxy, C 4-6 alkoxy, C 1-3 haloalkoxy, C 4-6 haloalkoxy, 4-6 membered heterocyclic group, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0030] In a more preferred embodiment, each R 1A is independently selected from hydroxyl, C 1-3 alkoxy, C 1-3 haloalkoxy, 4-6 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0031] Or in a more preferred embodiment, each R 1A is independently selected from hydroxyl, C 4 alkoxy, C5 Alkoxy, C 6 Alkoxy, C 4 Halogenated alkoxy, C 5 Halogenated alkoxy, C 6 Halogenated alkoxy, 7- to 8-membered heterocyclic group, 9- to 10-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B .

[0032] In a further preferred embodiment, each R 1A is independently selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropoxy, 4- to 6-membered heterocycloalkyl; the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S; the heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from R 1B .

[0033] In a further preferred embodiment, each R 1A is independently selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropoxy, oxetane, oxolane, tetrahydropyran, pyrrolidine, morpholine, piperidine; the oxetane, oxolane, tetrahydropyran, pyrrolidine, morpholine, piperidine are unsubstituted or substituted by one or more substituents selected from R 1B .

[0034] In a further preferred embodiment, each R 1A is independently selected from hydroxy, methoxy, morpholine, piperidine; the morpholine, piperidine are unsubstituted or substituted by one or more substituents selected from R 1B .

[0035] In a preferred embodiment, each R 1B is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 CH2 CH 2 CF 3 、 -CH 2 Cl、 -CHCl 2 、 -CCl 3 、 -CH 2 CH 2 Cl、 -CH 2 CHCl 2 、 -CH 2 CCl 3 、 -CH 2 CH 2 CH 2 Cl、 -CH 2 CH 2 CHCl 2 、 -CH 2 CH 2 CCl 3 。

[0036] Or in a preferred embodiment, each R 1B is independently selected from bromine, iodine, C 4 alkyl, C 5 alkyl, C 6 alkyl, bromomethyl, bromoethyl, bromopropyl, haloisopropyl, C 4 haloalkyl, C 5 haloalkyl, C 6 haloalkyl.

[0037] In a more preferred embodiment, each R 1B is independently selected from methyl, ethyl, propyl, isopropyl.

[0038] In an even more preferred embodiment, R 1 is selected from methyl, ethyl, propyl, isopropyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OCH 3 、 -CH 2 CH 2 OCH 3 、 -CH 2 OCH 3 、 -CH 2 CH 2 F, -CH 2 CHF 2 、 -CH 2 CH 2 CH 2 F, -CH 2 F, -CHF2 、 -CF 3 、 -CH 2 CH 2 F、 -CH 2 CHF 2 、 -CH 2 CF 3 、 -CH 2 CH 2 CH 2 F、 -CH 2 CH 2 CHF 2 、 -CH 2 CH 2 CF 3 、 -CH 2 Cl、 -CHCl 2 、 -CCl 3 、 -CH 2 CH 2 Cl、 -CH 2 CHCl 2 、 -CH 2 CCl 3 、 -CH 2 CH 2 CH 2 Cl、 -CH 2 CH 2 CHCl 2 、 -CH 2 CH 2 CCl 3 、

[0039]

[0040] In a further preferred embodiment, R 1 is selected from methyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OCH 3 、 -CH 2 CH 2 OCH 3 、 -CH 2 CH 2 F, -CH 2 CHF 2 、 -CH 2 CH 2 CH 2 F、

[0041]

[0042] In a further preferred embodiment, R 1 is selected from methyl.

[0043] In one embodiment, in the above-mentioned compound, or its deuterated compound, stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, pharmaceutically acceptable salt, R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 4-6 alkyl, C 1-3 haloalkyl, C 4-6 haloalkyl, C 1-3 alkoxy, C 4-6 alkoxy, C 1-3 haloalkoxy, C 4-6 haloalkoxy.

[0044] In a preferred embodiment, R 2 is selected from hydrogen, fluorine, chlorine, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy.

[0045] Or in a preferred embodiment, R 2 is selected from bromine, iodine, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 4 haloalkyl, C 5 haloalkyl C 6 haloalkyl, C 1-3 alkoxy, C 4-6 alkoxy, C 4 alkoxy, C 5 alkoxy, C 6 alkoxy, C 4 haloalkoxy, C 5 haloalkoxy, C 6 haloalkoxy.

[0046] In a more preferred embodiment, R 2 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy.

[0047] In an even more preferred embodiment, R 2Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 、-CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 Cl, -CHCl 2 、-CCl 3 、-CH 2 CH 2 Cl, -CH 2 CHCl 2 、-CH 2 CCl 3 、-CH 2 CH 2 CH 2 Cl, -CH 2 CH 2 CHCl 2 、-CH 2 CH 2 CCl 3 、methoxy, ethoxy, propoxy, isopropoxy, -OCH 2 F, -OCHF 2 、-OCF 3 、-OCH 2 CH 2 F, -OCH 2 CHF 2 、-OCH 2 CF 3 、-OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-OCH 2 Cl, -OCHCl 2 、-OCCl 3 、-OCH2 CH 2 Cl, -OCH 2 CHCl 2 , -OCH 2 CCl 3 , -OCH 2 CH 2 CH 2 Cl, -OCH 2 CH 2 CHCl 2 , -OCH 2 CH 2 CCl 3 .

[0048] In a further preferred embodiment, R 2 is selected from hydrogen, fluorine, methoxy, -OCH 2 CH 2 F, -OCH 2 CH 2 CH 2 F.

[0049] In a further preferred embodiment, R 2 is selected from hydrogen, fluorine, methoxy.

[0050] In one embodiment, in the above-mentioned compound, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt, R 1 and R 2 together with the carbon atom and oxygen atom to which they are attached form a 5- to 6-membered heterocyclic group, a 7- to 8-membered heterocyclic group, or a 9- to 10-membered heterocyclic group; the heterocyclic group contains 0 to 3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted with one or more substituents selected from R 1B .

[0051] In a more preferred embodiment, R 1 and R 2 together with the carbon atom and oxygen atom to which they are attached form a 5- to 6-membered heterocyclic group; the heterocyclic group contains 0 to 3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted with one or more substituents selected from R 1B .

[0052] Or in a more preferred embodiment, R 1 and R 2The carbon atom and oxygen atom connected thereto together form a 7- to 8-membered heterocyclic group or a 9- to 10-membered heterocyclic group; the heterocyclic group contains 0 to 3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B and is substituted by a substituent.

[0053] In a further preferred embodiment, R 1 and R 2 The carbon atom and oxygen atom connected thereto together form The heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B and is substituted by a substituent.

[0054] In a preferred embodiment, each R 1B is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CH 2 CH 2 CH 2 Cl, -CH 2 CH 2 CHCl 2 , -CH 2 CH 2 CCl 3 .

[0055] Or in a preferred embodiment, each R 1B is independently selected from bromine, iodine, C 4Alkyl, C 5 Alkyl, C 6 Alkyl, bromomethyl, bromoethyl, bromopropyl, haloisopropyl, C 4 Haloalkyl, C 5 Haloalkyl, C 6 Haloalkyl.

[0056] In a further preferred embodiment, R 1 and R 2 together with the carbon atom and oxygen atom to which they are attached form

[0057] In one embodiment, in the above-mentioned compound, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt, R 3 , R 6 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-3 alkyl, C 4-6 alkyl, C 1-3 haloalkyl, C 4-6 haloalkyl.

[0058] In a preferred embodiment, R 3 , R 6 are each independently selected from hydrogen, fluorine, chlorine, cyano, C 1-3 alkyl, C 1-3 haloalkyl.

[0059] Or in a preferred embodiment, R 3 , R 6 are each independently selected from bromine, iodine, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 4 haloalkyl, C 5 haloalkyl, C 6 haloalkyl, bromomethyl, bromoethyl, bromopropyl, haloisopropyl.

[0060] In a more preferred embodiment, R 3 , R 6 are each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl.

[0061] In an even more preferred embodiment, R 3 , R 6 are each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, -CH2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 , -CH 2 CH 2 CH 2 Cl, -CH 2 CH 2 CHCl 2 , -CH 2 CH 2 CCl 3 。

[0062] In a further preferred embodiment, R 3 is selected from hydrogen, fluorine.

[0063] In a further preferred embodiment, R 6 is selected from hydrogen, fluorine, chlorine, cyano, methyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2CF 3 ; R 6 is preferably hydrogen, fluorine, chlorine, methyl, -CH 2 F, -CHF 2 , -CF 3 .

[0064] In a further preferred embodiment, R 3 is selected from hydrogen, fluorine; R 6 is selected from hydrogen, fluorine, chlorine, cyano, methyl, -CH 2 F, -CHF 2 , -CF 3 .

[0065] In one embodiment, in the above compound, or its deuterated compound, stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, pharmaceutically acceptable salt, R 4 , R 5 , R 8 , R 9 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine.

[0066] In a preferred embodiment, R 4 , R 5 , R 8 , R 9 are each independently selected from hydrogen, deuterium, fluorine, chlorine.

[0067] In a more preferred embodiment, R 4 , R 5 are each independently selected from hydrogen, deuterium.

[0068] In a more preferred embodiment, R 8 , R 9 are each independently selected from hydrogen, deuterium, fluorine.

[0069] In a further preferred embodiment, R 4 and R 5 are both hydrogen.

[0070] In a further preferred embodiment, R 4 and R 5 are both deuterium.

[0071] In a further preferred embodiment, for R 4 and R 5 , one is hydrogen and the other is deuterium.

[0072] In a further preferred embodiment, R 8 and R 9 are both hydrogen.

[0073] In a further preferred embodiment, R 8 and R 9 are both deuterium.

[0074] In a further preferred embodiment, R 8 and R 9 are both fluorine.

[0075] In a further preferred embodiment, for R 8 and R 9 one is hydrogen and the other is deuterium; or one is hydrogen and the other is fluorine; or one is deuterium and the other is fluorine.

[0076] In one embodiment, in the above compound, or its deuterated compound, stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, pharmaceutically acceptable salt, ring A is selected from C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 7-8 cycloalkyl, C 9-10 cycloalkyl, benzene ring, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, 4-membered heterocyclic group, 5-6-membered heterocyclic group, 7-8-membered heterocyclic group, 9-10-membered heterocyclic group, 11-12-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, S.

[0077] In a preferred embodiment, ring A is selected from C 5-6 cycloalkyl, benzene ring, C 9 aryl, C 10 aryl, 5-6-membered heterocyclic group, 7-8-membered heterocyclic group, 9-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, S.

[0078] Or in a preferred embodiment, ring A is selected from C 3-4 cycloalkyl, C 7-8 cycloalkyl, C 9-10 cycloalkyl, C 7 aryl, C 8 aryl, 4-membered heterocyclic group, 11-12-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, S.

[0079] In a more preferred embodiment, ring A is selected from cyclohexane, 5-6-membered heterocycloalkyl, benzene ring, 5-membered heteroaryl, 6-membered heteroaryl, benzo-5-membered heteroaryl, benzo-6-membered heteroaryl, pyrido-5-membered heteroaryl, pyrido-6-membered heteroaryl; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O, S.

[0080] In a further preferred embodiment, ring A is selected from cyclohexane, tetrahydropyran, piperidine, pyrrolidine, morpholine, benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, benzothiazole, benzoxazole, pyrazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, imidazole, furan, thiophene, triazole, pyridine, pyrimidine, pyridazine, pyrazine, pyridinopyrazole, pyridinobenzimidazole, pyridinobenzisothiazole, pyridinofuran, pyridinobenzisoxazole, pyridinotriazole, pyridinothiophene, pyridinothiazole, pyridinobenzoxazole.

[0081] In a further preferred embodiment, ring A is selected from cyclohexane, tetrahydropyran, benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, pyrazole, isoxazole, thiazole, pyridinopyrazole, pyridinobenzimidazole, pyridine.

[0082] In a further preferred embodiment, ring A is selected from cyclohexane, tetrahydropyran, benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, pyrazole, isoxazole, thiazole, pyridinopyrazole, pyridinobenzimidazole.

[0083] In a further preferred embodiment, ring A is selected from

[0084] In a further preferred embodiment, ring A is selected from

[0085] In a preferred embodiment, each R 7 is independently selected from fluorine, chlorine, bromine, iodine, cyano, amino, C 1-3 alkyl, C 4-6 alkyl, C 1-3 haloalkyl, C 4-6 haloalkyl, C 1-3 alkoxy, C 4-6 alkoxy, C 1-3 haloalkoxy, C 4-6 haloalkoxy, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 7-8 cycloalkyl, C 9-10 cycloalkyl.

[0086] In a more preferred embodiment, each R 7 is independently selected from fluorine, chlorine, cyano, amino, C 1-3 alkyl, C 1-3Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl.

[0087] Or in a more preferred embodiment, each R 7 is independently selected from bromine, iodine, C 4 alkyl, C 5 alkyl, C 6 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, C 4 halogenated alkyl, C 5 halogenated alkyl, C 6 halogenated alkyl, C 4 alkoxy, C 5 alkoxy, C 6 alkoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, C 4 halogenated alkoxy, C 5 halogenated alkoxy, C 6 halogenated alkoxy, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl.

[0088] In a more preferred embodiment, each R 7 is independently selected from methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, cyclopropane, cyclobutane, cyclopentane, cyclohexane.

[0089] In an even more preferred embodiment, each R 7 is independently selected from methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF2 、 -CH 2 CH 2 CF 3 、 -CH 2 Cl, -CHCl 2 、 -CCl 3 、 -CH 2 CH 2 Cl, -CH 2 CHCl 2 、 -CH 2 CCl 3 、 -CH 2 CH 2 CH 2 Cl, -CH 2 CH 2 CHCl 2 、 -CH 2 CH 2 CCl 3 、 methoxy, ethoxy, propoxy, isopropoxy, -OCH 2 F, -OCHF 2 、 -OCF 3 、 -OCH 2 CH 2 F, -OCH 2 CHF 2 、 -OCH 2 CF 3 、 -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 、 -OCH 2 CH 2 CF 3 、 -OCH 2 Cl, -OCHCl 2 、 -OCCl 3 、 -OCH 2 CH 2 Cl, -OCH 2 CHCl 2 、 -OCH 2 CCl 3 、 -OCH 2 CH 2 CH 2 Cl, -OCH 2 CH 2 CHCl 2 、 -OCH 2 CH 2 CCl 3, cyclopropane, cyclobutane, cyclopentane, cyclohexane.

[0090] In a further preferred embodiment, each R 7 is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, isopropyl, methoxy, -CF 3 , -CH 2 F, -CHF 2 , -OCH 2 CF 3 , cyclopropane; preferably fluorine, methyl.

[0091] In a preferred embodiment, m is selected from 0, 1, 2, 3, 4.

[0092] In a more preferred embodiment, m is selected from 0, 1, 2.

[0093] In a further preferred embodiment, m is selected from 0, 1.

[0094] In a further preferred embodiment, is selected from

[0095] In a further preferred embodiment, is selected from

[0096]

[0097] In a further preferred embodiment,

[0098] is selected from

[0099] In a further preferred embodiment, is selected from

[0100] In a further preferred embodiment, is selected from

[0101] In one embodiment, in the above-mentioned compound, or its deuterated compound, stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, pharmaceutically acceptable salt, the compound has the structure represented by formula (II):

[0102]

[0103] Wherein, R 2Selected from hydrogen, fluorine or methoxy; R 4 and R 5 are both hydrogen or both deuterium; Ring A, R 3 、R 6 、R 7 and m are as defined above.

[0104] In one embodiment, the above-mentioned compound, or its deuterated compound, stereoisomer, tautomer, polymorph, eutectic, solvate, metabolite, prodrug, pharmaceutically acceptable salt, the compound of formula (I) is selected from 211 compounds: Compound I-1 to I-211.

[0105] In one embodiment, the deuterated compound of the above-mentioned compound means that at least one hydrogen in the compound can be replaced by deuterium. For example, the deuterated compound of the above-mentioned compound can be selected from

[0106] The term "pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is prepared from the compound with specific substituents found in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0107] The term "prodrug" refers to a derivative of the compound represented by formula (I) with specific substituents found in the present invention, which may have weak activity or even no activity by itself, but after administration, it is converted into the compound with specific substituents found in the present invention under physiological conditions (such as through metabolism, solvolysis or other means), and produces the corresponding biological activity in vivo.

[0108] The term "metabolite" refers to the product obtained by the metabolism of the compound represented by formula (I) with specific substituents found in the present invention in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compound, including the metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0109] The term "deuterated compound" refers to a compound of the invention that includes at least one deuterium atom, specifically one or more hydrogen atoms in the compound of the invention that can be replaced or substituted by a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.

[0110] When the structural formula of the compound of general formula (I) described in the present invention is inconsistent with the Chinese name, the structural formula shall prevail.

[0111] Preparation method:

[0112] Another aspect of the present invention also provides a method for preparing the above-mentioned compound according to the present invention. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0113] The definitions of the following variables are as described above, and the definitions of new variables are as described in this section. In addition, the compounds described by general formula (I) and the intermediates involved can be purified by common separation methods, such as extraction, recrystallization and silica gel column chromatography. The chromatography silica gel plates used were provided by Yantai Xinnuo New Materials Technology Co., Ltd., and the thin layer chromatography silica gel plates were provided by Shanghai Haohong Biomedicine Technology Co., Ltd. The chemical reagents used were analytically pure or chemically pure commercial products of general reagents and were used without further purification.

[0114] The present invention provides a method for preparing a compound represented by general formula (I), comprising the following steps:

[0115]

[0116] Step 1: The compound represented by formula (Ia) is reacted with the compound represented by formula (Ib) in a first solvent by a nucleophilic substitution reaction after being catalyzed by a first base to obtain the compound represented by formula (Ic);

[0117] Step 2: The compound represented by formula (Ic) is subjected to an ester hydrolysis reaction in a second solvent under the action of a second base or a first acid to obtain a compound represented by formula (Id);

[0118] Step 3: The compound shown in formula (I-d) and the compound shown in formula (I-e) react in a third solvent under the action of a first condensing agent and a third base to obtain the compound shown in formula (I) through an amide condensation reaction.

[0119] Wherein:

[0120] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、X, m, and the definition of ring A are as described above;

[0121] M is selected from chlorine, bromine, iodine, -OMs, -OTf, -OTs;

[0122] Z is selected from -CH 3 、-C 2 H 5 、-C(CH 3 ) 3 .

[0123] In some embodiments, the first solvent includes, but is not limited to, xylene, dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N-methylpyrrolidone (NMP), or a combination of two or more of these solvents.

[0124] In some embodiments, the first base includes, but is not limited to, 4-dimethylaminopyridine (DMAP), N-methylimidazole (NMI).

[0125] In some embodiments, the second solvent includes, but is not limited to, water, methanol (MeOH), 1,2-dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile, dichloromethane (DCM), 1,4-dioxane, or a combination of two or more of these solvents.

[0126] In some embodiments, the second base includes, but is not limited to, lithium hydroxide (LiOH), potassium hydroxide (KOH), sodium hydroxide (NaOH), trimethyltin hydroxide (Me 3 SnOH), lithium bromide / triethylamine (LiBr / TEA), (potassium trimethylsilanolate) TMSOK.

[0127] In some embodiments, the first acid includes, but is not limited to, hydrochloric acid, trifluoroacetic acid.

[0128] In some embodiments, the third solvent includes, but is not limited to, dichloromethane (DCM), 1,4 - dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N - methylpyrrolidone (NMP), or a mixed solvent of two or more of these solvents in different ratios.

[0129] In some embodiments, the first condensing agent includes, but is not limited to, 1-(3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (EDCI·HCl), 1 - hydroxybenzotriazole (HOBt), 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), and N - methylimidazole, where TCFH is particularly suitable for the condensation of amines with large steric hindrance, 1H - benzotriazol - 1 - yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), thionyl chloride, and carbonyldiimidazole (CDI).

[0130] In some embodiments, the third base is selected from triethylamine (TEA), N,N'-diisopropylethylamine (DIEA), or a combination thereof.

[0131] The present invention also provides another preparation method of the compound represented by the general formula (I), which includes the following steps:

[0132]

[0133] Step 1: The compound represented by formula (I - d) reacts with the nitrogen source represented by formula (I - f) in a fourth solvent under the action of a second condensing agent through a condensation reaction to obtain an amide compound represented by formula (I - g);

[0134] Step 2: The compound represented by formula (I - g) reacts with the compound represented by formula (I - h) in a fifth solvent under the action of a first catalyst, a first ligand, and a fourth base through a C - N coupling reaction to obtain the compound represented by formula (I).

[0135] Wherein:

[0136] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、X, m, and the definition of ring A are as described above;

[0137] W is selected from bromine, iodine, chlorine, -OTf.

[0138] In some embodiments, the fourth solvent includes, but is not limited to, methanol (MeOH), dichloromethane (DCM), 1,4 - dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), methyl tert - butyl ether (MTBE), and pyridine.

[0139] In some embodiments, the second condensing agent includes, but is not limited to, carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), thionyl chloride, 1-(3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (EDCI·HCl).

[0140] In some embodiments, the ammonia source includes, but is not limited to, ammonia gas, aqueous ammonia, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium bicarbonate.

[0141] In some embodiments, the fifth solvent includes, but is not limited to, 1,4 - dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N - methylpyrrolidone (NMP), toluene, and mixed solvents formed by these solvents and water in different ratios.

[0142] In some embodiments, the first catalyst is palladium - catalyzed and copper - catalyzed, including, but is not limited to, 1,1'-bis(dicyclohexylphosphino)ferrocene dichloropalladium (PdCl(dcypf)), palladium acetate (Pd(OAc)), palladium dichloride (PdCl), tris(dibenzylideneacetone) dipalladium (Pd(dba)), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (PdCl(dppf)), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (PdCl(dppf)·CHCl), tetrakis(triphenylphosphine)palladium (Pd(PPh)), bis(tricyclohexylphosphine)dichloropalladium (PdCl(P(Cy))) 2 (dcypf)) 2 ) 2 ) 2 (dba) 3 ) 2 (dppf)) 2 (dppf)·CH 2 Cl 2 ) 3 ) 4 ) 2 (P(Cy) 3 ) 2) Xphos Pd G4 ((SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium), copper(I) iodide, copper(I) acetate.

[0143] In some embodiments, the first ligand includes but is not limited to 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (BINAP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), bis(2-diphenylphosphinophenyl) ether (DPEPhos), 2-(di-tert-butylphosphino)biphenyl (Johnphos), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-isopropyl-1,1'-biphenyl (Brettphos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (Ruphos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), L-proline, ethylene glycol, 1,10-phenanthroline, 8-hydroxyquinoline.

[0144] In some embodiments, the fourth base is an organic base and an inorganic base, including but not limited to triethylamine (TEA), N,N'-diisopropylethylamine (DIEA), n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate (KOAc), sodium tert-butoxide (NaOBu-t), potassium tert-butoxide (KOBu-t), sodium hydride (NaH), potassium phosphate (K 3 PO 4 ) sodium carbonate (Na 2 CO 3 ) potassium carbonate (K 2 CO 3 ) cesium carbonate (Cs 2 CO 3 ) lithium hydroxide (KOH), sodium hydroxide (NaOH), lithium bis(trimethylsilyl)amide (LiHMDS).

[0145] Pharmaceutical composition:

[0146] The present invention also provides a pharmaceutical composition, which comprises any of the foregoing compounds, or their deuterated compounds, stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, pharmaceutically acceptable salts, and optionally a pharmaceutical carrier and / or adjuvant and / or diluent.

[0147] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing diseases related to the biological activity of PDGFRβ.

[0148] Methods for preparing various pharmaceutical compositions containing a certain amount of the active ingredient are known or will be apparent to those skilled in the art from the disclosure of the present invention. As described in REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), the methods for preparing the pharmaceutical compositions include incorporating suitable pharmaceutical excipients, carriers, diluents, etc.

[0149] Medical use:

[0150] Another aspect of the present invention relates to the compounds according to the present invention as described above, or their deuterated compounds, stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, pharmaceutically acceptable salts, and the above compositions, which are used for treating and / or preventing diseases related to the biological activity of PDGFRβ.

[0151] Term definitions

[0152] In the present invention, the term "heterocyclic group" used alone or in combination with other terms refers to a 4- to 8-membered monocyclic or bicyclic group, an 8- to 10-membered bicyclic or tricyclic group, and a 10- to 12-membered tricyclic or polycyclic group, wherein at least one ring has at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, with the limitation that the total number of heteroatoms in each ring is 4 or less, and a further limitation that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatoms refer only to N or O, and their total number does not exceed 3, preferably only containing 1-2 heteroatoms. The carbon and sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and when the valence allows, the ring atoms on the heterocycle may be optionally substituted with ═O (oxo). (For example: ). In some preferred embodiments, the heterocyclic group is a heteroaryl. In some preferred embodiments, the heterocyclic group is a heteroalicyclic. In some preferred embodiments, the heterocyclic group is a heterocycloalkyl. The fused rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated, aromatic or non-aromatic. The heterocyclic group may be attached at any available nitrogen or carbon atom.

[0153] Advantages of the invention:

[0154] The compound shown by formula (I) of the present invention has significant PDGFRβ kinase inhibitory activity and can be used as a drug related to the treatment and / or prevention of diseases related to this effect. Experiments show that the compound of the present invention has a PDGFRβ kinase inhibitory activity of more than 80%, more preferably more than 90%, and still more preferably more than 95% at 50 nM; at 5 nM, the PDGFRβ kinase inhibitory activity reaches more than 50%, more preferably more than 80%, and still more preferably more than 90%; whether at a concentration of 50 nM or 5 nM, the inhibitory activity on PDGFRβ kinase is stronger than that of the control molecule 01, indicating that the compound of the present invention has unexpectedly excellent inhibitory activity on PDGFRβ kinase. Furthermore, the IC 50 of the compound of the present invention for inhibiting PDGFRβ kinase activity is 5 nM or less, preferably 3 nM or less, more preferably 1 nM or less, which is more than 10 times stronger than that of the control molecule 01. This experimental data also shows that the compound of the present invention exhibits excellent inhibitory activity on PDGFRβ kinase. Detailed implementation manners

[0155] The examples and preparation examples provided in the present invention further illustrate and exemplify the compounds of the present invention and their preparation methods. It should be understood that the following preparation examples and examples do not limit the scope of the present invention in any way.

[0156] In addition, it should be understood that the terms used herein are intended to describe specific implementation manners and are not intended to be limiting. In addition, although any methods, devices and materials similar or equivalent to those described herein can be used to implement or test the present invention, the methods, devices and materials described now are preferred.

[0157] LC-MS analysis method:

[0158] Mass spectrometry conditions: Instrument Thermo ISQ EC; Ion source ESI (EA+EA-); Source temperature 300 °C; Sheath gas pressure 50.0 psi; Auxiliary gas pressure 5.0 psi; Purge gas pressure 0.5 psi; Vaporization chamber temperature 300 °C.

[0159] Chromatography conditions: Instrument Thermo U3000; Detector DAD-3000 (RS) (diode array detector); Chromatographic column Phenomenex Titank C18 3μm 4.6×50mm; Flow rate 2.0 mL / min, split flow; Column temperature 35 °C; Mobile phase B is water containing 0.05% formic acid and 5% acetonitrile, and mobile phase A is acetonitrile containing 0.05% formic acid; Elution method: within 0 - 1.0 min, phase B is linearly eluted from 100% to 5%, then phase B at 5% is held for 0.5 min, and finally rinsed with 100% phase A for 0.5 min.

[0160] HPLC analysis method:

[0161] Instrument: Thermo U3000; Detector: VWD-3×00(RS) (ultraviolet detector); Wavelength: 254 nm; Chromatographic column: Shimadzu inertsil 3μm 4.6×150 mm; Flow rate: 0.8 mL / min; Column temperature: 35 °C; Mobile phase A: water containing 0.05% formic acid and 5% acetonitrile, Mobile phase B: acetonitrile containing 0.05% formic acid; Elution method: First, hold with 100% of phase A for 1.0 min, then within 1.0 - 8.0 min, linearly elute phase A from 100% to 5%, and finally hold with 5% of phase A for 4.0 min.

[0162] 1 H-NMR analysis method:

[0163] 1 H-NMR was measured at room temperature using a BRUKER AVANCE-400 MHz nuclear magnetic resonance spectrometer in DMSO-d 6 or CDCl 3 etc. with TMS as the internal standard, and the signal peaks were expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doubledoublet). The unit of the coupling constant (J) is hertz (Hz).

[0164] According to the above-described method, the representative compounds I-1 - I-211 (see Table 1) of the present invention were prepared.

[0165] Table 1 Representative Compounds I-1 - I-211 of the Present Invention

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] The content of the present invention will be further elaborated below in combination with specific examples, but the protection scope of the present invention is not limited to these examples only. Unless otherwise specified, the percentages described in the present invention are all weight percentages. The numerical ranges described in the specification, such as measurement units, reaction conditions, physical states of compounds or percentages, are all provided for clear written reference. When those skilled in the art implement the present invention, it is still possible to obtain the expected results by using temperatures, concentrations, quantities, numbers of carbon atoms, etc. outside this range or different from single values. In addition, unless otherwise specified, the raw materials in the following examples can all be obtained commercially, for example, they can be purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd., Jiangsu Aikon Biopharmaceutical R & D Co., Ltd., Nanjing Pharmaceutical Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Herchun Biotechnology (Shanghai) Co., Ltd., Shanghai Haohong Biopharmaceutical Technology Co., Ltd., Anhui Zesheng Technology Co., Ltd.

[0175] Key Abbreviations

[0176]

[0177] Synthesis of Intermediate I-1b-4

[0178]

[0179] Step 1: Synthesis of Intermediate I-1b-2

[0180] Dissolve commercially available I-1b-1 (51.50 g, 367.59 mmol, 1.0 eq) in ACN (600 mL), displace nitrogen 3 times, and cool to 0 °C. Add NBS (68.70 g, 385.97 mmol, 1.05 eq) in batches, control the temperature below 5 °C, and react the resulting mixture at room temperature for 3 h. Dilute the reaction solution with EA (2000 mL), wash it twice with saturated NaHSO 3 solution (1000 mL), and dry it with anhydrous Na 2 SO 4 and concentrate. The obtained crude yellowish-brown solid I-1b-2 is directly used in the next step without purification. (76.53 g, yield 95.1%). LC-MS MS-ESI (m / z) 217.1 [M+H] - .

[0181] Step 2: Synthesis of Intermediate I-1b-3

[0182] Dissolve I-1b-2 (79.53 g, 363.15 mmol, 1.0 eq) in DMF (700 mL), displace nitrogen 3 times, and add CH 2 I 2 (99.20 g, 370.41 mmol, 1.02 eq) and K2 CO 3 (150.56 g, 1089.45 mmol, 3.0 eq), heated to 60 °C, reacted for 18 h, and cooled to room temperature. The reaction was quenched with water (2000 mL), and extracted three times with EA (800 mL). The organic phases were combined, washed three times with saturated brine (1000 mL), and dried over anhydrous Na 2 SO 4 and concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 10 / 1) to obtain white solid I-1b-3. (57.00 g, yield 67.9%). 1 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.91 (d, J = 9.2 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 6.04 (s, 2H), 3.89 (s, 3H).

[0183] Step 3: Synthesis of intermediate I-1b-4

[0184] Dissolve I-1b-3 (45.00 g, 194.81 mmol, 1.0 eq) in DCM (500 mL), displace nitrogen three times, and cool to 0 °C. Add dropwise a commercially available 2M BBr 3 DCM solution (194.81 mL, 389.62 mmol, 2.0 eq), and stir for 2 h. Slowly pour the reaction solution into 10% NaOH ice / water solution (1500 mL) to quench the reaction, stirring while adding. Then adjust the pH to 4 - 5 with 1M dilute hydrochloric acid, and extract twice with EA (1000 mL). The organic phases were combined, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 5 / 1 and 3 / 1) to obtain yellow solid I-1b-4. (27.98 g, yield 66.2%). 1 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.85 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 9.2 Hz, 1H), 6.04 (s, 2H), 4.89 (br s, 1H).

[0185] Synthesis of intermediate I-12b

[0186]

[0187] Step 1: Synthesis of intermediate I-12b-2

[0188] Dissolve commercially available I-12b-1 (52.00 g, 405.93 mmol, 1.0 eq) in DMF (800 mL), and add Cs 2 CO 3 (264.51 g, 811.87 mmol, 2.0 eq) and CH 2 I 2 (130.45 g, 487.12 mmol, 1.2 eq). Heat the resulting mixture to 100 °C, react for 18 h, and cool to room temperature. Quench the reaction with water (2000 mL), and extract twice with DCM (1000 mL). Combine the organic phases, wash three times with saturated brine (1000 mL), and dry over anhydrous Na 2 SO 4 . Concentrate below 30 °C. After separation of the crude product by silica gel column chromatography (PE / DCM (v / v) = 2 / 1), light yellow oily I-12b-2 is obtained. (34.50 g, yield 60.7%). 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 6.72 (m, 1H), 6.61 (m, 1H), 6.51 (m, 1H), 5.97 (s, 2H).

[0189] Step 2: Synthesis of intermediate I-12b-3

[0190] Dissolve I-12b-2 (5.50 g, 39.26 mmol, 1.0 eq) in ultradry THF (60 mL), displace nitrogen three times, cool to -70 °C, and dropwise add a THF / Hexane solution of 2M LDA (23.55 mL, 47.11 mmol, 1.2 eq). After stirring at this temperature for 30 min, dropwise add a THF (20 mL) solution of B(OMe) 3 (4.89 g, 47.11 mmol, 1.2 eq), and keep the temperature not exceeding -65 °C during the dropping process. Stir the resulting mixture at room temperature for 2 h, slowly pour it into saturated NH 4 Cl solution (200 mL) to quench, and extract twice with EA (150 mL). Combine the organic phases, and dry over anhydrous Na 2 SO 4 . Concentrate. After separation of the crude product by silica gel column chromatography (PE / EA (v / v) = 2 / 1), yellow solid I-12b-3 is obtained. (1.69 g, yield 23.4%). LC-MS MS-ESI (m / z) 185.0 [M+H] + .

[0191] Step 3: Synthesis of intermediate I-12b-4

[0192] Dissolve I-12b-3 (1.69 g, 9.19 mmol, 1.0 eq) in AC (20 mL), add H 2 O (20 mL) and Oxone (6.36 g, 18.38 mmol, 0.5 eq), and react the resulting mixture at room temperature for 18 h. Quench the reaction with water (200 mL) and extract twice with EA (100 mL). Combine the organic phases, dry over anhydrous Na 2 SO 4 and concentrate. After separation of the crude product by silica gel column chromatography (PE / EA (v / v) = 2 / 1), white solid I-12b-4 was obtained. (800.0 mg, yield 55.8%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.95 (s, 1H), 6.61 (dd, J = 11.8, 8.6 Hz, 1H), 6.37 (dd, J = 8.5, 3.7 Hz, 1H), 5.98 (s, 2H).

[0193] Step 4: Synthesis of intermediate I-12b-5

[0194] Dissolve I-12b-4 (16.00 g, 102.50 mmol, 1.0 eq) in AcOH (500 mL), add NIS (27.67 g, 123.00 mmol, 1.2 eq) portionwise, and displace nitrogen three times. Heat the resulting mixture to 40 °C and react for 4 h, then cool to room temperature. Dilute the reaction solution with EA (500 mL), wash twice with water (300 mL) and once with saturated brine (300 mL), dry over anhydrous Na 2 SO 4 and concentrate. After separation of the crude product by silica gel column chromatography (PE / EA (v / v) = 10 / 1), brown solid I-12b-5 was obtained. (19.05 g, yield 65.9%). 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 6.85 - 6.96 (m, 1H), 6.06 (s, 2H), 5.18 (br s, 1H).

[0195] Step 5: Synthesis of intermediate I-12b-7

[0196] Dissolve I-12b-5 (16.00 g, 56.74 mmol, 1.0 eq) in DMSO (320 mL), add I-12b-6 (33.19 g, 170.22 mmol, 3.0 eq), KF (19.78 g, 340.44 mmol, 6.0 eq), Pd(dppf)Cl 2 ·CH 2 Cl2 (4.62 g, 5.67 mmol, 0.1 eq) and H 2 O (32 mL), the nitrogen was displaced three times, heated to 120 °C, reacted for 3 h, and cooled to room temperature. NIS (27.67 g, 123.00 mmol, 1.2 eq) was added in batches, and the nitrogen was displaced three times. The resulting mixture was heated to 40 °C, reacted for 4 h, and cooled to room temperature. The reaction solution was quenched with water (1000 mL), washed three times with EA (500 mL), washed three times with saturated brine (500 mL), and anhydrous Na 2 SO 4 dried and concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 5 / 1) to obtain a brown solid I-12b-7. (7.20 g, yield 65.0%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 10.06 - 10.18 (m, 1H), 6.68 (d, J = 12.0 Hz, 1H), 6.06 (s, 2H), 3.81 (s, 2H).

[0197] Step 6: Synthesis of intermediate I-12b

[0198] Dissolve I-12b-7 (7.20 g, 36.90 mmol, 1.0 eq) in a solution of 4M HCl(g) in MeOH (70 mL). The resulting mixture was heated to 65 °C, reacted for 5 h, and cooled to room temperature. The reaction solution was concentrated, and the residue was diluted with EA (200 mL). The solid was collected by filtration, washed three times with n-hexane (50 mL), and then washed once by pulping with EA (20 mL). After drying in a blast drying oven at 50 °C for 3 h, a yellow-green solid I-12b was obtained. (5.86 g, yield 69.6%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.90 (s, 1H), 6.58 (d, J = 12.4 Hz, 1H), 5.98 (s, 2H), 3.61 (s, 3H), 3.51 (s, 2H).

[0199] Synthesis of intermediate I-14b

[0200]

[0201] Step 1: Synthesis of intermediate I-14b-5

[0202] Dissolve I-1b-4 (27.98 g, 128.94 mmol, 1.0 eq) in ACN (400 mL), and add NCS (17.73 g, 132.81 mmol, 1.03 eq) and 1 M dilute hydrochloric acid (0.26 mL, 0.26 mmol, 0.002 eq). The resulting mixture is reacted at room temperature for 18 h. Dilute the reaction solution with EA (1000 mL), and wash it twice with saturated NaHSO 3 solution (500 mL), and dry it with anhydrous Na 2 SO 4 and concentrate. After separation by silica gel column chromatography (PE / EA (v / v) = 10 / 1 and 5 / 1), yellow oily I-14b-5 is obtained. (29.80 g, yield 91.9%). 1 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.99 (s, 1H), 6.09 (s, 2H), 5.41 (s, 1H).

[0203] Step 2: Synthesis of intermediate I-14b-6

[0204] Dissolve I-14b-5 (29.80 g, 118.49 mmol, 1.0 eq) in DCM (400 mL), add TBSCl (35.71 g, 236.98 mmol, 2.0 eq), and add imidazole (24.21 g, 355.47 mmol, 3.0 eq) in batches. The resulting mixture is reacted at room temperature for 2 h. Quench the reaction with water (1000 mL), separate the organic phase, and extract the aqueous phase twice with DCM (500 mL). Combine the organic phases, and dry them with anhydrous Na 2 SO 4 and concentrate. After separation by silica gel column chromatography (PE / EA (v / v) = 30 / 1), yellow oily I-14b-6 is obtained. (40.10 g, yield 92.5%). 1 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.99 (s, 1H), 6.02 (s, 2H), 1.02 (s, 9H), 0.22 (s, 6H).

[0205] Step 3: Synthesis of intermediate I-14b-7

[0206] The commercially available Zn powder (25.20 g, 384.24 mmol, 10.0 eq) was added to ultradry THF (300 mL). The nitrogen was displaced three times, and then 1,2-dibromoethane (2.16 g, 11.48 mmol, 0.3 eq) and TMSCl (2.08 g, 19.14 mmol, 0.5 eq) were added. The resulting mixture was heated to 60 °C and stirred for 30 min. A solution of methyl bromoacetate (17.57 g, 114.85 mmol, 3.0 eq) in THF (100 mL) was slowly added dropwise. After the addition, the reaction continued at 60 °C for 1 h and then cooled to room temperature. To the above zinc reagent, I-14b-6 (14.00 g, 38.28 mmol, 1.0 eq), Xphos (1.82 g, 3.83 mmol, 0.1 eq) and Pd 2 (dba) 3 (1.75 g, 1.91 mmol, 0.05 eq) were added. The nitrogen was displaced three times, and the mixture was heated to 50 °C and reacted for 18 h, then cooled to room temperature. It was filtered through diatomaceous earth and washed three times with EA (20 mL). The filtrate was concentrated. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 10 / 1 and 5 / 1) to obtain the yellow solid I-14b-7. (8.60 g, yield 62.6%). 1 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.76 (s, 1H), 5.95 (s, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 1.03 (s, 9H), 0.02 (s, 6H).

[0207] Step 4: Synthesis of intermediate I-14b

[0208] I-14b-7 (8.60 g, 23.96 mmol, 1.0 eq) was dissolved in THF (45 mL), and the commercially available 1 M TBAF solution (31.15 mL, 31.15 mmol, 1.3 eq) was added. The resulting mixture was reacted at room temperature for 30 min. The reaction solution was diluted with EA (300 mL), washed three times with 0.5 M dilute hydrochloric acid (100 mL) and once with saturated brine (200 mL), and dried over anhydrous Na 2 SO 4 4. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 3 / 1 and 2 / 1), and then slurried with PE (60 mL) to obtain the white solid I-14b. (4.88 g, yield 83.3%). LC-MS MS-ESI (m / z) 243.2 [M+H] - . 1 1H-NMR (400 MHz, DMSO-d 6)δ ppm 10.06 (s, 1H), 6.79 (s, 1H), 6.02 (s, 2H), 3.61 (s, 3H), 3.54 (s, 2H).

[0209] Example 71: Synthesis of Compound I-71

[0210]

[0211] Step 1: Synthesis of Intermediate I-71c

[0212] Dissolve commercially available I-34a (480.00 mg, 2.15 mmol, 1.0 eq) and I-12b (489.70 mg, 2.15 mmol, 1.0 eq) in Xylene (12 mL) and DMSO (3 mL), and add DMAP (1.05 g, 8.58 mmol, 4.0 eq). Heat the resulting mixture to 130 °C by microwave for 3.5 h, and then cool to room temperature. Quench the reaction with water (60 mL) and extract 3 times with EA (60 mL). Combine the organic phases, wash 3 times with saturated brine (100 mL), and dry over anhydrous Na 2 SO 4 Dry and concentrate. The crude product is separated by silica gel column chromatography (PE / EA (v / v) = 1 / 1 and 0 / 1) to obtain yellow solid I-71c. (561.00 mg, yield 62.9%). LC-MS MS-ESI (m / z) 416.1 [M+H] + .

[0213] Step 2: Synthesis of Intermediate I-71d

[0214] Dissolve I-71c (516.00 mg, 1.24 mmol, 1.0 eq) in THF (20 mL), and add an aqueous solution of LiOH·H 2 O (521.70 mg, 12.42 mmol, 10.0 eq) in H 2 O (20 mL). Heat the resulting mixture to 60 °C for 2 h, and then cool to room temperature. Concentrate to remove THF, and adjust the pH of the remaining aqueous phase to 5-6 with 1 M dilute hydrochloric acid. Filter to collect the precipitated solid, wash 3 times with water (2 mL), and dry in a 60 °C forced-air drying oven for 5 h to obtain off-white solid I-71d. (280.00 mg, yield 56.2%). LC-MS MS-ESI (m / z) 402.1 [M+H] + .

[0215] Step 3: Synthesis of Compound I-71

[0216] Suspend I-71d (2.10 g, 5.23 mmol, 1.0 eq) and I-3e (1.05 g, 7.85 mmol, 1.5 eq) in THF (200 mL), add NMI (3.87 g, 47.10 mmol, 9.0 eq) and TCFH (4.41 g, 15.70 mmol, 3.0 eq). The resulting mixture is reacted at room temperature for 16 h, quenched with water (300 mL), and extracted twice with EA (200 mL). Combine the organic phases, wash once with saturated brine (200 mL), and dry over anhydrous Na 2 SO 4 Dry and concentrate. The crude product is separated by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1, 30 / 1, 20 / 1), and then slurried with MeOH (20 mL) to obtain an off-white solid I-71. (699.00 mg, yield 25.1%). LC-MS MS-ESI (m / z) 517.4 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 12.69 (s, 1H), 10.19 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.12 - 7.04 (m, 2H), 6.63 (d, J = 5.2 Hz, 1H), 6.15 (s, 2H), 3.95 (s, 6H), 3.83 (s, 2H).

[0217] Example 81: Synthesis of Compound I-81

[0218]

[0219] Step 1: Synthesis of Intermediate I-81c

[0220] Dissolve commercially available I-34a (671.10 mg, 3.00 mmol, 1.0 eq) and I-14b (733.80 mg, 3.00 mmol, 1.0 eq) in Xylene (12 mL) and DMSO (3 mL), and add DMAP (1.47 g, 12.00 mmol, 4.0 eq). The resulting mixture is heated to 130 °C by microwave and reacted for 3.5 h, then cooled to room temperature. Quench the reaction with water (80 mL), and extract three times with EA (80 mL). Combine the organic phases, wash three times with saturated brine (100 mL), and dry over anhydrous Na 2 SO 4Drying, concentration. After separation by silica gel column chromatography (PE / EA (v / v) = 1 / 1 and 0 / 1), a light yellow solid I-81c was obtained. (980.00 mg, yield 75.7%). LC-MS MS-ESI (m / z) 432.1 [M+H] + 。

[0221] Step 2: Synthesis of intermediate I-81d

[0222] Dissolve I-81c (980.00 mg, 2.27 mmol, 1.0 eq) in THF (30 mL), and add an aqueous solution of LiOH·H 2 O (1.91 g, 45.39 mmol, 20.0 eq) in H 2 O (30 mL). Heat the resulting mixture to 60 °C, react for 2 h, and cool to room temperature. Concentrate to remove THF, and adjust the pH of the remaining aqueous phase to 5-6 with 1 M dilute hydrochloric acid. Filter to collect the precipitated solid, wash it 3 times with water (2 mL), and dry it in a blast drying oven at 60 °C for 5 h to obtain an off-white solid I-81d. (576.00 mg, yield 60.7%). LC-MS MS-ESI (m / z) 418.1 [M+H] + 。Step 3: Synthesis of compound I-81

[0223] Suspend I-81d (1.70 g, 4.07 mmol, 1.0 eq) and I-1e (898.40 mg, 6.10 mmol, 1.5 eq) in THF (150 mL), and add NMI (1.50 g, 18.31 mmol, 3.0 eq) and TCFH (1.71 g, 6.10 mmol, 1.5 eq). React the resulting mixture at room temperature for 16 h, quench the reaction with water (300 mL), and extract it 2 times with EA (200 mL). Combine the organic phases, wash them once with saturated brine (200 mL), and dry them over anhydrous Na 2 SO 4 Dry, concentrate. After separation by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1, 30 / 1, 20 / 1), and then slurrying with MeOH (20 mL), a white solid I-81 was obtained. (1.02 g, yield 43.6%). LC-MS MS-ESI (m / z) 547.2 [M+H] + 。 1 H-NMR (400 MHz, DMSO-d 6)δ ppm 10.40 (s, 1H), 8.84 (d, J = 6.4 Hz, 1H), 8.34 (s, 1H), 7.74 - 7.69 (m, 2H), 7.66 (s, 1H), 7.38 - 7.32 (m, 2H), 7.30 (s, 1H), 7.05 (d, J = 6.4 Hz, 1H), 6.20 (s, 2H), 4.04 (s, 6H), 4.03 (s, 3H), 3.94 (s, 2H).

[0224] Example 140: Synthesis of Compound I-140

[0225]

[0226] The light yellow solid I-140 was prepared from I-71d (60.00 mg, 0.15 mmol, 1.0 eq), commercially available I-140e (45.00 mg, 0.29 mmol, 2.0 eq), NMI (100.00 mg, 1.22 mmol, 8.1 eq) and TCFH (120.00 mg, 0.43 mmol, 2.9 eq) according to the similar procedure in Example 1. (11.50 mg, yield 13.2%). LC-MS MS-ESI (m / z) 535.1 [M+H] + . 1 1H-NMR (400 MHz, DMSO-d 6 )δ ppm 12.79 (s, 1H), 10.28 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 11.2, 2.1 Hz, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.33 (dd, J = 8.6, 2.0 Hz, 1H), 7.07 (d, J = 12.0 Hz, 1H), 6.63 (d, J = 5.1 Hz, 1H), 6.15 (s, 2H), 3.96 (s, 6H), 3.85 (s, 2H).

[0227] Synthesis of Intermediate I-161d

[0228]

[0229] Step 1: Synthesis of Intermediate I-161c

[0230] The yellow solid I-161c was prepared by a similar procedure to that in Intermediate I-1c from I-156a (212.00 mg, 1.00 mmol, 1.0 eq), I-1b (210.00 mg, 1.00 mmol, 1.0 eq), DMAP (370.00 mg, 3.03 mmol, 3.0 eq), Xylene (12 mL) and DMSO (3 mL). (150.00 mg, yield 38.9%). LC-MS MS-ESI (m / z) 386.0 [M+H] + .

[0231] Step 2: Synthesis of Intermediate I-161d

[0232] Suspend I-161c (150.00 mg, 0.39 mmol, 1.0 eq) in MeOH (15 mL), and add an aqueous solution of LiOH·H 2 O (350.00 mg, 8.33 mmol, 21.4 eq) in H 2 O (15 mL). After stirring the resulting mixture at room temperature for 1 h, adjust the pH to 6 - 7 with 1 M dilute hydrochloric acid. Filter to collect the precipitated solid, wash it 3 times with water (1 mL), and dry it in a blast drying oven at 50 °C for 8 h to obtain the white solid I-161d. (125.00 mg, yield 86.5%). LC-MS MS-ESI (m / z) 372.0 [M+H] + .

[0233] Synthesis of Intermediate I-171d

[0234]

[0235] Step 1: Synthesis of Intermediate I-171c

[0236] Dissolve I-156a (846.00 mg, 4.00 mmol, 1.0 eq) and I-12b (913.00 mg, 4.00 mmol, 1.0 eq) in Xylene (10 mL) and DMSO (2 mL), and add 4-PPy (1.78 g, 12.00 mmol, 3.0 eq). Heat the resulting mixture to 150 °C by microwave for 3.5 h, and then cool it to room temperature. Quench the reaction with water (60 mL), and extract it 3 times with EA (60 mL). Combine the organic phases, wash them 3 times with saturated brine (100 mL), and use anhydrous Na 2 SO 4Drying, concentration. After separation by silica gel column chromatography (PE / EA (v / v) = 1 / 1 and 0 / 1), the crude product gave a pale yellow solid I-171c. (820.00 mg, yield 50.8%). LC-MS MS-ESI (m / z) 404.0 [M+H] + .

[0237] Step 2: Synthesis of intermediate I-171d

[0238] The pale yellow solid I-171d was prepared according to a similar procedure as in intermediate I-1d from I-171c (820.00 mg, 2.03 mmol, 1.0 eq) and LiOH·H 2 O (852.00 mg, 20.30 mmol, 10.0 eq). (560.00 mg, yield 70.8%). LC-MS MS-ESI (m / z) 390.0 [M+H] + .

[0239] Example 191: Synthesis of compound I-191

[0240]

[0241] Suspend I-171d (1.50 g, 3.85 mmol, 1.0 eq) and I-3e (769.80 mg, 5.78 mmol, 1.5 eq) in ACN (80 mL) and NMP (16 mL), add NMI (1.42 g, 17.34 mmol, 4.5 eq) and TCFH (1.62 g, 5.78 mmol, 1.5 eq), and stir the resulting solution at room temperature for 18 h. Concentrate the reaction mixture to remove ACN, dilute the residue with water (150 mL), filter to collect the precipitated solid, and wash it three times with water (5 mL). Dissolve the crude product in DCM / MeOH (10 / 1, 400 mL), separate the water. Concentrate the organic phase, separate by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1, 30 / 1, 20 / 1, 10 / 1), and then slurry with MeOH (50 mL) to give an off-white solid I-191. (1.10 g, yield 53.9%). LC-MS MS-ESI (m / z) 505.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6)δ ppm 12.65 (s, 1H), 10.15 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 11.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.14 - 7.02 (m, 2H), 6.73 (d, J = 5.1 Hz, 1H), 6.15 (s, 2H), 4.03 (s, 3H), 3.82 (s, 2H).

[0242] Synthesis of Intermediate I-210e

[0243]

[0244] Step 1: Synthesis of Intermediate I-210e-1

[0245] Dissolve commercially available I-206h (850.00 mg, 3.78 mmol, 1.0 eq) in dioxane (12 mL), add BocNH 2 (1.30 g, 11.10 mmol, 2.9 eq), Cs 2 CO 3 (3.40 g, 10.44 mmol, 2.8 eq) and Xphos-Pd-G4 (325.30 mg, 0.38 mmol, 0.1 eq). The resulting mixture was purged with nitrogen for 15 s, heated to 100 °C by microwave, reacted for 3 h, and cooled to room temperature. Quench the reaction with water (100 mL) and extract 3 times with EA (80 mL). Combine the organic phases, wash once with saturated brine (80 mL), and dry over anhydrous Na 2 SO 4 Dry and concentrate. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 2 / 1 and 1 / 1) to obtain I-210e-1 as a brown oil. (910.00 mg, yield 91.8%). LC-MS MS-ESI (m / z) 262.1 [M+H] + .

[0246] Step 2: Synthesis of Intermediate I-210e

[0247] Dissolve I-210e-1 (910.00 mg, 3.47 mmol, 1.0 eq) in DCM (20 mL), add TFA (10 mL), and stir the resulting mixture at room temperature for 0.5 h. Concentrate the reaction solution, neutralize the residue with saturated NaHCO 3 solution (100 mL), and extract 3 times with DCM (50 mL). Combine the organic phases, and dry over anhydrous Na 2 SO 4After drying and concentration, a brown solid I-210e was obtained. (540.00 mg, yield 96.5%). LC-MS MS-ESI (m / z) 162.0 [M+H] + 。

[0248] Example 210: Synthesis of Compound I-210

[0249]

[0250] The off-white solid I-210 was prepared according to a similar procedure as in Example 15 from I-71d (1.22 g, 3.04 mmol, 1.0 eq), I-210e (540.00 mg, 3.35 mmol, 1.1 eq), NMI (0.95 g, 11.60 mmol, 3.8 eq) and TCFH (1.80 g, 6.40 mmol, 2.1 eq). (1.44 g, yield 84.6%). LC-MS MS-ESI (m / z) 545.4 [M+H] + 。 1 1H-NMR (400 MHz, DMSO-d 6 ) δ ppm 10.25 (s, 1H), 8.69 (s, 1H), 8.20 (s, 1H), 7.59 (d, J = 14.3 Hz, 2H), 7.50 (s, 1H), 7.12 (s, 1H), 7.05 (d, J = 11.9 Hz, 1H), 6.92 (s, 1H), 6.15 (s, 2H), 3.97 (d, J = 11.9 Hz, 9H), 3.86 (s, 2H), 2.40 (s, 3H).

[0251] Intermediate: Synthesis of I-211e

[0252]

[0253] Dissolve I-183e (502.80 mg, 3.00 mmol, 1.0 eq) in dioxane (15 mL), add I-17d-1 (1.13 g, 9.00 mmol, 3.0 eq), K 2 CO 3 (1.24 g, 9.00 mmol, 3.0 eq) and Xphos Pd G4 (258.20 mg, 0.30 mmol, 0.1 eq). The resulting mixture was purged with nitrogen for 15 s, heated to 110 °C by microwave, reacted for 4 h, and cooled to room temperature. Quench the reaction with water (150 mL) and extract 3 times with EA (100 mL). Combine the organic phases, wash once with saturated brine (100 mL), and anhydrous Na 2 SO 4Drying, concentration. After the crude product was separated by silica gel column chromatography (PE / EA (v / v) = 1 / 1 and 0 / 1), gray solid I-211e was obtained. (353.00 mg, yield 79.9%). LC-MS MS-ESI (m / z) 148.1 [M+H] + 。

[0254] Example 211: Synthesis of Compound I-211

[0255]

[0256] Dissolve I-161d (450.00 mg, 1.21 mmol, 1.0 eq) and I-211e (214.10 mg, 1.45 mmol, 1.2 eq) in NMP (5 mL) and ACN (25 mL), add NMI (447.80 mg, 5.45 mmol, 4.5 eq) and TCFH (510.10 mg, 1.82 mmol, 1.5 eq), and react the resulting mixture at room temperature for 1 h. Concentrate the reaction solution to remove ACN, and dilute the residue with water (100 mL). Filter and collect the precipitated solid, wash it 3 times with water (2 mL), and dry it. The crude product was separated by silica gel column chromatography (DCM / MeOH (v / v) = 40 / 1 and 30 / 1), then slurried with EA (10 mL), and dried in a blast drying oven at 50 °C for 2 h to obtain off-white solid I-211. (363.00 mg, yield 58.9%). LC-MS MS-ESI (m / z) 501.1 [M+H] + 。 1 1H-NMR (400 MHz, DMSO-d 6 ) δ ppm 12.21 (s, 1H), 10.09 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 11.7 Hz, 1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.10 - 7.00 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 5.1 Hz, 1H), 6.09 (s, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 2.49 (s, 3H).

[0257] In addition, other compounds of the present invention can be prepared according to similar steps in the above examples.

[0258] In vitro biological evaluation

[0259] Example A Test of the inhibitory activity of the compounds of the present invention against PDGFRβ kinase

[0260] (1) Configuration of HTRF reaction system (HTRF KinEASE-TK kit, PerkinElmer, 62TK0PEJ)

[0261] Prepare 2× kinase & metal solution (PDGFRβ purchased from Carna, Cat#08-158) and 2× substrate & ATP solution (substrate is TK) according to the kit instructions. Transfer 50 nL of the compound to a 384-well plate. After centrifugation, add 2.5 μL of 2× kinase & metal solution and incubate at 25 °C for 10 minutes. Add 2.5 μL of 2× ATP & substrate solution and incubate at 25 °C for 50 minutes. Prepare 2× XL665 & antibody solution with Detection buffer and add 5 μL of 2× XL665 & antibody solution and incubate at 25 °C for 60 minutes. Detect the fluorescence signals at 620 nM and 665 nM using a microplate reader.

[0262] (2) Test for the inhibitory activity of the compound against PDGFRβ kinase

[0263] Compound preparation: Dissolve the compound in DMSO to 10000 nM, and then prepare gradient concentrations of 500 nM, 50 nM, and 5 nM. Configure the reaction solution according to the HTRF kit and perform the detection.

[0264] (3) Test for the inhibitory IC 50 activity of the compound against PDGFRβ kinase

[0265] Compound preparation: Dissolve the compound in DMSO to 10000 nM, and then prepare gradient concentrations of 300 nM, 100 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, 0.13 nM, 0.045 nM, 0.015 nM, and 0 nM. Configure the reaction solution according to the HTRF kit and perform the detection.

[0266] (4) Data analysis and processing

[0267] The positive control is the control compound (BIBF1120 or Staurosporine), and the negative control is set as 0.5% DMSO solvent control. The formula for calculating the % inhibition rate is % inhibition rate = 100% - (compound - positive control) / (negative control - positive control) * 100% (see Table 2); and calculate the half-maximal inhibitory concentration (IC 50 ) of each compound against the corresponding kinase using GraphPad 7.0 software (see Table 3).

[0268] Table 2 Inhibition rate of representative compounds of the present invention against PDGFRβ kinase

[0269]

[0270]

[0271]

[0272] The control molecule 01 is an example (No¬e

[36] ) disclosed in the patent US7973164B2 of AstraZeneca AB. The inventors synthesized this compound with reference to the synthesis method therein (the structure confirmation data includes LC-MS MS-ESI (m / z) 433.0 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.43 (s, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 7.30 (m, 2H), 6.95 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 3.64 (s, 2H), 2.11 (s, 3H).), which is used as a control molecule. The structural formula of this compound is as follows:

[0273]

[0274] As can be seen from the above results, the inhibitory activities of the compounds described in the present invention are all higher than 80% at a concentration of 50 nM, and all higher than 50% at a concentration of 5 nM. Whether at a concentration of 50 nM or 5 nM, the inhibitory activity against PDGFRβ kinase is stronger than that of the control molecule 01, indicating that the compounds of the present invention have unexpectedly excellent inhibitory activity against PDGFRβ kinase. The compounds of the general formula (I) described in the present invention also have excellent activity in inhibiting PDGFRβ kinase and can be used as drugs for treating or preventing diseases related to this effect.

[0275] Table 3 IC 50

[0276]

[0277] As can be seen from the above results, the IC 50 of the compounds described in the present invention for inhibiting PDGFRβ kinase are all below 3 nM, and have excellent inhibitory activity against PDGFRβ kinase. Compared with the IC 50 of the control molecule for inhibiting PDGFRβ kinase, the IC 50It is more than 10 times stronger and has significantly higher inhibitory activity against the PDGFRβ kinase.

Claims

1. A compound represented by formula (I), or a deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof: in, X is selected from CH or N; R 1 Selected from C 1-6 Alkyl, C 1-6 haloalkyl, 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the C 1-6 Alkyl is unsubstituted or substituted with one or more selected from R 1A The 4-10 membered heterocyclic group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Each R 1A Each independently selected from hydroxyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the 4-10 membered heterocyclic group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; R 2 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; or R 1 and R 2 The carbon atom and oxygen atom connected thereto together form a 5-10 membered heterocyclic group; the 5-10 membered heterocyclic group contains 0-3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the 5-10 membered heterocyclic group is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; Each R 1B Each independently selected from C 1-6 Alkyl, halogen, C 1-6 Haloalkyl substitution; R 3 , R 6 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl; R 4 , R 5 , R 8 , R 9 Each is independently selected from hydrogen, deuterium, and halogen; Ring A is selected from C 3-10 Cycloalkyl, C 6-10 Aryl, 4-12 membered heterocyclic group; the 4-12 membered heterocyclic group contains 1-4 heteroatoms selected from N, O, S; R 7 Selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl; m is selected from 0, 1, 2, 3, 4, 5, 6.

2. The compound according to claim 1, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt, characterized in that: R 1 Selected from C 1-3 Alkyl, C 4-6 Alkyl, C 1-3 Haloalkyl, C 4-6 haloalkyl, 4-6 membered heterocyclic group, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl group is unsubstituted or substituted with one or more selected from R 1A The heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B Substituents are substituted; Preferably, R 1 Selected from C 1-3 Alkyl, C 1-3 haloalkyl, 4-6 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl group is unsubstituted or substituted with one or more selected from R 1A The heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B Substituents are substituted; or preferably, R 1 is selected from C4 alkyl, C5 alkyl, C6 alkyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl, 4-6 membered heterocyclic group, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl is unsubstituted or substituted by one or more selected from R 1A The heterocyclic group is unsubstituted or substituted by one or more substituents selected from R 1B Substituents are substituted; More preferably, R 1 is selected from methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, 4-6 membered heterocycloalkyl; the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more selected from R 1A The heterocycloalkyl group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, R 1 is selected from methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, heterocyclobutane, heterocyclopentane, heterocyclohexane; the heterocyclobutane, heterocyclopentane, heterocyclohexane contains 1-2 heteroatoms selected from N, O, S; the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more selected from R 1A The heterocyclobutane, heterocyclopentane, heterocyclohexane are unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, R 1 is selected from methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, butylene oxide, pentane oxide, tetrahydropyran, pyrrolidine, morpholine, piperidine; the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more selected from R 1A The butylene oxide, pentylene oxide, tetrahydropyran, pyrrolidine, morpholine, piperidine is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, R 1 is selected from methyl, ethyl, propyl, isopropyl, -CH2CH2F, -CH2CHF2, -CH2CH2CH2F, pentyl oxide; the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more selected from R 1A Substituents are substituted; Preferably, each R 1A Each independently selected from hydroxyl, C 1-3 Alkoxy, C 4-6 Alkoxy, C 1-3 Halogenated alkoxy, C 4-6 haloalkoxy, 4-6 membered heterocyclic group, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the heterocyclic group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; More preferably, each R 1A Each independently selected from hydroxyl, C 1-3 Alkoxy, C 1-3 A halogenated alkoxy group, a 4-6 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; Or more preferably, each R 1A Each is independently selected from hydroxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C4 haloalkoxy, C5 haloalkoxy, C6 haloalkoxy, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the heterocyclic group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, each R 1A Each is independently selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropoxy, 4-6 membered heterocycloalkyl; the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the heterocycloalkyl is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, each R 1A Each is independently selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropoxy, butylene oxide, pentylene oxide, tetrahydropyran, pyrrolidine, morpholine, piperidine; the butylene oxide, pentylene oxide, tetrahydropyran, pyrrolidine, morpholine, piperidine is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Also preferably, each R 1A Each is independently selected from hydroxyl, methoxy, morpholine, piperidine; the morpholine, piperidine is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; Preferably, each R 1B Each is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3; Or preferably, each R 1B Each is independently selected from bromine, iodine, C4 alkyl, C5 alkyl, C6 alkyl, bromomethyl, bromoethyl, bromopropyl, haloisopropyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl; More preferably, each R 1B Each is independently selected from methyl, ethyl, propyl, isopropyl; Also preferably, R 1 Selected from methyl, ethyl, propyl, isopropyl, -CH2CH2OH, -CH2CH2CH2OCH3, -CH2CH2OCH3, -CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CH2F, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3 More preferably, R 1 Selected from methyl, -CH2CH2OH, -CH2CH2CH2OCH3, -CH2CH2OCH3, -CH2CH2F, -CH2CHF2, -CH2CH2CH2F, More preferably, R 1 Selected from methyl.

3. The compound according to claim 1, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt, characterized in that: R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl, C 4-6 Alkyl, C 1-3 Haloalkyl, C 4-6 Haloalkyl, C 1-3 Alkoxy, C 4-6 Alkoxy, C 1-3 Halogenated alkoxy, C 4-6 Haloalkoxy; Preferably, R 2 Selected from hydrogen, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy; Or preferably, R 2 Selected from bromine, iodine, C4 alkyl, C5 alkyl, C6 alkyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl, C 1-3 Alkoxy, C 4-6 Alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C4 haloalkoxy, C5 haloalkoxy, C6 haloalkoxy; More preferably, R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy; Also preferably, R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, methoxy, ethoxy , propoxy, isopropoxy, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3 , -OCH2Cl, -OCHCl2, -OCCl3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2CH2Cl, -OCH2CH2CHCl2, -OCH2CH2CCl3; More preferably, R 2 is selected from hydrogen, fluorine, methoxy, -OCH2CH2F, -OCH2CH2CH2F; More preferably, R 2 is selected from hydrogen, fluorine, methoxy; Preferably, R 1 and R 2 The carbon atom and oxygen atom connected thereto together form a 5-6-membered heterocyclic group, a 7-8-membered heterocyclic group, or a 9-10-membered heterocyclic group; the heterocyclic group contains 0-3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; More preferably, R 1 and R 2 The carbon atom and oxygen atom connected thereto together form a 5-6 membered heterocyclic group; the heterocyclic group contains 0-3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; Or more preferably, R 1 and R 2 The carbon atom and oxygen atom connected thereto together form a 7-8 membered heterocyclic group or a 9-10 membered heterocyclic group; the heterocyclic group contains 0-3 heteroatoms selected from N, O, and S in addition to the oxygen atom; the heterocyclic group is unsubstituted or substituted with one or more selected from R 1B Substituents are substituted; Also preferably, R 1 and R 2 The carbon and oxygen atoms connected to it together form The heterocyclic group is unsubstituted or substituted by one or more selected from R 1B Substituents are substituted; Preferably, each R 1B Each is independently selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3; Or preferably, each R 1B Each is independently selected from bromine, iodine, C4 alkyl, C5 alkyl, C6 alkyl, bromomethyl, bromoethyl, bromopropyl, haloisopropyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl; More preferably, R 1 and R 2 The carbon and oxygen atoms connected to it together form 4. The compound according to claim 1, or a deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, characterized in that: R 3 , R 6 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-3 Alkyl, C 4-6 Alkyl, C 1-3 Haloalkyl, C 4-6 Haloalkyl; Preferably, R 3 , R 6 are independently selected from hydrogen, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl; Or preferably, R 3 , R 6 Each is independently selected from bromine, iodine, C4 alkyl, C5 alkyl, C6 alkyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl, halomethyl, haloethyl, halopropyl, haloisopropyl; More preferably, R 3 , R 6 Each is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl; Also preferably, R 3 , R 6 Each is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3; More preferably, R 3 is selected from hydrogen and fluorine; More preferably, R 6 Selected from hydrogen, fluorine, chlorine, cyano, methyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3; preferably hydrogen, fluorine, chlorine, methyl, -CH2F, -CHF2, -CF3; More preferably, R 3 is selected from hydrogen, fluorine; R 6 Selected from hydrogen, fluorine, chlorine, cyano, methyl, -CH2F, -CHF2, -CF3.

5. The compound according to claim 1, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt, characterized in that: R 4 , R 5 , R 8 , R 9 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, and iodine; Preferably, R 4 , R 5 , R 8 , R 9 Each is independently selected from hydrogen, deuterium, fluorine, and chlorine; More preferably, R 4 , R 5 are each independently selected from hydrogen and deuterium; More preferably, R 8 , R 9 are each independently selected from hydrogen, deuterium, and fluorine; More preferably, R 4 and R 5 All are hydrogen; More preferably, R 4 and R 5 All are deuterium; More preferably, R 4 and R 5 Of these, one is hydrogen and the other is deuterium; More preferably, R 8 and R 9 All are hydrogen; More preferably, R 8 and R 9 All are deuterium; More preferably, R 8 and R 9 All are fluorine; More preferably, R 8 and R 9 One is hydrogen and the other is deuterium; or one is hydrogen and the other is fluorine; or one is deuterium and the other is fluorine.

6. The compound according to claim 1, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt, characterized in that: Ring A is selected from C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 7-8 Cycloalkyl, C 9-10 Cycloalkyl, benzene ring, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, 4-membered heterocyclic group, 5-6-membered heterocyclic group, 7-8-membered heterocyclic group, 9-10-membered heterocyclic group, 11-12-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, and S; Preferably, ring A is selected from C 5-6 Cycloalkyl, benzene ring, C9 aryl, C 10 Aryl, 5-6 membered heterocyclic group, 7-8 membered heterocyclic group, 9-10 membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, S; Or preferably, ring A is selected from C 3-4 Cycloalkyl, C 7-8 Cycloalkyl, C 9-10 Cycloalkyl, C7 aryl, C8 aryl, 4-membered heterocyclic group, 11-12-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from N, O, S; More preferably, ring A is selected from cyclohexane, 5-6 membered heterocycloalkyl, benzene ring, 5-membered heteroaryl, 6-membered heteroaryl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, pyrido 5-membered heteroaryl, pyrido 6-membered heteroaryl; the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S; Still more preferably, ring A is selected from cyclohexane, tetrahydropyran, piperidine, pyrrolidine, morpholine, a benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, benzothiazole, benzoxazole, pyrazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, imidazole, furan, thiophene, triazole, pyridine, pyrimidine, pyridazine, pyrazine, pyridopyrazole, pyridoimidazole, pyridisothiazole, pyridofuran, pyridoisoxazole, pyridotriazole, pyridothiophene, pyridothiazole, pyridooxazole; Still more preferably, ring A is selected from cyclohexane, tetrahydropyran, benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, pyrazole, isoxazole, thiazole, pyridopyrazole, pyridoimidazole, pyridine; Still more preferably, ring A is selected from cyclohexane, tetrahydropyran, benzene ring, benzopyrazole, benzimidazole, benzopyrrole, benzisothiazole, benzofuran, benzisoxazole, benzotriazole, benzothiophene, pyrazole, isoxazole, thiazole, pyridopyrazole, pyridoimidazole; Still preferably, ring A is selected from Still preferably, ring A is selected from Preferably, each R 7 Each independently selected from fluorine, chlorine, bromine, iodine, cyano, amino, C 1-3 Alkyl, C 4-6 Alkyl, C 1-3 Haloalkyl, C 4-6 Haloalkyl, C 1-3 Alkoxy, C 4-6 Alkoxy, C 1-3 Halogenated alkoxy, C 4-6 Halogenated alkoxy, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C 7-8 Cycloalkyl, C 9-10 Cycloalkyl; More preferably, each R 7 Each independently selected from fluorine, chlorine, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl; Or more preferably, each R 7 each independently selected from bromine, iodine, C4 alkyl, C5 alkyl, C6 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, C4 haloalkyl, C5 haloalkyl, C6 haloalkyl, C4 alkoxy, C5 alkoxy, C6 alkoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, C4 haloalkoxy, C5 haloalkoxy, C6 haloalkoxy, C7 cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, C 10 Cycloalkyl; More preferably, each R 7 Each is independently selected from methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, cyclopropane, cyclobutane, cyclopentane, cyclohexane; Also preferably, each R 7 each independently selected from methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, methoxy, ethoxy, propoxy, isopropoxy -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2CH2Cl, -OCH2CH2CHCl2, -OCH2CH2CCl3, cyclopropane, cyclobutane, cyclopentane, cyclohexane; Further preferably, each R 7 Each is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, isopropyl, methoxy, -CF3, -CH2F, -CHF2, -OCH2CF3, cyclopropane; preferably fluorine, methyl; Preferably, m is selected from 0, 1, 2, 3, 4; more preferably, m is selected from 0, 1, 2; further preferably, m is selected from 0, 1; More preferably, Selected from More preferably, Selected from More preferably, Selected from More preferably, Selected from Or more preferably, Selected from 7. The compound according to claim 1, 4 or 6, or a deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure of formula (II): Among them, R 2 is selected from hydrogen, fluorine or methoxy; R 4 and R 5 All are hydrogen or all are deuterium; Ring A, R 3 , R 6 , R 7 and m are as defined in claim 1, 4 or 6.

8. The compound according to any one of claims 1 to 7, or a deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a deuterated compound thereof is selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

10. Use of the compound according to any one of claims 1 to 8, or its deuterated compound, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing a disease associated with the biological activity of PDGFRβ kinase; Preferably, the disease associated with the biological activity of PDGFRβ kinase is a tumor or a hyperproliferative disease.

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