CN103304572A

CN103304572A - 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof

Info

Publication number: CN103304572A
Application number: CN2013100752901A
Authority: CN
Inventors: 万惠新; 李春丽; 韩雅男; 张永; 白蕊; 刘海燕; 马晨
Original assignee: Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2012-03-09
Filing date: 2013-03-08
Publication date: 2013-09-18

Abstract

The invention relates to a compound as shown in a formula I or a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, a tautomer, a polymorphic substance or metabolite, a pharmaceutical composition and medicinal usage of the compound. The compound as shown in the formula I or the pharmaceutically acceptable salt, the solvate, the prodrug, the stereoisomer, the tautomer, the polymorphic substance or metabolite and the pharmaceutical composition of the compound can be used as protein kinase inhibitors and particularly used for treating or preventing tumors.

Description

3-cyano quinoline compound and medicinal composition and application thereof

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to a compound with structural characteristics shown in a structural general formula I or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof. The invention also relates to a pharmaceutical composition containing the compound and application of the compound or the composition in preparing medicaments for treating or preventing tumors or protein kinase inhibitors.

Background

In recent years, the incidence of tumor diseases worldwide is on an increasing trend, and according to the statistical data of the world health organization, in 2007, newly diagnosed tumor patients reach more than 1200 million people, and malignant tumors (cancers) are one of the main diseases causing human death. It is expected that the number of new cases will reach 1500 million every year worldwide by 2020. According to the US IMS health data: in 2007, the market share of targeted antitumor drugs in 500-strength drugs in seven major medicine markets around the world reaches over 200 billion dollars, and is increased by 27.05% compared with the market share in the same period in the last year, and the increase rate of the targeted antitumor drugs is far higher than 19.94% of the market share in the global antitumor drugs. In 2008, the market of targeted antitumor drugs is in a remote lead with a sales volume of $ 290 hundred million, which is increased by 45% compared with the same period in the last year. Market analysts predict that by 2015, anti-tumor targeted therapeutic will exceed $ 500 billion with a compound annual growth rate of up to 11%, and that more than 8 new drugs will be grown in the field as "heavy pound bomb" products.

With the successive research and development of some novel tyrosine protein kinase inhibitors targeted antitumor drugs and the successful marketing of the drugs, the antitumor drugs are developing from the traditional non-selective single cytotoxic drugs to novel antitumor drugs aiming at the mechanism with multi-link effect, and the research and development of the antitumor drugs have entered a new era. The molecular target therapy of tumor is a therapeutic method based on that the key protein molecules closely related to the growth of tumor selectively kill tumor cells by chemical or biological means. The medicine has the characteristics of strong specificity, pertinence and effectiveness, good tolerance of patients and much lower toxic and side effects than the traditional chemotherapy medicines; when used together, can enhance the curative effect of the traditional radiotherapy and chemotherapy and reduce the relapse after operation. Imatinib, erlotinib, sunitinib, gefitinib, sorafenib, dasatinib, lapatinib, nilotinib and the like in the antitumor small-molecule targeted drugs which are currently on the market are protein kinase inhibitors.

At present, dozens of protein tyrosine kinase inhibitors are entering clinical trial stage, and some medicines are on the market and have obtained encouraging therapeutic results. The inhibitor, gleevec (imatinib mesylate), developed by Novartis corporation for tyrosine kinase Bcr-Abl in 5 months 2001, has a very good therapeutic effect on Chronic Myeloid Leukemia (CML), and has not been approved by FDA in advance for marketing in phase iii clinic, and is used for treating Philadelphia chromosome positive (Ph +) chronic myeloid leukemia patients, causing huge bombing. Gleevec is the second The successful development of a tumor treatment drug which is designed and developed after understanding the etiology of cancer and achieves remarkable effects can be said to be a milestone of cancer treatment. United states FDA re-approved Gleevec of Gleevec in month 2 2002^TMCan be used for treating gastrointestinal stromal tumors (GIST). In the 7 th 2002 year, Iressa TM (ZD1839 is approved by the US FDA to treat non-small cell lung cancer patients in the end stage that continue to deteriorate after standard platinum-containing schemes and docetaxel chemotherapy) developed by AstraZeneca, which is also the first target-specific challenge molecular tyrosine kinase inhibitor for solid tumor treatment, and the marketing of these small molecular tyrosine kinase inhibitor drugs further proves that the development of targeted antitumor drugs is the field of antitumor drugs that are most likely to be developed in breakthrough in the 21 st century, and has a very broad prospect.

Protein tyrosine kinases are proteins with tyrosine kinase activity, which can be divided into receptor type and non-receptor type, and can catalyze the transfer of phosphate groups on ATP to tyrosine residues of a plurality of important proteins to phosphorylate the proteins. Protein tyrosine kinase occupies a very important position in signal transduction pathways in cells, and regulates a series of biochemical processes such as growth, differentiation, death and the like in cells. The dysfunction of protein tyrosine kinase can cause a series of diseases in organisms. Data have shown that over 50% of proto-oncogenes and oncogene products have protein tyrosine kinase activity and that aberrant expression thereof leads to a disturbed regulation of cell proliferation and thus to tumorigenesis. In addition, the abnormal expression of tyrosine-based enzyme is closely related to the invasion and metastasis of tumors, the generation of tumor new vessels and the chemotherapy resistance of tumors.

At least nearly sixty receptor tyrosine kinases belonging to 20 families have been identified, for example, the Epidermal Growth Factor Receptor (EGFR) family comprises 4 members such as EGFR, ErbB2 and ErbB 4; the vascular endothelial cell growth factor receptor (VEGFR) family includes three members of VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1), VEGFR3 (Flt-4), etc.; the Platelet Derived Growth Factor Receptor (PDGFR) family includes members of PDGFR alpha, PDGFR beta, colony stimulating factor 1 receptor (CSF-1R), stem cell growth factor receptor (SCFR/KIT), FLK2/FLT3, and the like; the Fibroblast Growth Factor Receptor (FGFR) family comprises members of FGFR1 (flg), FGFR2 (bek), FGF3R, FGFR4 and the like; the Insulin receptor (instr) family includes three members of the Insulin receptor's related receptor (IRR) IRR1, IRR2, and IRR 3; receptors of the Hepatocyte Growth Factor Receptor (HGFR) family include members such as Met/HGFR and RON/MSPR; the Tie family includes two members: tie1 and Tie2 (Tek), and the like. There are mainly ten families of non-receptor tyrosine kinases, including SRC, ABL, JAK, CSK, FAK, FES, FRK, TEC, SYK, etc., which play important roles in signal transduction pathways, and recently, nearly half of the 32 cytoplasmic protein tyrosine kinases have been found to be closely related to human cancers. For example, the SRC family has identified members such as Fgr, Fyn, Sre, Yes, BIK, Hck, Lck, Lyn, etc.; the JAK (jamus kinase) family includes four members of TYK2, JAD1, JAK2, JAK 3; the ABL family includes two members, ABL and Arg; the JAK (jamus kinase) family includes four members of TYK2, JAD1, JAK2, JAK 3; the FAK family is Pyk2 (CAK. beta./RAFTK/cadTK/FAK 2) in addition to FAK.

Research shows that the occurrence and development of a plurality of tumors are closely related to protein kinase. EGFR is expressed in many tumor cells, such as non-small cell lung cancer, breast cancer, head and neck cancer, bladder cancer, gastric cancer, prostate cancer, ovarian cancer, glioma, and the like. In addition, EGFR depletion can also be detected in some tumors such as glioblastomas, non-small cell lung cancer, breast cancer, childhood gliomas, medulloblastomas, ovarian cancer, and the like. In addition, the abnormal expression of EGFR is closely related to angiogenesis, tumor invasion and metastasis, tumor chemotherapy resistance and prognosis. The tumor patients with high EGFR expression have high tumor malignancy degree, easy metastasis, short recurrence interval, high recurrence rate and short survival period of the patients. VEGF, the strongest known vascular penetrant and endothelial cell specific mitotic source, plays an important role in the proliferation, migration and vascular construction of endothelial cells, and the expression level of the VEGF has a clear positive correlation with the vascularization degree and malignancy degree of tumor tissues. PDGFR is mainly present in fibroblasts, smooth muscle cells, but is also expressed in the kidney, testis, and brain. PDGFR is closely related to tumorigenesis, and in most glioblastoma tumors, an autocrine loop formed by PDGF and its receptor exists, and this loop is very closely related to tumorigenesis and tumor development. In addition, similar circuits are also present in melanoma, meningioma, neuroendocrine tumor, ovarian cancer, prostate cancer, lung cancer, and pancreatic cancer. FGFs are mainly produced by mesoderm-derived cells, have strong proliferation and differentiation promoting effects, and have strong mitogenic effects on endothelial cells, vascular smooth muscle cells, fibroblasts and the like. In vivo and in vitro experiments show that the medicine has the function of promoting angiogenesis, and comprises the following components: (1) promoting proliferation and migration of vascular endothelial cells; (2) accelerate the release of protein kinase with the function of degrading basement membrane; (3) promoting endothelial cells to form tubular structures. In addition, FGF is also associated with the migration of tumor cells. IGF (Insulin-like growth factor) has the effects of promoting proliferation and inhibiting apoptosis on breast cancer, neck cancer, colon cancer, lung cancer and other tumors. IGF1R is overexpressed in breast cancer neck cancer and has a large impact on the pathological process of breast cancer. In addition, IGF1R is closely related to metastasis of melanoma on the fundus oculi and is a predictive factor for metastasis of such tumors. Receptors of Hepatocyte Growth Factor Receptor (HGFR) family include Met/HGFR and RON/MSPR, Met and HGF/SF are commonly expressed in various tumors such as breast cancer, colon cancer, gastric cancer, prostate cancer and the like, overexpression of Met and up-regulation of HGF/SF are closely related to metastasis and recurrence of the tumors, and existing researches show that Met is very likely to become an important index for diagnosing tumor metastasis and evaluating prognosis response. Further molecular mechanism research shows that HGF/SF can induce tyrosine phosphorylation of beta-catenin (beta-catenin) and break adhesion among tumor cells, thereby promoting cell movement. HGF/SF can also induce the expression of urokinase and its receptor, thus activating protein phosphorus signaling pathway, causing the degradation of extracellular matrix. Proteases degrade the extracellular matrix, disrupt cell adhesion, and increase cell motility are key to tumor cell invasion. The Tie family is mainly expressed in endothelial cells, and the expression of Tie1 and Tie2 can be detected in all endothelial cells in a fetus, while in the endothelial cells of adult tissues, the expression of Tie2 is mainly detected, and Tie1 is only expressed in part of vascular endothelial cells, and in addition, the over-expression of Tie is found in capillary hemangioblastoma, vascular endothelial cell tumor and gastric adenocarcinoma cells. Like VEGFR family members, Tie family members have a significant promoting effect on tumor neovascularization. The research of the knockout mice finds that the number of endothelial cells is normal and the cells are integrated in the Tie 2-deleted mice, but because of the lack of peripheral endothelial cells, the blood vessels are immature and scattered, and can not form network-like branches. Meanwhile, the endothelial cells are round and are loosely connected with the surrounding matrix, which shows that Tie-2 participates in the construction of the non-endothelial cells of the blood vessel, so that the structure of the blood vessel can be fixed; and the mice with Tie1 deficiency can die after birth, and vascular hemorrhage and edema are found under the microscope, which indicates that Tie-1 participates in the regulation of microvascular fluid exchange and hemodynamic processes. Overexpression of the SRC family proteins is associated with a number of neoplastic diseases and is thought to be synergistic with growth factors and to have oncogene activity. The SRC family plays an important role in growth factor-induced intracellular responses, including proliferation, survival, adhesion, and migration. There is a lot of direct evidence that c-Src is closely related to human cancers, such as breast, liver and colon cancers. In malignant cells c-Src accumulates in large numbers around the nucleus, whereas in normal cells c-Src spreads relatively evenly in the cytoplasm. c-Src has been found to be very active in colon cancer, especially after metastasis of tumors to the liver. Compared with normal mammary gland tissue, the activity of c-Src in human breast cancer is increased by 4-30 times, and the expression level of c-Src protein is increased correspondingly. Philadelphia chromosome (PH) is the first chromosomal abnormality found to date that is closely associated with a particular type of leukemia. The Bcr-Abl fusion protein is generally expressed in a patient with Chronic Myeloid Leukemia (CML), and is formed by that Philadelphia chromosome exists in the CML patient, translocation occurs between chromosome 9 and chromosome 22, a c-Abl protooncogene at the tail end of the long arm of chromosome 9 (9 q 34) is broken, and the c-Abl protooncogene is fused with the 3 end of a c-Bcr gene at the tail end of the long arm of chromosome 22 (22 q 11). The P210Bcr-Abl fusion protein has a key role in the malignant transformation of CML. Compared with Abl protein tyrosine kinase, the kinase activity of P210Bcr-Abl is greatly enhanced, and the autophosphorylation level is obviously improved. After P210Bcr-Abl is autophosphorylated, a binding site is provided for a series of adaptor protein molecules such as Grb-2, SHC, CRKL and the like, so that RAS/MAPK signal pathway or Jak/Stat signal pathway is activated initially, and the expression of nuclear genes such as c-myc, bcl-2, c-fos and the like is up-regulated. In addition, the actin binding function of the Abl protein was also improved in P210 Bcr-Abl. Abnormalities in these signaling pathways cause bone marrow precursor cells to become cancerous, proliferate abnormally, differentiate and apoptosis to be inhibited, and reduce the adhesion of these cells to the bone marrow stroma, allowing them to be released into the blood circulation into the chronic latent phase of CML. The jak (jamus kinase) family plays a crucial role in the initial steps of cytokine signaling. JAKs are closely associated with a few human leukemias, and in addition, its downstream substrates Stat3 and Stat5 are found in a phosphorylated, activated state in several malignancies. FAK is involved in the adhesion glycoprotein cellular response, the signaling of which is conducted through integrin receptors; it is also involved in the cellular response of mitogenic neuropeptides, which signals the first step of a key in the G protein-coupled receptor transduction pathway. FAK is thought to regulate cell morphology and migration, help cells grow adherent, and transmit signals of altered gene transcription into the nucleus. FAK is expressed in different tissues, and is particularly highly expressed in malignant metastases. FAK expression is different in different tumor tissues, and is improved in the occurrence process of prostate cancer, breast cancer, colon cancer, ovarian cancer, oral cancer and thyroid cancer. FAK expression is extremely high, especially in breast and colon cancer tissues. Bombesin, Hepatocyte Growth Factor (HGF), prolactin, etc. can stimulate the expression of FAK in tumor cells. FAK does not have the function of classical oncoprotein, but plays an important role in integrin signal transduction and the participation of integrin in the tumor development process and metastasis process, which means that FAK can become a target point in the multiple development process of malignant cells.

In summary, protein tyrosine kinase is closely related to the occurrence and development of tumors, and kinase inhibitors have become a hot spot in the research of antitumor drugs in the world. Although a series of documents disclose the medicinal use of quinoline and quinazoline derivatives and the preparation method thereof, the search and discovery of a protein kinase inhibitor with high activity and better pharmacokinetic and pharmacodynamic properties is still a major hot spot at present.

Disclosure of Invention

The invention relates to a compound with the structural characteristics of a general formula I, which can effectively inhibit the activity of more than one protein kinase and/or inhibit the growth of tumor cells and can show excellent pharmacokinetic and/or pharmacodynamic properties.

The invention provides a novel 3-cyano quinoline derivative which can inhibit one or more protein kinase activities closely related to the occurrence and development of tumors and/or inhibit the growth of tumor cells.

According to one aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof:

wherein,

a is selected from O, N or S (O) _m；

Ar is selected from aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more of the following substituents: halogen, alkyl (e.g. C)_1-6Alkyl), cycloalkyl (e.g. C)_3-5Cycloalkyl), heterocyclyl (e.g., heterocyclyl having 3-6 ring atoms), heterocyclyloxy (e.g., heterocyclyl-O-having 3-6 ring atoms), alkoxy (e.g., C)_1-6Alkoxy), cycloalkoxy (e.g. C)_3-5cycloalkyl-O-), cycloalkylalkoxy (e.g. C)_3-6cycloalkyl-C_1-6Alkoxy), cycloalkylalkyl (e.g. C)_3-6cycloalkyl-C_1-6Alkyl), heterocycloalkoxy (or heterocyclyl-alkoxy, e.g. heterocyclyl-C with 3-6 ring atoms_1-6Alkoxy), nitro, cyano, hydroxy, alkenyl (e.g. C)_2-6Alkenyl), alkynyl (e.g. C)_2-6Alkynyl), amino or substituted amino, hydroxyalkyl, carboxyl, aryl, arylalkyl (monocyclic or bicyclic aryl-C optionally substituted by halogen)_1-6Alkyl), cycloalkylalkyl, arylalkoxy (mono-or bicyclic aryl-C optionally substituted by halogen)_1-6Alkoxy), heteroarylalkoxy (monocyclic or bicyclic heteroaryl-C)_1-6Alkoxy), ureido (which may be cycloalkyl, e.g. C)_3-5Cycloalkyl substituted); the above substituents are optionally substituted with one or more of the following groups: halogen, alkyl and cycloalkyl; alternatively, the aryl and heteroaryl groups may further form a fused ring or a condensed ring with other saturated or partially unsaturated alkyl or heteroalkyl groups, etc.; or in the formula I, the substituent of Ar is selected from halogen and C _1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclyl with 3 to 6 ring atoms, heterocyclyl-O-, C with 3 to 6 ring atoms_1-6Alkoxy radical, C_3-6cycloalkyl-O-, C_3-6cycloalkyl-C_1-6Alkoxy radical, C_3-6cycloalkyl-C_1-6Alkyl, heterocyclyl-C with 3-6 ring atoms_1-6Alkoxy, nitro, cyano, hydroxy, C_2-6Alkenyl radical, C_2-6Alkynyl, amino or substituted amino, hydroxy C_1-6Alkyl, carboxyl, monocyclic or bicyclic aryl optionally substituted by halogen-C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl, monocyclic or bicyclic aryl-C optionally substituted by halogen_1-6Alkoxy, monocyclic or bicyclic heteroaryl-C_1-6Alkoxy, optionally substituted by C_3-6Cycloalkyl-substituted ureido; the above substituents are optionally substituted with one or more of the following groups: halogen, C_1-6Alkyl and C_3-6A cycloalkyl group;

R₁selected from the group consisting of H, halogen, nitro, amino, substituted amino, cyano, hydroxy, optionally substituted alkyl, cycloalkyl, heterocyclyl, alkoxy (including deuterated alkoxy), cycloalkoxy, heterocyclyloxy alkoxy, aryl, heteroaryl, and the like, wherein alkoxy may be substituted with alkoxy;

linker is selected from alkoxy, alkylamino, heterocyclyl, cycloalkylalkoxy, aryl, aralkyl, heteroarylalkoxy, alkenyl, alkynyl, alkylheteroaryl, acylalkenyl, alkylheteroarylalkynyl, alkylheteroarylalkenyl; and the above groups may be substituted with one or more substituents such as halogen, nitro, cyano, hydroxy, acyl (e.g., formyl), alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxy, carboxylate, amido, aryl or heteroaryl, respectively; alternatively, linker is an amide group wherein the nitrogen atom of the amide group is attached to the quinoline ring and Ar is phenyl or indazolyl optionally substituted with one or more of the following substituents: halogen, alkynyl, alkyl, cycloalkyl, aralkyl optionally substituted with halogen, alkoxy, and alkanoyl. The above-mentioned alkyl group is, for example, C _1-6Alkyl, cycloalkyl, e.g. C_3-6Cycloalkyl, alkynyl, e.g. C_2-6Alkynyl, alkoxy being, for example, C_1-6Alkoxy, alkanoyl, e.g. C_1-6Alkylacyl radicals, aralkyl radicals, e.g. being monocyclic or bicyclic aryl-C_1-6An alkyl group.

The ring A is selected from saturated or partially unsaturated spiro ring, bridged ring or condensed ring, etc.;

R₂selected from H, halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino (including monoalkylamino or dialkylamino), alkylOxy, cycloalkoxy, heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, acyl (e.g., alkylacyl, alkenylacyl), carboxyl, carboxylate, amido, alkoxyacyl (or alkoxycarbonyl), alkenoyl, alkoxyacylalkyl, cycloalkylacyl, heterocyclylacyl, oxo, aryl, or heteroaryl, and the like;

m is 0 to 2.

According to one embodiment of the invention, linker and R₁Are respectively connected at the 6 position and the 7 position or the 7 position and the 6 position of the quinoline ring.

According to one embodiment of the invention, Ar in the compounds of formula I according to the invention is aryl or heteroaryl, which may be monocyclic or bicyclic aryl; the heteroaryl group may be a monocyclic, bicyclic heteroaryl group comprising 1, 2, 3 heteroatoms selected from nitrogen, oxygen, sulfur; which is optionally substituted by substituents as defined above.

According to one embodiment of the present invention, Ar in the compounds of formula I according to the present invention includes, but is not limited to, the following structures:

wherein heteroaryl is selected from monocyclic or bicyclic heteroaryl groups containing one or more heteroatoms (e.g., pyridine, pyrimidine, thiophene, furan, thiazole, indole, etc.); the substituents Ra and Rb may each be selected from one or more of hydrogen, halogen, alkyl (e.g. C)_1-6Alkyl), cycloalkyl (e.g. C)_3-6Cycloalkyl), alkenyl (e.g. C)_2-6Alkenyl), alkynyl (e.g. C)_2-6Alkynyl), alkoxy (e.g. C)_1-6Alkoxy), cyano, aryl (e.g. monocyclic or bicyclic aryl), arylalkyl (e.g. monocyclic or bicyclic aryl-C)_1-6Alkyl), cycloalkyloxy (e.g. C)_3-6cycloalkyl-O-), cycloalkylalkoxy (e.g. C)_3-6cycloalkyl-C_1-6Alkoxy), amino, monoalkylamino (e.g. alkoxy)Single C_1-6Alkylamino), dialkylamino (e.g. di-C)_1-6Alkylamino groups, ureido groups (which may be substituted by cycloalkyl (e.g. C)_3-6Cycloalkyl), heterocyclyloxy (e.g., heterocyclyl-O-having 3-6 ring atoms); the substituents R and R', which may be the same or different, are independently selected from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl; rx and Ry are independently selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl; each of the above groups may be optionally substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxy, carboxylate, amido, aryl or heteroaryl; w represents the number of substituents Ra and Rb selected from 0,1,2,3,4, 5; x is selected from one or more of halogen, cyano, amino and hydroxy; v and v' represent the number of substituents X selected from 0,1,2,3, 4; z ₁And Z₂Independently selected from 1,2,3 and 4 (preferably, Z)₁And Z₂Both are 1). The above-mentioned alkyl group is, for example, C_1-6Alkyl, cycloalkyl, e.g. C_3-6Cycloalkyl, alkenyl, e.g. C_2-6Alkenyl, alkynyl, for example C_2-6Alkynyl, alkoxy being, for example, C_1-6Alkoxy, aryl being, for example, monocyclic or bicyclic aryl, arylalkyl being, for example, monocyclic or bicyclic aryl-C_1-6Alkyl, cycloalkyloxy, e.g. C_3-6cycloalkyl-O-cycloalkylalkoxy, e.g. C_3-6cycloalkyl-C_1-6Alkoxy, monoalkylamino, e.g. being mono C_1-6Alkylamino, dialkylamino, e.g. di-C_1-6Alkylamino, ureido radicals which may be substituted by cycloalkyl radicals (e.g. C)_3-6Cycloalkyl) is substituted, heterocyclyloxy is, for example, heterocyclyl-O-having 3 to 6 ring atoms.

According to one embodiment of the invention, Ar in the compound of formula I includes, but is not limited to, the following groups:

according to one embodiment of the invention, in the compounds of formula I, ring a includes, but is not limited to, the following structure:

wherein,

m, n, p, q are selected from 1,2,3, 4, 6 and 6;

b is selected from O, C, N, S and the like, and when B is a C atom or an N atom, it may be optionally substituted with one or more substituents selected from the group consisting of: halogen, nitro, cyano, hydroxy, mercapto, alkanoyl, alkenylacyl, alkoxyacyl, cycloalkylacyl, amino, monoalkylamino, dialkylamino, cycloalkyl, heterocycloyl, oxo, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxy, carboxylate, amido, aryl or heteroaryl, said groups being optionally substituted with one or more of the following substituents: hydroxy, halogen, cyano, mercapto, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, amino, monoalkylamino, dialkylamino, heterocyclyl, aryl, heteroaryl; meanwhile, olefinic bonds, acetylene bonds, carbonyl groups and other unsaturated bonds can be introduced into the ring respectively to form a partially unsaturated spiro ring, fused ring or condensed ring. The above-mentioned alkyl group is, for example, C _1-6Alkyl, cycloalkyl, e.g. C_3-6Cycloalkyl, alkenyl, e.g. C_2-6Alkenyl, alkynyl, for example C_2-6Alkynyl, alkoxy being, for example, C_1-6Alkoxy, aryl for example monocyclic or bicyclic aryl, heteroaryl for example monocyclic or bicyclic heteroaryl, arylalkyl for example monocyclic or bicyclic aryl-C_1-6Alkyl, cycloalkoxy, e.g. C_3-6cycloalkyl-O-cycloalkylalkoxy, e.g. C_3-6cycloalkyl-C_1-6An alkoxy group,monoalkylamino radicals being, for example, mono C_1-6Alkylamino, dialkylamino, e.g. di-C_1-6Alkylamino, ureido radicals which may be substituted by cycloalkyl radicals (e.g. C)_3-6Cycloalkyl) is substituted, heterocyclyloxy is, for example, heterocyclyl-O-having 3 to 6 ring atoms.

according to one embodiment of the present invention, in the compound of formula I, an unsaturated bond such as an ethylenic bond, an acetylene bond, or a carbonyl group may be introduced into ring a, respectively, to form a partially unsaturated spiro ring, fused ring, or condensed ring.

According to one embodiment of the invention, in the compound of formula I, linker is represented by-XQ, wherein X is selected from oxygen, sulfur or nitrogen, and Q is selected from one or more of the following groups: alkyl, acylalkyl, alkylacyl, alkenylacyl, heteroarylalkyl, heterocyclylalkyl, said groups being optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, alkoxy and alkanoyl groups, and linker is attached to the quinoline ring via X; alternatively, Q is selected from one or more of the following groups: cycloalkylalkyl, alkylcycloalkylalkyl, alkylacylalkyl, acylheteroarylalkyl, and linker is attached to the quinoline ring by X; q is selected from one or more of the following groups: alkynyl, alkenyl, acylalkenyl, alkylheteroarylalkynyl, alkylheteroarylalkenyl, wherein alkynyl or alkenyl is attached to the quinoline ring, or Q is selected from alkylheteroaryl, wherein heteroaryl is attached to the quinoline ring. Alkyl radicals mentioned above, alone or in combination, are for example C _1-6Alkyl, alkenyl, e.g. C_2-6Alkenyl, alkynyl, for example C_2-6Alkynyl, cycloalkyl being, for example, C_3-6Cycloalkyl, alkenyl, e.g. C_2-6Alkenyl, alkoxy, e.g. C_1-6Alkoxy, alkanoyl, e.g. C_1-6Alkanoyl, heteroaryl, e.g. areMonocyclic or bicyclic heteroaryl (e.g., having 1-3 heteroatoms), and heterocyclyl is, for example, heterocyclyl having 3-6 ring atoms.

According to one embodiment of the invention, in the compound of formula I, linker is represented by-XQ, wherein X is selected from oxygen, sulfur, nitrogen, unsaturated bonds, aryl, heteroaryl, and Q is selected from one or more of the following groups: alkyl, cycloalkylalkyl, alkylcycloalkylalkyl, acylalkyl, alkylacyl, alkanoylalkyl, acylheteroarylalkyl, alkylheteroarylacyl, acyl, heteroaryl, alkylheteroaryl, acylalkenyl, heteroarylalkyl, the alkyl groups mentioned being C, alone or in combination_1-6Alkyl, alkenyl being C_2-6Alkenyl, alkynyl being C_2-6Alkynyl, cycloalkyl being C_3-6Cycloalkyl, alkoxy being C_1-6Alkoxy, aryl or heteroaryl being monocyclic or bicyclic aryl or heteroaryl, heterocyclyl being heterocyclyl having 3-6 ring atoms, heterocyclyl or heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulphur; and linker is attached to the quinoline ring by X. According to one embodiment of the invention, the linker is represented by-XQ, wherein when X is selected from oxygen, sulfur or nitrogen, Q is selected from one or more of the following groups: alkyl, alkanoyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylaryl, alkylarylacyl, alkylheteroaryl, alkylheteroarylacyl, said groups being optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, alkoxy and alkanoyl groups, and linker is attached to the quinoline ring via X; or when X is selected from unsaturated bonds, aryl and heteroaryl, Q is selected from one or more of the following groups: alkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and linker is attached to the quinoline ring through X; alkyl radicals in the above definitions, alone or in combination, being C _1-6Alkyl, alkenyl being C_2-6Alkenyl, alkynyl being C_2-6Alkynyl, cycloalkyl being C_3-6Cycloalkyl, alkoxy being C_1-6Alkoxy, heteroaryl is monocyclic or bicyclic heteroaryl, heterocyclyl is heterocyclyl having 3-6 ring atoms, said heterocyclyl or heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur; the unsaturated bond is a double bond or a triple bond.

According to one embodiment of the present invention, the linker in the compound of formula I includes, but is not limited to, the following structure:

the oxygen atoms in the above groups are linked to the quinoline ring; and

(the benzene ring is directly connected with the quinoline ring),

(the alkynyl group is directly connected with the quinoline ring),(the alkynyl group is directly connected with the quinoline ring),(the double bond is directly attached to the quinoline ring),

(the furan ring is linked to the quinoline ring).

According to one embodiment of the invention, in the compounds of formula I, R₁Including but not limited to the following structures:

wherein,

Rm₁，Rm₂，Rm₃,Rm₄and Rm₅Each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, alkaneA group (including deuterium-containing alkyl), cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy (including deuterium-containing alkoxy), cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxyl, carboxylate, amide, aryl or heteroaryl; rm ₄And Rm₅Can form a 5-10 membered heterocyclic group together with the N atom to which it is attached, wherein the heterocyclic group is preferably a double-spiro ring, and the other non-nitrogen-containing ring is an oxygen-containing heterocyclic ring. The above-mentioned alkyl group is, for example, C_1-6Alkyl, cycloalkyl, e.g. C_3-6Cycloalkyl, alkynyl, e.g. C_2-6Alkynyl, alkoxy being, for example, C_1-6Alkoxy, aryl is for example monocyclic or bicyclic aryl, heteroaryl is for example monocyclic or bicyclic heteroaryl (e.g. having 1 to 3 heteroatoms), heterocyclyl is for example heterocyclyl having 3 to 6 ring atoms.

r is an integer selected from 1 to 6, preferably selected from 2, 3 and 4.

According to one embodiment of the invention, in the compounds of formula I, R₁Including but not limited to one or more structures selected from the group consisting of:

-OCH₃、-OCH₂CH₃、-OCD₃、-OH、

according to one embodiment of the invention, in the compounds of formula I, R₂Including but not limited to one or more of the following structures:

wherein Rc may be independently selected from one or more of H, oxo (oxo), halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxy, carboxylate, amido, aryl or heteroaryl, and the like;

according to one embodiment of the invention, in the compounds of formula I, R ₂Including but not limited to one or more groups selected from: hydroxy, halogen, cyano, mercapto, alkanoyl, alkenylacyl, alkoxyacyl, cycloalkylacyl, amino, monoalkylamino, dialkylamino, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylacyl, oxo, said groups being optionally substituted with one or more of the following substituents: hydroxyl, halogen, cyano, mercapto, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, amino, monoalkylamino, dialkylamino, heterocyclyl, aryl, heteroaryl. The above-mentioned alkyl group is, for example, C_1-6Alkyl, cycloalkyl, e.g. C_3-6Cycloalkyl, alkenyl, e.g. C_2-6Alkenyl, alkoxy, e.g. C_1-6Alkoxy, heterocyclyl is, for example, heterocyclyl having 3 to 6 ring atoms, alkynyl is, for example, C_2-6Alkynyl, aryl is for example monocyclic or bicyclic aryl, heteroaryl is for example monocyclic or bicyclic heteroaryl (e.g. having 1-3 heteroatoms), heterocyclyl is for example heterocyclyl having 3-6 ring atoms.

According to one embodiment of the invention, in the compounds of formula I, R₂Including but not limited to one or more groups selected from: -OH, fluorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclopropylformyl, cyclobutyl, tert-butoxycarbonyl, acetyl, levulinyl, methoxycarbonyl,

Oxo (oxo),

A dimethylamino group.

According to one embodiment of the invention, the compounds of formula I include, but are not limited to, the following compounds:

according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof. The pharmaceutical composition includes, but is not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal dosage forms. In some embodiments, the pharmaceutical composition is in oral dosage forms including tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions, and the like, in parenteral dosage forms including sterile solutions, suspensions or emulsions, in topical dosage forms including ointments, oils, emulsions, gels, suspensions, solutions, lotions or creams, and in rectal dosage forms including suppositories, drops. In some embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose. In other embodiments, the amount of the compound of formula I is in the range of about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In some embodiments, the amount of the compound of formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound of formula I is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In other embodiments, dosage levels above the upper limit of the range recited above may be desired. In some embodiments, the compound of formula I is administered in a single dose, once daily. In other embodiments, the compound of formula I is administered in multiple doses, more than once per day. In some embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times per day. In other embodiments, the compound of formula I is administered four times per day. In other embodiments, the compound of formula I is administered more than four times per day. In some embodiments, the pharmaceutical composition is administered to a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient, or adjuvant. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.

According to another aspect of the invention, the invention also relates to the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof in the preparation of a kinase inhibitor of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr-Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LYNA, FGR, EphB, ECK, FYN, MAP4K, SIK, MST1, YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3, RET, FGFR, PDK, Syk, etc. protein kinases, or any combination thereof.

In yet another aspect, the present invention provides a method of modulating the activity of a protein kinase, comprising contacting the protein kinase with a compound described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, prodrug or metabolite thereof. Preferably, the modulation of protein kinase activity is inhibition of protein kinase activity. The method can be used in vivo or in vitro. Preferably, the protein kinase is selected from at least one of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr-Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LYNA, FGR, EphB, ECK, FYN, MAP4K, SIK, MST1, YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3, RET, FGFR, PDK, Syk.

In a further aspect, the present invention relates to the use of a compound of the present invention, and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphs or metabolites thereof, for the manufacture of a medicament for the treatment or prevention of a tumor. According to one embodiment, the tumor is inhibited by inhibiting the protein kinase, thereby achieving a therapeutic or prophylactic effect.

In another aspect, the invention relates to a method of treating or preventing tumors by a compound of the invention and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphs or metabolites thereof. In one embodiment, the method comprises the step of contacting the active agent with a mammal in need of treatment.

According to an embodiment of the present invention, the tumor includes, but is not limited to, any one of leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

As understood by those skilled in the art, the compounds related to the invention and pharmaceutically acceptable salts, solvates or stereoisomers, tautomers and the like thereof can be used for preparing medicines for treating transitional proliferative diseases of human beings and other mammals, including diseases such as tumors and the like.

Detailed Description

The claims particularly set forth the features of the invention. Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.

While preferred embodiments of the present invention are described herein, these embodiments are provided by way of example only. It is to be understood that variations of the embodiments of the invention described herein may also be used in the practice of the invention. Those skilled in the art will appreciate that various modifications, changes, and substitutions can be made without departing from the scope of the invention. It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.

Can be found in the reference (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY4^THED. "Vols.A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH₂O is equivalent to OCH₂。

Unless otherwise indicated, the use of general chemical terms such as, but not limited to, "alkyl", "amine", "aryl" is equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopic atom compositions. The compounds of the invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetrically substituted carbon atoms may be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. The compounds of the invention also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton. The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. The compounds described herein may have one or more stereogenic centers, and each stereogenic center may exist in the R or S configuration or a combination thereof. Similarly, the compounds described herein may have one or more double bonds, and each double bond may exist in either the E (trans) or Z (cis) configuration, or a combination thereof. A particular stereoisomer, structural isomer (regioisomer), diastereoisomer, enantiomer or epimer is understood to include all possible isomers, such as stereoisomers, structural isomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds described herein include all configurationally different stereoisomers, structural isomers, diastereomers, enantiomers, or epimers, as well as the corresponding mixtures thereof. Techniques for converting or leaving intact a particular stereoisomer, as well as techniques for resolving mixtures of stereoisomers, are well known in the art and those skilled in the art will be able to select appropriate methods for a particular situation. See, e.g., Fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991,809-816; and Heller, Acc. chem. Res.1990,23,128.

The terms "optionally/any" or "optionally/optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an "optionally substituted alkyl" refers to an "unsubstituted alkyl" (alkyl unsubstituted by a substituent) or a "substituted alkyl" (alkyl substituted by a substituent), as defined below.

As used herein C₁-C_nComprising C₁-C₂、C₁-C₃、……C₁-C_n. For example, the "C" is₁-C₄By "group" is meant a moiety having 1 to 4 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, for example, "C₁-C₄Alkyl "means an alkyl group having 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Herein, a numerical range, such as "1 to 10" refers to each integer in the given range, such as "1 to 10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The term "heteroatom" or "hetero", as used herein, alone or in combination, refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon group. The "alkyl" groups herein may have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms or from 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentylA group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2, 2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, 2-methyl-l-propyl group, 2-methyl-2-propyl group, 2-methyl-1-butyl group, 3-methyl-l-butyl group, 2-ethylpropyl group, 1, 2-dimethylbutyl group, 1, 2-dimethylp, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl and octyl, and the like. When a group as defined herein, such as "alkyl" appears in a numerical range, e.g. "C ₁-C₆Alkyl "or" C₁-₆Alkyl "means an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkyl group herein also encompasses instances where no numerical range is specified. Alkyl is optionally substituted alkyl. When an alkyl group is substituted, the substituent may be substituted at any available point of attachment. The substituents may be one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

"alkyl" as used in combination herein includes alkyl in combination with other groups, such as alkyl in alkoxy, alkyl in alkylthio, hydroxyalkyl, haloalkyl, cyanoalkyl, monoalkylamino, "alkyl" in dialkylamino, and the like.

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl), non-limiting examples of which include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropylmethoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy is optionally substituted alkoxy. When the alkoxy group is substituted, the substituent may be substituted at any available point of attachment, and may be one or more of the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "hydroxy" as used herein, alone or in combination, refers to an-OH group.

The term "hydroxyalkyl" or "hydroxyalkyl" as used herein, alone or in combination, refers to a hydroxy-substituted alkyl group, i.e., -alkyl-OH.

The term "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term "carbonyl" or "acyl" as used herein, alone or in combination, refers to a-C (= O) -group.

The term "nitro" as used herein, alone or in combination, refers to-NO₂。

The term "cyano," as used herein, alone or in combination, refers to — CN.

The term "amino", as used herein, alone or in combination, refers to-NH₂。

The term "carboxylic acid" as used herein, alone or in combination, refers to-CO₂H。

The term "carboxylate", as used herein, alone or in combination, refers to-CO₂-an alkyl group.

The terms "cycloalkyloxy", "heterocyclyloxy", "aralkyloxy", and the like, as used herein, alone or in combination, refer to cycloalkyl-O-, heterocyclyl-O-, aralkyl-O-.

"haloalkyl" refers to one or more halo-substituted alkyl groups, e.g. CH₂F、CHF₂、CF₃、C₂F₅、CCl₃And the like.

The term "alkenyl", as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C = C double bonds. The alkenyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, 2 to about 10 carbon atoms, or 2 to about 8 carbon atoms, 2 to about 6 carbon atoms, 2 to about 4 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH = CH) ₂) 1-propenyl (CH)₂CH=CH₂) Isopropenyl (C (CH)₃)=CH₂) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C₂-C₆Alkenyl "or" C₂-₆The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified. Alkenyl is optionally substituted alkenyl. When an alkenyl group is substituted, the substituent may be substituted at any available point of attachment, and may be one or more of the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted, straight or branched chain, monovalent hydrocarbon radical having one or more C ≡ C triple bonds. The alkynyl group has, but is not limited to, 2 to about 18 carbon atoms, for example it has 2 to about 10 carbon atoms, or has 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C ₂-C₆Alkynyl "or" C₂-₆Alkynyl "isRefers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified. Alkynyl is optionally substituted alkynyl. When the alkynyl group is substituted, the substituent may be substituted at any available point of attachment, and may be one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The terms "halo" or "halogen-substituted" as used herein, alone or in combination, refer to an optionally substituted group (e.g., alkyl, alkenyl, and alkynyl) wherein one or more hydrogen atoms are replaced with a halogen, such as a fluorine, chlorine, bromine, iodine atom, or combinations thereof. In some embodiments, two or more hydrogen atoms are replaced with halogen atoms that are the same as each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not exactly the same as each other (e.g., 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is bromovinyl. A non-limiting example of a haloalkynyl group is chloroethynyl.

The terms "ring," "cyclic," and "… … -membered ring," as used herein, alone or in combination, refer to any covalently closed structure as described herein, including alicyclic, heterocyclic, aromatic, heteroaromatic rings, including polycyclic fused ring systems or polycyclic non-fused ring systems. The ring may be optionally substituted. The rings may form part of a fused ring system. The term "member" refers to the number of backbone atoms that make up the ring. Thus, for example, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.

The term "fused" as used herein, alone or in combination, refers to a ring structure wherein two or more rings have one or more bonds in common.

The term "aromatic/aromatic" as used herein, alone or in combination, refers to a planar ring portion of a ring or rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more than 10 atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic, such as bicyclic, tricyclic, and the like. The term aromatic compound includes all carbon-containing rings (e.g., benzene rings).

The term "aryl or aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20 or 6 to 14 or 6 to 10 ring-forming carbon atoms and includes fused aromatic rings (polycyclic with conjugated systems) and non-fused aromatic rings. The fused aromatic ring comprises 2 to 4 aromatic rings fused together, and the other optional independent rings may be aromatic rings, alicyclic rings, heterocyclic rings, aromatic heterocyclic rings, or any combination thereof. The aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring linked together with the parent structure is an aryl group. In addition, the term aryl also includes fused and non-fused rings containing from 6 to about 14 ring-forming carbon atoms, as well as fused and non-fused rings containing from 6 to about 10 ring-forming carbon atoms. Aryl herein includes monocyclic, bicyclic, tricyclic or higher rings. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups of 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; fused ring aryl groups include bicyclic, tricyclic or higher rings, such as naphthyl, phenanthryl, anthracenyl, azulenyl; non-fused bisaryl groups include biphenyl groups. Aryl is optionally substituted aryl. When the aryl group is substituted, the substituent may be substituted at any available point of attachment, and may be one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "heteroaryl or heteroaryl" as used herein, alone or in combination, refers to optionally substituted heteroaryl groups comprising from about 5 to about 20 or from 5 to about 14 or from 5 to 10 or from 6 to 10 backbone ring-forming atoms (otherwise referred to as 5-20 ring, 5-14 ring, 5-10 ring, 6-10 ring), wherein one or more (e.g., 1-6, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any ring-forming nitrogen atoms in the heteroaromatic ring may be oxidized to form a nitroxide component. In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryl groups having at least one heteroatom. In addition, the term heteroaryl also includes heteroaryl groups (fused and non-fused) having from 5 to about 12 backbone ring atoms, and heteroaryl groups (fused and non-fused) having from 5 to about 10 backbone ring atoms. The heteroaryl group may be bonded through a carbon atom or a heteroatom. Thus, for example, an imidazole may be attached to the parent molecule through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl). Similarly, heteroaryl groups may be further substituted by any or all of their carbon atoms and/or any or all of their heteroatoms. The fused heteroaryl group may comprise 2 to 4 fused rings fused with aromatic heterocycles, and the other optional independent rings may be alicyclic, heterocyclic, aromatic heterocycle, or any combination thereof. Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups of 5 to about 12, 5 to about 10, 5 to about 7, or 6 backbone ring atoms, for example, non-limiting examples thereof include pyridyl; fused ring heteroaryls include benzimidazolyl (benzimidazolyl), quinolyl (quinolyl), acridinyl (acridinyl), and non-fused bis-heteroaryls include bipyridyl (bipyridinyl). Other examples of heteroaryl groups include, but are not limited to: pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2, 4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine, and the like. Acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, isoquinolyl, indolizinyl, isothiazolyl, isoindolinyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxalinyl, triazinyl, thiadiazolyl, and the like, and oxides thereof, such as pyridyl-N-oxide (pyridyl-N-oxide), and the like. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl group, wherein the ring attached to the parent structure is heteroaryl. Heteroaryl is optionally substituted heteroaryl. When heteroaryl is substituted, the substituents may be substituted at any available point of attachment, and may be one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocyclic ring, and refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, including, for example, heterocycloalkyl and heterocycloalkenyl. Wherein one or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms, such as oxygen, nitrogen, or sulfur atoms (in various oxidation states). Heterocyclyl groups may include monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) ring systems, as well as spiro rings. The heterocyclyl group may have 3 to about 20 ring-forming atoms, such as 3 to about 10, 3 to about 8, 5 to about 8, or 5 to about 6 ring-forming atoms. Non-limiting examples of heterocyclyl groups include tetrahydropyrrolyl, homopiperazinyl, azinyl (azinyl), azetidinyl (azedinyl), oxetanyl (oxobutyl), thietanyl (thietanyl), homopiperidinyl (homopiperidinyl), oxypentanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl (1,2,3,6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), 3-pyrrolinyl (3-pyrrolinyl), indolinyl (indolinyl), 2H-pyranyl (2H-pyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1,3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl (pyrazolidinyl), dithiodiyl (dithiofuranyl), dithiofuranyl (dihydrofuranyl), dithiofuranyl (dithiofuranyl), dithiofuranyl, Pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), 3-azabicyclo [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3-azabicyclo [4.1.0] heptyl (3-azabicyclo [4.1.0] hexyl), 3H-indolyl (3H-indolyl) and quinolyl (quinolizinyl), and the like. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Examples also include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidinyl, and the like, as well as classes of spiroheterocycles, fused heterocycles, bridged heterocycles, and the like, consisting of these mono-and cycloalkyl or heterocyclic groups. Heterocyclic groups also include heterocycles having one or more aromatic rings fused (i.e., having a common bond), such as 2, 3-dihydrobenzofuran, 1, 3-benzodioxole, benzo-1, 4-dioxane, phthalimide, naphthalimide. The heterocyclic group having one or more aromatic condensed rings may be connected to other groups through an aromatic ring or a non-aromatic ring moiety. Other groups may be attached to the heterocycle via a heteroatom or carbon atom (i.e., the heterocycle is attached to the parent molecule or further substituted). The heterocyclyl group may be optionally substituted, and when substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "cycloalkyl" or "alicyclic" as used herein, alone or in combination, refers to a non-aromatic carbocyclic ring, and refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including spirocyclic rings. The cycloalkyl group may have 3 to 20 carbon atoms, for example 3 to about 15 ring-forming carbon atoms or 3 to about 12 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms, which may have 0, 1, 2 or 3 double bonds and/or 0, 1 or 2 triple bonds. Cycloalkyl also includes rings having one or more (e.g., 2, 3) aromatic ring fusions (i.e., having a common bond), for example, benzo derivatives fused pentanes, pentenes, hexanes, and the like. Cycloalkyl groups having one or more aromatic condensed rings may be linked to other groups through aromatic or non-aromatic ring moieties. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, adamantyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl is optionally substituted cycloalkyl. When a cycloalkyl group is substituted, the substituent may be substituted at any available point of attachment. The substituents may be one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocyclylalkylthio, carbonyl, carboxylic acid, or carboxylic acid ester.

The term "oxo" as used herein, alone or in combination, means "= O", i.e. an oxygen atom is attached to an X atom by a double bond, e.g., -X = O, wherein X may be a carbon atom, but also other atoms, such as sulfur, nitrogen, silicon, etc.

Certain pharmaceutical terms

Certain pharmaceutical terms as used herein with respect to the terms "subject", "patient" or "individual" refer to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

As used herein, the term "treating" and other similar synonyms include alleviating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating, or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating a symptom of a disease or disorder, or discontinuing a symptom of a disease or disorder, and further, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, such as those discussed in Goodman and Gilman, the pharmaceutical Basis of Therapeutics, current ed., Pergamon, and Remington's, pharmaceutical sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier, excipient, or adjuvant) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient, including but not limited to inert carriers, excipients, and/or auxiliaries, such as stabilizers, diluents, dispersants, suspending agents, thickeners and the like.

The term "carrier", "excipient" or "adjuvant" as used herein refers to an inert substance that aids in the introduction of a compound of the invention, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, into a cell or tissue.

The term "pharmaceutically acceptable salt" as used herein means that the retention meansSalts which are biologically or otherwise non-adverse in their biological or other aspects, and which are biologically or otherwise effective in determining the biological potency of the free acid and/or free base of the compound. The compounds of the present invention also include pharmaceutically acceptable salts. Pharmaceutically acceptable salts herein refer to those forms which convert a base group in the parent compound to a salt, or which convert an acid group in the parent compound to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups; or an ammonium, alkali metal or alkaline earth metal salt of an acidic group such as a carboxyl group. The pharmaceutically acceptable salts of the present invention may be synthesized from the parent compound by reacting the basic group of the parent compound with 1-4 equivalents of the acid in a solvent system. Suitable salts are listed in Remingtong's pharmaceutical sciences, 17^thed., Mack Publishing Company, Easton, Pa.,1985, p.1418 and Journal of pharmaceutical Science,66,2 (1977). Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Inorganic acids from which acid addition salts are derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which acid addition salts are derived include acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.

The term "solvate" as used herein refers to a combination of a compound of the invention formed by solvation with a solvent molecule. In some instances, a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the present invention and water forms a hydrate.

The term "polymorph" or "polymorph" as used herein refers to a compound of the invention in the form of different crystal lattices.

The term "prodrug or prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, enhance the bioavailability of the compounds of the invention (e.g., may allow an orally administered compound to be more readily absorbed into the blood), or facilitate delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system).

Prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternized derivatives of tertiary amines, N-Mannich bases (N-Mannich bases), Schiffbase (Schiffbase), amino acid conjugates, phosphates, metal salts, and sulfonates. Various prodrug forms are well known in the art. See, e.g., Design of precursors, Bundgaard, A.Ed., Elseview,1985 and Method in Enzymology, Widder, K.et al, Ed.; Academic,1985, vol.42, p.309-396; Bundgaard, H. "Design and Application of precursors" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed.,1991, Chapter 113 and 191; and Bundgaard, h., Advanced Drug Delivery Review,1992,8,1-38, which are incorporated herein by reference. Prodrugs described herein include, but are not limited to, those from the following group and combinations of such agents: an amine-derived prodrug; hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, and esters containing a disulfide bond.

The terms "pharmaceutical combination", "administering other therapy", "administering other therapeutic agent" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, including both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the administration of at least one compound described herein and at least one synergistic formulation to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapy, for example the administration of three or more active ingredients.

The terms "co-administration," "administration in combination with … …," and synonyms thereof, and the like, as used herein refer to the administration of a selected therapeutic agent to the same patient and are intended to encompass therapeutic strategies in which the agents are administered by the same or different routes of administration or the same or different numbers of administrations. In some embodiments, the compounds described herein are administered in combination with other agents. These terms encompass the administration of two or more agents to an animal such that the agents and/or metabolites thereof are present simultaneously within the animal. These terms include the simultaneous administration of different compositions, the administration of different compositions at different times and/or the administration of one composition containing different active ingredients. Thus, in some embodiments, the compounds of the present invention and other agents are administered in admixture in one composition.

The term "metabolite or metabolite" as used herein refers to a derivative of a compound that is formed upon metabolism of the compound.

The term "metabolism" as used herein refers to all processes (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions) in which an organism converts a particular substance. Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of redox reactions, while uridine diphosphate glucuronosyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. For more information on metabolism, see the pharmacological Basis of Therapeutics,9th Edition, McGraw-Hill (1996).

Pharmaceutical compositions are meant to comprise one or more compounds described herein, or a pharmaceutically acceptable salt, or prodrug, or stereoisomer, or tautomer thereof, in admixture with other chemical components, as well as other components, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.

The synthesis method of the compound comprises the following steps:

the invention provides a synthetic method of the compound. In some embodiments, the compounds described herein can be prepared by the following methods. The following methods and examples are intended to illustrate these methods. These schemes and examples should not be construed as limiting the invention in any way. The compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or using methods known in the art in combination with those described herein.

The invention relates to a preparation method of a compound shown in a general formula (I) and pharmaceutically acceptable salt, prodrug, solvate, polymorph, stereoisomer or tautomer thereof, and the like, which comprises the following preparation methods:

the method comprises the following steps: reacting the reaction raw material IA with aromatic amine, phenols or thiophenol under acid catalysis (such as hydrochloric acid, pyridine hydrochloride, sulfuric acid and the like) or base catalysis (such as potassium carbonate, sodium bicarbonate, triethylamine and the like) respectively to generate an intermediate IB; the intermediate IB is subjected to substitution reaction with halogenated hydrocarbon (or alcohol sulfonate and the like), or is subjected to Mitsunobu reaction with alcohol to obtain an intermediate IC; the intermediate IC undergoes substitution reactions with various amines (ring a) to give the target compound ID. Wherein n is an integer of 1, 2, 3, etc.; LG is a leaving group such as halogen, sulfonate, acetate and the like; a, Ar and R1 are as previously defined

The second method comprises the following steps: selectively protecting 6-hydroxyl by ID to obtain an intermediate IIB; reacting the intermediate IIB with aromatic amine, phenols or thiophenol under acid catalysis (such as hydrochloric acid, pyridine hydrochloride, sulfuric acid and the like) or base catalysis (such as potassium carbonate, sodium bicarbonate, triethylamine and the like) respectively to generate an intermediate IIC; the intermediate IIC is subjected to substitution reaction with halogenated hydrocarbon (or sulfonate of alcohol and the like), or is subjected to Mitsunobu reaction with alcohol to obtain an intermediate IID; removing a protecting group from the intermediate IID to obtain an intermediate IIE; the intermediate IIE is subjected to substitution reaction with halogenated hydrocarbon (or sulfonate of alcohol and the like), or is subjected to Mitsunobu reaction with alcohol to obtain an intermediate IIF; and carrying out substitution reaction on the intermediate IIF and various amines (ring A) to obtain a target compound IIG. Wherein PG is a common protective group converted from various organic synthetic functional groups; n is an integer of 1, 2, 3, etc.; LG is a leaving group such as halogen, sulfonate, acetate and the like; a, Ar and R1 are as defined in formula (I) above.

The third method comprises the following steps: the raw material IIIA reacts with aromatic amine, phenols or thiophenol and the like under acid catalysis (such as hydrochloric acid, pyridine hydrochloride, sulfuric acid and the like) or base catalysis (such as potassium carbonate, sodium bicarbonate, triethylamine and the like) respectively to generate an intermediate IIIB; when the group X is a halogen or a functional group such as trifluoromethanesulfonate, the intermediate IIIB is subjected to various coupling reactions (such as Suzuki reaction, Sonogashira reaction, Stille reaction and the like) to obtain an intermediate IIIC; the intermediate IIIC is reacted with different amines (ring A) to obtain the target compound IIID. Wherein, L1 is a linking group, which can be alkenyl, alkynyl, or alkenyl and alkynyl substituted by aromatic ring, etc.; GF is aldehyde group, hydroxymethyl, ester group and other functional groups; n is an integer of 1, 2, 3, etc.; a, Ar and R1 are as defined in formula (I) above.

Examples

The structure of the compounds was determined by nuclear magnetic resonance (1H-NMR) and/or liquid chromatography-mass spectrometer (LC-MS). The 1H-NMR shift (. delta.) is given in parts per million (ppm). 1H-NMR was measured using a Bruker Avance-400MHz or Varian-300MHz NMR spectrometer with deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3), hexadeuterated dimethyl sulfoxide (DMSO-d 6) as the solvent and Tetramethylsilane (TMS) as the internal standard; the LC-MS measurement was carried out using a 6110 SQ LC-MS (SB, C1850mmX4.6mm column) available from Agilent.

The silica gel column chromatography separation and purification adopts a rapid separation instrument (Isolera One, SNAP CatidgeKP-Sil, 10g-100g) of Biotage company, and the thin layer chromatography preparation plate purification adopts GF254 (0.4 mm-0.5 mm) of Qingdao ocean chemical industry. The eluent system adopted by column chromatography comprises: a: dichloromethane and methanol system, B: the volume ratio of the ethyl acetate to the petroleum ether system is adjusted according to different polarities of the compounds, and a small amount of reagents such as ammonia water or glacial acetic acid can be added for adjustment.

The starting materials of the present invention can be synthesized using literature procedures or according to procedures known in the art, or can be purchased from reagent brand suppliers such as Acros Organics, J & K Chemicals, TCI, Adamas, and the like. In the present invention, unless otherwise specified, all reactions are performed under the protection of nitrogen or argon.

Example 1

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Synthesizing a circuit:

the first step is as follows: 4-chloro-7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Anhydrous potassium carbonate (10.6g,6eq) was added to a DMF solution (30mL) of 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile (3g,12.7mmol) under ice-cooling, and after stirring for half an hour, 1-chloro-3-iodopropane (13 g, 63.9 mmol) was added to the suspension and stirred at room temperature overnight. The reaction was diluted with water (500 mL), extracted with dichloromethane (250 mLX 2), the organic phases combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 4-chloro-7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile as a yellow solid (3.1 g) in 77% yield.

¹H NMR(300MHz,DMSO-d₆):δ8.99(s,1H),7.59(s,1H),7.46(s,1H),4.36(t,J=6.00Hz,2H),4.02(s,3H),3.83(t,J=6.00Hz,2H)，2.28(m,2H).

MS m/z(ESI):311.0[M+H].

The second step is that: 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

2, 4-dichloro-5-methoxyaniline (1.9 g,10 mmol), pyridine hydrochloride (1.2 g,10 mmol) and 4-chloro-7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (3.1 g,10 mmol) were placed in a sealed tube, anhydrous 2-ethoxyethanol (30 mL) was added, and the mixture was heated at 140 ℃ for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (500 mL), extracted with dichloromethane (250 mLX 2), and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (grey solid, 3.0 g) in 67% yield.

¹H NMR(300MHz,DMSO-d₆):δ9.64(s,1H),8.41(s,1H),7.84(s,1H),7.73(s,1H),7.33(m,2H),4.29(t,J=5.4Hz,2H),3.90(m,8H)，2.26(m,2H).

MS m/z(ESI):466.0[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (46 mg,0.1 mmol) and 2-oxa-7-aza-spiro [3.5] nonane hydrochloride (49 mg,0.3 mmol) were dissolved in anhydrous N, N-dimethylformamide (2 mL), KI (5 mg) was added, and the mixture was heated to 100 ℃ overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (25 mLX 2), and the organic phases were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile as a yellow solid (35 mg).

¹H NMR(300MHz,CDCl3):δ8.71(s,1H),7.49(s,1H),7.42(s,1H),6.88(s,1H),6.71(s,1H),6.45(s,1H),4.41(s,4H),4.24(m,2H),3.77(s,3H),3.66(s,3H),2.49(m,2H),2.34(m,4H),2.09(m,2H),1.87(m,4H).

MS m/z(ESI):557.0[M+H].

Example 2

4- (2, 4-dichloro-5-methoxy-aniline) -7- [3- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using the intermediate obtained in the second step of example 1 and 8-aza-bicyclo [3.2.1] oct-3-ol as starting materials, a synthesis similar to the third step of example 1 gave the target compound 4- (2, 4-dichloro-5-methoxy-aniline) -7- [3- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (grey solid, 21 mg).

¹H NMR(300MHz,DMSO-d6):δ9.71(s,1H),8.41(s,1H),7.87(s,1H),7.74(s,1H),7.33(s,2H),4.22(m,2H),4.00(m,1H),3.95(s,3H),3.85(s,3H),3.41(m,2H),3.03(m,2H),2.10(m,2H),1.82(m,2H),1.55(m,2H).

MS m/z(ESI):531.2[M+H].

Example 3

6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-aniline) -6-methoxy-quinolin-7-yloxy ] -propyl } -octahydro-pyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester

Using the intermediate of the second step of example 1 and tert-butyl octahydro-pyrrolo [3,4-b ] pyridine-1-carboxylate as starting materials, a synthesis analogous to the third step of example 1 gave the title compound, tert-butyl 6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-aniline) -6-methoxy-quinolin-7-yloxy ] -propyl } -octahydro-pyrrolo [3,4-b ] pyridine-1-carboxylate (yellow solid, 60 mg).

¹H NMR(300MHz,CDCl3):δ8.69(s,1H),7.49(s,1H),7.36(s,1H),6.94(s,1H),6.50(s,1H),4.25(t,J=4.2Hz,2H),3.78(s,3H),3.68(s,3H),3.26(m,2H),3.08(m,1H),2.84(m,2H),2.47(m,4H),1.73(m,7H),1.46(s,9H).

MS m/z(ESI):656.2[M+H].

Example 4

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (octahydro-pyrrolo [3,4-b ] pyridin-6-yl) -propoxy ] -quinoline-3-carbonitrile

Tert-butyl 6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-aniline) -6-methoxy-quinolin-7-yloxy ] -propyl } -octahydro-pyrrolo [3,4-b ] pyridine-1-carboxylate (100mg,0.214mmol) was dissolved in dichloromethane (5mL), and a 4N solution of hydrogen chloride in dioxane (0.5 mL) was added with cooling on an ice bath and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to give 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (octahydro-pyrrolo [3,4-b ] pyridin-6-yl) -propoxy ] -quinoline-3-carbonitrile (yellow powder, 84 mg).

¹H NMR(400MHz,DMSO-d6):δ11.77(br,1H),11.39(br,1H),10.23(br,1H),9.71(br,1H),9.01(s,1H),8.29(s,1H),7.86(s,1H),7.54(s,2H),4.32(t,J=5.4Hz,2H),4.06(m,4H),3.90(m,5H),3.67(m,1H),3.47(m,1H),3.34(m,1H),3.24(m,1H),2.83(m,1H),2.62(m,1H),2.31(m,2H),1.70(m,4H)ppm.

MS m/z(ESI):556.2[M+H].

Example 5

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Using the intermediate of the second step of example 1 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate as starting materials, a synthesis similar to the third step of example 1 gave the title compound, tert-butyl 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 510 mg) in 78% yield.

¹H NMR(300MHz,CDCl3):δ8.71(s,1H),7.49(s,1H),7.42(s,1H),6.88(s,1H),6.72(s,1H),6.45(s,1H),4.25(m,2H),3.77(s,4H),3.66(s,3H),3.61(s,3H),2.54(m,2H),2.38(m,4H),2.11(m,2H),1.77(m,4H),1.44(s,9H).

MS m/z(ESI):656.2[M+H].

Example 6

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

The title compound, 7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile hydrochloride (yellow solid, 448 mg) was obtained in 92% yield by a synthesis method similar to that of example 4.

¹H NMR(300MHz,DMSO-d6):δ10.93(br,2H),10.67(br,1H),9.21(br,2H),8.85(s,1H),8.16(s,1H),7.82(s,1H),7.50(m,2H),4.30(m,2H),4.05(s,3H),3.87(s,3H),3.80(m,2H),3.72(m,2H),3.57(m,2H),3.18(m,2H),2.96(m,2H),2.32(m,2H),2.20(m,2H),2.01(m,2H)ppm.

MS m/z(ESI):556.2[M+H].

Example 7

7- [3- (2-acetyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (50mg,0.079mmol,1eq) and N, N-diisopropylethylamine (51mg,5eq) were dissolved in a mixed solution of anhydrous tetrahydrofuran (1.5mL) and N, N-dimethylformamide (0.5mL), acetyl chloride (9.0mg,1.5eq) was slowly added dropwise with cooling in an ice bath, and the reaction was continued for 2 hours after completion of the addition. The reaction mixture was diluted with distilled water, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, water, and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent was a solution of dichloromethane: methanol in a volume ratio of 20: 1) to give 7- [3- (2-acetyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 13 mg).

¹H NMR(300MHz,CDCl3):δ8.71(s,1H),7.49(s,1H),7.42(s,1H),6.89(s,1H),6.73(s,1H),6.46(s,1H),4.25(t,J=4.5Hz,2H),3.78(m,5H),3.67(m,5H),2.53(m,2H),2.41(m,4H),2.10(m,2H),1.87(s,3H),1.79(m,4H)ppm.

MS m/z(ESI):598.2[M+H].

Example 8

7- [3- (2-Endopropionyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, the synthesis method similar to that of example 7 was followed, using acryloyl chloride instead of acetyl chloride, to give the title compound 7- [3- (2-Enopropionyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 21 mg).

¹H NMR(300MHz,CD3OD):δ8.44(s,1H),7.77(s,1H),7.57(s,1H),7.34(s,1H),7.21(s,1H),6.29(m,2H),5.77(m,1H),4.34(t,J=4.5Hz,2H),4.17(m,2H),4.02(s,3H),3.90(s,3H),3.70(m,2H),3.42(m,2H),3.15(m,4H),2.40(m,2H),2.24(m,2H),2.05(m,2H)ppm.

MS m/z(ESI):610.2[M+H].

Example 9

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid methyl ester

Using the compound of example 6 as a starting material, the synthesis method similar to that of example 7 was employed, substituting methyl chloroformate for acetyl chloride, to give the target compound methyl 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 55 mg).

¹H NMR(300MHz,CD3OD):δ8.37(s,1H),7.68(s,1H),7.55(s,1H),7.29(s,1H),7.18(s,1H),4.23(m,2H),3.99(s,3H),3.89(s,3H),3.67(m,6H),2.60(m,6H),2.11(m,2H),1.83(m,4H)ppm.

MS m/z(ESI):614.2[M+H].

Example 10

(7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] non-2-yl) -acetic acid ethyl ester

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-methyl cyanide hydrochloride (100mg,0.16mmol,1eq) and N, N-diisopropylethylamine (102mg,5eq) were dissolved in anhydrous N, N-dimethylformamide (5mL) and ethyl bromoacetate (32 mg, 0.19 mmol) was added with stirring. After the addition, the reaction mixture was heated to 50 ℃ for overnight reaction. The reaction mixture was diluted with distilled water, extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent with dichloromethane: methanol in a volume ratio of 20: 1) to give the desired compound (7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] non-2-yl) -acetic acid ethyl ester (pale yellow solid, 32 mg).

¹H NMR(300MHz,CD3OD):δ8.39(s,1H),7.74(s,1H),7.56(s,1H),7.32(s,1H),7.19(s,1H),4.32(t,J=4.2Hz,2H),4.19(m,2H),4.01(s,3H),3.89(s,3H),3.55(m,2H),3.44(m,4H),2.34(m,2H),2.10(m,4H),1.27(t,J=3.6Hz,3H)ppm.

MS m/z(ESI):642.2[M+H].

Example 11

4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (2-ethyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (100mg,0.16mmol), 40% aqueous acetaldehyde (87mg,0.8mmol) and glacial acetic acid (47mg,0.8mmol) were dissolved in methanol and stirred at room temperature for 2 h. The reaction was cooled to 0 deg.C, sodium triacetoxyborohydride (170mg,0.8mmol) was added slowly in portions, and stirring was continued overnight. The reaction mixture was quenched with ice water, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent was dichloromethane: methanol at a volume ratio of 12: 1) to give 4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (2-ethyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile as a yellow solid (25 mg).

¹H NMR(300MHz,CD3OD):δ8.36(s,1H),7.68(s,1H),7.54(s,1H),7.27(s,1H),7.18(s,1H),4.23(t,J=6.0Hz,2H),3.99(s,3H),3.88(s,3H),3.69(s,4H),3.06(m,2H),2.67(m,2H),2.57(m,4H),2.12(m,2H),1.91(m,4H),1.14(m,3H).

MS m/z(ESI):584.2[M+H].

Example 12

7- [3- (2-Cyclopropylmethyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, the aqueous acetaldehyde solution was replaced with cyclopropanecarboxaldehyde by a synthesis method similar to that in example 11 to give the objective compound 7- [3- (2-cyclopropylmethyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 51 mg).

¹H NMR(300MHz,CD3OD):δ8.36(s,1H),7.69(s,1H),7.55(s,1H),7.27(s,1H),7.20(s,1H),4.23(t,J=6.0Hz,2H),4.00(s,3H),3.90(s,3H),3.82(m,4H),2.97(d,J=7.2Hz,2H),2.70(m,2H),2.59(m,4H),2.13(s,2H),1.95(s,4H),0.89(m,1H),0.66(m,2H),0.37(m,2H).

MS m/z(ESI):610.2[M+H].

Example 13

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, a synthesis method similar to that of example 11 was employed, substituting aqueous acetaldehyde with aqueous formaldehyde to give the objective compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 32 mg).

¹H NMR(300MHz,CD3OD):δ8.39(s,1H),7.70(s,1H),7.56(s,1H),7.30(s,1H),7.18(s,1H),4.25(m,2H),3.99(s,3H),3.89(s,3H),3.72(s,4H),2.78(s,3H),2.75(m,2H),2.59(m,4H),2.14(m,2H),1.92(m,4H).

MS m/z(ESI):570.2[M+H].

Example 14

7- [3- (2-cyclobutyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, the synthesis method similar to that of example 11 was followed, substituting cyclobutanone for acetaldehyde, to give the objective compound 7- [3- (2-cyclobutyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 19 mg).

¹H NMR(300MHz,CD3OD):δ8.38(s,1H),7.69(s,1H),7.55(s,1H),7.29(s,1H),7.17(s,1H),4.25(t,J=6.0Hz,2H),3.99(s,3H),3.88(s,3H),3.69(s,1H),3.60(s,4H),2.76(m,2H),2.64(m,4H),2.15(m,4H),2.01(m,2H),1.91(m,4H),1.82(m,2H).

MS m/z(ESI):610.2[M+H].

Example 15

4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (2-isopropyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, acetone was used instead of acetaldehyde by a synthesis method similar to that of example 11 to give the objective compound 4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (2-isopropyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(300MHz,CD3OD):δ8.38(s,1H),7.70(s,1H),7.56(s,1H),7.30(s,1H),7.18(s,1H),4.25(t,J=6.0Hz,2H),4.00(s,3H),3.89(s,3H),3.77(s,4H),3.24(m,1H),2.73(m,2H),2.63(m,4H),2.16(m,2H),1.93(m,4H).

MS m/z(ESI):598.2[M+H].

Example 16

7- [3- (2-Cyclopropylformyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, the synthesis method similar to that of example 7 was followed, using cyclopropanecarbonyl chloride instead of acetyl chloride, to give the target compound 7- [3- (2-cyclopropanecarbonyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(300MHz,CD3OD):δ8.39(s,1H),7.70(s,1H),7.56(s,1H),7.31(s,1H),7.18(s,1H),4.26(t,J=6.0Hz,2H),4.06(s,2H),4.00(s,3H),3.89(s,3H),3.72(s,2H),2.80(m,2H),2.71(m,4H),2.19(m,2H),1.92(m,4H),1.59(m,1H),0.84(m,4H).

MS m/z(ESI):624.2[M+H].

Example 17

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- {3- [2- (2-methoxy-ethyl) -2, 7-diaza-spiro [3.5] non-7-yl ] -propoxy } -quinoline-3-carbonitrile

Using the compound of example 6 as a starting material, and by a synthesis method similar to that of example 10, ethyl bromoacetate was replaced with 1-bromo-2-methoxyethane to give the target compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- {3- [2- (2-methoxy-ethyl) -2, 7-diaza-spiro [3.5] non-7-yl ] -propoxy } -quinoline-3-carbonitrile as a yellow solid (23 mg).

¹H NMR(300MHz,CD3OD):δ8.38(s,1H),7.70(s,1H),7.56(s,1H),7.29(s,1H),7.19(s,1H),4.24(t,J=4.2Hz,2H),4.00(s,3H),3.89(s,3H),3.63(s,4H),3.52(t,J=4.2Hz,2H),3.36(s,3H),3.12(m,2H),2.73(m,2H),2.62(m,4H),2.16(m,2H),1.92(m,4H).

MS m/z(ESI):614.2[M+H].

Example 18

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [4.4] octane-2-carboxylic acid tert-butyl ester

Using the intermediate obtained in the second step of example 1 and tert-butyl 2, 7-diaza-spiro [4.4] octane-2-carboxylate as starting materials, the desired compound, tert-butyl 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [4.4] octane-2-carboxylate (yellow solid, 532mg) was obtained in a similar manner to the third step of example 1.

¹H NMR(300MHz,CD3OD):δ8.38(s,1H),7.73(s,1H),7.56(s,1H),7.31(s,1H),7.21(s,1H),4.31(t,J=5.4Hz,2H),4.02(s,3H),3.90(s,3H),3.41(m,6H),3.24(m,4H),2.29(m,2H),2.05(m,4H),1.46(s,9H).

MS m/z(ESI):656.3[M+H].

Example 19

7- [3- (2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

The title compound, 7- [3- (2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 400 mg), was obtained by a synthesis similar to that of example 4.

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.68(s,1H),7.55(s,1H),7.29(s,1H),7.17(s,1H),4.24(t,J=6.3Hz,2H),3.99(s,3H),3.88(s,3H),2.54-3.03(m,10H),2.09-2.13(m,2H),1.80-1.89(m,4H).

MS m/z(ESI):556.2[M+H].

Example 20

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (7-methyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -quinoline-3-carbonitrile

Starting from the compound of example 19 and an aqueous solution of formaldehyde, the desired compound, 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (7-methyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 20 mg), was obtained by a synthesis method similar to that of example 11.

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.69(s,1H),7.54(s,1H),7.29(s,1H),7.19(s,1H),4.26(t,J=6.3Hz,2H),4.00(s,3H),3.89(s,3H),3.02-3.17(m,3H),2.88-2.96(m,6H),2.78-2.82(m,1H),2.65(s,3H),1.97-2.18(m,6H).

MS m/z(ESI):570.2[M+H].

Example 21

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (7-ethyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Starting from the compound of example 19 and acetaldehyde, the title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (7-ethyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 17 mg), was obtained by a synthesis similar to that of example 11.

¹H-NMR(300MHz,CD₃OD):δ8.38(s,1H),7.70(s,1H),7.55(s,1H),7.30(s,1H),7.18(s,1H),4.27(t,J=6.3Hz,2H),4.00(s,3H),3.88(s,3H),3.04-3.26(m,6H),2.78-2.97(m,6H),1.93-2.18(m,6H),1.28(t,J=7.2Hz,3H).

MS m/z(ESI):584.2[M+H].

Example 22

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [4.4] nonane-2-carboxylic acid methyl ester

Using the compound of example 19 and methyl chloroformate as starting materials, the synthesis method similar to that in example 7 was carried out to give the target compound, methyl 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [4.4] nonane-2-carboxylate (yellow solid, 23 mg).

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.70(s,1H),7.55(s,1H),7.30(s,1H),7.18(s,1H),4.27(t,J=6.0Hz,2H),4.00(s,3H),3.88(s,3H),3.67(s,3H),3.42-3.43(m,2H),3.36-3.38(m,2H),2.86-3.11(m,6H),2.16-2.20(m,2H),1.82-1.96(m,4H).

MS m/z(ESI):614.2[M+H].

Example 23

7- [3- (7-Cyclopropylmethyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 19 and cyclopropanecarboxaldehyde as starting materials, the synthesis method similar to example 11 was carried out to give the objective compound 7- [3- (7-cyclopropylmethyl-2, 7-diaza-spiro [4.4] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 16 mg)

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.71(s,1H),7.55(s,1H),7.30(s,1H),7.18(s,1H),4.28(t,J=6.3Hz,2H),4.00(s,3H),3.89(s,3H),2.87-3.02(m,8H),2.01-2.22(m,8H),1.06-1.12(m,1H),0.66-0.72(m,2H),0.36-0.41(m,2H).

MS m/z(ESI):610.2[M+H].

Example 24

5- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylic acid tert-butyl ester

Using the intermediate obtained in the second step of example 1 and tert-butyl hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylate as starting materials, the title compound, tert-butyl 5- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylate (yellow solid, 120 mg) was obtained in a similar manner to the third step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.42(s,1H),6.90(s,1H),6.76(s,1H),6.46(s,1H),4.26(t,J=4.8Hz,2H),3.78(s,3H),3.66(s,3H),3.54(m,2H),3.19(m,2H),2.71(m,6H),2.41(m,2H),2.11(m,2H),1.44(s,9H).

MS m/z(ESI):641.2[M+H].

Example 25

4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 106 mg), was obtained by a synthesis similar to that described in example 4.

¹H NMR(300MHz,DMSO-d6):δ11.42(br,1H),11.20(br,1H),10.08(br,1H),9.46(br,1H),8.89(s,1H),8.18(s,1H),7.84(s,1H),7.48(s,1H),4.32(t,J=6.0Hz,2H),4.01(s,3H),3.87(s,3H),3.72(m,2H),3.42(m,2H),3.31(m,2H),3.25(m,2H),3.17(m,2H),3.30(m,2H).

MS m/z(ESI):542.2[M+H].

Example 26

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (5-methyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -quinoline-3-carbonitrile

Starting from the compound of example 25 and an aqueous solution of formaldehyde, the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (5-methyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 18mg) was obtained by a synthesis process similar to that of example 11.

¹H-NMR(300MHz,CD₃OD):δ8.38(s,1H),7.69(s,1H),7.54(s,1H),7.33(s,1H),7.20(s,1H),4.21-4.29(m,2H),4.00(s,3H),3.89(s,3H),3.38-3.54(m,2H),3.04-3.21(m,5H),2.85-2.96(m,2H),2.78-2.85(m,2H),2.37-2.59(m,5H),2.16-2.20(m,1H).

MS m/z(ESI):556.2[M+H].

Example 27

7- [3- (5-Cyclopropylmethyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 25 and cyclopropanecarboxaldehyde as starting materials, the synthesis method similar to example 11 was carried out to give the objective compound 7- [3- (5-cyclopropylmethyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg)

¹H-NMR(300MHz,CD₃OD):δ8.41(s,1H),7.71(s,1H),7.55(s,1H),7.38(s,1H),7.19(s,1H),4.22-4.32(m,2H),4.01(s,3H),3.89(s,3H),3.50-3.59(m,2H),2.87-3.15(m,8H),2.48-2.57(m,2H),2.16-2.21(m,2H),2.01-2.03(m,1H),1.57-1.62(m,1H),0.86-0.89(m,1H),0.57-0.58(m,2H),0.22-0.41(m,2H).

MS m/z(ESI):596.6[M+H].

Example 28

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (5-isobutyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 25 as a starting material and the synthesis method similar to example 10, substituting isobutyl bromide for ethyl bromoacetate, the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (5-isobutyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 20 mg)

¹H-NMR(300MHz,CD₃OD):δ8.40(s,1H),7.70(s,1H),7.54(s,1H),7.38(s,1H),7.20(s,1H),4.27-4.29(m,2H),4.00(s,3H),3.90(s,3H),2.80-3.01(m,8H),2.75(s,2H),2.48-2.52(m,2H),2.18-2.19(m,2H),1.92-2.02(m,1H),0.96-1.02(m,6H).

MS m/z(ESI):598.3[M+H].

Example 29

7- [3- (5-acetyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 25 and acetyl chloride as starting materials, the synthesis method similar to example 7 was carried out to give the title compound 7- [3- (5-acetyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 42 mg)

¹H-NMR(300MHz,CDCl₃):δ8.67(s,1H),7.48(s,1H),7.40(s,1H),6.96(s,1H),6.51(s,1H),4.26(t,J=6.3Hz,2H),3.79(s,3H),3.69(s,3H),3.62-3.66(m,2H),3.36-3.48(m,2H),3.00-3.01(m,4H),2.80(t,J=6.3Hz,2H),2.61(s,2H),2.17-2.24(m,2H),2.03(s,3H).

MS m/z(ESI):584.2[M+H].

Example 30

7- [3- (5-Cyclopropylformyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 25 and cyclopropanecarbonyl chloride as starting materials, the synthesis method similar to example 7 was carried out to give the objective compound 7- [3- (5-cyclopropanecarbonyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 38 mg)

¹H-NMR(300MHz,CD₃OD):δ8.36(s,1H),7.87(s,1H),7.55(s,1H),7.28(s,1H),7.18(s,1H),4.26(t,J=4.8Hz,2H),3.60-3.71(m,2H),3.35-3.50(m,1H),4.00(s,3H),3.89(s,3H),3.02-3.09(m,3H),2.88-2.93(m,3H),2.67-2.76(m,2H),2.12-2.21(m,2H),1.76-1.81(m,1H),0.75-0.86(m,4H).

MS m/z(ESI):610.2[M+H].

Example 31

7- [3- (5-cyclopropyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that of example 11, substituting acetaldehyde with (1-methoxy-cyclopropoxy) -trimethyl-silane, the title compound, 7- [3- (5-cyclopropyl-hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 45 mg), was synthesized starting from the compound of example 25

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.69(s,1H),7.55(s,1H),7.28(s,1H),7.18(s,1H),4.30(m,1H),4.19(m,1H),4.00(m,3H),3.88(s,3H),3.47-3.58(m,3H),2.98-3.05(m,3H),2.84-2.90(m,2H),2.70-2.76(m,2H),2.53-2.56(m,1H),2.27-2.42(m,1H),1.86-2.03(m,1H),1.56-1.74(m,1H),0.41-0.55(m,1H).

MS m/z(ESI):582.2[M+H].

Example 32

3- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 6-diaza-bicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the third step of example 1 and tert-butyl 3, 6-diaza-bicyclo [3.2.1] octane-6-carboxylate, the title compound, tert-butyl 3- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 6-diaza-bicyclo [3.2.1] octane-6-carboxylate (yellow solid, 54 mg), was obtained by a synthesis method similar to the third step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.41(d,J=5.7Hz,1H),6.91(d,J=5.7Hz,1H),6.78(m,1H),6.45(s,1H)

MS m/z(ESI):642.2[M+H].

Example 33

7- [3- (3, 6-diaza-bicyclo [3.2.1] oct-3-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-anilino) -7- [3- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 51 mg) was obtained by a synthesis method similar to that of example 4

¹H NMR(300MHz,DMSO-d6):δ11.35(br,1H),10.50(br,1H),10.25(br,1H),8.94(s,1H),8.81(br,1H),8.31(s,1H),7.84(s,1H),7.58(s,1H),7.50(s,1H),4.31(t,J=5.7Hz,2H),4.14(m,1H),4.02(s,3H),3.87(s,3H),3.71(m,2H),3.56(m,2H),3.29(m,4H),2.83(m,1H),2.31(m,2H),2.10(m,1H),1.83(m,1H).

MS m/z(ESI):542.2[M+H].

Example 34

3- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 6-diaza-bicyclo [3.2.1] octane-6-carboxylic acid methyl ester

Using the compound obtained in example 33 and methyl chloroformate as starting materials, the synthesis method similar to that in example 7 was carried out to give the objective compound methyl 3- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 6-diaza-bicyclo [3.2.1] octane-6-carboxylate (yellow solid, 26 mg)

¹H NMR(300MHz,DMSO-d6):δ11.35(br,1H),10.50(br,1H),10.25(br,1H),8.94(s,1H),8.81(br,1H),8.31(s,1H),7.84(s,1H),7.58(s,1H),7.50(s,1H),4.31(t,J=6.0Hz,2H),4.14(m,1H),4.02(s,3H),3.87(s,3H),3.71(m,2H),3.56(m,2H),3.29(m,4H),2.83(m,1H),2.31(m,2H),2.10(m,1H),1.83(m,1H).

MS m/z(ESI):542.2[M+H].

Example 35

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -propoxy ] -quinoline-3-carbonitrile

Using the intermediate compound obtained in the second step of example 1 and 2-oxa-6-aza-spiro [3.3] heptane as starting materials, the desired compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 36 mg), was obtained by a synthesis method similar to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.67(s,1H),7.48(s,1H),7.38(s,1H),6.91(s,1H),6.90(s,1H),6.48(s,1H),4.74(s,1H),4.18-4.22(t,J=6.0Hz,2H),3.77(s,3H),3.67(s,3H),3.52(s,4H),2.67-2.71(t,J=6.0Hz,2H),1.97-2.00(m,2H).

MS m/z(ESI):529.2[M+H].

Example 36

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [4.4] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using the intermediate compound obtained in the second step of example 1 and 2-oxa-7-aza-spiro [4.4] nonane as starting materials, the desired compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [4.4] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 38 mg), was obtained by a synthesis method similar to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.41(s,1H),6.90(s,1H),6.75(s,1H),6.46(s,1H),4.25-4.29(t,J=6.0Hz,2H),3.83-3.88(m,2H),3.77(s,3H),3.70-3.73(m,1H),3.67(s,3H),3.58-3.61(m,1H),2.79-2.87(m,6H),2.21-2.24(m,2H),1.92-2.01(m,4H).

MS m/z(ESI):557.3[M+H].

Example 37

2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the second step of example 1 and tert-butyl 2, 8-diaza-spiro [4.5] decane-8-carboxylate, the title compound, tert-butyl 2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 8-diaza-spiro [4.5] decane-8-carboxylate (yellow solid, 532 mg), was obtained in a manner similar to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.69(s,1H),7.48(s,1H),7.42(s,1H),6.90(s,1H),6.77(s,1H),6.46(s,1H),4.23-4.28(m,2H),3.77(s,3H),3.66(s,3H),3.27-3.47(m,4H),2.59-2.64(m,4H),2.41(s,2H),2.08-2.13(m,2H),1.62-1.66(t,J=6.0Hz,2H),1.49-1.52(m,4H),1.44(s,9H).

MS m/z(ESI):656.3[M+H].

Example 38

7- [3- (2, 8-diaza-spiro [4.5] decan-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that in example 4, the target compound 7- [3- (2, 8-diaza-spiro [4.5] decan-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 245mg) was obtained from the compound of example 37.

¹H-NMR(300MHz,CD₃OD):δ8.73(s,1H),7.95(s,1H),7.52(s,1H),7.30-7.32(m,2H),4.33(t,J=6.0Hz,2H),3.97(s,3H),3.81(s,3H),3.13(m,3H),2.30-2.34(m,2H),2.08-2.14(m,1H),1.93-1.99(m,1H),1.89-1.90(m,4H).

MS m/z(ESI):570.2[M+H].

Example 39

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (8-methyl-2, 8-diaza-spiro [4.5] decan-2-yl) -propoxy ] -quinoline-3-carbonitrile

Using a synthesis method similar to that in example 11, substituting an aqueous solution of formaldehyde for acetaldehyde, the target compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (8-methyl-2, 8-diaza-spiro [4.5] decan-2-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 28mg) was synthesized from the compound of example 38.

¹H-NMR(300MHz,CD₃OD):δ8.37(s,1H),7.74(s,1H),7.54(s,1H),7.32(s,1H),7.20(s,1H),4.30(t,J=6.0Hz,2H),4.02(s,3H),3.89(s,3H),3.47-3.51(m,2H),3.36-3.38(m,2H),3.30(s,4H),3.22-3.26(m,2H),2.82(s,3H),2.33-2.36(m,2H),2.07-2.10(m,2H),1.96-2.00(m,4H).

MS m/z(ESI):586.2[M+H].

Example 40

2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 8-diaza-spiro [4.5] decane-8-carboxylic acid methyl ester

Using a synthesis method similar to that in example 7, using methyl chloroformate instead of acetyl chloride, the target compound, methyl 2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 8-diaza-spiro [4.5] decane-8-carboxylate (yellow solid, 28mg), was synthesized from the compound in example 38 as a starting material.

¹H-NMR(300MHz,CDCl₃)δ8.67(s,1H),7.48(s,1H),7.39(s,1H),6.94(s,1H),6.87-6.90(m,1H),6.50(s,1H),4.23(t,J=6Hz,2H),3.77(s,3H),3.68(s,4H),3.47(m,5H),3.38-3.46(m,2H),2.72-2.97(m,6H),2.27-2.31(m,2H),2.07-2.10(m,2H),1.96-2.00(m,4H),1.83(t,J=6.0Hz,2H),1.60-1.63(m,4H).

MS m/z(ESI):628.2[M+H].

EXAMPLE 41

9- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 9-diaza-spiro [5.5] undecane-3-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the second step of example 1 and tert-butyl 3, 9-diaza-spiro [5.5] undecane-3-carboxylate, the title compound, tert-butyl 9- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 9-diaza-spiro [5.5] undecane-3-carboxylate (yellow solid, 360mg), was obtained according to a synthesis method similar to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.42(s,1H),6.89(s,1H),6.74(s,1H),6.45(s,1H),4.22-4.27(m,2H),3.77(s,3H),3.66(s,3H),3.34-3.37(m,4H),2.54-2.58(m,2H),2.44(s,4H),2.10-2.14(t,J=6.0Hz,2H),1.52-1.55(m,4H),1.44(s,9H).

MS m/z(ESI):684.2[M+H].

Example 42

7- [3- (3, 9-diaza-spiro [5.5] undecan-3-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that in example 4, the target compound 7- [3- (3, 9-diaza-spiro [5.5] undecan-3-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 220mg) was obtained from the compound of example 41.

¹H-NMR(300MHz,CD₃OD):δ8.80(s,1H),8.00(s,1H),7.58(s,1H),7.38(m,2H),4.39(m,2H),4.03(s,3H),3.87(s,3H),3.66-3.68(m,1H),3.37-3.41(m,2H),3.28(m,2H),3.17(m,4H),2.40(m,2H),1.93-2.03(m,4H),1.79(m,2H),1.68(m,2H).

MS m/z(ESI):584.2[M+H].

Example 43

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (9-methyl-3, 9-diaza-spiro [5.5] undecan-3-yl) -propoxy ] -quinoline-3-carbonitrile

Using a synthesis method similar to that in example 11, substituting an aqueous solution of formaldehyde for acetaldehyde, the target compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [3- (9-methyl-3, 9-diaza-spiro [5.5] undecan-3-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 26mg) was synthesized from the compound of example 42.

¹H-NMR(300MHz,CD₃OD):δ8.36(s,1H),7.72(s,1H),7.54(s,1H),7.29(s,1H),7.20(s,1H),4.28-4.31(m,2H),4.01(s,3H),3.80(s,3H),3.29-3.31(m,2H),3.25-3.27(m,2H),3.16-3.23(m,4H),2.80(s,3H),2.32-2.35(m,2H),1.94(m,4H),1.86(m,4H).

MS m/z(ESI):598.2[M+H].

Example 44

9- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 9-diaza-spiro [5.5] undecyl-3-carboxylic acid methyl ester

Using a synthesis method similar to that in example 7, using methyl chloroformate instead of acetyl chloride, the target compound, methyl 9- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -3, 9-diaza-spiro [5.5] undecyl-3-carboxylate (yellow solid, 36mg), was synthesized from the compound in example 42 as a starting material.

¹H-NMR(300MHz,CDCl₃):δ8.69(s,1H),7.49(s,1H),7.39(s,1Hs),6.92(s,1H),6.83(s,1H),6.49(s,1H),4.23-4.37(m,2H),3.77(s,3H),3.67-3.68(m,4H),3.40-3.44(m,3H),2.74-2.89(m,6H),2.29-2.34(m,2H),1.69-1.81(m,4H),1.46-1.50(m,4H).

MS m/z(ESI):642.2[M+H].

Example 45

6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 6-diaza-spiro [3.3] heptane-2-carboxylic acid methyl ester

Starting from the intermediate obtained in step 2 of example 1 and tert-butyl 2, 6-diaza-spiro [3.3] heptane-2-carboxylate, the intermediate, tert-butyl 6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 6-diaza-spiro [3.3] heptane-2-carboxylate (183 mg, yellow solid), was synthesized in a similar manner to the third step of example 1.

¹H-NMR(300MHz,d-MeOD):δ=8.41(1H,s),7.75(1H,s),7.56(1H,s),7.28(1H,s),7.27(1H,s),4.23(2H,J=6.0Hz,d),4.10(3H,s),4.06(2H,s),3.88(3H,s),3.63(4H,s),2.87-2.89(2H,J=6.0Hz,d),1.97-2.03(4H,m),1.32(9H,s)。MS m/z(ESI):630.2[M+H].

The above yellow solid was directly dissolved in methylene chloride, and the compound 7- [3- (2, 6-diaza-spiro [3.3] hept-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 90 mg) was synthesized by a method similar to example 4 and used in the next reaction without further purification.

Using the above intermediate as a starting material, a synthesis method similar to that in example 7 was employed, in which methyl chloroformate was used in place of acetyl chloride, to synthesize the objective compound 6- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 6-diaza-spiro [3.3] heptane-2-carboxylic acid methyl ester (yellow solid, 24mg).

¹H-NMR(300MHz,CD₃OD)δ8.37(s,1H),7.70(s,1H),7.55(s,1H),7.27(s,1H),7.18(s,1H),4.20-4.23(m,2H),4.09(s,3H),4.00(s,3H),3.88(s,3H),3.63-3.67(m,6H),2.86-2.90(m,2H),1.98-2.02(m,4H).

MS m/z(ESI):588.2[M+H].

Example 46

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -propoxy ] -quinoline-3-carbonitrile

Starting from the intermediate compound of step 2 of example 1 and 7-oxa-2-aza-spiro [3.5] nonane, the procedure of example 1 was followed

The third step of the similar synthesis gave the target compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 40 mg).

¹H NMR(300MHz,DMSO-d6):δ8.39(s,1H),7.74(s,1H),7.56(s,1H),7.31(s,1H),7.19(s,1H),4.61(s,4H),4.27(t,J=6.0Hz,2H),4.02(s,3H),3.89(s,3H),3.74(s,2H),3.64(t,J=5.7Hz,2H),3.21(m,2H),2.15(m,2H),1.86(m,4H).

MS m/z(ESI):557.2[M+H].

Example 47

2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the second step of example 1 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-7-carboxylate, the title compound, tert-butyl 2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylate (yellow solid, 317 mg) was obtained using a synthesis method similar to the third step of example 1.

¹H-NMR(300MHz,CD₃OD):δ8.38(s,1H),7.72(s,1H),7.55(s,1H),7.29(s,1H),7.18(s,1H),4.26(m,2H),4.01(s,3H),3.88(s,3H),3.73(s,4H),3.39(m,4H),3.20-3.22(m,2H),2.11-2.16(m,2H),1.78-1.82(m,4H),1.44(s,9H).

MS m/z(ESI):656.2[M+H].

Example 48

7- [3- (2, 7-diaza-spiro [3.5] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that in example 4, the target compound 7- [3- (2, 7-diaza-spiro [3.5] non-2-yl) -propoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 280 mg) was obtained from the compound of example 47.

¹H-NMR(300MHz,CD₃OD):δ8.36(s,1H),7.67(s,1H),7.54(s,1H),7.27(s,1H),7.17(s,1H),4.20(t,J=6.0Hz,2H),3.98(s,3H),3.88(s,3H),3.13(s,4H),2.73-2.78(m,6H),1.93-1.98(m,2H),1.73-1.76(m,4H).

MS m/z(ESI):556.2[M+H].

Example 49

2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid methyl ester

Using a synthesis method similar to that in example 7, using methyl chloroformate instead of acetyl chloride, the target compound, methyl 2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylate (yellow solid, 26 mg), was synthesized from the compound in example 48.

¹H-NMR(300MHz,CD₃OD):δ8.38(s,1H),7.73(s,1H),7.55(s,1H),7.30(s,1H),7.18(s,1H),4.28(t,J=5.7Hz,2H),4.02(s,3H),3.89(s,3H),3.81(s,4H),3.67(s,3H),3.43-3.46(m,4H),3.26-3.29(m,2H),2.13-2.18(m,2H),1.81-1.85(m,4H).

MS m/z(ESI):614.2[M+H].

Example 50

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-methyl-2, 7-diaza-spiro [3.5] non-2-yl) -propoxy ] -quinoline-3-carbonitrile

Using a synthesis method similar to that of example 11, substituting aqueous formaldehyde for acetaldehyde, the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-methyl-2, 7-diaza-spiro [3.5] non-2-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 22 mg) was obtained from the compound of example 48.

¹H-NMR(300MHz,CD₃OD):δ8.38(s,1H),7.70(s,1H),7.55(s,1H),7.29(s,1H),7.18(s,1H),4.24(t,J=6.0Hz,2H),4.00(s,3H),3.88(s,3H),3.45(s,4H),2.89-3.03(m,2H),2.56(s,4H),2.38(s,3H),2.03-2.07(m,2H),1.89-1.91(m,4H).

MS m/z(ESI):570.2[M+H].

Example 51

4- (4-chloro-3-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthetic route is as follows:

the first step is as follows: 4- (4-chloro-3-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 4-chloro-3-methoxy-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-chloro-3-methoxy-anilino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H NMR(400MHz,CD3Cl):δ8.66(s,1H),7.38(s,1H),7.30(s,1H),6.85(m,2H),6.66(s,1H),6.59(m,1H),4.32(t,J=6.0Hz,2H),3.82(s,3H),3.78(m,2H),3.63(s,3H),2.37(m,2H).

MS m/z(ESI):432.1[M+H].

The second step is that: 4- (4-chloro-3-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure adopted in the third step of example 1 was followed to give the title compound 4- (4-chloro-3-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 23 mg).

¹H NMR(300MHz,CD3Cl):δ8.62(s,1H),7.31(m,2H),7.05(br,1H),6.92(s,1H),6.70(s,1H),6.61(s,1H),4.42(m,4H),4.23(t,J=5.7Hz,2H),3.83(s,3H),3.66(s,3H),2.60(m,6H),2.21(m,2H),2.05(m,4H).

MS m/z(ESI):523.2[M+H].

Example 52

6-methoxy-4- (1-methyl-1H-indazol-5-ylamine) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (3-chloro-propoxy) -6-methoxy-4- (1-methyl-1H-indazol-5-ylamino) -quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 1-methyl-1H-indazol-5-ylamine was used in place of 2, 4-dichloro-5-methoxyaniline to give intermediate 7- (3-chloro-propoxy) -6-methoxy-4- (1-methyl-1H-indazol-5-ylamino) -quinolin-3-carbonitrile (yellow solid, 70 mg).

¹H NMR(300MHz,CDCl₃):δ8.58(s,1H),7.94(s,1H),7.54(s,1H),7.41(s,1H),7.36(s,1H),7.25(m,2H),7.03(s,1H),6.87(s,1H),4.31(t,J=5.4Hz,2H),4.09(s,3H),3.77(t,J=5.7Hz,2H),3.47(s,3H),2.35(m,2H).

MS m/z(ESI):422.1[M+H].

The second step is that: 6-methoxy-4- (1-methyl-1H-indazol-5-ylamine) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 6-methoxy-4- (1-methyl-1H-indazol-5-ylamine) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 28 mg).

¹H NMR(300MHz,CDCl₃):δ8.56(s,1H),7.94(s,1H),7.54(s,1H),7.41(m,1H),7.30(m,2H),7.19(s,1H),6.92(s,1H),4.42(s,4H),4.21(t,J=6.0Hz,2H),4.09(s,3H),3.50(s,3H),2.60(m,6H),2.23(m,2H),2.06(m,4H).

MS m/z(ESI):513.3[M+H].

Example 53

4- (3-chloro-4-fluoro-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (3-chloro-4-fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 3-chloro-4-fluoro-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (3-chloro-4-fluoro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 250 mg).

¹H NMR(300MHz,CDCl₃):δ8.65(s,1H),7.41(s,1H),7.16(m,2H),6.96(m,1H),6.83(s,1H),6.79(s,1H),4.33(t,J=6.0Hz,2H),3.79(t,J=6.0Hz,2H),3.68(s,3H),2.37(m,2H).

MS m/z(ESI):420.1[M+H].

The second step is that: 4- (3-chloro-4-fluoro-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (3-chloro-4-fluoro-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 15 mg).

¹H NMR(300MHz,CDCl₃):δ8.59(s,1H),7.35(s,1H),7.14(m,3H),6.97(m,1H),6.88(s,1H),4.39(s,4H),4.20(t,J=6.3Hz,2H),3.69(s,3H),3.46(s,2H),2.49(m,2H),2.35(m,3H),2.07(m,5H).

MS m/z(ESI):510.2[M+H].

Example 54

4- (4-chloro-3-cyano-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (4-chloro-3-cyano-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 3-chloro-4-cyano-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-chloro-3-cyano-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow oil, 35 mg) which was used in the next reaction without further purification.

MS m/z(ESI):427.1[M+H].

The second step is that: 4- (4-chloro-3-cyano-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (4-chloro-3-cyano-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (pale yellow solid, 4 mg).

¹H NMR(300MHz,CDCl₃):δ8.63（s,1H）,7.63(s,1H),7.45(dd,J=8.7Hz,2.4Hz,1H),7.36(s,1H),7.12(s,1H),6.91(d,J=8.7Hz,1H),4.43(s,4H),4.22(t,J=6.3Hz,2H),3.86(s,3H),3.08(m,2H),2.56(m,6H),2.41(m,2H).

MS m/z(ESI):518.15[M+H].

Example 55

4- (2-chloro-5-methoxy-phenylamine) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (2-chloro-5-methoxy-anilino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 2, 4-dichloro-5-methoxyaniline was replaced with 2-chloro-5-methoxy-aniline to give the intermediate 4- (2-chloro-5-methoxy-anilino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (grey solid, 200 mg).

¹H NMR(300MHz,CDCl₃):δ8.71(s,1H),7.44–7.34(m,3H),6.90(s,1H),6.74(s,1H),6.65(m,1H),6.41(m,1H),4.35(t,J=5.7Hz,3H),3.84(m,4H),3.69(m,4H).

MS m/z(ESI):433.1[M+H].

The second step is that: 4- (2-chloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure adopted in the third step of example 1 was followed to give the target compound 4- (2-chloro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(300MHz,CDCl₃):δ11.96(s,1H),8.67(s,1H),7.38(m,2H),7.01(s,1H),6.68(m,1H),6.48(m,1H),4.48(s,4H),4.27(t,J=5.7Hz,2H),3.73(s,3H),3.69(m,5H),2.62–2.50(m,4H),2.43–2.18(m,2H),1.30(m,4H),1.25(s,2H).

MS m/z(ESI):524.2[M+H].

Example 56

5- {3- [4- (2-chloro-5-methoxy-phenylamino) -3-cyano-6-methoxy-quinolin-7-yloxy ] -propyl } -hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylic acid tert-butyl ester

Starting from the intermediate of the first step of example 55 and tert-butyl hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylate, the expected compound 5- {3- [4- (2-chloro-5-methoxy-phenylamino) -3-cyano-6-methoxy-quinolin-7-yloxy ] -propyl } -hexahydro-pyrrolo [3,4-c ] pyrrole-2-carboxylate (yellow solid, 57mg) was obtained by a synthesis analogous to the second step of example 55.

¹H NMR(300MHz,CDCl₃):δ8.66(s,1H),7.38(s,3H),6.95(m,2H),6.69–6.60(m,1H),6.43(m,1H),5.30–5.27(m,1H),4.70(m,2H),4.24(s,3H),3.73(s,4H),3.66(d,J=1.5Hz,4H),3.59–3.47(m,3H),3.26–3.17(m,3H),3.13–3.01(m,7H),2.85–2.69(m,7H),2.64(m,4H),2.40(dd,J=5.7,1.5Hz,4H),2.16–2.03(m,4H).

MS m/z(ESI):609.3[M+H].

Example 57

4- (2-chloro-5-methoxy-anilino) -7- [3- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that in example 4, the target compound 4- (2-chloro-5-methoxy-anilino) -7- [3- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (white solid, 15mg) was obtained from the compound of example 56.

¹H NMR(300MHz,DMSO-d₆):δ11.39(m,2H),10.35–9.94(m,2H),9.74–9.38(m,2H),8.91(s,1H),8.28–8.20(m,1H),7.60–7.50(m,2H),7.23(s,1H),7.15–7.06(m1H),4.32(d,J=0.6Hz,2H),4.02(s,3H),3.80(s,4H),3.12–3.00(m,8H),2.44–2.22(m,4H),2.13–1.91(m,2H).

MS m/z(ESI):509.2[M+H].

Example 58

4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (3-chloro-propoxy) -4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-quinoline-3-carbonitrile

4-chloro-7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (311 mg,1 mmol) was dissolved in anhydrous N, N-dimethylformamide (8 mL), and 4-fluoro-2-methyl-1H-indol-5-ol (165 mg,1 mmol) and anhydrous potassium carbonate powder (276 mg,2 mmol) were added in that order under nitrogen, and stirred at room temperature overnight. After the reaction, the reaction mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, and separation and purification of the concentrate by silica gel column chromatography gave intermediate 7- (3-chloro-propoxy) -4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H NMR(300MHz,DMSO-d₆):δ11.39(s,1H),8.73(s,1H),7.55(d,J=7.8Hz,1H),7.13(d,J=7.2Hz,1H),6.97(s,1H),6.27(s,1H),4.34(t,J=6.3Hz,2H),3.91(s,3H),3.83(t,J=6.0Hz,2H),2.40(s,3H),2.28(m,2H).

MS m/z(ESI):440.1[M+H].

The second step is that: 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (white solid, 12 mg).

¹H NMR(300MHz,CD3Cl):δ8.61(s,1H),8.27(s,1H),7.63(s,1H),7.42(s,1H),7.03(m,2H),6.33(s,1H),4.41(m,4H),4.27(t,J=5.7Hz,2H),4.01(s,3H),3.48(s,3H),2.51(t,J=6.0Hz,2H),2.35(m,4H),2.12(m,2H),1.88(m,4H).

MS m/z(ESI):531.2[M+H].

Example 59

4- (4-bromo-2-chloro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (4-bromo-2-chloro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 4-bromo-2-chloro-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-bromo-2-chloro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 110 mg).

¹H NMR(300MHz,CDCl₃):δ8.72(s,1H),7.66(d,J=2.2Hz,1H),7.44(s,1H),7.30(d,J=2.1Hz,1H),7.28(d,J=2.4Hz,1H),6.83(s,1H),6.72(d,J=8.6Hz,1H),6.69(s,1H),4.35(t,J=5.9Hz,2H),3.80(t,J=6.2Hz,3H),3.74(s,4H)。

MS m/z(ESI):482.1[M+H].

The second step is that: 4- (4-bromo-2-chloro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (4-bromo-2-chloro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 40 mg).

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.65(s,1H),7.40(s,1H),6.85(s,1H),6.73(m,2H),4.43(s,4H),4.26(t,J=6.3Hz,2H),3.75(s,3H),2.35–2.17(m,5H),2.16–1.95(m,7H).

MS m/z(ESI):572.1[M+H].

Example 60

4- (3-chloro-biphenyl-4-amino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 3-chloro-4-biphenylylamine

4-bromo-2-chloro-aniline (1 g, 4.8 mmol), phenylboronic acid (770 mg, 6.3 mmol), potassium carbonate powder (2.3 g,16.8 mmol) and triphenylphosphine (198 mg,0.8 mmol) were mixed, suspended in a mixed solvent of toluene and water (9 mL:1 mL), and bubbled with nitrogen for 10 minutes. Then palladium acetate (54 mg,0.2 mmol) is added into the mixed solution, the mixture is heated and refluxed for 8 hours under the protection of nitrogen, ethyl acetate is added for extraction after the reaction is finished, organic phases are respectively washed by water and saturated saline solution, dried by anhydrous sodium sulfate, filtered and concentrated. The concentrated solution was separated and purified by silica gel column chromatography (eluent was ethyl acetate: petroleum ether in a volume ratio of 1: 50) to give intermediate 3-chloro-terphenyl-4-ylamine (white solid, 365 mg).

¹H NMR(300MHz,CDCl₃):δ7.52（m,3H）,7.41(t,J=7.2Hz,2H),7.31(t,J=7.2Hz,2H),6.83(d,J=8.1Hz,1H),4.11(bs,2H).

MS m/z(ESI):203.1[M+H].

The second step is that: 4- (3-chloro-4-biphenylylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 3-chloro-4-biphenylylamine was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-bromo-2-chloro-phenylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (grey solid, 165mg).

¹H NMR(300MHz,CDCl₃):δ8.72(s,1H),7.75(s,1H),7.59–7.53(m,2H),7.49–7.35(m,5H),6.96(d,J=8.4Hz,1H),6.89(s,1H),6.83(s,1H),4.35(t,J=6.0Hz,2H),3.80(t,J=6.0Hz,2H),3.68(s,3H),2.41–2.36(m,2H).

MS m/z(ESI):479.1[M+H].

The third step: 4- (3-chloro-biphenyl-4-amino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (3-chloro-biphenyl-4-amino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (white solid, 46mg).

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.74(s,1H),7.54(s,2H),7.49–7.33(m,5H),6.97(d,J=8.4Hz,1H),6.91(m,2H),4.42(d,J=6.6Hz,4H),4.24(t,J=6.6Hz,2H),3.69(s,3H),2.62–2.50(m,2H),2.50–2.36(m,4H),2.17–2.10(m,2H),1.97–1.90(m,4H).

MS m/z(ESI):570.2[M+H].

Example 61

6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (2-oxo-2, 3-dihydro-1H-indol-5-ylamino) -quinoline-3-carbonitrile

The first step is as follows: 5-amino-1, 3-dihydro-indol-2-ones

5-Nitro-1, 3-dihydro-indol-2-one (500 mg,2.8 mmol) was dissolved in a mixed solvent of tetrahydrofuran and ethanol (15 mL/15 mL), and air was purged by nitrogen substitution. Then, a palladium on carbon catalyst (50mg) was added under nitrogen protection, and hydrogen gas was introduced thereinto and stirred at room temperature for 6 hours. After the reaction was complete, the catalyst was removed by filtration and the filtrate was directly concentrated to give 5-amino-1, 3-dihydro-indol-2-one (grey solid, 390 mg) which was used in the next reaction without further purification.

¹H NMR(300MHz,DMSO-d6):δ7.88(s,1H),7.27(d,J=6.6Hz,1H),7.26(m,2H),6.58(d,J=6.6Hz,1H),5.72(s,1H),4.16(s,2H).

MS m/z(ESI):148.2[M+H].

The second step is that: 7- (3-chloro-propoxy) -6-methoxy-4- (2-oxo-2, 3-dihydro-1H-indol-5-ylamino) -quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 5-amino-1, 3-dihydro-indol-2-one was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 7- (3-chloro-propoxy) -6-methoxy-4- (2-oxo-2, 3-dihydro-1H-indol-5-ylamino) -quinolin-3-carbonitrile (yellow solid, 206 mg).

¹H NMR(300MHz,DMSO-d6):δ9.69(s,1H),8.59(s,1H),8.44(s,1H),7.71(s,1H),7.63(d,J=6.3Hz,1H),7.42(s,1H),7.32(s,1H),7.26(d,J=6.3Hz,1H),4.34(s,2H),4.31(t,J=4.5Hz,2H),3.91(s,3H),3.83(t,J=4.8Hz,2H),2.27(m,2H)

MS m/z(ESI):422.2[M+H].

The third step: 6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (2-oxo-2, 3-dihydro-1H-indol-5-ylamino) -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (2-oxo-2, 3-dihydro-1H-indol-5-ylamino) -quinoline-3-carbonitrile (yellow solid, 23mg).

¹H NMR(300MHz,DMSO-d6):δ10.47(s,1H),9.43(s,1H),8.34(s,1H),7.79(s,1H),7.28(s,1H),7.13(s,1H),7.10(d,J=8.1Hz,1H),6.84(d,J=8.1Hz,1H),4.29(s,4H),4.19(m,2H),3.91(s,3H),3.50(s,2H),1.83-2.01(m,6H).

MS m/z(ESI):513.2[M+H].

Example 62

6-methoxy-4- (2-methyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2-bromomethyl-4-nitro-benzoic acid methyl ester

2-methyl-4-nitro-benzoic acid methyl ester (3.0 g,15 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (3.0 g,17 mmol) and benzoyl peroxide (100mg,0.4mmol) were added in this order, and the reaction was refluxed for 10 hours after the addition. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated solution was subjected to silica gel column chromatography (eluent using ethyl acetate: petroleum ether in a volume ratio of 70: 1) to give intermediate 2-bromomethyl-4-nitro-benzoic acid methyl ester (pale yellow solid, 1.9 g)

¹H NMR(300MHz,CDCl₃):δ8.34（s,1H），8.19（dd,J=2.1,8.4Hz,1H）,8.11(d,J=8.4Hz,1H),4.97(s,2H),3.99(s,3H).

The second step is that: 2-methyl-5-nitro-2, 3-dihydro-isoindol-1-ones

Methyl 2-bromomethyl-4-nitro-benzoate (1 g,3.6 mmol) was suspended in a small amount of tetrahydrofuran (5 mL), and a solution of methylamine in tetrahydrofuran (20 mL, 2M/L) was added and heated under reflux overnight. The reaction solution was cooled to room temperature, a white solid was precipitated, filtered under reduced pressure, and the filter cake was washed with distilled water and anhydrous ethanol, respectively, and dried to give an intermediate, 2-methyl-5-nitro-2, 3-dihydro-isoindol-1-one (white solid, 520 mg).

¹H NMR(300MHz,CDCl₃):δ8.51（s,1H），8.31(dd,J=1.8,6.3Hz,1H),7.90(d,J=6.3Hz,1H),4.59(s,2H),3.12(s,3H).

MS m/z(ESI):192.2[M+H].

The third step: 5-amino-2-methyl-2, 3-dihydro-isoindol-1-ones

Synthesis was carried out in a similar manner to the first step of example 61 to give intermediate 5-amino-2-methyl-2, 3-dihydro-isoindol-1-one (white solid, 360 mg).

¹H NMR(300MHz,CDCl₃):δ7.60(d,J=6.0Hz,1H),6.69(dd,J=1.5,6.0Hz,1H),6.65(d,J=1.5Hz,1H),4.25(s,2H),3.99(bs,2H),3.13(s,3H).

MS m/z(ESI):162.2[M+H].

The fourth step: 7- (3-chloro-propoxy) -6-methoxy-4- (2-methyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 5-amino-2-methyl-2, 3-dihydro-isoindol-1-one was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 7- (3-chloro-propoxy) -6-methoxy-4- (2-methyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinolin-3-carbonitrile (yellow solid, 87mg).

¹H NMR(300MHz,DMSO-d6):δ9.68(s,1H),8.58(s,1H),7.71(s,1H),7.63(d,J=6.6Hz,1H),7.41(s,1H),7.35(s,1H),7.26(m,1H),4.42(s,2H),4.30(t,2H),3.91(s,3H),3.82(t,2H),3.06(s,3H),2.27(m,2H).

MS m/z(ESI):437.1[M+H].

The fifth step: 6-methoxy-4- (2-methyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 6-methoxy-4- (2-methyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 36 mg).

¹H NMR(300MHz,CD₃OD):δ8.51(s,1H),7.75(d,1H),7.59(s,1H),7.33(m,3H),4.48(s,2H),4.44(s,4H),4.23(t,J=5.7Hz,2H),3.93(s,3H),3.18(s,3H),2.61(t,J=6.0Hz,2H),2.53(m,4H),2.13(m,2H),1.94(m,4H).

MS m/z(ESI):528.3[M+H].

Example 63

4- (4-chloro-5-cyclopropylmethyloxy-2-fluoro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 1-chloro-2-cyclopropylmethoxy-5-fluoro-4-nitro-benzene

2-chloro-4-fluoro-5-nitro-phenol (2 g,10.5 mmol) and anhydrous potassium carbonate powder (3.6 g,26 mmol) were suspended in anhydrous N, N-dimethylformamide (8mL), stirred at room temperature under nitrogen for half an hour, and cyclopropylmethyl bromide (1.5 g,11.5 mmol) was added to the suspension. After the addition, the reaction solution was heated to 50 ℃ and stirred overnight. After the reaction, the reaction solution was cooled to room temperature, diluted with distilled water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated solution was separated and purified by silica gel column chromatography (eluent was a solution of ethyl acetate: petroleum ether in a volume ratio of 1: 5) to give an intermediate, 1-chloro-2-cyclopropylmethoxy-5-fluoro-4-nitro-benzene (yellow solid, 2.3 g).

¹H-NMR(300MHz,CDCl₃):δ7.56-7.58(d,J=6.0Hz,1H),7.34-7.37(d,J=9.0Hz,1H),3.92-3.94(d,J=6.3Hz,2H),1.32(m,1H),0.68-0.71(m,2H),0.40-0.43(m,2H).

MS m/z(ESI):245.3[M+H].

The second step is that: 4-chloro-5-cyclopropylmethoxy-2-fluoro-aniline

1-chloro-2-cyclopropylmethoxy-5-fluoro-4-nitro-benzene (1.2 g,4.9 mmol) was dissolved in methanol (20 mL), and saturated aqueous ammonium chloride (8 mL) and zinc powder (956 mg,15.7 mmol) were added in that order, and the reaction was heated under nitrogen reflux overnight. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove excess zinc powder, and the filtrate was concentrated under reduced pressure to give 4-chloro-5-cyclopropylmethoxy-2-fluoro-aniline (yellow oil, 800 mg).

¹H-NMR(300MHz,CDCl₃):δ6.99-7.01(d,J=6.3Hz,1H),6.35-6.37(d,J=6.0Hz,1H),3.76-3.78(m,2H),3.69(s,2H),1.25-1.30(m,1H)，0.60-0.64(m,2H),0.32-0.36(m,2H).

MS m/z(ESI):215.1[M+H].

The third step: 4- (4-chloro-5-cyclopropylmethoxy-2-fluoro-aniline) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 4-chloro-5-cyclopropylmethoxy-2-fluoro-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-chloro-5-cyclopropylmethoxy-2-fluoro-aniline) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H-NMR(300MHz,CDCl₃):δ8.65(s,1H),7.41(s,1H),7.22(s,1H),6.94(s,1H),6.68(s,1H),6.56-6.59(d,J=9.0Hz,1H),4.31-4.35(m,2H),3.68-3.80(m,7H),2.35-2.39(m,1H),1.18-1.27(m,1H),0.56-0.59(m,2H),0.28-0.30(m,2H).

MS m/z(ESI):489.1[M+H].

The fourth step: 4- (4-chloro-5-cyclopropylmethyloxy-2-fluoro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (4-chloro-5-cyclopropylmethyloxy-2-fluoro-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile as a yellow solid (38 mg).

¹H-NMR(300MHz,CDCl₃):δ8.61(s,1H),7.36(s,1H),7.23(s,1H),6.98(s,1H),6.61-6.62(d,J=3.0Hz,1H),4.42(s,4H),4.21-4.24(m,2H),3.78(s,3H),3.70(d,J=6.0Hz,2H),2.56-2.74(m,6H),2.21(m,2H),2.04(m,2H),1.23-1.25(m,1H),0.58-0.60(m,2H),0.29-0.31(d,J=6.0Hz,2H).

MS m/z(ESI):581.1[M+H].

Example 64

4- (4-chloro-2-fluoro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene

Synthesized in a similar manner to the first step of example 63, substituting methyl iodide for cyclopropylmethyl bromide, to give the intermediate 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene (yellow solid, 930mg).

¹H-NMR(300MHz,CDCl₃):δ7.59(d,J=6.0Hz,1H),7.34-7.38(m,1H),3.97(s,3H).

MS m/z(ESI):205.1[M+H].

The second step is that: 4-chloro-2-fluoro-5-methoxy-aniline

Synthesis was carried out in a similar manner to the second step of example 63 to give 4-chloro-2-fluoro-5-methoxy-aniline (yellow solid, 600 mg).

¹H-NMR(300MHz,CDCl₃):δ7.00(d,J=6.0Hz,1H),6.34(d,J=6.3Hz,1H),3.81(s,3H),3.73(s,2H).

MS m/z(ESI):175.2[M+H].

The third step: 4- (4-chloro-2-fluoro-5-methoxy-anilino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 4-chloro-2-fluoro-5-methoxy-aniline was used instead of 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (4-chloro-2-fluoro-5-methoxy-anilino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 62 mg).

¹H-NMR(300MHz,CDCl₃):δ8.67(s,1H),7.42(s,1H),7.24(s,1H),6.94(s,1H),6.67(s,1H),6.57(s,1H),4.31(t,J=6.3Hz,1H),3.73-3.81(m,2H),2.33(t,J=6.3Hz,2H).

MS m/z(ESI):449.1[M+H].

The fourth step: 4- (4-chloro-2-fluoro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The target compound 4- (4-chloro-2-fluoro-5-methoxy-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 28mg) was obtained by a synthesis method similar to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.66(s,1H),7.40(s,1H),7.25-7.27(m,1H),6.93(s,1H),6.63(s,1H),6.56(s,1H),4.41(s,4H),4.22(t,J=6.0Hz,2H),3.77(s,3H),3.73(s,3H),2.53-2.57(m,2H),2.36-2.43(m,3H),2.11-2.16(m,2H),1.88-1.95(m,4H).

MS m/z(ESI):540.2[M+H].

Example 65

4- (3-ethynyl-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (3-chloro-propoxy) -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 2, 4-dichloro-5-methoxyaniline was replaced with 3-ethynyl-aniline to give intermediate 7- (3-chloro-propoxy) -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 340 mg).

¹H NMR(300MHz,CDCl₃):δ8.66(s,1H),7.39(s,1H),7.33–7.28(m,2H),7.20(s,1H),7.08–7.02(m,1H),6.83(m,2H),4.33(t,J=6.0Hz,2H),3.78(t,J=6.3Hz,2H),3.60(s,3H),3.08(s,1H),2.42–2.32(m,2H).

MS m/z(ESI):392.1[M+H].

The second step is that: 4- (3-ethynyl-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- (3-ethynyl-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 45 mg).

¹H NMR(300MHz,CDCl₃):δ8.65(s,1H),7.37(s,1H),7.30(m,2H),7.19(s,1H),7.06–7.01(m,1H),6.86(s,1H),6.82(s,1H),4.41(s,4H),4.22(t,J=6.3Hz,2H),3.60(s,3H),3.08(s,1H),2.50(d,J=6.3Hz,2H),2.45–2.29(m,4H),2.15–2.05(m,2H),1.94–1.84(m,4H).

MS m/z(ESI):483.2[M+H].

Example 66

4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [4.4] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using the intermediate obtained in the first step of example 65 and 2-oxa-7-aza-spiro [4.4] nonane as starting materials, the desired compound, 4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [4.4] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 23 mg), was obtained according to a synthesis procedure similar to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.55(s,1H),7.37–7.19(m,5H),4.21(t,J=5.7Hz,2H),3.89(s,3H),3.82(m,1H),3.59(m,1H),3.47(s,1H),2.87(m,4H),2.16–2.09(m,2H),2.07–1.80(m,6H).

MS m/z(ESI):483.2[M+H].

Example 67

7- {3- [ 3-cyano-4- (3-ethynyl-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the intermediate of the first step of example 65 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the title compound, tert-butyl 7- {3- [ 3-cyano-4- (3-ethynyl-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 360mg), was obtained using a synthesis procedure similar to the third step of example 1.

¹H NMR(300MHz,DMSO-d₆):δ8.65(s,1H),7.37(s,1H),7.32–7.28(m,2H),7.19(s,1H),7.07–7.01(m,1H),6.87–6.80(m,2H),4.23(s,2H),3.08(s,1H),2.55–2.46(m,2H),2.44–2.30(m,4H),2.13–2.02(m,2H),1.74(m,6H),1.72(s,9H).

MS m/z(ESI):582.3[M+H].

Example 68

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 67 as a starting material, the synthesis method similar to example 4 was carried out to give the target compound 7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 313 mg).

¹H NMR(300MHz,CD₃OD):δ8.81(s,1H),7.95(s,1H),7.68–7.42(m,4H),7.37(s,1H),4.42(t,J=5.7Hz,2H),4.04(s,6H),3.93(s,2H),3.68(s,2H),3.63(s,1H),3.47–3.34(m,2H),3.11(t,J=12.4Hz,2H),2.38(m,4H),2.16(m,2H),1.28(s,2H).

MS m/z(ESI):555.2[M+H].

Example 69

4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using the compound of example 68 as a starting material, acetaldehyde was replaced with an aqueous formaldehyde solution by a synthesis method similar to that of example 11 to give the objective compound 4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(300MHz,CDCl₃):δ8.65(s,1H),7.37(s,1H),7.29(s,1H),7.19(s),7.05(d,J=6.3Hz,1H),6.85(m,2H),5.34(m,2H),4.22(t,J=6.6Hz,2H),3.61(s,3H),3.32(m,4H),3.08(s,1H),2.53(m,2H),2.49(m,2H),2.36(s,4H),2.22(m,2H),2.12–2.05(m,4H).

MS m/z(ESI):496.3[M+H].

Example 70

7- {3- [ 3-cyano-4- (3-ethynyl-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid methyl ester

Using the compound of example 68 as a starting material, the synthesis method similar to that of example 7 was employed, substituting methyl chloroformate for acetyl chloride, to give the target compound methyl 7- {3- [ 3-cyano-4- (3-ethynyl-anilino) -6-methoxy-quinolin-7-yloxy ] -propyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 60 mg).

¹H NMR(300MHz,CD₃OD):δ8.53(s,1H),7.62(s,1H),7.42–7.23(m,5H),5.61(s,1H),4.28(t,J=6.3Hz,2H),3.89(s,3H),3.68(s,3H),3.63(s,4H),2.58(m,2H),2.55–2.23(m,4H),2.12(m,2H),1.81(t,J=5.4Hz,4H).

MS m/z(ESI):540.2[M+H].

Example 71

4- [ 3-chloro-4- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 3-chloro-4- (3-fluoro-benzyloxy) -aniline

Synthesized in a similar manner to the first and second steps of example 63, substituting cyclopropylmethyl bromide with 3-fluorobenzyl bromide to give the intermediate 3-chloro-4- (3-fluoro-benzyloxy) -aniline (white solid, 520mg).

¹H NMR(300MHz,CDCl₃):δ7.32-7.44(m,1H),7.19-7.22(m,2H),6.99-7.03(m,1H),6.96-6.98(m,2H),6.50(dd,J=8.7,2.7Hz,1H),3.49(s,2H).

MS m/z(ESI):251.1[M+H].

The second step is that: 4- [ 3-chloro-4- (3-fluoro-benzyloxy) -anilino ] -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 3-chloro-4- (3-fluoro-benzyloxy) -aniline was used instead of 2, 4-dichloro-5-methoxyaniline to give 4- [ 3-chloro-4- (3-fluoro-benzyloxy) -anilino ] -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile as an intermediate (white solid, 112 mg).

1H NMR(400MHz,CDCl₃):δ8.61(s,1H),7.37(s,2H),7.25–7.16(m,3H),7.06–6.96(m,2H),6.93(d,J=8.7Hz,1H),6.82(s,1H),6.73(s,1H),5.17(s,2H),4.32(t,J=5.7Hz,2H),3.78(t,J=6.0Hz,2H),3.60(s,3H),2.41–2.32(m,2H).

MS m/z(ESI):527.1[M+H].

The third step: 4- [ 3-chloro-4- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- [ 3-chloro-4- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (white solid, 35 mg).

¹H NMR(300MHz,CDCl₃):δ8.59(s,1H),7.36(d,J=6.8Hz,2H),7.24–7.15(m,3H),7.07–6.96(m,2H),6.92(d,J=8.7Hz,1H),6.81(d,J=8.4Hz,2H),5.16(s,2H),4.41(s,5H),4.21(t,J=6.5Hz,2H),3.61(s,3H),2.56–2.47(m,2H),2.48–2.25(m,4H),2.10(dd,J=8.6,5.2Hz,2H),1.90(s,4H).

MS m/z(ESI):618.2[M+H].

Example 72

4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2- (2-chloro-4-nitro-phenoxymethyl) -pyridine

Synthesized in a similar manner to the first step of example 63, substituting cyclopropylmethyl bromide with 2-bromomethylpyridine to give the intermediate 2- (2-chloro-4-nitro-phenoxymethyl) -pyridine (yellow solid, 520 mg).

¹H NMR(300MHz,CDCl₃):δ8.61(d,J=4.8Hz,1H),8.33(s,1H),8.13(dd,J=9.0Hz,2.7Hz,1H),7.77(m,1H),7.59(d,J=7.8Hz,1H),7.29(d,J=4.8Hz,1H),7.09(d,J=9.0Hz,1H),5.38(s,2H).

MS m/z(ESI):264.2[M+H].

The second step is that: 3-chloro-4- (pyridin-2-ylmethoxy) -aniline

Synthesis of intermediate 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamine (white solid, 315 mg) in a similar manner to the second step of EXAMPLE 63

MS m/z(ESI):234.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 3-chloro-4- (pyridin-2-ylmethoxy) -aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 7- (3-chloro-propoxy) -4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile (grey solid, 260mg).

¹H NMR(300MHz,CDCl₃):8.60(s,1H),7.75(dd,J=7.5,1.3Hz,1H),7.62(d,J=7.5Hz,1H),7.37(s,1H),7.24(s,1H),6.99(s,2H),6.83(m,2H),5.28(s,2H),4.32(t,J=5.7Hz,2H),3.81–3.74(m,2H),3.62(s,3H),2.37(m,2H).

MS m/z(ESI):510.1[M+H].

The fourth step: 4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (white solid, 40mg).

¹H NMR(300MHz,CDCl₃):δ8.59(s,1H),7.81–7.72(m,1H),7.63(dd,J=7.5,3.6Hz,1H),7.36–7.33(m,1H),7.23(s,1H),6.99(m,2H),6.87–6.79(m,2H),5.28(s,2H),4.41(s,4H),4.22(t,J=6.6Hz,2H),3.62(s,3H),2.64–2.52(m,2H),2.53–2.34(m,4H),2.18–2.09(m,2H),1.92(m,4H).

MS m/z(ESI):601.2[M+H].

Example 73

7- (3- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -3-cyano-6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the third step of example 72 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the title compound, tert-butyl 7- (3- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -3-cyano-6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 60mg), was obtained according to a synthesis similar to the third step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.58(d,J=6.6Hz,2H),7.76(t,J=7.8Hz,1H),7.62(d,J=7.8Hz,1H),7.32(s,1H),7.25–7.23(m,2H),6.99(s,2H),6.90(s,1H),5.27(s,2H),4.68(s,4H),4.22(s,2H),3.63(s,3H),2.66(m,6H),2.22(s,4H),1.44(s,9H).

MS m/z(ESI):700.3[M+H].

Example 74

4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 73 as a starting material, the synthesis method similar to example 4 was followed to give the objective compound 4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 40mg).

¹H NMR(300MHz,CD₃OD):δ8.90(s,1H),8.84–8.80(m,1H),8.68–8.59(m,1H),8.23(m,1H),8.08–7.99(m,2H),7.69(m,1H),7.56–7.48(m,1H),7.45–7.37(m,2H),5.64(s,2H),4.47–4.39(m,2H),4.11–4.03(m,5H),3.94(s,2H),3.72(m,2H),3.43(m,2H),3.19–3.05(m,2H),2.52–2.33(m,4H),2.24–2.07(m,2H).

MS m/z(ESI):600.2[M+H].

Example 75

7- (3- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -3-cyano-6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid methyl ester

Using the compound of example 74 as a starting material, and by a synthesis method similar to that of example 7, acetyl chloride was replaced with methyl chloroformate to give the objective compound methyl 7- (3- {4- [ 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino ] -3-cyano-6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 8 mg).

¹H NMR(300MHz,CDCl₃):δ8.58–8.53(m,1H),8.37(s,1H),7.95–7.86(m,1H),7.71(d,J=7.8Hz,1H),7.63(s,1H),7.40(m,2H),7.31–7.16(m,3H),5.29(s,2H),4.58(s,1H),4.24(s,2H),3.96(s,3H),3.72(s,4H),3.65(s,3H),2.79–2.61(m,4H),2.18(m,3H),2.03(s,2H),1.94–1.85(m,4H).

MS m/z(ESI):658.2[M+H].

Example 76

6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinoline-3-carbonitrile

The first step is as follows: 5-nitro-2, 3-dihydro-isoindol-1-ones

The second synthesis procedure, analogous to that of example 62, was used, substituting the tetrahydrofuran solution of methylamine with the tetrahydrofuran solution of ammonia to give the intermediate 5-nitro-2, 3-dihydro-isoindol-1-one (yellow solid, 360 mg).

¹H NMR(300MHz,CDCl₃):δ8.49（s,1H），8.32(dd,J=1.8,6.3Hz,1H),7.84(d,J=6.3Hz,1H),4.55(s,2H).

MS m/z(ESI):178.2[M+H].

The second step is that: 5-amino-2, 3-dihydro-isoindol-1-ones

Synthesis was carried out in a similar manner to the third step of example 62 to give intermediate 5-amino-2, 3-dihydro-isoindol-1-one (yellow solid, 302 mg).

¹H NMR(300MHz,DMSO-d6):δ7.88（s,1H），7.27(d,J=6.6Hz,1H),7.21(bs,1H),6.58(d,J=6.6Hz,1H),5.72(s,1H),4.16(s,2H).

MS m/z(ESI):148.1[M+H].

The third step: 7- (3-chloro-propoxy) -6-methoxy-4- (1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 5-amino-2, 3-dihydro-isoindol-1-one was substituted for 2, 4-dichloro-5-methoxyaniline to give 7- (3-chloro-propoxy) -6-methoxy-4- (1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinolin-3-carbonitrile as an intermediate (yellow solid, 90 mg).

¹H NMR(300MHz,DMSO-d6):δ9.69(s,1H),8.59(s,1H),8.44(s,1H),7.71(s,1H),7.63(d,J=6.3Hz,1H),7.42(s,1H),7.32(s,1H),7.26(d,J=6.3Hz,1H),4.30(m,4H),3.91(s,3H),3.83(t,J=4.8Hz,2H),2.27(t,J=4.8Hz,2H).

MS m/z(ESI):422.1[M+H].

The fourth step: 6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -4- (1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -quinoline-3-carbonitrile (yellow solid, 35 mg).

¹H NMR(300MHz,DMSO-d6):δ9.70(s,1H),8.58(d,J=2.1Hz,1H),8.44(s,1H),7.69(s,1H),7.63(d,J=6.0Hz,1H),7.37(s,1H),7.32(s,1H),7.25(dd,J=6.0,2.1Hz,1H),4.34(s,2H),4.28(s,4H),4.21(t,J=4.8Hz,2H),3.90(s,3H),2.4(m,4H),2.00(m,2H),1.80(m,4H).

MS m/z(ESI):513.2[M+H].

Example 77

1- (2-chloro-4- { 3-cyano-6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3-cyclopropylurea

The first step is as follows: 1- (2-chloro-4-hydroxy-phenyl) -3-cyclopropyl-urea

4-amino-3-chlorophenylphenol hydrochloride (2 g, 11 mmol) and pyridine (1.7 g, 22 mmol) were dissolved in anhydrous dimethylformamide (20 mL), p-nitrophenol chloroformate (2.2 g, 11 mmol) was slowly added to the reaction solution under cooling in an ice bath, and the mixture was stirred at room temperature overnight. After the reaction, distilled water was added for dilution, dichloromethane was used for extraction, the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 980mg of yellow solid, which was directly put into the next reaction without purification.

The above intermediate (611 mg, 2 mmol) was dissolved in anhydrous dimethylformamide (6 mL), to which cyclopropylamine (565 mg, 10 mmol) and diisopropylethylamine (1.2 g, 10 mmol) were added in this order under cooling on an ice bath, and stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent dichloromethane: methanol in a volume ratio of 30: 1) to obtain intermediate 1- (2-chloro-4-hydroxy-phenyl) -3-cyclopropyl-urea (light red oil, 200 mg).

¹H NMR(300MHz,DMSO):δ9.50(s,1H),7.70(m,1H),7.75(s,1H),6.78(m,2H),6.65(m,1H),2.52(m,1H),0.62(m,2H),0.39(m,2H).

MS m/z(ESI):227.1[M+H].

The second step is that: 1- { 2-chloro-4- [7- (3-chloro-propoxy) -3-cyano-6-methoxy-quinolin-4-yloxy ] -phenyl } -3-cyclopropyl-urea

4-chloro-7- (3-chloropropyl) -6-methoxyquinoline-3-carbonitrile (150 mg, 0.48 mmol) was dissolved in anhydrous dimethylformamide (3 mL), and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea (130 mg, 0.57 mmol) and cesium carbonate (234 mg, 0.72 mmol) were added to the reaction solution, respectively. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (dichloromethane: methanol =30: 1) to give intermediate 1- { 2-chloro-4- [7- (3-chloro-propoxy) -3-cyano-6-methoxy-quinolin-4-yloxy ] -phenyl } -3-cyclopropyl-urea (light red solid, 99 mg).

¹H NMR(300MHz,DMSO-d6):δ8.86(s,1H),8.18(d,1H),7.92(s,1H),7.56(s,1H),7.38(m,2H),7.15(m,2H),4.36(t,J=6.3Hz,2H),3.84(m,5H),2.55(m,1H),2.29(m,2H),0.64(m,2H),0.41(m,2H).

MS m/z(ESI):500.1[M+H].

The third step: 1- (2-chloro-4- { 3-cyano-6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3-cyclopropylurea

The synthesis procedure adopted in the third step of example 1 was similar to that described above to give the title compound 1- (2-chloro-4- { 3-cyano-6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3-cyclopropylurea (yellow solid, 55mg).

¹H NMR(300MHz,DMSO-d6):δ8.88(s,1H),8.15(d,J=6.0Hz,1H),7.92(s,1H),7.55(s,1H),7.37(m,2H),7.10(m,2H),4.32(m,5H),3.86(s,3H),2.99(m,4H),2.55(m,1H),2.19(m,2H),1.92(m,4H),0.64(m,2H),0.41(m,2H).

MS m/z(ESI):591.2[M+H].

Example 78

4- (2-benzyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 5-amino-2-benzyl-2, 3-dihydro-isoindol-1-ones

The second and third synthesis procedures were carried out in analogy to the second and third synthesis procedures described in example 62, substituting benzylamine in tetrahydrofuran for methylamine in tetrahydrofuran to give intermediate 5-amino-2-benzyl-2, 3-dihydro-isoindol-1-one (yellow solid, 320 mg).

¹H NMR(300MHz,DMSO-d6):δ7.68（d,J=6.6Hz,1H）,7.31(m,5H),6.75(d,J=6.6Hz,1H),4.75(s,2H),4.15(s,2H).

MS m/z(ESI):238.2[M+H].

The second step is that: 4- (2-benzyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 5-amino-2-benzyl-2, 3-dihydro-isoindol-1-one was used in place of 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (2-benzyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 90mg).

¹H NMR(300MHz,DMSO-d6):δ8.69(s,1H),7.81(d,J=6.0Hz,1H),7.41(s,1H),7.32(m,8H),7.12(s,1H),7.09(d,J=6.0Hz,1H),6.95(s,1H),6.93(d,J=6.0Hz,1H),4.76(s,2H),4.33(t,J=4.5Hz,2H),4.20(s,2H),3.79(t,J=4.5Hz,2H),3.59(s,3H),2.37(m,2H).

MS m/z(ESI):512.2[M+H].

The third step: 4- (2-benzyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- (2-benzyl-1-oxo-2, 3-dihydro-1H-isoindol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 34mg).

¹H NMR(300MHz,DMSO-d6):δ8.48（s,1H）,7.79(d,J=6.0Hz,1H),7.63(s,1H),7.34(m,8H),4.80(s,2H),4.49(s,4H),4.35(s,2H),4.30(t,J=4.2Hz,2H),3.96(s,3H),3.17(m,6H),2.32(m,2H),2.14(m,4H).

MS m/z(ESI):603.2[M+H].

Example 79

4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2, 4-dichloro-5- (3-fluoro-benzyloxy) -aniline

The intermediate 2, 4-dichloro-5- (3-fluoro-benzyloxy) -aniline (yellow solid, 560 mg) was synthesized using a similar procedure to the first and second steps of example 63.

¹H NMR(400MHz,CD₃OD):δ7.35(m,2H),7.18(m,4H),7.01(m,2H),6.34(s,2H).

MS m/z(ESI):287.2[M+H].

The second step is that: 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 2, 4-dichloro-5- (3-fluoro-benzyloxy) -aniline was used instead of 2, 4-dichloro-5-methoxyaniline to give 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile as an intermediate (white solid, 100 mg).

¹H NMR(300MHz,CDCl₃):δ8.71(s,1H),7.52(s,1H),7.43(s,1H),6.92(d,J=8.4Hz,3H),6.72(s,1H),6.61(s,1H),6.34(s,1H),4.90(s,2H),4.37(t,J=6.0Hz,2H),3.83(t,J=6.3Hz,2H),3.66(s,3H),2.46–2.36(m,2H)。

MS m/z(ESI):561.1[M+H].

The third step: 4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure similar to the third step of example 1 was used to give the title compound 4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile as a white solid (25 mg).

¹H NMR(300MHz,CDCl₃):δ8.72(s,1H),7.75(m,2H),7.59–7.53(m,1H),7.49–7.35(m,1H),6.96(m,3H),6.89(s,1H),6.83(s,1H),4.35(t,J=6.0Hz,2H),3.80(t,J=6.3Hz,2H),3.68(s,3H),2.70-2.55(m,2H),2.41–2.36(m,4H),2.10(m,2H),2.00(m,4H).

MS m/z(ESI):652.2[M+H].

Example 80

7- (3- { 3-cyano-4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the compound obtained in the second step of example 79 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the title compound, tert-butyl 7- (3- { 3-cyano-4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 390 mg), was obtained by a synthesis similar to the third step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.69(s,1H),7.51(s,1H),7.40(s,1H),7.22–7.14(m,1H),6.93(m,3H),6.72(s,1H),6.63(s,1H),6.34(s,1H),4.90(s,2H),4.26(m,3H),3.64(m,10H),2.54(m,2H),2.40(s,4H),2.14(d,J=6.3Hz,2H),1.77(m,4H),1.66(s,9H).

MS m/z(ESI):751.3[M+H].

Example 81

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (7-oxa-2-aza-spiro [3.5] non-2-yl) -but-1-ynyl ] -quinoline-3-carbonitrile

The first step is as follows: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (4-hydroxy-but-1-ynyl) -6-methoxy-quinoline-3-carbonitrile

Trifluoromethanesulfonic acid 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ester (800mg,1.53mmol), 3-butyn-1-ol (129mg,1.84mmol) and N, N-diisopropylethylamine (990mg,7.65mmol) were mixed and dissolved in N, N-dimethylformamide (10ml), the mixture was bubbled with nitrogen for 15 minutes and Pd (PPh) was added rapidly₃)₂Cl₂(54mg,0.077mmol) and cuprous iodide (29mg,0.153mmol) were reacted at 80 ℃ for 12h under nitrogen. After the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, distilled water, and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (4-hydroxy-but-1-ynyl) -6-methoxy-quinoline-3-carbonitrile (650mg, yellow solid).

¹H NMR(400MHz,CD₃OD):δ8.39(s,1H),7.98(s,1H),7.71(s,1H),7.57(s,1H),7.22(s,1H),4.01(s,3H),3.90(s,3H),3.78(t,J=6.7Hz,2H),2.73(t,J=6.7Hz,2H).

MS m/z(ESI):443.3[M+H].

The second step is that: methanesulfonic acid 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -but-3-ynyl ester

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (4-hydroxy-but-1-ynyl) -6-methoxy-quinoline-3-ca-rbonitrile (650mg,1.47mmol) was dissolved in dichloromethane (20 mL) and DIPEA (950mg,7.35mmol) and methanesulfonyl chloride (505mg,4.409mmol) were added sequentially with ice-cooling and reacted at 0 ℃ for 2 h. After the reaction, dichloromethane was extracted, and the organic phase was washed with saturated aqueous sodium bicarbonate, distilled water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and separated by silica gel column chromatography to give 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -but-3-ynyl methanesulfonate (790 mg, yellow solid).

¹H NMR(400MHz,CD₃OD):δ8.10(s,1H),8.00(s,1H),7.50(s,1H),7.02(s,1H),6.60(s,1H),4.44(t,J=6.7Hz,2H),3.82(s,3H),3.73(s,3H),3.09(s,3H),2.95(s,2H).

MS m/z(ESI):521.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (7-oxa-2-aza-spiro [3.5] non-2-yl) -but-1-ynyl ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (7-oxa-2-aza-spiro [3.5] non-2-yl) -but-1-ynyl ] -quinoline-3-carbonitrile (yellow solid, 32 mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.40(s,1H),7.91(s,1H),7.74(s,1H),7.57(s,1H),7.22(s,1H),4.02(s,3H),3.89(s,3H),3.64–3.59(m,8H),3.13(t,J=6.8Hz,2H),2.76(t,J=6.8Hz,2H),1.86–1.81(m,4H).

MS m/z(ESI):552.2[M+H].

Example 82

7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -but-3-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the compound obtained in the second step of example 81 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the expected compound, tert-butyl 7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -but-3-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 49 mg), was synthesized in a similar manner to the third step of example 1.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),7.93(s,1H),7.76(s,1H),7.58(s,1H),7.24(s,1H),4.04(s,3H),3.90(s,3H),3.66(s,4H),3.63(s,3H),2.67(s,4H),1.86(d,J=4.9Hz,4H),1.44(s,9H).

MS m/z(ESI):637.2[M+H].

Example 83

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile

Using a synthesis method similar to that in example 4, the target compound 7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 327mg) was obtained from the compound of example 80.

¹H NMR(300MHz,CD₃OD):δ8.84(s,1H),7.98(s,1H),7.71(s,1H),7.47–7.34(m,3H),7.30–7.16(m,2H),7.05(s,1H),5.25(s,2H),4.43(t,J=5.7Hz,2H),4.06(m,5H),3.93(m,2H),3.69(m,2H),3.41(m,2H),3.30(m,6H),3.18–3.05(m,2H),2.50–2.32(m,4H),2.25–2.08(m,2H).

MS m/z(ESI):651.2[M+H].

Example 84

4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Using a synthesis method similar to that of example 11, substituting aqueous formaldehyde for acetaldehyde, the target compound 4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -phenylamino ] -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 20 mg) was obtained from the compound of example 83.

¹H NMR(300MHz,DMSO-d₆):δ8.68(s,1H),7.51(s,1H),7.40(s,1H),7.19(m,1H),6.97–6.91(m,3H),6.75(s,1H),6.68(s,1H),6.36(s,1H),4.91(s,2H),4.25(t,J=6.6Hz,2H),3.68(s,3H),3.50(m,7H),2.54(t,J=6.6Hz,2H),2.44–2.33(m,4H),2.11(m,4H),2.01(m,2H).

MS m/z(ESI):665.2[M+H].

Example 85

7- (3- { 3-cyano-4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid methyl ester

Using a synthesis method similar to that of example 7, substituting methyl chloroformate for acetyl chloride, the target compound methyl 7- (3- { 3-cyano-4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-quinolin-7-yloxy } -propyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 68mg) was obtained from the compound of example 83.

¹H NMR(300MHz,CDCl₃):δ8.69(s,1H),7.52(s,1H),7.39(s,1H),7.20(m,1H),6.98–6.90(m,3H),6.74(s,1H),6.37(s,1H),4.91(s,2H),4.27(t,J=6.3Hz,2H),3.71(s,4H),3.67(m,6H),2.88–2.71(m,2H),2.61(d,J=5.1Hz,2H),2.39–2.26(m,2H),2.13–1.81(m,6H).

MS m/z(ESI):709.2[M+H].

Example 86

6-methoxy-4- (3-methoxy-phenylthio) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (3-chloro-propoxy) -6-methoxy-4- (3-methoxy-phenylsulfide) -quinoline-3-carbonitrile

4-chloro-7- (3-chloropropyloxy) -6-methoxyquinoline-3-carbonitrile (150mg,0.48mmol), 3-methoxybenzenethiol (104.8mg,0.74mmol) and triethylamine (97.6mg,0.96mmol) were dissolved in anhydrous tetrahydrofuran (5mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove most of the solvent by evaporation, and purified by silica gel column chromatography to give 7- (3-chloro-propoxy) -6-methoxy-4- (3-methoxy-phenylsulfide) -quinoline-3-carbonitrile (yellow solid, 120mg).

¹H NMR(300MHz,DMSO-d₆):δ9.00(s,1H),7.55(s,1H),7.50(s,1H),7.24(t,J=6.0Hz,1H),6.94(t,J=1.5Hz,1H),6.89(t,J=1.5Hz,1H),6.82(m,1H),4.33(t,J=4.5Hz,2H),3.80(t,J=4.5Hz,2H),3.77(s,3H),3.69(s,3H),2.26(t,J=4.5Hz,2H).

MS m/z(ESI):415.1[M+H].

The second step is that: 6-methoxy-4- (3-methoxy-phenylthio) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 6-methoxy-4- (3-methoxy-phenylthio) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 67 mg) was synthesized in a similar manner to the third step of example 1.

¹H NMR(300MHz,DMSO-d₆):δ8.83(s,1H),7.57(s,1H),7.44(s,1H),7.23(t,J=6.0Hz,1H),6.86(m,3H),4.43(s,4H),4.25(t,J=4.5Hz,2H),3.79(s,3H),3.72(s,3H),2.61(t,J=6.0Hz,2H),2.49(m,4H),2.12(m,2H)，1.92(m,4H)。

MS m/z(ESI):506.2[M+H].

Example 87

4- (2, 4-dichloro-5-cyclopropylmethyloxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5]]Non-7-yl) -propoxy]_-Quinolines_-3_-Methyl cyanide

The first step is as follows: 1, 5-dichloro-2-cyclopropylmethoxy-4-nitro-benzene

The intermediate 1, 5-dichloro-2-cyclopropylmethoxy-4-nitro-benzene was synthesized in a similar manner to the first step of example 63 (yellow solid, 1.3 g).

¹H-NMR(300MHz,CDCl₃):δ7.56(s,1H),7.45(s,1H),3.93(d,J=3Hz,2H),1.32(m,1H),0.69-0.71(m,2H),0.40-0.42(m,2H).

MS m/z(ESI):262.1[M+H].

The second step is that: 2, 4-dichloro-5-cyclopropylmethoxy-aniline

Synthesis was carried out in a similar manner to the second step of example 63 to give 2, 4-dichloro-5-cyclopropylmethoxy-aniline (yellow solid, 0.8 g).

¹H-NMR(300MHz,CDCl₃):δ7.21(s,1H),6.32(s,1H),4.00(s,2H),3.80(s,2H),1.25-1.27(m,1H)，0.62-0.64(m,2H),0.35-0.36(m,2H).

MS m/z(ESI):232.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-cyclopropylmethoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

Using a synthesis similar to the second step of example 1, 2, 4-dichloro-5-cyclopropylmethoxy-aniline was substituted for 2, 4-dichloro-5-methoxyaniline to give the intermediate 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-cyclopropylmethoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 180 mg).

¹H-NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),6.69(s,1H),6.44(s,1H),4.33-4.36(m,2H),3.76-3.81(m,5H),3.62-3.65(m,2H),2.36(t,J=6Hz,2H),1.25-1.31(m,1H),0.55(d,J=6Hz,2H),0.26(d,J=6Hz,2H).

MS m/z(ESI):505.1[M+H].

The fourth step: 4- (2, 4-dichloro-5-cyclopropylmethyloxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-cyclopropylmethyloxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 45 mg) was synthesized in a similar manner to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.68(s,1H),7.48(s,1H),7.39(s,1H),6.89(s,1H),6.76(s,1H),6.45(m,4H),4.42(s,4H),4.22-4.25(m,2H),3.76(s,3H),3.62(d,J=6Hz,2H),2.70(m,2H),2.55-2.58(m,4H),2.19-2.23(m,2H),2.02-2.03(m,6H),1.40(m,1H),0.55-0.57(m,2H),0.26-0.29(m,2H).

MS m/z(ESI):596.2[M+H].

Example 88

4- [ 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2- (2-chloro-4-fluoro-5-nitro-phenoxymethyl) -pyridine

Synthesized in a similar manner to the first step of example 63, substituting cyclopropylmethyl bromide with 2-bromomethylpyridine to give the intermediate 2- (2-chloro-4-fluoro-5-nitro-phenoxymethyl) -pyridine (yellow solid, 1.5 g).

¹H-NMR(300MHz,CDCl₃):δ8.61(d,J=3.6Hz,1H),7.73-7.79(m,2H),7.55-7.58(m,1H),7.37-7.40(m,1H),7.26-7.30(m,1H),5.31(2H,s).

MS m/z(ESI):282.1[M+H].

The second step is that: 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -aniline

Synthesis was carried out in a similar manner to the second step of example 63 to give 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -phenylamine as an intermediate (yellow solid, 760 mg).

¹H-NMR(300MHz,d-CDCl₃):δ8.55(d,J=6.0Hz,1H),7.71-7.76(m,1H),7.60(d,J=6.0Hz,1H),7.20-7.25(m,2H),7.02-7.05(m,1H)，6.40-6.43(m,1H),5.17(s,2H).

MS m/z(ESI):252.2[M+H].

The third step: 4- [ 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -anilino ] -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -aniline for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- [ 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -anilino ] -7- (3-chloro-propoxy) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H-NMR(300MHz,CDCl₃):δ8.67(s,1H),8.32(m,1H),7.65-7.70(m,1H),7.52(s,1H),7.46-7.49(m,1H),7.42(s,1H),7.15(s,1H),6.77(s,1H),6.62-6.64(m,1H),6.49(s,1H),5.01(s,2H),4.34(t,J=6.0Hz,2H),3.80-3.84(t,J=6.0Hz,2H),3.69(s,3H),2.38-2.42(m,2H).

MS m/z(ESI):526.1[M+H].

The fourth step: 4- [ 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- [ 4-chloro-2-fluoro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 48 mg).

¹H-NMR(300MHz,CDCl₃):δ8.60(s,1H),8.40-8.41(m,1H),7.69-7.72(m,1H),7.53-7.56(m,1H),7.36(s,1H),7.29(s,1H),7.17-7.21(m,1H),6.89(s,1H),5.07(s,2H),4.22-4.26(m,2H),3.86(s,4H),3.73(s,3H),3.58(m,2H),2.74-2.82(m,2H),2.59-2.69(m,2H),2.19-2.24(m,2H),1.99-2.01(m,2H).

MS m/z(ESI):617.2[M+H].

Example 89

4- (2-cyclopropylmethyl-2H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2-cyclopropylmethyl-5-nitro-2H-indazole and 1-cyclopropylmethyl-5-nitro-1H-indazole

The synthesis was carried out in a similar manner to the first step of example 63, and the intermediate a 2-cyclopropylmethyl-5-nitro-2H-indazole (yellow solid, 700 mg) having a higher polarity and b 1-cyclopropylmethyl-5-nitro-1H-indazole (yellow solid, 600 mg) having a lower polarity were obtained from the silica gel column by separation and purification (eluent was 1/5 v/v ethyl acetate/petroleum ether) in a yield of 52% and 46%, respectively.

Intermediate a:

¹H-NMR(300MHz,CDCl₃):δ8.73(d,J=3.0Hz,1H),8.33(s,1H),8.08(d,J=3.0Hz,1H),7.76-7.73(s,1H),4.34(d,J=6.0Hz,2H)，1.44-1.49(m,1H),0.74-0.80(m,2H),0.48-0.51(m,1H).

MS m/z(ESI):217.1[M+H].

an intermediate b:

¹H-NMR(300MHz,CDCl₃):δ8.72-8.73(d,J=3.0Hz,1H),8.20-8.28(m,2H),7.47-7.50(s,1H),4.30-4.32(d,J=6.0Hz,2H),1.33-1.38(m,1H),0.60-0.66(m,2H),0.41-0.46(m,2H).

MS m/z(ESI):217.2[M+H].

the second step is that: 2-cyclopropylmethyl-2H-indazol-5-ylamine

Synthesis of intermediate 2-cyclopropylmethyl-2H-indazol-5-ylamine (yellow solid, 520 mg) was carried out in a similar manner to the second step of example 63.

¹H-NMR(300MHz,CDCl₃):δ7.76(s,1H),7.54-7.56(d,J=6.0Hz,1H),6.77-6.82(m,2H),4.18(d,J=6.0Hz,2H),1.40(m,1H)，0.65-0.68(m,2H),0.40-0.44(m,2H).

MS m/z(ESI):187.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- (2-cyclopropylmethyl-2H-indazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile

Synthesized in a second similar manner to example 1, substituting 2-cyclopropylmethyl-2H-indazol-5-ylamine for 2, 4-dichloro-5-methoxyaniline to give intermediate 7- (3-chloro-propoxy) -4- (2-cyclopropylmethyl-2H-indazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H-NMR(300MHz,d-CDCl₃):δ8.59(s,1H),7.99(s,1H),7.72(d,J=9.0Hz,1H),7.34(d,J=9.0Hz,1H),7.12-7.16(m,1H),7.05(s,1H),6.89(s,1H),4.26-4.31(m,4H),3.73-3.78(m,2H),3.40(s,3H),2.32-2.36(t,J=6.0Hz,2H),1.40-1.46(m,1H),0.72-0.74(d,J=6.0Hz,2H),0.46-0.47(m,2H).

MS m/z(ESI):461.2[M+H].

The fourth step: 4- (2-cyclopropylmethyl-2H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2-cyclopropylmethyl-2H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 38 mg) was obtained by a synthesis analogous to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.58(s,1H),7.99(s,1H),7.72-7.74(d,J=6.0Hz,1H),7.39(s,1H),7.32(s,1H),7.12-7.15(m,1H),7.04(s,1H),6.88(s,1H),4.40(s,4H),4.26-4.28(m,2H),4.17-4.22(m,2H),3.40(s,3H),2.53-2.56(m,2H),2.40-2.43(m,3H),2.09-2.11(d,J=6.0Hz,2H),1.91-1.94(m,4H),1.39-1.48(m,1H),0.70-0.74(m,2H),0.44-0.47(m,2H).

MS m/z(ESI):522.3[M+H].

Example 90

4- (1-cyclopropylmethyl-1H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 1-cyclopropylmethyl-1H-indazol-5-ylamine

Synthesized in a similar manner as the second step of example 63, substituting 1-cyclopropylmethyl-5-nitro-1H-indazole for 1-chloro-2-cyclopropylmethoxy-5-fluoro-4-nitrobenzene to give intermediate 1-cyclopropylmethyl-1H-indazol-5-ylamine (yellow solid, 320 mg).

¹H-NMR(300MHz,CDCl₃):δ7.77(s,1H),7.23(s,1H),6.92(d,J=3.0Hz,1H),6.84(d,J=3.0Hz,1H),4.17-4.20(m,2H)，3.66-3.73(m,4H),1.27-1.30(m,1H),0.52-0.56(m,2H),0.36-0.38(d,J=6.0Hz,2H).

MS m/z(ESI):187.2[M+H].

The third step: 7- (3-chloro-propoxy) -4- (1-cyclopropylmethyl-1H-indazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 1-cyclopropylmethyl-1H-indazol-5-ylamine for 2, 4-dichloro-5-methoxyaniline to give intermediate 7- (3-chloro-propoxy) -4- (1-cyclopropylmethyl-1H-indazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H-NMR(300MHz,CDCl₃):δ8.58(s,1H),7.96(s,1H),7.54(s,1H),7.43-7.46(d,J=9.0Hz,1H),7.35(s,1H),7.21-7.24(m,1H),7.08(s,1H),6.82(s,1H),4.27-4.32(m,4H),3.74-3.78(m,2H),3.40(s,3H),2.32-2.36(t,J=6.0Hz,2H),1.30-1.31(m,2H),0.58-0.60(d,J=6.0Hz,2H),0.39-0.41(d,J=6.0Hz,2H).

MS m/z(ESI):461.2[M+H].

The fourth step: 4- (1-cyclopropylmethyl-1H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (1-cyclopropylmethyl-1H-indazol-5-ylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 38mg) was obtained by a synthesis analogous to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.58(s,1H),7.95(d,J=3.0Hz,1H),7.54(d,J=3.0Hz,1H),7.43-7.46(m,1H),7.33(s,1H),7.21-7.25(m,1H),7.02(s,1H),6.80(s,1H),4.40(s,4H),4.27-4.30(m,2H),4.18-4.22(t,J=6.0Hz,2H),2.53-2.55(m,2H),2.39-2.44(m,4H),2.09-2.14(m,2H),1.93(m,4H),1.31-1.34(m,2H),0.56-0.61(m,2H),0.39-0.41(d,J=6.0Hz,2H).

MS m/z(ESI):522.1[M+H].

Example 91

4- [2, 4-dichloro-5- (tetrahydrofuran-3-yloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 3- (2, 4-dichloro-5-nitro-phenoxy) -tetrahydrofuran

2, 4-dichloro-5-nitro-phenol (100 mg,0.48mmol), tetrahydrofuran-3-ol (43mg,0.48mmol) and triphenylphosphine (151 mg,0.57 mmol) were suspended in anhydrous tetrahydrofuran (10 mL), and to the above mixture was added dropwise azodiisopropyl diethyl ester (115. mu.L, 0.57 mmol) with cooling on an ice bath. After the addition, the mixture was stirred at room temperature overnight until the reaction was complete. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid, water, and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: 20: 1 in petroleum ether: ethyl acetate volume ratio) to give intermediate 3- (2, 4-dichloro-5-nitro-phenoxy) -tetrahydrofuran (white solid, 81 mg).

¹H NMR(300MHz,CDCl₃):δ7.58(s,1H),7.43(s,1H),5.01(m,1H),4.05(m,4H),2.36–2.17(m,2H).

MS m/z(ESI):279.1[M+H].

The second step is that: 2, 4-dichloro-5- (tetrahydro-furan-3-yloxy) -aniline

Synthesized in a similar manner as the second step of example 63, substituting 1-cyclopropylmethyl-5-nitro-1H-indazole for 3- (2, 4-dichloro-5-nitro-phenoxy) -tetrahydrofuran to give the intermediate 2, 4-dichloro-5- (tetrahydro-furan-3-yloxy) -aniline (yellow solid, 64 mg).

MS m/z(ESI):247.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (tetrahydro-furan-3-yloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile

The second synthesis procedure analogous to example 1, substituting 2, 4-dichloro-5- (tetrahydro-furan-3-yloxy) -aniline for 2, 4-dichloro-5-methoxyaniline gave the intermediate 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (tetrahydro-furan-3-yloxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 55 mg).

MS m/z(ESI):537.1[M+H].

The fourth step: 4- [2, 4-dichloro-5- (tetrahydrofuran-3-yloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- [2, 4-dichloro-5- (tetrahydrofuran-3-yloxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 30 mg).

¹H NMR(300MHz,CDCl₃):δ8.71(s,1H),7.51(s,1H),7.42(s,1H),6.90(s,1H),6.69(s,1H),6.39(s,1H),4.66(s,1H),4.43(s,4H),4.26(t,J=6.3Hz,2H),3.79(s,1H),3.71(m,8H),2.50(m,6H),2.20(m,2H),2.01(m,4H).

MS m/z(ESI):628.2[M+H].

Example 92

4- [2, 4-dichloro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2- (2, 4-dichloro-5-nitro-phenoxymethyl) -pyridine

Synthesized in a similar manner to the first step of example 63, substituting cyclopropylmethyl bromide with 2-bromomethylpyridine to give the intermediate 2- (2, 4-dichloro-5-nitro-phenoxymethyl) -pyridine (yellow solid, 1.3g).

¹H-NMR(300MHz,CDCl₃):δ8.60(d,J=6.0Hz,1H),7.74-7.79(m,1H),7.54-7.62(m,3H),7.27-7.30(m,1H),5.31(s,2H).

MS m/z(ESI):299.1[M+H].

The second step is that: 2, 4-dichloro-5- (pyridin-2-ylmethoxy) -aniline

The intermediate 2, 4-dichloro-5- (pyridin-2-ylmethoxy) -aniline (yellow solid, 400mg) was synthesized in a similar manner to the second step of example 63.

¹H-NMR(300MHz,CDCl₃):δ8.56(d,J=3.0Hz,1H),7.70-7.56(m,1H),7.58-7.61(m,2H),7.21-7.25(m,2H),6.38(s,1H)，5.20(s,2H),4.03(s,2H).

MS m/z(ESI):268.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (pyridin-2-ylmethoxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 2, 4-dichloro-5- (pyridin-2-ylmethoxy) -aniline for 2, 4-dichloro-5-methoxyaniline to give the intermediate 7- (3-chloro-propoxy) -4- [2, 4-dichloro-5- (pyridin-2-ylmethoxy) -anilino ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 70 mg).

¹H-NMR(300MHz,CDCl₃):δ8.67(s,1H),8.32(s,1H),7.65-7.70(m,1H),7.52(s,1H),7.46-7.49(m,1H),7.42(s,1H),7.15(s,1H),6.77(s,1H),6.62-6.64(m,1H),6.49(s,1H),5.01(s,2H),4.34-4.38(m,2H),3.80-3.84(t,J=6.0Hz,2H),3.69(s,3H),2.38-2.42(t,J=6.0Hz,2H).

MS m/z(ESI):542.1[M+H].

The fourth step: 4- [2, 4-dichloro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- [2, 4-dichloro-5- (pyridin-2-ylmethoxy) -phenylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile as a yellow solid (39 mg).

¹H-NMR(300MHz,CDCl₃):δ8.66(s,1H),8.32-8.34(m,1H),7.66-7.68(m,1H),7.52(s,1H),7.48-7.50(d,J=6.0Hz,1H),7.40(s,1H),7.15-7.17(m,1H),6.77(s,1H),6.62(s,1H),6.47(s,1H),5.00(s,2H),4.42(s,4H),4.24-4.27(m,2H),3.70(s,3H),2.57-2.64(m,2H),2.39-2.50(m,4H),2.20-2.23(t,J=6.0Hz,2H),1.93-2.00(m,4H),0.70-0.74(m,2H),0.44-0.47(m,2H).

MS m/z(ESI):633.2[M+H].

Example 93

4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 1- (3-fluoro-benzyl) -5-nitro-1H-indazole

Synthesized in a similar manner to the first step of example 63, substituting cyclopropylmethyl bromide with 3-fluorobenzyl bromide to give intermediate 1- (3-fluoro-benzyl) -5-nitro-1H-indazole (yellow solid, 400 mg).

¹H-NMR(300MHz,CDCl₃):δ8.83-8.84(d,J=3.0Hz,1H),8.46(s,1H),8.21-8.25(m,1H),7.94-7.97(d,J=9.0Hz,1H),7.34-7.37(d,J=9.0Hz,1H)，7.03-7.10(m,3H),5.78(s,2H).

MS m/z(ESI):271.1[M+H].

The second step is that: 1- (3-fluoro-benzyl) -1H-indazol-5-ylamine

Synthesis of intermediate 1- (3-fluoro-benzyl) -1H-indazol-5-ylamine (yellow solid, 230mg) was obtained in a similar manner to the second step of example 63.

¹H-NMR(300MHz,CDCl₃):δ7.84(s,1H),7.21-7.28(m,1H),7.11-7.14(d,J=9.0Hz,1H),6.92-6.95(m,3H),6.80-6.84(m,2H),5.51(s,2H).

MS m/z(ESI):241.1[M+H].

The third step: 7- (3-chloro-propoxy) -4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino ] -6-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 1- (3-fluoro-benzyl) -1H-indazol-5-ylamine for 2, 4-dichloro-5-methoxyaniline to give intermediate 7- (3-chloro-propoxy) -4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 54 mg).

¹H-NMR(300MHz,CDCl₃):δ8.59(s,1H),8.02(s,1H),7.55(s,1H),7.19-7.35(m,5H),6.94-7.01(m,1H),6.78(s,1H),6.75(s,1H),5.61(s,2H),3.74(m,2H),3.32(s,3H),2.32-2.36(t,J=6.0Hz,2H),3.80-3.84(t,J=6.0Hz,2H),3.69(s,3H),2.38-2.42(m,2H).

MS m/z(ESI):515.2[M+H].

The fourth step: 4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the third step of example 1 was used to give the title compound 4- [1- (3-fluoro-benzyl) -1H-indazol-5-ylamino ] -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 32 mg).

¹H-NMR(300MHz,CDCl₃):δ8.58(s,1H),8.02(s,1H),7.55(s,1H),7.32-7.35(m,2H),7.27-7.30(m,1H),7.19-7.23(m,1H),6.94-7.00(m,3H),6.73-6.77(d,J=12Hz,1H),5.61(s,2H),4.40(s,4H),4.17-4.22(m,2H),3.32(s,3H),2.51-2.54(m,2H),2.35-2.42(m,4H),2.07-2.12(m,2H),1.91(m,4H).

MS m/z(ESI):606.3[M+H].

Example 94

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [ 2-methyl-3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: toluene-4-sulfonic acid-3-hydroxy-2-methyl-propyl ester

2-methyl-1, 3-propanediol (3g,33mmol), DMAP (203mg,1.7mmol) and triethylamine (10.1g,0.10mmol) were dissolved in dichloromethane, and p-toluenesulfonyl chloride (6.3g,33mmol) was added under ice bath to react at room temperature overnight. After the reaction, distilled water was added to dilute the reaction mixture, the mixture was extracted with dichloromethane, and the organic phase was washed with 1N diluted hydrochloric acid, water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure were carried out, and the concentrated solution was purified by silica gel column chromatography (eluent was methanol: dichloromethane at a volume ratio of 1: 20) to give intermediate toluene-4-sulfonic acid-3-hydroxy-2-methyl-propyl ester (colorless oil, 601 mg).

¹H NMR(300MHz,DMSO-d₆):δ7.78(d,J=6.0Hz,2H),7.44(d,J=6.0Hz,2H),4.04(dd,J=4.2,7.2Hz,1H),3.91(dd,J=4.2,7.2Hz,1H),3.40(m,2H),2.44(s,3H),1.92(m,1H),0.88(d,J=5.4Hz,3H).

MS m/z(ESI):245.1[M+H].

The second step is that: toluene-4-sulfonic acid-3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -2-methyl-propyl ester

4- (2, 4-dichloro-5-methoxyphenylamino) -7-hydroxy-6-methoxyquinoline-3-carbonitrile (200mg,0.51mmol), toluene-4-sulfonic acid-3-hydroxy-2-methyl-propyl ester (250mg,1.03mmol), and triphenylphosphine (301mg,1.16mmol) were suspended in anhydrous tetrahydrofuran (10ml), and ethyl azodicarboxylate (370mg,2.06mmol) was added under cooling on an ice bath, and the reaction was allowed to proceed overnight at room temperature. After the reaction, ethyl acetate was added for extraction, and the organic phase was washed with distilled water, saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and separation and purification of the concentrated solution by silica gel column chromatography (eluent methanol: dichloromethane at a volume ratio of 1: 50) gave the intermediate toluene-4-sulfonic acid-3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxy ] -2-methyl-propyl ester (colorless oil, 300 mg).

MS m/z(ESI):616.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [ 2-methyl-3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [ 2-methyl-3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 11 mg) was obtained by a synthesis analogous to the third step of example 1.

¹H NMR(300MHz,DMSO-d₆):δ8.70(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),6.73(s,1H),6.45(s,1H),4.44(m,6H),3.77(s,3H),3.66(s,3H),2.36(m,4H),2.21(m,3H),1.09(m,4H),1.05(d,J=6.0Hz,3H).

MS m/z(ESI):571.2[M+H].

Example 95

4- (2, 4-dichloro-5-methoxy-phenylamino) -6, 7-bis- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4-chloro-6, 7-bis- (3-chloro-propoxy) -quinoline-3-carbonitrile

Synthesis was carried out in a similar manner to the first step of example 1 to give intermediate 4-chloro-6, 7-bis- (3-chloro-propoxy) -quinoline-3-carbonitrile (white solid, 210 mg).

¹H NMR(300MHz,CDCl₃):δ8.78(s,1H),7.44(s,2H),4.35(m,4H),3.80(m,4H),2.38(m,4H).

MS m/z(ESI):373.0[M+H].

The second step is that: 6, 7-bis- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -quinoline-3-carbonitrile

The intermediate 6, 7-bis- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -quinoline-3-carbonitrile was synthesized using a similar procedure as the second step of example 1 (white solid, 165 mg).

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.43(s,1H),6.96(s,1H),6.74(s,1H),6.48(s,1H),4.34(t,J=6.0Hz,2H),4.03(t,J=6.0Hz,2H),3.76(m,4H),3.68(s,3H),2.36(m,2H),2.24(m,2H).

MS m/z(ESI):528.0[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6, 7-bis- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6, 7-bis- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (white solid, 48mg) was obtained by a synthesis analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.70(s,1H),7.55(s,1H),7.31(s,1H),7.17(s,1H),4.44(m,8H),4.24(m,4H),3.88(s,3H),2.76(m,12H),2.16(m,4H),1.99(m,8H).

MS m/z(ESI):710.3[M+H].

Example 96

4- (2, 4-dichloro-5-ethoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-ethoxy-anilino) -6-methoxy-quinoline-3-carbonitrile

The second synthesis procedure, analogous to that of example 1, was used to replace 2, 4-dichloro-5-methoxyaniline with 2, 4-dichloro-5-ethoxy-aniline to give the intermediate 7- (3-chloro-propoxy) -4- (2, 4-dichloro-5-ethoxy-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 80 mg).

¹H NMR(300MHz,CDCl₃):δ8.71（s,1H）,7.49(s,1H),7.44(s,1H),6.90(s,1H),6.72(s,1H),6.45(s,1H),4.35(t,J=6.0Hz,2H),3.80(m,5H),2.37(t,J=6.0Hz,2H),2.07(m,2H),1.63(t,J=6.0Hz,3H).

MS m/z(ESI):479.1[M+H].

The second step is that: 4- (2, 4-dichloro-5-ethoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-ethoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 31mg) was obtained by a synthesis analogous to the third step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.41(s,1H),6.89(s,1H),6.45(s,1H),4.42(s,4H),4.25(t,J=6.5Hz,2H),3.83(q,J=6.9Hz,2H),3.77(s,3H),2.72–2.56(m,3H),2.56–2.26(m,3H),2.25–2.13(m,3H),2.11–1.90(m,6H).

MS m/z(ESI):572.2[M+H].

Example 97

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7-hydroxy-quinolin-6-yl ester

A solution of 4-chloro-6, 7-dihydroxyquinoline-3-carbonitrile (2g,9.1mmol) and triethylamine (1.8g,2eq) in dichloromethane (70mL) was cooled to-10 ℃ under an ice salt bath, and pivaloyl chloride (1.1g,1eq) was slowly added dropwise to the above solution. After 5 hours of reaction, distilled water was added to quench the reaction, dichloromethane was extracted, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 2, 2-dimethyl-propionic acid-4-chloro-3-cyano-7-hydroxy-quinolin-6-yl ester (white solid, 1 g).

¹H NMR(400MHz,DMSO-d6):δ11.70（s，1H）,9.04(s,1H),7.94(s,1H),7.49(s,1H),13.59(s,9H).

MS m/z(ESI):305.1[M+H].

The second step is that: 2, 2-dimethyl-propionic acid 4-chloro-7- (3-chloro-propoxy) -3-cyano-quinolin-6-yl ester

The intermediate 2, 2-dimethyl-propionic acid-4-chloro-7- (3-chloro-propoxy) -3-cyano-quinolin-6-yl ester (white solid, 860 mg) was synthesized in a similar manner to the first step of example 1.

¹H NMR(300MHz,DMSO-d6):δ9.133(s,1H),8.01(s,1H),7.41(s,1H),4.37(t,J=5.7Hz,2H),3.75(t,J=6.0Hz,2H),2.22(m,2H),1.36(s,9H)。

MS m/z(ESI):381.1[M+H].

The third step: 2, 2-dimethyl-propionic acid-7- (3-chloro-propoxy) -3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -quinolin-6-yl ester

The intermediate 2, 2-dimethyl-propionic acid-7- (3-chloro-propoxy) -3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -quinolin-6-yl ester (yellow solid, 823 mg) was synthesized by a procedure analogous to the second step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.48(s,1H),8.10(s,1H),7.55(s,1H),7.43(s,1H),7.18(s,1H),4.34(t,J=6.0Hz,2H),3.88(s,3H),3.74(t,J=6.3Hz,2H),2.29(m,2H),1.42(s,9H).

MS m/z(ESI):536.1[M+H].

The fourth step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

2, 2-dimethyl-propionic acid-7- (3-chloro-propoxy) -3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -quinolin-6-yl ester (180mg,0.335mmol), potassium iodide (55mg,1eq), and 2-oxa-7-aza-spiro [3.5] nonane (127mg,3eq) were dissolved in anhydrous N, N-dimethylformamide (2mL) and heated to 100 ℃ until the reaction was complete. After the reaction mixture was cooled to room temperature, 2mL of a methanol solution of ammonia (concentration: 7M/L) was directly added to the reaction mixture under cooling in an ice bath, and the mixture was stirred for 5 hours. The reaction was diluted with water (10 mL), extracted with dichloromethane (25 mLX 2), the organic phases combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and isolated by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile as a yellow solid (130 mg).

¹H NMR(300MHz,CD₃OD):δ8.35(s,1H),7.60(s,1H),7.53(s,1H),7.32(s,1H),7.11(s,1H),4.48(m,4H),4.32(t,J=5.4Hz,2H),3.87(s,3H),3.15(m,2H),3.04(m,2H),2.93(m,2H),2.26(m,2H),2.09(m,4H).

MS m/z(ESI):543.2[M+H].

Example 98

4- (2, 4-dichloro-5-methoxy-anilino) -6-ethoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (40 mg,0.07 mmol) was dissolved in anhydrous N, N-dimethylformamide (5 mL), anhydrous potassium carbonate powder (20 mg,2 eq) was added under nitrogen and stirred for half an hour, then bromoethane (10 mg,1.2 eq) was added, and the reaction was heated to 50 ℃ and stirred overnight. The reaction solution was diluted with distilled water (20 mL), extracted with dichloromethane (25 mLX 2), the organic phases were combined, washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative thin layer chromatography to give 4- (2, 4-dichloro-5-methoxy-anilino) -6-ethoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (pale yellow solid, 10 mg).

¹H NMR(400MHz,CD₃OD):δ8.37(s,1H),7.67(s,1H),7.55(s,1H),7.30(s,1H),7.17(s,1H),4.48(s,4H),4.24(m,4H),3.88(s,3H),2.65(m,6H),2.17(m,2H),1.96(m,4H),1.48(s,3H).

MS m/z(ESI):571.2[M+H].

Example 99

4- (2, 4-dichloro-5-methoxy-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Synthesized in a similar manner to example 98, substituting 1-bromo-2-methoxyethane for the bromoethane to give the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 45 mg).

¹H NMR(400MHz,CD₃OD):δ8.39(s,1H),7.72(s,1H),7.56(s,1H),7.32(s,1H),7.17(s,1H),4.46(s,4H),4.29(m,4H),3.88(s,3H),3.84(m,2H),3.46(s,3H),2.83(m,6H),2.19(m,2H),2.01(m,4H).

MS m/z(ESI):601.2[M+H].

Example 100

4- (3-ethynyl-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2, 2-dimethyl-propionic acid 7- (3-chloro-propoxy) -3-cyano-4- (3-ethynyl-anilino) -quinolin-6-yl ester

Synthesized in a similar manner to the third step of example 97, substituting 3-ethynylaniline for 2, 4-dichloro-5-methoxyaniline to give 7- (3-chloro-propoxy) -3-cyano-4- (3-ethynyl-anilino) -quinolin-6-yl 2, 2-dimethyl-propionate (yellow solid, 520 mg).

¹H NMR(300MHz,CDCl₃):δ8.63(d,J=2.1Hz,1H),7.41–7.37(m,2H),7.35–7.30(m,2H),7.22(s,1H),7.18–7.13(m,1H),7.09–7.04(m,1H),4.29(t,J=5.9Hz,2H),3.69(t,J=6.4Hz,2H),3.10(s,1H),2.35–2.27(m,2H),1.38(s,9H).

MS m/z(ESI):462.2[M+H].

The second step is that: 4- (3-ethynyl-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Synthesized in a similar manner to the fourth step of example 97 to give 4- (3-ethynyl-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 170 mg).

¹H NMR(300MHz,CDCl₃):δ8.58(s,1H),7.52(s,1H),7.31(m,2H),7.20(s,1H),7.14(s,1H),7.08–7.03(m,1H),6.76(s,1H),4.43(s,4H),4.18(t,J=5.4Hz,2H),3.50(s,1H),3.08(m,2H),2.62(d,J=6.3Hz,2H),2.06(m,4H),1.98(m,6H).

MS m/z(ESI):469.2[M+H].

The third step: 4- (3-ethynyl-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-ethynyl-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile, was synthesized by a method analogous to that of example 98 (yellow solid, 38 mg).

¹H NMR(300MHz,CD₃OD):δ8.41(s,1H),7.56(s,1H),7.29(m,5H),4.42(s,4H),4.21(m,4H),3.82–3.74(m,2H),3.51(s,1H),3.42(s,3H),2.80–2.73(m,2H),2.70–2.54(m,4H),2.19–2.09(m,2H),1.99–1.93(m,4H).

MS m/z(ESI):527.3[M+H].

Example 101

4- (3-chloro-4-fluoro-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (3-ethynyl-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

Synthesized in a similar manner to the third step of example 97, substituting 3-chloro-4-fluoro-aniline for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (3-ethynyl-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 320 mg).

¹H NMR(300MHz,CDCl₃):δ8.63(s,1H),7.42(s,1H),7.38(s,1H),7.22–7.17(m,1H),7.14(d,J=8.7Hz,1H),7.05(s,1H),7.00(d,J=8.7,1H),4.30(t,J=5.7Hz,2H),3.70(t,J=6.0Hz,2H),2.34–2.26(m,2H),1.38(s,9H).

MS m/z(ESI):491.1[M+H].

The second step is that: 4- (3-chloro-4-fluoro-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The intermediate 4- (3-chloro-4-fluoro-anilino) -6-hydroxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 175mg) was synthesized by a method analogous to the fourth step of example 97.

¹H NMR(300MHz,CDCl₃):δ8.56(s,1H),7.52(s,1H),7.16(m,1H),7.13(m,1H),7.02–6.95(m,1H),6.76(s,1H),4.43(s,4H),4.18(t,J=5.4Hz,2H),2.63(m,2H),2.13–2.02(m,4H),1.99(m,6H).

MS m/z(ESI):497.2[M+H].

The third step: 4- (3-chloro-4-fluoro-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-chloro-4-fluoro-phenylamino) -6- (2-methoxy-ethoxy) -7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 21mg) was synthesized by a method similar to that of example 98.

¹H NMR(300MHz,CD₃OD):δ8.38(s,1H),7.63(s,1H),7.41(d,J=6.3Hz,1H),7.33–7.19(m,3H),4.45(s,4H),4.26(m,4H),3.84–3.76(m,2H),3.42(m,3H),3.05–2.99(m,2H),2.98–2.86(m,4H),2.23(m,2H),2.06(s,4H).

MS m/z(ESI):556.2[M+H].

Example 102

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4-chloro-7- (4-chloro-butoxy) -6-methoxy-quinoline-3-carbonitrile

Synthesis of 4-chloro-7- (4-chloro-butoxy) -6-methoxy-quinoline-3-carbonitrile (off-white powder, 1.2 g) as an intermediate was carried out in a similar manner to the first step of example 1, substituting 1-chloro-4-iodobutane for 1-chloro-3-bromopropane.

¹H NMR(300MHz,CDCl₃):δ8.77(s,1H),7.41(m,2H),4.25(m,2H),4.06(s,3H),3.66(m,2H),2.08(m,4H).

MS m/z(ESI):325.1[M+H].

The second step is that: 7- (4-chloro-butoxy) -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

The intermediate 7- (4-chloro-butoxy) -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 1 g) was synthesized in a similar manner to the second step of example 1.

¹H NMR(300MHz,DMSO-d6):δ9.62(s,1H),8.41(s,1H),7.83(s,1H),7.75(s,1H),7.34(m,2H),4.21(m,2H),3.94(s,3H),3.85(s,3H),3.76(m,2H),1.93(m,4H).

MS m/z(ESI):480.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile (yellow solid, 64 mg) was synthesized by a method analogous to the third step of example 1.

¹H-NMR(300MHz,CDCl₃):δ8.70(s,1H),7.49(s,1H),7.39(s,1H),6.88(s,1H),6.72(s,1H),6.45(s,1H),4.40(s,4H),4.19-4.22(m,2H),3.77(s,3H),3.66(s,3H),2.34-2.40(m,6H),1.89-2.04(m,8H).

MS m/z(ESI):573.1[M+H].

Example 103

4- (3-ethynyl-phenylamino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The first step is as follows: 7- (4-chloro-butoxy) -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 3-ethynylaniline for 2, 4-dichloro-5-methoxyaniline to give intermediate 7- (4-chloro-butoxy) -4- (3-ethynyl-anilino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 560 mg).

¹H NMR(300MHz,CD₃OD):δ8.66(s,1H),7.35(s,1H),7.29(m,2H),7.04(m,1H),6.79(m,2H),4.21(t,J=6.0Hz,2H),3.64(t,J=6.0Hz,2H),3.60(s,3H),3.08(s,1H),2.05(m,4H).

MS m/z(ESI):405.2[M+H].

The second step is that: 4- (3-ethynyl-phenylamino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-ethynyl-phenylamino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile (yellow solid, 35mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.44(s,1H),7.58(s,1H),7.47–7.16(m,5H),4.43(s,4H),4.22(t,J=5.7Hz,2H),3.93(s,3H),3.52(s,1H),2.70(s,6H),1.91(m,8H).

MS m/z(ESI):497.2[M+H].

Example 104

4- (3-ethynyl-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [4.4] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

Using the compound obtained in the first step of example 103 and 2-oxa-7-aza-spiro [4.4] nonane as starting materials, a target compound, 4- (3-ethynyl-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [4.4] non-7-yl) -butoxy ] -quinoline-3-carbonitrile (yellow solid, 30mg) was synthesized in a similar manner to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.44(s,1H),7.60(s,1H),7.46–7.14(m,5H),4.57(s,2H),4.23(d,J=5.7Hz,2H),3.94(s,3H),3.87(m,2H),3.66(m,2H),3.52(s,1H),3.25–3.19(m,2H),3.14(s,4H),2.02(m,8H).

MS m/z(ESI):497.2[M+H].

Example 105

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7- (2-methoxy-ethoxy) -quinolin-6-yl ester

2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7-hydroxy-quinolin-6-yl ester (304mg,1mmol), 2-methoxy-ethanol (380mg,5mmol), triphenylphosphine (526mg,2mmol) were mixed and suspended in anhydrous tetrahydrofuran (20mL), diethyl azodicarboxylate (435mg,2.5mmol) was slowly added dropwise with cooling in an ice bath, and after completion of the addition, stirring was carried out at room temperature overnight. The reaction mixture was quenched with distilled water, extracted with dichloromethane (100 mLX2), the organic phases were combined, washed with saturated sodium bicarbonate solution, water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 2, 2-dimethyl-propionic acid-4-chloro-3-cyano-7- (2-methoxy-ethoxy) -quinolin-6-yl ester (yellow solid, 290 mg).

¹H NMR(400MHz,CDCl₃):δ8.86(s,1H),7.89(s,1H),7.52(s,1H),4.31(t,2H),3.78(m,2H),3.41(s,3H),1.43(s,9H).

MS m/z(ESI):363.1[M+H].

The second step is that: 4-chloro-6-hydroxy-7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

2, 2-dimethyl-propionic acid-4-chloro-3-cyano-7- (2-methoxy-ethoxy) -quinolin-6-yl ester (180 mg,0.5 mmol) was dissolved in dry N, N-dimethylformamide (2mL), and a solution of ammonia at a concentration of 7M/L in methanol (5mL) was added slowly with ice-cooling, and stirring was continued for 5 hours. After the reaction, the reaction mixture was diluted with distilled water, extracted with dichloromethane (50ml x2), the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography (eluent dichloromethane: methanol at a volume ratio of 20: 1) to give 4-chloro-6-hydroxy-7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile as an intermediate (yellow solid, 102 mg).

¹H NMR(400MHz,CD₃OD):δ8.57(s,1H),7.34(s,1H),7.30(s,1H),4.34(t,J=6.0Hz,2H),3.90(m,2H),3.46(s,3H).

MS m/z(ESI):279.1[M+H].

The third step: 4-chloro-6- (3-chloro-propoxy) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

The intermediate 4-chloro-6- (3-chloro-propoxy) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile (yellow solid, 88 mg) was synthesized by a method analogous to the first step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.77(s,1H),7.44(s,1H),7.43(s,1H),4.35(m,4H),3.86(m,4H),3.48(s,3H),2.39(m,2H).

MS m/z(ESI):355.1[M+H].

The fourth step: 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

The intermediate 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile (yellow solid, 90 mg) was synthesized by a method analogous to the second step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.69(s,1H),7.48(s,1H),7.41(s,1H),6.98(s,1H),6.83(br,1H),6.48(s,1H),4.31(m,2H),4.04(m,2H),3.86(m,2H),3.73(m,2H),3.67(s,3H),3.47(s,3H),2.25(m,2H).

MS m/z(ESI):510.1[M+H].

The fifth step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 32 mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.38(s,1H),7.69(s,1H),7.55(s,1H),7.31(s,1H),7.17(s,1H),4.43(s,4H),4.32(m,2H),4.21(m,2H),3.88(s,3H),3.85(m,2H),3.46(s,3H),2.65(m,2H),2.51(m,4H),2.10(m,2H),1.93(m,4H).

MS m/z(ESI):601.2[M+H].

Example 106

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4-chloro-6- (4-chloro-butoxy) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

Synthesized in analogy to the third step of example 105, substituting 1-chloro-4-iodo-butane for 1-chloro-3-iodo-propane to give the intermediate 4-chloro-6- (4-chloro-butoxy) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile (yellow solid, 115 mg).

¹H NMR(300MHz,CDCl₃):δ8.77(s,1H),7.42(s,1H),7.39(s,1H),4.33(m,2H),4.23(m,2H),3.88(m,2H),3.72(m,2H),3.49(s,3H),2.09(m,4H).

MS m/z(ESI):369.1[M+H].

The second step is that: 6- (4-chloro-butoxy) -4- (2, 4-dichloro-5-methoxy-aniline) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

Synthesized in a similar manner to the fourth step of example 105 to give the intermediate 6- (4-chloro-butoxy) -4- (2, 4-dichloro-5-methoxy-aniline) -7- (2-methoxy-ethoxy) -quinoline-3-carbonitrile (yellow solid, 100 mg).

¹H NMR(300MHz,CDCl₃):δ8.69(s,1H),7.48(s,1H),7.40(s,1H),6.89(s,1H),6.76(br,1H),6.46(s,1H),4.30(m,2H),3.88(m,4H),3.66(s,3H),3.48(s,3H),1.96(m,4H).

MS m/z(ESI):524.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (2-methoxy-ethoxy) -6- [4- (2-oxa-7-aza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile (yellow solid, 40mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.38(s,1H),7.67(s,1H),7.55(s,1H),7.32(s,1H),7.17(s,1H),4.42(s,4H),4.32(m,2H),4.18(m,2H),3.88(s,3H),3.86(m,2H),3.46(s,3H),2.56(m,6H),1.92(m,6H),1.81(m,2H).

MS m/z(ESI):615.2[M+H].

Example 107

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (7-oxa-2-aza-spiro [3.5] non-2-) -butoxy ] -quinoline-3-carbonitrile

Using the intermediate obtained in the second step of example 102 and 7-oxa-2-aza-spiro [3.5] nonane as starting materials, a target compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (7-oxa-2-aza-spiro [3.5] non-2-) -butoxy ] -quinoline-3-carbonitrile (yellow solid, 60mg), was synthesized in a similar manner to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.72(s,1H),7.56(s,1H),7.30(s,1H),7.18(s,1H),4.24(t,J=5.7Hz,2H),4.01(s,3H),3.89(m,7H),3.62(m,4H),3.26(m,2H),1.97(m,2H),1.81(m,6H).

MS m/z(ESI):571.2[M+H].

Example 108

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7-methoxy-quinolin-6-yl ester

Synthesized in analogy to the first step of example 105, substituting methyl iodide for 1-bromo-2-methoxy-ethane to give the intermediate 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7-methoxy-quinolin-6-yl ester (yellow solid, 1.6 g).

¹H NMR(300MHz,CDCl₃):δ8.88(s,1H),7.89(s,1H),7.53(s,1H),4.01(s,3H),1.58(s,9H).

MS m/z(ESI):319.1[M+H].

The second step is that: 4-chloro-6-hydroxy-7-methoxy-quinoline-3-carbonitrile

Synthesis was carried out in a similar manner to the second step of example 105 to give intermediate 4-chloro-6-hydroxy-7-methoxy-quinoline-3-carbaldehyde (yellow solid, 0.8 g).

MS m/z(ESI):235.1[M+H].

The third step: 4-chloro-6- (3-chloro-propoxy) -7-methoxy-quinoline-3-carbonitrile

The intermediate 4-chloro-6- (3-chloro-propoxy) -7-methoxy-quinoline-3-carbonitrile (yellow solid, 680 mg) was synthesized in a similar manner to the first step of example 1.

¹H NMR(300MHz,CDCl₃):δ8.78(s,1H),7.45(m,2H),4.37(t,J=5.7Hz,2H),4.05(s,3H),3.83(t,J=6.0Hz,2H),2.47–2.36(m,2H).

MS m/z(ESI):312.1[M+H].

The fourth step: 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7-methoxy-quinoline-3-carbonitrile

The intermediate 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7-methoxy-quinoline-3-carbonitrile (yellow solid, 650 mg) was obtained by a synthesis analogous to the second step of example 1.

¹H NMR(400MHz,CDCl₃):δ8.71(s,1H),7.50(s,1H),7.42(s,1H),6.97(s,1H),6.76(s,1H),6.48(s,1H),4.05(d,J=6.4Hz,2H),4.03(s,3H),3.74(s,2H),3.67(s,3H),2.31–2.22(m,2H).

MS m/z(ESI):467.1[M+H].

The fifth step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 25 mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.37(s,1H),7.68(s,1H),7.53(s,1H),7.29(s,1H),7.15(s,1H),4.43(s,4H),4.22(t,J=5.7Hz,2H),3.99(s,3H),3.86(s,3H),2.84(m,2H),2.80–2.54(m,4H),2.16(m,2H),1.99(s,4H).

MS m/z(ESI):558.2[M+H].

Example 109

4- (3-ethynyl-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 6- (3-chloro-propoxy) -4- (3-ethynyl-anilino) -7-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 3-ethynylaniline for 2, 4-dichloro-5-methoxyaniline to give intermediate 6- (3-chloro-propoxy) -4- (3-ethynyl-anilino) -7-methoxy-quinoline-3-carbonitrile (yellow solid, 165 mg).

¹H NMR(400MHz,CDCl₃):δ8.66(s,1H),7.37(s,1H),7.30(m,2H),7.19(s,1H),7.09–7.03(m,1H),6.88(s,1H),4.01(s,3H),3.88(t,J=6.0Hz,2H),3.68(t,J=6.0Hz,2H),3.08(s,1H),2.21–2.13(m,2H).

MS m/z(ESI):392.1[M+H].

The second step is that: 4- (3-ethynyl-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-ethynyl-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 40 mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.41(s,1H),7.58(s,1H),7.39–7.21(m,5H),4.44(s,4H),4.18(t,J=5.7Hz,2H),3.98(s,3H),3.52(s,1H),2.98–2.90(m,2H),2.85(m,4H),2.17(t,J=6.3Hz,2H),2.02(m,4H).

MS m/z(ESI):483.2[M+H].

Example 110

4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (3-chloro-4-fluoro-anilino) -6- (3-chloro-propoxy) -7-methoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 3-chloro-4-fluoroaniline for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (3-chloro-4-fluoro-anilino) -6- (3-chloro-propoxy) -7-methoxy-quinoline-3-carbonitrile (yellow solid, 100 mg).

¹H NMR(400MHz,CDCl₃):δ8.65(s,1H),7.39(s,1H),7.21–7.12(m,2H),7.02–6.95(m,1H),6.91(s,1H),6.80(s,1H),4.01(s,3H),3.97(t,J=6.0Hz,2H),3.72(t,J=6.0Hz,2H),2.28–2.19(m,2H).

MS m/z(ESI):421.1[M+H].

The second step is that: 4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 28mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.61(s,1H),7.40(s,1H),7.31–7.21(m,3H),4.44(s,4H),4.21(t,J=5.7Hz,2H),3.98(s,3H),3.01–2.93(m,2H),2.96–2.76(m,4H),2.26–2.13(m,2H),2.04(m,4H).

MS m/z(ESI):511.2[M+H].

Example 111

7-ethoxy-4- (3-ethynyl-phenylamino) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4-chloro-6- (3-chloropropoxy) -7-ethoxyquinoline-3-carbonitrile

Using a synthesis similar to that of the first, second and third steps of example 108, methyl iodide was replaced with ethyl bromide to give the intermediate 4-chloro-6- (3-chloropropyloxy) -7-ethoxyquinoline-3-carbonitrile (yellow solid, 720 mg).

¹H NMR(300MHz,CD₃OD):δ8.78(s,1H),7.49(s,1H),7.42(s,1H),4.35(t,J=5.7Hz,2H),4.28(d,J=6.0Hz,2H),3.83(t,J=6.0Hz,2H),2.34(m,2H),1.52(t,J=5.7Hz,3H).

MS m/z(ESI):326.1[M+H].

The second step is that: 6- (3-chloro-propoxy) -7-ethoxy-4- (3-ethynyl-anilino) -quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 3-ethynylaniline for 2, 4-dichloro-5-methoxyaniline to give intermediate 6- (3-chloro-propoxy) -7-ethoxy-4- (3-ethynyl-anilino) -quinoline-3-carbonitrile (yellow solid, 120 mg).

¹H NMR(300MHz,CD₃OD):δ8.43(s,1H),7.60(s,1H),7.41–7.23(m,5H),4.23(m,4H),3.80(t,J=6.3Hz,2H),3.51(s,1H),2.33–2.24(m,2H),1.50(t,J=6.0Hz,3H).

MS m/z(ESI):406.1[M+H].

The third step: 7-ethoxy-4- (3-ethynyl-phenylamino) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound 7-ethoxy-4- (3-ethynyl-phenylamino) -6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 35mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.43(s,1H),7.57(s,1H),7.41–7.21(m,5H),4.44(s,4H),4.25(d,J=6.9Hz,2H),4.17(t,J=6.0Hz,2H),3.53(s,1H),2.93–2.85(m,2H),2.86–2.70(m,4H),2.16(m,2H),2.02(m,4H),1.50(t,J=6.9Hz,3H).

MS m/z(ESI):497.3[M+H].

Example 112

4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4- (3-chloro-4-fluoro-phenylamino) -6- (3-chloro-propoxy) -7-ethoxy-quinoline-3-carbonitrile

Synthesized in a similar manner as the second step of example 1, substituting 3-chloro-4-fluoroaniline for 2, 4-dichloro-5-methoxyaniline to give the intermediate 4- (3-chloro-4-fluoro-phenylamino) -6- (3-chloro-propoxy) -7-ethoxy-quinoline-3-carbonitrile (yellow solid, 236 mg).

¹H NMR(300MHz,CD₃OD):δ8.41(s,1H),7.63(s,1H),7.42(m,1H),7.32–7.22(m,3H),4.26(m,4H),3.81(t,J=6.3Hz,2H),2.36–2.25(m,2H),1.50(t,J=6.3Hz,3H).

MS m/z(ESI):435.1[M+H].

The second step is that: 4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-chloro-4-fluoro-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 45mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.40(s,1H),7.59(s,1H),7.41(m,1H),7.32–7.20(m,3H),4.42(s,4H),4.28–4.14(m,4H),2.75–2.66(m,2H),2.66–2.49(m,4H),2.17–2.05(m,2H),1.94(m,4H),1.49(t,J=6.9Hz,3H).

MS m/z(ESI):526.2[M+H].

Example 113

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7-ethoxy-quinoline-3-carbonitrile

The intermediate 6- (3-chloro-propoxy) -4- (2, 4-dichloro-5-methoxy-anilino) -7-ethoxy-quinoline-3-carbonitrile (yellow solid, 210 mg) was synthesized by a similar procedure as the second step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.38(s,1H),7.72(s,1H),7.55(s,1H),7.30(s,1H),7.16(s,1H),4.34–4.21(m,4H),3.87(s,3H),3.82(t,J=6.3Hz,2H),2.38–2.27(m,2H),1.51(t,J=6.9Hz,3H).

MS m/z(ESI):481.1[M+H].

The second step is that: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7-ethoxy-6- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 54mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.38(s,1H),7.69(s,1H),7.55(s,1H),7.29(s,1H),7.15(s,1H),4.44(s,4H),4.23(m,4H),3.87(s,3H),2.87(m,2H),2.84–2.66(m,4H),2.18(m,2H),2.06–1.94(m,4H),1.50(t,J=6.9Hz,3H).

MS m/z(ESI):572.2[M+H].

Example 114

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The first step is as follows: 2-hydroxy-7-aza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Tert-butyl 2-oxa-7-aza-spiro [3.5] nonane-7-carboxylate (2 g, 8.3 mmol) was dissolved in ethanol (10 mL), to which sodium borohydride (1.6 g,41.5 mmol) was slowly added with ice-cooling, and stirring was continued at room temperature for 1.5 h. After the reaction, a saturated ammonium chloride solution was added to quench the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give an intermediate, tert-butyl 2-hydroxy-7-aza-spiro [3.5] nonane-7-carboxylate (pale yellow oily substance, 2 g), which was used in the next reaction without purification.

¹H NMR(CDCl3):δ4.28(m,1H),3.27(m,4H),2.24(m,2H),1.68(m,2H),1.48(m,4H),1.41(s,9H).

MS m/z(ESI):264.1[M+Na].

The second step is that: 7-aza-spiro [3.5] nonan-2-ols

Tert-butyl 2-hydroxy-7-aza-spiro [3.5] nonane-7-carboxylate (2 g, 8.3 mmol) was dissolved in dichloromethane (10 mL), and a 4N dioxane solution of hydrogen chloride (10 mL) was added to the solution with ice-cooling and stirred at room temperature overnight. After the reaction was complete, it was directly concentrated to give the intermediate 7-aza-spiro [3.5] nonan-2-ol (yellow syrup, 1.4 g).

¹H NMR(CD₃OD):δ4.21(m,1H),3.05(m,4H),2.27(m,2H),1.72(m,6H).

MS m/z(ESI):142.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 60mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.73(s,1H),7.56(s,1H),7.31(s,1H),7.19(s,1H),4.29(m,3H),4.01(s,3H),3.89(s,3H),3.15(m,6H),2.32(m,4H),1.80(m,6H).

MS m/z(ESI):517.2[M+H].

Example 115

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxo-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (50mg, 0.1mmol) was dissolved in a solution of dichloromethane (5 mL) and tetrahydrofuran (5 mL), and a solution of Torsel-martin oxidant (15% in dichloromethane, 8 mL) was slowly added dropwise to the reaction solution. After the addition was complete, stirring was continued at 80 ℃ overnight. After the reaction, the mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate, water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solution was separated and purified by silica gel column chromatography (eluent was dichloromethane: methanol at a volume ratio of 10: 1) to obtain the objective product 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxo-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 18 mg).

¹H NMR(300MHz,DMSO-d6):δ11.04(s,1H),10.38(m,2H),8.90(s,1H),8.19(s,1H),7.84(s,1H),7.50(m,2H),4.31(t,J=5.4Hz,2H),4.01(s,3H),3.87(s,3H),3.43(m,4H),3.24(m,2H),2.91(m,4H),2.33(m,2H),1.93(m,4H).

MS m/z(ESI):569.2[M+H].

Example 116

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-dimethylamino-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 115 and dimethylamine as starting materials, the desired compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2-dimethylamino-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 43mg) was obtained by a synthesis process similar to that described in example 11.

¹H NMR(300MHz,CD3OD):δ8.39(s,1H),7.72(s,1H),7.56(s,1H),7.31(s,1H),7.18(s,1H),4.30(t,J=6.3Hz,2H),4.00(s,3H),3.89(s,3H),3.00(m,6H),2.54(s,6H),2.21(m,5H),1.84(m,6H).

MS m/z(ESI):598.2[M+H].

Example 117

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2, 2-difluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The first step is as follows: 2, 2-difluoro-7-aza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Tert-butyl 2-oxa-7-aza-spiro [3.5] nonane-7-carboxylate (1g,4.2mmol) was dissolved in dichloromethane (20 mL), diethylaminosulfur trifluoride (1.4 g, 10.4 mmol) was added dropwise to the solution under cooling in an ice bath, and after completion of the addition, the mixture was stirred at room temperature for 48 hours. After the reaction, the reaction was quenched with a saturated sodium bicarbonate solution, diluted with dichloromethane, and the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether: ethyl acetate in a volume ratio of 8: 1) to give an intermediate, tert-butyl 2, 2-difluoro-7-aza-spiro [3.5] nonane-7-carboxylate (colorless oil, 500 mg).

¹H NMR(CD₃OD):δ3.36(m,4H),2.36(m,4H),1.60(m,4H),1.44(s,9H).

MS m/z(ESI):284.1[M+Na].

The second step is that: 2, 2-difluoro-7-aza-spiro [3.5] nonanes

Synthesis was carried out in a similar manner to the second step of example 114 to give intermediate 2, 2-difluoro-7-aza-spiro [3.5] nonane (yellow syrup, 370 mg).

¹H NMR(CD₃OD):δ3.15(m,4H),2.47(m,4H),1.90(m,4H).

MS m/z(ESI):162.1[M+Na].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2, 2-difluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [3- (2, 2-difluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 54mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,DMSO-d6):δ10.93(m,2H),10.49(s,1H),8.85(s,1H),8.16(s,1H),7.82(s,1H),7.50(m,2H),4.32(t,J=5.4Hz,2H),4.00(s,3H),3.87(s,3H),3.22(m,2H),2.95(m,2H),2.32(m,2H),2.03(m,2H),1.83(m,2H).

MS m/z(ESI):591.2[M+H].

Example 118

4- (2, 4-dichloro-5-methoxyphenylamino) -7- [3- (2-fluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The first step is as follows: 2-fluoro-7-aza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Synthesized in a similar manner to the first step of example 117 to give tert-butyl 2-fluoro-7-aza-spiro [3.5] nonane-7-carboxylate (colorless oil, 250 mg).

¹H NMR(CD₃OD):δ5.85(m,1H),5.14(m,2H),3.87(m,2H),3.06(m,2H),2.38(m,2H),1.77(m,2H),1.45(s,9H).

MS m/z(ESI):266.1[M+Na].

The second step is that: 2-fluoro-7-aza-spiro [3.5] nonanes

Synthesis was carried out in a similar manner to the second step of example 114 to give 2-fluoro-7-aza-spiro [3.5] nonane as intermediate (yellow syrup, 165 mg).

¹H NMR(CD₃OD):δ5.86(m,1H),5.19(m,2H),3.34(m,2H),3.19(m,2H),2.45(m,2H),2.06(m,2H),1.89(m,2H).

MS m/z(ESI):144.1[M+Na].

The third step: 4- (2, 4-dichloro-5-methoxyphenylamino) -7- [3- (2-fluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxyphenylamino) -7- [3- (2-fluoro-7-aza-spiro [3.5] non-7-yl) -propoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 50mg), was synthesized by a method similar to the third step of example 1.

¹H NMR(300MHz,DMSO-d6):δ10.77(m,3H),8.89(s,1H),8.19(s,1H),7.83(s,1H),7.50(m,2H),5.81(m,1H),5.21(m,2H),4.31(t,J=5.7Hz,2H),4.00(s,3H),3.87(s,3H),3.30(m,2H),3.10(m,2H),2.34(m,4H),2.02(m,4H).

MS m/z(ESI):573.2[M+H].

Example 119

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-hydroxy-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 38mg) was synthesized in a manner analogous to the third step of example 1.

¹H NMR(300MHz,CD3OD):δ8.39(s,1H),7.71(s,1H),7.56(s,1H),7.30(s,1H),7.18(s,1H),4.24(m,3H),4.00(s,3H),3.89(s,3H),3.13(m,6H),1.98(m,4H),1.77(m,8H).

MS m/z(ESI):585.2[M+H].

Example 120

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2, 2-difluoro-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2, 2-difluoro-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 50mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.72(s,1H),7.56(s,1H),7.30(s,1H),7.19(s,1H),4.26(m,2H),4.01(s,3H),3.89(s,3H),3.73(m,2H),3.22(m,4H),2.49(m,4H),1.97(m,8H).

MS m/z(ESI):605.2[M+H].

Example 121

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-fluoro-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-fluoro-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 54mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(300MHz,CD₃OD):δ8.39(s,1H),7.71(s,1H),7.56(s,1H),7.30(s,1H),7.18(s,1H),5.84(m,1H),5.14(m,2H),4.24(t,J=6.0Hz,2H),4.00(s,3H),3.89(s,3H),3.11(m,2H),2.87(m,2H),2.74(m,2H),2.44(m,2H),1.94(m,8H).

MS m/z(ESI):587.2[M+H].

Example 122

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-pyrrolidin-1-yl-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-pyrrolidin-1-yl-7-aza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 20mg) was obtained by a synthesis method similar to that of example 11.

¹H NMR(300MHz,CD₃OD):δ8.37(s,1H),7.70(s,1H),7.55(s,1H),7.29(s,1H),7.17(s,1H),4.25(t,J=5.7Hz,2H),3.99(s,3H),3.88(s,3H),3.53(m,1H),3.04(m,4H),2.71(m,6H),2.25(m,4H),2.00(m,6H),1.76(m,4H).

MS m/z(ESI):624.3[M+H].

Example 123

7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyryl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

The first step is as follows: 4- (4-chloro-3-cyano-6-methoxy-quinolin-7-yloxy) -butyric acid ethyl ester

4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile (500mg,2.13mmol) was dissolved in anhydrous N, N-dimethylformamide (25mL), anhydrous potassium carbonate (1.47g,5eq) was added under nitrogen, stirring was carried out for 0.5 h, ethyl 4-bromobutyrate (1.25g,6.39mmol) was further added, and the reaction was heated to 90 ℃ overnight. The reaction mixture was diluted with water, the pH was adjusted to 7 with 1N dilute hydrochloric acid, and a solid was precipitated, filtered under reduced pressure, washed with water, and dried to give 4- (4-chloro-3-cyano-6-methoxy-quinolin-7-yloxy) -butyric acid ethyl ester (gray solid, 690 mg).

¹H NMR(300MHz,DMSO-d₆):δ8.94(s,1H),7.49(s,1H),7.38(s,1H),4.24(t,J=5.7Hz,2H),4.10(m,2H),4.00(s,3H),2.55-2.48(m,3H),2.13-2.04(m,2H),1.18(t,J=6.90Hz,3H).

MS m/z(ESI):349.1[M+H].

The second step is that: 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyric acid ethyl ester

The intermediate 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyric acid ethyl ester (grey solid, 580 mg) was synthesized in a similar manner to the second step of example 1.

¹H NMR(300MHz,DMSO-d₆):δ9.61(s,1H),8.39(s,1H),7.87(s,1H),7.73(s,1H),7.32(s,2H),4.16(d,J=6.3Hz,2H),4.06(d,J=7.2Hz,2H),3.93(s,3H),3.84(s,3H),2.48(m,2H),2.04(m,2H),1.16(t,J=7.2Hz,3H).

MS m/z(ESI):504.1[M+H].

The third step: 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyric acid

Ethyl-4- (3-cyano-4- (2, 4-dichloro-5-methoxyphenylamino) -6-methoxyquinolin-7-yloxy) butanoate (80mg,0.158mmol,1eq) was dissolved in tetrahydrofuran (4mL) and an aqueous potassium hydroxide solution (a solution of 44.5mg of solid potassium hydroxide in 0.5mL of water) was added dropwise in an ice bath. After the addition was complete, the reaction solution was stirred overnight at room temperature. After the reaction, the reaction mixture was adjusted to pH 6.0 with 1N diluted hydrochloric acid to precipitate a solid, which was then filtered under reduced pressure, washed with water and dried to give 4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyric acid as a white solid (71 mg).

¹H NMR(300MHz,DMSO-d₆):δ8.37(s,1H),7.83(s,1H),7.70(s,1H),7.29(s,2H),4.15(d,J=6.6Hz,2H),3.93(s,3H),3.84(s,3H),2.38(d,J=6.6Hz,2H),2.00(m,2H).

MS m/z(ESI):476.1[M+H].

The fourth step: 7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyryl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

4- (3-cyano-4- (2, 4-dichloro-5-methoxyphenylamino) -6-methoxyquinolin-7-yloxy) butyric acid (50mg,0.105mmol), tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate (24mg) and diisopropylethylamine (81.4mg,0.63mmol) were dissolved in anhydrous N, N-dimethylformamide (5 mL), benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (52mg,0.21mmol) was added with cooling on an ice bath, and stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with 0.1N dilute hydrochloric acid, saturated sodium bicarbonate solution, water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give tert-butyl 7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yloxy ] -butyryl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 42mg).

¹H NMR(300MHz,CD₃OD):δ8.71(s,1H),7.87(s,1H),7.64(s,1H),7.33(m,2H),4.29(t,J=6.0Hz,2H),4.05(s,3H),3.92(s,3H),3.67(s,4H),3.54(m,4H),2.67(t,J=5.4Hz,2H),2.20(m,2H),1.74(m,4H),1.44(s,9H).

MS m/z(ESI):684.2[M+H].

Example 124

7- [4- (2, 7-diaza-spiro [3.5] non-7-yl) -4-oxo-butoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 123 as a starting material, the synthesis method similar to example 4 was carried out to give the target compound 7- [4- (2, 7-diaza-spiro [3.5] non-7-yl) -4-oxo-butoxy ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 38 mg).

¹H NMR(300MHz,DSMO-d6):δ11.59(s,1H),9.25(m,2H),9.06(s,1H),8.33(s,1H),7.86(s,1H),7.61(s,1H),7.54(s,1H),4.23(t,J=6.9Hz,2H),4.03(s,3H),3.87(s,3H),3.69(m,4H),3.40(m,4H),2.53(m,2H),2.05(m,2H),1.70(m,4H).

MS m/z(ESI):584.2[M+H].

Example 125

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -4-oxo-butoxy ] -quinoline-3-carbonitrile

Using the compound of example 124 as a starting material, and by a synthesis method similar to example 11, substituting aqueous formaldehyde for acetaldehyde, the desired compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -4-oxo-butoxy ] -quinoline-3-carbonitrile, was obtained (yellow solid, 19 mg).

¹H NMR(300MHz,CD₃OD):δ8.37(s,1H),7.69(s,1H),7.56(s,1H),7.28(s,1H),7.18(s,1H),4.24(t,J=5.7Hz,2H),4.00(s,3H),3.89(s,3H),3.51(m,4H),3.24(m,4H),2.65(t,J=6.0Hz,2H),2.45(s,3H),2.18(m,2H),1.74(m,4H).

MS m/z(ESI):598.2[M+H].

Example 126

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile

The first step is as follows: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-3-yl) -6-methoxy-quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-trifluoromethanesulfonic acid methyl ester-6-methoxy-quinoline-3-carbonitrile (3.5g,6.77mmol), 5-formylfuran-3-boronic acid (1.9g,13.5mmol) and sodium bicarbonate powder (1.7g,20.3mmol) were mixed in 1, 4-dioxane (50mL), bubbled with nitrogen for 15 minutes and then Pd (dppf) was added quickly₂Cl₂(553mg,0.677mmol) and reacted at 110 ℃ for 12h under nitrogen. After the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane, the organic phase was washed with distilled water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered under reduced pressure, and separated and purified by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-3-yl) -6-methoxy-quinoline-3-carbonitrile (2 g, yellow solid).

¹H NMR(400MHz,CD₃OD):δ9.69(s,1H),8.56(s,1H),8.44(s,1H),8.16(s,1H),8.03(s,1H),7.86(s,1H),7.58(s,1H),7.25(s,1H),4.13(s,3H),3.91(s,3H).

MS m/z(ESI):469.3[M+H].

The second step is that: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-3-yl) -6-methoxy-quinoline-3-carbonitrile (30mg,0.064mmol) and 7-oxa-2-aza-spiro [3.5] nonane (16mg,0.097mmol) were dissolved in dichloromethane (5mL), reacted at room temperature for 5 hours after 2 drops of glacial acetic acid were added dropwise, followed by slow addition of sodium borohydride powder (68mg,0.32mmol) and reaction at 0 ℃ for 2 h. After the reaction, the reaction was quenched with a saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the objective compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile (yellow solid, 11 mg).

¹H NMR(400MHz,CD₃OD):δ8.45(s,1H),8.30(s,1H),8.10(s,1H),7.85(s,1H),7.60(s,1H),7.25(s,1H),7.08(s,1H),4.14(s,3H),4.02(s,2H),3.93(s,3H),3.67–3.59(m,4H),3.52(s,4H),1.86–1.79(m,4H).

MS m/z(ESI):580.2[M+H].

Example 127

7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-3-yl) -6-methoxy-quinoline-3-carbonitrile and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the expected compound 7- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester (yellow solid, 234 mg).

¹H NMR(400MHz,CD₃OD):δ8.73（s,1H），8.18(s,1H),8.09(s,1H),7.52(s,1H),7.09(s,1H),6.85(s,1H),6.74(s,1H),6.55(s,1H),3.85(s,3H),3.69(s,3H),3.57-3.63（m,8H）,1.75-1.79(m,4H),1.44(s,9H).

MS m/z(ESI):580.2[M+H].

Example 128

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [5- (2-oxa-7-aza-spiro [3.5] nonan-7-oyl) -furan-2-ylmethoxy ] -quinoline-3-carbonitrile

The first step is as follows: 5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethoxy ] -furan-2-carboxylic acid ethyl ester

4- (2, 4-dichloro-5-methoxy-anilino) -7-hydroxy-6-methoxy-quinoline-3-carbonitrile (200 mg,0.51 mmol) and cesium carbonate anhydrous (334mg,1.02mmol) were mixed in anhydrous N, N-dimethylformamide (5mL), and ethyl 5-chloromethyl-furan-2-carboxylate (115 mg,0.61 mmol) was added under nitrogen and stirred at room temperature overnight. After the reaction, water was added for dilution, dichloromethane was extracted, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent was ethyl acetate: petroleum ether at a volume ratio of 1: 3) to give ethyl 5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethoxy ] -furan-2-carboxylate (100 mg, white solid) as an intermediate.

¹H NMR(300MHz，CD₃OD):δ8.39(s,1H),7.72(s,1H),7.56(s,1H),7.43(s,1H),7.23(d,J=3.6Hz,1H),7.19(s,1H),6.76(d,J=3.6Hz,1H),5.31(s,2H),4.34(q,J=7.2Hz,2H),3.99(s,3H),3.88(s,3H),1.36(t,J=7.2Hz,3H)。

MS m/z(ESI):541.1[M+H].

The second step is that: 5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethyl ] -furan-2-carboxylic acid

Ethyl 5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethoxy ] -furan-2-carboxylate (80 mg, 0.145 mmol) was dissolved in methanol (2mL) and tetrahydrofuran (2mL), to which an aqueous potassium hydroxide solution (40 mg potassium hydroxide in 3mL water) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was adjusted to pH 5 with dilute hydrochloric acid to precipitate a yellow solid, which was collected by filtration, washed with distilled water and dried to give an intermediate 5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethyl ] -furan-2-carboxylic acid (yellow solid, 56 mg).

¹H NMR(400MHz,CD₃OD):δ7.88(s,1H),7.83(s,1H),7.26(s,1H),7.10(s,1H),6.92(d,J=3.2Hz,1H),6.73(s,1H),6.59(d,J=3.2Hz,1H),5.18(s,2H),3.92(s,3H),3.83(s,3H)。

MS m/z(ESI):541.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [5- (2-oxa-7-aza-spiro [3.5] nonan-7-oyl) -furan-2-ylmethoxy ] -quinoline-3-carbonitrile

The synthesis procedure analogous to the fourth step of example 123 was used to give the title compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [5- (2-oxa-7-aza-spiro [3.5] nonan-7-acyl) -furan-2-ylmethoxy ] -quinoline-3-carbonitrile (white solid, 15 mg).

¹H NMR(400MHz,CD₃OD):δ8.41(s,1H),7.74(s,1H),7.57(s,1H),7.49(s,1H),7.20(s,1H),7.00(d,J=3.6Hz,1H),6.75(d,J=3.6Hz,1H),5.35(s,2H),4.45(m,6H),4.00(s,2H),3.89(s,2H),3.16(t,J=5.6Hz,4H),1.86(t,J=5.6Hz,4H)。

MS m/z(ESI):623.1[M+H].

Example 129

4- (3-chloro-4-fluoro-phenylamino) -6- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -propoxy ] -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

The first step is as follows: 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7- (tetrahydro-furan-3-yloxy) -quinolin-6-yl ester

2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7-hydroxy-quinolin-6-yl ester (1g,3.28mmol), tetrahydro-furan-3-ol (1.445g,16.4mmol), triphenylphosphine (1.118g,4.264mmol) were mixed in anhydrous tetrahydrofuran (20mL), DIAD (0.826g,4.264mmol) was slowly added dropwise at 0 ℃ under nitrogen, and the reaction was continued for 12h after completion of the addition. After the reaction, dichloromethane was added for extraction, and the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to give the compound 2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7- (tetrahydro-furan-3-yloxy) -quinolin-6-yl ester (200 mg, white solid).

¹H NMR(300MHz,CDCl₃):δ8.88(s,1H),7.91(s,1H),7.47(s,1H),1.61(s,6H),1.44(s,1H),1.26(d,J=6.3Hz,9H).

MS m/z(ESI):375.1[M+H].

The second step is that: 4-chloro-6-hydroxy-7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

2, 2-dimethyl-propionic acid 4-chloro-3-cyano-7- (tetrahydro-furan-3-yloxy) -quinolin-6-yl ester (200 mg) was dissolved in methanol (5 mL), and 2N ammonia in methanol (10mL) was added dropwise to the solution under ice-cooling, and the reaction was continued for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product (yellow solid, 187 mg) which was used in the next reaction without purification.

The third step: 4-chloro-6- (3-chloro-propoxy) -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

4-chloro-6-hydroxy-7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile (187 mg,0.643 mmol), 1-chloro-3-iodopropane (656mg,3.12mmol) and anhydrous potassium carbonate powder (430.6mg,3.12mmol) were mixed in N, N-dimethylformamide (10mL) and reacted at room temperature under nitrogen for 12 h. After the reaction, dichloromethane was extracted and purified by silica gel column chromatography to give 4-chloro-6- (3-chloro-propoxy) -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile (124 mg, white powder).

¹H NMR(300MHz,CDCl₃):δ8.78(s,1H),7.46(s,1H),7.34(s,1H),5.13(dd,J=4.8,2.8Hz,1H),4.33(s,2H),4.12(d,J=4.0Hz,2H),4.04(m,1H),3.96(m,1H),3.82(s,2H),2.43–2.32(m,4H),2.24(m,2H).

MS m/z(ESI):368.2[M+H].

The fourth step: 4- (3-chloro-4-fluoro-phenylamino) -6- (3-chloro-propoxy) -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

4-chloro-6- (3-chloro-propoxy) -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile (110mg,0.327mmol), 3-chloro-4-fluoro-phenylamino (71.4mg,0.49mmol) and pyridine hydrochloride (37.6mg,0.327mmol) were mixed in 2-methoxyethanol (5mL) and reacted at 140 ℃ for 2 h. Cooled to room temperature, triethylamine (5mL) and methanol (20 mL) were slowly added dropwise to precipitate a white solid, which was filtered, washed with a small amount of anhydrous methanol and dried to give the compound 4- (3-chloro-4-fluoro-phenylamino) -6- (3-chloro-propoxy) -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile (140 mg, white solid) which was used in the next reaction without purification.

The fifth step: 4- (3-chloro-4-fluoro-phenylamino) -6- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -propoxy ] -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

The title compound, 4- (3-chloro-4-fluoro-phenylamino) -6- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -propoxy ] -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile (white solid, 33 mg) was synthesized by a method analogous to the third step of EXAMPLE 1.

¹H NMR(400MHz,CD₃OD):δ8.44(s,1H),7.66(s,1H),7.42(dd,J=6.4,2.4Hz,1H),7.32–7.22(m,3H),5.24(d,J=1.6Hz,1H),4.20(t,J=5.6Hz,2H),4.09–3.98(m,3H),3.90(td,J=8.4,4.8Hz,1H),3.34(s,1H),3.14–3.07(m,2H),2.48–2.36(m,1H),2.23–2.14(m,2H),2.09–1.99(m,3H),1.84–1.79(m,4H),1.32(dd,J=11.2,8.4Hz,4H),0.89(s,1H).

MS m/z(ESI):568.2[M+H].

Example 130

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The first step is as follows: 4-cyano-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester

A solution of tert-butyl 4-cyano-piperidine-1-carboxylate (10.0g, 47.6mmol) in tetrahydrofuran (200mL) was slowly added to a solution of lithium diisopropylamide in tetrahydrofuran (57mL, 1.0M) at-78 deg.C, and after dropwise addition, the mixture was stirred at the same temperature for 0.5 hour, then ethyl chloroformate (6.2g, 57.4mmol) was slowly added to the reaction mixture and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent was a solution of petroleum ether and ethyl acetate at a volume ratio of 10: 1) to give an intermediate, 1-tert-butyl 4-ethyl 4-cyano-piperidine-1, 4-dicarboxylate (yellow oil, 6.5 g).

¹H NMR(400MHz,CDCl₃):δ4.30（q,J=7.2Hz,2H）,4.11(t,J=7.2Hz,2H),3.12(m,2H),1.92-2.08(m,4H),1.46(s,9H),1.34(t,J=7.2Hz,3H).

MS m/z(ESI):283.2[M+H].

The second step is that: 4-aminomethyl-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester

To a solution of 4-cyano-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (5.0 g, 17.7 mmol) in methanol (100mL) at room temperature was added Raney nickel (1.0 g), and the mixture was stirred under a hydrogen atmosphere at a pressure of 30psi overnight. The reaction mixture was filtered and concentrated under reduced pressure to give 4-aminomethyl-piperidine-1, 4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (yellow oil, 4.7 g).

¹H NMR(400MHz,CDCl₃):δ3.85-3.88（m，2H）,3.71(s,3H),2.78-2.90(m,2H),2.66(s,2H),2.08-2.11(m,2H),1.75(m,2H),1.36(s,9H),1.04(m,2H).

MS m/z(ESI):273.2[M+H].

The third step: 1-oxa-2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

To a solution of 4-aminomethyl-piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (6g, 21mmol) in tetrahydrofuran (100mL) at-78 deg.C was slowly added dropwise a solution of n-butyllithium in tetrahydrofuran (19mL, 2.5M), and after completion of the addition, the mixture was stirred at the same temperature for 1 hour. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent was a solution of petroleum ether and ethyl acetate at a volume ratio of 10: 1) to give the intermediate tert-butyl 1-oxa-2, 7-diaza-spiro [3.5] nonane-7-carboxylate (pale yellow solid, 4 g).

¹H NMR(400MHz,CDCl₃):δ5.82（s,1H）,3.69-3.76(m,2H),3.33-3.48(m,2H),3.16(s,2H),1.91-1.97(m,2H),1.72-1.77(m,2H),1.46(s,9H).

MS m/z(ESI):241.2[M+H].

The fourth step: 2-methyl-2, 7-diaza-spiro [3.5] nonan-1-ones

Compound 1-oxa-2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester (2g, 8.3mmol) was dissolved in N, N-dimethylformamide (20mL), and to the above solution was added 60% sodium hydride (0.37g) in portions under cooling in an ice bath. After the addition was completed, stirring was continued at the same temperature for 0.5 hour, and methyl iodide (1.3g, 9.1mmol) was then slowly added and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (4 g) was added to the above solution with ice cooling. After the completion of the dropwise addition, stirring was continued at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give intermediate 2-methyl-2, 7-diaza-spiro [3.5] nonan-1-one (pale yellow solid, 1.8 g).

¹H NMR(400MHz,CD₃OD):δ3.40-3.46(m,2H),3.22-3.28(m,4H),2.87(s,3H),2.03-2.19(m,4H).

MS m/z(ESI):155.2[M+H].

The fifth step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 27mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(400MHz,CD₃OD):δ8.40(s,1H),7.55(s,1H),7.30(s,1H),7.24(s,1H),7.18(s,1H),4.27(t,J=7.2Hz,2H),4.00(s,3H),3.88(s,3H),3.22(s,2H),3.17(m,2H),3.12(m,2H),2.92(s,3H),2.77(m,2H),2.23(m,2H),2.19(m,2H),1.97(m,2H).

MS m/z(ESI):583.2[M+H].

Example 131

4- (3, 5-dimethoxy-anilino) -6- [4- (7-oxa-2-aza-spiro [3.5] nonan-2-oyl) -phenyl ] -quinoline-3-carbonitrile

The first step is as follows: 6-chloro-4- (3, 5-dimethoxy-anilino) -quinoline-3-carbonitrile

Synthesized in a similar manner to the first step of example 1, substituting 3, 5-dimethoxy-aniline for 2, 4-dichloro-5-methoxyaniline to give an intermediate (yellow solid, 600 mg).

¹H NMR(300MHz,DMSO-d₆):δ9.87(s,1H),8.57–8.47(m,2H),7.83(m,2H),6.38(m,2H),6.32(s,1H),3.32(s,6H).

MS m/z(ESI):340.1[M+H].

The second step is that: 4- [ 3-cyano-4- (3, 5-dimethoxy-anilino) -quinolin-6-yl ] -benzoic acid ethyl ester

6-chloro-4- (3, 5-dimethoxy-anilino) -quinoline-3-carbonitrile (100 mg,0.29 mmol), ethyl 4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoate (162 mg,0.29 mmol), and sodium carbonate (95 mg,0.89 mmol) were suspended in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL). After bubbling nitrogen gas for 15 minutes, a tetrakistriphenylphosphine palladium catalyst (35 mg,0.03 mmol) was added to the reaction mixture, and the reaction was carried out at 90 ℃ for 12 hours while closing the tube. After the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dilute hydrochloric acid, water, and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give intermediate 4- [ 3-cyano-4- (3, 5-dimethoxy-anilino) -quinolin-6-yl ] -benzoic acid ethyl ester (grey solid, 150 mg).

¹H NMR(300MHz,CDCl₃):δ8.76(s,1H),8.08(m,4H),8.04–7.99(m,2H),7.52(d,J=8.4Hz,2H),6.36(m,2H),4.41(q,J=5.1Hz,2H),3.76(s,6H),1.42(t,J=5.1Hz,3H).

MS m/z(ESI):454.2[M+H].

The third step: 4- [ 3-cyano-4- (3, 5-dimethoxy-anilino) -quinolin-6-yl ] -benzoic acid

Ethyl 4- [ 3-cyano-4- (3, 5-dimethoxy-anilino) -quinolin-6-yl ] -benzoate (50 mg,0.11 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and then a 4M aqueous solution (0.8 mL) of sodium hydroxide was added dropwise to the solution, and the mixture was heated at 80 ℃ for 2 hours after completion of the addition. After the reaction, it was cooled to room temperature, the pH was adjusted to about 4.0 with 2M/L dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4- [ 3-cyano-4- (3, 5-dimethoxy-anilino) -quinolin-6-yl ] -benzoic acid as an intermediate (yellow solid, 35 mg).

MS m/z(ESI):426.1[M+H].

The fourth step: 4- (3, 5-dimethoxy-anilino) -6- [4- (7-oxa-2-aza-spiro [3.5] nonan-2-oyl) -phenyl ] -quinoline-3-carbonitrile

Synthesized by a method similar to the third step of EXAMPLE 128 to give the title compound 4- (3, 5-dimethoxy-anilino) -6- [4- (7-oxa-2-aza-spiro [3.5] nonane-2-acyl) -phenyl ] -quinoline-3-carbonitrile (yellow solid, 8 mg).

¹H NMR(300MHz,CD₃OD):δ8.65(s,1H),8.56(s,1H),8.18(d,J=8.7,1H),8.03(d,J=8.7Hz,1H),7.91(m,2H),7.83–7.77(m,2H),6.52(m,2H),6.46(m,1H),4.18(s,2H),3.95(s,2H),3.79(s,6H),3.63(d,J=5.4Hz,4H),1.83(t,J=5.4Hz,4H).

MS m/z(ESI):535.2[M+H].

Example 132

4- (3, 5-dimethoxy-anilino) -6- [4- (2-oxa-7-aza-spiro [3.5] nonan-7-oyl) -phenyl ] -quinoline-3-carbonitrile

Synthesized by a method similar to the third step of EXAMPLE 128 to give the title compound 4- (3, 5-dimethoxy-anilino) -6- [4- (2-oxa-7-aza-spiro [3.5] nonan-7-oyl) -phenyl ] -quinoline-3-carbonitrile (yellow solid, 12 mg).

¹H NMR(300MHz,CD₃OD):δ8.63(s,1H),8.55(s,1H),8.17(d,J=8.7,1H),8.02(d,J=8.7Hz,1H),7.89(m,2H),7.53(m,2H),6.51(m,2H),6.45(m,1H),4.49(d,J=4.5Hz,4H),3.18–3.11(m,6H),2.02(d,J=4.5Hz,4H),1.84(s,4H).

MS m/z(ESI):535.2[M+H].

Example 133

4- (3-chloro-4-fluoro-phenylamino) -6- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile

Starting from the intermediate compound obtained in the fourth step of example 129 and 1-oxo-2, 7-diaza-spiro [3.5] nonane, the title compound, 4- (3-chloro-4-fluoro-phenylamino) -6- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -7- (tetrahydro-furan-3-yloxy) -quinoline-3-carbonitrile, was synthesized in a similar manner to the third step of example 1 (white solid, 18 mg).

¹H NMR(400MHz,CD₃OD):δ8.44(s,1H),7.65(s,1H),7.43(d,J=2.4Hz,1H),7.34–7.22(m,3H),5.26–5.20(m,1H),4.20(t,J=6.0Hz,2H),4.02(m,3H),3.91(d,J=4.6Hz,1H),3.20(s,2H),3.06–2.96(m,2H),2.64–2.49(m,1H),2.40(m,1H),2.23–2.10(m,3H),2.06–1.96(m,3H),1.91–1.83(m,2H),1.35–1.31(m,2H),0.89(s,1H).

MS m/z(ESI):595.2[M+H].

Example 134

4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -cyclohexylmethoxy ] -quinoline-3-carbonitrile

The first step is as follows: toluene-4-sulfonic acid-4-hydroxymethyl-cyclohexylmethyl ester

Synthesized in a similar manner to the first step of example 94, substituting (4-hydroxymethyl-cyclohexyl) -methanol for 2-methyl-propane-1, 3-diol to give intermediate toluene-4-sulfonic acid-4-hydroxymethyl-cyclohexylmethyl ester (colorless oil, 1.8 g).

¹H NMR(400MHz,CDCl₃):δ7.76(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),3.81(d,J=6.4Hz,2H),3.42(d,J=6.4Hz,2H),2.44(s,3H),1.77(m,4H),1.61(m,1H),1.38(m,1H)，0.92(m,4H)。

MS m/z(ESI):321.1[M+Na].

The second step is that: toluene-4-sulfonic acid-4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethyl ] -cyclohexylmethyl ester

Synthesized in a similar manner as the second step of EXAMPLE 94 to give the intermediate toluene-4-sulfonic acid-4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-quinolin-7-yloxymethyl ] -cyclohexylmethyl ester (yellow solid, 255 mg).

¹H NMR(400MHz,CD₃OD):δ8.38(s,1H),7.79(d,J=8.4Hz,2H),7.68(s,1H),7.56(s,1H),7.45(d,J=8.4Hz,2H),7.25(s,1H),7.18(s,1H),3.98(m,5H),3.87(m,5H),1.20(m,10H)。

MS m/z(ESI):670.1[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -cyclohexylmethoxy ] -quinoline-3-carbonitrile

Synthesized in a similar manner to the third step of EXAMPLE 94 to give the title compound 4- (2, 4-dichloro-5-methoxy-anilino) -6-methoxy-7- [4- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -cyclohexylmethoxy ] -quinoline-3-carbonitrile (yellow solid, 60 mg).

¹H NMR(400MHz,CD₃OD):δ8.39(s,1H),7.70(s,1H),7.56(s,1H),7.27(s,1H),7.18(s,1H),4.48(s,4H),4.01(m,5H),3.89(s,3H),2.19(m,2H),2.06(m,2H),1.92(m,2H),1.19(m,10H)。

MS m/z(ESI):625.2[M+H].

Example 135

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-hydroxy-2-methyl-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile

The first step is as follows: 2-hydroxy-2-methyl-7-aza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Tert-butyl 2-oxo-7-aza-spiro [3.5] nonane-7-carboxylate (239 mg,1 mmol) was dissolved in dry tetrahydrofuran (10 mL) in a 50mL three-necked flask, and under cooling in an ice bath, a methylmagnesium bromide solution (1M, 2 mL) was slowly added dropwise under a nitrogen atmosphere, and after completion of the addition, the mixture was stirred at room temperature for 3 hours. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 2-hydroxy-2-methyl-7-aza-spiro [3.5] nonane-7-carboxylate (white solid, 210 mg).

¹H NMR(400MHz,CD₃OD):δ1.89-2.00(m,4H),1.59(t,J=5.6Hz,2H),1.50(t,J=5.6Hz,2H),1.39-1.44(m,13H),1.23(s,3H).

MS m/z(ESI):256.2[M+H].

The second step is that: 2-methyl-7-aza-spiro [3.5] nonan-2-ol

Tert-butyl 2-hydroxy-2-methyl-7-aza-spiro [3.5] nonane-7-carboxylate (200 mg,0.78 mmol) was dissolved in dichloromethane (5 mL), 4N hydrogen chloride in dioxane (5 mL) was added dropwise, stirred at room temperature for 2 hours, and concentrated under reduced pressure to give 2-methyl-7-aza-spiro [3.5] nonane-2-ol (white solid, 110mg) which was used in the next reaction without purification.

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-hydroxy-2-methyl-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [4- (2-hydroxy-2-methyl-7-aza-spiro [3.5] non-7-yl) -butoxy ] -6-methoxy-quinoline-3-carbonitrile (yellow solid, 45 mg) was synthesized by a method analogous to the third step of example 1.

¹H NMR(400MHz,CDCl₃):8.30(s,1H),7.38(s,1H),7.23(s,1H),7.13(s,1H),6.69(s,1H),4.24(t,J=5.7Hz,2H),3.82(s,3H),3.69(s,3H),1.98(m,2H),1.89-2.02(m,4H),1.82(m,6H),1.57(t,J=5.6Hz,2H),1.53(t,J=5.6Hz,2H),1.39-1.44(m,4H),1.25(s,3H).

MS m/z(ESI):599.2[M+H].

Example 136

4- (3-ethynyl-anilino) -6-methoxy-7- [4- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-ethynyl-anilino) -6-methoxy-7- [4- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -butoxy ] -quinoline-3-carbonitrile, was synthesized by a method analogous to the third step of example 1 (yellow powder, 36 mg).

¹H NMR(400MHz,CD₃OD):δ8.43（s,1H）,7.57(s,1H),7.28-7.38(m,5H),5.48(s,1H),4.21(m,2H),3.93(s,3H),3.53(s,1H),3.18(s,2H),2.97(m,2H),2.81(s,3H),2.62(m,2H),2.47(m,2H),1.95(m,4H),1.82(m,4H).

MS m/z(ESI):523.2[M+H].

Example 137

4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (3-ethynyl-anilino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 35 mg) was synthesized by a method similar to the third step of example 1.

¹H NMR(400MHz,CD₃OD):δ8.42（s,1H）,7.58(s,1H),7.29-7.36(m,5H),5.48(s,1H),4.24(m,2H),3.94(s,3H),3.53(s,1H),3.08(s,2H),3.03(m,2H),2.82(s,3H),2.79(m,2H),2.61(m,2H),2.19(m,2H),2.05(m,2H),1.99(m,2H).

MS m/z(ESI):509.2[M+H].

Example 138

4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The synthesis of the target compound 4- [2, 4-dichloro-5- (3-fluoro-benzyloxy) -anilino ] -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow powder, 30 mg) was carried out in a similar manner to the third step of example 1.

¹H NMR(400MHz,CD₃OD):δ8.34(s,1H),7.62(s,1H),7.59(s,1H),7.38(m,1H),7.28(s,1H),7.21(s,1H),7.18(m,2H),7.05(m,1H),5.18(s,2H),4.25(m,2H),3.95(s,3H),3.21(s,2H),3.06(m,2H),2.83(m,3H),2.56(m,2H),2.17(m,2H),2.04(m,2H),1.99(m,2H).

MS m/z(ESI):678.2[M+H].

Example 139

4- (2, 4-dichloro-5-ethoxy-anilino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-ethoxy-anilino) -6-methoxy-7- [3- (2-methyl-1-oxo-2, 7-diaza-spiro [3.5] non-7-yl) -propoxy ] -quinoline-3-carbonitrile (yellow solid, 23 mg) was synthesized by a method similar to the third step of example 1.

¹H NMR(400MHz,CD₃OD):δ8.34(s,1H),7.68(d,J=4.0Hz,1H),7.54(s,1H),7.27(s,1H),7.17(s,1H),4.26(m,2H),4.11(m,2H),3.99(s,3H),3.34(s,3H),3.16-3.22(m,4H),2.95(t,J=7.2Hz,2H),2.76-2.78(m,5H),2.22(m,2H),2.06(m,2H),1.95(m,2H),1.44(t,J=7.2Hz,3H).

MS m/z(ESI):598.2[M+H].

Example 140

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -3-oxo-propenyl ] -quinoline-3-carbonitrile

The first step is as follows: 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -acrylic acid ethyl ester

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-trifluoromethanesulfonic acid methyl ester-6-methoxy-quinoline-3-carbonitrile (250mg,0.47mmol), ethyl acrylate (96mg,0.975mmol) and triethylamine (238 mg,2.35 mmol) were mixed in N, N-dimethylformamide (10 mL), and after bubbling with nitrogen for 15 minutes, Pd (PPh) was added rapidly₃)₄(27mg,0.0253mmol) and reacted at 80 ℃ for 12 hours. After the reaction is finished, dichloromethane is added for extraction, the organic phase is respectively washed by saturated sodium bicarbonate solution, water and saturated brine, dried by anhydrous sodium sulfate, filtered, decompressed and concentrated, and separated and purified by silica gel column chromatography to obtain the compound 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl]-ethyl acrylate (156 mg, yellow solid).

MS m/z(ESI):473.2[M+H].

The second step is that: 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -acrylic acid

3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -acrylic acid ethyl ester (70mg,0.148mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (2mL/3mL), and a 4M aqueous solution of sodium hydroxide (1mL) was added and refluxed for 1 h. After the reaction was completed, the reaction mixture was acidified to pH4 with 2M aqueous hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -acrylic acid (60 mg, yellow solid).

¹H NMR(400MHz,CD₃OD):δ8.43(s,1H),8.13(s,1H),8.05(d,J=16.2Hz,1H),7.81(s,1H),7.57(d,J=3.4Hz,1H),7.23(s,1H),6.78(d,J=16.2Hz,1H),4.08(s,3H),4.01(s,1H),3.90(s,3H).

MS m/z(ESI):445.2[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -3-oxo-propenyl ] -quinoline-3-carbonitrile

3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -acrylic acid (60mg,0.135mmol) and 7-oxa-2-aza-spiro [3.5] nonane (66.3mg,0.405mmol) were dissolved in anhydrous N, N-dimethylformamide (5mL), followed by the addition of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (154mg,0.405mmol) and N, N-diisopropylethylamine (87.2mg,0.675mmol) in that order and allowed to react at room temperature overnight. The reaction mixture was extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, distilled water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the objective compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -3-oxo-propenyl ] -quinoline-3-carbonitrile (yellow solid, 16 mg).

¹H NMR(400MHz,CD₃OD):δ8.44(s,1H),8.15(s,1H),7.99(d,J=15.8Hz,1H),7.80(s,1H),7.58(d,J=3.8Hz,1H),7.24(s,1H),6.98(d,J=15.9Hz,1H),4.19(s,3H),4.07(s,4H),4.03(d,J=6.6Hz,2H),3.90(s,6H),3.87(s,3H).

MS m/z(ESI):554.1[M+H].

Example 141

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

The first step is as follows: 7- [3- (tert-butyl-dimethyl-siloxy) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-trifluoromethanesulfonic acid methyl ester-6-methoxy-quinoline-3-carbonitrile (1g,1.91mmol), tert-butyl-dimethyl-siloxy-prop-1-yne (978mg,5.74mmol) and N, N-diisopropylethylamine (743mg,5.74mmol) were mixed in anhydrous N, N-dimethylformamide (10mL), and Pd (PPh) was added rapidly after bubbling nitrogen for 15 minutes₃)₂Cl₂(134mg,0.191mmol) and cuprous iodide (36mg,0.191mmol) were reacted at room temperature for 24 h. After the reaction, dichloromethane was extracted, and the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product (1g, yellow solid) which was used in the next reaction without purification.

The second step is that: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (3-hydroxy-prop-1-ynyl) -6-methoxy-quinoline-3-carbonitrile

7- [3- (tert-butyl-dimethyl-siloxy) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (1g,1.84mmol) was dissolved in tetrahydrofuran (20mL), tetrabutylammonium fluoride (756mg,2.4mmol) was added and the reaction was carried out at room temperature for 3 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to give 7- [3- (tert-butyl-dimethyl-siloxy) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carba-nitrile (660 mg, yellow powder).

¹H NMR(400MHz,CD₃OD):δ8.64–8.35(m,1H),7.96(d,J=1.6Hz,1H),7.76(d,J=0.7Hz,1H),7.57(s,1H),7.24(s,1H),4.64(s,1H),4.48(s,2H),4.02(s,3H),3.89(s,3H).

MS m/z(ESI):429.1[M+H].

The third step: methanesulfonic acid 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl ester

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (3-hydroxy-prop-1-ynyl) -6-methoxy-quinoline-3-carbonitrile (300mg,0.7mmol) was dissolved in dichloromethane (20mL) and N, N-diisopropylethylamine (452.2mg,3.5mmol) and methanesulfonyl chloride (241mg,2.1mmol) were added sequentially with cooling on an ice bath. After the dropwise addition, the reaction was continued at 0 ℃ for 2 hours, dichloromethane extraction was carried out, the organic phase was washed with a saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography for separation and purification to give methanesulfonic acid 3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl ester (150 mg, yellow solid).

¹H NMR(400MHz,CD₃OD):8.36(s,1H),7.93(s,1H),7.73(s,1H),7.51(s,1H),7.17(s,1H),5.16(s,2H),3.97(s,3H),3.83(s,3H),3.21(s,3H).

MS m/z(ESI):507.2[M+H].

The fourth step: 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

The title compound, 7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester (yellow solid, 49 mg), was synthesized by a method analogous to the third step of EXAMPLE 1.

MS m/z(ESI):637.2[M+H].

Example 142

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-2-yl ] -quinoline-3-carbonitrile

The first step is as follows: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-2-yl) -6-methoxy-quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7-trifluoromethanesulfonic acid methyl ester-6-methoxy-quinoline-3-carbonitrile (300mg,0.574mmol), 5-formylfuran-2-boronic acid (161mg,1.149mmol) and sodium bicarbonate powder (145mg,1.722mmol) were mixed in 1,4 dioxane (10mL), nitrogen bubbled for 15 min and Pd (PPh) was added rapidly₃)₄(66.3mg,0.0574mmol) and reaction continued at 110 ℃ for 12 h. After the reaction, the reaction mixture was cooled to room temperature, dichloromethane was added for extraction, the organic phase was washed with a saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and separated and purified by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-2-yl) -6-methoxy-quinoline-3-carbonitrile (150 mg, yellow solid).

¹H NMR(400MHz,DMSO-d):δ9.96(s,1H),9.72(s,1H),8.53(s,1H),8.36(s,1H),8.07(s,1H),7.81(s,1H),7.72(d,J=3.7Hz,1H),7.45(d,J=16.5Hz,1H),4.13(s,3H),3.88(s,3H).

MS m/z(ESI)：469.2[M+H].

The second step is that: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-2-yl ] -quinoline-3-carbonitrile

4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-2-yl) -6-methoxy-quinoline-3-carbonitrile (20mg,0.043mmol) and 7-oxa-2-aza-spiro [3.5] nonane (11mg,0.064mmol) were dissolved in dichloromethane (5mL), reacted dropwise with 2 drops of glacial acetic acid at room temperature for 5 hours, followed by addition of sodium borohydride powder (46mg,0.215mmol) and continued reaction for 2 hours. After the reaction, saturated ammonium chloride solution was added to quench, dichloromethane was used for extraction, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and separated and purified by silica gel column chromatography to give the objective compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -furan-2-yl ] -quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(400MHz,CD₃OD):δ8.43(s,1H),8.34(s,1H),7.84(s,1H),7.58(s,1H),7.23(s,1H),7.22(d,J=3.4Hz,1H),6.58(d,J=3.4Hz,1H),4.13(s,3H),4.05(s,2H),3.90(s,3H),3.63–3.59(m,4H),3.56(s,4H),1.83–1.79(m,4H).

MS m/z(ESI)：580.2[M+H].

Example 143

7- {5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the first step of EXAMPLE 142 and 2, 7-diaza-spiro [3.5] nonane, the title compound, tert-butyl 7- {5- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 185 mg), was synthesized in a similar manner to the second step of EXAMPLE 142.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),8.34(s,1H),7.83(s,1H),7.58(s,1H),7.23(s,1H),7.20(d,J=3.2Hz,1H),6.50(d,J=3.2Hz,1H),4.13(s,3H),3.90(s,3H),3.70(s,2H),3.60(s,4H),2.56(s,4H),1.82(t,J=5.2Hz,4H),1.42(s,9H).

MS m/z(ESI)：679.2[M+H].

Example 144

7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

7- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester (150 mg) was dissolved in dichloromethane (5mL), and after a 4N hydrogen chloride/dioxane solution (5mL) was added dropwise, the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and dried to give 7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 85 mg) which was used in the next reaction without further purification.

¹H NMR(400MHz,CD₃OD):δ8.97(s,1H),8.26–8.13(m,1H),7.68(s,1H),7.44(s,1H),4.48(s,1H),4.14(s,1H),4.09(s,1H),3.94(s,1H),3.80(s,1H),3.34(s,1H),2.44(s,1H),2.15(s,1H).

MS m/z(ESI)：573.1[M+H].

Example 145

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -pyridine

The first step is as follows: 5-ethynyl-pyridine-3-carbaldehyde

5-Bromocinninaldehyde (558g,3mmol) and ethynyltrimethylsilane (589mg,6mmol) were dissolved in anhydrous N, N-dimethylformamide (5mL), N-diisopropylethylamine (0.99mL,6mmol) and cuprous iodide (114mg,0.134mmol) were added thereto, and Pd (PPh) was added thereto under argon protection₃)₄(347mg,10mol%) and then heated to 80 ℃ for 18 hours. After TLC detection reaction, cooling to room temperature, extracting reaction liquid by ethyl acetate, drying organic phase by anhydrous sodium sulfate, and evaporating solvent to obtain brown oily liquid. This brown oily liquid was dissolved in a mixed solvent of tetrahydrofuran and water (12/0.6mL), and tetrabutylammonium fluoride (1.23g,3.9mmol) was added thereto and reacted at room temperature for 0.5 h. After TLC detection reaction, the reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 151mg of a yellow solid.

MS m/z(ESI)：132.0[M+H].

The second step is that: 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-pyridin-3-ylalkynyl) -6-methoxy-quinoline-3-carbonitrile

3-cyano-4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinolin-7-yl trifluoromethanesulfonate (350g,0.67mmol) and 5-ethynylnicotinaldehyde (130mg,1mmol) were dissolved in anhydrous N, N-dimethylformamide (5mL), to which was added cuprous iodide (26mg,0.134mmol) and N, N-dimethylformamide (0.22mL,1.34mmol), to which was added Pd (PPh) under argon protection ₃)₂Cl₂(47mg,10mol%) was heated to 80 ℃ and reacted for 18 h. After the TLC detection reaction, the reaction solution was cooled to room temperature, ethyl acetate and water were added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (5-formyl-pyridin-3-yl-alkynyl) -6-methoxy-quinoline-3-carbonitrile (213 mg, yellow solid).

¹H-NMR(300MHz,d-DMSO):δ=10.15(1H,s),9.94(1H,s),9.09(2H,d),8.51(1H,s),8.47(1H,s),8.18(1H,s),8.00(1H,s),7.80(1H,s),7.43(1H,s),4.05(3H,s),3.87(3H,s).

MS m/z(ESI)：502.7[M+H].

The third step: 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -pyridin-3-ynynyl ] -quinoline-3-carbonitrile

4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((5-formylpyridin-3-yl) ethynyl) -6-methoxyquinoline-3-carbonitrile (80mg,0.16mmol) was dissolved in dichloromethane (2mL), to which 7-oxa-2-azaspiro [3.5] was added]Nonane hydrochloride (39mg,0.24mmol) and two drops of glacial acetic acid, and the mixture is stirred at room temperature overnight. To which NaBH (OAc) is added₃(170mg,0.8mmol) and stirred at room temperature for 2 h. After TLC detection reaction, adding water, extracting with dichloromethane, evaporating solvent, purifying the residue by silica gel column chromatography to obtain 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-oxa-2-aza-spiro [3.5]]Non-2-ylmethyl) -pyridin-3-ylalkynyl ]-quinoline-3-carbonitrile (9 mg, yellow solid).

¹H-NMR(300MHz,CD₃OD):δ=8.71(1H,s),8.55(1H,s),8.44(1H,s),8.05(2H,d),7.81(1H,s),7.58(1H,s),7.25(1H,s),4.08(3H,s),3.95(2H,s),3.90(3H,s),3.61(4H,t,J=3.9Hz),3.42(4H,s),1.82(4H,t,J=3.9Hz).

MS m/z(ESI)：307.4[M+H].

Example 146

7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-2-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 143 as a starting material, the title compound 7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-2-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 53 mg) was synthesized in a similar manner to example 4.

¹H NMR(400MHz,DMSO-d₆):δ11.38–11.17(m,1H),9.28(m,2H),8.95(dd,J=1.6,0.8Hz,1H),8.56(s,1H),8.39(dd,J=22.8,1.2Hz,1H),7.85(s,1H),7.52(s,1H),7.36(s,1H),6.96(s,1H),4.48(s,2H),4.16(s,3H),3.88(s,3H),3.82(s,2H),3.71(s,2H),3.44(s,2H),3.07(m,2H),2.27(m,2H),2.02(m,2H).

MS m/z(ESI)：651.1[M+H].

Example 147

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile

In a manner similar to that of example 11, starting from 7- [3- (2, 7-diaza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and an aqueous formaldehyde solution, sodium borohydride is reduced and aminated with a reducing agent to give the desired compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile (yellow solid, 10 mg).

¹H NMR(400MHz,CD₃OD):δ8.40(s,1H),7.91(s,1H),7.75(s,1H),7.57(s,1H),7.22(s,1H),4.02(s,3H),3.89(s,3H),3.60(s,2H),3.19(s,4H),2.63(m,4H),2.41(s,3H),1.85(t,J=4.8Hz,4H).

MS m/z(ESI)：551.2[M+H].

Example 148

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-2-yl ] -quinoline-3-carbonitrile

In a manner similar to example 11, starting from 7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-2-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and aqueous formaldehyde, sodium borohydride is reduced and aminated with a reducing agent to give the desired product 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-2-yl ] -quinoline-3-carbonitrile (yellow solid, 32 mg).

¹H NMR(400MHz,,CD₃OD):δ8.42(s,1H),8.32(s,1H),7.83(s,1H),7.57(s,1H),7.23(s,1H),7.21(d,J=3.2Hz,1H),6.53(d,J=3.2Hz,1H),4.12(s,3H),3.93(s,4H),3.90(s,3H),3.78(s,2H),2.90(s,3H),2.74–2.55(m,4H),1.95(t,J=5.2Hz,4H).

MS m/z(ESI)：593.2[M+H].

Example 149

7- [4- (2, 7-diaza-spiro [3.5] non-7-yl) -but-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using example compound 82 as a starting material, the synthesis method similar to that in example 4 was used to obtain the target compound 7- [4- (2, 7-diaza-spiro [3.5] non-7-yl) -but-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 26 mg) which was used without further purification.

MS m/z(ESI)：550.2[M+H].

Example 150

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -but-1-ynyl ] -quinoline-3-carbonitrile

Using a method similar to example 11, starting from 7- [4- (2, 7-diaza-spiro [3.5] non-7-yl) -but-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and an aqueous formaldehyde solution, the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [4- (2-methyl-2, 7-diaza-spiro [3.5] non-7-yl) -but-1-ynyl ] -quinoline-3-carbonitrile was obtained by reductive amination with sodium borohydride as a reducing agent (yellow solid, 6 mg).

¹H NMR(400MHz,CD₃OD):δ8.40(s,1H),7.87(s,1H),7.73(s,1H),7.57(s,1H),7.22(s,1H),4.01(s,3H),3.90(s,7H),2.89(s,3H),2.75(s,4H),2.60(dd,J=3.2,1.2Hz,4H),1.93(m,4H).

MS m/z(ESI)：565.2[M+H].

Example 151

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (7-oxa-2-aza-spiro [3.5] non-2-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile (yellow solid, 40 mg) was synthesized by a method analogous to the fourth step of example 141.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),7.96(s,1H),7.78(s,1H),7.57(s,1H),7.23(s,1H),4.02(s,3H),3.89(s,3H),3.78(s,2H),3.65–3.60(m,4H),3.49(s,4H),1.85–1.80(m,4H).

MS m/z(ESI)：538.1[M+H].

Example 152

2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-nia-drug

The title compound, 2- {3- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -prop-2-ynyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester (yellow solid, 15mg) was synthesized in a manner similar to the fourth step of EXAMPLE 141.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),7.96(s,1H),7.78(s,1H),7.58(s,1H),7.23(s,1H),4.03(s,3H),3.89(s,3H),3.71(s,2H),3.40(s,4H),3.38(s,4H),1.78–1.74(m,4H),1.44(s,9H).

MS m/z(ESI)：637.2[M+H].

Example 153

7- [3- (2, 7-diaza-spiro [3.5] non-2-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound 152 of example as a starting material, the synthesis method similar to that of example 4 was carried out to give the target compound 7- [3- (2, 7-diaza-spiro [3.5] non-2-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 5 mg).

¹H NMR(400MHz,CD₃OD):δ8.96(s,1H),8.21(s,1H),8.16(s,1H),7.69(s,1H),7.44(s,1H),4.58(s,2H),4.28(s,4H),4.15(s,3H),3.94(s,3H),3.26(dd,J=1.6,0.8Hz,4H),2.28–2.15(m,4H).

MS m/z(ESI)：537.2[M+H].

Example 154

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile

In a manner similar to that of example 11, starting from 7- [3- (2, 7-diaza-spiro [3.5] non-2-yl) -prop-1-ynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and aqueous formaldehyde, sodium borohydride is reduced and aminated with a reducing agent to give the desired compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile (yellow solid, 15 mg).

¹H NMR(400MHz,CD₃OD):δ8.43(s,1H),7.97(s,1H),7.79(s,1H),7.58(s,1H),7.23(s,1H),4.04(s,3H),3.90(s,3H),3.70(s,2H),3.40(s,4H),3.28–2.99(m,4H),2.78(s,3H),2.12–1.98(m,4H).

MS m/z(ESI)：551.2[M+H].

Example 155

2- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Starting from the intermediate compound of the first step of example 126 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-7-carboxylate, the title compound, tert-butyl 2- {4- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -furan-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylate (234 mg, yellow solid), was synthesized in a similar manner to example 142.

¹H NMR(400MHz,CDCl₃)：δ8.73(s,1H),8.19(s,1H),8.09(s,1H),7.52(s,1H),7.01(s,1H),6.73(s,1H),6.56(s,1H),3.85(s,3H),3.71(m,5H),3.33(t,J=5.6Hz,4H),3.17(s,4H),1.71(t,J=5.6Hz,4H),1.45(s,9H).

MS m/z(ESI)：679.2[M+H].

Example 156

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile

The title compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (2-oxa-7-aza-spiro [3.5] non-7-yl) -prop-1-ynyl ] -quinoline-3-carbonitrile (yellow solid, 29 mg) was synthesized by a method analogous to the fourth step of example 141.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),7.96(s,1H),7.78(s,1H),7.58(s,1H),7.23(s,1H),4.04(s,3H),3.89(s,3H),3.83(s,2H),3.54(s,4H),2.90(d,J=4.8Hz,4H),1.68–1.64(m,4H).

MS m/z(ESI)：538.1[M+H].

Example 157

7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 155 as a starting material, a target compound, 7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 80 mg) was synthesized by a method similar to example 144.

¹H NMR(400MHz,CD₃OD):δ8.42(s,1H),8.25(s,1H),8.06(s,1H),7.83(s,1H),7.57(s,1H),7.24(s,1H),6.99(s,1H)4.12(s,3H),3.91(s,3H),3.85(s,4H),3.74(s,2H),1.97(m,4H),1.29(m,4H).

MS m/z(ESI)：579.1[M+H].

Example 158

Using a synthesis method similar to that of example 144, starting from 7- [5- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and 35% formalin solution, sodium borohydride was reductively aminated as a reducing agent to give the desired compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(400MHz,CD₃OD)δ(ppm):8.43(s,1H),8.27(s,1H),8.07(s,1H),7.84(s,1H),7.59(s,1H),7.25(s,1H),7.00(s,1H)4.13(s,3H),3.95(s,3H),3.94(s,4H),3.74(s,2H),2.92(s,3H),1.98(m,4H),1.30(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 159

7- [5- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 155 as a starting material, a target compound, 7- [5- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 105mg) was synthesized by a method similar to example 144.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.72(s,1H),8.18(s,1H),8.07(s,1H),7.51(s,1H),6.98(s,1H),6.71(s,1H),6.54(s,1H),3.84(s,3H),3.68(m,5H),3.12(s,4H),2.75(t,J=5.6Hz,4H),1.72(t,J=5.6Hz,4H).

MS m/z(ESI)：579.2[M+H].

Example 160

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile

Using a synthesis method similar to that of example 144, starting from 7- [5- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile and 35% formalin solution, sodium borohydride was reductively aminated as a reducing agent to give the desired compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [5- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -furan-3-yl ] -quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.73(s,1H),8.20(s,1H),8.09(s,1H),7.52(s,1H),6.99(s,1H),6.77(s,1H),6.56(s,1H),3.84(s,3H),3.74(s,2H),3.70(s,3H),3.23(s,4H),2.41(s,3H),1.92(m,4H),1.28(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 161

E-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile

The first step is as follows: 6-vinyl-pyridine-2-carbaldehyde

6-bromo-pyridine-2-carbaldehyde (3.72 g, 20 mmol) and tetratriphenylphosphine palladium (1.16 g, 1 mmol) were put in a 50mL eggplant-shaped bottle, and argon gas was introduced thereinto. Tributylvinyltin reagent (6.43 mL,22 mmol) was slowly added to the system, the temperature was raised to 100 ℃ and the reaction was carried out for two days. Heating was stopped, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated by silica gel column chromatography to give 6-vinyl-pyridine-2-carbaldehyde (pale yellow liquid, 1.51 g).

MS m/z(ESI)：134[M+H].

¹H NMR(400MHz,CD₃OD)δ(ppm):10.08(s,1H),7.84(m,2H),7.57(m,1H),6.90(dd,J=17.4,10.8Hz,1H),6.34(d,J=17.44Hz,1H),5.60(d,J=10.8,1H).

The second step is that: e-4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [2- (6-carboxaldehyde-pyridin-2-yl) -vinyl ] -6-methoxy-quinoline-3-carbonitrile

6-vinyl-pyridine-2-carbaldehyde (382 mg, 2.87 mmol) and 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl trifluoromethanesulfonate (1.0 g, 1.91 mmol), palladium acetate (43 mg, 0.19 mmol) and triphenylphosphine (100 mg, 0.38 mmol) were suspended in acetonitrile (10 mL) and replaced by argon. Triethylamine (0.73 mL,2.87 mmol) was added to the system, the temperature was raised to 100 ℃ and the reaction was allowed to proceed overnight. Heating was stopped, the solvent was spun off under reduced pressure and purified by silica gel column chromatography to give 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [2- (6-carboxaldehyde-pyridin-2-yl) -vinyl ] -6-methoxy-quinoline-3-carbonitrile as a brown solid (450 mg).

MS m/z(ESI)：506[M+H].

¹H NMR(400MHz,CD₃OD)δ(ppm):10.15(s,1H),8.75(s,1H),8.36(s,1H),8.21(d,J=16.2Hz,1H),7.88(m,2H),7.66(m,1H),7.56(s,1H),7.52(m,1H),7.02(s,1H),6.58(s,1H),3.86(s,3H),3.71(s,3H).

The third step: (E) -7- (2- (6- ((7-oxa-2-aza-spiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) vinyl) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile

At room temperature, the E-4- (2, 4-dichloro-5-methoxy-phenylamino) -7- [2- (6-carboxaldehyde-pyridin-2-yl) -vinyl]-6-methoxy-quinoline-3-carbonitrile (60 mg, 0.119 mmol) and 7-oxa-2-aza-spiro [3.5]]Nonane hydrochloride (29 mg, 0.178 mmol) was dissolved in dichloromethane (5 mL), a drop of glacial acetic acid was added dropwise, and the mixture was stirred overnight. Reacting NaBH₃CN (23 mg) was carefully added to the system, and reacted for three hours. TLC showed the reaction was complete, and 5mL of water was added to quench the reaction. And (4) extracting and layering. The organic phase is separated off and the aqueous phase is extracted with a further 5mL of dichloromethane. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, removing solvent under reduced pressure, and purifying the residue by column chromatography to obtain (E) -7- (2- (6- ((7-oxa-2-aza-spiro [ 3.5))]Nonan-2-yl) methyl) pyridin-2-yl) vinyl) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile (N-methyl-N-ethyl-N-methyl-N-ethyl-N- (N-methyl-N-methylYellow solid, 31 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.63(s,1H),8.27(s,1H),8.01(d,J=16Hz,1H),7.72-7.74(m,1H),7.39-7.46(m,4H),7.12(s,1H),6.68(s,1H),4.31(s,2H),4.10-4.12(m,4H),3.87(s,3H),3.74(s,3H),3.58-3.60(m,4H),1.93-2.06(m,4H).

MS m/z(ESI)：616.5[M+H].

Example 162

E-7- (6- {2- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -vinyl } -pyridin-2-ylmethyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the second step of example 161 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the title compound, tert-butyl 6- {2- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -vinyl } -pyridin-2-ylmethyl) -2, 7-diaza-spiro [3.5] nonane-2-carboxylate (yellow solid, 80mg), was synthesized in a similar manner to the third step of example 161.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.74(s,1H),8.32(s,1H),8.00(d,J=16Hz,1H),7.61-7.75(m,1H),7.50-7.521(m,2H),7.35-7.37(m,2H),6.96(s,1H),6.84(s,1H),6.53(s,1H),3.83(s,3H),3.70(s,3H),3.69(s,2H),3.63(s,4H),2.48-2.52(m,4H),1.68-1.80(m,4H),1.44(s,9H).

MS m/z(ESI)：715.7[M+H].

Example 163

E-7- {2- [6- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound obtained in example 162 as a starting material, the synthesis method similar to that described in example 144 was carried out to give the target compound 7- {2- [6- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.30(s,1H),7.97(d,J=16Hz,1H),7.63-7.72(m,1H),7.49-7.51(m,2H),7.36-7.38(m,2H),6.98(s,1H),6.53(s,1H),3.83(s,3H),3.41-3.69(m,7H),3.03(s,2H),2.03-2.42(m,4H),1.77-1.84(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 164

E-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile

Using the compound obtained in example 163 and an aqueous solution of formaldehyde as starting materials, a target compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile (yellow solid, 40 mg) was synthesized in a similar manner to example 11.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.72(s,1H),8.31(s,1H),8.01(d,J=16Hz,1H),7.65-7.72(m,1H),7.49-7.51(m,2H),7.31-7.37(m,2H),6.93(s,1H),6.82(s,1H),6.51(s,1H),3.81(s,3H),3.69(s,3H),3.67(s,2H),3.61(s,4H),2.53(s,3H),2.47-2.51(m,4H),1.68-1.80(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 165

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile

By using the same synthesis method as in example 145, 6-bromo-pyridine-2-carbaldehyde was substituted for 5-bromo-pyridine-3-carbaldehyde and trimethylsilylacetylene was substituted for tributylvinyltin, to synthesize the objective compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile (yellow solid, 32 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.69(s,1H),8.21(s,1H),7.68-7.71(m,1H),7.47-7.52(m,2H),7.23(d,J=8.0Hz,1H),7.02(s,1H),6.63(s,1H),4.43(s,4H),3.82(s,3H),3.79(s,3H),3.70(s,2H),1.87-2.01(m,4H),1.78-1.81(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 166

7- {6- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-ylethynyl ] -pyridin-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester

Starting from the intermediate 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (6-carboxaldehyde-pyridin-2-ylethynyl) -6-methoxy-quinoline-3-carbonitrile from example 165 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-2-carboxylate, the title compound 7- {6- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-ylethynyl ] -pyridin-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-2-carboxylate was synthesized in a manner analogous to the third step of example 145 in the form of a yellow solid, 40 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.69(s,1H),8.22(s,1H),7.68-7.70(m,1H),7.47-7.51(m,2H),7.25(d,J=8.0Hz,1H),7.06(s,1H),6.60(s,1H),4.11(s,3H),3.83(s,3H),3.63(s,2H),3.60(s,4H),2.39-2.52(m,4H),1.74-1.77(m,4H),1.43(s,9H).

MS m/z(ESI)：613.6[M+H-Boc].

Example 167

7- [6- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using example 166 as a starting material, the synthesis method similar to example 4 was used to obtain the target compound 7- [6- (2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 15 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.31(s,1H),7.97(d,J=8.0Hz,1H),7.48-7.51(m,1H),7.35-7.37(m,2H),6.99(s,1H),6.55(s,1H),3.85(s,3H),3.79(s,3H),3.69(s,2H),3.44(s,4H),2.19-2.22(m,4H),1.83-1.85(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 168

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile

Using the compound obtained in example 167 and an aqueous solution of formaldehyde as starting materials, a target compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (2-methyl-2, 7-diaza-spiro [3.5] non-7-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile (yellow solid, 20 mg) was synthesized in a similar manner to that of example 11.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.25(s,1H),7.68-7.71(m,1H),7.50-7.52(m,2H),7.45-7.47(d,J=8.0Hz,1H),7.05(s,1H),6.59(s,1H),3.83(s,3H),3.72(s,3H),3.64(s,2H),3.30(s,4H),2.73-2.75(m,4H),2.49(s,3H),1.80-1.83(m,4H).

MS m/z(ESI)：627.3[M+H].

Example 169

E-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile

Using the intermediate compound obtained in the second step of example 161 and 2-oxa-7-aza-spiro [3.5] nonane as starting materials, the title compound, E-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (2-oxa-7-aza-spiro [3.5] non-7-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile, was synthesized in a similar manner to the third step of example 161 (yellow solid, 30 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.31(s,1H),7.94(s,1H),7.68-7.72(m,1H),7.49-7.51(m,2H),7.37-7.45(m2H),6.96(s,1H),6.55(s,1H),4.33(s,4H),3.83(s,3H),3.70-3.76(m,5H),2.21-2.24(m,4H),1.94-2.04(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 170

E-2- (6- {2- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -vinyl } -pyridin-2-ylmethyl) -2, 7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Starting from the intermediate compound obtained in the second step of example 161 and 2, 7-diaza-spiro [3.5] nonane, the title compound, tert-butyl 2- (6- {2- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-yl ] -vinyl } -pyridin-2-ylmethyl) -2, 7-diaza-spiro [3.5] nonane-7-carboxylate (yellow solid, 70 mg), was synthesized in a similar manner to the third step of example 161.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.33(s,1H),8.00(d,J=16Hz,1H),7.67-7.71(m,1H),7.49-7.52(m,2H),7.35(s,1H),7.25(d,J=8.0Hz,1H),7.00(s,1H),6.54(s,1H),3.89(s,2H),3.85(s,3H),3.68(s,3H),3.21(s,4H),2.62-2.69(m,4H),1.86-1.89(m,4H),1.43(s,9H).

MS m/z(ESI)：593.1[M+H].

Example 171

E-7- {2- [6- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-yl ] -vinyl } -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 170 as a starting material, the synthesis method similar to that of example 4 was used to obtain the target compound 7- {2- [6- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-yl ] -vinyl } -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 20 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.73(s,1H),8.32(s,1H),8.00(d,J=16Hz,1H),7.65-7.70(m,1H),7.49-7.52(m,2H),7.31-7.33(m,1H),7.23-7.25(m,1H),6.93(d,J=16Hz,1H),6.53(s,1H),3.86(s,2H),3.82(s,3H),3.69(s,3H),3.18(s,4H),2.78(t,J=4.8Hz,4H),1.77(t,J=4.8Hz,4H).

MS m/z(ESI)：615.2[M+H].

Example 172

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile

Using the compound obtained in example 171 and an aqueous solution of formaldehyde as starting materials, a target compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- {2- [6- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-yl ] -vinyl } -quinoline-3-carbonitrile (yellow solid, 18 mg) was synthesized in a similar manner to example 11.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.72(s,1H),8.32(s,1H),8.00(d,J=16Hz,1H),7.65-7.70(m,1H),7.45-7.52(m,2H),7.37(s,1H),7.24(d,J=8.0Hz,1H),6.99(s,1H),6.56(s,1H),3.89(s,2H),3.83(s,3H),3.70(s,3H),3.22(s,4H),2.62-2.70(m,4H),2.29(s,3H),1.86-1.89(m,4H).

MS m/z(ESI)：629.1[M+H].

Example 173

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile

Starting from the intermediate 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (6-carboxaldehyde-pyridin-2-ylethynyl) -6-methoxy-quinoline-3-carbonitrile from example 165 and 7-oxa-2-aza-spiro [3.5] nonane, the title compound 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (7-oxa-2-aza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile (yellow solid, 30 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.66(s,1H),8.23(s,1H),7.76(d,J=8.0Hz,1H),7.58-7.62(m,2H),7.50(s,1H),7.11(s,1H),6.66(s,1H),4.17(s,2H),3.85(s,3H),3.74(s,3H),3.68(s,4H),1.87-1.90(m,4H).

MS m/z(ESI)：593.1[M+H].

Example 174

2- {6- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-ylethynyl ] -pyridin-2-ylmethyl } -27-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester

Starting from the intermediate 4- (2, 4-dichloro-5-methoxy-phenylamino) -7- (6-carboxaldehyde-pyridin-2-ylethynyl) -6-methoxy-quinoline-3-carbonitrile from example 165 and tert-butyl 2, 7-diaza-spiro [3.5] nonane-7-carboxylate, the title compound, tert-butyl 2- {6- [ 3-cyano-4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinolin-7-ylethynyl ] -pyridin-2-ylmethyl } -2, 7-diaza-spiro [3.5] nonane-7-carboxylate (yellow solid, 120 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.68(s,1H),8.22(s,1H),7.70(t,J=8.0Hz,1H),7.49-7.51(m,2H),7.39(d,J=8.0Hz,1H),7.20(s,1H),7.05(s,1H),6.59(s,1H),3.87(s,2H),3.80(s,3H),3.70(s,3H),3.31-3.33(m,4H),3.18-3.24(m,4H),1.70-1.72(m,4H),1.44(s,9H).

MS m/z(ESI)：713.6[M+H].

Example 175

7- [6- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile

Using the compound of example 174 as a starting material, the synthesis method similar to example 4 was carried out to give the objective compound 7- [6- (2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 40 mg).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.71(s,1H),8.25(s,1H),7.72(t,J=8.0Hz,1H),7.51-7.53(m,2H),7.40(d,J=8.0Hz,1H),7.19(s,1H),7.04(s,1H),6.57(s,1H),3.85(s,2H),3.82(s,3H),3.65(s,3H),3.29-3.32(m,4H),3.14-3.23(m,4H),1.71-1.74(m,4H),

MS m/z(ESI)：593.1[M+H].

Example 176

4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile

Using the compound obtained in example 175 and an aqueous solution of formaldehyde as starting materials, a target compound, 4- (2, 4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [6- (7-methyl-2, 7-diaza-spiro [3.5] non-2-ylmethyl) -pyridin-2-ylethynyl ] -quinoline-3-carbonitrile (yellow solid, 20 mg) was synthesized in a similar manner to example 11.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.67(s,1H),8.24(s,1H),7.71(t,J=8.0Hz,1H),7.49-7.52(m,2H),7.38(d,J=8.0Hz,1H),7.22s,1H),7.03(s,1H),6.58(s,1H),3.85(s,2H),3.76(s,3H),3.64(s,3H),3.30-3.35(m,4H),3.18-3.24(m,4H),2.51(s,3H),1.70-1.72(m,4H).

MS m/z(ESI)：593.1[M+H].

Test example

Test example kinase inhibition test

The kinase inhibitory activity assay described in this test example was performed to determine the in vitro inhibitory activity of the compounds of the present invention against kinases such as c-Src, Bcr-Abl, EGFR and the like, and the inhibitory activity of the test compounds against the enzymatic activity of kinases was determined by the half inhibitory concentration: IC (integrated circuit) ₅₀A value. The assay uses homogeneous time-resolved fluorescence (HTRF) technology for determination, and the method comprises the following steps: incubating a series of concentration gradients of test compound with an enzyme solution of a specific concentration for 5 minutes at room temperature; then the appropriate amount of enzyme reaction substrate is added: ATP, the initiation of the enzymatic reaction process; after 30 minutes, adding a proper amount of reaction stopping solution and detection solution into an enzyme reaction system; after incubation for 1 hour, determining the enzyme activity under specific compound concentration on a Flexstation III multifunctional enzyme-labeling instrument of Molecular device company, and calculating the inhibitory activity of compounds with different concentrations on the enzyme activity; then fitting the inhibitory activity of the enzyme activity under compounds with different concentrations according to a four-parameter equation, and calculating IC₅₀The value is obtained. Kinase c used in this test exampleSrc, Bcr-Abl were purchased from Carna biosciences, inc, EGFR was purchased from Sigma Aldrich, and used in HTRF assay was the detection kit HTRF kinase-TK (purchased from Cisbio Bioassays) and ATP was purchased from Sigma Aldrich.

1. IC for kinase inhibitory Activity of Compounds of the present invention₅₀Value is represented by, wherein IC₅₀<10nM is represented by the symbol +++; 10nM<IC₅₀<100nM is represented by the symbol +++; 100nM <IC₅₀<500nM is denoted by the symbol + +; IC (integrated circuit)₅₀>500nM is indicated by the + sign; ND means not tested.

The kinase inhibitory activity results for some of the examples are shown in the following table:

examples

IC₅₀(EGFR)

IC₅₀(Bcr-Abl)

IC₅₀(c-Src)

Examples

IC₅₀(EGFR)

IC₅₀(Bcr-Abl)

IC₅₀(c-Src)

1

+++

++++

31

+++

++++

2

+++

++++

33

+++

++++

4

+++

++++

34

+++

++++

6

++++

35

++

++++

7

++

++++

36

+++

++++

8

+++

++++

39

+++

++++

9

++

++++

40

++

++++

10

++++

43

+++

++++

11

++++

44

++

++++

12

+++

++++

45

+++

++++

14

+++

++++

46

++

++++

17

++

++++

49

++

++++

19

+++

++++

50

+++

++++

20

+++

++++

51

+++

++++

22

++

++++

52

++

+

25

+++

++++

53

++++

+++

26

+++

++++

54

++

++++

28

+++

++++

57

+++

++++

29

+++

++++

58

++

+++

++

30

+++

++++

59

++

Examples

IC₅₀(EGFR)

IC₅₀(Bcr-Abl)

IC₅₀(c-Src)

Examples

IC₅₀(EGFR)

IC₅₀(Bcr-Abl)

IC₅₀(c-Src)

61

+

99

+

++++

62

++

+

100

++++

+++

++

64

++

++++

101

++++

+++

++

65

++++

+++

102

+++

++++

66

++++

+++

103

++++

+++

69

++++

+++

++

104

++++

+++

++

70

++++

+++

105

+++

++++

71

++++

+

106

++

++++

72

++++

+

108

++

++++

74

++++

++

109

++

+++

75

+++

+

111

++++

+

77

++

+

114

++

+++

++++

86

+

+++

++

115

+++

++++

89

++

+

116

++

++++

90

++

+

117

+++

++++

93

++++

+

118

++++

94

+

++++

119

++

++++

95

+++

++++

120

++

++++

97

++

++++

121

++

++++

98

++

++++

122

++

++++

Examples

IC₅₀(EGFR)

IC₅₀(Bcr-Abl)

IC₅₀(c-Src)

Examples

IC50(EGFR)

IC50(Bcr-Abl)

IC50(c-Src)

124

+++

++++

156

ND

++++

125

++++

157

ND

++++

126

ND

++++

158

ND

++++

127

ND

++

+++

159

ND

++++

128

ND

+

160

ND

++++

133

ND

++++

161

ND

++++

134

ND

++++

162

ND

+++

135

ND

++++

163

ND

++++

137

ND

+++

164

ND

++++

139

ND

+

165

ND

++++

140

ND

++++

+++

166

ND

+++

141

ND

+++

167

ND

++++

142

ND

+++

168

ND

++++

144

ND

++++

169

ND

++++

145

ND

++++

170

ND

+++

146

ND

++++

171

ND

++++

147

ND

++++

172

ND

++++

148

ND

++++

173

ND

++++

149

ND

++++

174

ND

+++

150

ND

++++

175

ND

++++

151

ND

++++

176

ND

++++

153

ND

++++

154

ND

++++

2. The compounds of the present invention have certain inhibitory activity against a plurality of kinases, and the inhibitory activity against each of the different kinases in some of the examples is shown below (the inhibitory activity is represented by the inhibition rate of the test compound at a concentration of 1 micromole against the different kinases, wherein the inhibition rate is less than 75% and + is used, and the inhibition rate is more than 75% and + + is used).

Test example two cell inhibition test

The cell growth inhibitory activity test described in this test example was conducted to determine the present inventionThe proliferation inhibitory activity of the compounds on highly expressed cell lines such as EGFR, Bcr-Abl, etc. the inhibitory activity of the test compounds on cell proliferation is determined by the half inhibitory concentration: IC (integrated circuit)₅₀To indicate. The protocol for this type of test is as follows: selecting different cells, such as K-562 cells, A431 cells, A549 cells, DU145 cells, H1650 cells, H1975 cells (cells purchased from China academy of sciences type culture Collection cell Bank/China academy of sciences Shanghai Life sciences cell resource center), and inoculating the cells on white opaque 384-well culture plates at a suitable cell concentration (eg.25000 cells/ml medium); the cells were then placed at 37 ℃ in 5% CO ₂Culturing in the environment of (1); after 24 hours, a series of concentration gradients of drug, typically 10 concentrations, were added to the cultured cell culture medium; the cells were then returned to the original culture environment for further culture for 48 hours, after which the effect of the test compound on the proliferation of different cells was determined and the inhibitory activity of compounds at different concentrations on the proliferation of cells was calculated according to the method of CellTiter-Glo luminescennt Cell Viability Assay. (CellTiter-Glo Luminescent CellViability Assay reagent purchased from Promega); then, four-parameter fitting is carried out on the cell proliferation inhibition activity under different concentrations of compounds, and IC is calculated₅₀And (4) data.

1. The compounds of the present invention have activity of inhibiting K562 cell proliferation, and the results of cell proliferation inhibitory activity of some examples are shown below (IC for inhibitory activity)₅₀Value is represented by, wherein IC₅₀<100nM is represented by the symbol +++; 100nM<IC₅₀<500nM is denoted by the symbol + +; IC (integrated circuit)₅₀>500nM in + sign).

Examples	IC₅₀(nM)	Examples	IC₅₀(nM)	Examples	IC₅₀(nM)	Examples	IC₅₀(nM)	Examples	IC₅₀(nM)
										1	+++	43	+++	93	+	126	+++	154	+++
2	+	44	++	94	++	127	++	155	++
										4	++	45	++	95	++	128	+	156	+++
6	++	46	+++	97	+	129	+	157	+++
										7	++	49	++	98	++	130	+	158	+++
8	+++	50	+++	99	++	131	+	159	+++
										9	++	51	++	100	+	132	+	160	+++
10	+++	52	+	101	+	133	++	161	+++
										11	++	55	++	102	+++	134	++	162	+
12	++	56	++	103	+	135	++	163	+++
										14	++	57	++	104	+	136	+	164	+++
15	++	58	+	105	+	137	+	165	+++
										16	++	59	+	106	+	138	+	166	+
17	++	61	+	108	+	139	+	167	+++
										20	++	62	+	109	+	140	+	168	+++
22	++	64	++	110	+	141	+	169	+++
										23	++	65	+	114	++	142	+	170	+
26	++	69	+	115	++	143	+	171	+++
										29	++	70	+	116	++	144	+	172	+++
30	++	71	+	117	++	145	++	173	+++
										31	++	72	+	118	++	146	++	174	+
33	++	74	+	119	+++	147	+++	175	+++
										34	++	75	+	120	+++	148	++	176	+++
35	++	77	+	121	+++	149	+++
										36	++	81	++	122	+++	150	+++
39	++	89	+	123	++	151	++
										40	++	90	+	125	++	153	++

2. The compounds of the present invention have inhibitory activities against proliferation of a431, DU145, a549, H1650, H1975 and other cell lines, and the inhibitory activities against proliferation of various cell lines in some examples are shown below (inhibitory activity IC) ₅₀<5 μ M in ++, IC₅₀>5 μ M is represented by + and not tested for ND).

Examples	A431	DU145	A549	H1650	H1975
						4	++	++	ND	ND	ND
8	++	++	ND	ND	ND
						25	++	++	ND	ND	ND
51	++	++	ND	ND	ND
						65	++	++	ND	ND	ND
70	++	++	ND	ND	ND
						119	+	ND	ND	ND	++
121	+	ND	++	ND	ND
						127	+	ND	ND	ND	++
128	+	ND	ND	ND	++
						136	+	ND	ND	++	ND
137	+	ND	++	+	++

Test example three pharmacokinetic evaluations

Pharmacokinetic testing of the compounds of the invention: the rats are used as test animals, the LC/MS/MS method is used for measuring the drug concentration in plasma of the rats at different moments after the rats are respectively administered with the compound of the embodiment by gastric perfusion and intravenous injection, the pharmacokinetic behavior of the compound in the rats is researched, and the pharmacokinetic characteristics of the compound are evaluated.

The experimental scheme is as follows: the test animals are healthy adult male SD rats provided by Shanghai Sepalybika laboratory animals Co., Ltd; administration mode and sample collection: respectively administering the test compound to SD rats by intravenous injection and intragastric administration, and taking blood from rat fundus venous plexus 2, 5, 15, 30, 60, 90, 120, 240, 360, 480 and 1440min before and after administration; adding the plasma sample into acetonitrile solution containing internal standard to precipitate protein, vortexing for 10min, and centrifuging at 6000g for 10 min; taking 6000g of supernatant, and centrifuging for 10min again; taking 75 mu L of supernatant, adding a gradient initial mobile phase for dilution, and centrifuging at 6000g for 10 min; and finally, sampling 70 mu L of the supernatant in a 96-well plate, wherein the sampling amount is 5 mu L, and performing LC-MS-MS analysis.

The pharmacokinetic parameters of some examples of the invention are shown below, and the results show that the compound of the invention has better pharmacokinetic properties in rats.

Examples	1	46	102	103	109	121
							Half-life T1/2(min)	708	165	455	235	165	287
Oral bioavailability F	17%	24%	30%	16%	17%	13%

Meanwhile, in the experimental process, the compound of each embodiment has good tolerance of tested animals under the condition of high-dose intragastric administration (150 mg/kg-250 mg/kg), and has no obvious weight loss (the weight fluctuation is less than +/-20 percent after single administration or continuous multiple administrations) and other common clinical adverse reactions (such as diarrhea, rash and the like), which indicates that the compound of the embodiment has better safety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof:

wherein,

a is selected from O, N or S (O)_m；

Ar is selected from aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more of the following substituents: halogen, alkyl, cycloalkyl, heterocyclyl, heterocyclyloxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, cycloalkyloxy, heterocyclyloxy, nitro, cyano, hydroxy, alkenyl, alkynyl, amino or substituted amino, hydroxyalkyl, carboxy, aryl, arylalkyl, cycloalkylalkyl, arylalkoxy, heteroarylalkoxy, ureido, said substituents being optionally substituted with one or more of the following groups: halogen, alkyl, cycloalkyl; alternatively, the aryl or heteroaryl groups may form a fused or fused ring with a saturated or partially unsaturated alkyl or heteroalkyl group;

R₁selected from H, halogen, nitro, amino, substituted amino, cyano, hydroxy, optionally substituted: alkyl, cycloalkyl, heterocyclyl, alkoxy, cycloalkoxy, heterocyclylalkoxy, heterocyclyloxy, aryl, and heteroaryl;

Linker is selected from alkoxy, alkylamino, heterocyclyl, cycloalkylalkoxy, aryl, aralkyl, heteroarylalkoxy, alkenyl, alkynyl, alkylheteroaryl, acylalkenyl, alkylheteroarylalkynyl, alkylheteroarylalkenyl; and the above groups may be substituted with one or more substituents such as halogen, nitro, cyano, hydroxy, alkanoyl, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxy, carboxylate, amido, aryl or heteroaryl, respectively;

ring A is selected from a saturated or partially unsaturated spiro, bridged or fused ring having two rings;

R₂selected from the group consisting of H, halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, amino or substituted amino, alkoxy, cycloalkoxy, heterocyclylalkyl, heterocycloalkoxy, hydroxyalkyl, acyl, carboxy, carboxylate, amide, alkoxyacyl, alkenoxyacyl, alkoxyacylalkyl, cycloalkylacyl, heterocyclylacyl, oxo, aryl or heteroaryl;

ar and R are as defined above₁、Linker、R₂Alkyl groups as defined in (1) alone or in combination are selected from C _1-6Alkyl, cycloalkyl selected from C_3-6Cycloalkyl, alkynyl selected from C_2-6Alkynyl, alkenyl selected from C_2-6Alkenyl, alkoxy is selected from C_1-6Alkoxy, alkyl acyl selected from C_1-6Alkyl acyl, aralkyl selected from monocyclic or bicyclic aryl-C_1-6Alkyl, aryl is monocyclic or bicyclic aryl, heterocyclyl is heterocyclyl with 3-6 ring atoms, heteroaryl is monocyclic or bicyclic heteroaryl, said heterocyclyl or heteroaryl having 1, 2, 3 heteroatoms selected from nitrogen, oxygen, sulfur; and

m is 0 to 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein linker and R in formula I₁Respectively to the 6 and 7 or 7 and 6 positions of the quinoline ring.

3. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein Ar is selected from the following structures:

wherein,

heteroaryl is selected from monocyclic or bicyclic heteroaryl having 1-3 heteroatoms;

ra and Rb are selected from hydrogen, halogen, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C _2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, cyano, monocyclic or bicyclic aryl-C_1-6Alkyl radical, C_3-6Cycloalkyloxy radical, C_3-6cycloalkyl-C_1-6Alkoxy, amino, mono C_1-6Alkylamino, di-C_1-6Alkyl radicalAmino, optionally substituted by C_3-6Cycloalkyl-substituted ureido, heterocyclyloxy having 3 to 6 ring atoms;

r and R' are the same or different and are independently selected from hydrogen, optionally substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl, monocyclic or bicyclic aryl-C_1-6An alkyl group;

rx and Ry are independently selected from optionally substituted C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, monocyclic or bicyclic aryl-C_1-6An alkyl group;

each of the above groups may be optionally substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C_1-6Alkyl radical, C_3-6Cycloalkyl, monocyclic or bicyclic heterocyclic radical having 3 to 6 ring atoms, C_2-6Alkenyl radical, C_2-6Alkynyl, amino or substituted amino, C_1-6Alkoxy radical, C_3-6Cycloalkoxy, mono-or bicyclic heterocycloxy having 3 to 6 ring atoms, hydroxy C_1-6Alkyl, carboxyl, carboxylate, amido, monocyclic or bicyclic aryl or heteroaryl;

The above heterocyclic group or heteroaryl group has 1 to 3 hetero atoms;

the heteroatoms are selected from oxygen, sulfur and nitrogen;

w represents the number of substituents Ra and Rb selected from 0,1,2,3,4, 5;

x is selected from one or more of halogen, cyano, amino and hydroxy; and

v and v' represent the number of substituents X selected from 0,1,2,3, 4;

Z₁and Z₂Independently selected from 1,2,3 and 4.

4. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is selected from the following structures:

wherein

m, n, p, q = an integer of 1-6, and

b is selected from at least one of O, C, N and S, and when B is a C atom or an N atom, it is optionally substituted with one or more substituents selected from the group consisting of: hydrogen, halogen, nitro, cyano, hydroxy, mercapto, C_1-6Alkyl acyl radical, C_2-6Alkenyl acyl, C_1-6Alkoxyacyl group, C_3-6Cycloalkyl acyl, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino radical, C_3-6Cycloalkyl, heterocycloyl having 3-6 ring atoms, oxo, C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclyl having 3 to 6 ring atoms, C _2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkoxy, C_3-6Heterocyclic alkoxy, hydroxy C_1-6Alkyl, carboxyl, carboxylate, C_1-6Alkylamido, monocyclic or bicyclic aryl or heteroaryl; the above substituents are optionally substituted with one or more of the following groups: hydroxy, halogen, cyano, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino, heterocyclyl having 3 to 6 ring atoms, monocyclic or bicyclic aryl or heteroaryl; all of the above heterocyclic or heteroaryl groups have 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen atoms.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, characterized in that the ring a may have separately introduced unsaturated bonds, forming a partially unsaturated spiro, fused or fused ring.

6. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is selected from the following structures:

7. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, in formula I, R is₁Selected from the following structures:

wherein Rm₁，Rm₂，Rm₃,Rm₄And Rm₅Each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclyl having 3 to 6 ring atoms, C_2-6Alkenyl radical, C_2-6Alkynyl, amino or substituted amino, C_1-6Alkoxy radical, C_3-6Cycloalkoxy, heterocyclic radical-C_1-6Alkoxy, hydroxy C_1-6Alkyl, carboxyl, carboxylate, C_1-6Alkylamido, monocyclic or bicyclic aryl or heteroaryl; the above heterocyclic group has 3 to 6 ring atoms, and the heterocyclic group or heteroaryl group has 1 to 3 hetero atoms selected from nitrogen, oxygen, sulfur; rm₄And Rm₅Can form a 5-10 membered heterocyclic group together with the N atom to which it is attached; r is selected from 1, 2, 3, 4, 5 and 6.

8. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate thereofA prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, in formula I, R₁A structure selected from:

-OCH₃、-OCH₂CH₃、-OCD₃、-OH、

9. A compound of formula I according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, in formula I, R₂Selected from the following structures:

wherein Rc can be respectively selected from one or more of H, oxo, halogen, nitro, cyano, hydroxyl and C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclyl, C_2-6Alkenyl radical, C_2-6Alkynyl, amino or substituted amino, C_1-6Alkoxy radical, C_3-6Cycloalkoxy, heterocyclic radical-C_1-6Alkoxy, hydroxy-C_1-6Alkyl, carboxyl, carboxylic ester, amide, mono-or bicyclic aryl or heteroaryl, wherein the above heterocyclic group has 3 to 6 ring atoms, and the heterocyclic or heteroaryl group has 1 to 3 hetero atoms selected from nitrogen, oxygen, sulfur.

10. A compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, in formula I, R is₂A group selected from one or more of: hydroxy, halogen, cyano, mercapto, C_1-6Alkyl acyl radical, C_2-6Alkenyl acyl, C_1-6Alkoxyacyl group, C_3-6Cycloalkyl acyl, ammonia Radical, mono C_1-6Alkylamino, di-C_1-6Alkylamino radical, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkyl, heterocycloyl, oxo, said groups being optionally substituted with one or more of the following substituents: hydroxy, halogen, cyano, mercapto, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino, heterocyclyl, monocyclic or bicyclic aryl or heteroaryl, said heterocyclyl having 3 to 6 ring atoms, and said heterocyclyl or heteroaryl having 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur.

11. A compound of general formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof according to any preceding claim, wherein, in formula I, R₂A group selected from one or more of: -OH, fluorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclopropylformyl, cyclobutyl, tert-butoxycarbonyl, acetyl, levulinyl, methoxycarbonyl,Oxo, oxo,

A dimethylamino group.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein linker is represented by-XQ, wherein X is selected from oxygen, sulphur, nitrogen, unsaturated bonds, aryl, heteroaryl, and Q is selected from one or more of the following: alkyl, cycloalkylalkyl, alkylcycloalkylalkyl, acylalkyl, alkylacyl, alkanoylalkyl, acylheteroaralkyl Arylalkyl, alkylheteroarylacyl, acyl, heteroaryl, alkylheteroaryl, acylalkenyl, heteroarylalkyl, the alkyl radicals mentioned being, individually or in combination, C_1-6Alkyl, alkenyl being C_2-6Alkenyl, alkynyl being C_2-6Alkynyl, cycloalkyl being C_3-6Cycloalkyl, alkoxy being C_1-6Alkoxy, aryl or heteroaryl being monocyclic or bicyclic aryl or heteroaryl, heterocyclyl being heterocyclyl having 3-6 ring atoms, heterocyclyl or heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulphur; and linker is attached to the quinoline ring by X.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein in formula I linker is represented by-XQ, wherein

When X is selected from oxygen, sulfur or nitrogen, Q is selected from one or more of the following groups: alkyl, alkanoyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylaryl, alkylarylacyl, alkylheteroaryl, alkylheteroarylacyl, said groups being optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, alkoxy and alkanoyl groups, and linker is attached to the quinoline ring via X; or

When X is selected from unsaturated bonds, aryl and heteroaryl, Q is selected from one or more of the following groups: alkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and linker is attached to the quinoline ring through X;

alkyl radicals present individually or in combination in the above radical definitions are C_1-6Alkyl, alkenyl being C_2-6Alkenyl, alkynyl being C_2-6Alkynyl, cycloalkyl being C_3-6Cycloalkyl, alkoxy being C_1-6Alkoxy, heteroaryl is monocyclic or bicyclic heteroaryl, heterocyclyl is heterocyclyl having 3-6 ring atoms, said heterocyclyl or heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur; the unsaturated bond is a double bond or a triple bond.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein in formula I the linker is selected from the following structures:

the oxygen atoms in the above groups are linked to the quinoline ring;

the benzene ring is directly connected with the quinoline ring;

the alkynyl is directly connected with the quinoline ring;

the alkynyl is directly connected with the quinoline ring;

the double bond is directly connected with the quinoline ring;

the furan ring is linked to the quinoline ring.

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein said compound has the structure:

。

16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, and a pharmaceutically acceptable carrier, excipient, or adjuvant.

17. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, for the manufacture of a protein kinase inhibitor, wherein the protein kinase is selected from at least one of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr-Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LYNA, FGR, EphB, ECK, FYN, MAP4K, SIK, MST1, YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3, RET, FGFR, PDK, Syk.

18. Use of a compound of any one of claims 1-15, and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphs, or metabolites thereof, for the manufacture of a medicament for the treatment or prevention of a tumor.

19. The use according to claim 18, wherein the tumor is at least one selected from leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous lung cancer, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer and oral cancer.