WO2013170774A1

WO2013170774A1 - Acetylene derivative having antineoplastic activity

Info

Publication number: WO2013170774A1
Application number: PCT/CN2013/075753
Authority: WO
Inventors: 万惠新; 李春丽; 韩雅男; 周兆丽; 马珂; 刘海燕; 张乐多
Original assignee: 上海医药集团股份有限公司
Priority date: 2012-05-16
Filing date: 2013-05-16
Publication date: 2013-11-21
Also published as: CN103420977B; CN103420977A; CN103421005A; WO2013170770A1

Abstract

The present invention relates to an aromatic ring disubstituted acetylene derivative of formula I, a pharmaceutical composition comprising the compound, and a use of the compound and of the pharmaceutical composition in the treatment and/or prevention of tumors, where A, B, T, M, Ra, Rb, Rt, m, n, and p are as defined in the present document.

Description

Ethylene block derivatives with antitumor activity

The present invention relates to an ethylene block derivative, particularly an aromatic ring disubstituted ethyl block derivative having antitumor activity, a pharmaceutical composition comprising the same, and the use of the compound and the pharmaceutical composition for treating and/or preventing a tumor. Background technique

In recent years, the incidence of cancer diseases in the world is on the rise. According to statistics from the World Health Organization, in 2007, the number of newly diagnosed tumor patients has reached more than 12 million. Malignant tumors (cancers) are the main cause of human death. One of the symptoms. It is estimated that by 2020, the number of new cases worldwide will reach 15 million per year. According to the US IMS Healath data: In 2007, among the top 500 drugs in the world's seven major pharmaceutical markets, the market share of targeted anti-tumor drugs has reached more than 20 billion US dollars, an increase of 27.05% over the same period of the previous year, far higher than the global resistance. The cancer drug market has a growth rate of 19.94%. In 2008, despite the impact of the international financial crisis, the pharmaceutical market continued to show strong growth in the anti-tumor drug market, driven by rigid demand and inertia, reaching US$48.189 billion, an increase of 15.54% year-on-year. Among them, the targeted anti-cancer drug market was in a leading position with sales of US$29 billion, an increase of 45% over the same period of the previous year. Market analysts predict that by 2015, anti-tumor targeted therapies will exceed $50 billion, with compound annual growth rates of 11%, and more than eight new drugs in the field will grow into "blockbuster" products.

With the successful development and market launch of some novel tyrosine protein kinase inhibitor-targeted anti-tumor drugs, anti-tumor drugs are moving from traditional non-selective single cytotoxic drugs to new mechanisms targeting multiple mechanisms The development of oncology drugs, research and development of anti-tumor drugs has entered a new era. Molecular targeted therapy of tumors is a therapeutic approach based on the selective killing of tumor cells by chemical or biological means of key protein molecules closely related to tumor growth. It is characterized by specificity, pertinence and effectiveness, and patients are well tolerated, and the side effects are much lower than traditional chemotherapy drugs; when combined, it can enhance the efficacy of traditional radiotherapy and chemotherapy, and reduce postoperative recurrence. Currently, imatinib, erlotinib, sunitinib, gefitinib, sorafenib, dasatinib, lapatinib and nilotinib in anti-tumor small molecule targeted drugs It is already the main breed in the clinic.

However, the resistance of protein kinase inhibitors encountered during clinical use has attracted much attention. More protein-targeted drugs in the morning have had serious consequences for treatment failure due to drug resistance. Therefore, research on drug resistance mechanisms and their overcoming methods has become one of the key points in the research of targeted kinase drugs. The drug resistance mechanisms of protein kinase-targeted drugs have been clarified: secondary mutations in the kinase itself; compensatory effects of other kinase signaling pathways; other target-independent mechanisms such as high expression of drug resistance genes.

Imatinib (trade name: Gleevec) is the first small molecule protein kinase inhibitor to be used in the treatment of chronic myeloid leukemia, and is known as a milestone in molecular targeted therapy for tumors. Subsequently, the US FDA approved the second application of imatinib for the treatment of gastrointestinal stromal tumors. After extensive clinical use worldwide, it has been highly praised by the medical community. On December 23, 2002, it was officially recognized by the US FDA. It was approved as a first-line treatment for chronic myeloid leukemia, and it has been praised by the medical community as "sometimes in recent years." A major breakthrough "anti-tumor targeted small molecule oral pharmaceutical preparation. Imatinib has been approved for use as a rare disease in countries such as the United States, the European Union, and Japan, and has been approved for use in chronic myeloid leukemia in more than 80 countries around the world, and is also approved for use in many developed and developing countries. Treatment of gastrointestinal stromal cell tumors. Imatinib inhibits Abl non-receptor tyrosine kinase activity and is a first-line treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), but patients with relapse after treatment often develop severe resistance to it. Sex. Molecular pathology studies revealed that its resistance mechanisms include: 1) Abl kinase mutations, accounting for 35%-45% of patients with overall resistance. 2) The compensatory effect of the Src family kinase pathway accounts for 30%-50% of the overall drug resistance. Patients with advanced tumors may activate the Src family kinase pathway, further promoting disease progression, resulting in a reduced dependence on the original BCR-Abl kinase pathway. In Imatinib-sensitive tumors, Src family members Src, Lyn, and Hck are downstream of BCR-Abl and are activated by Abl to promote cell growth, survival, and differentiation; however, in some tumors resistant to Imatinib, despite BCR-Abl Activity is suppressed, downstream of Src, Lyn and Hck signaling pathways Still in an active state, it shows that compensatory bypass is involved in the development of Imatinib resistance. 3) Other resistance mechanisms include overexpression of BCR-Abl itself and overexpression of drug resistance protein BCRP/ABCG2.

In response to Imatinib resistance, the second-generation Abl kinase targeting drug Dasatinib (trade name: Sprycel; Bristol-Myers Squibb) was developed. Dasatinib is a dual inhibitor of Abl-Src, which was approved by the FDA in June 2006 for the treatment of patients with CML who are resistant or intolerant to Imatinib. Due to its completely different structure from Imatinib, Dasatinib binds to the active form of BCR-Abl; its ability to inhibit wild-type BCR-Abl kinase is 325 times that of Imatinib, and its binding site is different from Imatinib, thus it is resistant to Imatinib. The BCR-Abl mutant kinase has a good inhibitory effect except for one site (T315I site). More strikingly, Dasatinib also inhibits the activity of Src, and is therefore still effective against tumors that are imatinib-resistant due to Src overactivation. Clinical trials have shown that Dasatinib has a good effect on many different types of Imatinib-resistant patients. However, Dasatinib has not effectively solved the drug resistance caused by BCR-Abl due to the T315I site mutation. Therefore, it is imperative to develop a third-generation BCR-Abl inhibitor.

How to overcome the drug resistance caused by existing drugs such as imatinib is an important topic in oncology medicine today. One of the important ways is to find a novel small molecule inhibitor of tyrosine kinase that is effective against the above mutants. For example, the small molecule inhibitors Nilotinib and Dasatinib are effective against some, but not all (except T315I) Bcr-Abl mutations in imatinib-resistant cases. Therefore, it is necessary and urgent to find effective solutions to find novel small-molecule tyrosine kinase inhibitors that are effective against various mutants, especially T315I and D816V, in global tumor prevention and treatment.

With the deepening of research on the pathogenesis of lung cancer, the role of targeted therapy in the treatment of NSCLC is becoming more and more important. Among them, the targeted drugs of epidermal growth factor receptor tyrosine kinase inhibitor represented by erlotinib and gefitinib have achieved certain effects. However, most studies have shown that patients with clinical remission or even regression of NSCLC develop resistance and even disease progression after a period of maintenance therapy. To this end, the EGFR TKI resistance mechanism has become a hot topic in the field of oncology. The TK activity of EGFR in cells is activated by binding to ligands including EGF, transforming growth factor alpha, amphiregulin, etc., resulting in the formation of homodimers of EGFRs or heterodimers with other family members, the most common Is HER2. TK activation of EGFR leads to autophosphorylation of EGFR intracellular regions, and these phosphorylated residues can serve as docking sites for a variety of adaptor molecules, leading to mitogen-activated protein kinase (MAPK) Activation of the pathway, PI3K/Akt pathway, and signal transducer and transcriptional pathway activators promotes cell proliferation, angiogenesis, metastasis, and inhibition of apoptosis, thereby increasing tumor cell survival, proliferation, invasion, and metastasis. TK activation of tumor cell EGFR can be disrupted by a variety of oncogene mechanisms, including increased gene copy number and EGFR protein overexpression caused by EGFR gene mutations. More than 60% of NSCLC patients have overexpressed EGFR in their tumor cells, and these patients have a poor prognosis. These findings have led to the development of anticancer drugs that target EGFR. Reversible EGFR TKIs (erlotinib and gefitinib) have significant anti-tumor efficacy in a subset of NSCLC patients: approximately 10% of European patients and 30% of East Asian patients have clinical remission. EGFR gene sequencing revealed that most tumors that responded to EGFR TKIs treatment contained mutations in the EGFR TK region. Overall, the mutation frequency of EGFR is 5%-20%, depending on the study population. Tumor patients carrying EGFR mutations have a response rate of approximately 75% for erlotinib and gefitinib, suggesting that these mutations can cause malignant transformation of cells. All NSCLCs that initially responded to EGFR TKI treatment developed secondary resistance. The efficacy of gefitinib and erlotinib is currently considered to be limited, mainly due to resistance caused by the second point mutation in the TK region. 50% of patients with secondary drug resistance in EGFR TKI develop a threonine-790 mutation to methionine (T790M, although EGFR TKIs can also achieve significant efficacy in these patients, but T790M is included in patients who do not have T790M detected. The progression-free survival of patients was relatively short (7.7 months vs 16.5 months; P < 0.001). Preclinical studies also found that T790M is a potential resistance mechanism, and in vitro tests confirmed that this mutation significantly inhibited erlotinib and The effect of fentanyl, however, is still present in TK activity. Similarly, introduction of T790M into gefitinib-sensitive tumor cells, activated EGFR mutations or increased EGFR copy number can lead to gefitinib resistance. However, the mechanism by which T790M causes the resistance of tumor cells to EGFR TKIs remains unclear. It is likely that the T790M mutation causes a change in the topology of the ATP-binding pocket of TK and prevents EGFR TKIs from binding through the steric group phenomenon, thereby secondary resistance. A recent study suggests another mechanism by which T790M increases the binding of ATP to the kinase domain, which in turn reduces the efficacy of any ATP competitor. Study reports, other point mutations leading to drug resistance, such as The aspartate-761 mutation to tyrosine (D761Y) attenuates the interaction between the EGFR TKI and its target. Skin malignant melanoma is one of the most malignant tumors and is prone to invasion and metastasis. In recent years, BRAF gene has been found to have high frequency mutations in human melanoma. Clinically, there is a BRAF V600E mutation in about 50% of melanomas. . The B-raf gene is a member of the RAF family, which encodes a silk/threonine-specific kinase and is an important transduction factor in the RAS/RAF/MEK/ERKMAPK pathway, involved in the regulation of various biological events in cells. , such as cell growth, differentiation and apoptosis. Recent studies have shown that BRAF tumor gene mutations can be found in some human malignancies. Most literature reports that the rate of B-raf mutation in colorectal cancer is about 15%, and more than 90% are V600E mutations, and negatively correlated with K-ras mutation. Recent studies have shown that BRAF gene mutations have important predictive and prognostic significance in clinical practice. Patients with B-raf mutations cannot benefit from targeted drug therapy for EGFR, and patients with B-raf mutations have a prognosis. Poor. Phase I and phase II clinical trials of an oral BRAF kinase inhibitor vemurafenib (PLX4032/RO5185426) have demonstrated greater than 50% efficiency (RR; CR+PR) in BRAF V600E mutant melanoma patients. BRAF~(;V600E) mutant gene can promote the growth and proliferation of human melanoma cells, which can make tumor cells secrete more MMPs and VEGF, enhance the ability of tumor cells to invade and angiogenesis, and improve their ability to metastasize, suggesting BRAF ( V600E) mutations play an important role in melanoma growth, invasion and metastasis, and gene therapy targeting them can inhibit the growth of experimental melanoma.

In fact, the study of Imatinib resistance mechanisms and their pathways of overcoming has established an excellent model for molecularly targeted drugs. For example, about 50% of Gefitinib or Erlotinib-resistant tumors targeting EGFR have a point mutation (T790M) similar to the T315I mutation in BCR-Abl, which is the "guardian" residue of the enzyme activity center (Gatekeeper residue). The mutation causes the binding of the drug molecule to the active site of the enzyme to be attenuated without affecting the activity of the enzyme on the catalytic substrate. Therefore, reversible inhibitors such as Gefitinib and Erlotinib are affected; some EGFR irreversible inhibitors, such as Canertinib, are in clinical research and are expected to improve the efficacy of point-mutant drug-resistant tumors. Similarly, EGFR inhibitors can also develop resistance through a bypass compensatory mechanism, such as Met or PDGFR gene amplification. When EGFR is inhibited by an inhibitor and cannot bind to ErbB3, Met or PDGFR can compensatoryly bind to ErbB3, replacing the function of the original EGFR, and activating the downstream PBK signaling pathway, causing the inhibitor to lose its inhibitory effect on tumor cells. Therefore, the combination of an EGFR inhibitor and a Met or PDGFR inhibitor would be an alternative to clinically overcoming EGFR inhibitor resistance.

Early marketed protein kinase inhibitors are mainly specific inhibitors for single targets. Although they have made remarkable achievements in cancer treatment at the time of market launch, with the prolongation of use time and the increase in treatment cases, the problem gradually Exposed. One of them is the problem of drug resistance. Because the target is single, it is easy to cause drug resistance after the target kinase mutation. Second, the use of such drugs is limited by the fact that it must be a case of high expression or overactivation of its target kinase. Its efficacy. Compared to broad-spectrum kinase inhibitors, it shows certain advantages. By simultaneously targeting multiple kinase kinase molecules and multiple signal pathways, not only the resistance caused by single target mutations can be avoided, but also the anti-tumor spectrum can be significantly expanded. Representative drugs include Sunitinib and Sorafenib, as well as the recently marketed multi-targeted kinase inhibitor Vandetanib (trade name: Zactima; AstraZeneca;). Vandetanib also targets tyrosine kinases such as EGFR, VEGFR and RET, and was approved by the FDA in 2005 as a therapeutic agent for follicular, medullary, undifferentiated or locally advanced and metastatic papillary thyroid cancer.

In summary, expanding the scope of research on cancer indications, eliminating or delaying the emergence of drug resistance will be the mainstream direction of protein kinase inhibitor anti-tumor drug development. Therefore, it is still very important to continue to find and discover novel protein kinase inhibitors as anti-tumor drugs, especially resistant to drug resistance caused by existing drugs. Summary of the invention

The object of the present invention is to provide a new class of protein kinase inhibitors.

In one aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof,

(I)

Its towel:

Ring A is an aryl group, preferably . An aryl group, more preferably a phenyl group;

m is the number of substituents Ra on ring A, and m is 0, 1, 2, 3 or 4, preferably 1 or 2;

m Ra are each independently selected from halogen, -R ₂ , -OH, -SH, -OR ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC (0) OR ₂ , -NR ₃ C(0)R ₂ ;

Ring T is a heteroaryl group containing at least one nitrogen atom, wherein M is selected from the group consisting of N atoms, CH and CR, wherein R is selected from the group consisting of halogen, -R ₂ , -OR ₂ , -CN, -OH, -SH, -COOH, -C(0)-R ₂ , -C(0)0-R ₂ , -OC(0)-R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NR ₃ C(0)R ₂ ;

p is the number of substituents Rt on ring T, and t is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;

Each of p R1 is independently selected from the group consisting of halogen, -R ₂ , -CN, -COOH, -OH, -SH, -OR ₂ , -C(0)-R ₂ , -C(0)0-R ₂ , OC(0)-R ₂ , -S(0) _x -R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC(0)OR ₂ , -NR ₃ C(0)R ₂ , wherein x is 0, 1 or 2;

Ring B is an aryl group, preferably . An aryl group, more preferably a phenyl group;

n is the number of substituents Rb on ring B, and n is 0, 1, 2, 3, 4 or 5, preferably 1 or 2, more preferably

2;

Each of R Rb is independently selected from the group consisting of halogen, -R ₂ , -CN, -COOH, -OH, -SH, -OR ₂ , -C(0)-R ₂ , -C(0)0-R ₂ , OC(0)-R ₂ , -S(0) _x -R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC(0)OR ₂ , -NR ₃ C(0)R ₂ , where x is 0, 1 or 2; or

Two adjacent Rbs together with a carbon atom on ring B to which they are attached form a heterocyclic group; said heterocyclic group optionally being selected from one or more selected from -R ₂ , -C(0)0-R ₂ a group substituted with -C(0)-R ₂ ;

L is a linking group selected from -CONR _r or -NR CO-, wherein it is selected from a H atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aryl group, a heteroaryl group or a heterocyclic group,

Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4 -C(OP-R4, -OC(0)-R ₄ ,

-C(0)N(R4) ₂ , -S(0) _x -R4, -NH ₂ , -NH , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , a group substituted by -NR ₅ C(0)R ₄ , wherein x is 0, 1 or 2;

Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino adenyl, amphoteric amide, alkoxycarbonylamino-based, ring-based base, heterocyclic-based, aromatic-based, alkyl ring Alkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl)(alkyl)amino, (alkylcarbonyl) Substituent of the (alkyl)amino group.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former The drug, and a pharmaceutically acceptable carrier. Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for inhibiting the activity of a protein kinase.

Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for preventing and/or treating a tumor.

Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Use of a composition for the preparation of a medicament for inhibiting protein kinase activity.

Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor.

A further aspect of the invention relates to a method of modulating protein kinase activity, which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof , solvate, prodrug or metabolite contact. Preferably, the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.

Another aspect of the invention relates to a method of inhibiting protein kinase activity in a mammal, particularly a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.

Another aspect of the invention relates to a method of treating and/or preventing a tumor in a mammal, in particular a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, pharmaceutically thereof Acceptable salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention. According to one embodiment, the tumor is inhibited by inhibition of a protein kinase.

Another aspect of the invention relates to the use of a compound of the invention in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs for the treatment and/or prevention of a tumor. detailed description

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that, unless the context clearly dictates otherwise, the singular forms used in the specification and the claims are in the plural. It should also be noted that "or", "or" means "and / or" unless otherwise stated. In addition, the terms "including" and "including", "including", "include", and "include" are not limiting.

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^th ED." s. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in relation to analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, a group and its substituents can be selected by those skilled in the art to provide a stable knot. Fractions and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH ₂ 0- is equivalent to -OCH ₂ -.

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

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, _-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specified.

In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group as defined below which is substituted by a hydroxy group (-OH).

"Carbonyl" means a -C(=0)- group.

"Nitro" means -N0 ₂ .

"Cyano" means -CN.

"Amino" means -NH ₂ .

"Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.

"Several bases" means -COOH.

¹ in the present application, as part of the group or other group (e.g., halogen-substituted with an alkyl group and the like), the term "alkyl" means consisting solely of carbon and hydrogen atoms, containing no A saturated bond, a linear or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and bonded to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.

In the present application, the term "alkoxy" refers to _a radical of the formula -OR _a where is alkyl as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

In the present application, the term "alkylcarbonyl" refers to a -C(O)-R _a group, wherein R _a is alkyl as defined above. In the present application, the term "alkoxycarbonyl" refers to a -C(0)0-R _a group, wherein R _a is alkyl as defined above.

In the present application, the term "monoalkylamino" refers to _a radical of the formula -NHR _a where is alkyl as defined above. Examples of monoalkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, and the like.

In the present application, the term "dialkylamino" refers to _a radical of the formula -NR _a R _b wherein each is independently alkyl as defined above. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like.

In the present application, the term "alkenyl" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) More preferably, 2 to 6) a straight or branched hydrocarbon chain group having a carbon atom and attached to the remainder of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.

In the present application, the term "block group" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) a straight or branched hydrocarbon chain group having a carbon atom and attached to the remainder of the molecule by a single bond, such as, but not limited to, an ethyl group, a propan-1-yl group, But-1-blockyl, pent-1-ene-4-block, and the like.

In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing A ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed The carbon atom is connected to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctene , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo[3丄1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl,adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

In the present application, the term "cycloalkyloxy" refers to a radical of the formula wherein Re is cycloalkyl as defined above.

In the present application, the term "heterocyclyl" as a group or part of another group means a stable consisting of 2 to 14 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur. A 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be bonded to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond. In the heterocyclic group containing a fused ring, one or more of the rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, a heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene. Alkan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.

In the present application, the term "heterocyclyloxy" refers to a radical of the formula -0, wherein is a heterocyclic radical as defined above.

In the present application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2Η-1, 4-benzoxazine-3(4Η)-keto-7-yl and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above. In the present application, the term "heteroaryl" as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the hetero The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heteroaryl group preferably contains from 1 to 5 selected from nitrogen, oxygen and a stable 5- to 12-membered aromatic group of a hetero atom of sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur or 1 Up to 3 5- to 6-membered aromatic groups selected from heteroatoms of nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, dinaphthyl, naphthyridyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Phenyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-6] pyridazine, [1,2,4]triazolo[4,3-α]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-α]pyridine, imidazo[1,2-α]pyridine, imidazo[1,2-6] Pyridazine, imidazo[1,2-α]pyrazine and the like.

In the present application, the term "heteroarylalkyl" refers to a fluorenyl group as defined above which is substituted by a heteroaryl group as defined above.

In the present application, "optional" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.

In the present application, when a group is described as "optionally substituted", the group may be optionally substituted at one or more suitable positions with the following groups: alkyl, alkenyl, block , halogen, haloalkyl, haloalkenyl, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, trimethylsilyl, -OR _1Q , -C(O)-R ₁₀ -C(O)OR ₁₀ -OC(O)-R ₁₀ , -N(R ₁₀ ) ₂ , -C(O)N(R ₁₀ ) ₂ , -N(R ₁₀ )C(O)R _u , -N(R ₁₀ )C(O)OR _n -N(R ₁₀ )S(O) _t R _u (where t is 1 or SX -SO ORu (where t is 1 or SX - SO Ru (where t is 0 , 1 or 2), - S(O) _t N(R ₁₀ ) ₂

(wherein t is 1 or 2), wherein each R _{1Q is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl , heteroaryl or heteroarylalkyl; and each Ru is independently alkyl, 3⁄4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl A heteroaryl or heteroarylalkyl group.

The terms "part", "structural moiety", "chemical moiety", "group", and "chemical group" as used herein mean a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.

"Stereoisomer" means a compound composed of the same atom, bonded by the same bond, but having a different three-dimensional structure. The invention will cover various stereoisomers and mixtures thereof.

When the compound of the present invention contains an olefinic double bond, the compound of the present invention is intended to contain Ε- and Ζ-geometric isomers unless otherwise stated.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. The preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. For example, see Gerald Giibitz and M artin G. Schmid (Eds.), Chiral Se arations, M ethods and Protocols, Methods in Molecular Biology, No. 243, 2004; AM . Stalcup , Chiral Separations, Annu. Rev. Anal Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.si3⁄4) .TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128. In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" means a salt formed with an inorganic base or an organic base capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" means a different solid crystalline phase of certain compounds of the present invention which are produced in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.

Generally, crystallization will result in a solvate of the compound of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules. The solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention form true solvates, but in some cases, it is also possible to retain only a variable amount of water or a mixture of water and a portion of the indefinite solvent. The compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

In the present application, "metabolite" refers to a functional group reaction (I phase biotransformation reaction, including oxidation, reduction, hydrolysis, etc.) and binding reaction (phase biotransformation) of a drug after being absorbed by the body and under the action of an enzyme. Reaction) A compound produced by biological transformation.

The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood. Prodrug compounds generally provide the advantage of solubility, histocompatibility or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxy protecting groups. For specific preparation methods of prodrugs, see Saulnier, M. G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, RB, et al., J. Med. Chem. 2000 , 43, 475.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. Drug The purpose of the composition is to promote the administration of the organism, to facilitate the absorption of the active ingredient and to exert biological activity. The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.

In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvants, carriers, excipients, glidants, sweeteners approved by the relevant government authorities for acceptable use by humans or domestic animals. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsions.

The term "subject", "patient" or "individual" as used herein refers to an individual having a disease or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or deterioration of a disease or condition by a patient.

The term "treatment" and other similar synonyms as used herein includes the following meanings:

(Prevention of a disease or condition in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(ii) inhibiting a disease or condition, ie curbing its development;

(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or

(iv) alleviate the symptoms caused by the disease or condition.

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

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

The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like as used herein mean a medical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one of the compounds 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 "unfixed combination" refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.

Its towel:

2;

L is a linking group selected from -CONRi - or -NR O-, wherein is selected from the group consisting of H atom, alkyl group, cycloalkyl group, hydroxyalkyl group, aryl group, heteroaryl group or heterocyclic group,

Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4 -C(OP-R4, -OC(0)-R ₄ , -C(0)N(R4) ₂ , -S(0) _a group substitution of _x -R4, -NH ₂ , -ΝΗ , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , -NR ₅ C(0)R ₄ , Where x is 0, 1 or 2;

Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino adenyl, amphoteric amide, alkoxycarbonylamino-based, ring-based base, heterocyclic-based, aromatic-based, alkyl ring Alkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl X alkyl)amino, (decylcarbonyl X-alkyl) Substituted by a group of amino groups.

In one embodiment, the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, A conformation, solvate, polymorph, tautomer, metabolite or prodrug, wherein:

m Ra are each independently selected from halogen, alkyl, cycloalkyl, heterocyclic, -OH, alkoxy, -NH _{2 ;} and the alkyl, cycloalkyl, heterocyclyl, alkoxy optionally Substituted with one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy, -NH ₂ , -NH , -N(R ₄ ) ₂ ; alkoxyalkyl, cycloalkyl group and heterocyclyl group optionally substituted with one or more groups selected from -OH, -CN, -NH _2, substituted alkyl groups.

In another embodiment, the present invention is also directed to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

m Ra are each independently selected from halogen, alkyl, and the alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy Replace.

m Ra are each independently selected from halogen, d- ₆ alkyl, and the alkyl is optionally selected from one or more selected from the group consisting of halogen, -OH, C alkoxy, C ₃ _-8 cycloalkyloxy, Substituent substitution of a 4- to 8-membered heterocyclic oxy group containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur.

In one embodiment, the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:

In Formula I, the E-block moiety and the L moiety are meta-substituted on Ring A, and at least one Ra is located in the para position of the L moiety on Ring A.

M is CH;

Ring T is selected from a 5- to 12-membered monocyclic or fused heteroaryl group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein at least one hetero atom is a nitrogen atom;

Each of p Rt is independently an alkyl group, preferably a d ₆ alkyl group;

Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Substituted with one or more groups selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl; The alkyl group in the carbonyl group is optionally substituted by an alkoxyamido group, the heterocyclic group in the heterocyclylalkyl group is optionally substituted by an alkoxycarbonyl group, and the heterocyclic group in the heterocyclic carbonyl group is optionally a Or a plurality of groups selected from the group consisting of an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, and a hydroxyalkyl group.

In a preferred embodiment, the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or Medicine, where:

Ring T is selected from the following structures:

Two adjacent Rbs together with them form a structure selected from the following:

And the structure is optionally one or more selected from the group consisting of an alkoxycarbonyl group, a d- ₆ alkylcarbonyl group, a 4- to 8-membered heterocyclic carbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, Containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur 5- to 6-membered heteroarylcarbonyl, C ₃ _-8 cycloalkyl-d- ₆ alkyl, 4- to 8-membered heterocyclic-d_ containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur ₆ alkyl, Q^. a group substituted with an aryl-d- ₆ alkyl group; and the alkyl group in the alkylcarbonyl group is optionally substituted with a Ci- ₆ alkoxyamido group, and the heterocyclic group in the heterocyclylalkyl group is optionally alkoxy The carbonyl group is substituted, and the heterocyclic group in the heterocyclic carbonyl group is optionally substituted by one or more groups selected from the group consisting of an alkyl group, a d- ₆ alkylcarbonyl group, a d- ₆ alkoxycarbonyl group, and a hydroxy-Ci- ₆ alkyl group.

M is a N atom;

Ring T is selected from a 5- to 12-membered heteroaryl group containing 2 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, wherein at least two of the heteroatoms are nitrogen atoms;

Each of p R1 is independently selected from halogen; -OH; -NH ₂ ; alkyl; alkenyl; aryl optionally substituted by alkoxyalkyl; optionally alkyl, hydroxyalkyl, 3⁄4 An alkoxy-substituted heterocyclic group; a heteroaryl group optionally substituted by -ΝΗ ₂ , alkyl, wherein the alkyl group is optionally further selected from -CN, alkoxy, cycloalkyl, heterocyclic Substituted by a group of a monoalkylamino group, a dialkylamino group; an alkoxy group optionally substituted by a dialkylamino group, a cycloalkyl group; a heterocyclic oxy group optionally substituted by an alkyl group; a cycloalkane Alkylamino; a monoalkylamino group; a dialkylamino group; the alkyl group in the monoalkylamino group and the dialkylamino group optionally further substituted with an alkoxy group, a dialkylamino group, an alkyl S0 ₂ -, a dialkyl group Aminocarbonyl substitution;

Each of R Rb is independently selected from a 3⁄4 alkyl group; a cycloalkyl group; a heterocyclic group optionally substituted by an alkyl group; a heterocyclylalkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally One or more selected from the group consisting of -indole, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkylcarbonylalkyl, heterocyclylalkyl, Cycloalkylalkyl, aryl-based, single-yard amino-based, secondary-base amino-based, oxycarbonylamino-based, oxycarbonyl, ring-based carbonyl, single-hospital amino, second Substituted by a group of a base amino group, a (homoyloxycarbonyl) (homo-based) amino group, a (homo-oxyl group) (homo-based) amino group, a (homo-based carbonyl group) (fluorenyl) amino group.

Structure

ρ a R1 are each independently selected from halogen; -OH; -NH _2; d- ₆ alkyl; C ₂ - ₆ alkenyl; optionally substituted C ^ alkoxy-C ^ alkyl. An aryl group; a 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur, optionally substituted by d- ₆ alkyl, hydroxy-d- ₆ alkyl, halogen, d- ₆ alkoxy a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by -NH ₂ , d ₆ alkyl, wherein the alkyl group optionally further 4- to 8-membered heterocyclic group, mono- ₆ -alkane selected from -CN, d- ₆ alkoxy, C ₃ _-8 cycloalkyl, heteroatoms containing from 1 to 3 selected from nitrogen, oxygen and sulfur yl) amino, di (^ _ ₆ alkyl) amino groups; ₆ alkoxy optionally substituted with bis (^ _ ₆ alkyl) amino, C ₃ _ ₈ cycloalkyl substituted D_; optionally a 4- to 8-membered heterocyclic oxy group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, substituted by d ₆ alkyl; C ₃ _-8 cycloalkylamino; mono(d- ₆ alkyl) An amino group; a di(d- ₆ alkyl)amino group; the alkyl group in the monoalkylamino group and the dialkylamino group optionally further alkoxy group, di(C^alkyl)amino group, d- ₆ alkyl-S0 ₂ -, di(d- ₆ alkyl)aminocarbonyl substitution;

Each of R Rb is independently selected from halo-d- ₆ alkyl; C ₃ _-8 cycloalkyl; optionally substituted by C _w alkyl a 4- to 8-membered heterocyclic group to 3 hetero atoms selected from nitrogen, oxygen and sulfur; a 4- to 8-membered heterocyclic group-d_ ₆ containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur An alkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally one or more selected from the group consisting of -OH, d- ₆ alkyl, hydroxy-^- ₆ alkyl, amino- _Cw alkyl, including 1 to 3 heteroatoms selected from nitrogen, 4-8 yuan heterocyclic groups, oxygen and sulfur, d_ ₆ alkoxy -d_ ₆ alkyl, hydroxy -d_ ₆ -d_ ₆ alkoxy group, d_ ₆ alkoxy ylcarbonyl -d_ ₆ alkyl group, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur heteroatoms 4- to 8-membered heterocyclic group - ^ _ ₆ alkyl, C ₃ _ ₈ cycloalkyl -d_ ₆ homes Base, C ₆ _10 aryl-Ci-6 yard base, single (Ci-6 yard base) amino-Ci-6 yard base, two (Ci-6 yard base) amino-Ci-6 yard base, Ci- ₆ alkoxy Alkylcarbonylamino-c^alkyl, d- ₆ alkoxycarbonyl, C ₃ _-8 cycloalkylcarbonyl, mono(d- ₆ alkyl)amino, bis(d- ₆ )amino, (Ci-6)oxy A group of a carbonyl group (Ci-6)-amino group, a (Ci- _6- yard oxy-based group) (C-institutional) amino group, (Ci-6-yard carbonyl XCw alkyl)amino group.

Μ is CR, wherein R is selected from halogen, alkyl, cycloalkyl and the alkyl group, cycloalkyl group optionally substituted with one or more halogen; preferably, R is selected from Ci_ ₆ alkyl or C ₃ _ ₈ -cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halogens;

The ring T is selected from a 9- to 12-membered fused heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, wherein at least one of the hetero atoms is a nitrogen atom;

Each of p R1 is independently halogen, heterocyclic, aryl, heteroaryl; preferably halogen, 4 to 8 membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C An aryl group, a 5- to 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; and the heterocyclic group, aryl or heteroaryl group is optionally substituted by one or more alkyl groups Replace

Each of R Rb is independently an alkyl or alkyl-substituted heteroaryl group, preferably a d- ₆ alkyl group or a d- ₆ alkyl group substituted with 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur to 5 a 6-membered heteroaryl group, and each alkyl group is optionally selected from one or more selected from the group consisting of halogen, -OH, mono(d- ₆ alkyl)amino, di(Ci- ₆ alkyl)amino, and 1 to 3 selected from Substituted by a 4- to 8-membered heterocyclic group of a hetero atom of nitrogen, oxygen and sulfur; and the heterocyclic group is optionally selected from one or more selected from the group consisting of fluorene, C _1-6 alkyl, and mono (Ci_ ₆ Alkylamino, bis(Ci- ₆ alkyl)amino, 4 to 8 membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and 1 to 3 substituted by d- ₆ alkyl heteroatom selected from nitrogen, oxygen and sulfur 4- to 8-membered heterocyclic group, hospital light -Ci- _6-yl group, Ci- ₆ alkoxy hospital hospital -Ci- _6-yl, C ₃ - ₈ cycloalkyl group homes - Ci- _{6 is} substituted with a group of a C _6- yard oxycarbonyl group or a (Ci- ₆ alkoxycarbonyl) (d- ₆ alkyl)amino group.

Ring T is selected from

In another embodiment, the present invention is also directed to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:

Is selected from H, alkyl, cycloalkyl and hydroxyalkyl, preferably H atom, d_ ₆ alkyl, ¾ ₈ cycloalkyl group and country. 1-6 焼 base;

Preferably, it is selected from a H atom or a ₆ alkyl group;

More preferably, it is 11 atoms.

In a preferred embodiment, the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or a drug, wherein the compound is selected from the group consisting of

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

20

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former A drug and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.

The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof with sterilized distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and ^{Practice), 20 th Edition (Philadel hia} Colle ^ of Pharmacy and Science, 2000).

Routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like. The compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like. The above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or suspension with the above carriers. The specific mode of administration and dosage form will depend on the physical and chemical properties of the compound itself, as well as the severity of the disease being applied. Those skilled in the art will be able to determine the specific route of administration based on the above factors in combination with their own knowledge. For example, see: Li Jun, Clinical Pharmacology, People's Medical Publishing House, 2008.06; Ding Yufeng, On Clinical Formulation Factors and Rational Use of Medicine, Medical Herald, 26(5), 2007; Howard C. Ansel, Loyd V Allen, Jr Nicholas G. Po ovich, Jiang Zhiqiang, “Pharmaceutical Formulation and Drug Delivery System”, China Medical Science and Technology Press, 2003.05.

Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for inhibiting the activity of a protein kinase.

The compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof can effectively inhibit the growth of various tumor cells, and Bcr-Abl, c-KIT, PDGFR, c-Src, KDR, RET, FYN, FES, AXL, RSK, FER, SYK, HER2, LTK, ZAP70, ARG, LYN, LCK, BRAF, BRAFV600E, AblT315I, FGR, Inhibition of kinases such as HCK, HER4, p38, MINK, MAPK, EphB, YES, BRK, TIE, C SK, MUSK, FGFR, JAK, EphA, KKB, P70S6K, FLT, EGFR, BTK, ITK, PDGFR, etc. It is effective against mutants AblT315I, BRAFV600E, etc., and can be used to prepare antitumor drugs.

In the present application, the term "tumor" includes but is not limited to: leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer , prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

A further aspect of the invention relates to a method of modulating protein kinase activity, which comprises combining said protein kinase with a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polycrystal thereof Shape, solvate, The prodrug or metabolite or the pharmaceutical composition of the invention is contacted. Preferably, the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.

Generally, a therapeutically effective daily dose is from about 0.001 mg/kg to about 100 mg kg; a preferred therapeutically effective dose is from about 0.01 mg/kg to about 50 mg/kg; a more preferred therapeutically effective dose is from about 1 mg^kg to About 25 mg/kg.

The range of effective dosages provided herein is not intended to limit the scope of the invention, but rather to the preferred dosage range. However, the most preferred dosages can be adjusted for individual individuals, as will be appreciated and determined by those skilled in the art (see, for example, Berkow et al., Merck Handbook, 16th Edition, Merck, Rahway, NJ, 1992). .

The compounds of the invention may be used in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs to treat and/or prevent tumors. Drugs that can be used in combination with the compounds of the invention include, but are not limited to, docetaxel, gemcitabine, cisplatin, carboplatin, Gleevec, temozolomide, doxorubicin, dacarbazine, trococaine, etoposide, soft red And cytarabine and the like. Preparation of the compounds of the invention

The following reaction scheme exemplifies the preparation method of the compound of the present invention.

Those skilled in the art will appreciate that in the following description, combinations of such substituents are permissible only if a combination of substituents results in a stable compound.

It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C(0)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein.

Use of protecting groups are detailed in Greene, TW and PG M. Wuts, Protective Groins in Organi Synthesis, (1999), 4 th Ed., Wiley medium. The protecting group can also be a polymeric resin.

The compounds of the formula I according to the invention can be prepared by the method AE.

Method A

Process A comprises the steps of: (1) subjecting mercapto compound A-1 (which is commercially available or prepared by methods known to those skilled in the art) under typical condensation conditions (e.g., condensing agent method, mixed anhydride) Method, activation method, etc.) is condensed with A-2 to give hydrazide A-3; (2) hydrazide hydrazide A-3 is condensed to give intermediate A-4, and the ring can be used in a suitable solvent (such as water, methanol, ethanol). , isopropanol, toluene, xylene, glacial acetic acid, DMF, THF, etc.) by acid catalysis (such as glacial acetic acid, hydrochloric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc.) or base catalysis (such as Potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, etc.); (3) removing the protecting group from the intermediate A-4 to obtain A-5, and deprotecting using a reagent such as dilute hydrochloric acid, potassium carbonate or TBAF; 4) The intermediate A-5 and A-6 are subjected to a coupling reaction under transition metal catalysis to obtain a compound of the formula 1 (A), and the coupling reaction is carried out by using a palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , _{_{Pd 2 (Dba) 3, PdPPh}} 3 Cl 2 , etc.), copper salt (e.g. cuprous chloride, cuprous bromide, cuprous iodide, etc.) And various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees) get. In Method A, M l, M2, M3 and M4 are C atoms or heteroatoms, when C

Method B

Process B comprises the steps of: (1) heating a mercapto compound B-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate Guanhuan gives intermediate B-2; (2) intermediate B-2 is halogenated under various halogenating reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Substituting to give intermediate B-3; (3) coupling intermediate B-3 with TMS protected block B under transition metal catalysis to obtain intermediate B-4, the coupling reaction using palladium catalyst (such as Pd ( PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd(PPh) ₃ Cl _{2 ,} etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases or Inorganic base (such as Triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) are obtained by reaction in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees); (4) intermediate B- 4 Removal of the protecting group to obtain B-5, deprotection can be carried out using reagents such as dilute hydrochloric acid, potassium carbonate or TBAF; (5) coupling intermediates B-5 and B-6 under transition metal catalysis to obtain formula 1 The compound shown in (B) is a palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ , PdPPh ₃ Cl _{2 ,} etc.), a copper salt such as (copper chloride, brominated). Cuprous, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in suitable solvents (such as THF, toluene, DMF, etc.) and temperature (eg 20-150 degrees) the reaction is obtained. In method B, M l, M 2 , M 3 and M 4 are C atoms or N atoms, when

Method C

Process C comprises the steps of: (1) heating a mercapto compound C-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate Guanhuan gives intermediate C-2; (2) intermediate C-2 is halogenated under various halogenating reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Substituting to obtain intermediate C-3; (3) coupling intermediate C-4 with TM S protected block B under transition metal catalysis to obtain intermediate C-5, coupling reaction using palladium catalyst (such as Pd) (PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd(PPh) ₃ Cl _{2 ,} etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases Or an inorganic base (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) is obtained by reacting in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees); (4) The intermediate C-5 is deprotected to obtain a C-6, and the deprotection may be carried out using a reagent such as dilute hydrochloric acid, potassium carbonate or TBAF; (5) intermediates C-3 and C-6 in a transition metal The coupling reaction of the resulting 1 (C), the coupling reaction using a palladium catalyst (e.g. _{_{Pd (PPh 3) 4, PdAc}} 2, Pd 2 (Dba) 3, Pd (PPh) 3 Cl 2 , etc.), copper ( Such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in a suitable solvent (such as THF) , toluene, DMF, etc.) and temperature (such as 20-150 degrees) reaction. In Method C, M l, M2, M 3 and M4 are C atoms or N atoms, when C atoms

Method D

Process D comprises the steps of: (1) rendering an aromatic amine D-1 (which is commercially available or prepared by methods known to those skilled in the art) with various halogenated aldehydes, ketones or corresponding acetals , ketal (such as 2-chloroacetaldehyde, 2-bromoacetaldehyde, 2-chloroacetaldehyde acetal, 2-bromoacetone, 1-bromo-2-butanone, 2-bromo-1 -cyclopropylethanone , 3-bromo-1-trifluoromethyl-2-propanone or methyl bromopyruvate, etc.) cyclized under the catalysis of acid (concentrated hydrochloric acid, hydrobromic acid, etc.) or alkali (TEA, sodium carbonate, etc.) Intermediate D-2; (2) Intermediate D-2 is subjected to halogenation reaction under various halogen reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Intermediate D-3; (3) coupling intermediate D-3 with D-4 under transition metal catalysis to obtain 1(D), the coupling reaction using palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd (PPh) ₃ Cl _2, etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as three B Amine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) are obtained by reaction in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (e.g., 20-150 degrees). In Method D, M l, M2, M3 and M4 are C atoms or N atoms, as C original; X is halogen

Method E

The method E comprises the following steps: (1) obtaining an aryl b-block intermediate E-1 and an intermediate E-2 by a method of the method AD or other literature methods, wherein La and Lb are an acyl group and an amino group or an amino group and an acyl group, respectively; (2) The target compound 1 (E) is synthesized by a conventional amide bond condensation method.

Intermediate preparation

Intermediate 1: 3-Ethyl- 1,2,4]triazole [4,3-a]pyridine

First step: Trimethylsilyl-propionic acid -Ν'-pyridine-2-yl-hydrazide

Ν-Methylmorpholine (0.27 mL, 2.5 mmol) was slowly added to a solution of trimethylsilylpropanoic acid (0.39 g, 2.75 mmol) in ethyl acetate (20 mL). Isopropyl chloroformate (2.0 M toluene solution, 1.25 mL, 2.5 mmol) was slowly added dropwise, and stirring was continued for 2 hours after the completion of the dropwise addition. After completion of the reaction, ice water (20 mL) was added to the reaction mixture to quench the reaction, and the organic phase was separated. The organic layer was washed with aq. EtOAc (EtOAc m. This oil was dissolved in anhydrous tetrahydrofuran (30 mL). <EMI ID=9.1 > The solvent was concentrated under reduced pressure and the residue was crystallijjjjjlililililililililililili 1H-NMR (300MHz, CDC1 ₃ ): δ 8.15 (s, 1H), 7.53-7.57 (m, 1H), 6.80-6.83 (m, 1H), 6.74 (s, lH), 0.21 (s, 9H). MS m / z (ESI): 234.1 [M+H].

Step 2: 3-Trimethylsilylethane-yl-[1,2,4]triazole [4,3-a]pyridine

Trimethylsilyl-propionic acid-Ν'-pyridin-2-yl-hydrazide (0.5 _& 2.1 mmol) was dissolved in phosphorus oxychloride (5 mL). The mixture was stirred with heating at 60 ° C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove excess phosphorus oxychloride. The residue was dissolved in dichloromethane (50 mL) and neutralized with saturated sodium hydrogen carbonate solution to give an organic phase. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated.

Step 3: 3-Ethyl-[1,2,4]triazole [4,3-a]pyridine

The concentrate was dissolved in tetrahydrofuran (8 mL), and then a tetrabutylammonium fluoride aqueous solution (809 mg of tetrabutylammonium fluoride dissolved in 0.5 mL of water) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Purification of the intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 Mg), yield 85%. 1H-NMR (300MHz, DMSO-d6): δ 8.48 (d, J = 6.6 Hz, IH), 7.91 (d, J = 9.3 Hz, IH) 7.51 (t, J = 8.1 Hz, 1H), 7.15 (t , J = 6.6 Hz, 1H), 5.34 (s, 1H). MS m / z (ESI): 144.1 [M+H].

Using different pyridyl pyridine, mercaptopyrimidine and decylpyrazine as raw materials, a synthesis method similar to that of intermediate 1 is employed.

Intermediate 11: 3-Ethyl-6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine

First step: 2-benzyloxy-5-bromo-pyrimidine

5-Bromo-2-chloro-pyrimidine (10 g, 51.7 mmol) and benzyl alcohol (6.4 ml, 62 mmol) were dissolved in N,N-dimethylformamide (140 mL), and t-butanol was added thereto. Potassium (6.96 g, 62 mmol) was reacted at room temperature for 2 h. After the reaction, Water was added to the reaction liquid to precipitate a solid. The solid was collected by filtration under reduced pressure, the filter cake was washed with small amount of methanol, and dried to give 2-benzyloxy-5-bromo - pyrimidine (white solid, 10.2 g -NMR (400MHz, CD 3 OD): 8.65 (2Η, d, J=0.8 Hz) 7.44-7.47 (2Η, m), 7.31-7.44 (3Η, m), 5.42 (2Η, s) MSm/z (ESI): 265.80 [M+H].

Step 2: 4-(2-Benzyloxy-pyrimidin-5-yl)-morpholine

2-Benzyloxy-5-bromo-pyrimidine (5.3 g, 20 mmol) and morpholine (2.1 mL, 24 mmol) were dissolved in 1,4-dioxane (60 mL) under argon Pd ₂ dba) ₃ (920 mg, 1 mmol), 2- (; di-tert-butylphosphino)-biphenyl (1.2 g, 4 mmol) and sodium tert-butoxide (2.3 g, 24 mmol), mixture Heat to 50 ^Q C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature, and water was added to the mixture, and the mixture was evaporated. Pyrimidin-5-yl)-morpholine (yellow solid, 4.75 g). 1H-NMR (400MHz, CD ₃ OD): 8.29(2H, s), 7.43-7.45(2Η, m), 7.27-7.37(3Η, m), 5.38(2Η, s), 3.83(4H, t, J = 4.8 Hz), 3.11 (4H, t, J = 4.8 Hz MS m/z (ESI): 271.90 [M+H].

Step 3: 5-morpholine-4-yl-pyrimidine-2-ol

4-0 (; Benzyloxy)pyrimidin-5-yl)morpholine (4.75 g, 17.489 mmol) was dissolved in 4N hydrogen chloride in dioxane (57 mL) and heated to 50 ^Q C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with petroleum ether and dried to give 5- morpholine-4-yl-pyrimidine-2-ol (yellow solid, 3.81 g). 1H-NMR (400 MHz DMSO-d6): 8.56 (2 s, s), 3.71 (4H, t, J = 4.8 Hz), 3.02 (4 Η, t, J = 2.0 Hz). MSm/z (ESI):

181.95[M+H

Step 4: 4-(2-Chloro-pyrimidin-5-yl)-morpholine

5-morpholine-2-hydroxypyrimidine hydrochloride (3.76 _& 17.3 mmol) and diethyl aniline (5.54 ml, 34.64 mmol) dissolved in acetonitrile (75 ml), and phosphorus oxychloride (8 mL, 86.6) Methyl), then heated to reflux for 3.5 h. After the reaction is completed, it is cooled to room temperature, and the mixture is neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -Chloro-pyrimidin-5-yl)-morpholine (yellow solid, 2.26 g) ^-NMRi^OMMz^DCls): 8.22 (2H, s), 3.87 (4 Η, t, J = 4.8 Hz), 3.20 (4 Η , t, J = 4.8 Hz). MS m/z (ESI): 195.90 [M+H].

Step 5: (5-morpholine-4-yl-pyrimidin-2-yl)-oxime

4-(2-Chloropyrimidin-5-yl)morpholine (2.06 g, 10.34 mmol) was dissolved in ethanol (6 mL), then EtOAc (EtOAc, EtOAc (EtOAc) . After the completion of the TLC reaction, the mixture was cooled to room temperature, and a solid was precipitated, which was filtered under reduced pressure. The filter cake was washed with cold water and dried to give (5-morpholine-4-yl-pyrimidin-2-yl)-indole (yellow solid, 1.57 g) . 1H-NMR (400 MHz, CD ₃ OD): 8.18 (2 Η, s), 3.83 (4 Η, t, J = 4.8 Hz), 3.04 (4 Η, t, J = 4.8 Hz). MS m/z (ESI): 196.00 [M+H].

Step 6: Trimethylsilyl-propionic acid N'-(5-morpholine-4-yl-pyrimidin-2-yl)-hydrazide

3-Methylsilylpropanoic acid (1.49 g, 14.478 mmol) and 4-methylmorpholine (0.97 mL, 8.86 mmol) were dissolved in anhydrous ethyl acetate (30 mL), and isopropyl chloroformate was added thereto. ester (2M solution, 4.43 mL, 8.86 mmol), stirred at room temperature after 3h, the organic phase washed with water, saturated NaHC0 ₃ solution and saturated NaCl solution, the organic phase was evaporated to dryness, the residue was dissolved in anhydrous tetrahydrofuran (20 mL), the (5-Morpholin-2-yl)indole (1.57 g, 8.06 mmol) was added slowly, and stirred at room temperature for 0.5 h. After the TLC reaction was completed, water was added thereto, extracted with dichloromethane, dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness eluting with silicagel g 1H-NMR (400MHz, CDC1 ₃ ): δ 8.15 (2H, s), 3.84 (4H, t, J = 4.8 Hz), 3.05 (4H, t, J = 4.8 Hz), 0.18 (9H, s). MS m / z (ESI): 319.90 [M+H].

Step 7: 6-morpholine-4-yl-3-trimethylsilylethidyl-[1,2,4]triazole [4,3-a]pyrimidine

N-methylsilyl-propionic acid N'-(5-morpholine-4-yl-pyrimidin-2-yl)-hydrazide (1.98 g, 6.23 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen Triphenylphosphine (1.96 g, 7.47 mmol), azide trimethylsilane (1.07 mL, 8.10 mmol) and diisopropylazodicarboxylate (1.35 mL, 6.85 mmol) were added. This mixture was stirred at room temperature for 3 h. After the TLC reaction was completed, water was added thereto, and dichloromethane was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, and evaporated to silica gel column chromatography to afford 6-morpholine-4-yl-3-trimethyl Silyl-branched-[1,2,4]triazole [4,3-a]pyrimidine (987 mg, yellow solid). 1H-NMR (400MHz, CDC1 ₃ ): δ 8.63 (1H, d, J = 2.8 Hz), 7.56 (1H, d, J = 2.8 Hz), 3.92 (4H, t, J = 4.8 Hz), 3.18 (4H , t, J = 4.8 Hz), 0.32 (9H, s). MSm/z (ESI):

301.90[M+H] o

Step 8: 3-Ethyl -6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine

The intermediate 3-ethylidene-6-morphinolin-4-yl-[1,2,4]triazole [4,3-a]pyrimidine (yellow solid) was synthesized in the same manner as in the third step of Intermediate 1. , 228mg) o 1H-NMR (400MHz, CDC1 ₃ ): δ 8.68(1H, d, J=2.8Hz), 7.64(1H, d, J=2.8Hz), 3.93(4H, t, J=4.8Hz) , 3.83 (1H, s), 3.20 (4H, t, J = 4.8 Hz). MS m/z (ESI): 229.95 [M+H] o

First step: 5-cyclopropyl -2-fluoro-pyridine

5-Bromo-2-fluoro-pyridine (1.41 g, 8 mmol) and cyclopropylboronic acid (1.37 g, 16 mmol) were mixed in toluene/water (26 mL / 1.3 mL), and potassium phosphate (7.46) was added thereto. g, 28 mmol), Pd(OAc) ₂ (90 mg, 0.4 mmol) and tricyclohexylphosphine (224 mg, 0.8 mmol) were added thereto under argon atmosphere, and the mixture was heated to 80 ^Q C for 16 h. After the completion of the TLC reaction, the mixture was cooled to room temperature, water was added thereto, ethyl acetate was evaporated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Pyridine (yellow oil, 647 mg). 1H-NMR (400MHz, CD ₃ OD): δ 7.99(1H, s), 7.59 (1Η, td, J=10.0, 2.0Hz), 6.95(1H, d, J=8.4Hz), 1.95-1.99 (lH , m), 1.01-1.05 (2H, m), 0.69-0.73 (2H, m). MS m/z (ESI): 138.00 [M+H].

Second step: (5-cyclopropyl-pyridin-2-yl)-oxime

5-Cyclopropyl-2-fluoro-pyridine (0.32 g, 2.34 mmol) was dissolved in ethanol (2 mL). EtOAc (EtOAc:EtOAc: After the completion of the TLC reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification, direct injection into the next reaction. MS m/z (ESI): 150.00 [M+H]. The third step: trimethylsilyl-propionic acid N'-(5-cyclopropyl-pyridin-2-yl)-hydrazide

3-Methylsilylpropanoic acid (0.41 g, 2.86 mmol), 4-methylmorpholine (0.29 mL, 2.6 mmol) was dissolved in ethyl acetate (10 mL), and isopropyl chloroformate was added thereto. 2M, 1.3 mL, 2.6 mmol), after stirring at room temperature for 3 h, the reaction solution was washed with water, saturated NaHC0 ₃ solution and saturated NaCl solution, evaporated to dryness, and the residue was dissolved in tetrahydrofuran (10 mL) and then slowly added thereto ( 5-cyclopropyl-2-yl)indole (0.35 g, 2.34 mmol), stirred at room temperature for 0.5 h. After TLC was applied, water was added and dichloromethane was evaporated. The solvent was evaporated to dryness crystalljjjjlilililililililililililili 1H-NMR (400MHz, CDC1 ₃ ): δ 7.90 (1H, d, J = 1.6 Hz), 7.26-7.29 (lH, m), 6.69 (lH, d, J = 8.4 Hz), 1.77-1.83 (1H, m), 0.90-0.95 (2H, m), 0.58-0.62 (2H, m), 0.22 (9H, s). MS m/z (ESI): 273.95 [M+H].

Fourth step: 6-cyclopropyl-3-trimethylsilylethyl bromide-[1,2,4]triazole [4,3-a]pyridine

N-methylsilyl-propionic acid N'-(5-cyclopropyl-pyridin-2-yl)-hydrazide (0.1 g, 0.366 mmol) was dissolved in tetrahydrofuran (2 mL) and added under N ₂ Triphenylphosphine (0.115 g, 0.439 mmol), azide trimethylsilane (0.063 ml, 0.476 mmol) and diisopropylazodicarboxylate (0.079 mL, 0.403 mmol). The mixture was stirred at room temperature for 2 h. After TLC was applied, water was added, dichloromethane was evaporated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -trimethylsilylethylidene-[1,2,4]triazole [4,3-a]pyridine (yellow oil, 44 mg) 1H-NMR (400 MHz, CDCl ₃ ): δ 7.91 (1H , s), 7.73 (1Η, d, J=9.2Hz), 7.07(1H, dd, J=9.2, 1.2Hz), 1.95-1.99(1H, m), 1.03-1.08(2H, m), 0.74- 0.78 (2H, m), 0.34 (9H, s). OP

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First step: 3-iodo-imidazole [l,2-a]pyridine

Imidazole [l,2-a]pyridine (1.18 g, 0.1 mol) was dissolved in N,N-dimethylformamide (10 mL), and N-iodosuccinimide was added portionwise in an ice bath. (2.7 _& 0.12 m _O l), continue to stir at room temperature overnight. After the reaction was completed, a saturated sodium hydrogencarbonate solution (20 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour, and then the mixture was stirred for 1 hour to precipitate a yellow solid. The solid was collected by filtration under reduced pressure. Imidazole [l,2-a]pyridine (yellow solid, 1.85 g), yield 76%. 1H-r R (300MHz, DMSO-d6): δ 8.35 (d, J=5.4Hz, IH), 7.75(s, 1H), 7.62(d, J=6.9Hz IH), 7.36(t, J=5.4 Hz, 1H), 7.09 (d, J = 5.4 Hz, 1H). MS m / z (ESI): 244.9 [M+H].

Step 2: 3-Trimethylsilylethylidene-imidazole [l,2-a]pyridine

3-Isoimidazo[l,2-a]pyridine (3.6 g, 15 mmol) was dissolved in N,N-dimethylformamide (30 mL), and ethyltrimethylsilane (2.16) was added thereto. mL, 19.5 mmol) and diisopropylethylamine (3.72 mL, 22.5 mmol), and the mixture was bubbled with nitrogen for 5 min and placed in a sealed tube, and then was added tetratriphenylphosphine palladium (867 mg, 0.75 mmol) and Cuprous iodide (214 mg, 1.125 mmol) was heated to 60 ^Q C under nitrogen for overnight reaction. After completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated to ethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate

Step 3: 3-Ethyl-imidazole [l,2-a]pyridine

The above oil was dissolved in tetrahydrofuran (20 mL), and then a solution of tetrabutylammonium fluoride (809 mg of tetrabutylammonium fluoride in 0.5 mL of water) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 mg) was obtained, eluted, yield, yield: 85% o 1H-NMR (300 MHz, CDC1 ₃ ): δ 8.29 ( d, J = 5.4 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.28 (m, 1H), 6.94 (d, J = 5.4 Hz, 1H), 3.81 (s, 1H). MS m/z (ESI): 143.1 [M+H] o

Taking 6-chloro-imidazole [l,2-a]pyridine, 6-chloro-imidazole [l,2-b]pyridazine, imidazo[l,2-b]pyridazine, 1-methyl-1H-imidazole, The following intermediates 15 to 20 were synthesized by a similar method to Intermediate 14 using 1H-carbazole and 1H-pyrazole [3,4-b]pyridine as starting materials. .

(300MHz, DMSO-d6): δ 13.4(s, IH), 7.69(d, J=8.4Hz, 1H), 7.58(d,

19 143.1

J=8.4Hz, IH), 7.40(t, J=7.5Hz, IH), 7.21(t, J=7.5Hz, IH), 4.47(s, IH)

(300MHz, DMSO-d6): δ 14.0(s, IH), 8.59 (dd, J=1.8, 4.8Hz, 1H),

20 144.2

2.21 (d, J = 4.8 Hz, IH), 7.30 (dd, J = 4.8, 7.8 Hz, lH), 4.56 (s, IH)

(400MHz, CDC1 ₃ ): 5 9.14 (s, 1H), 8.23 (d, J=4.4Hz, IH) , 8.04(d,

21 144.1

J=4.4Hz, lH), 8.00(s, lH), 3.85(s, IH). Intermediate 22: 3-

First step: Imidazole [l,2-a]pyridine 2-carboxylic acid ethyl ester

2-Aminopyridine (3 g, 32 mmol) was dissolved in absolute ethanol (15 mL), and ethyl 3-bromopyruvate (6.4 _& 38 mmol) was slowly added dropwise to the above solution under ice-cooling, and added dropwise. After completion, the reaction solution was heated to 80 ° C and stirred for 2 hours. The reaction was monitored by thin-layer chromatography. The solvent was evaporated to dryness, and the residue was evaporated, evaporated, evaporated, evaporated, concentrate. The concentrate was separated and purified by silica gel column chromatography toield of Intermediate <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDCI3): δ 8.17(s, 1H), 8.12 (d, J=6.0Hz, 1H), 7.67 (d, J=6.0Hz, IH), 7.22-7.24(m, IH), 6.86 (t, J = 6.0 Hz, IH), 4.42-4.48 (q, J = 6.0 Hz, 2H), 1.41-1.45 (t, J = 6.0 Hz, 3H). MS m/z (ESI): 190.2 [M+H

Step 2: Imidazole [l,2-a]pyridine-2-yl-methanol

A solution of 2 μm of imidazo [l,2-a]pyridine-2-carboxylate (10.5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to lithium tetrahydrogenate (1.2) cooled in ice bath. _& 31.5 mmol) in tetrahydrofuran (5 mL). After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and the reaction was continued for 2 hours until the end of the reaction. The reaction solution was again cooled with an ice bath, and the mixture was slowly quenched with 15% aqueous sodium hydroxide and stirring was continued for one hour. Filtration under reduced pressure, and the filtrate was concentrated and purified using silica gel column chromatography to afford intermediate <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDC1 ₃ ): δ 7.98 (d, J = 3.0 Hz, IH), 7.43 (d, J = 9.0 Hz, 2H), 7.05-7.10 (m, IH), 6.89 (s, 2H) , 6.66-6.89 (m, 1H), 4.73 (s, 2H MS m/z (ESI): 148.2 [M+H].

Step 3: 2-fluoromethyl-imidazole [l,2-a]pyridine

The imidazole [l,2-a]pyridin-2-yl-methanol (0.5 g, 3.38 mmol) was dissolved in dichloromethane (8 mL), and diethylamine trifluorotide was slowly added dropwise to the above solution under ice cooling. Sulfur reagent (0.5 mL, 4.10 mmol), continue to react at room temperature overnight. After the reaction is completed, the reaction solution is cooled to 0 ° C, quenched with saturated ammonium chloride solution, extracted with dichloromethane, and organic phase is used separately. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. a]pyridine (yellow solid, 0.4 g), yield 79% 1H-NMR (300MHz, CDC1 ₃ ): δ 8.10 (d, J = 6.0 Hz, IH), 7.65 (s, IH), 7.58 (d, J = 9.0Hz, IH), 7.17-7.2 l(m, 1H), 6.78-6.81(m, 1H), 5.61(s, 1H), 5.49(s, 1H) MS m/z (ESI): 150.2[ M+H]. Step 4: 2-fluoromethyl-3-iodo-imidazole [l,2-a]pyridine

The intermediate 2-fluoromethyl-3-iodo-imidazole [l,2-a]pyridine (yellow solid, 260 mg) was obtained by the analogous procedure of Intermediate 14 . 1H-NMR (300MHz, CDC1 ₃ ): δ 8.13 (d, J = 7.2 Hz, IH), 7.60 (d, J = 7.2 Hz, 1H), 7.26-7.30 (m, IH), 6.94-6.97 (m, IH), 5.55 (d, J = 66.9 Hz, 2H). MS m / z (ESI): 276.1 [M+H]. Step 5: 2-fluoromethyl-3-trimethylsilyl b-imidazole [l,2-a]pyridine

The intermediate 2-fluoromethyl-3-trimethylsilylethyl bromide-imidazole [l,2-a]pyridine (yellow solid, 300 mg) was obtained. 1H-NMR (300MHz, CDC1 ₃ ): δ 8.23 (d, J = 5.4 Hz, IH), 7.64 (d, J = 6.6 Hz, IH), 7.28-7.32 (m, IH), 6.97 (d, J = 5.4 Hz, IH), 5.58 (d, J = 36.0 Hz, 2H).

Step 6: 3-Ethyl-2-fluoromethyl-imidazole [l,2-a]pyridine

The intermediate 3-ethylidene-2-fluoromethyl-imidazole [l,2-a]pyridine (yellow solid, 106 mg) was obtained by the procedure of the intermediate step. 1H-r R (300MHz, CDC1 ₃ ): δ 8.28(d, J=6.3Hz, IH), 7.66(d, J=9.3Hz, 1H), 7.33(t, J=6.9Hz, IH), 6.97( t, J = 6.9 Hz, IH), 5.60 (d, J = 48.0 Hz, 2H), 3.93 (s, 1H). MS m/z (ESI): 174.1 [M+H] o

Using aminopyridine, aminopyridazine, aminopyrimidine and 1-bromo-butan-2-one, 1-bromo-propan-2-one, 2-bromo-1-cyclopropyl-ethanone as raw materials, using intermediate 22 A similar method was synthesized to give the following intermediate 23 to intermediate 28.

Intermediate 29: 2-Difluoromethyl-3-ethylidene-imidazole l,2-a]pyridine

First step: Imidazole [l,2-a]pyridine-2-carbaldehyde

Imidazole [l,2-a]pyridin-2-yl-methanol 500 mg, 3.38 mmol) was dissolved in dichloromethane (8 mL) and slowly added to the Dess-Martin reagent (1.7 _& 4.05) under ice cooling. Mm). After the completion of the reaction, the reaction was continued at room temperature for 2 h, and the reaction was completed by TLC. EtOAc (EtOAc m.). , filtered, concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography toield of intermediate <RTI ID=0.0>#</RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDC1 ₃ ) δ 10.157(s, IH), 8.15-8.17(m, 2H), 7.67-7.70 (dd, J=6.9, 0.6Hz, IH), 7.26-7.31(m, 1H) , 6.91-6.92(d, J=0.6Hz, lH)o MS m/z (ESI): 146.1 [M+H] o Second step: 2-difluoromethyl-imidazole [l,2-a]pyridine

The intermediate 2-difluoromethyl-imidazo[1,2-a]pyridine (yellow solid, 200 mg) was obtained in a similar manner to the intermediate step. H-NMR (300MHz, CDC1 ₃ ) δ 8.12-8.14(m, IH), 7.79(s, 1H), 7.62 (dd, J=6.9, 0.6Hz, IH), 7.22-7.26(m, IH), 6.85 (t, J = 51.4 Hz, IH), 6.87 (m, 1H). MS m/z (ESI): 168.1 [M+H].

Step 3: 2-Difluoromethyl-3-iodo-imidazole [l,2-a]pyridine

The intermediate 2-difluoromethyl-3-iodo-imidazole [l,2-a]pyridine (yellow solid, 270 mg) was synthesized using a similar method in the first step of Intermediate 14. o 1H-NMR (300 MHz, CDC1 ₃ δ 8.18-8.21(m, IH), 7.65(td, J=6.9, 0.9Hz, 1H), 7.31-7.35(m, IH), 6.99-7.03 (m, IH), 6.79(d, J=40.5 Hz, 1H). MS m / z (ESI): 294.1 [M+H].

Step 4: 2-Difluoromethyl-3-trimethylsilylethylidene-imidazole [l,2-a]pyridine

The intermediate 2-difluoromethyl-3-trimethylsilylethylidene-imidazole [l,2-a]pyridine (yellow solid, 170 mg) was obtained in a similar manner to the intermediate step. 1H-NMR (300MHz, CDC1 ₃ ) δ 8.25-8.28 (m, IH), 7.66-7.69 (m, IH), 7.32-7.38 (m, IH), 6.98-7.03 (m, 1 H), 6.90 (t , J = 54.3 Hz, 1H).

Step 5: 2-Difluoromethyl-3-ethylidene-imidazole [1, 2-a]pyridine

The intermediate 2-difluoromethyl-3-ethlyl-imidazo[1,2-a]pyridine (yellow solid, 76 mg 1H-NMR (300MHz, CDC1 ₃ ) δ 8.32 (d, J = 3.0Hz, IH), 7.68-7.70 (m, 1H), 7.35-7.39 (m, IH), 7.02-7.04 (m, IH), 6.91 (t, J = 40.8 Hz, 1H). MS m / z (ESI): 192.2 [M+H]. Intermediate 30: 2-Difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine

First step: 6-chloro-imidazole [l,2-b]pyridazine-2-carboxylic acid ethyl ester

6-Chloro-3-aminopyridazine (10 _& 77.2 mmol) was dissolved in absolute ethanol (120 mL), then ethyl bromopyruvate (11.70 mL, 92.6 mmol) was slowly added thereto, and the reaction mixture was added. Heat to reflux overnight. After the TLC reaction was completed, the reaction solution was cooled to room temperature, and most of the solvent was removed under reduced pressure. The residue was dissolved in saturated sodium bicarbonate and extracted with dichloromethane (50mL×3), and the organic phase was washed with water, saturated brine, anhydrous sulfuric acid The mixture was dried with EtOAc EtOAc EtOAc m. 1H-NMR (300MHz, CDC1 ₃ ): δ 8.44 (d, J = 0.6 Hz, 1H), 7.96 (dd, J = 6.9, 0.6 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 4.46 (q, J = 5.4 Hz, 2H), 1.43 (t, J = 5.4 Hz, 3H). MS m / z (ESI): 226.0 [M+H].

Step 2: Imidazole [l,2-b]pyridazine-2-carboxylic acid ethyl ester

Ethyl 6-chloro-imidazole [l,2-b]pyridazine-2-carboxylate (8.2 g, 36 mmol) was dissolved in methanol (250 mL), and 10% Pd/C (lg) Then, the system was replaced with hydrogen three times and continued to react at room temperature for 2 h. After completion of the TLC reaction, the catalyst was removed by filtration, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (1,2-b]pyridazine-2-carboxylic acid ethyl ester (yellow solid, 6.4 g). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.64-8.67(m, 2H), 8.54(s, IH), 7.54(d, J=4.5Hz, IH), 4.5 l(q, J=6.9Hz, 2H ), 1.47 (t, J = 6.9 Hz, 3H) o MS m/z (ESI): 192.1 [M+H].

Step 3: Imidazole [l,2-b]pyridazine-2-yl-methanol

Lithium tetrahydrogen aluminum (3.8 g, 100 mmol) was placed in a nitrogen-protected 250 mL three-necked flask, and anhydrous tetrahydrofuran (100 mL) was slowly poured into it under ice cooling, and slowly added to the bubble-free gas. Ethyl imidazo[l,2-b]pyridazine-2-carboxylate (6.4 _& 33.5 mmol) was reacted at room temperature for 4 h. After the reaction was completed by thin layer chromatography, the reaction solution was cooled to 0 ^Q C in an ice bath, and water (3.8 mL) and a 10% sodium hydroxide solution (3.8 mL) were slowly added dropwise thereto, and stirred for half an hour. Filtration under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford intermediate imid[l,2-b]pyridazin-2-yl-methanol (yellow solid, 2.7 g) o 1H-NMR (300MHz, CDC1 ₃ ): δ 8.28 (d, J=3.3Hz, 1H), 7.88-7.94 (m, 2H), 7.03 (dd, J = 9.0, 4.5 Hz, 1H), 4.88 (s, 2H). MS m/z (ESI): 150.1 [M+H]. Step 4: Imidazo[l,2-b]pyridazine-2-carboxaldehyde

Imidazo[l,2-b]pyridazin-2-ylmethanol (270 mg, 1.8 mmol) was dissolved in dichloromethane (20 mL). , 2.7 mmol) and sodium bicarbonate powder (457 mg, 5.4 mmol), continue to react at room temperature for 2 h. After the TLC detection reaction was completed, a saturated sodium thiosulfate solution (20 mL) was added to the reaction mixture, and after stirring for 10 minutes, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phase was combined. Washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. Mg), yield 90.0%. 1H-NMR (300MHz, DMSO-d6):

10.05(s, 1H), 8.98(s, 1H), 8.65(d, J=4.5Hz, 1H), 8.24(d, J=9.6Hz, 1H), 7.36(dd, J= 9.6, 4.2Hz, 1H ). MS m/z (ESI): 148.1 [M+H].

Step 5: 2-Difluoromethyl-imidazole [l,2-b]pyridazine

Imidazo[l,2-b]pyridazine-2-carboxaldehyde (350 mg 2.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C under ice-cooling, and slowly added dropwise thereto under nitrogen. After the dropwise addition of the ethylamine trifluoride reagent (0.58 ml, 4.76 mmol), the ice bath was removed and allowed to react at room temperature overnight. After the TLC detection reaction was completed, the reaction solution was cooled to 0 ^Q C in an ice bath, and a saturated sodium hydrogen carbonate solution was slowly added thereto to adjust the pH to 6-7, and the aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phase was combined. The organic layer was washed with water and aq. The residue was purified by silica gel column chromatography eluting elute 1H-NMR (300MHz, CDC1 ₃ ): 8.38 (dd, J = 4.2, 1.2 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J = 10.2, 1.2 Hz, 1H), 7.13 (dd, J = 9.6, 4.2 Hz, 1H), 6.88 (t, J = 55.2 Hz, 1H). MSm/z (ESI): 170.1 [M+H]

Step 6: 2-Difluoromethyl-3-iodo-imidazole [l,2-b]pyridazine

The intermediate 2-difluoromethyl-3-iodo-imidazole [l,2-b]pyridazine (white solid, 285 mg 1H-NMR (300MHz, CDC1 ₃ ) : 8.52 (dd, J=3.3, 1.2 Hz, 1H), 7.97 (dd, J=7.2, 1.2 Hz, 1H), 7.19 (dd, J=7.2, 3.3 Hz, 1H), 6.88 (t, J=40.2) Hz, 1H) MSm/z (ESI): 295.9 [M+H]. Step 7: 2-Difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine

Intermediate 14 was synthesized in a similar manner to the second step. 2-Difluoromethyl-3-ethylidene-imidazole

[l,2-b]pyridazine (white solid, 64 mg). 1H-NMR (300MHz, CDC1 ₃ ): 8.52-8.53(m, 1H), 8.03 (dd, J=6.3, 1.5Hz, 1H), 7.02-7.25(m, 1H), 6.93(t, J=40.5Hz , 1H), 3.93(s, 1H). MS m/z (ESI): 194.1 [M+H Intermediate 3 -ethyl-bromomethyl-IH-carbazole and 3-ethyl-bromo-2-methyl-2H-carbazole

Using a 1H-carbazole as a starting material, an intermediate a-1 (1.7 g, yellow solid) and a-2 (0.6 & yellow solid) were synthesized by the method of Journal of Organometallic Chemistry, 2000, 604, 2, 157-169. ). A-1 : 1H-NMR (300MHz, CDC13): δ 7.79 (d, J=8.1Hz, 1 H), 7.39-7.4 l(m, 2H), 7.24(m, IH), 4,07(s, 3H). M S m/z (ESI): 259.1 [M+H]. A-2: IH-NMR (300MHz, CDC13): δ 7.67-7.7 l(m, 2H), 7.30- 7.32(m, IH), 7.12-7.17(t, J=7.8Hz, lH), 4.23(s , 3H).

Using a-1 and a-2 as starting materials, the intermediate 3-ester-1-1-methyl-1Η-carbazole and 3-ethylidene-2-methyl-2H were synthesized by the same method as Intermediate 13. - carbazole. 3-ethylidene-1-methyl-1H-carbazole: 1H-NMR (300MHz, CDC1 ₃ ): δ 7.79 (d, J:::60 Hz, IH), 7.4 -7.43 (m, 2H), 7.22-7.24(m, IH), 4 08(s, 3H), 3.38(s, 1H). MS m/z (ESI): 157.2 [M 十 H]. 3-Ethyl-2-methyl-2H-carbazole: ^-NMR (300MHz, CDC1 ₃ ): 7.67-7.73 (m, 2H), 7.31 (td, J = 4.8, 0.9 Hz, 1H), 7.15 -7.19 (m, 1H), 4.26 (s, 3H), 3.90 (s, 1H). MS m/z (ESI): 157.1 [M+H Intermediate 32:: <RTI ID=0.0> Amide

First step: 1-bromomethyl-4-nitro-2-trifluoromethyl-benzene

1-Methyl-4-nitro-2-(trifluoromethyl)benzene (0.5 g, 2.5 mmol) was dissolved in glacial acetic acid (15 mL), then N-bromosuccinyl was added to the above solution. The imine (0.7 _& 3.7 mmol) and benzoyl peroxy (6 m _& 0.024 mmol) were heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. One step reaction.

Step 2: 4-(4-Nitro-2-trifluoromethyl-benzyl)-morpholine

The above concentrate was dissolved in dichloromethane (10 mL), then triethylamine (0.17 mL) and morpholine (0.11 mL, 0.12 mmol). After the completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the organic layer was separated, and the organic layer was evaporated. 4-Nitro-2-(trifluoromethyl)benzyl)morpholine (yellow solid, 2.8 g), yield 100%. 1H-NMR (300MHz, DMSO-d6): 8.50 (d, J = 8.4 Hz, IH), 8.40 (s, IH), 8.10 (d, J = 8.7 Hz, IH), 3.72 (s, 2H), 3.58 -3.61 (m, 4H), 2.35-2.45 (m, 4H). MS m / z (ESI): 291.1 [M+H].

Step 3: 4-morpholine-4-ylmethyl-3-trifluoromethyl-aniline

Dissolve 4-(4-nitro-2-(trifluoromethyl)benzyl)morphinphyrin (276 mg 0.95 mmol) in methanol (20 mL), replace the system with nitrogen, then add 10% palladium on carbon catalyst (100 mL) The reaction solution was stirred at room temperature for 2 hours under a hydrogen atmosphere, and the reaction was completed. The reaction mixture was filtered under reduced pressure and evaporated to ethylamine. 1H-丽R (300MHz, DMSO-d6): 7.28 (d, J=8.4Hz, 1H), 6.84(s, IH), 6.73(d, J=8.4Hz, 1H), 5.44(s, 2H), 3.52-3.55 (m, 4H), 3.37 (s, 2H), 2.29 (s, 4H MS m/z (ESI): 261.1 [M+H].

Step 4: 3-iodo-4-methyl-N-(4-morpholine-4-ylmethyl-3-trifluoromethyl-phenyl)-benzamide

3-iodo-4-methylbenzoic acid (0.25 g, 0.93 mmol) and 4-morpholine-4-methyl-3-trifluoromethyl-phenylamine (0.22 g, 0.85 mmol) were dissolved in N,N- Dimethylformamide (10 mL) was added to 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (0.39) under ice cooling. _& 1.02 mmol) and diisopropylethylamine (0.20 mL, 1.27 mmol). The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. 3-iodo-4-methyl-N-(4-morpholine-4-methyl-3-trifluoromethyl-phenyl)-benzamide (yellow oil, 0.23 g), yield 53% . 1H-NMR (300MHz, CDC1 ₃ ): 8.29 (d, J = 0.9Hz, IH), 7.85-7.90 (m, 3H), 7.74-7.80 (m, 2H), 7.34 (d, J = 6.0Hz, IH ), 3.72 (m, 4H), 2.48-2.50 (m, 7H). MS m/z (ESI): 505.1 [M+H].

Using 3-iodo-4-methyl-benzoic acid and 3-fluoro-5-iodo-4-methyl-benzoic acid as starting materials, using different piperazine and its derivatives, piperidine and its derivatives and high piperazine The following intermediate 33 to intermediate 51 were synthesized by the same method as Intermediate 32 by substituting a cyclic amine such as a azine or a derivative thereof for morpholine.

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CS.S.0/CT0ZN3/X3d Intermediate 52: N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

First step: 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester

4-Methyl-3-trifluoromethylbenzoic acid (2.0 g 9.80 mmol) and concentrated sulfuric acid (0.5 mL) were dissolved in anhydrous ethanol (30 mL) and heated to 85 ° C under N2 overnight. After the completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystals crystals 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester (light yellow oil, 2.2 g 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.26 (s, IH), 8.08 (dd, J = 6.0, 0.9 Hz, IH), 7.35 (d, J = 6.0 Hz, IH), 4.39 (q, J = 5.4 Hz, 2H), 2.52 (s, 3H), 1.39 (t, J = 5.4 Hz, 3H) MSm/z (ESI): 233.1 [M+H].

Second step: 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester

Ethyl 4-methyl-3-trifluoromethylbenzoate (2.2 g, 9.6 mmol) and benzoyl peroxide (0.02 _& 0.1 mmol) were dissolved in anhydrous carbon tetrachloride (100 mL). N-bromosuccinimide was added to the above reaction solution under nitrogen (1.9 _& 10.6 mmol), and the reaction mixture was heated to 85 ° C and stirred overnight. After the reaction was completed, most of the solvent was removed under reduced pressure. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Benzyl-3-trifluoromethyl-benzoic acid ethyl ester (light yellow solid, 1.4 g). 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.25 (d, J = 6.0 Hz, 1H), 8.21 (s , 1H), 7.80(d, J=6.0Hz, 1H), 4.72(s, 2H), 4.42(q, J=5.4Hz, 2H), 1.41(t, J=5.4Hz, 3H) MS m/ z (ESI): 311.0 [M+H].

Step 3: 4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester

Ethyl 4-bromomethyl-3-trifluoromethyl-benzoate (1.3 _& 4.4 mmol) was dissolved in anhydrous N,N-dimethylformamide

(10 mL), N-methylpiperazine (657 m _& 6.6 mmol) was added dropwise thereto under ice cooling, and the mixture was added dropwise, and the mixture was allowed to react at room temperature overnight. After the reaction, the reaction mixture was diluted with EtOAc EtOAc. The concentrate was purified by silica gel column chromatography eluting eluting elut elut eluting eluting . 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.20-8.24 (m, 2 Η), 7.97 (d, J = 7.2 Hz, 1H), 4.39 (q, J = 5.4 Hz, 2H), 3.72 (s, 2H), 2.85 (m, 4H), 3.72 (m, 4H), 2.29 (s, 3H), 1.41 (t, J = 5.4 Hz, 3H). MS m/z (ESI): 331.2 [M+H]

Step 4: 4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid

Methyl 4-((4-methylpiperazinyl)methyl)-3-trifluoromethylbenzoate (1.35 _& 4.1 mmol) was dissolved in methanol (15 mL). Aqueous sodium hydroxide solution (0.82 g of sodium hydroxide dissolved in 3.5 mL of water) was added and stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to about 6.0 with dilute hydrochloric acid and concentrated under reduced pressure. The concentrate was diluted with tetrahydrofuran, the solid was filtered, and the filtrate was concentrated to give 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid as a white solid. (300MHz, DMSO-d ₆ ): δ 8.48(s, IH), 8.27(s, 1H), 8.15(d, J=6.0Hz, IH), 7.82(d, J=6.0Hz, IH), 3.78( s, 2H), 3.20(m, 4H), 2.78(s, 3H), 2.7 l(m, 4H) MS m/z (ESI): 303.1 [M+H

Step 5: N-(3-Iodo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

The intermediate N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-piperazine small group methyl)-3-three was synthesized by the similar condensation method of Intermediate 32. Fluoromethyl-benzamide (light yellow solid, 908 mg). 1H-NMR (300MHz, DM SO-d ₆ ): δ 8.24(s, IH), 8.23(s, IH), 8.09(d, J=6.0Hz, 1H), 7.92(d, J=6.0Hz, IH ), 7.58 (dd, J=6.0, 1.5Hz, IH), 7.2 l(d, J=6.0Hz, 1H), 3.70(s, 2H), 2.23-2.55(m, 8H), 2.36(s, 3H) ), 2.27(s, 3H). MS m/z Si-3⁄41⁄2o -3⁄4 - -3⁄4i 5-3⁄4i ii-s ot7

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CS.S.0/CT0ZN3/X3d LLOL iOZ OAV 2-Bromomethyl-4-nitro-benzoic acid methyl ester (2 g, 10.9 mmol) was dissolved in tetrahydrofuran (6 mL). EtOAc (1 & 14.1 mmol) ), the reaction solution was heated and refluxed for 8 hours. The reaction solution was cooled to room temperature, a white solid was precipitated, filtered, and the filter cake was washed with a small amount of ethanol and dried to give 2-cyclopropylmethyl-5-nitro-2,3-dihydro-isoindole-1-one (yellow Solid, 1 g). Ifi-NMR (300MHz, DMSO-d ₆ ): δ 8.5 l (m, IH), 8.33 (m, IH), 7.9 l (m, 1H), 4.69 (s, 2H), 3.43 (m, 2H), 1.06 (m, IH), 0.53 (m, 2H), 0.343 (m, 2H). MS m/z (ESI): 233.1 [M+H]. The third step: 5-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one

The intermediate 5-amino-2-cyclopropanyl-2,3-dihydro-isoindole-1-one (yellow solid, 502 mg) was obtained using a similar procedure from Intermediate 32. 1H-NMR (300MHz, DM SO-d ₆ ): S 7.29 (m, IH), 6.59 (m, 2H), 5.71 (s, 2H), 4.34 (s, 2H), 3.26 (m, 2H), 0.98 (m, 1H), 0.48 (m, 2H), 0.24 (m, 2H). MS m/z (ESI): 203.1 [M+H

Step 4: N-(2-Cyclopropylmethyl-1-oxo-2,3-dihydro-IH-isoindole-5-yl 3-iodo-4-methylbenzamide

The intermediate Ν-(2-cyclopropylmethyl-1-oxo-2,3-dihydro-1Η-isoindol-5-yl)-3- is synthesized by a similar condensation method in the fourth step of intermediate 31. Iodo-4-methylbenzamide (yellow solid, 463 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.42 (s, IH), 8.32 (m, IH), 8.21 (s, IH), 7.77 (m, 2H), 7.42 (m, IH), 7.33 (m, IH), 4.49 (s, 2H), 3.45 (m, 2H), 2.48 (s, 3H), 1.03 (m, IH), 0.57 (m, 2H), 0.3 l (m, 2H). MS m/z (ESI): 447.1 [M+H]. Intermediate 55: N-(2-cyclopropylmethyl-3-oxo-2,3-dihydro-IH-isoindole-5-yl 3-iodo-4-methyl-benzamide

The same procedure as Intermediate 54 was carried out to give the intermediate N-(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindole-5-yl)-3-iodo-4. -Methyl-benzamide (orange solid, 490 mg).

First step: 2-bromomethyl-5-nitro-benzoic acid methyl ester

1H-NMR (300MHz, DM SO-d ₆ ): δ 8.57 (d, J = 6.0 Hz, IH), 8.43 (dd, J = 1.5, 6.0 Hz, IH), 7.90 (d, J = 6.0 Hz, IH) ), 5.07(s, 2H), 3.91(s, 3H). MS m / z (ESI): 274.0 [M+H].

Step 2: 2-Cyclopropylmethyl-6-nitro-2,3-dihydro-isoindole-1-one

1H-NMR (300MHz, DM SO-d ₆ ): δ 8.47 (dd, J = 1.5, 6.0 Hz, IH), 8.33 (d, J = 1.5 Hz, 1H), 7.91 (d,

J = 6.0 Hz, 1H), 4.73 (s, 2H), 3.42 (d, J = 5.4 Hz, 2H), 1.06 (m, 1H), 0.53 (m, 2H), 0.32 (m, 2H). MS m/z (ESI): 233.1 [M+H

The third step: 6-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one

1H-NMR (300MHz, DMSO-d ₆ ): δ 7.20 (d, J = 6.0 Hz, IH), 6.82 (s, IH), 6.78 (d, J = 6.0 Hz, IH), 5.28 (s, 2H) , 4.34 (d, J = 5.4 Hz, 2H), 0.99 (m, 1H), 0.49 (m, 2H), 0.27 (m, 2H). MS m/z (ESI): 203.1 [M+H

Fourth step: N-(2-cyclopropanyl-3-oxo-2,3-dihydro-IH-isoindole-5-yl)-3-iodo-4-methyl-benzamide

1H-NMR (300MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 6.0 Hz, IH), 7.93 (d, J=6.0Hz, IH), 7.59(d, J=6.0Hz, IH), 7.51(d, J=6.0Hz, IH), 4.53(s, IH), 2.88(s, 3H), 2.72(s, 2H), 2.44 (s, 3H), 1.05 (m, IH), 0.52 (m, 2H), 0.3 l (m, 2H). MS m / z (ESI): 447.1 [M+H]. Intermediate 56: 3-iodo-4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-benzamide

First step: 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-aniline

3-bromo-5-(trifluoromethyl)aniline (500 mg, 2.1 mmol), 4-methyl-1H-imidazole (205 mg, 2.5 mmol) and potassium carbonate (345 mg 2.5 mmol) and iodide Copper (60 m _& 0.3 mmol) and 8-hydroxyquinoline (44 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide (3 mL), argon was bubbled for 5 minutes, and the reaction mixture was heated to 120 ° C under argon atmosphere. Stir overnight. After completion of the reaction, the mixture was diluted with EtOAc EtOAc. The residue was separated and purified by silica gel column chromatography to give Intermediate 3- (4-methyl - imidazol-1-yl) -5-trifluoromethyl - phenylamine (yellow solid, 400 mg -NMR (300MHz, CDCl 3): δ 7.74(s, IH), 6.99(s, 1H), 6.92(s, 1H), 6.83(s, lH), 6.77(s, 1H), 4.13(s, 2H), 2.27(s, 3H). MS m / z (ESI): 242.1 [M+H].

Step 2: 3-iodo-4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-benzamide

Intermediate 3-iodo-4-methyl-N-[3-(4-methyl-imidazole) was synthesized by the similar condensation method of Intermediate 32.

-1-yl)-5-trifluoromethyl-phenyl]-benzamide (yellow solid, 355 mg). 1H-NMR (300MHz, CDCl ₃ ): δ 8.32 (s, IH), 8.18 (m, 2H), 7.79 (m, 3H), 7.38 (m, 2H), 7.09 (s, 1H), 2.51 (s, 3H), 2.30(s, 3H). MS m/z (ESI): 485.1 [M+H Intermediate 57: 3-iodo-4-benzamide

First step: 3-(1-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-aniline

3-Bromo-5-(trifluoromethyl)aniline (500 mg, 2.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolan-2-yl)-1H-pyrazole (655 mg, 3.1 mmol) and tetratriphenylphosphine palladium (121 mg, 0.1 mmol) and sodium carbonate (668 mg, 6.3 mmol) dissolved in water (3 In a mixed solvent of mL) and dioxane (6 mL), argon was bubbled for 5 minutes, heated to 80 ° C and stirred overnight. After completion of the reaction, the mixture was extracted with methylene chloride. The residue was purified by silica gel column chromatography eluting eluting eluting eluting _{iH-NMR (300MHz, CDCl 3} ): δ 7.73 (s, IH), 7.60 (s, IH), 7.06 (s, IH), 6.91 (s, IH), 6.75 (s, lH), 3.94 (s, 3H). MS m / z (ESI): 242.1 [M+H].

Step 2: 3-iodo-4-methyl-N-[3-(l-methyl-IH-pyrazol-4-yl)-5-trifluoromethyl-phenyl]-benzamide

The intermediate 3-iodo-4-methyl-N-[3-(l-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl was synthesized by the similar condensation method of Intermediate 32. Base-phenyl]-benzamide (yellow solid, 420 mg). 1H-NMR (300MHz, CDCl ₃ ): δ 8.32 (s, IH), 8.05 (m, 2H), 7.80 (s, 1H), 7.77 (m, 1H), 7.70 (m, 2H), 7.47 (s, IH), 7.34 (m, IH), 3.95 (s, 3H), 2.50 (s, 3H). MS m/z (ESI): 486.1 [M+H]. Intermediate 58: N-(3-imidazole-

The intermediate N-(3-imidazol-1-yl-5-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide (yellow solid, 235) Mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.32(s, IH), 8.18(m, 2H), 7.79(m, 3H), 7.38(m, 2H), 7.09(s, lH), 2.51(s, 3H). MS m/z (ESI): 4721. [M+H]. Intermediate 59: N-(3-Iodo-4-methyl-phenyl)-4-(4-methyl-imidazolium-1-yl)-3-trifluoromethyl-benzamide

3-Iodo-4-methylaniline _& 5.2 mmol) and 4-(4-methyl-1H-imidazolyl)-3-(trifluoromethyl)benzoic acid [synthesized by the method of WO2004/29038A1] (1.5 _& 7.1 mmol) was used as the starting material, and the intermediate N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-imidazole- 1-yl)-3-trifluoromethyl-benzamide (light yellow solid, 1.4 g, yield 56.3%). 1H-NMR (300MHz, CD ₃ OD): δ 9.48s, IH), 8.54 (s, 1H), 8.49 (s, IH), 8.32-8.34 (m, 4H), 7.96 (s, 1H), 7.66 ( Dd, J = 8.0, 2.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H). MS m / z (ESI): 486.2 [M+H]. Intermediate 60: N-[4-(4-Cyclopropylmethyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo -4-methyl-benzamide

4-[4-(3-Iodo-4-methyl-benzamide)-2-trifluoromethyl-]]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (450 mg, 0.73 mmol) was dissolved in dichloromethane (10 mL), and 4N hydrogen chloride in 1,4-dioxane solution (2 mL) was added dropwise under ice-cooling. 2 hours. Excess solvent and hydrogen chloride were removed under reduced pressure to precipitate a white solid (480 mg) which was used directly for the next step.

The above white solid (150 mg, 0.29 mmol) and cyclopropylcarbaldehyde (61 mg, 0.87 mmol) were dissolved in methanol (5 mL). Sodium borohydride solid (29 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight, and the mixture was monitored by thin-layer chromatography. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was combined and washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography toield toield of N-[4-(4-cyclopropylmethyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl -Phenyl]-3-iodo-4-methyl-benzamide (yellow solid, 120 mg). 1H-NMR (300MHz, CDCl ₃ ) S 9.18(s, IH), 8.37 (d, J=1.2Hz, IH), 7.95-7.97(m, 2H), 7.82-7.85 (dd, J=7.8, 1.2Hz , IH), 7.62-7.64 (d, J=8.1Hz, IH), 7.28-7.3 l(d, J=7.8Hz, 1H), 3.72(s, 2H), 3.18(t, J=2.1Hz, 2H ), 3.05-3.07(m, 2H), 2.77-2.82(m, 2H), 2.69-2.70(m, 4H), 2.46(s, 3H), 0.84-0.87(m, IH), 0.62-0.67(m , 2H), 0.59-0.61 (m, 2H), 0.21-0.23 (m, 2H). MS m/z (ESI): 572.1 [M+H

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CS.S.0/CT0ZN3/X3d LLOL iOZ OAV Step 4: 3-Iodo-4-(tetrahydro-2H-pyran-2-oxomethyl)aniline

1-(Tetrahydro-2H-pyran-2-oxomethyl)-3-iodo-4-nitrobenzene (400 mg, 1.1 mmol) iron powder (368 mg, 6.6 mmol) and ammonium chloride (528) Mg, 9.9 mmol) Dissolved in ethanol (5 mL) and water (5 mL). The reaction mixture was stirred at 80 ° C. After the reaction was completed, the mixture was filtered and evaporated to dryness. Washing, drying and evaporation of solvent gave a white solid (360 mg, 98%). 1H-NMR (CDC1 ₃ , 400ΜΗζ): δ 1.60_1.92 (m, 6Η), 3.57-3.59 (m, 1Η), 3.95_3.97 (m, 1H), 4.41_4.44 (m, 1H), 4.69_4.77(m, 2H), 6.67_6.70 (m, 1H), 7.20-7.28 (m, 1H), 8.68 (m, 1H). MS m/z (ESI): 333.8 [M+H].

Step 5: N-[3-Iodo-4-(tetrahydro-2H-Bpyran-2-oxomethyl)phenyl]-3-trifluoromethyl-4-(4-methylpiperazinyl) Small methyl)benzamide

3-Trifluoromethyl-4-(4-methylpiperazinylmethyl)benzoic acid (88 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (10 mL). N-diisopropylethylamine (66 L, 0.39 mmol) and B 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate ( 120 g, 0.31 mmol), after stirring for 5 min, 3-iodo-4-(tetrahydro-2H-pyran-2-oxomethyl)aniline (89 mg, 0.27 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to give a white solid (60 mg, 36%) o 1H-NMR (CD 3 OD, 400MHz): δ 1.70-1.92 (m, 6Η), 2.67 (br, 8H), 3.01 (s , 4H), 3.58— 3.61(m, 1H), 3.87(s, 2H), 3.95-3.97(m, 1H), 4.48-4.5 l(m, 1H), 4.74_4.90(m, 2H), 7.46 _7.48(m, 1H), 7.73-7.75(m, 1H), 8.01— 8.02(m, 1H), 8.19— 8.21(m, 1H), 8.30— 8.36(m, 2H). MS m/z( ESI): 617.7 [M+H]. Medium-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

First step: 3-iodo-4-methylbromomethylbenzoate

Methyl 3-iodo-4-methylbenzoate (200 mg, 0.7 mmol) was dissolved in carbon tetrachloride (5 mL). N-bromosuccinimide (180 mg, 1.0 mmol) Benzoyl peroxide (17.5 mg, 0.07 mmol) was stirred at 100 °C for 24 h. After the reaction was completed, the solvent was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj It was used in the next reaction without further purification.

Step 2: Methyl 3-iodo-4-hydroxymethylbenzoate

The above crude methyl 3-iodo-4-bromomethylbenzoate (300 mg) was dissolved in a mixed solvent of ethanol (14 mL) and water (3.6 mL), and sodium formate solid (220 mg, 2.1 mmol), 90 ° The reaction was stirred for 5 h. After completion of the reaction, most of the solvent was evaporated.

1H-NMR (CDC1 ₃ , 400MHz): δ 3.94 (s, 3H), 4.73 (s, 2H), 7.58 - 7.60 (m, 1H), 8.05_8.07 (m, 1H),

8.49-8.50 (m, 1H). MS m / z (ESI): 292.7 [M+H].

Step 3: Methyl 3-iodo-4-fluoromethylbenzoate

Methyl 3-iodo-4-hydroxymethylbenzoate (300 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), cooled in ice-cooling, and diethylamine trifluorosulfide was slowly added under argon ( 0.25 mL, 2.0 mmol), the ice bath was removed and the reaction was stirred for 24 h. After completion of the reaction, the solvent was evaporated. mjjjjjjjjjjjjj 1H-NMR (CDC1 ₃ , 400MHz): S 3.95 (s, 3H), 5.37 (s, 1H),

5.48(s, lH), 7.52-7.54(m, 1H), 8.07_8.09(m, 1H), 8.51(s, 1H). MS m / z (ESI): 294.7 [M+H]. Step 4: 3-iodo-4-fluoromethylbenzoic acid

Methyl 3-iodo-4-fluoromethylbenzoate (280 mg, 0.95 mmol) was dissolved in methanol (10 mL), 4N sodium hydroxide solution (0.88 mL, 3.5 mmol), and stirred at 75 ° C for 2.5 h . After the reaction is completed, the solvent is distilled off, and the residue is used.

2N Hydrochloric acid was adjusted to pH 3 and extracted with ethyl acetate twice. The organic layers were combined and evaporated to give 3-iodo-4-fluoromethylbenzene. Acid (white solid, 245 mg).

400ΜΗζ): 5.42(s, 1H), 5.54(s, 1H), 7.58— 7.60(m, 1H), 8.00— 8.02(m, 1H), 8.37(s, 1H). MS m / z (ESI): 280.7 [M+Na].

Step 5: 4-Fluoromethyl-3-iodo-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl-phenyl]-benzamide

3-Iodo-4-fluoromethylbenzoic acid (225 mg, 0.8 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (180 L, 1.09 mmol), 2-(7-azobenzotriazole) - hydrazine, hydrazine, hydrazine, Ν'-tetramethyluron hexafluorophosphate (610 mg, 1.6 mmol), stirred for 5 min, then added 3 -Trifluoromethyl-4-(4-methylpiperazinylmethyl)aniline (198 mg, 0.72 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to give 4-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl] -benzamide (white solid, 420 mg 1H-NMR (CD ₃ OD, 400 ΜΗζ): 2.49 (s, 4 Η), 2.92 (s, 3H), 3.01 (s, 4H), 3.79 (s, 2H), 5.43 (s, 1H), 5.54(s, 1H), 7.61— 7.63(m, 1H), 7.78— 7.80(m, 1H), 8.01— 8.05(m, 1H), 8.15(s, 1H), 8.48(s , 1H) MSm/z (ESI): 535.7 [M+H] Intermediate 66: 3-iodo-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl Phenyl-phenyl]-4-(tetrahydro-B-pyran-2-yloxymethyl)-benzene

First step: 3-iodo-4-(tetrahydro-2H-pyran-2-yloxy)methyl

Methyl 3-iodo-4-hydroxymethylbenzoate (300 mg, 1.0 mmol) and 3,4-dihydropyran (0.47 mL, 5.1 mmol) were dissolved in dichloromethane (10 mL). The sulfonic acid monohydrate (19.5 mg, 0.1 mmol) was stirred at room temperature and the solvent was evaporated. The residue was evaporated,jjjjjjjjjjjj Methyl oxy)methylbenzoate (colorless oil, 303 mg). 1H-NMR (CDC1 ₃ , 400 MHz): 1.60—1.82 (m, 6Η), 3.58— 3.61 (m, 1Η), 3.90—3.92 (m, 1H), 3.94(s, 3H), 4.52(d, 1H) , J = 14.4 Hz), 4.80 (d, lH, J = 17.2 Hz), 7.58 - 7.60 (m, 1H), 8.02_8.05 (m, 1H), 8.49_8.50 (m, 1H). MS m/z (ESI): 376.90 [M+H]

Step 2: 3-iodo-4-(tetrahydro-2H-pyran-2-yloxy)methylbenzoic acid

Methyl 3-iodo-4-(tetrahydro-2H-pyran-2-oxy)methylbenzoate (300 mg, 0.79 mmol) was dissolved in methanol (10 mL). mL, 2.9 mmol), stir at 75 °C for 3 h. After completion of the reaction, the solvent was evaporated, and the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methyl benzoic acid (white solid, 305 mg). 1H-NMR (DMSO-d6, 400MHz):

1.50— 1.78(m, 6Η), 3.50—3.52(m, 1Η), 3.77-3.82(m, 1Η), 3.94(s, 3Η), 4.46(d, 1H, J=13.8Hz), 4.67(d, 1 H, J = 13.8 Hz), 4.79 (s, 1H), 7.57 - 7.59 (m, 1H), 7.96 - 7.98 (m, 1H), 8.33 (s, 1H). MS m/z (ESI): 384.7 [M+Na]

Step 3: N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-(tetrahydro-2H-pyran-2 -oxymethyl)benzamide

3-iodo-4-fluoromethylbenzoic acid (1.08 g, 2.98 mmol) was dissolved in N,N-dimethylformamide (40 mL). N,N-diisopropylethylamine (672 L) , 4.07 mmol) 卩 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (1.23 g, 3.23 mmol), after stirring for 5 min Further, 3-trifluoromethyl-4-(4-methylpiperazinyl-1-methyl)aniline (742 mg, 2.72 mmol) was added, and the mixture was stirred at room temperature for 26 h. After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to afford N-(4-(4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4- (tetrahydro-2H) - pyran-2-oxomethyl)benzamide (white solid, 1.1 g). 1H-NMR (CD ₃ OD, 400 MHz): 1.60 - 1.92 (m, 6 Η), 2.67 (s, 7 Η), 3.01 (s, 4H), 3.59 - 3.61 (m, 1H), 3.73 (s, 2H) , 3.91— 3.96(m, 1H), 4.53—4.57(m, 1H), 4.78— 4.84(m, 2H), 7.63-7.65(m, 1H), 7.77-7.79(m, 1H), 7.96-8.00 ( m, 2H), 8.15 (s, 1H), 8.44 (s, 1H). MS m/z (ESI): 617.70 [M+H]. Intermediate 67: 4-Difluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

First step: 4-formyl-3-iodo-benzoate ³

Methyl 3-iodo-4-hydroxymethylbenzoate (1 g, 3.4 mmol) was dissolved in dichloromethane (20 mL) EtOAc (EtOAc:EtOAc: 863 mg, 10.3 mmol), stir the reaction for 5 h at room temperature. After the reaction was completed, the mixture was evaporated. The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc 1H-NMR (CDC1 ₃ , 400 MHz): δ 3.98 (s, 3 Η), 5.54 (s, 1 Η), 7.93- 7.95 (m, 1 Η), 8.11— 8.12 (m, 1 Η), 8.63 ( s, 1 Η), 10.14(s, 1 Η). MS m / z (ESI): 291.8 [M+H].

Step 2: Methyl 3-iodo-4-difluoromethylbenzoate

Methyl 3-iodo-4-oxobenzoate (920 mg, 3.1 mmol) was dissolved in dichloromethane (10 mL), cooled in ice-cooled, and then diethylamine trifluorosulfide reagent was slowly added under argon ( 777 L, 6.3 mmol), after the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was evaporated. EtOAcjjjjjjjjjj 1H-NMR (CDCl ₃ , 400 MHz): δ 3.97 (s, 3 H), 6.80 (t, 1H, J = 56 Hz), 7.70-7.72 (m, 1H), 8.12_8.14 (m, 1H), 8.56 (s, 1H). MS m/z (ESI): 312.7 [M+H] o

The third step: 3-iodo-4-difluoromethylbenzoic acid

Methyl 3-iodo-4-difluoromethylbenzoate (900 mg, 2.88 mmol) was dissolved in methanol (10 mL). 4N aqueous sodium hydroxide (2.6 mL, 10.4 mmol) The reaction was 2.5 h. After the end of the reaction, the solvent was evaporated, and the residue was evaporated to m. The organic layers were combined and evaporated to dryness crystals crystals 1H-NMR (CDC1 ₃ , 400 MHz): δ 6.82 (t, 1H, J = 56 Hz), 7.74-7.76 (m, 1H), 8.18 - 8.21 (m, 1H), 8.63 (s, 1H). MS m / z (ESI): 298.7 [M+H].

Step 4: N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylbenzamide

3-iodo-4-difluoromethylbenzoic acid (860 mg, 2.88 mmol) was dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (668 L) , 4.04 mmol) 2-(7-azobenzotriazole)-N,N,N,,N,-tetramethylurea hexafluorophosphate (1.2 g, 3.2 mmol), stirred for 5 min, then added 3-Trifluoromethyl-4-(4-methylpiperazinyl-1-methyl)phenylamine (737 mg, 2.69 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to afford N-(4-(4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylbenzene Formamide (white solid, 1.5 g). 1H-NMR (CD ₃ 0D, 400MHz): δ 2.76(br, 4 Η), 2.90(s, 3 Η), 3.29(br, 4 Η), 3.78(s, 2 Η), 6.94(t, 1 Η , J=56Hz), 5.54(s, 1 H), 7.75- 7.82(m, 2 H), 7.99-8.16(m, 3 H), 8.53(s, 1 H).MSm/z (ESI): 554.7 [M+H]. Intermediate 68: Amine

First step: bromomethyl- ₂ -iodo-4-nitro-benzene

3-iodo-4-methylnitrobenzene (263 mg, 1.0 mmol) was dissolved in carbon tetrachloride (5 mL), then N-bromosuccinimide (180 mg, 1.0 mmol) was added and Benzoyl peroxide (17.5 mg, 0.07 mmol) was stirred at 100 °C for 24 h. After the reaction was completed, the solvent was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Not entering One-step purification was used directly for the next reaction.

Step 2: Iodine-4-nitro-benzyl)-4-methyl-piperazine

Dissolve 1-bromomethyl-2-iodo-4-nitro-benzene in dichloromethane (10 mL) and add 4-methylpiperazine (120 m _& 1.2 mmol) once at room temperature with stirring. Stir overnight. After completion of the reaction, the mixture was diluted with water and dichloromethane, and the organic layer was evaporated. EtOAcjjjjjjjjjjj -Nitro-benzyl)-4-methyl-piperazine (yellow solid, 250 mg). ESI-M S m/z 362 (M + H) ⁺ third step: 1-(2-cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine

1-(2-Iodo-4-nitro-benzyl)-4-methyl-piperazine (250 mg, 0.95 mmol), cyclopropylboronic acid (163 mg, 1.9 mmol), potassium phosphate powder (700 m _& 3.3 mmol) was mixed with N,N-dimethylformamide (10 mL) in a reaction flask. After bubbling nitrogen for 10 minutes, the catalyst palladium acetate (22 m _& 0.095 mmol) and tricyclohexylphosphine were quickly added. Ligand (53 mg, 0.19 mmol), the mixture was reacted at room temperature under nitrogen for 24 hours. After completion of the reaction, the mixture was extracted with methylene chloride. The organic layer was washed with EtOAc EtOAc. 4-Nitro-pyrimidinyl)-4-methyl-piperazine (yellow solid, 160 mg).

Step 4: 3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-aniline

The reduced iron powder (637 m _& 11.37 mmol) was placed in a 25 mL reaction flask, 5 mL of water and 0.5 mL of glacial acetic acid were added, heated to reflux and stirred for 20 minutes. A solution of lO cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine (626 m _& 2.27 mmol) in ethanol (1 mL) was added to the reaction mixture. The pH of the system was adjusted to 8 to 9 with a saturated sodium carbonate solution while hot. After the system was cooled to room temperature, the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave 3-cyclopropyl-4-(4-methyl-piperazinylmethyl)-phenylamine (yield: ¹ l·^-MR (400MHz, CDC1 ₃ ) δ 7.04 (d, J=8.0Hz, 1H), 6.46 (dd, J=8.0, 2.4Hz, 1H), 6.30(d, J=2.4Hz, 1H) , 3.59 (m, 4H), 3.50 (s, 2H), 2.43 (m, 4H), 2.27 (s, 3H), 2.13 (m, 1H), 0.89 (m, 2H), 0.59 (m, 2H). ESI-M S m/z 246 (M + H) Step 5: N-[3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-6- Difluoromethyl-5-iodo-benzamide

6-Difluoromethyl-5-iodo-benzoic acid (74 mg, 0.245 mmol), 3-cyclopropyl-4-(4-methyl-piperazinemethylidenemethyl)-aniline (40 mg, 0.163 Ment) and 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (94 mg, 0.245 mmol) dissolved in N, N-dimethyl N,N-dimethylformamide (42 m _& 0.326 mmol) was slowly added to the carbamide (3 mL) and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and purified to silicagel eluting -Difluoromethyl-5-iodo-benzamide (yellow oil, 72 mg). ESI-M S m/z 526 (M + H)+

3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 5-iodo-6-methyl-benzoic acid, 6-fluoromethyl-5-iodine- Benzoic acid was used as the starting material, and the following intermediate 69 N-[3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-5 was synthesized by the same procedure as Intermediate 68. -iodo-6-methyl-benzamide, ESI-M S m/z 491 (M+H) and intermediate 70 N-[3-cyclopropyl-4-(4-methyl-piperazine-1 /z 509 (M+H).

Intermediate 69 Intermediate 70 Preparation Examples

General Procedure One: Dissolve the aryl b-block intermediate (1.1 eq), the bromo or iodo-benzamide intermediate (1 eq.), N,N-diisopropylethylamine (2 eq.) in In anhydrous N,N-dimethylformamide, after bubbling nitrogen for 10 minutes, tetrakistriphenylphosphine palladium (5 mol%) and cuprous iodide (7.5 mmol%) were quickly added to the above solution. The reaction mixture was heated and stirred at 60 °C for 18 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate and ethyl acetate. Filter and concentrate under reduced pressure. The concentrate is separated and purified by silica gel column chromatography. Target compound. Example 1: 4-Methyl-N-(4-morpholin-4-methyl-3-trifluoromethyl-phenyl)-3-[1,2,4]triazole [4,3-a Pyridine-3-ethylidene-benzamide

3-Ethyl-[1,2,4]triazole [4,3-a]pyridine (24 mg, 0.168 mmol), 3-iodo-4-methyl-N-(4-morpholine- 4-Methyl-3-trifluoromethyl-phenyl)-benzamide (74 mg 0.146 mmol) N,N-diisopropylethylamine (42 L, 0.25 mmol) dissolved in anhydrous N, N In dimethylformamide (1 mL), after bubbling nitrogen for 10 minutes, the same tetrakistriphenylphosphine palladium (10 m _& 5 mol %) and cuprous iodide (3 m _& 7.5 mmol %) were placed in 10 The mL is sealed in the tube. The reaction mixture was heated and stirred at 60 ° C for 18 hours. After the reaction was completed, the mixture was stirred and evaporated, evaporated, evaporated, evaporated. concentrate. The concentrate was separated and purified by silica gel column chromatography to give the title compound 4-methyl-N-(4-morpholin-4-methyl-3-trifluoromethyl-phenyl)-3-[1,2,4] Triazole [4,3-a]pyridine-3-ethylidene-benzamide (yellow solid, 27 mg - NMR (300MHz, CDC1 ₃ ): δ 8.3 l (m, 2 Η), 8.12 (s, 1H) , 7.07-7.02(m, IH), 3.74-3.71(m, 4H), 3.64(s, 2H), 2.50(s, 3H), 2.49(m, 4H) MSm/z (ESI): 521.1[M +H].

The compound of Example 2 to Example 97 was obtained by the same general procedure as in Example 1 using different aryl b-blocks and halogens as starting materials.

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Example 106: 4-Methyl-N-[4-(4-methylpiperazin-1-methyl)-3-[4,3-b]pyridazine-3-ethyl

3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin Pyrazin-1-methyl)-3-trifluoromethylphenyl]-benzamide (30 m _& 0.05 mmol) was dissolved in morpholine (2 mL) and heated to 100 overnight. The reaction mixture was cooled to room temperature, diluted with methylene chloride. The residue was purified by silica gel column chromatography (eluent eluting with dichloromethane: methanol: 10:1) to give the title compound 4-methyl-N-[4-(4-methylpiperazine) -3-trifluoromethylphenyl]-3-(6-morpholin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-3-ethylidene) -benzamide (yellow solid, 12 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.15-8.20 (m, 2H), 7.93-8.03 (m, 3H), 7.77 (d, J = 9.0 Hz, IH), 7.50 (d, J = 8.1 Hz) , IH), 7.40-7.43 (m, IH), 3.81-3.86 (m, 4H), 3.72 (s, 2H), 3.65-3.68 (m, 4H), 3.00 (s, 4H), 3.66-3.67 (m , 10H). MS m/z (ESI): 619.3 [M+H]

3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin The following implementation was carried out by the method of Example 106 using azine-1-methyl)-3-trifluoromethylphenyl]-benzamide and piperazine and its derivatives, pyrrole, piperidine and its derivatives as raw materials. Example 107 - Example 111.

General Method 3: The aryl halide starting material (1 eq.) is dissolved in a dry solvent such as 1,4-dioxane, N,N-dimethylformamide, etc., and organic is quickly added thereto under the protection of nitrogen. Amine (2 eq.) such as morpholine, piperazine, pyrrolidine and its derivatives, amino acids and derivatives thereof, and chain amines, etc., palladium catalyst (0.1 eq.) such as Pd ₂ (dba) ₃ , palladium acetate, chlorine Palladium, etc., phosphine ligand (0.2 eq.) such as BINAT, X-Phous and XantPhous, and inorganic bases (2 eq.) such as sodium t-butoxide, potassium t-butoxide, cesium carbonate and potassium carbonate, etc., heated to ioo °c reaction. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. The residue was purified by silica gel column chromatography to give the title compound. Example 112: 4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(6-morpholine-4 -yl-[1,2,4] triazole [4,3-a]pyridine-3-

3-( 6-Chloro-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethylidene)-4-methyl-indole-(4-( Φmethyl) Piperazine-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (57 mg, 0.1 mmol) was dissolved in dry 1,4-dioxane (2 mL). Rapidly added morpholine (17 mg, 0.2 mmol) Pd ₂ (dba) ₃ (9 mg, 0.01 mmol), BINAP (12 mg, 0.02 mmol) and sodium tert-butoxide (19 mg, 0.2 mmol) under nitrogen. , heat to the reaction overnight. After the reaction was completed, the mixture was cooled to room temperature, EtOAc EtOAc m. The residue was separated and purified by silica gel column chromatography (eluent eluting with methylene chloride: methanol: 90:10) to give the title compound 4-methyl-N-[4-(4-methyl-piperazine- 1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(6-morpholine-4-yl-[1,2,4]triazole[4,3-a]pyridine-3 -benyl block) -benzamide (yellow solid, 15 mg). iH-NMR (300MHz, CD ₃ OD): δ 8.14 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.72- 7.84 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H), 3.81 (t, J = 4.2 Hz, 4H), 3.73 (s, 2H), 3.57 (t, J = 4.8 Hz, 4H), 3.18 (m, 4H), 2.60-2.79 (m, 10H). MS m/z (ESI): 618.3 [M+H

Starting from various aryl halides, using morpholine and its derivatives, piperazine and its derivatives, piperidine and its derivatives, piperidinol, tetrahydrofuranol, substituted ethylamine and its derivatives and substitutions The aminoethanol derivative was used as another starting material, and Example Compound 113 to Example Compound 139 were obtained by the same synthetic method as in General Method 3.

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3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin Pyrazin-1-methyl)-3-trifluoromethylphenyl]-benzamide (30 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21 mg, 0.10 mmol) and potassium carbonate (21 m _& 0.15 mmol) dissolved in N,N-dimethylformamide (2 In a mixed solvent of mL) and water (0.5 mL), place in a 10 mL sealed tube. The system was sparged with nitrogen for 10 minutes, and tetratriphenylphosphine palladium (6 mg, 0.005 mmol) was quickly added and heated to 90 ° C overnight. The reaction mixture was cooled to room temperature, diluted with methylene chloride, and the organic layer was evaporated. The residue was purified by silica gel column chromatography to give the title compound 4-methyl-indole-[4-(p-methylpiperazin-1-methyl)-3-trifluoromethylbenzene-3-[6-(1 Methyl-1 -pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene]-benzamide (yellow solid, 16 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.35(s, 1Η), 8.11-8.22(m, 4H), 7.92-7.97(m, 2H), 7.71-7.76(m, 2H), 7.47(d, J=7.8Hz, 1H), 7.90(s, 1H), 3.95(s, 3H), 3.70(s, 2H), 2.95(m, 4H), 2.54-2.70(m, 10H)o MSm/z (ESI ): 614.2 [M+H].

Starting from various types of aryl halides and arylboronic acids or boric acid esters, the compounds of Examples 142 to 171 were obtained by the general method.

ESI+ structure 1H-NMR

No. [M+H]

_{(300MHz, CDC1 3): δ} 8.52-8.58 (m, 1H),

8.16-8.22(m, 2H), 7.90-8.02(m, 5H), 7.73(d,

142 J=8.4Hz, 1H), 7.65(d, J=9.9Hz, 1H), 7.50-7.56(m, 610.2

3H), 7.41 (d, J=8.1Hz, 1H), 3.66(s, 2H), 2.61-2.68

(m, HH), 2.42(s, 3H)

(300MHz, CD3OD): δ 8.26-8.2 l(m, 1H),

8.17-8.1 l(m, 2H), 8.08-8.05(m, 1H), 7.98-7.92(m,

143 1H), 7.89-7.83 (m, 2H), 7.79-7.73 (m, 1H), 7.54 (d, 627.3

J=9.3Hz, 1H), 7.48-7.42(m, 1H), 3.95(s, 3H),

3.68(s, 2H), 2.81-2.52(m, 14H), 2.47(s, 3H)

(300MHz, CD3OD): δ 8.12 (d, J=2.1Hz, 1H),

8.10-8.04(m, 3H), 7.96-7.90 (m, 2H), 7.82 (dd,

144 J=8.1, 2.1Hz, 1H), 7.74(m, 2H), 7.48 (dd, J=5.1, 551.1

1.8Hz, 3H), 7.40 (d, J=8.1Hz, 1H), 3.67(s, 2H),

2.75-2.50(m, 14H), 2.43(s, 3H)

(300MHz, CDCI3): δ 8.54(s, 1H), 8.07(d, J=1.2Hz,

1H), 8.01(s, 1H), 8.00(s, 1H), 7.94-7.96(m, 3H),

7.85 (d, J = 6.9 Hz, 1H), 7.81 (dd, J = 6.3, 1.5 Hz, 1H),

145 613.3

7.74 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H),

7.27 (d, J = 6.3 Hz, 1H), 3.98 (s, 3H), 3.66 (s, 2H),

2.70(s, 3H), 2.57(m, 8H), 2.37(s, 3H)

(300MHz, CDCI3): δ 8.74(s, 1H), 8.06(s, 1H),

8.03 (d, J = 1.5 Hz, 1H), 7.92-8.01 (m, 5H), 7.82 (dd,

146 J=6.0, 1.5Hz, 1H), 7.67(d, J=6.3 Hz, 1H), 7.53(d, 610.3

J=7.2Hz, 1H), 7.47-7.50(m, 3H), 7.36(d, J=6.3 Hz,

1H), 3.67(s, 2H), 2.70-2.72(m, 11H), 2.47(s, 3H)

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Example 172: 3-[6-(l-Butyl-IH-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene ]-4-Methyl- _N- [4-(4-A

First step: 1-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)-1pyridazole

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-l-pyrazole (194 mg, 1 mmol) was dissolved in N,N- To dimethylformamide (5 mL), 0.13 mL of 1-iodo-n-butane, 1.1 mmol) and anhydrous cesium carbonate ( 489 mg, 1.5 mmol) were added thereto, and the mixture was heated to 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Base-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (colorless oil, 180 mg). i i-NMR (300MHz, CDCI3): δ 7.77(s, 1Η), 7.67(s, 1Η), 4.1 l(t, J=5.4Hz, 2Η), 1.79-1.87(m, 2H), 1.27-1.35 (m, 14H), 0.91 (t, J = 5.4 Hz, 3H M Sm/z (ESI): 251.2 [M+H].

Second step: 3-[6-(l-butyl-IH-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene -4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

3-( 6-Chloro-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethylidene)-4-methyl-indole-(4-( Φmethyl) Piperazine-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (57 mg, 0.1 mmol) dissolved in N,N-dimethylformamide (2 mL) In a mixed solution of 0.5 mL), 1-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H was added in sequence with stirring. - pyrazole 50 mg, 0.2 mmol) and anhydrous potassium carbonate 41 mg, 0.3 mmol). The system was bubbled with nitrogen for 15 minutes and then rapidly added to the catalyst PdCl ₂ (dppf) CH ₂ Cl ₂ (8 mg, 0.01 mmol) , after the addition, the reaction solution is heated to 100 reaction Overnight. After completion of the reaction, the mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated. The residue was purified by column chromatography on silica gel eluting eluting eluting eluting eluting eluting eluting with )-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene]-4-methyl-N-[4-(4-methyl-piperazin-1- Methyl)-3-trifluoromethyl-phenyl]-benzamide (yellow solid, 30 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.26 (d, J = 3.0 Hz, IH), 8.15 (d, J = 1.5 Hz, 1H) _: 8.06 (m, 2H), 7.90-7.96 (m, 2H) ), 7.80-7.87 (m, 2H), 7.73 (d, J = 8.4 Hz, IH), 7.53-7.57 (m, 1H), 7.35-7.39 (m, IH), 4.16 (t, J = 6.9 Hz, 2H), 3.73(s, 2H), 3.17(m, 4H), 2.62-2.79(m, 10H), 1.79-1.89(m, 2H), 1.26-1.35(m, 2H), 0.93(t,J= 7.2 Hz, 3H). MS m/z (ESI): 655.3 [M+H].

By isopropyl bromide, 3-bromopropionitrile, 4-(2-chloro-ethyl)-morpholine hydrochloride, (2-chloro-ethyl)-dimethylamine hydrochloride and 1-chloro The compound of Example 173 to Example 181 was synthesized in the same manner as in Example 172 by substituting a substituted pyrazole boronic acid ester with a halide such as 2-methoxy-ethane.

General Method 5: Dissolve the free base (l eq.) in a dry solvent such as anhydrous N,N-dimethylformamide, dichloromethane, etc., and add an organic base (2 eq.) such as triethylamine. Diisopropylethylamine, DMAP, etc., slowly add an acid chloride, a chloroformate or an acid anhydride (1.5 eq.), etc. under ice cooling, and react at room temperature until the starting material disappears. The organic phase is extracted with an organic solvent such as dichloromethane, and the organic phase is washed with saturated aqueous sodium hydrogen carbonate, water, and brine, dried, filtered, and evaporated. Example 182: N-(2-acetyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine-3-ethylidene-4 -methyl-benzamide

N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 40 m _& 0.1 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). Acetyl chloride (16 m _& 0.2 mmol) was added dropwise, and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction mixture was combined with methylene chloride and aq. The residue was purified by silica gel column chromatography to give the title compound N-(2-acetyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine 3-Ethyl 4-methyl-benzamide (yellow solid, 16 mg). iH-NMR (300MHz, CDC1 ₃ ): δ 8.61(s, IH), 8.33(m, IH), 8.07(s 1H), 7.96(s, 1H), 7.72-7.92(m, 2H), 7.59-7.65(m, 2H), 7.38-7.42(m, 2H), 7.29-7.3 l(m, 1H), 6.97-7.00 (m, 1H), 4.79 (m, 4H), 2.60 (s, 3H), 2.16 (s, 3H). MS m/z (ESI): 435.2 [M+H]. Example 183: NOcyclopropylmethyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridin-3-ethlyl-4-yl Base-benzamide

N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 40 m _& 0.1 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). Cyclopropylmethyl bromide (27 m _& 0.2 mmol) was added dropwise, and the addition was completed, and the reaction was continued until 50 < €. After completion of the reaction, the reaction mixture was quenched with methylene chloride and saturated aqueous sodium hydrogen carbonate, and the organic phase was separated. The organic phase was washed with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The title compound N-(2-cyclopropylmethyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine was isolated and purified by silica gel column chromatography. 3-Ethyl 4-methyl-benzamide (yellow solid, 14 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.74(s, 1Η), 8.43(d, J=4.8Hz, 1H), 8.18(s, 1H), 7.94(s, 1H), 7.87(m, 1H) , 7.79(s, 1H), 7.65(m, 1H), 7.54(m, 1H), 7.37(s, 1H), 7.26-7.32(m, 1H), 7.14(s, 1H), 6.97-7.00(m , 1H), 4.29 (m, 4H), 2.88 (m, 2H), 2.59 (s, 3H), 0.86 (m, lH), 0.65 (m, 2H), 0.32 (m, 2H). MS m/z (ESI): 447.2 [M+H].

Ν-(2,3-Dihydro-1 Η-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide The starting materials were replaced with benzyl bromide and 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester, respectively, using the same formula as in Example 183.

Example 186: 2-[5-(3-Imidazo[l,2-a]pyridine-3-ethylidene-4-methyl-benzamide)-1,3-dihydro-isoindoline- 2-Acylpyrroline-1-carboxylic acid tert-butyl ester

N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[1,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 200 mg, 0.47 mmol) and 2-(7-azabenzotriazole)-^-tetramethylurea hexafluorophosphate (213 mg, 0.56 mmol) dissolved in anhydrous N,N-dimethyl In the amide (10 mL), the (S)-l-(tert-butoxycarbonyl) port ratio was sequentially added thereto under ice cooling. R.sub.2-carboxylic acid (121 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.70 mmol). After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography to give the title compound 2-[5-(3-imidazo[l,2-a]pyridin-3-ethylidyl-4-methyl-benzamide)-1,3- Dihydro-isoindoline-2-yl]-pyrroline-1-carboxylic acid tert-butylate (yellow solid, 116 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.45(s, 1Η), 7.94-8.13(m, 2H), 7.82-7.86(m, 2H), 7.73-7.78(m, 2H), 7.35-7.44(m , 3H), 7.05-7.15(m, 2H), 4.45-5.07(m, 5H), 3.41-3.65(m, 2H), 2.60(s, 3H), 2.09-2.29(m, 2H), 1.44-2.00 (m, 2H), 1.43 (s, 9H). MS m/z (ESI): 590.3 [M+H]

N-(2,3-dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide The starting material, the valine tert-butyl ester was replaced with various amino acid derivatives and nicotinic acid, and Example Compound 187 to Example 191 were synthesized in the same manner as in Example 186.

Example 192: 4-{4-[4-(4-methyl-3-[l,2,4]triazolo[4,3-a]pyridin-3-ylethylidene-benzamide) -2-trifluoromethyl-benzyl]-piperazine-1-piperidine-1-carboxylic acid tert-butyl ester

4-Methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[l,2,4]triazole [4,3-a] Pyridin-3-ylethylidene-benzamide (160 mg, 0.31 mmol) was dissolved in methanol (5 ml), then 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (309 m _& 1.55) Ethyl acetate and glacial acetic acid (19 m _& 0.31 mmol), heated to reflux for 24 h, then cooled to room temperature and then slowly added sodium borohydride (329 m _& 1.55 mmol), and allowed to react at room temperature for 2 h and then heated to reflux for 24 h. After completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated to dryness. concentrate. The residue was purified by silica gel column chromatography eluting 1H-NMR (300MHz, CD ₃ OD): δ 8.56 (d, J = 6.0Hz, IH), 8.29(s, 1H), 8.13(s, IH), 7.95(m, 2H), 7.87(d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H) _: 7.59 (t, J = 6.9 Hz, 1H), 7.51 (dd, J = 8.1, 3.6 Hz, 1H), 7.23 (t, J =7.2Hz, 1H), 4.12(m, 2H), 3.64(s, 2H),

2.40-2.73 (m, 14H), 1.91 (m, 2H), 1.44 (s, 9H), 1.33-1.38 (m, 2H). MS m/z (ESI): 604.3 [M+H].

Using Example Compounds 185, 191, and 192 as raw materials, the general method 2 was used to obtain Examples 193 to #Examples.

195.

Example 196: 3-imidazo[1,2-a]pyridin-3-ethenyl-4-methyl-N-[2-(l-methyl-B-pyrrol-2-yl)-2, 3-dihydro-1H-isoindoline-5-yl]-benzamide

3-Imidazo[1,2-a]pyridin-3-ylethylidene-4-methyl-N-[2-(B-pyrrolidino-2-yl)-2,3-dihydro-1H- Isoindole-5-yl]-benzamide was used as a starting material, which was synthesized by a similar method as in Example 184, and Cyclomethicone was replaced with methyl iodide to obtain Standard compound 3-imidazole [l,2-a]pyridine-3-ethylidene-4-methyl-N-[2-(l-methyl-B-pyroline-2-yl)-2,3- Dihydro-1H-isoindoline-5-yl]-benzamide (light yellow solid, 31 mg - NMR (300MHz, CDC1 ₃ ): δ 8.79 (1 Η, s), 8.32 (d J = 8.1 Hz, IH), 8.08(s, IH), 7.95(s, IH), 7.75-7.89(m, 2H), 7.59-7.62(m, 2H), 7.30-7.45(m, 2H), 7.20-7.26(m, IH), 6.94-6.99(m, IH), 4.74-4.97(m, 5H), 3.48-3.53(s, IH), 3.30(s, IH), 2.58(s, 3H) _: 2.5 l(m, IH ), 2.18-2.32 (m, 2H), 1.94-2.06 (m, 4H) MS m/z (ESI): 504.2 [M+H]. Pyridin-4-yl)-2,3-dihydro-IH-isoindoline-5-yl]-3-imidazo[l,2-a]pyridine-3-ethylidene-4-methyl-benzene Formamide

3-Imidazo[l,2-a]pyridin-3-ylethyl ylethynyl-4-methylmethyl-N-[2-(piperidinylpiperidine-4-ylcarbonyl)-2,3-dihydrodi ydro-lH-isoindole-5-yl-yl]-benzamide benzamide is used as a raw material, and the target compound N-[2-(l-acetyl-piperidin-4-yl)-2 is obtained by the general method. 3-Dihydro-1H-isoindoline-5-yl]-3-imidazole [l,2-a pyridine-3-ethylidene-4-methyl-benzamide (yellow solid, 30 mg). 1H-NMR (300MHz, CD ₃ OD): S 8.55 (s, IH), 8.14 (s, IH), 7.94 (s, lH), 7.83 (m, 2H), 7.42-7.70 (m, 5H), 7.29 (m, 2H), 7.20(m, lH), 4.96(m, 2H), 4.69(m, 2H), 4.56(m, IH), 3.99(m, IH), 3.23(m, IH), 2.89- 2.96 (m, IH), 2.75 (m, IH), 2.61 (s, 3H), 2.11 (s, 3H), 1.55-1.90 (m, 4H). MS m / z (ESI): 546.2 [M+H]. Example 198: 4-Methyl-N-[4-(4-n-propyl-piperazine-1-methyl)-3-trifluoromethylphenyl]-3-[l,2,4] Azole [4,3-a]pyridine-3-ethylidene-benzamide

4-Methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[1,2,4]triazole [4,3-a] Pyridin-3-ylethylidene-benzamide (52 mg, 0.1 mmol), n-propanal (29 mg, 0.5 mmol) and glacial acetic acid (0.1 mL) dissolved in methanol (3 mL) Thereafter, under ice cooling, sodium borohydride (20 mg, 0.5 mmol) was slowly added to the above reaction mixture, and after the addition was completed, stirring was continued at room temperature overnight. After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography toield toield of 4-methyl-N-[4-(4-n-propyl-piperazine-1-methyl)-3-trifluoromethylphenyl]-3- [1,2,4]triazolo[4,3-a]pyridin-3-ethlyl-benzamide (yellow solid, 26 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.57(s, 1H), 8.31(s, 1H), 8.15(s, 1H), 7.96-8.01(m, 2H), 7.98(d, J=9.3Hz , 1H), 7.76(d J =8.7Hz, 1H), 7.58-7.64(m, 1H), 7.53(d, J=8.1Hz, 1H), 7.25(t, J=7.2Hz, 1H), 4.58( m, 1H), 3.76(s, 2H), 3.13-3.31(m, 4H), 2.95-3.05(m, 2H), 2.55-2.88(m, 7H), 1.69-1.80(m, 2H), 1.01( t, J=7.5 Hz, 3H MSm/z (ESI): 561.3 [M+H]. 4-methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl- Phenyl)-3-[l,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide, 4-methyl-N-[4-(3-A Benzyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene -benzamide, 3-imidazo[l,2-a]pyridin-3-ethenyl-4-methyl-N-[2-(piperidin-4-yl)-2,3-dihydro-1H - isoindol-5-yl] - benzamide and 4-methyl-3- (2-methyl - imidazo [l, 2-a] pyridin-3-yl acetylene-yl) - _N - (4- Piperazine-1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide or the like as a starting material, using 2-bromoethanol, 3-bromopropanol, 1-bromo-3-methoxy-propane , 2-(2-bromo-ethoxy)-ethanol, 1-bromo-2-methoxy-B Alkanes, 1-bromoacetone, 4-(2-chloro-ethyl)-morpholine, cyclopropylmethyl bromide, benzyl bromide, (2-bromoethyl)-carbamate and (3-bromopropyl) ) - tert-butyl carbamate, etc.

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CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV Using the example compounds 98, 191, and 193 as raw materials, the following Examples 216 to 220 were obtained by the general method.

Example 221: N-{4-[4-(3-Hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-triazole [4,3-a]pyridine- 3-ylethylidene-benzamide

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First step: 3-hydroxy-2-methyl-propyl toluene-4-sulfonate 2-Methyl-1,3-propanediol (0.9 g, 10 mmol) was dissolved in pyridine (10 mL), cooled to 0 ° C in an ice bath, and 4-methylbenzenesulfonyl chloride (2.0 g, 11 mmol), after the addition was completed, the ice bath was removed and stirring was continued at room temperature overnight. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained intermediate toluene-4-sulfonic acid 3-hydroxy-2-methyl purified by silica gel column chromatography separation - ester (; colorless oil, 1.3 g 1H-NMR (300MHz , CDC1 3): δ 7.79 (m, 2Η), 7.35(m, 2H), 3.98-4.05(m, 2H), 3.49-3.60(m, 2H), 2.45(s, 3H), 1.96-2.04(m, 1H), 0.92(d , J = 5.4 Hz, 3H MSm/z (ESI): 267.1 [M+H].

Second step: _N- {4-[4-(3-hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-phenyl 4-methyl- 3-[l,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide

3-([1,2,4]Triazolo[4,3-a]pyridin-3-ylethylidene)-indole-(4-((4-(3-aminopropyl)piperazine)- 1-yl)methylH-trifluoromethyl)phenyl)-4-methylbenzamide (52 mg 0.10 mmol) was dissolved in hydrazine, dimethyl-dimethylformamide (2 mL), toluene-4 3-Hydroxy-2-methyl-propyl sulfonate (49 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.20 mmol). After the completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography toield of the title compound N-{4-[4-(3-hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl -Phenyl}-4-methyl-3-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene-benzamide (yellow solid, 10 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.58 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 1.5 Hz, IH), 7.95- 8.00(m, 2H), 7.88(d, J=7.2Hz, IH), 7.77(d, J=6.6Hz, IH), 7.59-7.63(m, 1H), 7.54(d, J=6.0Hz, IH ), 7.25(t, J=5.1Hz, 1H), 3.69(m, 2H), 3.47-3.56(m, 2H), 2.49-2.98(m, 13H), 2.00-2.1 l(m, IH), 0.87 -0.92 (m, 3H). MS m/z (ESI): 591.2 [M+H]. Example 222: N-{4-[4-(3-Dimethylamino-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-phenyl}-4-methyl- 3-[l,2,4] Triazole [4,3-a]pyridin-3-ylethylidene-benzene

N-{4-[4-(3-Amino-propyl)-piperazin-1-methyl]-3-trifluoromethyl-phenyl}-4-methyl-3-[1,2, 4] Triazole [4,3-a]pyridine-3-ethylidene-benzamide 46 mg, 0.08 mmol) was dissolved in methanol (2 mL), and 37% aqueous formaldehyde solution (65 mg, 0.80) was added thereto. Ethyl acetate and glacial acetic acid (0.1 mL) were reacted at room temperature for 2 h, then sodium borohydride (15 mg, 0.4 mmol) was slowly added to the mixture and cooled overnight. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography to afford the title compound N-{4-[4-(3-dimethylamino-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-benzene 4-methyl-3-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide (yellow solid, 13 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.56 (d, J = 6.9 Hz, IH), 8.28 (d, J = 1.8 Hz, IH), 8.15 (d, J = 2.4 Hz, IH), 7.93- 7.96(m, 2H), 7.85(d, J=9.6Hz, IH), 7.74(d, J=8.7Hz, IH), 7.59-7.62(m, IH), 7.48(d, J=8.1Hz, IH ), 7.24(t, J=6.6Hz, IH), 3.69(s, 2H), 3.17(t, J=7.2Hz, 2H), 2.64-2.86(m, 19H), 1.99(t,J=6.9 Hz , 2H). MS m/z (ESI): 604.3 [M+H]. Example 223: 3-(6-allyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylethylidene)-4-methyl-N-[4 -(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzoyl

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3-([1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-N-(4-((3,4-dimethylpiperazin-1-) Methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide C37 mg, 0.07 mmol) dissolved in N,N-dimethylformamide (2 mL) After the anhydrous potassium carbonate powder () was reacted at room temperature for 10 minutes, methyl iodide () was slowly added thereto, and the reaction was continued at room temperature overnight after the addition. After the reaction was completed, the reaction was quenched with EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography to give the title compound N-[4-(3,4-dimethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4- 3-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene-benzamide (white solid, 34 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.58 (d, J = 5.1 Hz, IH), 8.31 (s, IH), 8.15 (m, IH), 7.97-8.00 (m, 2H), 7.88 (d) , J=7.2Hz, IH), 7.76(d, J =6.6Hz, IH), 7.52-7.63(m, 2H), 7.25(t, J=5.1Hz, IH), 3.73(m, 2H), 3.35 -3.38(m, IH), 3.18(m, IH), 3.07-3.12 (m, IH), 2.94-2.96(m, 2H), 2.80(s, 3H), 2.68(s, 3H), 2.5 l ( m, 1H),

In the examples, the compounds are used as raw materials, and the following examples are used to obtain the following examples to the examples.

Example 232: N-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-[1,2,4]triazole [4,3-a]pyridine-3 - base block - benzamide

4-methyl-3-((6-morpholino-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(4-( Piperazine-1- 1 -methyl)-3-(trifluoromethyl)phenyl)benzamide (81 mg, 0.12 mmol) dissolved in N,N-dimethylformamide (2 mL) (Bromomethyl)cyclopropane (64 mg, 0.5 mmol) and anhydrous potassium carbonate powder (66 mg, 0.48 mmol). After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. N-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-3-(6-morpholine-4-yl -[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene)-benzamide (yellow solid, 14 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.14 (1H, d, J = 1.8Hz), 8.06 (1Η, d, J=1.5Hz), 7.95(1Η, d, J=8.7Hz), 7.73- 7.84(4Η, m), 7.41(1Η, d _: J=8.4Hz), 7.21(1H, d, J=9.6Hz), 3.80-3.83(4H, m), 3.72(2H, s), 3.56-3.59 (4H, m), 3.16(4H, s), 2.83(2H, d, J=7.5Hz), 2.72(4H, s), 2.60(3H, s), 1.00-1.09(1H, m), 0.67- 0.73 (2H, m), 0.33-0.38 (2H, m). MS m/z (ESI): 329.4 [M+2].

4-methyl-3-((6-morpholino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(4-( Piperazine-1 -ylmethyl)-3-(trifluoromethyl)phenyl)benzamide as starting material, replaced with 3-bromo-propan-1-ol and 1-bromo-3-methoxy-propane, respectively Example 233 to Example 235 were synthesized in the same manner as in Example 232.

4-methyl-3-[6-(l-methyl-1H-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-yl-ethyl Block base] -N-(4-piperazine

-1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide as a starting material, replacing the ring with 1-bromo-2-methoxy-ethane and ethyl bromide, respectively

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3-((8-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethlyl)-4-methyl-indole-(4-((Φ) Example 241 was synthesized in the same manner as in Example 240, using methyl piperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide as a starting material. Example 244.

Example 245: 4-{4-[3-(8-Methoxy-[1,2,4]triazolo[4,3-a]B-pyrazin-3-ylethylidene)-4- Methyl-benzamide]-2-trifluoromethyl-benzyl U-dimethyl-piperazine-1

3-[2-(8-Hydroxy-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethidyl]-4-methyl-N-[4- [(4-Methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide (50 mg 0.091 mmol) and anhydrous potassium carbonate powder (19 mg, 0.137 mmol) Methyl iodide (0.06 mL, 0.11 mmol) was added to dry EtOAc (2 mL). After the completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with EtOAc EtOAc. 4-{4-[3-(8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine-3-ylethylidene)-4-methyl-phenyl Amido]-2-trifluoromethyl-benzyl}-1,1-dimethyl-piperazine-1-iodonium salt (12 mg, yellow solid). 1H-NMR (400MHz, CD ₃ OD): δ 8.30 (1Η, d, J=1.6Hz), 8.15(1H, d, J=2.0Hz), 7.99-8.02(2H, m), 7.77(1H, d , J=8.8Hz), 7.53-7.58(2H, m), 7.24(1H, d, J=6.0Hz), 3.85(2H, s), 3.59(3H, s), 3.51(4H, t, J= 4.8 Hz), 3.21 (6H, s), 2.87 (4H, t, J = 4.4 Hz), 2.67 (3H, s). MSm/z (ESI): 578.8 [M+H]. Example 246: 3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-N-[4-( 4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzoyl

N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-(6-chloro-1,2,4-triazolo[4 ,3-a]pyridine-3-ethylidene)-4- 4-(tetrahydro-2H-pyran-2-oxomethyl)benzamide (200 mg, 0.3 mmol) dissolved in methanol (5 mL) Toluenesulfonic acid monohydrate (66 mg, 0.34 mmol) was stirred at room temperature for 3 h. After the reaction was completed, the solvent was evaporated, and the residue was evaporated. The organic layer was combined and purified by column chromatography to give the title compound 3-(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl -N-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (yellow solid, 94 mg). 1H-NMR (CD30D, 400 ΜΗζ): δ 2.3 l (s, 3H), 2.54 (s, 8H), 3.67 (s, 2H), 5.02 (s, 2H), 7.41 - 7.44 (m, 1H), 7.77- 7.79 (m, 2H), 7.94 - 8.18 (m, 6H). MS m/z (ESI) Example 247: N-[3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-phenyl] -4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

N-[3-(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-(tetrahydropyran-2-yloxy) Methyl)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide was used as a starting material, and the title compound was obtained by the same procedure as in Example 246. N-[3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-phenyl]-4-( 4-Methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-benzamide. 1H-NMR (CD ₃ OD, 400 ΜΗζ): δ 2.38 (s, 3 H), 2.61 (br, 8 H), 3.79 (s, 2 H), 4.95 (s, 2 H), 7.42_7.45 (m) , 1 H), 7.60_7.62(m, 1 H), 7.80- 7.82(m, 1 H), 8.01-8.14(m, 4 H), 8.20— 8.22(m, 1 H), 8.30(s, 1 H). LC-MS m/z 291.9 [M+2H].

Example 250: 3-(2-Difluoromethyl-imidazo[l,2-a]pyridin-3-ylethylidene)-4-methyl-N-(4-morphinolin-4-ylmethyl -3-fluoromethyl-phenyl)-benzamide

Dissolving N-(4-hydroxymethyl-3-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide (20 mg) in anhydrous N,N-dimethylformamide (5 mL) and dichloromethane (5 mL) were mixed with N,N-diisopropylethylamine (1 mL), the system was cooled in an ice bath, and methanesulfonyl chloride (200 uL) was added dropwise and stirred. Two hours, TLC monitored the end of the reaction. Then morpholine (500 uL) was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water and then evaporated and evaporated. The crude product was isolated and purified to give the title compound 3-(2-difluoromethyl-imidazo[l,2-a]pyridin-3-ylethylidene)-4-methyl-N-(4-morpholine-4 -ylmethyl-3-trifluoromethyl-phenyl)-benzamide (20 mg, pale yellow solid R (400MHz, DMSO-d6): δ 10.60 (s, 1H), 8.73-8.71 (m, 1H), 8.29-8.22(m, 2H), 8.08-7.94(m, 2H), 7.82-7.73(m, 2H), 7.58-7.46(m, 2H), 7.28(m, 1H), 3.62 (m, 6H), 2.88 (s, 3H), 2.49 (m, 4H). MS m/z (ESI): 569.5 [M+H].

Starting from N-(4-hydroxymethyl-3-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide, piperazine and its derivatives, piperidine and Its derivatives, pyrrolidine and its derivatives, methylamine and its derivatives are substituted for morpholine, using examples

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Test Example 1: Kinase inhibition test

The kinase inhibitory activity assay described in the test examples is for determining the in vitro inhibitory activity of the compound of the present invention against kinases such as c-Src and Bcr-Abk EGFR, and the test compound inhibits kinase activity by a semi-inhibitory concentration. : IC ₅ . The value is expressed. This type of test is performed by homogeneous time-resolved fluorescence (HTRF) technique as follows: A series of concentration gradient test compounds are incubated with a specific concentration of enzyme solution for 5 minutes at room temperature; then an appropriate amount of enzyme reaction is added. Substrate: ATP, start the enzyme reaction process; 30 minutes later, add appropriate amount of reaction stop solution and detection solution to the enzyme reaction system; after 1 hour of incubation, determine the specificity on the Molecular device Flexstation III multi-function microplate reader The enzyme activity at the concentration of the compound, and the inhibitory activity of the compound at different concentrations on the enzyme activity were calculated. Then, according to the four-parameter equation, the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted to calculate IC ₅ . value. The kinases used in this test example: c-Src, Bcr-Abl were purchased from Cama Biosciences, Inc, the test kit HTRF KinEASE-TK was purchased from Cisbio Bioassays, and ATP was purchased from Sigma Aldrich.

1. The inhibitory activity of the compound of the present invention against kinase is IC ₅ . Value table ^. The results of the kinase inhibitory activity of some of the compounds of the Examples are shown in the following table (wherein IC _5Q < 100 nM is represented by the symbol ++++; 100 nM < IC ₅₀ < 500 nM by the symbol +++)

Example Bcr-Abl c-Src Example Bcr-Abl c-Src Example Bcr-Abl c-Src

27 ++ + 116 ++ +++ 202 ++++ +

28 ++++ + 117 ++++ ++++ 203 ++++ +

30 +++ + 118 ++++ ++++ 204 ++++ +

31 + + 119 ++++ ++++ 205 +++ +

32 ++++ + 120 ++++ ++++ 206 +++ +

33 ++++ + 121 +++ +++ 207 ++++ +

34 +++ + 122 ++++ ++++ 208 +++ +

35 ++ + 123 +++ +++ 210 ++++ +

36 +++ + 124 ++++ ++++ 211 ++++ +

37 +++ + 125 ++++ ++++ 212 +++ +

38 ++ + 126 +++ +++ 213 ++ +

39 ++ + 127 ++++ ++++ 214 +++ +

40 ++++ ++ 128 ++++ ++++ 215 +++ +

41 ++++ + 129 ++++ +++ 216 ++++ +

42 ++++ + 130 +++ +++ 217 ++++ +

43 ++++ + 131 ++++ ++++ 218 ++++ +

44 ++++ + 132 +++ +++ 219 +++ +

45 ++++ + 133 ++++ ++++ 220 ++++ +

46 ++++ +++ 134 +++ ++ 221 ++++ +

47 ++ + 135 ++ ++ 222 +++ +

48 ++++ +++ 136 +++ +++ 223 ++++ +

49 ++++ + 137 ++++ ++++ 224 +++ ++

50 ++ + 138 +++ +++ 225 +++ ++

51 +++ +++ 139 ++++ +++ 226 +++ +

52 +++ + 140 ++++ + 227 ++++ +

53 ++ + 141 ++++ ++ 228 ++++ +

54 ++ + 142 ++++ ++ 229 ++++ +

55 ++ + 143 ++ ++ 230 ++++ ++++

58 ++ + 144 +++ ++ 231 ++++ +

59 ++++ + 145 ++ ++ 232 ++++ ++++

60 ++ + 146 ++++ ++++ 233 ++++ ++++

61 ++ + 147 +++ +++ 234 +++ ++++

62 +++ + 148 ++++ ++++ 235 +++ ++++

63 +++ + 149 ++++ ++++ 236 +++ +++

64 ++++ + 150 ++++ ++++ 237 ++++ ++++

65 ++++ +++ 151 ++++ ++++ 238 ++++ ++++

66 ++ +++ 152 ++++ ++++ 239 ++++ ++++

67 ++ + 153 +++ ++ 240 ++++ ++++

68 + + 154 ++++ ++++ 241 +++ ++

69 + + 156 ++++ ++++ 242 ++++ ++

70 ++++ +++ 157 ++++ ++++ 243 +++ ++

71 + + 159 ++++ ++++ 244 +++ ++

72 ++++ + 160 +++ +++ 245 +++ ++ Example Bcr-Abl c-Src Example Bcr-Abl c-Src Example Bcr-Abl c-Src

73 ++ + 161 +++ +++ 246 +++ ++

74 ++++ ++++ 162 ++++ ++++ 247 ++++ ++++

77 ++++ ++++ 163 +++ +++ 248 ++++ ++++

78 +++ +++ 164 +++ +++ 249 + +

79 +++ + 165 +++ +++ 250 + +

80 ++++ ++ 166 +++ +++ 251 + +

81 + + 167 ++++ ++++ 252 +++ +

82 ++++ ++++ 168 +++ +++ 253 +++ ++

83 +++ +++ 169 +++ +++ 254 ++++ +++

84 +++ +++ 170 ++++ ++++ 255 ++++ +

85 ++++ +++ 171 ++++ ++++ 256 +++ +

86 +++ +++ 172 ++++ ++++ 257 + +

87 +++ + 173 +++ +++ 258 ++ +

88 + + 174 +++ +++ 259 + +

89 ++ + 175 ++++ ++++ 260 +++ +

90 ++ + 176 ++++ ++++ 261 +++ ++

92 ++ + 177 ++++ ++++ 262 ++ +

94 + + 178 ++++ ++++ 263 ++ +

95 ++ ++ 179 +++ +++ 264 ++ +

2. The compounds of the present invention have good inhibitory activities against dozens of kinases such as Abl, EGFR, VEGFR, JAK, PDGFR, BRAF, RET, KIT, LYN, LCK, FGFR, EphB, Src and the like. As shown in the example compounds 10, 112, 146, 201, etc., the inhibition rate of different kinases at luM concentration was greater than 90%, indicating better kinase inhibitory activity.

3. The compound of the present invention has good inhibitory activity against different kinase mutants such as AblT315I, BrafV600E and the like. The inhibitory activity of some of the compounds of the compounds against AWT315I kinase is shown in the following table (where IC ₅ < 100 nM is represented by the symbol ++++; 100 nM < IC ₅₀ < 500 nM is represented by the symbol +++; 500 nM < IC ₅₀ < 1000 nM is represented by the symbol ++; IC ₅₀ > ΙΟΟΟ ηΜ is represented by the symbol +).

EXAMPLE IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I)

4 + 85 ++++ 154 ++++

5 +++ 87 +++ 156 ++++

7 ++++ 98 ++++ 159 ++++

8 +++ 99 ++ 160 +++

9 +++ 101 +++ 161 +++

10 +++ 103 ++++ 162 +++

11 ++++ 106 ++++ 176 ++++

12 +++ 108 +++ 177 ++++

16 ++++ 110 ++++ 181 ++++

22 +++ 112 ++++ 199 +++

25 ++++ 113 +++ 200 ++++

26 ++ 114 ++ 201 +++

32 ++++ 115 ++++ 203 +++ EXAMPLE IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I)

33 ++++ 117 +++ 204 +++

40 ++ 118 +++ 207 ++++

41 +++ 120 ++++ 208 +

42 +++ 122 ++++ 210 ++++

43 +++ 123 +++ 214 +++

44 ++ 125 ++++ 215 ++++

46 ++++ 129 ++++ 216 ++++

51 +++ 136 ++++ 222 +++

64 +++ 140 + 224 +++

65 +++ 141 +++ 225 +++

72 ++++ 142 ++++ 228 +++

78 ++++ 143 +++ 229 +++

79 +++ 144 +++ 236 ++++

80 +++ 146 ++++ 237 ++++

82 ++++ 149 ++++ 238 ++++

83 ++++ 151 ++++ 239 ++++

84 +++ 152 ++++ 242 ++++ Test Example 2: Cell proliferation inhibition test

The cell proliferation inhibitory activity test described in the test example is for measuring the proliferation inhibitory activity of the compound of the present invention against a cell line highly expressed such as EGFR, Bcr-Abl, etc., and the test compound inhibits cell proliferation by a half inhibitory concentration. : IC ₅ . To represent. The experimental protocol for this type of test is as follows: Select different cells, such as K-562 cells, A431 cells, etc. (The cells are purchased from the Cell Culture Bank of the Chinese Academy of Sciences, The Culture Collection Committee of the Chinese Academy of Sciences/The Shanghai Institute of Life Sciences, Chinese Academy of Sciences) Cell concentration (for example, 25,000 cells/mL medium) The cells were seeded on a white opaque 384-well culture plate; the cells were then cultured at 37 ° C in a 5% CO ₂ atmosphere; after 24 hours, A series of concentration gradients are added to the cultured cell culture medium, generally 10 concentrations are selected; the cells are then returned to the original culture environment for further 48 hours, and then the test compound is determined according to the CellTiter-Glo Luminescent Cell Viability Assay method. Effects on different cell proliferation, and calculation of inhibitory activities of different concentrations of compounds on cell proliferation (CellTiter-Glo Luminescent Cell Viability Assay was purchased from Promega); four-parameter fit was then performed on cell proliferation inhibitory activity at different concentrations of compounds. , calculate IC ₅ . data.

The compound of the present invention has an activity of inhibiting proliferation of K-562 cells, and the results of cell proliferation inhibitory activity of some of the compounds of the examples are shown below (inhibition activity is represented by an IC ₅ value, wherein IC ₅ . < ΙΟΟ η 表示 is represented by a symbol +; 100 nM < IC < 500 nM is represented by the symbol ++; IC ₅ > 500 nM is represented by the symbol +)

EXAMPLE IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM)

24 +++ 96 +++ 163 ++++ 216 ++++

25 ++++ 97 +++ 164 ++++ 217 +++

26 ++++ 106 ++++ 165 ++++ 219 ++

27 ++++ 110 ++++ 166 ++++ 220 ++++

28 +++ 111 ++++ 167 ++++ 225 ++++

30 +++ 113 ++++ 168 ++++ 227 ++++

32 ++++ 114 ++++ 169 ++++ 228 ++++

33 ++++ 115 ++++ 170 ++++ 229 ++++

34 +++ 116 ++++ 171 ++++ 233 ++++

40 ++++ 120 ++++ 172 ++++ 234 ++++

41 ++++ 121 ++++ 173 ++++ 235 ++++

43 ++++ 122 ++++ 174 ++++ 242 ++++

44 ++++ 123 ++++ 176 ++++ 243 +++

48 ++++ 125 ++++ 177 ++++ 244 ++++

54 +++ 126 ++++ 178 ++++ 247 ++++

55 +++ 127 ++++ 179 ++++ 248 ++++

59 ++++ 128 ++++ 180 ++++ 249 ++++

61 +++ 131 ++++ 181 ++++ 250 ++++

65 +++ 132 ++++ 182 ++++ 252 +++

66 ++++ 133 ++++ 187 +++ 260 +++

72 ++++ 136 ++++ 190 +++ 261 +++

73 ++++ 137 ++++ 199 ++++ 263 +++

74 ++++ 140 ++++ 200 ++++ 264 +++

77 ++++ Test Example 3: Pharmacokinetic Evaluation

Pharmacokinetic test of the compound of the present invention: Rat or mouse is used as a test animal, and the plasma or the mouse is administered by the LC/MS/MS method at different times after intragastric administration and intravenous administration of the compound of the example. Drug concentration, the pharmacokinetic behavior of the compounds of the invention in rats or mice was investigated and their pharmacokinetic characteristics were evaluated.

Experimental protocol: The test animals were healthy adult male SD rats or mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: intravenous injection into SD rats or mice (3 mg/ Kg, l mg/mL suspension of test compound) and intragastric administration (10 mg/kg, l mg/mL suspension of test compound), before and after administration 2, 5 , 15, 30, 60, 90, 120, 240, 360, 480, 1440 min. Take 0.4 mL of blood from the fundus venous plexus of rats or mice; take plasma sample 50 and add 200 acetonitrile solution containing internal standard to precipitate protein, vortex 10 min, centrifuged at 6000 g for 10 min; centrifuge 200 g of 6000 g for another 10 min; then take 75 supernatant, add gradient initial mobile phase to dilute, centrifuge at 6000 g for 10 min; finally take supernatant 70 at 96 wells. In-plate injection, injection volume 5 for LC-M SM S analysis.

The compounds of the examples 8, 10, 11, 28, 41, 44, 49, 70, 74, 77, 112, 134, 146, 207, etc. have good stability in the plasma of large mice, and the half-lives are 196 min, 600 min, 1194 min, 702, respectively. Min, 398min, 396min, 150 min, 1061min, 210min, 655min, 873min, 178min, 428min, 284min _{; the} area under the plasma concentration-time curve after intravenous administration was 92uM.min, lOOuM.min, 210uM.min , 68uM .min , 202uM .min, 216uM .min, 230uM .min, 73uM .min, 193uM .min, 174uM .min, 68uM .min, 120uM .min, 165uM .min, the highest blood concentration is 0.37~1.75uM The relative bioavailability is between 20% and 80%. Cause Thus, the results indicate that the compounds of the present invention have better pharmacokinetic properties in rats or mice. Test Example 4: Pharmacodynamic test in nude mice

Experimental materials and methods: BALB/c nude mice (Shanghai Xipuer-Beikai Experimental Animals Co., Ltd.) were used, weighing 16-18 g, female. BD Matrigel, K562 cells or 32DT315I cells. Collect logarithmic growth phase cells, medium and matrigel 1:1, adjust the cell concentration to 5.0× ^{10 7} /ml, place in ice box, inoculate 0.2ml/only in the lower side of mouse armpit, and select tumor above 100mm3 The tumor-bearing mice were tested for drug administration. The drug was administered once a day for 5 days, and the drug was stopped for 2 days for a total of 9 days. The tumor volume and body weight were measured daily. The tumor diameter was measured with a vernier caliper to measure the long diameter and the broad diameter of the tumor. Then, the volume and relative volume of the tumor were calculated according to the formula: Tumor volume (Tumor \Wume, TV), and the calculation formula is: TV= l/2XaXb ² , where a and b represent the length and width, respectively; relative tumor volume (Relative Tumor \3⁄4lume, RTV), the formula is: RTV=TV _t /TV. , where TV. For the case of cage (ie d.) tumor volume, TV _t is the tumor volume at each measurement; relative tumor growth rate T/C (%), calculated as: T/C (%) = T _RTV / C _RTV x l00, where T _RTV : treatment group RTV, C _RTV was negative control group RTV. The test results were based on the relative tumor growth rate T/C (%) as an evaluation index for anti-tumor activity.

Using the above method, the compound of the example, 11, 74, 77, 112, 134, 247, etc., at a dose of 2.5 mg/kg to 10 mg kg, significantly inhibited the growth of the K562 xenograft model nude mice until the regression, giving On the 9th day, the T/C ratio of the drug was less than 10%, and the test animals were better tolerated, and the body weight change range was less than 20%; and the example compounds 11, 74, 77, 112, 134, 247, etc. were at the dose of 15 mg/kg. The nude mice with 32DT315I cell xenograft model also had significant inhibition of growth until regression. The T/C ratio was less than 50% on the 9th day of administration, and the survival time of the experimental animals was significantly prolonged. The median survival time was 11 - 13 days to 15-18 days.

Therefore, some embodiments of the present invention have a good effect of inhibiting the growth of xenografted tumors in nude mice after intragastric administration, and can significantly prolong the survival of the experimental tumor-bearing nude mice.

Claims

Claim

A compound of the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a former

(I)

Its towel:

m Ra are each independently selected from the group consisting of halogen, -R ₂ , -OH, -SH, -OR ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ ,

-NHC(0)OR ₂ , -NR ₃ C(0)R ₂ ;

2;

Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4, -C(OP-R4, -OC(0)-R ₄ , -C(0)N(R4) ₂ , -S(0 a group substitution of _x -R4, -NH ₂ , -NH , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , -NR ₅ C(0)R ₄ Where x is 0, 1 or 2;

Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino-based, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, amphoteric, amphoteric, a heterocyclic, a Alkylcycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl)(alkyl)amino, (alkane) Substituted by a group of (carbonyl)amino groups.

2. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof according to claim 1, wherein:

m Ra are each independently selected from halogen, alkyl, cycloalkyl, heterocyclic, -OH, alkoxy, -NH _{2 ;} and the alkyl, cycloalkyl, heterocyclyl, alkoxy optionally Substituted with one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy, -NH ₂ , -NH , -N(R ₄ ) ₂ ; alkoxyalkyl, cycloalkyl group and heterocyclyl group optionally substituted with one or more groups selected from -OH, -CN, -NH _2, a substituted alkyl group;

Preferably, m Ra are each independently selected from halogen, alkyl, and the alkyl is optionally selected from one or more selected from halogen,

Substituent substitution of -OH, alkoxy, cycloalkyloxy, heterocyclyloxy;

More preferably, m of Ra is independently selected from halogen, d_ ₆ alkyl group, and the alkyl is optionally substituted with one or more groups selected from halo, -OH, d_ ₆ alkoxy, C ₃ _ ₈ cycloalkyl The group is substituted with a group of 4 to 8 membered heterocyclic oxy groups containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur.

3. A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

4. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof, according to any of the preceding claims, wherein:

M is CH;

Each of p Rt is independently an alkyl group, preferably a d ₆ alkyl group;

Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Substituted with one or more groups selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl; The alkyl group in the carbonyl group is optionally substituted by an alkoxyamido group, the heterocyclic group in the heterocyclylalkyl group is optionally substituted by an alkoxycarbonyl group, and the heterocyclic group in the heterocyclic carbonyl group is optionally a Or a plurality of groups selected from the group consisting of an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, and a hydroxyalkyl group. Structure, solvate, more

Two adjacent Rbs together with the carbon atoms on the ring B to which they are attached form a structure selected from the group consisting of:

And the structure is optionally one or more selected from the group consisting of an alkoxycarbonyl group, a d- ₆ alkylcarbonyl group, a 4- to 8-membered heterocyclic carbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroarylcarbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C ₃ _-8 cycloalkyl-d- ₆ alkyl group, containing 1 to 3 selected from nitrogen, oxygen and 4-8 yuan heterocyclyl -d_ sulfur heteroatoms ₆ alkyl, Q ^. a group substituted with an aryl-d- ₆ alkyl group; and the alkyl group in the alkylcarbonyl group is optionally substituted with an alkoxyamido group, and the heterocyclic group in the heterocyclylalkyl group is optionally substituted with an alkoxycarbonyl group The heterocyclic group in the heterocyclic carbonyl group is optionally substituted by one or more groups selected from the group consisting of an alkyl group, a d- ₆ alkylcarbonyl group, a d- ₆ alkoxycarbonyl group, a hydroxy-C^alkyl group.

6. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

M is a N atom;

Each of R Rb is independently selected from a 3⁄4 alkyl group; a cycloalkyl group; a heterocyclic group optionally substituted by an alkyl group; a heterocyclylalkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally One or more selected from the group consisting of -indole, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkylcarbonylalkyl, heterocyclylalkyl, Cycloalkylalkyl, aryl-based, single-yard amino-based, secondary-base amino-based, oxycarbonylamino-based, oxycarbonyl, ring-based carbonyl, single-hospital amino, second Substituted by a group of a base amino group, a (homoyloxycarbonyl) (hospital) amino group, an (homo-oxyl group) (homo-based) amino group, a (homo-based carbonyl) (alkyl)amino group.

7. A compound according to claim 6, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

Ring

ρ R1 are each independently selected from halogen; -OH; -NH ₂ ; d- ₆ alkyl; C ₂ _-6 alkenyl; optionally substituted by d- ₆ alkoxy C^alkyl. Aryl; optionally substituted by C^alkyl, hydroxy-C^alkyl, halogen, Cw alkoxy a 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; optionally substituted by -NH ₂ , d ₆ alkyl, 1 to 4 selected from nitrogen, oxygen and a 5- to 10-membered heteroaryl group of a sulfur hetero atom, wherein the alkyl group is optionally further selected from the group consisting of -CN, Ci- ₆ alkoxy, C ₃ _-8 cycloalkyl, and 1 to 3 selected from nitrogen Substituted by a 4- to 8-membered heterocyclic group of a hetero atom of oxygen and sulfur, a mono(d- ₆ alkyl)amino group, a bis(d- ₆ alkyl)amino group; optionally a di(d- ₆ alkyl) group Amino, C ₃ _-8 cycloalkyl substituted alkoxy; 4 to 8 membered heterocyclooxy containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by Ci- ₆ alkyl group; C ₃ _ ₈ cycloalkyl group; mono (d_ ₆ alkyl) amino; two (d_ ₆ alkyl) amino; the monoalkylamino and dialkylamino groups are optionally further substituted Ci_ ₆ Alkoxy, bis(d- ₆ alkyl)amino, d- ₆ alkyl-S0 ₂ -, di(C^alkyl)aminocarbonyl;

Each of R Rb is independently selected from halo-d- ₆ alkyl; C ₃ _-8 cycloalkyl; optionally substituted by d- ₆ alkyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur a 4- to 8-membered heterocyclic group; a 4- to 8-membered heterocyclic-d- ₆ alkyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the heterocyclic ring in the heterocyclic alkyl group The base is optionally one or more selected from the group consisting of -OH, d- ₆ alkyl, hydroxy-d- ₆ alkyl, amino-d- ₆ alkyl, heteroatoms containing from 1 to 3 selected from nitrogen, oxygen and sulfur. a meta- to 8-membered heterocyclic group, a ₆ -alkoxy-d- ₆ alkyl group, a hydroxy- ₆ -alkoxy-d- ₆ alkyl group, a ₆ -alkylcarbonyl-d- ₆ alkyl group, and contains 1 to 3 selected 4 yuan heteroatom from nitrogen, oxygen and sulfur to 8-membered heterocyclyl -d_ ₆ alkyl, C ₃ _ ₈ cycloalkyl group hospital -d_ _6, C ₆ - ₁₀ aryl group -Ci- 6 hospital, Mono (Ci-6 yard base) amino-Ci-6 yard base, bis(Ci-6 yard base) amino-Ci-6 yard base, C ₆ alkoxycarbonylamino-Cw alkyl group, d- ₆ alkoxycarbonyl group , C ₃ _ ₈ cycloalkyl-carbonyl group, mono (d_ ₆ alkyl) amino, di (d_ ₆ hospital yl) amino, (Ci_ ₆ hospital butoxycarbonyl) (Ci- 6 hospital yl) amino, (Ci_ ₆ hospital oxygen base Yl) (Cw of hospital-yl) amino, (Ci_ ₆ hospital-ylcarbonyl) ₍₆ alkyl) amino groups.

The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

M is CR, wherein R is selected from halogen, alkyl, cycloalkyl and the alkyl group, cycloalkyl group optionally substituted with one or more halo; Preferably, R is selected from Ci_ ₆ alkyl or C ₃ _ ₈ -cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halogens;

9. A compound according to claim 8, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

Ring T is selected from the following structures:

A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof according to any of the preceding claims, wherein:

Preferably, it is selected from a H atom or a ₆ alkyl group;

More preferably, it is 11 atoms.

The compound according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein the compound is selected From:

ʼnll

HI

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

CS.S.0/CT0ZN3/X3d LLOL iOZ OAV

116

A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph thereof, a tautomer, Metabolite or prodrug and a pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or The pharmaceutical composition according to claim 12 for use in the prevention and/or treatment of a tumor.