WO2013170770A1

WO2013170770A1 - Acetylene derivatives having antitumor activity

Info

Publication number: WO2013170770A1
Application number: PCT/CN2013/075738
Authority: WO
Inventors: 万惠新; 李春丽; 石辰; 刘海燕; 李萍
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: CN103421005A; CN103420977A; CN103420977B; WO2013170774A1

Abstract

The present invention relates to disubstituted aromatic ring acetylene derivatives having a general formula I, a pharmaceutical composition containing the compound, and applications of the compound and the pharmaceutical composition for curing and/or preventing tumors, A, B, T, M, Ra, Rb, Rt, m, n, and p being defined in the text.

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 CML patients 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 inhibitor Nilotinib Dasatinib is 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). Pathway, PI3K/Akt pathway and activation of signal transducers and transcriptional pathway activators promote cell proliferation, angiogenesis, metastasis and inhibition of apoptosis, thereby increasing the survival, proliferation, invasion and metastasis of tumor cells. 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) o although EGFR TKIs can achieve significant results in these patients, but compared with those who do not have T790M detected, Patients with T790M had a relatively short progression-free survival (7.7 months vs 16.5 months; P < 0.001). Preclinical studies have also found that T790M is a potential mechanism of resistance, and in vitro tests have demonstrated that this mutation significantly inhibits the effects of erlotinib and gefitinib, whereas TK activity remains. 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 tumor cells to resist EGFR TKIs remains unclear. It is possible 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. Studies have reported that other point mutations that cause 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 more malignant tumors and is prone to invasion and metastasis. In recent years, it has been found that the BRAF gene has a high frequency of mutations in human melanoma, and it has been clinically proven that there is a BRAF V600E mutation in about 50% of melanomas. The B-raf gene is a member of the RAF family and encodes a silk/threonine-specific kinase. It is an important transduction factor in the RAS/RAF/MEK/ERK/MAPK pathway and is involved in the regulation of various organisms in cells. Learn about events 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 CPLX4032/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 bind to ErbB3 compensatoryly, replacing the function of the original EGFR, and activating the downstream PI3K 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. In addition to the above-mentioned Sunitinib and Sorafenib, the representative drugs include 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 selected from heteroaryl;

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

0 or 1 ;

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 or 1;

Each of p Rt 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 a C ₆ _ _1Q 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 the ring B to which they are attached form a heterocyclic group; said heterocyclic group is optionally substituted by one or more -R ₂ ;

L is a linking group selected from -C0NR - or -NR CO-, wherein 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 from one or more Halogen, -OH, -R ₄ , -OR ₄ , -C(0)-R ₄ , -C(0)0-R ₄ , -OC(0)-R ₄ , -NH ₂ , -NHR ₄ , - a group substituted with N(R ₄ )2, -NHC(0)R ₄ , -NHC(0)OR ₄ , -NR ₅ C(0)R ₄ ;

Each F and R _{5 are} independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₄ , R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, light-based, oxy-based, light-based oxy-based, amino-based Base, the second base, the base of the base, the base of the oxycarbonylamino, the base of the ring, the base of the ring, the base of the heterocyclic base, the base of the aryl, the base of the base, the carbonyl of the ring, the oxycarbonyl, the alkane Substituted by a group of an oxycarbonyl heterocyclic group, an (alkoxycarbonyl)(alkyl)amino group, or a (decyloxyalkyl)(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 thereof, a solvent a compound, a polymorph, a tautomer, a metabolite or a prodrug or a pharmaceutical composition of the invention 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 such as Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^th ED." Vols. 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 stable structural moieties 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, d- 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 R _a 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 Ra is alkyl as defined above. In the present application, the term "alkoxycarbonyl" refers to a -C(0)0-R _a group, wherein Ra is alkyl as defined above.

In the present application, the term "monoalkylamino" refers to _a radical of the formula -NHR _a , wherein is alkyl as defined above. Examples of monoalkylamino include, but are not limited to, methylamino, ethylamino, isopropyl Amino group, etc.

In the present application, the term "dialkylamino" refers to _a radical of the formula -NR _a R _b wherein each of Ra and R _{b 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, pent-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) carbon atoms and a linear or branched hydrocarbon chain bonded to the rest of the molecule by a single bond A group such as, but not limited to, an ethyl group, a propan-1-yl group, a but-1-block group, a pent-1-en-4-yl group, 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[3.1.1]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 -OR _e , wherein! ^ is a cycloalkyl group 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 heteroatoms selected from nitrogen, oxygen and sulfur. a 3- to 20-membered non-aromatic cyclic group. Unless otherwise specifically indicated 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 in the heterocyclic group may be optionally 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, the heterocyclic group is preferably a stable 4 to 11 member comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-aromatic monocyclic, bicyclic, bridged or spiro group, 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 not Limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]decane-7-yl, 2- Oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl , tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolidyl, Thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl, phthalimido Wait.

In the present application, the term "heterocyclyloxy" refers to a radical of the formula -OR _d where is a heterocyclyl 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 atom on the aromatic ring is bonded to the rest of the molecule through a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindole Base, 2-benzoxazolinone, 2Η-1,4-benzoxazine-3(4Η)-keto-7-yl and the like.

In the present application, the term "aralkyl" 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 is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, or from 1 to 4 selected from 1 to 4 Nitrogen, oxygen and sulfur miscellaneous A stable 5- to 9-member aromatic group. 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] Triazine, imidazo [1,2-α] pyrazine.

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 ₁₍₎ , -C(O) -R ₁₀ -C(O)OR ₁₀ -OC(0)-Rio -N(R ₁₀ ) ₂ , -C(O)N(R ₁₀ ) ₂ , -N(R ₁₀ )C(O)R _u , -N(R ₁₀ )C(O)OR _u , -N(R ₁₀ )S(O) _t R _u (where t is 1 or 2), -S(0) _t ORi i (where t is 1 or 2) ), -S(0) _t Rii (where t is 0, 1 or 2), -S(O) _t N(R ₁₀ ) ₂ (where t is 1 or 2), wherein each R _{1Q is} independently hydrogen, An alkyl group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group, a heterocycloalkyl group, a heteroaryl group or a heteroarylalkyl group; and each Ru is independently an alkane Alkyl, 3⁄4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

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 Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 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.sup.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, ^-monoenoate, 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" refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. 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. a compound produced by biotransformation, such as reaction.

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, MG, 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 present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.

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

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:

(i) preventing a disease or condition from occurring 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.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, 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.

(I)

Its towel:

Ring A is selected from heteroaryl;

0 or 1 ;

2;

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 the formula I, the ethyl group moiety and the L moiety are meta-substituted on ring A, and ring A is a 5- to 12-membered heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur. .

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:

In the formula I, the ethyl group moiety and the L moiety are meta-substituted on ring A, and ring A is a 5- to 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur. .

In the formula I, the ethyl group moiety and the L moiety are meta-substituted on the ring A, and the ring A is a pyridyl group, a furyl group or a thiazolyl group.

In the formula I, the ethyl group moiety and the L moiety are meta-substituted on the ring A, and the ring A is a pyridyl group.

m Ra are each independently selected from halogen, -R ₂ , -OR ₂ ; each R _{2 is} independently selected from alkyl, cycloalkyl, and each R _{2 is} optionally selected from one or more selected from halogen, -R ₄ , a group of -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ is substituted; each F is independently selected from an alkyl group or a cycloalkyl 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:

m Ra are each independently selected from halogen, -R ₂ , -OR ₂ ; each R _{2 is} independently selected from d- ₆ alkyl, C ₃ _-8 cycloalkyl, and each R _{2 is} optionally one or more Substituted with a group selected from the group consisting of halogen, -F, -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ ; each F is independently selected from the group consisting of d- ₆ alkyl, C ₃ _-8 cycloalkyl.

m Ra are each independently selected from the group consisting of alkyl, 3⁄4 alkyl, alkoxyalkyl.

Each of m Ra is independently selected from the group consisting of d- ₆ alkyl, halogenated d- ₆ alkyl, d- ₆ alkoxy d- ₆ alkyl.

Each of R _{2 is} independently selected from the group consisting of halogen, —R ₂ , —OR ₂ , —NHR ₂ , —N(R ₂ ) ₂ , wherein each R _{2 is} independently selected from alkyl, cycloalkyl, and each R _{2 is} Optionally substituted with one or more groups selected from the group consisting of halogen, -R ₄ , -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ ; each R _{4 is} independently selected from alkyl, cycloalkyl, heterocycle And each R _{4 is} optionally substituted by one or more groups selected from the group consisting of alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, alkoxyalkyl ; or

Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a heterocyclic group; said heterocyclic group is optionally substituted by one or more alkyl groups, optionally one or more A cycloalkyl group is substituted.

Each of R Rb is independently selected from the group consisting of halogen, -R ₂ , -OR ₂ , -NHR ₂ , -N(R ₂ ) ₂ , wherein each R _{2 is} independently selected from d- ₆ alkyl, C ₃ _-8 cycloalkyl And each R _{2 is} optionally substituted with one or more groups selected from the group consisting of halogen, —R ₄ , —OR ₄ , —NHR ₄ , —N(R 4 ) ₂ ; each R 4 is independently selected from d ₆ alkyl, a C ₃ _-8 cycloalkyl group, a stable 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and each F is optionally selected from one or more selected from d- ₆ alkyl, mono d_ ₆ alkylamino, di-d_ ₆ alkylamino, C ₃ _ ₈ cycloalkyl group, comprising a stable 4-11 yuan heterocycle with 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur a group substituted with a group, a d ₆ alkoxy group, a d ₆ alkoxy group d ₆ alkyl group; or

Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a heterocyclic group; said heterocyclic group is optionally substituted by one or more d- ₆ alkyl groups, optionally an alkyl group Or a plurality of C ₃ _-8 cycloalkyl groups.

Each of R Rb is independently d- ₆ alkyl or C ₃ _-8 cycloalkyl, and the alkyl or cycloalkyl is optionally one or more selected from -R ₄ , -NHR ₄ , -N(R ₄₎ _{2-substituted} group; each independently selected from F d_ ₆ alkyl, _[3 _ ₈ cycloalkyl group, comprising a stable 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur is 4-8 yuan a heterocyclic group, and each R4 is optionally substituted with one or more groups selected from the group consisting of d- ₆ alkyl, mono d- ₆ alkylamino, di- ₆ alkylamino;

Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more d_ ₆ alkyl substituted, the alkyl group is optionally substituted with one or more C ₃ _ ₈ cycloalkyl substituted.

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:

The two adjacent Rbs together with the carbon atoms on the ring B to which they are attached form a structure selected from the following:

The structure and optionally substituted with one or more d_ ₆ alkyl substituted, the alkyl group is optionally substituted with one or more C ₃ _ ₈ cycloalkyl substituted.

Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 5-membered heterocyclic group containing one nitrogen atom, which is optionally substituted by one or more alkyl groups, the alkane The group is optionally substituted by one or more cycloalkyl groups.

M is selected from the group consisting of N atom, CH and B CR, wherein R is selected from alkyl or haloalkyl, preferably d- ₆ alkyl or halogenated d- ₆ fluorenyl;

The ring T is selected from a 5- 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.

Ring T is selected from

Each of p Rt is independently selected from halo, -R _{2 ;} each R _{2 is} independently selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{2 is} optionally one or more a group selected from a halogen, an alkyl group;

In a preferred embodiment, the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug, wherein: preferably, p Rt are each independently selected from halogen, -R _{2 ;} each R _{2 is} independently selected From a D ₆ alkyl group, a C ₃ _-8 cycloalkyl group, a stable 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C. An aryl group, a stable 5- to 9-membered heteroaryl group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and each R _{2 is} optionally selected from one or more selected from halogen, d- ₆ alkyl Replaced by the group.

R is selected from the group consisting of H atom, alkyl group, cycloalkyl group and hydroxyalkyl group, preferably H atom, d- ₆ alkyl group, C ₃ _-8 cycloalkyl group and hydroxy-d- ₆ alkyl group; preferably, R is selected from H atom , d ₆ alkyl; more preferably, 11 atoms.

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, Wherein the compound is selected from:

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 (Philadelphia College} 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 syrup 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 particular mode of administration and dosage form will depend on the physicochemical 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. Popovich, 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, AG, LYN, LCK, BRAF, BRAFV600E, AblT315I, FGR, Inhibition of HCK, HER4, p38, MINK, MAPK, EphB, YES, BRK, TIE, CSK, MUSK, FGFR, JAK, EphA, IKKB, P70S6K, FLT, EGFR, BTK, ITK, PDGFR, etc. The mutants AblT315I, BRAFV600E, etc. are effective and can be used for the preparation of 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 The form, solvate, prodrug or metabolite or 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.

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 An acceptable salt, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Composition. According to one embodiment, the tumor is inhibited by inhibition of a protein kinase. 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 about 1 mg/kg Up to approx. 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.

The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis WQ^ ^ EcU Wiley. The protecting group can also be a polymeric resin.

The present invention is prepared by -E.

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 dilute salt a reagent such as acid, potassium carbonate or TBAF; (4) coupling intermediates A-5 and A-6 under a transition metal catalysis to obtain a compound of the formula 1 (A), and a coupling reaction using a palladium catalyst (eg Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ PdPPh ₃ Cl _{2 ,} etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.), and various organic bases or Inorganic bases (e.g., triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) are obtained by reaction in a suitable solvent (e.g., THF, toluene, DMF, etc.) and temperature (e.g., 20-150 degrees). In Method A, Ml, M2, M3 and M4 are C atoms or heteroatoms, as C original

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 The ring is intermediate to obtain the intermediate B-2; (2) the intermediate B-2 is subjected to halogenation under various halogenating agents (e.g., 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 bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) are obtained by reacting in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees); (4) Intermediate B-4 removes the protecting group to obtain B-5, and deprotection can use dilute hydrochloric acid, potassium carbonate or TBAF; (5) intermediates B-5 and B-6 in transition metal catalysis The coupling reaction is carried out to obtain a compound of the formula 1 (B), and the coupling reaction is carried out by using a palladium catalyst (for example, Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ , PdPPh ₃ Cl _{2 ,} etc.), a copper salt. Such as (copper chloride, cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in appropriate solvents (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees) are obtained. In Method B, Ml, M2, M3, and M4 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 The ring is intermediate to obtain intermediate C-2; (2) intermediate C-2 is subjected to various halogenating agents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Halogenation reaction to obtain intermediate C-3; (3) coupling intermediate C-4 with TMS protected block B under transition metal catalysis to obtain intermediate C-5, the coupling reaction using palladium catalyst (such as Ρ ΡΡ1ι 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 C-6, and the deprotection can be carried out by using a reagent such as dilute hydrochloric acid, potassium carbonate or TBAF; (5) coupling intermediate C-3 and C-6 under transition metal catalysis The reaction gives 1 (C), and the coupling reaction uses a palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd(PPh) ₃ Cl _{2 ,} etc.), a copper salt (such as cuprous chloride, Cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) in a suitable solvent (such as THF, Toluene, DMF, etc.) and temperature (such as 20-150 degrees) are obtained. In Method C, Ml, M2, M3, and M4 are C atoms or N atoms, and when C atoms are

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.) (B) intermediate D-2 is subjected to a halogenation reaction under the action of various halogenating agents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) to obtain a middle (3) The intermediate D-3 and D-4 are subjected to a coupling reaction under transition metal catalysis to obtain 1 (D), and the coupling reaction is carried out using a palladium catalyst (for example, 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 triethylamine) , DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in a suitable solvent (eg THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees) are obtained. In Method D, Ml, M2, M3, and M4 are C atoms or N atoms.

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 I(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). The solvent was concentrated under reduced pressure and the residue was evaporated, mjjjjjjjj 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, 1H), 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 g, 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 methylene chloride (50 mL) and neutralized with a saturated sodium hydrogen carbonate solution to give an organic phase. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

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 (a solution of 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 afforded the intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 mg). 1H-NMR (300MHz, DMSO-d6): δ 8.48 (d, J = 6.6 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 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]. Intermediate 2: 6-Chloro-3-ethylidene-[1,2,4]triazole [4,3-a]pyridine

Using 2-mercapto-5-chloropyridine as starting material, a similar synthesis to Intermediate 1 was used to obtain the intermediate 6-chloro-3-ethylidene-[1,2,4]triazole [4,3- a] pyridine (yellow solid, 125 mg). 1H-NMR (300MHz, DMSO-d6): δ 8.27 (s, 1 Η), 7.83 (d, J = 9.6 Hz, 1 Η), 7.32 (d, J = 9.6 Hz, 1H), 3.88 (s, 1H). MS m/z (ESI): 178.0 [M+H]. Intermediate 3: 3-Ethyl -6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine

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 tert-butanol was added thereto. Potassium (6.96 g, 62 mmol), reacted at room temperature for 2 h. After completion of the reaction, water was added to the reaction mixture to precipitate a solid. The solid was collected by filtration <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI> 1H-NMR (400MHz, CD30D): δ 8.65 (2 Η, d, J = 0.8 Hz), 7.44-7.47 (2H, m), 7.31-7.44 (3H, m), 5.42 (2H, s). MS m/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) were added. 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, CD30D): δ 8.29 (2Η, s), 7.43-7.45(2H, m), 7.27-7.37(3H, m), 5.38(2H, 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 (400MHz _: DMS0-d6): δ 8.56 (2 Η, s), 3.71 (4 Η, t, J = 4.8 Hz), 3.02 (4H, t, J = 2.0 Hz). MS m/z (ESI):

181.95 [M+H].

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

5-morpholine-2-hydroxypyrimidine hydrochloride (3.76 g, 17.3 mmol) and diethyl aniline (5.54 mL, 34.64 mmol) were dissolved in acetonitrile (75 ml), and phosphorus oxychloride (8 mL, 86.6 mmol), 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). 1H-NMR (400MHz, CDC13): δ 8.22 (2 Η, s), 3.87 (4H, t, J = 4.8 Hz), 3.20 (4H, 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), and 64% hydrazine hydrate (4.05 g, 51.71 mmol) was added thereto, and the reaction mixture was heated to reflux. h. 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 (400MHz, CD30D): δ 8.18 (2 Η, s), 3.83 (4H, t, J = 4.8 Hz), 3.04 (4H, 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. The ester (2M solution, 4.43 mL, 8.86 mmol) was stirred at room temperature for 3 h. The organic phase was washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and evaporated to dryness. The residue was dissolved in anhydrous tetrahydrofuran (20 mL) (5-Morpholinyrimidin-2-yl)indole (1.57 g, 8.06 mmol) was slowly added thereto, and stirred at room temperature for 0.5 h. After the TLC reaction was completed, water was added thereto and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness. Solid, 1.98 g). iH-NMR (400 MHz, CDC13): δ 8.15 (2 Η, s), 3.84 (4 Η, t, J = 4.8 Hz), 3.05 (4 Η, t, J = 4.8 Hz), 0.18 (9 Η, 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 is in the room Stir 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, CDC13): 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). MS m/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].

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), palladium acetate (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 layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Pyridine (yellow oil, 647 mg). 1H-NMR (400MHz, CD30D): δ7.99(1Η, s), 7.59(1H, td, J=10.0, 2.0Hz), 6.95(1H, d, J=8.4Hz), 1.95-1.99 (1H, 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-pyridyl 3⁄4- ² -yl)-肼

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. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 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). 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 THF (10 mL) 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 crystalljjjjlilililililililililililililili 1H-NMR (400MHz, CDC13): δ7.90 (1Η, d, J=1.6Hz), 7.26-7.29(1Η, m), 6.69(1H, d, J=8.4Hz), 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

The trimethylsilyl - propionic acid N '- (5- cyclopropyl - pyridin-2-yl) - hydrazide (0.1 g, 0.366 mmol) was dissolved in THF (2 mL), and thereto was added under N ₂ Triphenylphosphine (0.115 g, 0.439 mmol), azide trimethylsilane (0.063 ml, 0.476 mmol) and diisopropyl azodicarboxylate (0.079 mL, 0.403 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was completed by TLC, 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 (400MHz, CDC13): δ7.91 (1Η, s), 7.73 (1H, 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). MS m/z (ESI): 255.90 [M+H]

Step 5: 6-Cyclopropyl-3-ethylidene-[1,2,4]triazole [4,3-a]pyridine

6-Cyclopropyl-3-(trimethylsilyl)ethylidene H1,2,4]triazolo[4,3-a]pyridine (44 mg, 0.173 mmol) in THF (2 mL) To this was added tetra-n-butylammonium fluoride trihydrate (71 mg, 0.224 mmol) and allowed to react at room temperature for 20 min. After the TLC reaction was completed, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to silica gel column chromatography to afford 6-cyclopropyl-3-ethylidene-[ 1,2,4]triazole [4,3-a]pyridine (white solid, 19 mg). 1H-NMR (400MHz, CDC13): δ7.96(1Η, s), 7.79(1H, d, J=9.6Hz), 7.12(1H, d, J=9.2Hz), 3.84(1H, s), 1.93 -2.03 (1H, m), 1.04-1.09 (2H, m), 0.74-0.78 (2H, m). MS m/z (ESI):

184.00 [M+H]. Intermediate 5: 3-ethylidene

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-iodo-succinimide was added in portions with ice-cooling. Amine (2.7 g, 0.12 mol) was added and stirred 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-NMR (300MHz, DMSO-d6): δ 8.35 (d, J = 5.4 Hz, 1H), 7.75 (s, 1H) ), 7.62 (d, J = 6.9 Hz, 1H), 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. The organic layer was washed with water and brine, dried over sodium sulfate The third step: 3-ethylidene-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%, 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]

Taking 6-chloro-imidazole [l,2-a]pyridine, 6-chloro-imidazole [l,2-b]pyridazine, imidazole [l,2-b]pyridazine, 1-methyl-1H-imidazole, 1H-carbazole and 1H-pyrazole [3,4-b]pyridine were used as starting materials, and the following intermediates 6 to 9 were synthesized in a similar manner to Intermediate 5.

Intermediate 10 -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 g, 77.2 mmol) was dissolved in absolute ethanol (120 mL), and then ethyl bromopyruvate (11.70 mL, 92.6 mmol) was slowly added thereto. The liquid was heated to reflux overnight. After the reaction was completed by TLC, the reaction mixture was cooled to room temperature, and the solvent was evaporated to dryness. The residue was dissolved in saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane (50 mL×3). The residue was dried with EtOAc EtOAc m. 1H-NMR (300MHz, CDC1 ₃ ): 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: Imidazo[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% palladium carbon catalyst was added thereto under nitrogen atmosphere (lg Then, the system was replaced with hydrogen three times and continued to react at room temperature for 2 h. After the TLC detection reaction was completed, the catalyst was removed by filtration, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to dryness crystalljjjjjjjjjjj 1H-NMR (300MHz, CDCI3): 8.64-8.67 (m, 2H), 8.54 (s, 1H), 7.54 (d, J = 4.5 Hz, 1H), 4.51 (q, J = 6.9 Hz, 2H), 1.47 (t, J = 6.9 Hz, 3H 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 g, 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). 1H-NMR (300MHz, CDC1 ₃ ): 8.28 (d, J = 3.3 Hz, 1H), 7.88-7.94 (m, 2H), 7.03 (dd, J= 9.0, 4.5Hz, 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). g, 2.7 mmol) and sodium bicarbonate powder C457 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): δ 10.05 (s, 1H), 8.98 (s, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 9.6 Hz, 1H), 7.36 (dd, J= 9.6, 4.2 Hz, 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 in an ice bath and slowly added dropwise under nitrogen. DAST reagent (0.58 ml, 4.76 mmol). After the addition was completed, 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 ): δ 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). MS m/z (ESI): 170.1 [M+H]

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

Intermediate 2 was used to synthesize the intermediate 2-difluoromethyl-3-iodo-imidazole [l,2-b]pyridazine (white solid, 285 mg). 1H-NMR (300MHz, CDCI3): δ 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). MS m/z (ESI): 295.9 [M+H]

Step 7: 2-Difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine

The intermediate 2, difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine (white solid, 64 mg) was obtained in a similar manner to Intermediate 5, second. 1H-NMR (300MHz, CDCI3): δ 8.52-8.53 (m, 1H), 8.03 (dd, J= 6.3, 1.5 Hz, 1H), 7.02-7.25 (m, 1H), 6.93 (t, J = 40.5 Hz , 1H), 3.93 (s, 1H). MS m/z (ESI): 194.1 [M+H]

The following intermediates 11 to 13 were synthesized by a similar procedure from Intermediate 10 using 2-aminopyridine, 3-chloro-6-aminopyridazine and 2-aminopyrimidine and 2-bromoacetone as starting materials.

Intermediate 14: 3-Ethyl-2-methyl-2H-carbazole

First and second steps: 3-iodo-2-methyl-2H-carbazole

Using the 1H-carbazole as a starting material, the intermediate 3-iodo-2-methyl-2H-indole (0.6 g, yellow solid) was obtained by the method of the literature (Journal of Organometallic Chemistry, 2000, 604, 2, 157 169). 1H-NMR (300MHz, CDC13): δ 7.67-7.71(111, 2Η), 7.30- 7.32(m, 1H), 7,12-7,17(t, J=7.8Hz, 1H), 4.23(s, 3H).

Third and fourth steps: 3-ethylidene-2-methyl-2H-carbazole

The intermediate 3-ethylidene-2-methyl-2H-carbazole was synthesized by the same method as the intermediate 5 using 3-iodo-2methyl-2H-carbazole as a starting material. 1H-NMR (300MHz, CDC1 ₃ ): δ 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].

First step: 2-bromomethyl-4-nitro-benzoic acid methyl ester

Methyl 2-methyl- 4-nitro-benzoate (3.0 g, 15 mmol) was dissolved in carbon tetrachloride (50 mL), followed by N-bromosuccinimide (3.0 g, 17 mmol) and benzoyl peroxide (100 mg, 0.4 mmol), and the reaction mixture was refluxed for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and evaporated. The concentrate was separated and purified by silica gel column chromatography toield of ethyl 2-bromomethyl-4-nitro-benzoic acid (light yellow solid, 1.9 g) o 1H-NMR (300 MHz, CDCI3): δ 8.34 (s, 1H), 8.19 (dd, J = 2.1, 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 3.99 (s, 3H).

The second step: 2-cyclopropylmethyl-5-nitro-2,3-dihydro-isoindole-1-one

2-Bromomethyl-4-nitro-benzoic acid methyl ester (2 g, 10.9 mmol) was dissolved in tetrahydrofuran (6 mL), and cyclopropylmethylamine (1 g, 14.1) Methyl), 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). 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.51 (m, 1Η), 8.33 (m, 1H), 7.91 (m, 1H), 4.69 (s, 2H), 3.43 (m, 2H), 1.06 ( m, 1H), 0.53 (m, 2H), 0.343 (m, 2H). MS m/z (ESI): 233.1 [M+H] o

The third step: 5-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one

2-Cyclopropylmethyl-5-nitro-2,3-dihydro-isoindolinone (696 mg, 3 mmol) was dissolved in methanol/water (10 mL / 2 mL) and reduced iron powder (280 mg, 5 mmol) And ammonium chloride (530 mg, 10 mmol), the reaction was heated to reflux for 2 hours and the reaction was completed. The mixture was made basic with saturated sodium bicarbonate solution, extracted with dichloromethane, dried and concentrated to give 5-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one (yellow solid, 502 mg). 1H-NMR (300MHz, DMSO-de): δ 7.29 (m, 1Η), 6.59 (m, 2H), 5.71 (s, 2H), 4.34 (s, 2H), 3.26 (m, 2H), 0.98 (m , 1H), 0.48 (m, 2H) and 0.24 (m, 2H). MS m/z (ESI): 203.1 [M+H].

The fourth step: 4-iodo-pyridine-2-carboxylic acid (2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl)-amide

5-Amino-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one and 4-iodo-2-isonicotinic acid are dissolved in N,N-dimethylformamide

(10 mL), 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (0.39 g, 1.02 mmol) were added separately under ice-cooling. And diisopropylethylamine (0.20 mL, 1.27 mmol), stirring was continued overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc. The intermediate 4-iodo-pyridine-2-carboxylic acid (2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide (yellow solid, 380 mg ). 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.57 (m, IH), 8.37 (m, 1H), 8.19 (m, 1H), 8.03 (m, 1H), 7.83 (m, 1H), 7.75 (m, 1H), 4.62 (s, 2H), 3.48 (s 2H) , 1.11 (m, IH), 0.60 (m, 2H), 0.36 (m, 2H). MS m/z (ESI): 434.0 [M+H]. Medium-iodo-6-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide

First step: 5-bromo-6-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide

5-Bromo-6-methyl-nicotinic acid (0.20 g, 0.93 mmol) and 4-(4-methyl-piperazinemethyl)-3-trifluoromethyl-phenylamine (0.23 g, 0.85 mmol ) dissolved in N,N-dimethylformamide CIO mL), added 2-(;7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethyl, respectively, under ice cooling Urea hexafluorophosphate (0.39 g, 1.02 mmol) and diisopropylethylamine (0.20 mL, 1.27 mmol) were stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. EtOAc (EtOAc m. 5-Bromo-6-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide (yellow solid, 0.26 g) ), the yield is 65%.

Step 2: 5-iodo-6-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide

3-Bromo-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide (566 mg, 1.2 mmol) dissolved in l,4-dioxane (10 mL), added cuprous iodide (23 mg, 0.12 mmol), potassium iodide solid (398 mg, 2.4 mmol) and hydrazine, Ν'-dimethyl Ethylethane-1,2-diamine (0.026 ml, 0.24 mmol). This mixture was heated to 110 ^Q C and stirred for 16 h. After the completion of the TLC reaction, the mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. 6-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide (white solid, 384 mg). 1H-NMR (400MHz, CD ₃ OD): δ 8.95 (1Η, d, J=2.0Hz), 8.73 (1Η, d, J=2.0Hz), 8.11(1H, d, J=2.0Hz), 7.93( 1H, dd, J=8.8, 2.4Hz), 7.77(1H, d, J=8.4Hz), 3.66(2H, s), 2.79(3H, s), 2.45-2.58 (10H, m), 2.30(3H , s). MS m/z (ESI): 518.7 [M+H].

Using ₆ -bromo- ₅ -methyl-B-pyridyl- ₂ -carboxylic acid and 4-iodo-5-methyl-pyridine-2-carboxylic acid as the starting materials, the same formula as the intermediate 16 was used.

Intermediate 19: N-(5-iodo-6-methyl-pyridin-3-yl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzene Amide

First step: 5-bromo-6-methyl-pyridine-3-ylamine

5-Bromo-6-methyl-pyridine-3-carboxylic acid (1 g, 4.63 mmol) was dissolved in t-butanol (6.6 mL) and N,N-dimethylformamide (15 mL) Triethylamine (5.15 mL, 37.04 mmol) and diphenylphosphoryl azide (0.51 mL, 5.093 mmol) were added in that order. This mixture was heated to 100 ^Q C reaction 2h, after the end of the reaction by TLC, the solvent was evaporated to dryness, the residue was dissolved in saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated, the residue on silica gel Purification by column chromatography gave a white solid. The above white solid was dissolved in dichloromethane (10 mL), and 4N hydrogen chloride in dioxane solution was added and stirred at room temperature for 2 hr. After completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals 1H-NMR (400 MHz, CDC1 ₃ ): δ 7.90 (1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 2.4 Hz). MS m/z (ESI): 186.90 [M+H].

Second step: N-(5-bromo-6-methyl-pyridin-3-yl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzene Amide

4-[(4-Methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzoic acid (297 mg, 0.754 mmol), 2-(7-azabenzotriazole) -Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (317 mg, 0.834 mmol) and N,N-diisopropylethylamine (0.17 mL, 1.043 mmol) dissolved in N,N - in dimethylformamide (5 mL). After the mixture was stirred at room temperature for half an hour, 5-bromo-6-methyl-3-aminopyridine (130 mg, 0.695 mmol) was added and the mixture was stirred at room temperature overnight. After the completion of the TLC reaction, the mixture was cooled to room temperature, and water was added thereto, and the mixture was combined with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. 6-Methyl-pyridin-3-yl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide (yellow solid, 80 mg) 0 1H- NMR (400MHz, CD3OD): δ 8.74 (1H, d, J=2.0Hz), 8.52 (1H, d, J=2.0Hz), 8.31(1H, s), 8.21(1H, d, J=7.6Hz) , 8.02 (1H, d, J = 8.4 Hz), 3.87 (2H, s), 3.48 (2H, s), 3.21 (2H, s), 3.04 (2H, s), 2.92 (3H, s), 2.62 ( 3H, s), 2.50 (2H, s). MS m/z (ESI): 236.90 [M+2].

Third step: N-(5-iodo-6-methyl-pyridin-3-yl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzene Amide

N-(5-Bromo-6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide ( 80 mg, 0.17 mmol) dissolved in 1,4-dioxane (2 mL), added with cuprous iodide (3 mg, 0.017 mmol), potassium iodide (56 mg, 0.34 mmol) and hydrazine under argon. Ν'-Dimethylethyl-1,2-diamine (0.004 mL, 0.034 mmol). This mixture was heated to EtOAc and stirred for 16 h. After the completion of the TLC reaction, the mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -6-Methyl-pyridin-3-yl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide (yellow solid, 45 mg). 1H-NMR (400MHz, CD3OD): δ 8.76 (1H, d, J = 2.4Hz), 8.72 (1H, d, J = 2.4Hz), 8.29(1H, s), 8.19(1H, d, J=8.0 Hz), 8.00 (1H, d, J = 8.4 Hz), 3.81 (2H, s), 2.86 (4H, s), 2.62-2.69 (7H, m), 2.56 (3H _: s). MS m/z (ESI): 259.90 [M+2].

First step: 3-iodo-4-bromomethylnicotinic acid ethyl ester

Ethyl 3-iodo-4-methylnicotinate (200 mg, 0.7 mmol) was dissolved in carbon tetrachloride (5 mL) and N-bromosuccinimide (180 mg, 1.0 mmol) was added sequentially. 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, and the residue was evaporated to m. The combined organic layers were washed with EtOAc EtOAc.

Step 2: 3-iodo-4-hydroxymethylnicotinic acid ethyl ester

The above crude ethyl 3-iodo-4-bromomethylnicotinate (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, evaporated, mjjjjjjj 1H NMR (CDC1 ₃ , 400MHz): 53.94 (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].

The third step: 3-iodo-4-fluoromethylnicotinic acid ethyl ester

Ethyl 3-iodo-4-hydroxymethylnicotinate (300 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, and slowly added with diethylamine trifluorosulfide DAST under argon (0.25 mL, 2.0 mmol), the ice bath was removed and the reaction was stirred for 24 h. After the reaction was completed, the solvent was evaporated. mjjjjjjjjjjjjj 1H NMR (CDCI3, 400 MHz): δ 3.95 (s, 3H), 5.37 (s, 1H) _: 5.48 (s, 1H), 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-fluoromethylnicotinic acid

Methyl 3-iodo-4-fluoromethylnicotinate (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 completion of the reaction, the solvent was evaporated, and the residue was evaporated to m. The organic layers were combined, the solvent was evaporated to give 3-fluoro-iodo-4-methylbenzoic acid (white solid ^{A, 245 mg) o 1 H} NMR (DMSO-d6, 400 MHz): 55.42 (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-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide

3-iodo-4-fluoromethylnicotinic acid (225 mg, 0.8 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (180 μ, 1.09 mmol) and 2-(7-azabenzotriazole)-Ν, Ν, Ν', Ν'-tetramethylurea hexafluorophosphate (610 mg, 1.6 mmol), stir for 5 min and add 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 combined organic layers were purified by column chromatography to afford 4-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl] - Niacinamide (white solid, 420 mg). 1H NMR (CD ₃ OD, 400 MHz): δ 2.49 (s, 4 Η), 2.92 (s, 3 Η), 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). MS m/z (ESI): 535.7 [M+H]. Medium-difluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

First step: 4-formyl-3-iodo-nicotinic acid ethyl ester

Ethyl 3-iodo-4-hydroxymethylnicotinate (lg, 3.4 mmol) was dissolved in dichloromethane (20 mL), and then was added to Dess-Martin reagent (2.18 g, 5.1 mmol) and solid sodium hydrogen carbonate powder (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 and evaporated tolulululululululululu 1H NMR (CDCI3, 400 MHz): δ 3.98 (s, 3 Η), 5.54 (s, 1H), 7.93_7.95 (m, 1H), 8.11_8.12 (m, 1H), 8.63 (s, 1H) , 10.14(s, 1 H). MS m/z (ESI): 291.8 [M+H].

The second step: 3-iodo-4-difluoromethylnicotinic acid ethyl ester

Dissolve 4-formyl-3-iodo-nicotinic acid ethyl ester (920 mg, 3.1 mmol) in dichloromethane (10 mL), cool in ice-cooling, and slowly add DAST reagent (777 L, 6.3 mmol) under argon After the addition is completed, the ice bath is removed, and the reaction is stirred at room temperature. After completion of the reaction, the solvent was evaporated. mjjjjjjjjj 1H-NMR (CDC1 ₃ , 400MHz): 53.97(s, 3H), 6.80(t, 1H, J=56Hz), 7.70-7.72(m, 1H), 8.12_8.14(m, 1H), 8.56(s , 1H). MS m/z (ESI): 312.7 [M+H].

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

Ethyl 3-iodo-4-difluoromethyl nicotinic acid (900 mg, 2.88 mmol) was dissolved in methanol (10 mL), 4N aqueous sodium hydroxide (2.6 mL, 10.4 mmol), and stirred at 75 °C The reaction was 2.5 h. After completion of the reaction, the solvent was evaporated, and the residue was adjusted to pH 3 with 2N hydrochloric acid and ethyl acetate. The organic layers were combined and evaporated to dryness crystals crystals 1H-NMR (CDCI3, 400 MHz): 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].

The fourth step: N-^K4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylnicotinamide

3-iodo-4-difluoromethylnicotinic acid (860 mg, 2.88 mmol) was dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (668 L) , 4.04 mmol) and 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (1.2 g, 3.2 mmol), stirred for 5 min and 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 give N-(4-(4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethyl Amide (white solid, 1.5 g). 1H-NMR (CD3OD, 400 MHz): 52.76 (br, 4H), 2.90 (s, 3H), 3.29 (br, 4H), 3.78 (s, 2H), 6.94 (t, 1 H, J = 56 Hz), 5.54 (s, 1H), 7.75- 7.82 (m, 2H), 7.99-8.16 (m, 3H), 8.53 (s, lH MS m/z (ESI): 554.7 [M+H].

The following intermediate 22 to intermediate 23 were synthesized by the same synthesis method as Intermediate 20 and Intermediate 21 using 5-iodo-6-methyl-nicotinic acid as a starting material.

Intermediate

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 It was used in the next reaction without further purification. Step 2: lp-iodo-4-nitro-benzyl)-4-methyl-piperazine

Dissolve 1-bromomethyl-2-iodo-4-nitro-benzene in dichloromethane (10 mL) and add 4-methylpiperazine (120 mg, 1.2 mmol) 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). MS m/z (ESI): 3621. [M+H]. Step 3: l-(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 mg , 3.3 mmol) and N,N-dimethylformamide (10 mL) were mixed and placed in a reaction flask. After bubbling nitrogen for 10 minutes, the catalyst palladium acetate (22 mg, 0.095 mmol) and tricyclohexylphosphine were quickly added. Ligand (53 mg, 0.19 mmol), the mixture was reacted overnight 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-benzyl)-4-methyl-piperazine (yellow solid, 160 mg). MS m/z (ESI): 276.2 [M+H].

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

The reduced iron powder (637 mg, 11.37 mmol) was placed in a 25 mL reaction flask, 5 mL water and 0.5 mL glacial acetic acid were added, heated to reflux and stirred for 20 minutes. A solution of 1-(2-cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine (626 mg, 2.27 mmol) in ethanol (1 mL) was added to the reaction mixture and refluxed for 15 minutes. Stop heating. 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-piperazin-1-ylmethyl)-phenylamine (yel. 1H NMR (400 MHz, CDC1 ₃ ) δ 7.04 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 8.0, 2.4 Hz, 1H), 6.30 (d, J = 2.4 Hz, 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). MS m/z (ESI): 246.3 [M+H].

Step 5: N-[3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-6-difluoromethyl-5-iodo-nicotinamide

6-Difluoromethyl-5-iodo-nicotinic acid (74 mg, 0.245 mmol), 3-cyclopropyl-4-(4-methyl-piperazinemethylidenemethyl)-aniline (40 mg, 0.163 Ment) and 2-(7-azabenzotriazole)^^^'^'-tetramethylurea hexafluorophosphate (94 mg, 0.245 mmol) dissolved in N,N-dimethylformamide ( In 3 mL), N,N-dimethylformamide (42 mg, 0.326 mmol) was slowly added to the system 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-nicotinamide (yellow oil, 72 mg). MS m/z (ESI): 526.2 [M+H].

3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-aniline and 5-iodo-6-methyl-nicotinic acid, 6-fluoromethyl-5-iodine- Niacin was used as a raw material, and the following intermediate 25 was synthesized by the same method as Intermediate 24: N-[3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]- 6: N-[3-cyclopropyl-4-(4-methyl-piperazine-1 M+H]

Intermediate 25 Intermediate 26

First step: 6-chloromethyl-5-iodo-nicotinic acid ethyl ester

Ethyl-6-(hydroxymethyl)-5-iodo-pyridine-3-carboxylate (386 mg, 1.25 mmol) was dissolved in dichloromethane (5 mL), pyridine (0.1 mL) Sulfoxide (0.18 mL, 2.5 mmol) was stirred at room temperature for 1 h. After the completion of the TLC reaction, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated. , 227 mg). 1H-NMR (400MHz, CD ₃ OD): δ 9.12 (1Η, d, J=2.0Hz), 8.71(1Η, s), 4.87(2Η, s), 4.42(2Η, q, J=7.2Hz), 1.41 (3H, t, J = 7.2 Hz). MS m/z (ESI): 325.8 [M+H].

Step 2: 5-iodo-6-methoxymethyl-nicotinic acid

Ethyl-6-(chloromethyl)-5-iodo-pyridine-3-carboxylate (194 mg, 0.593 mmol) was dissolved in methanol (3 mL), and sodium methoxide solution (25% in MeOH, 0.5 mL). The reaction was heated to 75 ^Q C for 30 min. After the TLC detection reaction, the solvent was evaporated to dryness, and the residue was dissolved in water. The mixture was adjusted to pH 3-4 with 2N aqueous hydrochloric acid, and the solid was precipitated, filtered, washed with a small amount of water, and dried to give 5-iodo-6-methoxy Methyl-nicotinic acid (white solid, 116 mg). 1H-NMR (400 MHz, CD ₃ OD): δ 9.05 (1H, s), 8.76 (1 Η, s), 4.70 (2 Η, s), 3.48 (3 Η, s). MS m/z (ESI): 293.7 [M+H].

Step 3: 5-iodo-6-methoxymethyl-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide

Using ₅ -iodo-6-methoxymethyl-nicotinic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine as starting materials, using intermediate 16 In the same manner as in the first step, 5-iodo-6-methoxymethyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl] - Niacinamide (yellow solid, 53 mg). 1H-NMR (400MHz, CD3OD): δ 9.04 (1H, d, J=2.0Hz), 8.78 (1H, d, J=2.0Hz), 8.14(1H, s), 7.99(1H, d, J=8.4 Hz), 7.79(1H, d, J=8.8Hz), 4.72(2H, s), 3.76(2H, s), 3.49(3H, s), 3.24(4H, s), 2.73-2.85 (7H, m ). MS m/z (ESI): 548.8 [M+H]. Intermediate-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide

First step: 4-(tert-butyl-dimethyl-silyloxymethyl)-3-trifluoromethyl-aniline

2-Trifluoromethyl-4-hydroxymethylaniline (500 mg), tert-butyldimethylsilyl chloride (395 mg) and imidazole (196 mg) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 3 h The reaction is complete. Adding water, extracting with ethyl acetate, washing with saturated brine, drying, and evaporated to dryness to give 4-(t-butyl-dimethyl-silyloxymethyl)-3-trifluoromethyl-phenylamine (colorless oil) , 410 mg, 51%): 1H-NMR (DMSO-d6, 400 MHz): δ 0.05 (s, 6 Η), 0.88 (s, 9 Η), 4.64 (s, 2 Η), 5.51 (s, 2H), 6.76 -6.79 (m, 1H), 6.87 (d, 2H), 7.28 (d, 2H). MS m/z (ESI): 305.7 [M+H].

Second step: N-[4-(tert-butyl-dimethyl-silyloxymethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide

3-iodo-4-methylnicotinic acid (396 mg) was dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (333 L) and 2-(7) -azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (613 mg), stirred for 15 min, then added 4-(tert-butyl-dimethyl-silicon Oxymethyl)-3-trifluoromethyl-phenylamine (410 mg) was stirred at room temperature for 4 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-(ter-butyl-dimethyl-siloxymethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide (white solid, 790 mg). 1H-NMR (CDC1 ₃ , 400 MHz): δ 0.15 (s, 6 Η), 0.98 (s, 9 Η), 2.84 (s, 3 Η), 4.91 (s, 2H), 7.81 - 7.91 (m, 4H), 8.58 (s, 1H), 8.93 (s, 1H). MS m/z (ESI): 550.8M+H]. Step 3: N-(4-Hydroxymethyl-3-trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide

Dissolving N-[4-(tert-butyl-dimethyl-silyloxymethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide (790 mg) in methanol ( 10 mL), 2 N HCl (1 mL) was added. After stirring for 2 h, the reaction was completed. EtOAc was evaporated and evaporated. 1H-NMR (CD ₃ OD, 400MHz): ^ 2.81 (s, 3H), 4.79 (s, 2H), 7.77 (d, 1H), 7.96 (d, 1H), 8.14 (s, 1H), 8.74 (d) , 1H), 8.96 (d, 1H). MS m/z (ESI): 436.8 [M+H].

Fourth step: 4-[(5-iodo-6-methyl-pyridine-3-yl)-amino]-2-trifluoromethyl-benzyl sulfonate

_N- (4-Hydroxymethyl-3-trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide (90 mg) was dissolved in N,N-dimethylformamide (5 mL) N,N-diisopropylethylamine (73 L) was added, and methanesulfonyl chloride (50 L) was added dropwise under ice-cooling, and stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc. EtOAc (EtOAc)

Step 5: N-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide

The above crude product (106 mg) was dissolved in N,N-dimethylformamide (5 mL), and anhydrous potassium carbonate (57 mg) and dimethyl-pyrrolidin-3-yl-amine (76 μ^, The reaction was stirred at rt EtOAc EtOAc (EtOAc m. Intermediate 29: 5-iodo-6-methyl-N-[4-(5-methyl-ylmethyl)-3-trifluoromethylphenyl]-nicotinamide

Using N-methylhomopiperazine as the starting material, the same synthesis as in Example 28 was used to obtain the intermediate 5-iodo-6-methyl- _N- [4-(5-methyl-[1,4]diazepine. Heptan-1-ylmethyl)-3-trifluoromethylphenyl]-nicotinamide. MS m/z (ESI): 532.7 [M+H] o Intermediate 30: N-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-3- Trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide

The N-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl 3 intermediate was obtained by the same synthesis method as in Example 28 using N-methylhomopiperazine as the starting material. -Trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide. MS m/z (ESI): 261.2 [M+2].

Preparation example

General Procedure One: Dissolve the aryl b-block intermediate (1.1 eq), the bromo or iodo-pyridinecarboxamide 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 hydrogen carbonate. Filter and concentrate under reduced pressure. The concentrate was separated and purified by silica gel column chromatography to give the title compound. Example 1: 6-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-[1,2,4] Azole [4,3-a]pyridin-3-ylethylidene-nicotinamide

3-Ethyl-[1,2,4]triazole [4,3-a]pyridine (24 mg, 0.168 mmol), 5-iodo-6-methyl-N-[4-(4- Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide (76 mg, 0.146 mmol), N,N-diisopropylethylamine (42 μM, 0.25 mmol Dissolved in anhydrous hydrazine, hydrazine-dimethylformamide (1 mL), nitrogen bubbling for 10 minutes, with tetrakistriphenylphosphine palladium (10 mg, 5 mol%) and cuprous iodide (3 mg) , 7.5 mmol %) was placed in a 10 mL sealed 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 6-methyl-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethylphenyl] -5- [1,2,4]Triazolo[4,3-a]pyridin-3-ylethylidene-nicotinamide (yellow solid, 27 mg). 1H-NMR (400MHz, CD ₃ OD): δ 9.05 (1Η, d, J=2.4Hz), 8.62-8.66(2Η, m), 8.15(1Η, d, J=2.0Hz), 7.99(1H, dd , J=8.4, 2.0Hz), 7.91(1H, d, J=9.6Hz), 7.79(1H, d, J=8.4Hz), 7.62-7.66(lH, m), 7.26-7.29(lH, m) , 3.73 (2H, s), 2.92-2.93 (7H, m), 2.62-2.70 (7H, m). MS m/z (ESI): 533.8 [M+H].

The compound of Example 2 to Example 26 was obtained by the same general procedure as in Example 1 using different aryl b-block and halogenated intermediates as starting materials.

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Example 34: 6-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-[l,2-b]pyridazin-3-yl

5-(6-Chloro-imidazo[l,2-b]pyridazin-3-ylethylidene)-6-methyl-N-[4-(4-methyl-piperazin-1-yl-) Benzyl-3-trifluoromethylphenyl]-nicotinamide (57 mg, Ol mmol) was dissolved in dry 1,4-dioxane (2 mL), and morpholine was rapidly added thereto under nitrogen atmosphere. 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), heated to 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, EtOAc EtOAc m. The residue was purified by silica gel column chromatography (eluent eluting with methylene chloride:methanol:90:10) to give the title compound 6-methyl-N-[4-(4-methyl-piperazine Methyl)-3-trifluoromethylphenyl]-5-(6-morpholine-4-yl-imidazo[l,2-b]pyridazin-3-ylethylidene)-nicotinamide (yellow Solid, 15 mg). 1H-NMR (400 MHz, CD ₃ OD): δ 8.91 (1 Η, d, J = 2.4 Hz), 8.38 (1 Η, d, J = 2.0 Hz), 8.13 (1H, d, J = 2.4 Hz), 7.94- 7.96(lH, m), 7.75-7.81 (3H, m), 7.23(1H, d, J=10.0Hz), 3.83(4H, t, J=4.8Hz), 3.70(2H, s), 3.59(4H , t, J = 4.4 Hz), 2.80-2.89 (7H, m), 2.58-2.65 (4H, m), 2.54 (3H, s). MS m/z (ESI): 309.9 [M+2]. Example 35: 6-Methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-[6-(l-methyl- IH-pyrazol-4-yl)-imidazole [l,2-b]pyridazin-3-ylethyl block-nicotinamide

5-(6-Chloro-imidazo[l,2-b]pyridazin-3-ylethylidene)-6-methyl-N-[4-(4-methyl-piperazin-1-yl-) Benzyl-3-trifluoromethylphenyl]-nicotinamide (30 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2] Dioxaboran-2-yl)-1H-pyrazole (21 mg, 0.10 mmol) and potassium carbonate (21 mg, 0.15 mmol) dissolved in N,N-dimethylformamide (2 mL) and water (0.5 In a mixed solvent of 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 6-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-[ 6-(1-Methyl-1H-pyrazol-4-yl)-imidazole [l,2-b]pyridazin-3-ylethylidene]-nicotinamide (yellow solid, 16 mg). ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.89 (1 Η, d, J = 2.4 Hz), 8.37 (1 Η, d, J = 2.4 Hz), 8.21 (1H, s), 8.14 (1H, d, J=2.0Hz), 8.03(1H, s), 7.92-7.96(3H, m), 7.75(1H, d, J=8.4Hz), 7.57(1H, d, J=9.2Hz) _: 3.95(3H, s), 3.70 (2H, s), 2.89-2.91 (7H, m), 2.58-2.65 (7H, m). MS m/z (ESI): 307.4 [M+2]. Example 36: 6-Methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-(6-pyridin-3-yl- Imidazole [l,2-b]pyridazin-3-ylethylidene)-nicotinamide

5-(6-Chloro-imidazo[l,2-b]pyridazin-3-ylethylidene)-6-methyl-N-[4-(4-methyl-piperazin-1-yl) Starting from the same synthesis as in Example 34, 6-methyl-N-[4-(4-methylpiperazine- 1-ylmethyl)-3-trifluoromethylphenyl]-5-(6-pyridin-3-yl-imidazo[l,2-b]pyridazin-3-ylethylidene)-nicotinamide Yellow solid, 24 mg). ¹ H-NMR (400 MHz, CD ₃ OD): δ 9.26 (1 Η, d, J = 2.0 Hz), 8.91 (1 Η, d, J = 2.4 Hz), 8.67 (1H, dd, J = 5.2, 1.6 Hz) , 8.50-8.53(lH, m), 8.40 (1H, d, J=2.0Hz), 8.08-8.17(3H, m), 7.90-7.95(2H, m), 7.75(1H, d, J=8.4Hz), 7.59-7.62(lH, m), 3.68(2H, s), 2.87(3H, s), 2.65-2.75 (4H, m), 2.54-2.60(4H, m), 2.46(3H, s). MS m/z (ESI): 305.9 [M+2]. Example 37: 5-Imidazo[l,2-b]pyridazin-3-ylethylidene-6-methyl-N-[4-(4-methyl-[1,4]diazepine -1-ylmethyl)-3-trifluoromethylphenyl]-nicotinamide

5-Iodo-6-methyl-N-[4-(5-methyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethylphenyl]-smoke Amide (90 mg,), 3-ethylidene-imidazole [l,2-b]pyridazine (32 mg) dissolved in anhydrous N,N-dimethylformamide (5 mL), Pd (PPh ₃₎ ₂ Cl ₂ ( 12 mg), cuprous iodide Cul (7 mg) and N,N-diisopropylethylamine (56 μΐ reaction system with nitrogen gas for 10 minutes, under argon protection at 60 °C) The reaction was stirred and stirred for 18 h. After the reaction was completed, water was added to the mixture, and ethyl acetate was extracted twice. The organic layer was combined and purified by column chromatography to give 5-imidazo[l,2-b]pyridazin-3-ylethylidene-6 -methyl-N-[4-(4-methyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethylphenyl]-nicotinamide (yellow solid, 75 Mg) 1H NMR (CD ₃ OD, 400 MHz): δ 2.05-2.11 (m, 4 Η), 2.75 - 2.95 (m, 10 Η), 3.45 - 3.46 (m, 2H), 3.89 (s, 2H), 7.40- 7.43(m, 1H), 7.88(d, 1H), 8.05(d, 1H), 8.13— 8.16(m, 3H), 8.52(d, 1H), 8.68— 8.67(m, 1H), 8.99(d, 1H) MS m/z (ESI): 274.2 [M+2H] </RTI> Example 38: N-[4-(3-dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethyl Phenyl]-5- Imidazole [l,2-b]pyridazin-3-ylethylidene-6-methyl-nicotinamide

Using N-[4-(3-dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide as a raw material, Example 37 Synthesis of N-[4-(3-dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethylphenyl]-5-imidazole [l,2-b] by the same method Pyridazin-3-ylethylidene-6-methyl-nicotinamide (yellow solid, 34 mg). 1H-NMR (CD ₃ OD, 400 MHz): δ 1.87-2.17 (m, 3 Η), 2.49 (s, 6H), 2.63 - 2.80 (m, 4H), 2.89 (s, 3H), 3.81 (s, 2H) , 7.39-7.42(m, 1H), 7.75(d, 1H), 7.98(d, 1H), 8.12— 8.16(m, 3H), 8.50(d, 1H), 8.66(d, 1H), 8.99(d , lH) o MS m/z (ESI): 274.6 [M+2H]. Example 39: N-(4-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-3-trifluoromethylphenyl)-5-imidazole [l, 2 -b]pyridazin-3-ylethylidene-6-methyl-nicotinamide ■

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18 +++ +++ 37 ++++ ++++

19 +++ +++ 38 +++ +++

2. The compounds of the present invention have good inhibitory activities against different kinase mutants such as AblT315I BrafV600E and the like. The inhibitory activity of some of the compounds on 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 ₅ > 1000 nM is represented by the symbol +).

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, and the inhibitory activity of the test compound on cell proliferation is determined 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, 25000 cells/ml medium) The cells were seeded on a white opaque 384-well culture plate; the cells were then placed in an environment of 37 ° C 5% CO ₂ for culture; after 24 hours, culture was performed. A series of concentration gradients were added to the cell culture medium, and 10 concentrations were generally selected. After the cells were returned to the original culture environment for 48 hours, the test compound was determined according to the method of CellTiter-Glo Luminescent Cell Viability Assay. The effect of cell proliferation, and the inhibitory activity of different concentrations of compounds on cell proliferation was calculated (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. Out 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 IC ₅ values, wherein IC ₅ . < 50 nM is represented by the symbol ++++ 50 nM < IC ₅ < 500 nM is represented by the symbol +++; 500 nM < IC ₅₀ < 1000 nM is represented by the symbol ++; IC ₅ Q > 1000 nM is denoted by the symbol +).

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

6 +++ 16 ++++ 26 ++++ 36 ++++

7 ++++ 17 ++++ 27 ++++ 37 ++++

8 ++++ 18 +++ 28 +++ 38 +++

9 ++++ 19 +++ 29 +

10 ++++ 20 ++++ 30 + Test Case 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, I mg/mL suspension of test compound) and intragastric administration (10 mg/kg, I mg/mL suspension of test compound), before and after administration 2, 5 , 15, 30, 60, 90, 120, 240, 360, 480, 1440 min in the rat or mouse fundus venous plexus to take blood 0.4 mL; take 50 L of plasma samples, respectively, add 200 internal standard acetonitrile solution to precipitate protein, Vortex for 10 min, centrifuge at 6000 g for 10 min; take 200 μΐ^ supernatant 6000 g and centrifuge again for 10 min; then take 75 μΐ^ supernatant, add gradient initial mobile phase to dilute, centrifuge at 6000 g for 10 min; The clear solution 70 was injected into a 96-well plate at an injection volume of 5 L for LC-MS-MS analysis.

The compound of the example 2, 3, 9, 13, 22, 27, 34 was stable in the plasma of mice and mice after intravenous administration, and the half-life was 160 min to 300 min; the plasma concentration-time curve after intragastric administration The lower area AUC is 60-200uM.min, the highest blood concentration is greater than 0.5uM, and the relative bioavailability is 20%~60%. Therefore, the results indicate that the compound of the present invention has good 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 (TV), and the formula is: TV=l /2XaXb ² , where a and b represent the length and width, respectively; relative tumor volume (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 Xl00, where T _RTV: treatment group RTV, C _RTV is 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 compounds of Examples 2, 9, 13, 22, 27, 34, etc., at a dose of 2.5 mg/kg to 10 mg/kg, significantly inhibited the growth of the K562 xenograft tumor nude mice until the regression. On the 9th day of administration, the T/C ratio was less than 10%, and the test animals were better tolerated, and the change in body weight was less than 20%; and the compound of Example 2, 9, 13, 22, etc. was administered to the 32DT315I cells at a dose of 15 mg/kg. Tumor model nude mice also have a significant effect of inhibiting growth until regression. The T/C ratio on day 9 of administration is less than 50%, and the survival time of experimental animals can be significantly prolonged. The median survival time is increased from 13 days to 13 days. 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

Its towel:

Ring A is selected from heteroaryl;

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

2;

Each F and R _{5 are} independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₄ , R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, light-based, oxy-based, light-based oxy-based, amino-based Base, the second base, the base of the base, the base of the oxycarbonyl amino group, the base of the ring, the base of the ring, the base of the heterocyclic base, the base of the aryl, the base of the base, the carbonyl of the ring, the oxycarbonyl group, Substituted by a group of an alkoxycarbonyl heterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl)(alkyl)amino group.

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

In the formula I, the ethyl group moiety and the L moiety are meta-substituted on ring A, and ring A is a 5- to 12-membered heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur. It is preferably a 5- to 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, more preferably a pyridyl group, a furyl group or a thiazolyl group, still more preferably a pyridyl group.

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

m Ra are each independently selected from halogen, -R ₂ , -OR ₂ ; each R _{2 is} independently selected from alkyl, cycloalkyl, and each R _{2 is} optionally selected from one or more selected from halogen, -R ₄ , -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ group substitution; each F is independently selected from a hospital base, a ring base;

Preferably, m Ra are each independently selected from halogen, -R ₂ , -OR ₂ ; each R _{2 is} independently selected from d- ₆ alkyl, C ₃ _-8 cycloalkyl, and each R _{2 is} optionally one Or a plurality of groups selected from the group consisting of halogen, -R ₄ , -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ ; each R _{4 is} independently selected from the group consisting of d- ₆ alkyl, C ₃ _-8 cycloalkyl;

Preferably, m Ra are each independently selected from the group consisting of alkyl, 3⁄4 alkyl, alkoxyalkyl;

Preferably, m Ra are each independently selected from the group consisting of d- ₆ alkyl, halo d- ₆ alkyl, d- ₆ alkoxy d- ₆ alkyl.

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

Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a heterocyclic group; said heterocyclic group is optionally substituted by one or more alkyl groups, optionally one or more Cycloalkyl substituted;

Preferably, each of R Rb is independently selected from the group consisting of halogen, -R ₂ , -OR ₂ , -NHR ₂ , -N(R ₂ ) ₂ , wherein each R _{2 is} independently selected from d- ₆ alkyl, C ₃ _ ₈ a cycloalkyl group, and each R _{2 is} optionally substituted by one or more groups selected from the group consisting of halogen, -R ₄ , -OR ₄ , -NHR ₄ , -N(R ₄ ) ₂ ; each R _{4 is} independently selected From a D ₆ alkyl group, a C ₃ _-8 cycloalkyl group, a stable 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and each R 4 is optionally one or a plurality of stable 4 selected from the group consisting of d- ₆ alkyl, mono d- ₆ alkylamino, di d- ₆ alkylamino, C ₃ _-8 cycloalkyl, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur a group substituted with a 11-membered heterocyclic group, a d ₆ alkyloxy group, or a d ₆ alkyloxy d ₆ alkyl group;

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

Each of R Rb is independently d- ₆ alkyl or C ₃ _-8 cycloalkyl, and the alkyl or cycloalkyl is optionally one or more selected from -R ₄ , -NHR ₄ , -N(R group ₄₎ ₂ substituents; each independently selected from F d_ ₆ alkyl, C ₃ _ ₈ cycloalkyl group, comprising a stable 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur is 4-8 yuan a heterocyclic group, and each R4 is optionally substituted with one or more groups selected from the group consisting of d- ₆ alkyl, mono d- ₆ alkylamino, di- ₆ alkylamino;

Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; Optionally substituted with one or more d- ₆ alkyl groups, which are optionally substituted by one or more C ₃ _-8 cycloalkyl groups; 2 adjacent Rbs with their structure from:

6. 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 selected from the group consisting of N atom, CH and CR, wherein R is selected from alkyl or haloalkyl, preferably d- ₆ alkyl or halo d- ₆ fluorenyl;

7. A compound according to any of the preceding claims, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate

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:

Preferably, p Rt are each independently selected from halogen, -R _{2 ;} each R _{2 is} independently selected from d- ₆ alkyl, _-8 cycloalkyl, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Stable 4 to 8 membered heterocyclic group, C. An aryl group, a stable 5- to 9-membered heteroaryl group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and each R _{2 is} optionally selected from one or more selected from halogen, d- ₆ alkyl Replaced by the group.

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:

R is selected from the group consisting of H atom, alkyl group, cycloalkyl group and hydroxyalkyl group, preferably H atom, d- ₆ alkyl group, _-8 cycloalkyl group and hydroxy-d- ₆ alkyl group;

Preferably, R is selected from the group consisting of H atoms and d- ₆ alkyl groups;

More preferably, it is 11 atoms.

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

A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph thereof, a tautomer, Metabolite or prodrug and a pharmaceutically acceptable carrier.

The compound of any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, or The pharmaceutical composition according to claim 11 for use in the prevention and/or treatment of a tumor.