TWI546304B - Protein tyrosine kinase inhibitors and their use - Google Patents

Description

Protein tyrosine kinase inhibitor and its application

The present invention relates to the field of chemical medicine, and in particular to a compound having a protein tyrosine kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same The use of these compounds or compositions in the preparation of pharmaceuticals.

Protein tyrosine kinases (PTKs) are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, which catalyze the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues to initiate functional proteins. The role of the protein enzyme system. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis. In addition, the abnormal expression of protein tyrosine kinase is also closely related to tumor invasion and metastasis, tumor angiogenesis, and chemotherapy resistance of tumors. Tyrosine kinase inhibitors act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, competitively bind to tyrosine kinases, block tyrosine kinase activity, and inhibit cell proliferation. Several tyrosines already exist. Acid protein kinase inhibitors have been successfully developed.

Chromosome translocation in patients with chronic myeloid leukemia (CML) forms BCR-ABL fusion The genomic and expressed BCR-ABL protein tyrosine kinase plays an important role in cell signal transduction and transformation, and promotes the infinite proliferation of CML mature granulocytes through phosphorylation and the like. BCR-ABL is not expressed in normal cells and has become an ideal drug target for the treatment of CML.

Imatinib is the first molecularly targeted therapeutic protein tyrosine kinase inhibitor that competitively inhibits the binding site of adenosine triphosphate (ATP) to thymidine kinase (TK) receptors (such as KIT) and blocks TK phosphorylation. Inhibition of signal transduction, and inhibition of kinase-related KIT mutations and wild-type KIT, has therapeutic effects on various types of cancer. Imatinib inhibits BCR-ABL tyrosine kinase at the cellular level in vitro and in vivo, selectively inhibits BCR-ABL-positive cell lines and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphocytes The proliferation of fresh leukemia cells in leukemia patients induces apoptosis. In addition, imatinib also inhibits the receptor tyrosine kinase of platelet-derived growth factor (PDGF) and the receptor tyrosine kinase c-Kit of stem cell factor (SCF), thereby inhibiting cells mediated by PDGF and stem cell factors. behavior. Clinically, it is mainly used for the treatment of chronic myeloid leukemia (CML) blast crisis, accelerated phase or chronic phase after failure of α-interferon therapy, malignant gastrointestinal stromal tumor (GIST) patients who cannot be surgically removed or metastasized; For the treatment of CD117 positive gastrointestinal stromal tumors (GIST).

The development and clinical use of imatinib has opened a new era of tumor molecular targeting. However, long-term use of imatinib will produce drug resistance, leading to recurrence of the disease. With the widespread clinical application of imatinib, the problem of drug resistance has become increasingly prominent. The main reason for acquired tolerance is due to point mutations in BCR-ABL that result in the inability of imatinib to bind to BCR-ABL. Moreover, hundreds of BCR-ABL point mutations have been found to be associated with imatinib resistance, with 15 to 20% of imatinib-tolerant patients having a T315I mutation.

The emergence of imatinib resistance has ignited a wave of research and development of a new generation of tyrosine kinase inhibitors, with a view to developing better CML, Ph+ ALL for the treatment of leukemia, such as drug resistance or non-resistance. New drugs.

It is an object of the present invention to provide a class of compounds of the general formula I having a broad spectrum of BCR-ABL inhibitory effects, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; X is selected from N and C(R ₅ ), wherein R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino , alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ and its attached carbon atom form C (=O), the amino group, monoalkylamino group, dialkylamino group, nonylamino group, alkyl fluorenylamino group, aryl decylamino group, heteroaryl decylamino group, sulfonylamino group, alkyl sulfonylamino group, aromatic The sulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; Y is selected from N, NH and C(R ₆ ), wherein R _{6 is} selected from hydrogen, amino, Monoalkyl , bis-alkylamino, decylamino, alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, Amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino, aryl hydrazino, heteroaryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, hetero An arylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; "Expresses a single or double bond, when X is C (=O)," "is a single bond; provided that the compound is not the compound: 3-((2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)- 4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-methylamino-) [1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazin-1-yl) )methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridine-7 -yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide.

Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

A further object of the present invention is to provide a composition comprising a compound of Formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another protein tyrosine kinase inhibitor.

A further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for treating and/or preventing a tumor, and the method of the invention Use of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a tumor.

In view of the above, the present invention provides the following technical solutions: In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; X is selected from N and C(R ₅ ), wherein R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino , alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ and its attached carbon atom form C (=O), the amino group, monoalkylamino group, dialkylamino group, nonylamino group, alkyl fluorenylamino group, aryl decylamino group, heteroaryl decylamino group, sulfonylamino group, alkyl sulfonylamino group, aromatic The sulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups; Y is selected from N, NH and C(R ₆ ), wherein R _{6 is} selected from hydrogen, amino, Monoalkyl , bis-alkylamino, decylamino, alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, Amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino, aryl hydrazino, heteroaryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, hetero An arylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; "Expresses a single or double bond, when X is C (=O)," "is a single bond; provided that the compound is not the compound: 3-((2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)- 4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-methylamino-) [1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazin-1-yl) )methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridine-7 -yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide.

In some embodiments of the compounds of formula I, X is N and Y is N," "" indicates a double bond.

In some embodiments of the compounds of formula I, X is N and Y is C(R ₆ )," " represents a double bond, and R _{6 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl hydrazine amino, heteroaryl fluorenylamino, sulfonylamino, alkyl sulfonium sulfonium. Amino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl decylamino, sulfonate The oxime amino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups.

In some embodiments of the compounds of formula I, X is C(R ₅ ) and Y is N," "Represents a double bond, said R ₅ is selected from hydrogen, amino, monoalkylamino, dialkylamino, acyl amino, acyl amino group, an aryl group amino acyl, heteroaryl acyl group, sulfonylurea group, an alkoxy Alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorene The amino group, the sulfonylamino group, the alkylsulfonylamino group, the arylsulfonylamino group, and the heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, or cyano groups.

In some embodiments of the compounds of formula I, X is C(=O) and Y is NH," "" means a single button.

In some embodiments of compounds of formula I, X is C (R _5), Y is C (R _6), " " represents a double bond, and said R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorenylamino. , sulfonium amino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monoalkylamino group, dialkylamino group, decylamino group, alkyl fluorenylamino group, aryl hydrazine The amino group, heteroarylamino group, sulfonylamino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl group, amino group, cyano group.

In some preferred embodiments of the compound of Formula I, R _{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkane Oxyl, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, halo, amino, acyl, mono C _1-6 alkylamino Aminoguanidino, bis-C _1-6 alkylaminoindenyl and cyano; and R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, -OH, hydroxy C _1-6 alkyl, halo C _1-6 alkane base.

In some preferred embodiments of the compound of Formula I, R _{1 is} selected from the group consisting of hydrogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkane Oxyl, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, halo, amino, acyl, mono C _1-4 alkyl Aminoguanidino, bis-C _1-4 alkylaminoindenyl and cyano; and R _{4 is} selected from hydrogen, C _1-4 alkyl, -OH, hydroxy C _1-4 alkyl, halo C _1-4 alkane base.

More preferably, in an embodiment of the compound of Formula I, R _{1 is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkyl, halo C _1-3 Alkoxy, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkyl, halo C _{1- 3} alkoxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, C _1-3 alkyl, halogenated C _1-3 alkyl, halogen, aminoguanidino, mono C _1-3 alkane a hydrazino group, a bis C _1-3 alkylamino fluorenyl group and a cyano group; and R _{4 is} selected from the group consisting of hydrogen, C _1-3 alkyl, -OH, hydroxy C _1-3 alkyl, halogenated C _1-3 alkyl.

Preferably, the invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; X is selected from N and C(R ₅ ), wherein R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino , alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ and its attached carbon atom form C (=O), the amino group, monoalkylamino group, dialkylamino group, nonylamino group, alkyl fluorenylamino group, aryl decylamino group, heteroaryl decylamino group, sulfonylamino group, alkyl sulfonylamino group, aromatic The sulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups; Y is selected from N, NH and C(R ₆ ), wherein R _{6 is} selected from hydrogen, amino, Monoalkyl , bis-alkylamino, decylamino, alkyl hydrazino, aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, Amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino, aryl hydrazino, heteroaryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, hetero An arylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; "Expresses a single or double bond, when X is C (=O)," " represents a single bond; when X is N, Y is C(R ₆ ), and the ring containing X, Y together with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached constitutes [1, 2, 4] - In the case of a triazolo[1,5-a]pyridine-7-ethynyl group, R _{6 is} selected from the group consisting of hydrogen, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl decylamino group, a sulfonylamino group, Alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said nonylamino, alkylnonylamino, arylnonylamino, heteroarylphosphoniumamino, sulfonylamino, alkylsulfonylamino The arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups.

In some embodiments of the compound of Formula Ia, X is N and Y is N," "" indicates a double bond.

In some embodiments of the compound of Formula Ia, X is N and Y is C(R ₆ )," " represents a double bond, and the ring containing X, Y together with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached constitutes [1,2,4]-triazolo[1,5-a]pyridine- In the case of a 7-ethynyl group, R _{6 is} selected from the group consisting of hydrogen, decylamino, alkyl fluorenylamino, aryl hydrazine amino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, hetero Arylsulfonylamino, the indenylamino group, the alkylguanidino group, the arylsulfonylamino group, the heteroarylphosphoniumamino group, the sulfonylamino group, the alkylsulfonylamino group, the arylsulfonylamino group, the heteroarylsulfonylamino group It may be substituted by one or more halogen, alkyl, amino, cyano groups.

In some embodiments of the compound of Formula Ia, X is N and Y is C(R ₆ )," " represents a double bond, and the ring containing X, Y together with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached constitutes [1,2,4]-triazolo[1,5-a]pyridine- In the case of a 6-ethynyl group, R _{6 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl decylamino, sulfonylamino, alkane Alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorene The amino group, the sulfonylamino group, the alkylsulfonylamino group, the arylsulfonylamino group, and the heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, or cyano groups.

In some embodiments of the compound of Formula Ia, X is C(R ₅ ) and Y is N," " represents a double bond, and said R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl fluorenylamino, heteroaryl decylamino, sulfonylamino, alkane Alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorene The amino group, the sulfonylamino group, the alkylsulfonylamino group, the arylsulfonylamino group, and the heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, or cyano groups.

In some embodiments of the compound of Formula Ia, X is C(=O) and Y is NH," ” means a single key.

In some embodiments of compounds of formula Ia, X is C (R _5), Y is C (R _6), " " represents a double bond, and said R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorenylamino. , sulfonium amino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monoalkylamino group, dialkylamino group, decylamino group, alkyl fluorenylamino group, aryl hydrazine The amino group, heteroarylamino group, sulfonylamino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl group, amino group, cyano group.

In some preferred embodiments of the compound of Formula Ia, R _{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkane Oxyl, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, halo, amino, acyl, mono C _1-6 alkylamino Aminoguanidino, bis-C _1-6 alkylaminoindenyl and cyano; and R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, -OH, hydroxy C _1-6 alkyl, halo C _1-6 alkane base.

In some preferred embodiments of the compound of Formula Ia, R _{1 is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkyl, halo C _1-3 alkane Oxyl, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkyl, halo C _1-3 Alkoxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from hydrogen, C _1-3 alkyl, halo C _1-3 alkyl, halogen, aminoguanidino, mono C _1-3 alkyl Aminoguanidino, bis-C _1-3 alkylaminoindenyl and cyano; and R _{4 are} selected from the group consisting of hydrogen, C _1-3 alkyl, -OH, hydroxy C _1-3 alkyl, halo C _1-3 alkane base.

Further preferably, the present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; R _{6 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, hetero Aryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, alkyl, amino, cyano The condition is that the compound is not the following compound: 3-((2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl -N-[4-((4-methylpyridazine) -1-yl)methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-methylamino-[1,2,4]triazolo[1,5-a] Pyridyl-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide 3-((2-Dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-( (4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide.

Further preferably, the invention provides a compound of formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; Y is selected from N and NH; and R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ forms a C(=O) with the attached carbon atom An amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkylsulfonylamino group, an arylsulfonylamino group. , a heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; " means a single bond or a double bond, when R ₅ forms a C(O) with the carbon atom to which it is attached," "" means a single bond, Y is NH.

Further preferably, the present invention provides a compound of the formula Ia-a or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; R _{6 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, hetero Aryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, alkyl, amino, cyano .

When [1,2,4]-triazole forms a [1,2,4]-triazolo[1,5-a]pyridine-7 together with the fused pyridine ring and the acetylene group attached to the pyridine ring In the case of an ethynyl group, said R _{6 is} selected from the group consisting of hydrogen, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino , a heteroarylsulfonylamino group, said mercaptoamino group, alkyl nonylamino group, arylsulfonylamino group, heteroarylphosphoniumamino group, sulfonylamino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonyl group The oxime amino group may be substituted by one or more halogen, alkyl, amino, cyano groups.

Still more preferably, the invention provides a compound of formula I-a', or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, alkyl, haloalkyl, halo, amino, acyl, acyl monoalkylamino, dialkylamino acyl, and cyano; R & lt _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; R _{6 is} selected from the group consisting of hydrogen, amino, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, hetero Aryl fluorenylamino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl hydrazino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, alkyl, amino, cyano .

Still more preferably, the present invention provides a compound of Formula Ia", or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R ₁ is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH _2, halo and CN; R ₂ is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; R _{6 is} selected from the group consisting of hydrogen, monoalkylamino, bisalkylamino, decylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl Anthracene amino group, sulfonium amino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said fluorenylamino group, alkyl fluorenylamino group, aryl decylamino group, heteroaryl decylamino group, sulfonium sulfonate The amino group, alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups; provided that the compound is not the following compound: 3-(( 2-methylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylindole) Pyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-Dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-(( 4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide.

Still more preferably, the invention provides a compound of formula 1-4', or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, alkyl, haloalkyl, halo, amino, acyl, acyl monoalkylamino, dialkylamino acyl, and cyano; R & lt _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; Y is selected from N and NH; and R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl fluorenylamino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ forms a C(=O) with the carbon atom to which it is attached An amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkylsulfonylamino group, an arylsulfonylamino group. , a heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; "Expresses a single bond or a double bond, when R ₅ forms a C (=O) with the carbon atom to which it is attached," "" means a single bond, Y is NH.

Even more preferably, the present invention provides a compound of Formula Ib", or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; Y is selected from N and NH; and R _{5 is} selected from the group consisting of hydrogen, amino, monoalkylamino, dialkylamino, decylamino, alkyl fluorenylamino , aryl fluorenylamino, heteroaryl hydrazino, sulfonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or R ₅ forms a C(=O) with the carbon atom to which it is attached An amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkylsulfonylamino group, an arylsulfonylamino group. , a heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano; "Expresses a single bond or a double bond, when R ₅ forms a C (=O) with the carbon atom to which it is attached," "" means a single bond, Y is NH.

Still more preferably, the invention provides a compound of formula Ia-a', or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein: R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl and cyano; R _{4 is} selected from the group consisting of hydrogen, alkyl, -OH, hydroxyalkyl, haloalkyl; R _{6 is} selected from the group consisting of hydrogen, decylamino, alkyl fluorenylamino, aryl fluorenylamino, heteroaryl decylamino, sulfonylamino, alkyl sulfonate Amidino, arylsulfonylamino, heteroarylsulfonylamino, said fluorenylamino, alkyl fluorenylamino, aryl decylamino, heteroaryl decylamino, sulfonylamino, alkylsulfonylamino, aryl The sulfonium amino group, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups.

In a preferred embodiment of the invention, R _{1 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen and CN.

In a more preferred embodiment of the invention, R _{1 is} selected from the group consisting of methyl and trifluoromethyl.

In a preferred embodiment of the invention, R _{2 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen and CN.

In a more preferred embodiment of the invention, R _{2 is} selected from the group consisting of methyl, ethyl, propyl and isopropyl.

In a preferred embodiment of the invention, R _{3 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, halogen, aminoguanidino, mono C _1-6 alkylaminoindenyl, double C _1-6 alkylamino group and cyano group.

In a more preferred embodiment of the invention, R _{3 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, halogen and methylamino.

In a preferred embodiment of the invention, R _{4 is} selected from the group consisting of hydrogen, C _1-6 alkyl, -OH, hydroxy C _1-6 alkyl, halo C _1-6 alkyl.

In a more preferred embodiment of the invention, R _{4 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, -OH, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, tri Fluoroethyl.

In a preferred embodiment of the invention, R _{5 is} selected from the group consisting of amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino, methyl hydrazine amino, ethyl hydrazine amino, propyl hydrazine amino, cyclopropyl guanidine amino group. , cyclobutyl acyl group, a phenyl acyl amino, trifluoromethyl acetylamino, amino acyl methanesulfonic, ethanesulfonic acyl amino, acyl amino benzenesulfonamide, or R ₅ and the carbon atoms are attached form C (= O).

In a more preferred embodiment of the invention, R _{5 is} selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Alkylamino, ethylpropylamino, formamidineamino, ethylamino, propylamino, cyclopropylnonylamino, cyclobutylguanidino, trifluoroacetamido, methylsulfonylamino, ethylsulfonylamino, or R ₅ forms C(=O) with the carbon atom to which it is attached.

In a preferred embodiment of the invention, R _{6 is} selected from the group consisting of amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino, methyl hydrazine amino, ethyl hydrazine amino, propyl hydrazine amino, cyclopropyl guanidine amino group. , cyclobutylphosphonium amino group, benzoquinone amino group, trifluoroethylamino group, methanesulfonylamino group, ethylsulfonylamino group, benzenesulfonylamino group.

In a more preferred embodiment of the invention, R _{6 is} selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Amino group, ethyl propylamino group, formamidine amino group, ethyl hydrazine amino group, propyl hydrazine amino group, cyclopropyl hydrazine amino group, cyclobutyl hydrazine amino group, trifluoroethyl hydrazine amino group, methanesulfonylamino group, ethyl sulfonylamino group.

The present invention provides the following specific compounds:

In another aspect, the invention provides a process for the preparation of a compound of the formula of the invention. The preparation method of the compound of the formula I comprises the following steps: (1) Preparation of the intermediate of the formula 5:

a) a compound of formula 1 is reacted with a compound of formula 2 to give an intermediate of formula 3; b) an intermediate of formula 3 is reacted with trimethylsulfonium acetylene to give an intermediate of formula 4; c) an intermediate of formula 4 is removed Methyl decyl group to give an intermediate of formula 5; (2) preparation of a compound of formula I:

d) The intermediate of formula 5 is reacted with an intermediate of formula 6 to give a compound of formula I.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , X, Y have the meanings in the formula I, and M is selected from the group consisting of chlorine, bromine and iodine.

Similarly, those skilled in the art can prepare the formula I, formula Ia, formula Ia, formula Ib, formula Ia-a, formula I-a of the present invention by referring to the preparation method of the compound of formula I of the present invention. ', Formula Ia', a compound of the formula I-b', Formula Ib" and Formula Ia-a'.

Specifically, the preparation method of the compound of the formula Ia comprises the following steps: (1) Preparation of the intermediate of the formula 9:

e) reacting a compound of formula 7 with ethyl isothiocyanate to give an intermediate of formula 8; f) reacting an intermediate of formula 8 with hydroxylamine hydrochloride to give an intermediate of formula 9; (2) synthesizing an intermediate of formula 10

g) an intermediate of formula 9 is prepared by conventional alkylation, thiolation or sulfonylation to produce an intermediate of formula 10; (3) preparation of a compound of formula Ia: or

h) an intermediate of formula 9 or an intermediate of formula 10 is reacted with an intermediate of formula 5 to give a compound of formula Ia; wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₆ have the meanings of formula Ia, M is selected from chlorine, bromine, and iodine.

Specifically, a process for preparing a compound of the formula Ib wherein R ₅ and its attached carbon atom form C(=O) and Y is NH comprises the following steps: (1) Preparation of the intermediate of formula 13

i) an intermediate of formula 11 is reacted with hydrazine hydrate to give an intermediate of formula 12; j) an intermediate of formula 12 is reacted with triphosgene to give an intermediate of formula 13; (2) preparation of the target compound of formula Ib

k) an intermediate of formula 13 is reacted with an intermediate of formula 5 to give a compound of formula Ib wherein R ₅ and its attached carbon atom form C(=O), Y is NH; wherein R ₁ , R ₂ , R ₃ And R ₄ have the meaning in the formula Ib, and M is selected from the group consisting of chlorine, bromine and iodine.

In a third aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof A pharmaceutical composition of a solvate, crystal or prodrug for use in the treatment or prevention of cancer, including solid tumors and various forms of leukemia, including leukemia resistant to other therapies.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more selected from the group consisting of a tyrosine protease inhibitor , EGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.

The compound, isomer, solvate, crystal or prodrug of the present invention may be formulated into a pharmaceutical preparation by mixing with a pharmaceutically acceptable carrier, diluent or excipient to be suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulation can be prepared by methods known in the art and includes the field of pharmaceutical formulations. The carrier, diluent or excipient used.

In a fourth aspect, the present invention provides a method, a method for treating and/or preventing a tumor of a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention, and in the preparation of a medicament for preventing and/or treating cancer Use of a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention, to a tumor-prone population or tumor patient The pharmaceutical composition is effective to reduce the incidence of tumors and prolong the life of tumor patients.

In some embodiments, the invention provides methods for treating and/or preventing a tumor comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound, isomer, solvate, crystal of the invention Or a prodrug or a pharmaceutical composition of the invention. The compounds, isomers, solvates, crystals or prodrugs of the invention or pharmaceutical compositions of the invention may be administered to a mammal in need thereof to inhibit tumor growth, progression and/or metastasis, including solid tumors , for example, breast cancer, colon cancer, gastric cancer, pancreatic cancer, central nervous system tumors, and head and neck cancers, as well as various forms of leukemia, including leukemia and other cancers that are resistant to other treatments, such as resistance to imatinib or other kinase inhibitors. The kinase is inhibited by a compound or composition of the invention.

The "alkyl group" of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably a C _1-6 alkyl group. For example, a suitable C _1-6 alkyl group includes, but is not limited to, a methyl group, a Base, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl. Herein, the alkyl group is further preferably a C _1-3 alkyl group, and a suitable C _1-3 alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group. As used herein, an alkyl group in the present invention includes a substituted or unsubstituted alkyl group, which may be optionally substituted with one or more groups selected from the group consisting of an alkyl group, an alkoxy group, an aryloxy group, Alkylamino, arylamino, halogen, hydroxy, amino, nitro, cyano, alkyl fluorenyl, amino fluorenyl, alkylamino fluorenyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl . 3

The "alkoxy group" of the present invention means an alkyl-O- group, preferably a C _1-6 alkyl-O- group, further preferably a C _1-3 alkyl-O- group, a suitable C _1-3 alkyl group - O- is methoxy, ethoxy, propoxy or isopropoxy.

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen, preferably a halogenated C _1-6 alkyl group, further preferably a halogenated C _1-3 alkyl group, a suitable halogenated C _1-3 alkane. Base is chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chloroethyl, fluoroethyl, dichloroethyl, difluoroethyl, trichloro Ethyl, trifluoroethyl.

The "haloalkoxy group" of the present invention means an alkoxy group substituted with at least one halogen, preferably a C _1-6 alkoxy group substituted with at least one halogen, and further preferably a halogenated C _1-3 alkoxy group, suitably Halogenated C _1-3 alkoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy , difluoroethoxy, trichloroethoxy, trifluoroethoxy.

The "nonylamino group" of the present invention means HC(O)-NH-.

The "alkyl fluorenylamino group" of the present invention means an alkyl-C(O)-NH- group, preferably a C _1-6 alkyl-C(O)-NH- group, and further preferably a C _1-3 alkyl group-C. (O)-NH-.

The "aryl fluorenylamino group" of the present invention means aryl-C(O)-NH-.

The "heteroarylnonylamino group" of the present invention means a heteroaryl-C(O)-NH- group.

The "sulfonylamino group" of the present invention means HS(O) ₂ -NH-.

The "alkylsulfonylamino group" of the present invention means an alkyl-S(O) ₂ -NH- group, preferably a C _1-6 alkyl-S(O) ₂ -NH- group, more preferably a C _1-3 alkane. Base-S(O) ₂ -NH-.

The "arylsulfonylamino group" of the present invention means an aryl-S(O) ₂ -NH- group.

The "heteroarylsulfonylamino group" of the present invention means a heteroaryl-S(O) ₂ -NH- group.

The "aryl group" of the present invention means an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.

The "heteroaryl" of the present invention means an aromatic group in which at least one carbon atom of the aryl group is replaced by a hetero atom. The hetero atom is O, S, N.

The "solvate" of the present invention means, in a conventional sense, a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.

"Crystalline" as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.

By "isomer" of the invention is meant an isomer of the cis or trans configuration of the compound. Accordingly, the invention includes each cis isomer or trans isomer substantially free of other isomers and mixtures of such isomers.

The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.

The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt of the compound of the present invention and an acid, which includes, but is not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, and Malay. Acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.

By "pharmaceutical composition" is meant a compound comprising any of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically A mixture of carriers is acceptable.

The "pharmaceutically acceptable carrier" of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipient, a dispersing agent, and a surface active agent. Agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof, such as sodium carboxymethylcellulose, and Cellulose and cellulose acetate; malt, gelatin, and the like.

"Excipient" as used herein refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

The "application in the preparation of a medicament for treating and/or preventing a tumor" of the present invention means that the growth, development and/or metastasis of the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof. The compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.

The compounds of the present invention refer to all compounds of the formula of the present invention, including Formula I, Formula Ia, Formula Ia, Formula Ib, Formula Ia-a, Formula I-a', Formula Ia", A compound of the formula I-b', formula Ib" and formula Ia-a' and specific compounds.

The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention.

Example 1 3-((2-Methylamino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 1-(4-methyl-5-bromopyridin-2-yl)-3-ethoxycarbonylthiourea

Add 2-amino-4-methyl-5-bromopyridine (1.87 g, 10 mmol) in a 50 mL round bottom flask, add dichloromethane (DCM, 20 mL), and then add isothiocyanate. Ethyl phthalate (EtOC(O)NCS, 1.4 g, 10.6 mmol) was reacted at 5 ° C for 15 min, and reacted for 2 h at room temperature. Concentrated at 40 ° C, 50 ml of petroleum ether (PE) was added, a large amount of solid was precipitated, filtered, and the filter cake was washed 3 times with PE and dried to give the title compound.

ESI-MS m/z: [M+H] ⁺ = 317.9.

Step 2 Preparation of 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine

To a 100 mL eggplant-shaped flask, 1-(4-methyl-5-bromopyridin-2-yl)-3-ethoxycarbonylthiourea (1.21 mg, 4 mmol), hydroxylamine hydrochloride (1.38 g, 20 mmol) and N,N-diisopropylethylamine (DIEA, 1.65 mL) was further added with 40 ml of a mixed solution of methanol and ethanol (V: V = 1:1), stirred at room temperature for 1 hour, and heated to 70 ° C for 4 h. After 4 h of reaction, the mixture was quenched with EtOAc.

1H NMR (300 MHz, DMSO-d6) δ: 8.88 (s, 1H), 7.36 (s, 1H), 6.04 (s, 2H), 2.37 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 227.1.

Step 3 Preparation of 2-methylamino-6bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine

In a dry 100 ml two-necked flask, the compound 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.88 mmol) was added. Phenol (264 mg, 8.8 mmol), sodium methoxide (190 mg, 3.52 mmol) and methanol (5 ml), reacted at 80 ° C for 2 h under nitrogen atmosphere, cooled to room temperature, and sodium borohydride (167.2 mg, 4.4 mmol) in portions. After adding to the reaction system, the mixture was heated to 80 ° C and stirred for 2 hours, and then the excess sodium borohydride was quenched by adding acetone under ice bath, and concentrated. Water (20 ml), EtOAc (EtOAc)

ESI-MS m/z: [M+H] ⁺ = 241.1.

Step 4: Preparation of 3-iodo-4-methyl-N-[4-(4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide

To the reactor was added 4-(4-methylpyridazin-1-ylmethyl)-3-trifluoromethylaniline (2.27 g, 8.3 mmol), 3-iodo-4-methylbenzhydryl chloride ( 10 mmol), 15 ml of tetrahydrofuran, 10 ml of triethylamine, and stirred at room temperature for 4 hours. End of the reaction, the solution was washed with saturated NaHCO ₃ with ethyl acetate / water and extracted, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO _4, the solvent was removed by distillation under reduced pressure, silica gel column chromatography to give the title compound.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.39 (s, 1H, NH), 8.29 (s, 1H, Ar-H), 7.88 (d, 1H, Ar-H), 7.86 (s, 1H, Ar- H), 7.75 (d, 1H, Ar-H), 7.73 (d, 1H, Ar-H), 7.28 (d, 1H, Ar-H), 3.62 (s, 2H, PhCH ₂ ), 2.60 (b, 8H, 4x-CH ₂ ), 2.47 (s, 3H, -CH ₃ ), 2.31 (s, 3H, -CH ₃ ).

Step 5: 3-Trimethyldecyl ethynyl-4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzene Preparation of formamide

3-iodo-4-methyl-N-[4-(4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide (3.1 g, 6.1 mmol) Pd(PPh ₃ ) ₂ Cl ₂ (426 mg, 0.61 mmol), CuI (231 mg, 1.21 mmol) was placed in a reactor, 30 ml of toluene was added as a solvent, and 1 ml of triethylamine was maintained in an alkaline environment. Under an inert gas atmosphere, trimethyldecyl acetylene (3.0 g, 30.3 mmol) was added to the mixture, and the mixture was stirred at 58 ° C for 24 hours. End of the reaction, the organic layer was extracted, and the combined reaction mixture were added ethyl acetate and water, washed with saturated NaCl solution, dried over anhydrous added Na ₂ SO _4. The organic layer was concentrated under reduced

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.30 (s, 1H, NH), 7.86 (s, 1H, Ar-H), 7.83 (d, 1H, Ar-H), 7.72 (s, 1H, Ar- H), 7.55 (d, 1H, Ar-H), 7.41 (d, 1H, Ar-H), 7.24 (d, 1H, Ar-H), 3.60 (s, 2H, PhCH ₂ ), 2.48 (b, 8H, 4x-CH ₂ ), 2.45 (s, 3H, -CH ₃ ), 2.28 (s, 3H, -CH ₃ ), 0.26 (s, 9H, 3×-CH ₃ ).

Step 6: Preparation of 3-ethynyl-4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

The reaction product of the reaction of the step 5 (1.59 g, 3.3 mmol), potassium carbonate (1.82 g, 13.2 mmol), and 20 ml of methanol were mixed in the reactor, and the mixture was stirred at room temperature for 3 hours under an inert gas atmosphere. The reaction completed, the methanol was removed by rotary evaporation, ethyl acetate and the organic layer was extracted with water, combined, washed with saturated NaCl solution, dried over anhydrous added Na ₂ SO _4. The organic solution was then concentrated on a rotary evaporator.

_{^{1 H NMR (500MHz, CDCl 3}} ) δ: 10.47 (s, 1H, NH), 8.19 (s, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 8.04 (d, 1H, Ar- H), 7.91 (d, 1H, Ar-H), 7.70 (d, 1H, Ar-H), 7.47 (d, 1H, Ar-H), 4.50 (s, 1H, ≡CH), 3.56 (s, 2H, PhCH ₂ ), 2.50 (s, 3H, -CH ₃ ), 2.36 (b, 8H, -4 × CH ₂ ), 2.15 (s, 3H, -CH ₃ ).

Step 7 3-((2-Methylamino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

3-Ethynyl-4-methyl-N-[4-(4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide (126 mg, 0.3 mmol) , 2-methylamino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (60 mg, 0.3 mmol), Pd(Pph ₃ ) ₂ Cl ₂ (22 mg, 0.03 mmol), tricyclohexylphosphine (Pcy 3, 16 mg, 0.06 mmol), CuI (6 mg, 0.03 mmol), cesium carbonate (100 mg, 0.3 mmol). Then 6 drops of diisopropylethylamine (DIPEA) and 6 mL of DMF were added to the sealed tube. After argon gas was purged for 5 minutes, it was sealed and stirred at 80 ° C overnight. Each reaction was placed in a 10 mL sealed tube, DMF was added to a half volume, argon gas was purged for 5 minutes, sealed, and stirred at 80 ° C overnight. The next day, the reaction mixture was washed twice with aqueous ammonia and extracted with EtOAc (EtOAc).

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.92 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.70 (d, 1H), 7.52 (d, 1H), 7.34 (s, 1H), 6.58 (q, 1H), 3.57 (s, 2H), 2.82 (s, 3H), 2.57 (s, 3H) ), 2.53 (s, 3H), 2.38 (m, 8H), 2.16 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 576.3.

Example 2 3-((2-Amino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-5-bromo-6-trifluoromethylpyridine as the starting material.

1H NMR (300 MHz, DMSO-d6) δ: 7.77 (d, 1H), 7.59 (d, 1H), 6.48 (s, 2H).

Step 2 3-((2-Amino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4 The title compound was obtained by the procedure of Step 7 of Example 1 using (4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 8.04 (d, 1H), 7.76 (d, 1H), 7.74 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 6.61 (s, 2H), 3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H) ), 2.18 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 616.4.

Example 3 3-((2-Amino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine as 2-amino-4-methyl-5-bromopyridine For the raw materials, according to the first step and the second step of the first embodiment Compound.

1H NMR (300 MHz, DMSO-d6) δ: 8.88 (s, 1H), 7.36 (s, 1H), 6.04 (s, 2H), 2.37 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 227.1.

Step 2 3-((2-Amino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( 4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.06 (d, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.33 (s, 1H), 6.13 (s, 2H), 3.58 (s, 2H), 2.58 (s, 6H), 2.40 (m, 8H) ), 2.19 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.4.

Example 4 3-((2-Amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

The title compound was obtained according to the steps 1 and 2 of Example 1 using 2-amino-3-methyl-5-bromopyridine as the starting material.

Step 2 3-((2-Amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( 4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

^{1 H NMR (300MHz, DMSO- d} 6) δ: 10.52 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.06 (d, 1H), 7.91 ( d, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.42 (s, 1H), 6.16 (s, 2H), 3.58 (s, 2H), 3.26 (s, 6H), 2.42 (m) , 8H), 2.20 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.3.

Example 5 3-((2-Amino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was obtained according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-6-methyl-5-bromopyridine as the starting material.

Step 2 3-((2-Amino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( 4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.58 (d, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 6.21 (s, 2H), 3.58 (s, 2H), 2.85 (s, 3H), 2.58 (s, 3H) ), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.5.

Example 6 3-((2-Dimethylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-6-methyl-5-bromopyridine, the title compound was obtained according to the procedure of Step 1 and Step 2 of Example 1.

Step 2 Preparation of 2-dimethylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.06 mg, in a 50 mL eggplant-shaped flask under ice bath 5 mmol), dry THF 20 ml, additional sodium hydride (240 mg, 10 mmol) was added, stirred for 15 min, then 2 ml of iodomethane was added and reacted at room temperature for 4 h. The mixture was evaporated to dryness crystals crystals crystals crystals

Step 3 3-((2-Dimethylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-Dimethylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl -N-[4-(4-Methyloxazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.53 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.06 (d, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.64 (d, 1H), 7.53 (d, 1H), 7.37 (s, 1H), 3.57 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H) ), 2.58 (s, 3H), 2.39 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 590.3.

Example 7 3-((2-Dimethylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-dimethylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Example 1 Step 1 and Step 2 from 2-amino-3-methyl-5-bromopyridine.

Step 2 3-((2-Dimethylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-Dimethylamino-8-methyl-6bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.87 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.72 (d, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 3.58 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H) ), 2.58 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 590.3.

Example 8 3-((2-Methylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-3-methyl-5-bromopyridine, the title compound was obtained according

^{1 H NMR (300MHz, DMSO- d} 6) δ: 8.83-8.79 (m, 1H), 7.43 (s, 1H), 6.53-6.52 (m, 1H), 3.32 (s, 3H), 2.39 (s, 3H ).

ESI-MS m/z: [M+H] ⁺ = 241.0.

Step 2 3-((2-Methylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-Methylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.82 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.44 (s, 1H), 6.62 (q, 1H), 3.57 (s, 2H), 3.26 (s, 3H), 2.84 (d, 3H) ), 2.56 (d, 3H), 2.41 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 576.3.

Example 9 3-((2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)acetylene 4-methyl-N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-3-fluoro-5-bromopyridine as the starting material. ^{1 H NMR (300MHz, DMSO- d} 6) δ: 8.30 (s, 1H), 7.27 (dd, 1H), 4.58 (m, 2H).

Step 2 3-((2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The target compound was prepared according to the method of Step 7 of Example 1 using m-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.56 (s, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 8.14(s,1H), 8.05(d,1H), 7.91(d,1H), 7.69(d,1H), 7.64(d,1H),7.51(d,1H),6.44(s,2H),3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H), 2.25 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 566.4.

Example 10 3-((2-Methylamino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-A --N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-5-bromo-6-trifluoromethylpyridine, the title product was obtained according to the procedure of Step 1-3 of Example 1.

1H NMR (500MHz, DMSO- d6 ) δ: 7.79-7.77 (m, 1H), 7.63 - 7.61 (m, 1H), 6.91 (s, 1H), 2.85 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 296.0.

Step 2 3-((2-Methylamino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylphthalazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-5-trifluoromethyl-6-bromo[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4 -(4-Methyloxazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.20 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.96 (dd, 1H), 7.77 (dd, 2H), 7.71 (d, 1H), 7.54 (d, 1H), 7.02 (q, 1H), 3.58 (s, 2H), 2.87 (d, 3H), 2.55 (s, 3H), 2.41 (m, 8H) ), 2.21 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 630.3.

Example 11 3-((2-Amino-8-methylaminomethylmethyl [1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-Amino-6-bromo-8-methylaminomethylmethyl [1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-5-bromo-N-methyl-s-s-s-ssamine.

Step 2 3-((2-Amino-8-methylaminomethylmethyl [1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-8-methylaminomercapto[1,2,4]triazolo[1,5-a]pyridine]pyridine and 3-ethynyl-4-methyl-N- [4-(4-Methyloxazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material to give the title compound.

1H NMR (300MHz, DMSO-d6) δ: 10.51 (s, 1H), 9.17 (d, 2H), 8.20 (s, 2H), 8.14 (s, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 6.63 (s, 2H), 3.57 (s, 2H), 2.95 (d, 3H), 2.58 (s, 3H), 2.40 (m, 8H) ), 2.17 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 605.5.

Example 12 3-((2-Amino-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-4-chloro-5-br.

1H NMR (300 MHz, DMSO-d6) δ: 7.25 (t, 2H), 7.17 (d, 2H).

Step 2 3-((2-Amino-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The target compound was prepared according to the method of Step 7 of Example 1 using m-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.55 (s, 1H), 9.09 (s, 1H), 8.20 (d, 1H), 8.16 (s, 1H), 8.06 (d, 1H), 7.94 (d, 1H), 7.72 (s, 1H), 7.71 (s, 1H), 7.53 (d, 1H), 6.36 (s, 2H), 3.57 (s, 2H), 2.58 (s, 3H), 2.35 (s, 3H) ), 2.31 (m, 8H).

ESI-MS m/z: [M+H] ⁺ = 582.2.

Example 13 3-((2-Methylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title product was synthesized according to the procedure of Step 1-3 of Example 1 using 2-amino-5-bromo-6-methyl as starting material.

ESI-MS m/z: [M+H] ⁺ = 241.6.

Step 2 3-((2-Methylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.56 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.53 (d, 1H), 7.33 (d, 1H), 6.69 (m, 1H), 3.58 (s, 2H), 2.87 (m, 6H), 2.58 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 576.3.

Example 14 3-((2-Amino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-3-chloro-5-bromopyridine as the starting material.

1H NMR (300 MHz, DMSO-d6) δ: 8.38 (s, 1H), 7.59 (s, 1H), 4.67 (m, 2H).

Step 23-((2-Amino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[4 -((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-amino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The target compound was prepared according to the method of Step 7 of Example 1 using m-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.96 (s, 1H), 8.21 (s, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 6.45 (s, 2H), 3.62 (s, 2H), 2.57 (s, 3H), 2.45 (m, 8H) ), 1.75 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 5821.

Example 15 3-((2-Dimethylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-3-fluoro-5-bromopyridine, the title compound was obtained according to the procedure of Step 1-2 of Example 1.

Step 2 Preparation of 2-dimethylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

In a dry 100 ml two-necked flask, compound 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (160 mg, 0.69 mmol), sodium hydride (138 mg, 3.47 mmol) and tetrahydrofuran (10 mL). The reaction system was reacted at 0 ° C under nitrogen for 30 minutes. Then, methyl iodide (199 mg, 1.38 mmol) was added dropwise to tetrahydrofuran (10 mL), and the mixture was added dropwise to the mixture, and the mixture was stirred at room temperature for 12 h. TLC detection. Under ice bath conditions, excess sodium hydride was quenched by the addition of methanol and concentrated. Join Water (20 ml), EtOAc (EtOAc m.

^{1 H NMR (500MHz, DMSO- d} 6) δ 8.95 (s, 1H), 7.78 (d, 1H), 3.04 (s, 6H).

Step 3 3-((2-Dimethylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-Dimethylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.97 (s, 1H), 8.20 (s, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.93 (d, 1H), 7.70 (d, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 3.57 (s, 2H), 3.25 (s, 3H), 3.08 (s, 3H), 2.56 (s, 3H) ), 2.40 (m, 8H), 2.18 (s, 3H).

ESI-MS m / z: [ M + H] + = 594.3.

Example 16 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[4- ((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-5-bromopyridine, the title compound was obtained according to the procedure 1H NMR (300MHz, DMSO-d6) δ: 8.95 (d, 1H), 7.56 (dd, 1H), 7.34 (d, 1H), 6.54 (d, 1H), 2.81 (d, 3H).

ESI-MS m/z: [M+H] ⁺ = 227.2.

Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.52 (s, 1H), 8.99 (s, 1H), 8.21 (s, 1H), 8.16 (d, 1H), 8.06 (d, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 7.42 (d, 1H), 6.64 (m, 1H), 3.57 (s, 2H), 2.86 (dd, 3H) ), 2.56 (s, 3H), 2.37 (m, 8H), 2.16 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.2.

Example 17 3-((2-Methylamino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-3-chloro-5-bromopyridine, the title compound was obtained according to the procedure

1H NMR (300 MHz, DMSO-d6) δ: 9.00 (s, 1H), 7.78 (s, 1H), 6.81 (s, 1H), 2.82 (d, 3H).

ESI-MS m/z: [M+H] ⁺ =260.9

Step 2 3-((2-Methylamino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl -N-[4-(4-Methyloxazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.73 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 6.94 (m, 1H), 3.57 (s, 2H), 2.86 (s, 3H), 2.73 (s, 3H) ), 2.37 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 596.2.

Example 18 3-((2-Methylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

Starting from 2-amino-3-fluoro-5-bromopyridine, the title compound was obtained according to the procedure of Step 1 1-3.

1H NMR (300 MHz, DMSO-d6) δ: 8.34 (s, 1H), 7.37-7.35 (m, 1H), 3.49 (s, 1H), 3.06 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 245.0.

Step 2 3-((2-Methylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( 4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.94 (s, 1H), 8.20 (s, 1H), 8.16 (d, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.52 (d, 1H), 6.87 (m, 1H), 3.57 (s, 2H), 2.85 (d, 3H), 2.56 (s, 3H) ), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 580.2.

Example 19 3-((2-Isopropylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[ 4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared by the procedure of Step 1 and Step 2 using 2-amino-4-bromopyridine as the starting material.

Step 2 Preparation of 2-isopropylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

In a dry 50 ml two-necked flask, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.4 mmol), sodium hydrogen (280 mg, 7.0 mmol) was added. , quality score 60%) and DMF (5ml). The reaction system was reacted at 10 ° C under nitrogen for 1 hour. Then, isopropyl bromide (512 mg, 4.2 mmol) was added dropwise to the above reaction mixture in portions and stirred at room temperature for 2 h. TLC detection. The reaction mixture was poured into EtOAc (EtOAc m.

^{1 H NMR (300MHz, DMSO- d} 6) δ: 8.53 (d, 1H), 7.67 (d, 1H), 7.01 (dd, 1H), 6.53 (d, 1H), 3.82-3.73 (m, 1H), 1.16 (d, 6H).

ESI-MS m / z: [ M + H] + = 255.0.

Step 3 3-((2-Isopropylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4 -((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-isopropylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4- The target compound was prepared according to the method of Step 7 of Example 1 using methylene phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.63 (d, 1H), 8.20 (s, 2H), 8.06 (d, 1H), 7.94 (d, 1H), 7.71 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 7.01 (d, 1H), 6.57 (d, 1H), 3.85 (m, 1H), 3.57 (s, 2H), 2.57 (s, 3H), 2.39 (m, 8H), 2.17 (s, 3H), 1.18 (s, 6H).

ESI-MS m/z: [M+H] ⁺ = 590.2.

Example 20 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethynyl)-4-methyl-N-[4- ((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-5-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared by the procedure of Step 1 to 3, using 2-amino-6-bromopyridine as the starting material.

ESI-MS m/z: [M+H] ⁺ = 227.0.

Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-5-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.58 (s, 1H), 8.25 (s, 1H), 8.21. (d, 1H), 8.06(d,1H),8,02(d,1H), 7.72(d,1H), 7.58(d,1H), 7.48(d,2H), 7.27(d,1H),6.61(m,1H) , 3.58 (s, 2H), 2.88 (dd, 3H), 2.68 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.3.

Example 21 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethynyl)-4-methyl-N-[4- ((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared by the procedure of Step 1 to Step 3 using 2-amino-3-bromopyridine as the starting material.

^{1 H NMR (300MHz, DMSO- d} 6) δ: 8.62 (d, 1H), 7.73 (d, 1H), 6.82-6.77 (m, 1H), 6.69-6.67 (m, 1H), 2.82 (d, 3H ).

ESI-MS m/z: [M+H] ⁺ = 227.0.

Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylamino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.56 (s, 1H), 8.68 (d, 1H), 8.21 (s, 1H), 8.18(d,1H), 8.06(d,1H), 7.94(d,1H),7.73(s,1H), 7.70(s,1H),7.54(d,1H),6.93(d,1H),6.68 (m, 1H), 3.57 (s, 2H), 2.85 (d, 3H), 2.61 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 562.3.

Example 22 3-((2-(2,2,2-Trifluoroethylamino)imidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4 -((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-p-toluenesulfonylamino-4-bromopyridine

2-Amino-4-bromopyridine (1.72 g, 10 mmol), pyridine (5 mL) was added to a 50 mL round bottom flask, and p-toluenesulfonium chloride (2.29 g, 12 mmol) was slowly added dropwise to the mixture. After reacting for 6 h, water was added, and ethyl acetate was evaporated.

Step 2 Preparation of 2-(4-bromo-2p-toluenesulfonimidopyridine-1(2H)-yl)acetamide

Add 2-p-toluenesulfonylamino-4-bromopyridine (327 mg, 1.0 mmol), DMF (5 Ml), 2-bromoacetamide (152 mg, 1.1 mmol) and diisopropylethyl in a 25 mL round bottom flask. The amine (142 mg, 1.1 mmol) was reacted at room temperature for 24 h. Add water, extract with ethyl acetate and dry over anhydrous sodium sulfate. The title compound was obtained by column chromatography on silica gel.

Step 3 2-(2,2,2-Trifluoroethylamino)-7-bromo-imidazo[1,2-a]pyridine

Add 2-(4-bromo-2p-toluenesulfonimidopyridine-1(2H)-yl)acetamide (385 mg, 1.0 mmol) in a 25 mL round bottom flask, trifluoroacetic anhydride (2.10 g, 10 mmol) And methylene chloride (5 mL), refluxed for 2 h, the reaction was completed by TLC, water was added, and the mixture was extracted with dichloromethane, and the organic phase was combined, washed with saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate The title compound was obtained by chromatography on silica gel column chromatography.

1H NMR (300MHz, DMSO-d6) δ: 12.51 (s, 1H), 8.57 (d, 1H), 8.28 (s, 1H), 7.85 (s, 1H), 7.14 (dd, 1H).

ESI-MS m/z: [M+H] ⁺ = 329.9.

Step 4 3-((2-(2,2,2-Trifluoroacetamidoamino)imidazo[1,2-a]pyrazin-7-yl)ethynyl)-4-methyl-N-[ 4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-(2,2,2-trifluoroethylamino)-7-bromo-imidazo[1,2-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4- Methyl pyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as raw material, according to the examples The method of 1 step 7 produces the target compound.

1H NMR (300MHz, DMSO-d6) δ: 10.50 (s, 1H), 8.63 (d, 1H), 8.31 (s, 1H), 8.17 (s, 2H), 8.03 (d, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.50 (d, 1H), 7.07 (d, 1H), 3.54 (s, 2H), 2.55 (s, 3H) ), 2.36 (m, 8H), 2.16 (s, 3H).

ESI-MS m / z: [ M + H] + = 643.3.

Example 23 3-((2-Ethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4 -((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 from 2-amino-4-bromopyridine.

Step 2 Preparation of 2-ethylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

In a dry 50 ml two-necked flask, the compound 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (213 mg, 1 mmol) and acetic anhydride (10 ml) were added, followed by Pyridine (118 mg, 1.5 mmol) was added. The reaction system was refluxed at 85 ° C and allowed to react overnight. The title compound was obtained by EtOAc (EtOAc).

ESI-MS m/z: [M+H] ⁺ = 255.0.

Step 3 3-((2-Ethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4- Preparation of ((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-Ethylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4--4- The title compound was prepared according to the method of Step 7 of Example 1, using hydrazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.84 (s, 1H), 10.54 (s, 1H), 8.90 (d, 1H), 8.22 (d, 1H), 8.21 (d, 1H), 8.07 (d, 1H), 7.98 (d, 1H), 7.97 (s, 1H), 7.71 (d, 1H), 7.55 (s, 1H), 7.27 (dd, 1H), 3.58 (s, 2H), 2.60 (s, 3H) ), 2.41 (m, 8H), 2.19 (s, 3H), 2.16 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 590.3.

Example 24 3-((2-Methanesulfonylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[ 4-((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 from 2-amino-4-bromopyridine.

Step 2 Preparation of 2-methanesulfonylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

In a dry 100 mL two-necked flask, THF (5 mL) was added first, followed by the compound 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (213 mg, 100 mmol) , methyl sulfonium chloride (3ml), Pyridine (5 mL). The reaction was carried out at room temperature for 24 hours. The TLC detected the disappearance of the raw materials. Water (10 ml), EtOAc (3 mL)EtOAc.

1H NMR (300 MHz, DMSO-d6) δ: 9. s (d, 1H), 8.35 (s, 1H), 7.58 (dd, 1H), 3.68 (s, 3H).

Step 3 3-((2-Methanesulfonylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4 -((4-Methyloxazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

2-methylsulfonylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4- The target compound was prepared according to the method of Step 7 of Example 1 using methylene phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 10.53 (s, 1H), 8.81 (d, 1H), 8.21 (d, 2H), 8.06 (d, 1H), 7.95 (d, 1H), 7.88 (s, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.21 (d, 1H), 3.58 (s, 2H), 3.26 (s, 3H), 2.96 (b, 1H), 2.59 (s, 3H) ), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 626.2.

Example 25 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-4-A --N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-mercapto-3-bromopyridine

2-Fluoro-3-bromopyridine (3.52 g, 20 mmol), hydrazine hydrate (200 mmol) and THF (25 mL) were stirred in a 250 ml round bottom flask, stirred at room temperature for 6 h, concentrated to 30% by volume, cooled in ice bath Crystallization, filtration, crystals were collected and dried in vacuo to give the title compound.

Step 2 Preparation of 8-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

In a dry 100 ml two-necked flask, triphosgene (888 mg, 300 mmol) and tetrahydrofuran solution (100 mL) were added. The compound 2-mercapto-3-bromopyridine (188 mg, 100 mmol) was added portionwise, and reacted for 3 hours, and the TLC spot material disappeared. 100 mL of water was slowly added under an ice bath. The 70% solvent was removed by distillation under reduced pressure. Then, it was allowed to stand for precipitation, and the solid was filtered and dried, and dried under air for 8 hours to give the title compound.

Step 3 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylphthalazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

8-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- The target compound was prepared according to the method of Step 7 of Example 1 using methylene phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 12.67 (s, 1H), 10.58 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.95 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.55 (d, 1H), 7.54 (s, 1H), 6.65 (t, 1H), 3.58 (s, 2H), 2.59 (s, 3H) ), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 549.3.

Example 26 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethynyl)-4-A --N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

The title compound was prepared in the same manner as in Example 25 Step 1 and Step 2 from 2-fluoro-4-bromopyridine.

ESI-MS m/z: [M+H] ⁺ = 214.0.

Step 2 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylphthalazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

7-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- Methyl pyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as raw material, according to the examples The method of 1 step 7 produces the target compound.

1H NMR (300MHz, DMSO-d6) δ: 12.66 (s, 1H), 10.52 (s, 1H), 8.19 (d, 2H), 8.06 (d, 1H), 7.95 (d, 1H), 7.85 (d, 1H), 7.71 (d, 1H), 7.54 (t, 2H), 6.62 (d, 1H), 3.58 (s, 2H), 2.56 (s, 3H), 2.42 (m, 8H), 2.36 (s, 3H) ).

ESI-MS m/z: [M+H] ⁺ = 549.2.

Example 27 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethynyl)-4-A --N-[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 5-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

The title compound was prepared in the same manner as in Example 25 Step 1 and Step 2 from 2-fluoro-6-bromopyridine.

ESI-MS m/z: [M+H] ⁺ = 214.0.

Step 2 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylphthalazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

5-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- The target compound was prepared according to the method of Step 7 of Example 1 using methylene phthalazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H NMR (300MHz, DMSO-d6) δ: 12.68 (s, 1H), 10.59 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.55 (d, 1H), 7.54 (d, 1H), 6.65 (t, 1H), 3.61 (s, 2H), 2.59 (s, 3H) ), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 549.3.

Example 28 3-((2-Methylaminoimidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazine-1) -yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-methylamino-7-bromo-imidazo[1,2-a]pyridine

Add 2-(2,2,2-trifluoroethylamino)-7-bromo-imidazo[1,2-a]pyridine (308 mg, 1.0 mmol) in a 100 mL round bottom flask, iodomethane (170 mg, 1.2) Methyl acetate (414 mg, 3.0 mmol) and acetone (5 mL). Water (5 mL) was added to the mixture, and the mixture was evaporated.

1H NMR (300MHz, DMSO-d6) δ: 8.71 (d, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.54 (dd, 1H), 3.76 (s, 3H), 2.67 (b, 1H).

ESI-MS m/z: [M+H] ⁺ = 226.0.

Step 2 3-((2-Methylaminoimidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpyridazine-1-) Preparation of methyl)methyl)-3-trifluoromethylphenyl]benzamide

2-Methylamino-7-bromo-imidazo[1,2-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methylpyridazin-1-ylmethyl) Starting from -3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure of Step 7 of Example 1.

1H NMR (300MHz, DMSO-d6) δ: 10.56 (s, 1H), 8.82 (d, 1H), 8.39 (s, 1H), 8.23 (d, 2H), 8.22 (s, 1H), 8.07 (d, 1H), 7.98 (d, 1H), 7.72 (d, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 4.03 (q, 1H), 3.83 (s, 3H), 3.58 (s, 2H) ), 2.62 (s, 3H), 2.40 (m, 8H), 2.17 (s, 3H).

ESI-MS m/z: [M+H] ⁺ = 561.4.

Example 29 3-((2-Cyclopropylcarbamimido-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpyridazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

Step 1 Preparation of 2-cyclopropylcarboxamido-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

Weigh 172 mg of cyclopropanecarboxylic acid in a reaction flask, add 5 mL of DMA to dissolve, add 238 mg of hydrazine chloride, stir at room temperature for 2 h, and add 426 mg of 2-amino-6-bromo-[1,2,4]triazole. And [1,5-a]pyridine, The reaction was carried out at 50 ° C for 16 h, EtOAc (EtOAc)

Step 2 3-((2-Cyclopropylcarbamimido-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpyrazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

The product obtained in Step 1 is 2-cyclopropylmethylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and the product obtained in Step 6 of Example 1 is 3-ethynyl- 4-methyl-N-[4-(4-methylpyridazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material, according to the method of Step 7 of Example 1. The target compound is obtained.

^{1 H NMR (500MHz, DMSO- d} 6) δ: 11.13 (s, 1H), 11.54 (s, 1H), 8.89 (d, 1H), 8.21 (d, 2H), 8.06 (d, 1H), 7.96- 7.97 (m, 2H), 7.71 (d, 1H), 7.55 (d, 1H), 7.25-7.27 (m, 1H), 3.57 (s, 2H), 2.60 (s, 3H), 2.38 (m, 8H) , 2.16 (s, 3H), 2.01 (m, 1H), 0.83-0.85 (m, 4H).

ESI-MS m/z: [M+H] ⁺ = 616.

Experimental Example 1 Evaluation of in vitro cell viability of the compound of the present invention Test material 1.1 compound

The compound of the present invention prepared in the above examples, each compound was dissolved in DMSO to 10 mM, diluted to 50 μM with complete medium, and then diluted to 10 μM with complete medium containing 0.1% DMSO, and then diluted 10-fold. A total of 10 concentrations.

1.2 cells

K562 leukemia cells: purchased from ATCC, USA

1.3 reagent

Dimethyl sulfoxide (DMSO), purchased from Sigma, USA; CellTiter-Glo ^® Luminescent Cell Viability Assay Kit, purchased from Promega, USA; IMEM medium (IMEM medium), Purchased from Gibco, USA; penicillin/streptomycin (Pen/Strep), purchased from Gibco, USA; Fatal bovine serun (FBS), purchased from Gibco, USA; 0.25% containing EDTA trypsin (0.25% Trypsin) -EDTA), purchased from Gibco, USA; 10cm cell culture dish, purchased from Corning, USA; 50mL centrifuge tube, purchased from Corning, USA; 384-well flat-bottomed whiteboard (384Well) Flat Clear Bottom White), purchased from Corning, USA; Phosphate Buffered Saline (PBS), prepared weekly.

1.4 Instrument

Autofocus fluorescent multi-function microplate reader (PHERAstar Plus), purchased from BMG Labtech, Germany.

2. Experimental method:

1) the collection of log phase cells, the cell suspension adjusted to a concentration of 1 × 10 ⁵ cells / ml, were added per well of 384 well plate 40 μ L of cell suspension, number of cells per well is 4 × 10 ³ cells / well. Edge of the hole is filled with sterile PBS; 2) 10 μ L or more of a concentration gradient of the compounds of the present invention is added. Each compound was repeated three times for each concentration. Blank control was added L equivalent concentration 10 μ DMSO; 3) cells were incubated at 37 ℃ / 5% CO ₂ incubator; 4) Dosing was added 30 μ L of cell viability chemiluminescence detection reagent mixture after 72h; 5) 37 ℃ Incubate for 10 min in a /5% CO ₂ incubator; determine chemiluminescence values on a PHERAstar plate reader after low-speed centrifugation; 6) Cell Viability = (RLU _sample /RLU _negative ) × 100%, where RLU _sample is Dosing hole RLU (relative light unit) value, RLU _negative is the unfilled hole RLU value (ie, the same concentration of DMSO-treated cell control), using Graphpad Prism 4.0 data processing software four-parameter logic fitting module for processing data calculation IC ₅₀ . The IC ₅₀ value indicates the concentration of the compound corresponding to 50% cell growth inhibition of the compound compared to the compound-free treated group. The IC ₅₀ results are shown in Table 1.

"-" means not tested.

As can be seen from the above experimental results, the compound of the present invention has a strong inhibitory activity against the leukemia cells with an IC ₅₀ value at the nM level. Jia HY et al ( Jia HY, et al. ZD6474 inhibits Stc kinase leading to apoptosis of imatinib-resistant K562 cells. Leuk Res (2009), doi: 10.1016/j.leukres.2009.03.033 ) Studies show that imatinib against K562 cells The IC ₅₀ value is 280 nM, H Luo et al ( H Luo, et al. HH-GV-678, a novel selective inhibitor of Bcr-Ab1, outperforms imatinib and beneficial overrides imatinib resistance. Leukemia (2010) 24, 1807-1809; doi: 10.1038 / leu.2010.169; Published online 12 August 2010) experimental evidence Mingyi Ma imatinib K562 cells IC ₅₀ value of 296nM. Thus, it can be seen that the compound of the present invention has comparable and even superior effects to imatinib for non-resistant leukemia cells.

Experimental Example 2 Evaluation of ABL1 (T315I) Tyrosine Kinase Activity

This experiment tests the inhibition of ABL(T315I) kinase activity by the compounds prepared in the examples of the present invention. Imatinib was used as a control. Imatinib was prepared by the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.

ABL (T315I) tyrosine kinase activity was tested using a commercially available human ABL T315I mutant enzyme (Human ABL1 (T315I), active, Cat # 14-522, Millipore, USA). Kinase activity assays were performed according to the manufacturer's instructions. The Peptide substrate was Abltide (EAIYAAPFAKKK) and was purchased from Millipore Corporation of the United States. Ion exchange chromatography paper (P81) was purchased from Whatman Company of the United Kingdom. [γ-33P] ATP was purchased from Perkin Elmer.

The compound of the present invention and imatinib were serially diluted 3 times from 1 μM, respectively, for a total of 10 concentrations (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0 nM and 1.0). μM). Each well was added 5.0 μ M Abltide, followed by addition of humanized T315I mutant enzymes. [γ- ³³ P]ATP was added at room temperature to a final concentration of 1.0 μM, and the reaction was carried out for 120 minutes. A 20 μl aliquot was transferred to a P81 ion exchange chromatography paper. The chromatography paper was then washed thoroughly 3 times with a 0.75% phosphoric acid solution and once with acetone. Finally, a gamma- ^33P radioactivity assay was performed. The experimental results are shown in Table 2.

The above experimental results show that the compound of the present invention has a significantly better IC ₅₀ for the T315I mutant enzyme than imatinib, and has potent ability to inhibit the T315I mutant enzyme.

From the experimental results of the present invention, it can be concluded that the compound of the present invention not only has a very good effect on leukemia cells without mutation, but also can significantly inhibit the T315I mutant enzyme, and thus is a broad-spectrum BCR-ABL inhibitor. For patients with cancer resistant or resistant to tyrosine kinase inhibitor (TKI) treatment, such as chronic myeloid leukemia (CML) chronic, blast, accelerated, and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia Patients with acute lymphoblastic leukemia should have good prospects.

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention.

Claims (10)

a compound of formula Ia or a pharmaceutically acceptable salt or isomer thereof, Wherein R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, and CN; and R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane alkoxy, -OH, -NH _2, halo and CN; R ₃ is selected from hydrogen, alkyl, haloalkyl, halo, amino, acyl, acyl monoalkylamino, dialkylamino acyl, and cyano; R & lt ₄ is a methyl group; and R _{6 is} selected from the group consisting of hydrogen, an amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkyl sulfonate. An amino group, an arylsulfonylamino group, and a heteroarylsulfonylamino group, said amino group, monoalkylamino group, dialkylamino group, nonylamino group, alkyl fluorenylamino group, aryl decylamino group, heteroaryl decylamino group, The sulfonium amino group, alkylsulfonylamino group, arylsulfonylamino group or heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino or cyano groups. The compound of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein the compound is a compound of the formula I-a', Wherein R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, CN; R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxyl, -OH, -NH ₂ , halogen, CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl, cyano; R ₄ is a methyl group; and R _{6 is} selected from the group consisting of hydrogen, an amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl decylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkyl sulfonate. An amino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkylamino group, an arylamino group, a heteroarylamino group, The sulfonium amino group, the alkylsulfonylamino group, the arylsulfonylamino group, and the heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, or cyano groups. The compound of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein the compound is a compound of the formula Ia", Wherein R _{1 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH ₂ , halogen, CN; R _{2 is} selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkane Oxyl, -OH, -NH ₂ , halogen, CN; R _{3 is} selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, aminoguanidino, monoalkylaminoindenyl, dialkylaminoindenyl, cyano; R ₄ is a methyl group; and R _{6 is} selected from the group consisting of hydrogen, a monoalkylamino group, a dialkylamino group, a decylamino group, an alkyl fluorenylamino group, an aryl fluorenylamino group, a heteroaryl fluorenylamino group, a sulfonylamino group, an alkylsulfonylamino group. , an arylsulfonylamino group, a heteroarylsulfonylamino group, the above mercaptoamino group, an alkylphosphoniumamino group, an arylsulfonylamino group, a heteroarylphosphoniumamino group, a sulfonylamino group, an alkylsulfonylamino group, an arylsulfonyl group The amino, heteroarylsulfonylamino group may be substituted by one or more halogen, alkyl, amino, cyano groups. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or isomer thereof, wherein R _{6 is} selected from the group consisting of hydrogen, amino, mono C _1-6 alkylamino, double C _{1 -6} alkylamino group, formamidine amino group, ethyl hydrazine amino group, propyl hydrazine amino group, cyclopropyl hydrazine amino group, cyclobutyl fluorenylamino group, benzoquinone amino group, trifluoroethylamino group, methanesulfonylamino group, ethyl sulfonylamino group. The compound of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein the compound is a compound selected from the group consisting of: A compound according to any one of claims 1 to 3, wherein R _{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halogenated C _1-6 , or a pharmaceutically acceptable salt or isomer thereof Alkyl, halogen, CN; R _{2 is} selected from the group consisting of hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, halogen, CN; R _{3 is} selected from hydrogen, C _1-6 alkyl, halogen C _{1 -6} alkyl, halogen, amino, acyl, mono acyl C _1-6 alkylamino, di-C _1-6 alkylamino, acyl, cyano group; and R ₄ is methyl. The patentable scope herein Item 6 The compound or a pharmaceutically acceptable salt or isomer thereof, wherein R ₁ is selected from methyl and trifluoromethyl; R ₂ is selected from methyl, ethyl, propyl and isopropyl Propyl; R _{3 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, halogen and methylaminoindenyl; and R ₄ is methyl. A pharmaceutical composition comprising the compound of claim 1, 2, 3 or 5, or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier. A use of a compound as described in claim 1, 2, 3 or 5, or a pharmaceutically acceptable salt or isomer thereof, for the manufacture of a medicament for the treatment and/or prevention of a tumor. Use of a pharmaceutical composition according to claim 8 of the patent application for the preparation of a medicament for the treatment and/or prevention of a tumor.