TWI707853B - 1,2-dihydro-1,6-naphthyridine derivatives, preparation method thereof, pharmaceutical composition and use in medicine - Google Patents

Abstract

The invention relates to 1,2-dihydro-1,6-naphthyridine derivatives, a preparation method thereof, a pharmaceutical composition and Its use in medicine. Specifically, the present invention relates to a 1,2-dihydro-1,6-naphthyridine derivative represented by general formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof, and Their use as therapeutic agents, especially c-KIT inhibitors.

Description

1,2-dihydro-1,6-naphthyridine derivatives, preparation method thereof, pharmaceutical composition and the same Use in medicine

The present invention relates to a new 1,2-dihydro-1,6-naphthyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially as a c-KIT inhibitor use.

c-KIT (also known as KIT, CD117, and stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that serves as a type III receptor. The c-KIT proto-oncogene located on chromosome 4q11-21 encodes c-KIT, and its ligand is stem cell factor. The receptor has tyrosine protein kinase activity and binding to the ligand SCF leads to autophosphorylation of c-KIT and its association with substrates such as phosphoinositide 3-kinase (PI3K). The phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signal transduction and can mediate major cellular processes, such as signals of proliferation, survival, differentiation, apoptosis, connection, invasion and migration. The c-KIT mutation usually occurs in the DNA (exon 11) that encodes the domain of the membrane region. They also appear in exons 7, 8, 9, 11, 13, 14, 17, and 18 at a lower frequency. The mutation makes c-KIT function independent of activation by SCF, resulting in a high cell division rate and possible genome instability. Increased function mutations of c-KIT gene and the expression of constitutively phosphorylated c-KIT can be found in most gastrointestinal stromal tumors (GIST), mastocytosis and acute myelogenous leukemia. There are mutations at different positions in different exons. The first-generation c-KIT mutations and related drugs are mainly imatinib, sunitinib, dasatinib and PKC412.

c-KIT has been used in the germ cell tumors of gastrointestinal stromal tumors, acute myelogenous leukemia, melanoma, breast tumors, cervical tumors, glioblastoma multiforme, ovarian tumors, seminoma or dysgerminoma , Teratoma, mast cell leukemia and other tissues are found, and its protein expression concentration is closely related to the occurrence and development of tumors. Among them, gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. According to the current GIST diagnostic criteria, epidemiological studies have shown an incidence rate of 0.66 to 2.20 per 100,000. GIST is extremely insensitive to traditional chemotherapy, the effective rate of chemotherapy drugs is less than 5%, and the median survival rate in the advanced stage is only about 18 months. Even if the tumor is completely removed, the 5-year survival rate of GIST is only 35%-65%, and the recurrence and metastasis rate within 2 years is 40%-50%, and as many as 15%-50% of patients have metastasis at the first diagnosis. Studies have found that the functional activating mutations of the transmembrane tyrosine kinase receptor c-KIT on the surface of stem cell factors and the platelet-derived growth factor receptor PDGFRα genes are the key to the development of GIST. Platelet-derived growth factor receptor (PDGF-R) is a cell surface tyrosine kinase receptor of a member of the platelet-derived growth factor (PDGF) family. PDGF subunits PDGFα and PDGFβ are important regulators that regulate cell proliferation, cell differentiation, cell growth, development and many diseases, including cancer.

With the clinical application of the first-generation inhibitor Imatinib, the problem of acquired resistance of Imatinib has gradually become a serious challenge in the clinical use of this type of inhibitor. Therefore, it is urgent to research and develop new c-KIT inhibitors to meet market demand. A series of c-KIT inhibitor patents have been published, including WO2014039714, WO2014100620, WO2015134536A1 and WO2013184119, etc. The research and application of c-KIT inhibitors have made certain progress, but the room for improvement is still huge and there is still a need Continue to research and develop new c-KIT inhibitors.

In order to overcome the shortcomings of the conventional technology, the purpose of the present invention is to provide a new class of 1,2-dihydro-1,6-naphthyridine derivatives represented by general formula (I), or its stereoisomers Compounds, tautomers, or pharmaceutically acceptable salts thereof, the compounds of the present invention have large structural differences with those specifically disclosed in the prior art, and can be used to treat or prevent gastrointestinal and gastrointestinal compounds by regulating the activity of c-KIT and PDGFα. Tract stromal tumor, acute myeloid leukemia and systemic mast cell hyperplasia diseases.

The compound represented by the general formula (I) of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

Wherein: R ^{1 is} selected from a hydrogen atom, an alkyl group or -C(O)R ⁵ , wherein the alkyl group is optionally further selected from halogen, hydroxyl, alkoxy, cycloalkyl, and heterocycle. Base, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ is substituted by a substituent; R ^{2 is} selected from alkyl, wherein the alkyl is further substituted with one or more halogens; R ^{3 is the} same or different, each independently Selected from hydrogen atom, alkyl group, alkoxy group, hydroxyl group, cyano group, nitro group, halogen, cycloalkyl, heterocyclic group, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O )OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ , wherein the alkyl group, alkoxy group Group, cycloalkyl or heterocyclic group is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ is substituted with a substituent; R ^{4 is} selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further selected from alkyl by one or more , Alkoxy, hydroxy, cyano, nitro, halogen, cycloalkyl, heterocyclyl, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ is substituted by a substituent; wherein the alkyl or alkoxy group is any Optionally further substituted by one or more halogens; R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocycle Group, aryl group or heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro , Cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituted by a substituent; or, R ⁶ and R ⁷ are The connected N atoms together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O or S(O) _n , and the 4- to 8-membered heterocyclic ring may optionally further By one or more selected from hydroxyl, halogen, nitro , Cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O) R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituted by substituents; R ⁸ , R ⁹ And R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate M is selected from 1, 2, 3, or 4; and n is selected from 0, 1, or 2.

In a preferred embodiment of the present invention, a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof is a compound of general formula (II) or its stereoisomers Isomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: R ^{3 is} selected from hydrogen atom, alkyl group, alkoxy group, hydroxyl group, cyano group, nitro group, halogen, cycloalkyl group, heterocyclic group, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ , wherein the alkane Group, alkoxy, cycloalkyl or heterocyclic group is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl , Heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ is substituted; R ¹ , R ² , R ⁴ to R ¹⁰ and n are as defined in the general formula (I).

In a preferred embodiment of the present invention, a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R ^{1 is} selected from hydrogen atom or C _1-4 alkyl, wherein the C _1-4 alkyl is optionally further substituted by one or more C _1-6 alkoxy; wherein the C _1-6 alkoxy is preferably methoxy base.

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R ^{2 is} selected from C _1-4 Alkyl group, wherein the C _1-4 alkyl group is further substituted by one or more halogens; wherein the halogen is preferably fluorine, chlorine or bromine; more preferably fluorine.

In a preferred embodiment of the present invention, a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ² is trifluoroethyl.

In a preferred embodiment of the present invention, a compound of general formula (I) or (II) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R ^{3 is} selected from hydrogen atom, C _1-4 alkyl or halogen; wherein the C _1-4 alkyl is preferably methyl or ethyl; and the halogen is preferably fluorine, chlorine or bromine.

In a preferred embodiment of the present invention, a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R ^{4 is} selected from phenyl or benzene And thienyl group, wherein said phenyl or benzothienyl group is optionally further substituted by one or more substituents selected from halogen, C _1-4 alkyl or C _1-6 alkoxy; wherein said The C _1-4 alkyl group or C _1-6 alkoxy group is optionally further substituted with one or more halogens; wherein the C _1-4 alkyl group is preferably methyl or ethyl; and wherein The halogen of is preferably fluorine, chlorine or bromine; more preferably fluorine.

In a preferred embodiment of the present invention, a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R ^{1 is} selected from hydrogen atom or alkane Group, preferably C _1-4 alkyl, wherein said alkyl is optionally further substituted by one or more C _1-6 alkoxy; wherein said C _1-6 alkoxy is preferably methyl Oxy.

R ^{2 is} selected from an alkyl group, wherein the alkyl group is further substituted by one or more halogens; preferably the alkyl group is a C _1-4 alkyl group, more preferably an ethyl group; the halogen is preferably fluorine, Chlorine or bromine, more preferably fluorine.

R ^{3 is} selected from a hydrogen atom, an alkyl group or a halogen, wherein the alkyl group is optionally further substituted with one or more halogens; the alkyl group is preferably a C _1-4 alkyl group, more preferably methyl or ethyl And the halogen is preferably fluorine, chlorine or bromine.

R ^{4 is} selected from phenyl or benzothienyl, wherein said phenyl or benzothienyl is optionally further substituted with one or more substituents selected from halogen, alkyl or alkoxy; wherein said The alkyl or alkoxy group of is optionally further substituted with one or more halogens; the alkyl group is preferably a C _1-4 alkyl group; the alkoxy group is preferably a C _1-6 alkoxy group; and The halogen is preferably fluorine, chlorine or bromine; more preferably fluorine.

Typical compounds of the present invention include, but are not limited to:

Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (IA) and the compound of general formula (IB) are reacted under basic conditions to obtain the compound of general formula (I); wherein: R ¹ to R ⁴ and m are defined as described in general formula (I).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, Preferably two different Propyl ethylamine or triethylamine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably cesium carbonate or potassium carbonate.

The present invention provides a method for preparing a compound of general formula (II) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of the general formula (IIA) and the compound of the general formula (IB) are reacted under basic conditions to obtain the compound of the general formula (II); wherein: R ¹ to R ⁴ are defined as described in the general formula (II).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, Preferably it is diisopropylethylamine and/or triethylamine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably cesium carbonate and/or potassium carbonate.

Furthermore, the present invention provides an intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: R ¹ to R ³ and m are defined as described in the general formula (I).

The present invention provides an intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is the intermediate compound of general formula (IIA) or its stereoisomers Isomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: R ¹ to R ³ are defined as described in the general formula (II).

Typical intermediate compounds of the general formula (IA) of the present invention include, but are not limited to:

Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

The present invention provides a method for preparing an intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (Ia) and the compound of general formula (Ib) are subjected to a condensation reaction under heating to obtain a compound of general formula (Ic); the compound of general formula (Ic) and the compound of general formula (Id) are reacted under heating, general formula (IA), intermediate compound; wherein: X is halogen; R ^a is alkyl; and the R ¹ ~ R ³ and m are as defined for formula (IA) the, and R ¹ is not a hydrogen atom .

The present invention provides a method for preparing an intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (Ia) and the compound of general formula (Ib) are subjected to a condensation reaction under heating to obtain a compound of general formula (Ic); the compound of general formula (Ic) and the compound of general formula (Ie) are condensed under heating the reaction to give the compound of formula (If); the general formula (If) compound in the presence of trifluoroacetic acid, to give the intermediate compound of formula (IA); wherein: X is halogen; R ¹ is a hydrogen atom; R ^a Is an alkyl group; R ^b is an alkyl group; and R ² , R ³ and m are as defined in the general formula (IA).

The present invention provides a method for preparing an intermediate compound of general formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (Ia) and the compound of general formula (IIa) are subjected to a condensation reaction under heating to obtain a compound of general formula (IIb); the compound of general formula (IIb) and the compound of general formula (Id) are reacted under heating, An intermediate compound of the general formula (IIA) is obtained; wherein: X is a halogen; R ^a is an alkyl group; and R ¹ to R ³ are as defined in the general formula (IIA), and R ^{1 is} not a hydrogen atom.

The present invention provides a method for preparing an intermediate compound of general formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (Ia) and the compound of general formula (IIa) are subjected to a condensation reaction under heating to obtain a compound of general formula (IIb); the compound of general formula (IIb) and the compound of general formula (Ie) are subjected to condensation reaction under heating to give the compound of formula (IIc); (IIc) compound of formula in the presence of trifluoroacetic acid was reacted to give the intermediate compound of formula (IIA); and wherein: X is halogen; R ¹ is a hydrogen atom; R ^a is an alkyl R ^b is an alkyl group; and R ² and R ³ are as defined in the general formula (IIA).

Furthermore, the present invention provides a pharmaceutical composition which contains an effective dose of the compound of general formula (I) or (II) or its stereoisomers, tautomers or its pharmaceutically acceptable , And pharmaceutically acceptable carriers, excipients, or combinations thereof.

The present invention provides a method for inhibiting c-KIT, which comprises combining a c-KIT receptor with a compound of general formula (I) or (II) or its stereoisomers, tautomers or its pharmaceutically acceptable Salt, or its pharmaceutical composition.

The present invention provides a compound of general formula (I) or (II) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of treatments caused by c-KIT or mutation The use of c-KIT-mediated diseases in medicines, wherein the diseases mediated by c-KIT or mutant c-KIT are preferably gastrointestinal stromal tumors, systemic mastocytosis, acute bone marrow Leukemia, ovarian cancer, melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; more preferably gastrointestinal stromal tumor, systemic Mast cell hyperplasia, glioblastoma multiforme and acute myelogenous leukemia, preferably gastrointestinal stromal tumor, glioblastoma multiforme and systemic mastocytosis; preferably the mutant c -KIT mutations are located at exons 9, 11, 13, 14, 17, and/or 18, or at the 816th, 670th, 560th and/or 654th amino acid residues, wherein the The mutation at amino acid residue 816 is preferably D816V or D816H; the mutation at amino acid residue 670 is preferably T670I; the mutation at amino acid residue 560 is preferably V560G; the mutation at amino acid residue 560 is preferably V560G; The mutation at amino acid residue 654 is preferably V654A.

The present invention provides a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition for preparing c-KIT inhibitors use.

The present invention provides a compound of general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the use of its pharmaceutical composition in the preparation of PDFGRα inhibitors.

The present invention provides a compound of general formula (I) or (II) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation and treatment of mutant or wild-type PDFGRα-mediated diseases, wherein the diseases mediated by mutant or wild-type PDFGRα are preferably gastrointestinal stromal tumors, systemic mastocytosis, acute myelogenous leukemia, ovarian cancer, Melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; more preferably gastrointestinal stromal tumor, systemic mastocytosis, multiple Shape Glioblastoma and acute myelogenous leukemia, preferably gastrointestinal stromal tumor, glioblastoma multiforme, and systemic mastocytosis; preferably the mutation of the mutant PDFGRα is located in exon 18 and/ Or at the 842th amino acid residue, the mutation at the 842th amino acid residue is preferably the D842V mutation.

The present invention provides a method for treating diseases mediated by c-KIT or mutant c-KIT, which comprises administering to a patient a therapeutically effective dose of a compound of general formula (I) or (II) or its stereoisomers, A tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the c-KIT or mutant c-KIT-mediated disease is preferably gastrointestinal stromal tumor, systemic mastocytosis , Acute myelogenous leukemia, ovarian cancer, melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; more preferably gastrointestinal stromal tumor , Systemic mastocytosis, glioblastoma multiforme and acute myelogenous leukemia, preferably gastrointestinal stromal tumor, glioblastoma multiforme and systemic mastocytosis; the mutations described therein The mutation of c-KIT is located at exon 9, 11, 13, 14, 17, and/or 18, or at the 816th, 670th, 560th and/or 654th amino acid residues, wherein the The mutation at the 816th amino acid residue is preferably D816V or D816H; the mutation at the 670th amino acid residue is preferably T670I; the mutation at the 560th amino acid residue is preferably V560G; The mutation at amino acid residue 654 of V654A is preferred.

The present invention provides a method for treating diseases mediated by PDFGRα or mutant PDFGRα, which comprises administering to a patient a therapeutically effective dose of a compound of general formula (I) or (II) or its stereoisomers or tautomers Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PDFGRα or mutant PDFGRα-mediated disease is preferably gastrointestinal stromal tumor, systemic mastocytosis, acute myelogenous leukemia, ovarian cancer , Melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; more preferably gastrointestinal stromal tumor, systemic hypertrophy Cell hyperplasia, glioblastoma multiforme and acute myelogenous leukemia, preferably gastrointestinal stromal tumor, glioblastoma multiforme and systemic mastocytosis; wherein the mutation of the mutant PDFGRα is located Exon 18 and/or the 842th amino acid residue, wherein the mutation at the 842th amino acid residue is preferably the D842V mutation.

Detailed description of the invention

Unless stated to the contrary, part of the terms used in the specification and the scope of the patent application of the present invention are defined as follows: "Alkyl" when regarded as a group or part of a group means including C ₁ -C ₂₀ straight chain or With branched aliphatic hydrocarbon groups. It is preferably a C ₁ -C ₁₀ alkyl group, and more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.

"Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched. Representative examples include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1- , 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.

"Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight or branched. Preferred are C ₂ -C ₁₀ alkynyl groups, more preferred are C ₂ -C ₆ alkynyl groups, most preferably C ₂ -C ₄ alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.

"Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused ring, bridged ring and spirocyclic carbocyclic ring, but none of the rings has a fully conjugated π-electron aromatic system. It is preferably a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, and most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl.

"Spirocyclyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other. One or more rings may contain One or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyls are classified into monospiro, dispiro or polyspirocycloalkyls, preferably monospiro and dispirocycloalkyls, preferably 4 members/5 members , 4 members/6 members, 5 members/5 members or 5 members/6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

"Fused ring group" refers to a 5- to 18-member, all-carbon polycyclic group containing two or more ring structures that share a pair of carbon atoms with each other. One or more rings may contain one or more double bonds, but An aromatic system in which none of the rings has fully conjugated π electrons is preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, pyridone or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-member/5-member or 5-member/6-member bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decahydronaphthyl or tetradecahydrophenanthryl.

"Bridged ring group" refers to 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups that are not directly connected to carbon atoms, one or more rings may contain one or more A double bond, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 To 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups can be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, in which one or more ring-forming atoms are heteroatoms, such as oxygen, Nitrogen, sulfur atoms, etc., including single rings, fused rings, bridged rings and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7 to 10-membered di- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Group, 2-oxo-pyridinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, pyrazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Pirazinyl. The heterocyclic group may be substituted or unsubstituted.

"Spiroheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other. The ring contains one or more double bonds, but no A ring has a fully conjugated π-electron aromatic system, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) _n (where n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the ring and the ring, the spirocyclic alkyl group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxa Heterosspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain one or more double bonds, but no ring has a complete A conjugated π-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _n (where n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicyclic fused heterocyclic group . Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine.

"Bridged heterocyclic group" refers to a polycyclic group with 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, and sharing two atoms that are not directly connected to each other. One or more rings may Aromatic systems containing one or more double bonds, but none of the rings have fully conjugated π electrons, where one or more ring atoms are selected from nitrogen, oxygen or S(O) _n (where n is selected from 0, 1 or 2) Heteroatoms, the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[2.2.2]octyl Cyclo[3.3.2]decyl. The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings can be joined together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred is phenyl. Aryl groups can be substituted or unsubstituted. The "aryl group" can be fused with a heteroaryl group, a heterocyclic group or a cycloalkyl group, wherein the aryl ring is connected to the parent structure. Non-limiting examples include but are not limited to:

"Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring or 9 to 10-membered bicyclic ring, which contains 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , Oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoin Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzo Isothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl groups can be substituted or unsubstituted. The heteroaryl ring may be fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include but are not limited to:

"Alkoxy" refers to (alkyl-O-) groups. Among them, the alkyl group is defined in this article. C ₁ -C ₆ alkoxy is preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Amino" refers to -NH ₂ .

"Cyano" refers to -CN.

"Nitro" refers to -NO ₂ .

"Benzyl" refers to -CH ₂ -phenyl.

"Carboxy" refers to -C(O)OH.

"Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as described above.

"DMSO" refers to dimethyl sulfoxide.

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those with ordinary knowledge in the art can determine (through experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

The "substituted" or "substituted" mentioned in this specification, unless otherwise specified, mean that the group can be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy , Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ .

R ⁵ , R ⁶ and R ⁷ are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein The alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O) NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituents; or, R ⁶ and R ⁷ together with the connected N atom form a 4~8 Membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O, S(O) _n atoms, and the 4- to 8-membered heterocyclic ring is optionally further selected by one or more selected from hydroxyl, halogen , Nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC (O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ are substituted.

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Group or heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxyl And n is selected from 0, 1, or 2.

"Pharmaceutically acceptable salt" refers to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by formula ( I ) may be an amine salt formed by a metal salt and a suitable acid.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

Synthetic method of the compound of the present invention

In order to accomplish the purpose of the present invention, the present invention adopts the following technical means: The preparation method of the compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof of the present invention includes the following steps :

The compound of general formula (Ia) and the compound of general formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of general formula (Ic); the compound of general formula (Ic) and the compound of general formula (Id) are reacted under heating to obtain formula (IA) compounds; a compound of formula (IA) and formula (IB) under basic conditions a compound of general formula (I) compound; wherein: X is halogen; R ^A is alkyl; and R ¹ to R ⁴ and m are as defined in the general formula (I), and R ^{1 is} not a hydrogen atom.

The method for preparing the compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof of the present invention includes the following steps:

The compound of general formula (Ic) and the compound of general formula (Ie) are subjected to condensation reaction under heating conditions to obtain the compound of general formula (If); the compound of general formula (If) is reacted in the presence of trifluoroacetic acid to obtain general formula (IA ); the compound of general formula (IA) and the compound of general formula (IB) are reacted under basic conditions to obtain the compound of general formula (I); wherein: X is a halogen; R ¹ is a hydrogen atom; R ^b is Alkyl; and R ² to R ⁴ are as defined in the general formula (I).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, Preferably it is diisopropylethylamine or triethylamine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably cesium carbonate or potassium carbonate.

The method for preparing the compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof of the present invention includes the following steps:

The compound of general formula (Ia) and the compound of general formula (IIa) are subjected to a condensation reaction under heating to obtain a compound of general formula (IIb); the compound of general formula (IIb) and the compound of general formula (Id) are reacted under heating, compounds of general formula (IIA); the compound of formula (IIA) with a compound of formula (IB) under basic conditions to give a compound of formula (II); wherein: X is halogen; R ^a is alkyl; R ¹ to R ⁴ are as defined in the general formula (II), and R ^{1 is} not a hydrogen atom.

In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methyl piperazine, 4-dimethylaminopyridine, Preferably it is diisopropylethylamine and/or triethylamine; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably cesium carbonate and/or potassium carbonate.

The method for preparing the compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof of the present invention includes the following steps:

The compound of general formula (IIb) and the compound of general formula (Ie) are reacted under heating to obtain the compound of general formula (IIc); the compound of general formula (IIc) is reacted in the presence of trifluoroacetic acid to obtain the intermediate of general formula (IIA) Compounds; reacting compounds of general formula (IIA) with compounds of general formula (IB) under basic conditions to obtain compounds of general formula (II); wherein: X is a halogen; R ¹ is a hydrogen atom; R ^b is an alkyl group; And the definitions of R ² to R ⁴ are as described in the general formula (II).

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example

The examples show the preparation of representative compounds represented by formula ( I ) and related structure identification data. It must be noted that the following examples are used to illustrate the present invention but not to limit the present invention. ^{The 1} H NMR spectrum was measured with a Bruker instrument (400MHz), and the chemical shift was expressed in ppm. Use tetramethylsilane internal standard (0.00ppm). ¹ H NMR expression method: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, its unit is Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization method can be ESI or APCI.

Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography (TLC)

The size of the silicone plate used is 0.15mm~0.2mm, and the size of the thin-layer chromatography separation and purification product is 0.4mm~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. The commercially available materials and reagents are not further purified. For direct use, unless otherwise instructed, commercial vendors including but not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd. purchase.

CD ₃ OD: Deuterated methanol.

CDCl ₃ : Deuterated chloroform.

DMSO- d ₆ : Deuterated dimethyl sulfoxide.

Argon means that the reaction flask is connected to an argon balloon with a volume of about 1L.

There is no special description in the examples, and the solution in the reaction refers to an aqueous solution.

To purify the compound, use silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: Dichloromethane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added to adjust, such as acetic acid or triethylamine.

Example 1

1-(4-Chloro-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-phenylurea

first step

6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinic acid ethyl ester

Ethyl 4,6-dichloronicotinate 1a (10.1g, 45.9mmol), 2,2,2-trifluoroethylamine (15.5g, 157mmol) and N,N-diisopropylethylamine (17.8g ,138mmol) was dissolved in 200mL of dimethyl adipate and reacted at 100°C for 8 hours. Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (extract: system A) to obtain ethyl 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinate 1b (4g, white solid), yield: 31%.

MS m/z(ESI): 282.9[M+1]

Second step

(6-Chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol

Dissolve 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinic acid ethyl ester 1b (4g, 14.18mmol) in 50mL tetrahydrofuran, add lithium aluminum tetrahydrogen in batches at -50℃ (1.89g, 51mmol), slowly increase the temperature to 0°C, and react at 0°C for 1.5 hours. 20mL 10% sodium hydroxide solution was slowly added dropwise to quench the reaction at 0°C, filtered, the filtrate was extracted with ethyl acetate (30mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30mL×2), and then washed with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain (6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol 1c (3.4g, yellow solid) as a product Rate: 100%.

MS m/z(ESI): 240.9[M+1]

third step

6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde

Combine (6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol 1c (3.4g, 14.18mmol) and active manganese dioxide (18.5g, 212.7mmol) Dissolve in 52 mL of dichloromethane and stir overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: system A) to obtain 6-chloro-4-((2,2,2-trifluoroethyl) Amino)nicotinaldehyde 1d (2.4 g, white solid), yield: 71%.

MS m/z(ESI): 238.9[M+1]

the fourth step

3-(5-Amino-2-chloro-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

Add 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde 1d (1g, 4.2mmol), 2-(5-amino-2-chloro-4-fluorophenyl)acetic acid Ethyl ester 1e (970mg, 4.2mmol, prepared according to published patent application WO2013184119), potassium carbonate (1.74g, 12.6mmol) were dissolved in 70mL of N,N-dimethylformamide and toluene (V: V=2: In the mixed solvent of 5), react at 150°C for 12 hours. 100mL ethyl acetate was added, washed with water (100mL×2) and saturated sodium chloride solution (100mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (washing Extract: System A) to obtain 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6- Naphthyridin-2(1H)-one 1f (870 mg, yellow solid), yield: 48%.

MS m/z(ESI): 405.8[M+1]

the fifth step

3-(5-Amino-2-chloro-4-fluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2( 1H)-ketone

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- Ketone 1f (300mg, 0.74mmol) and methylamine tetrahydrofuran solution (3mL, 6mmol) were dissolved in 20mL 1,4-dioxane and reacted in a sealed tube at 100°C for 16 hours. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 3-(5-amino-2-chloro-4-fluorophenyl)-7-(methylamino)- 1-(2,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 1g (150mg, yellow solid), yield: 50%.

MS m/z(ESI): 400.8[M+1]

Sixth step

1-(4-Chloro-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-phenylurea

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2 (1H)-ketone 1g (100mg, 0.25mmol), phenyl isocyanate 1h (33mg, 0.28mmol, prepared according to published patent application WO2005113626) and triethylamine (126mg, 1.25mmol) dissolved in 2mL of dichloromethane In, reaction at room temperature overnight. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-chloro-2-fluoro-5-(7-(methylamino)-2-oxo) -1-(2,2,2-Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea 1 (20mg, white solid) , Yield: 18%.

MS m/z(ESI): 520.1[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.17(s,1H), 8.76(s,1H), 8.46(s,1H), 8.21(d, J =8.8Hz,1H), 7.87(s,1H) ),7.56(d, J =10.8Hz,1H),7.43(d, J =8.4Hz,2H),7.28(t, J =7.2Hz,2H),7.21-7.20(m,1H),6.99(t , J =7.6Hz,1H), 6.37(s,1H), 5.13-5.11(m,2H), 2.87(d, J =4.8Hz,3H).

Example 2

1-(4-Chloro-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

1-(4-Chloro-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2 (1H)-ketone 1g (100mg, 0.25mmol), 1-fluoro-3-phenylisocyanate 2a (51mg, 0.375mmol) and triethylamine (75mg, 0.75mmol) were dissolved in 2mL of dichloromethane. Warm the reaction overnight. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-chloro-2-fluoro-5-(7-(methylamino)-2-oxo) -1-(2,2,2-Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea 2 ( 13mg, white solid), yield: 10%.

MS m/z(ESI): 537.9[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.35(s,1H),8.80(s,1H),8.45(s,1H), 8.19(d, J =6.8Hz,1H),7.87(s,1H) ), 7.58(d, J =11.2Hz, 1H), 7.48(d, J =10.8Hz, 1H), 7.32-7.29(m, 1H), 7.21(s, 1H), 7.10-7.08(m, 1H) ,6.81-6.79(m,1H), 6.37(s,1H), 5.76(s,1H), 5.13-5.09(m,1H), 2.87(d, J =4.8Hz,3H).

Example 3

1-(2-Fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

3-(5-Amino-4-fluoro-2-methylphenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- ketone

Add 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde 1d (1g, 4.2mmol), 2-(5-amino-4-fluoro-2-methylphenyl) Ethyl acetate 3a (890mg, 4.2mmol, prepared according to published patent application WO2013184119), potassium carbonate (1.74g, 12.6mmol) dissolved in 70mL N,N-dimethylformamide and toluene (V: V= 2:5) In the mixed solvent, react at 150°C for 8 hours. Add 50mL ethyl acetate, wash with water (50mL×2) and saturated sodium chloride solution (50mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is subjected to silica gel column chromatography (Elute: System A) Purify to obtain 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1 ,6-Naphthyridin-2(1H)-one 3b (620mg, yellow solid), yield: 39%.

MS m/z(ESI): 385.8[M+1]

Second step

3-(5-amino-4-fluoro-2-methylphenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2 (1H)-ketone

Add 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H) -Ketone 3b (620mg, 1.61mmol) and methylamine in tetrahydrofuran (6mL, 12mmol) were dissolved in 36mL of 1,4-dioxane and reacted in a sealed tube at 100°C for 48 hours. Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: system A) to obtain 3-(5-amino-4-fluoro-2-methylphenyl)-7-(methylamino) )-1-(2,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 3c (550 mg, yellow solid), yield: 89%.

MS m/z(ESI): 380.9[M+1]

third step

1-(2-Fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add 3-(5-amino-4-fluoro-2-methylphenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine- 2(1H)-ketone 3c (183mg, 0.48mmol), 1-fluoro-3-phenylisocyanate 2a (198mg, 1.44mmol) and triethylamine (243mg, 2.41mmol) dissolved in 20mL tetrahydrofuran, room temperature React overnight. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(2-fluoro-4-methyl-5-(7-(methylamino)-2- Oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea 3 (50 mg, white solid), yield: 20%.

MS m/z(ESI): 517.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.25(s,1H),8.57(s,1H),8.45(s,1H),7.95(d, J =8.4Hz,1H),7.79(s,1H) ),7.51-7.47(m,1H),7.33-7.27(m,1H),7.18-7.13(m,2H),7.07(d, J =7.6Hz,1H),6.79(dt, J =8.8,2.4 Hz, 1H), 6.37 (s, 1H), 5.14-5.12 (m, 2H), 2.86 (d, J=4.8 Hz, 3H), 2.08 (s, 3H).

Example 4

1-(2-Fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

first step

1-(2-Fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

Add 3-(5-amino-4-fluoro-2-methylphenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine- 2(1H)-ketone 3c (183mg, 0.48mmol), 1-fluoro-4-phenylisocyanate 4a (198mg, 1.44mmol) and triethylamine (243mg, 2.41mmol) dissolved in 20mL tetrahydrofuran, room temperature React overnight. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(2-fluoro-4-methyl-5-(7-(methylamino)-2- Oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea 4 (50 mg, white solid), yield: 20%.

MS m/z(ESI): 517.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.07(s,1H),8.50(s,1H),8.44(s,1H),7.95(d, J =8.4Hz,1H),7.78(s,1H) ),7.46-7.42(m,2H),7.17-7.09(m,4H),6.37(s,1H),5.14-5.12(m,2H),2.86(d, J =4.8Hz,3H),2.07( s, 3H).

Example 5

1-(2,4-Difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

3-(5-amino-2,4-difluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

Add 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde 1d (300mg, 1.26mmol), 2-(5-amino-2,4-difluorophenyl) ethyl acetate Ester 5a (271.7mg, 1.26mmol, prepared according to published patent application patent WO2013184119) and potassium carbonate (522mg, 3.78mmol) were dissolved in 28mL N,N-dimethylformamide and toluene (V: V=2: 5) In the mixed solvent, react at 150°C for 8 hours. Add 50mL ethyl acetate, wash with water (50mL×2) and saturated sodium chloride solution (50mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is subjected to silica gel column chromatography (Elute: System A) Purify to obtain 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6 -Naphthyridin-2(1H)-one 5b (237 mg, pale yellow solid), yield: 48%.

MS m/z(ESI): 389.8[M+1]

Second step

3-(5-amino-2,4-difluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H )-ketone

Add 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one 5b (237mg, 0.61mmol) and methylamine in tetrahydrofuran (3mL, 6mmol) were dissolved in 20mL 1,4-dioxane and reacted in a sealed tube at 100°C for 12 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (extract: System A) to obtain 3-(5-amino-2,4-difluorophenyl)-7-(methylamino)- 1-(2,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 5c (168mg, pale yellow solid), yield: 72%.

MS m/z(ESI): 384.9[M+1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.43 (s, 1H), 7.86 (s, 1H), 7.17 (d, J = 4.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.82(t, J =8.0Hz,1H), 6.34(s,1H), 5.11-5.09(m,2H), 5.04(s,2H), 2.85(d, J =4.0Hz,3H).

third step

1-(2,4-Difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add 3-(5-amino-2,4-difluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2( 1H)-ketone 5c (168mg, 0.44mmol), 1-fluoro-3-phenylisocyanate 2a (90mg, 0.66mmol) and triethylamine (727mg, 7.2mmol) dissolved in 10mL of dichloromethane at room temperature React overnight. Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (extract: System A) to obtain 1-(2,4-difluoro-5-(7-(methylamino)-2-oxo) -1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea 5 ( 4.5 mg, pale yellow solid), yield: 2%.

MS m/z(ESI): 521.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.32(s,1H),8.66(s,1H),8.46(s,1H),8.13(t, J =8.5Hz,1H),7.93(s,1H) ),7.49(d, J =11.8Hz,1H),7.41(t, J =10.3 Hz,1H),7.31(q, J =7.9Hz,1H),7.23(d, J =5.1Hz,1H), 7.10(d, J =8.2Hz,1H),6.80(t, J =8.1Hz,1H),6.37(s,1H),5.14-5.11(m,2H),2.87(d, J =4.7Hz,3H ).

Example 6

1-(2,4-Difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

first step

1-(2,4-Difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

Add 3-(5-amino-2,4-difluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2( 1H)-ketone 5c (300mg, 0.78mmol), 1-fluoro-4-phenylisocyanate 4a (321mg, 2.34mmol) and triethylamine (394mg, 3.9mmol) were dissolved in 20mL tetrahydrofuran and reacted overnight at room temperature . Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (extract: System A) to obtain 1-(2,4-difluoro-5-(7-(methylamino)-2-oxo) -1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea 6 ( 160 mg, white solid), yield: 39%.

MS m/z(ESI): 521.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.58(s,1H),8.83(s,1H),8.65(s,1H),8.40(s,1H), 8.18(t, J =8.4Hz,1H ), 8.10 (s, 1H), 7.86-7.45 (m, 3H), 7.13 (t, J = 8.4 Hz, 2H), 6.76 (s, 1H), 5.21 (s, 2H), 3.00 (s, 3H) .

Example 7

1-(4-Bromo-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-phenylurea

first step

3-(5-Amino-2-bromo-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

Add 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde 1d (600mg, 2.52mmol), 2-(5-amino-2-bromo-4-fluorophenyl)acetic acid Ethyl 7a (698mg, 2.52mmol, prepared according to published patent application WO2013184119) and potassium carbonate (1.04g, 7.56mmol) were dissolved in 70mL of N,N-dimethylformamide and toluene (V: V=2: In the mixed solvent of 5), react at 150°C for 12 hours. Add 100mL ethyl acetate, Washed with water (100mL×2), saturated sodium chloride solution (100mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (extractant: System A) Purification to obtain 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H )-Ketone 7b (660 mg, pale yellow solid), yield: 58%.

MS m/z(ESI): 449.7[M+1]

Second step

3-(5-amino-2-bromo-4-fluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2( 1H)-ketone

Add 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- Ketone 7b (160mg, 0.35mmol) and methylamine tetrahydrofuran solution (1.5mL, 3mmol) were dissolved in 5mL 1,4-dioxane, and reacted in a sealed tube at 100°C for 8 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 3-(5-amino-2-bromo-4-fluorophenyl)-7-(methylamino) -1-(2,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 7c (123 mg, yellow solid), yield: 78%.

MS m/z(ESI): 444.8[M+1]

third step

1-(4-Bromo-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1 ,6-Naphthyridin-3-yl)phenyl)-3-phenylurea

Add 3-(5-amino-2-bromo-4-fluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2 (1H)-ketone 7c (114mg, 0.26mmol), phenyl isocyanate 1h (34mg, 0.28mmol) and triethylamine (130mg, 1.28mmol) were dissolved in 20mL of toluene and dichloromethane (V:V=1: In the mixed solution of 1), react overnight at room temperature. Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (extract: System A) to obtain To 1-(4-bromo-2-fluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro- 1,6-Naphthyridin-3-yl)phenyl)-3-phenylurea 7 (20 mg, white solid), yield: 12%.

MS m/z(ESI): 563.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.16(s,1H), 8.76(s,1H), 8.45(s,1H), 8.22(d, J =8.8Hz,1H), 7.84(s,1H) ),7.69(d, J =10.8Hz,1H),7.43(d, J =7.6Hz,2H),7.28(t, J =7.6Hz,2H),7.22-7.20(m,1H),6.99(t , J = 7.2Hz, 1H), 6.37 (s, 1H), 5.14-5.11 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H).

Example 8

1-(Benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2, 2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea

first step

Benzo[b]thiophene 3-isocyanate

Benzo[b]thiophene-3-carboxylic acid 8a (500mg, 2.8mmol) and triethylamine (319mg, 3.2mmol) were dissolved in 10mL of toluene, and stirred at room temperature until all 8a was dissolved. Add diphenyl azide phosphate (847 mg, 3.1 mmol), react at 50°C for 1 hour, and continue to react at 100°C for 0.5 hour. Concentrated under reduced pressure to obtain the crude product 3-isocyanate benzo[b]thiophene ester 8b (490 mg, colorless oil), yield: 100%.

Second step

1-(Benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(7-(methylamino)-2-oxo-1-(2,2, 2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea

Add 3-(5-amino-4-fluoro-2-methylphenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine- 2(1H)-ketone 3c (183mg, 0.48mmol), 3-isocyanate benzo[b]thiophene 8b (252mg, 1.44mmol) and triethylamine (243mg, 2.41mmol) were dissolved in 20mL tetrahydrofuran, Warm the reaction overnight. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl) Base-5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl )Phenyl)urea 8 (60 mg, yellow solid), yield: 22%.

MS m/z(ESI): 555.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.42(s,1H),8.86(s,1H),8.46(s,1H),8.10(d, J =8.8Hz,1H),7.97(d, J =8.0Hz,1H),7.89(d, J =8.4Hz,1H),7.81(s,1H),7.70(s,1H),7.51(t, J =6.4Hz,1H),7.43(t, J =8.0Hz,1H),7.20(d, J =12Hz,1H),7.15-7.13(m,1H),6.38(s,1H),5.15-5.10(m,2H),2.87(d, J =4.8 Hz, 3H), 2.09 (s, 3H).

Example 9

1-(Benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2- (Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea

first step

1-(Benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-(2,2,2- (Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea

Add 3-(5-amino-2,4-difluorophenyl)-7-(methylamino)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2( 1H)-ketone 5c (200mg, 0.52mmol), benzo[b]thiophene 3-isocyanate 8b (91mg, 0.52mmol) and triethylamine (157mg, 1.56mmol) were dissolved in 5mL tetrahydrofuran and reacted at room temperature overnight. Concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: System A) to obtain 1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro- 5-(7-(methylamino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)benzene Yl)urea 9 (50 mg, white solid), yield: 17%.

MS m/z(ESI): 559.8[M+1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 8.89 (s, 1H), 8.48 (s, 1H), 8.28 (t, J = 8.4 Hz, 1H), 7.99-7.96 (m ,2H),7.89(d, J =8.0Hz,1H),7.71(s,1H),7.51(t, J =7.6Hz,1H),7.46-7.41(m,2H),7.23-7.20(m, 1H), 6.37 (s, 1H), 5.14-5.09 (m, 2H), 2.87 (d, J = 4.8Hz, 3H).

Example 10

1-(4-Bromo-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

3-(5-amino-2-bromo-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1, 6-naphthyridin-2(1H)-one

Add 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- Ketone 7b (340mg, 0.76mmol), 2-methoxyethylamine (568mg, 7.57mmol) and 1,8-diazabicycloundec-7-ene (DBU) (230mg, 1.51mmol) are dissolved in In 7 mL of N-methylpyrrolidone, react in microwave at 180°C for 1.5 hours. Add 70 mL of water, extract with dichloromethane (100 mL×2), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is layered with a silica gel column Analytical method (extract: A system) to obtain 3-(5-amino-2-bromo-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2 ,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 10a (370mg, yellow oil), yield: 100%.

MS m/z(ESI): 488.8[M+1]

Second step

1-(4-Bromo-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add 3-(5-amino-2-bromo-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1 ,6-Naphthyridine-2(1H)-one 10a (100mg, 0.21mmol), 1-fluoro-3-phenylisocyanate 2a (42mg, 0.31mmol) and triethylamine (62mg, 0.62mmol) are dissolved in In 3 mL of dichloromethane, react overnight at room temperature. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-bromo-2-fluoro-5-(7-((2-methoxyethyl)) Amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3- Fluorophenyl)urea 10 (30 mg, white solid), yield: 23%.

MS m/z(ESI): 625.7[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.36(s,1H),8.81(s,1H),8.45(s,1H), 8.18(d, J =8.8Hz,1H),7.83(s,1H) ),7.71(d, J =10.4Hz,1H),7.48(d, J =12.4Hz,1H),7.31(q, J =8.4Hz,1H),7.27-7.23(m,1H),7.08(d , J =8.0Hz,1H),6.81(t, J =8.8Hz,1H),6.51(s,1H),5.06-5.04(m,2H),3.53-3.50(m,4H),3.29(s, 3H).

Example 11

1-(4-Bromo-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

first step

1-(4-Bromo-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

Add 3-(5-amino-2-bromo-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1 ,6-Naphthyridine-2(1H)-one 10a (100mg, 0.21mmol), 1-fluoro-4-phenylisocyanate 4a (42mg, 0.31mmol) and triethylamine (62mg, 0.62mmol) are dissolved in In 3 mL of dichloromethane, react overnight at room temperature. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-bromo-2-fluoro-5-(7-((2-methoxyethyl)) Amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4- Fluorophenyl)urea 11 (10 mg, white solid), yield: 8%.

MS m/z(ESI): 625.7[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.21(s,1H),8.76(s,1H),8.44(s,1H), 8.19(d, J =8.4Hz,1H),7.83(s,1H) ), 7.69(d, J =10.8Hz,1H),7.46-7.43(m,2H),7.25-7.24(m,1H),7.13(t, J =8.8Hz,2H),6.50(s,1H) , 5.07-5.02 (m, 2H), 3.53-3.50 (m, 4H), 3.29 (s, 3H).

Example 12

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

3-(5-amino-2-chloro-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1, 6-naphthyridin-2(1H)-one

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- Ketone 1f (400mg, 1mmol), 2-methoxyethylamine (750mg, 10mmol) and 1,8-diazabicycloundec-7-ene (DBU) (304mg, 2mmol) dissolved in 8mL N- In methylpyrrolidone, microwave reaction at 180°C for 1 hour. Add 100 mL of water, extract with dichloromethane (50 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is purified by silica gel column chromatography (extractant: System A) , To obtain 3-(5-amino-2-chloro-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)- 1,6-naphthyridin-2(1H)-one 12a (400mg, yellow oil), yield: 90%.

MS m/z(ESI): 444.9[M+1]

Second step

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1 ,6-Naphthyridine-2(1H)-one 12a (70mg, 0.16mmol), 1-fluoro-3-phenylisocyanate 2a (26mg, 0.19mmol) and triethylamine (48mg, 0.47mmol) were dissolved in 3mL of dichloromethane and reacted overnight at room temperature. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)) Amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3- Fluorophenyl)urea 12 (9 mg, white solid), yield: 10%.

MS m/z(ESI): 581.8[M+1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.36 (s, 1H), 8.80 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.86 (s, 1H) ), 7.58(d, J =10.8Hz,1H), 7.50-7.43(m,2H), 7.31(q, J =6.8Hz,1H), 7.08(d, J =8.4Hz,1H), 6.83-6.79 (m, 1H), 6.51 (s, 1H), 5.06-5.03 (m, 2H), 3.51-3.50 (m, 4H), 3.29 (s, 3H).

Example 13

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

first step

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluorophenyl)urea

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1 ,6-Naphthyridin-2(1H)-one 12a (100mg, 0.225mmol), 1-fluoro-4-phenylisocyanate 4a (37mg, 0.27mmol) and triethylamine (68mg, 0.675mmol) were dissolved in 3mL of dichloromethane and reacted overnight at room temperature. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)) Amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4- Fluorophenyl)urea 13 (9 mg, white solid), yield: 10%.

MS m/z(ESI): 581.8[M+1]

¹ H NMR(400MHz, DMSO- d ₆ ) δ 9.15(s,1H), 8.71(s,1H), 8.45(s,1H), 8.19(d, J =8.8Hz,1H), 7.86(s,1H) ), 7.57(d, J =11.2Hz,1H),7.46-7.43(m,2H),7.25-7.23(m,1H),7.13(d, J =8.8Hz,2H),6.51(s,1H) ,5.06-5.04(m,2H),3.53-3.48(m,4H), 3.29(s,3H).

Example 14

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

first step

1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1 ,2-Dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-((2-methoxyethyl)amino)-1-(2,2,2-trifluoroethyl)-1 , 6-naphthyridin-2(1H)-one 12a (100mg, 0.225mmol), 1-isocyanate-4-(trifluoromethyl)phenyl ester 14a (50mg, 0.27mmol) and triethylamine (68mg, 0.675mmol) was dissolved in 3mL of dichloromethane and reacted overnight at room temperature. Concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: System A) to obtain 1-(4-chloro-2-fluoro-5-(7-((2-methoxyethyl)) Amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4- (Trifluoromethyl)phenyl)urea 14 (16 mg, white solid), yield: 11%.

MS m/z(ESI): 631.8[M+1]

¹ H NMR(400MHz, DMSO- d ₆ )δ 9.67(s,1H), 8.91(s,1H), 8.45(s,1H), 8.18(d, J =8.4Hz,1H), 7.87(s,1H) ), 7.64(s, 4H), 7.59(d, J =11.2Hz, 1H), 7.25-7.24(m, 1H), 6.51(s, 1H), 5.06-5.04(m, 2H), 3.53-3.50( m,4H),3,29(s,3H).

Example 15

( R )-1-(4-chloro-2-fluoro-5-(7-((1-methoxyprop-2-yl)amino)-2-oxo-1-(2,2,2- (Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

first step

(R)-3-(5-amino-2-chloro-4-fluorophenyl)-7-((1-methoxyprop-2-yl)amino)-1-(2,2,2-tri Fluoroethyl)-1,6-naphthyridin-2(1H)-one

Add 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2(1H)- Ketone 1f (202mg, 0.4mmol), (R)-1-methoxypropan-2-amine (223mg, 2.5mmol) and 1,8-diazabicycloundec-7-ene (DBU) ( 152mg, 1mmol) dissolved in 4mL N-methylpyrrolidone, Microwave reaction at 180°C for 1.5 hours. Add 40 mL of water, extract with dichloromethane (30 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is purified by silica gel column chromatography (extractant: System A) To obtain (R)-3-(5-amino-2-chloro-4-fluorophenyl)-7-((1-methoxyprop-2-yl)amino)-1-(2,2,2 -Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 15a (229 mg, yellow solid), yield: 100%.

MS m/z(ESI): 458.9[M+1]

Second step

(R)-1-(4-chloro-2-fluoro-5-(7-((1-methoxyprop-2-yl)amino)-2-oxo-1-(2,2,2- (Trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea

Add ( R )-3-(5-amino-2-chloro-4-fluorophenyl)-7-((1-methoxyprop-2-yl)amino)-1-(2,2,2- Trifluoroethyl)-1,6-naphthyridine-2(1H)-one 15a (100mg, 0.22mmol), 1-fluoro-3-phenylisocyanate 2a (45mg, 0.33mmol) and triethylamine ( 66mg, 0.65mmol) was dissolved in 2mL of dichloromethane and reacted at room temperature overnight. Concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography (developing solvent: System A) to obtain ( R )-1-(4-chloro-2-fluoro-5-(7-((1-methoxy Propyl-2-yl)amino)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl )-3-(3-Fluorophenyl)urea 15 (12 mg, white solid), yield: 10%.

MS m/z(ESI): 595.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.38(s,1H),8.81(s,1H),8.44(s,1H),8.18(d, J =8.4Hz,1H),7.85(s,1H) ),7.58(d, J =10.8Hz,1H),7.48(d, J =11.6Hz,1H),7.32-7.29(m,1H),7.11-7.08(m,2H),6.83-6.79(m, 1H), 6.48 (m, 1H), 5.06-5.034 (m, 2H), 4.25-4.22 (m, 1H), 3.53-3.50 (m, 2H), 3.30 (s, 3H), 1.16 (d, J = 7.2Hz, 3H).

Example 16

1-(5-(7-amino-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-Difluorophenyl)-3-(4-fluorophenyl)urea

first step

3-(5-amino-2,4-difluorophenyl)-7-((4-methoxybenzyl)amino)-1-(2,2,2-trifluoroethyl)-1,6 -Naphthyridin-2(1H)-one

Add 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one 5b (500mg, 1.28mmol) was dissolved in 5mL 4-methoxybenzylamine 16a and reacted overnight at 130°C. After the reaction, it was cooled to room temperature, 10 mL of a mixed solvent of ethyl acetate and water (V:V=1:1) was added, and the mixture was stirred at room temperature for 30 minutes. Extracted with ethyl acetate (30mL×2), combined the organic phases, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to a silica gel column Chromatography (extract: System A) to obtain 3-(5-amino-2,4-difluorophenyl)-7-((4-methoxybenzyl)amino)-1-(2 ,2,2-Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 16b (375 mg, pale yellow solid), yield: 60%.

MS m/z(ESI): 490.9[M+1]

Second step

7-Amino-3-(5-amino-2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

The 3-(5-amino-2,4-difluorophenyl)-7-((4-methoxybenzyl)amino)-1-(2,2,2-trifluoroethyl)-1, 6-Naphthyridin-2(1H)-one 16b (375 mg, 0.76 mmol) was dissolved in 4 mL of trifluoroacetic acid and reacted at 60°C overnight. After the reaction, cool to room temperature, concentrate under reduced pressure, add saturated sodium bicarbonate solution (20mL) at 0°C, extract with ethyl acetate (30mL×2), combine the organic phases, and use saturated sodium chloride solution (30mL) Washed, dried with anhydrous sodium sulfate, filtered, and concentrated under pressure. The obtained residue was purified by silica gel column chromatography (extractant: System A) to obtain 7-amino-3-(5-amino-2,4- Difluorophenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one 16c (200 mg, pale yellow solid), yield: 71%.

MS m/z(ESI): 370.9[M+1]

third step

1-(5-(7-amino-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-Difluorophenyl)-3-(4-fluorophenyl)urea

Dissolve triethylamine (40.4mg, 0.4mmol) in 1mL tetrahydrofuran, add 7-amino-3-(5-amino-2,4-difluorophenyl)-1-(2,2,2) at 0℃ -Trifluoroethyl)-1,6-naphthyridine-2(1H)-one 16c (50mg, 0.1mmol), then 1-fluoro-4-phenyl isocyanate 4a (13.7mg, 0.1mmol) , React overnight at room temperature. After the reaction, it was concentrated under reduced pressure, and the residue obtained was separated and purified by preparative chromatography to obtain 1-(5-(7-amino -2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl )-3-(4-Fluorophenyl)urea 16 (9 mg, pale yellow solid), yield: 15%.

MS m/z(ESI): 507.8[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.10(s,1H), 8.58(s,1H), 8.42(s,1H), 8.10(t, J =12.0Hz,1H), 7.94(s,1H) ), 7.47-7.37(m,3H), 7.12(t, J =8.0Hz,2H), 6.78(s,2H), 6.42(s,1H), 5.01(d, J =8.0Hz,2H).

Example 17

1-(5-(7-amino-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-Difluorophenyl)-3-(3-fluorophenyl)urea

first step

1-(5-(7-amino-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-Difluorophenyl)-3-(3-fluorophenyl)urea

Dissolve triethylamine (54.6mg, 0.54mmol) in 3mL tetrahydrofuran, add 7-amino-3-(5-amino-2,4-difluorophenyl)-1-(2,2,2 at 0℃) -Trifluoroethyl)-1,6-naphthyridin-2(1H)-one 16c(100 mg, 0.27mmol), then 1-fluoro-3-phenylisocyanate 2a (40.76mg, 0.29mmol) was added dropwise, and reacted overnight at room temperature. After the reaction, it was concentrated under reduced pressure, and the residue obtained was separated and purified by preparative chromatography to obtain 1-(5-(7-amino-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-Dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea 17 (54 mg, white solid), produced Rate: 41%.

MS m/z(ESI): 507.9[M+1]

¹ H NMR(400MHz,DMSO- d ₆ )δ 9.31(s,1H),8.68(s,1H),8.48(s,1H),8.10(t, J =8.0Hz,1H),7.99(s,1H) ), 7.51-7.40(m,2H),7.34-7.28(q, J =8.0Hz,1H), 7.10(d, J =8.0Hz,3H), 6.82-6.78(m,1H), 6.53(s, 1H),5.04(d, J =8.0Hz,2H).

Biological evaluation

Test Example 1. Determination of the compound of the present invention on the activity of recombinant human c-KIT[D816V] kinase

The following method is used to determine the degree of inhibition of the kinase activity of recombinant human c-KIT [D816V] (D816V mutation) by the compounds of the present invention under in vitro conditions.

This method uses Cisbio’s HTRF®KinEASE-TK Tyrosine Kinase Kit (Cat. No. 62TK0PEB). The principle of the kit is based on time-resolved fluorescence energy resonance transfer (TF-FRET), which measures protein-mediated biotinylation The degree of phosphorylation of the peptide substrate reflects the strength of the compound’s inhibition of protein kinase activity. For detailed experimental operations, please refer to the kit instructions. Recombinant human c-KIT[D816V] protein kinase was purchased from Carna bioscience (Japan, the product number is c-KIT[D816V]#08-505).

The experimental procedure is briefly described as follows: the test compound (the compounds listed in Table 1) is first dissolved in DMSO to prepare a storage solution, and then diluted with the buffer provided in the kit. The final test compound in the reaction system The concentration range is 10μM~0.1nM. The concentration of the ATP solution used in the test (Sangong Bioengineering (Shanghai) Co., Ltd., #A600311) is the pre-determined ATP Km concentration corresponding to each kinase, and the ATP Km concentration of c-KIT[D816V] is 30μM . The reaction was carried out in a 384-well microtiter plate. First, the test compound and 0.66 ng of the test protein were added to the empty wells, and incubated at room temperature for 5 minutes, and then ATP solution and biotinylated peptide receptor were added to the reaction solution. After incubating for 50 minutes with shaking at room temperature, add anti-phosphotyrosine antibody coupled with europium compound and streptavidin coupled with modified allophycocyanin XL665 to the reaction , And continue to incubate with shaking for 1 hour at room temperature. After the incubation, the fluorescence intensity value of each well at the excitation wavelength of 304nm, emission wavelength of 620nm and 665nm was measured in the microplate reader in TF-FRET mode. Calculate the percentage inhibition rate of the compound at each concentration by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and use GraphPad Prism 5 software to perform a nonlinear regression analysis of the compound concentration vs. the inhibition rate to obtain the compound The IC ₅₀ value is shown in Table 1.

Conclusion: The compound of the present invention has a good inhibitory effect on c-KIT D816V.

Remarks: Imatinib was purchased from Jingyan Chemical (CAS: 152459-95-5, purity: 98.87%, batch number 1604105, off-white solid); reference compounds 1, 2 and 3 are respectively Example 31 and Examples disclosed in WO2013184119 59 and the compound prepared in Example 15; the specific structure is as follows:

For its preparation method and structure identification, refer to Example 31, Example 59 and Example 15 of WO2013184119 respectively; for the preparation method of Reference Compound 4, refer to Example 15 of WO2013184119. The structure identification is as follows: MS m/z(ESI): 468.8[M+1]; ¹ H NMR(400MHz,DMSO- d ₆ )δ 9.07(s,1H),8.55(s,1H),8.45(s,1H),8.12(t, J =12.0Hz,1H ), 7.84(s,1H),7.45-7.35(m,3H),7.15-7.08(m,3H), 6.25(s,1H), 4.16(q, J =4.0Hz,2H), 2.88(d, J =8.0Hz,3H),1.23(t, J =4.0Hz,3H).

Test Example 2. Determination of the kinase activity of the compounds of the present invention on recombinant human c-KIT[T670I] and c-KIT[V560G/D816V]

The following method is used to determine the degree of inhibition of the kinase activity of recombinant human c-KIT[T670I] and c-KIT[V560G/D816V] protein kinases under in vitro conditions by the compounds of the present invention.

This method uses Cisbio’s HTRF®KinEASE-TK Tyrosine Kinase Kit (Cat. No. 62TK0PEB). The principle of the kit is based on time-resolved fluorescence energy resonance transfer (TF-FRET), which measures protein-mediated biotinylation The degree of phosphorylation of the peptide substrate reflects the strength of the compound's inhibition of protein kinase activity. For detailed experimental operations, please refer to the kit instructions. Recombinant human c-KIT[T670I] protein kinase and c-KIT[V560G/D816V] were purchased from Carna bioscience (Japan, the catalog number is c-KIT[T670I]#08-195 and c-KIT[V560G/D816V#08- 535).

The experimental procedure is briefly described as follows: the test compound (the compound described in Table 2) is first dissolved in DMSO to prepare a storage solution, and then diluted with the buffer provided in the kit, and the final concentration of the test compound in the reaction system The range is 10μM~0.1nM. The concentration of the ATP solution used in the test (Sangong Bioengineering (Shanghai) Co., Ltd., #A600311) is the pre-determined ATP Km concentration corresponding to each kinase, and the ATP Km concentration of c-KIT[T670I] is 30μM , C-KIT[V560G/D816V] has an ATP Km concentration of 10μM. The reaction is carried out in a 384-well microtiter plate. First, add the test compound and the test protein (c-KIT[T670I]0.66ng or c-KIT[V560G/D816V]0.03ng) to the empty wells, and at room temperature Incubate for 5 minutes, then add ATP solution and biotinylated polypeptide substrate solution to the reaction solution, and incubate with shaking at room temperature for 50 minutes, then add anti-phosphotyrosine coupled with europium compound to the reaction Acid antibody and streptavidin coupled with modified allophycocyanin XL665 were incubated for 1 hour with shaking at room temperature. After the incubation, the fluorescence intensity value of each well at the excitation wavelength of 304nm, emission wavelength of 620nm and 665nm was measured in the microplate reader in TF-FRET mode. Calculate the percentage inhibition rate of the compound at each concentration by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and use GraphPad Prism 5 software to perform a nonlinear regression analysis of the compound concentration vs. the inhibition rate to obtain the compound The IC ₅₀ value is shown in Table 2.

Conclusion: The compound of the present invention has a good inhibitory effect on c-KIT T760I and c-KIT V560G/D816V.

Test Example 3. Determination of the compound of the present invention on the kinase activity of recombinant human PDFGRα[D842V]

The following method is used to determine the inhibitory effect of the representative compound of this application on the kinase activity of recombinant human PDGFRα[D842V] (D842V mutation) under in vitro conditions.

This method uses Cisbio’s HTRF®KinEASE-TK Tyrosine Kinase Kit (Cat. No. 62TK0PEB). The principle of the kit is based on time-resolved fluorescence energy resonance transfer (TF-FRET), which measures protein-mediated biotinylation The degree of phosphorylation of the peptide substrate reflects the strength of the compound’s inhibition of protein kinase activity. For detailed experimental operations, please refer to the kit instructions. Recombinant human PDGFRα[D842V] protein kinase was purchased from Carna bioscience (Japan, the product number is PDFGRα[D842V]#08-506).

The experimental procedure is briefly described as follows: the test compound is first dissolved in DMSO to prepare a storage solution, and then the test compound is gradually diluted with the buffer provided in the kit. The final concentration of the test compound in the reaction system ranges from 10 μM to 0.1 nM. The concentration of the ATP solution (Sangong Bioengineering (Shanghai) Co., Ltd., #A600311) used in the test is the pre-determined ATP Km concentration of 30 μM. The reaction was carried out in a 384-well microtiter plate. First, the test compound and 0.66 ng of the test protein were added to the empty wells, and incubated at room temperature for 5 minutes, and then ATP solution and biotinylated peptide receptor were added to the reaction solution. After incubating for 50 minutes with shaking at room temperature, add anti-phosphotyrosine antibody coupled with europium compound and streptavidin coupled with modified allophycocyanin XL665 to the reaction , And continue to incubate with shaking for 1 hour at room temperature. After the incubation, the fluorescence intensity value of each well at the excitation wavelength of 304nm, emission wavelength of 620nm and 665nm was measured in the microplate reader in TF-FRET mode. Calculate the percentage inhibition rate of the compound at each concentration by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and use GraphPad Prism 5 software to perform a nonlinear regression analysis of the compound concentration vs. the inhibition rate to obtain the compound The IC ₅₀ value is shown in Table 3.

Conclusion: The representative compounds 16 and 17 of this application have a good inhibitory effect on PDGFRα[D842V].

Test Example 4. Determination of the activity of the compound of the present invention on mouse mastocytoma P815

The following method is used to determine the effect of the compound of the present invention on tumor cell proliferation by using the Cell Counting Kit-8 kit (Dojindo, Dongren Chemical Technology) to perform the determination, and the specific operation is carried out according to its instructions. For c-KIT[D816V], mouse mastocytoma P815 (purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was used for culture.

The experimental method is briefly described as follows: the test compound (the compound described in Table 3) is first dissolved in DMSO to prepare a storage solution, and then diluted with the medium of the corresponding cell to prepare a test sample. The final concentration of the compound is in the range of 30μM~ 0.01nM. The tumor cells in the logarithmic growth phase were seeded into a 96-well cell culture dish at a density of 1000 cells/well, and after overnight in a 37°C, 5% CO ₂ incubator, the test compound samples were added and the cells were cultured for 48 hours. After the incubation, add 10μL of CCK-8 detection solution to each well, and incubate at 37°C for 1 to 2 hours, and then read the absorbance value of each well of the sample at 450nm on a microplate reader. Calculate the percentage inhibition rate of the compound at each concentration point by comparing the absorbance value with the control group (0.3% DMSO), and then perform nonlinear regression analysis on the compound concentration-inhibition rate in the GraphPad Prism 5 software to obtain the compound inhibiting cells The IC ₅₀ value of proliferation is shown in Table 4.

Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of mouse mastocytoma P815.

Test Example 5. Pharmacokinetic test of the compound of the present invention

1. Summary

Taking SD rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in the plasma of rats after intragastric administration of reference compound 1 and compound 6 of the present invention at different times to study the effects of the compound of the present invention in rats. Pharmacokinetic characteristics.

2. Experimental program

2.1 Experimental drugs and animals

Reference compound 1 and compound 6 of the present invention; 6 healthy adult male SD rats, divided into 3 groups, were purchased from Cipuer-Bikai Experimental Animal Co., Ltd.

2.2 Drug preparation and administration

Weigh an appropriate amount of the experimental drug, add 0.5% sodium carboxymethyl cellulose (CMC-Na), ultrasonic wave to dissolve, use a pipette to draw 100μL for concentration determination, configure the solution concentration to 0.3mg/mL.

Six healthy adult male SD rats were divided into 3 groups. After fasting overnight, they were administered by gavage. The dosage was 3 mg/kg and the dosage was 10 mL/kg.

2.3 Operation

At 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration, 0.25 mL of blood was collected from the neck vein and placed in a heparinized test tube at 2-8°C , 8000 rpm, centrifugation for 6 minutes, store at -70°C, and eat 2 hours after administration. The LC-MS/MS method was used to determine the content of the test compound in the plasma of SD male rats after oral administration of different compounds. Based on blood drug concentration data at different time points, WinNonlin was used to calculate pharmacokinetic parameters.

3. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the invention are shown in Table 5.

Conclusion: Compared with the reference compound 1, the compound 6 of the present invention has a higher plasma concentration and area under the drug-time curve, and at the same time, has a prolonged half-life and better pharmacokinetic properties.

Test Example 6. Pharmacokinetic test of the preferred compound of the present invention in ICR mice

1. Summary

Using ICR mice as the test animals, the LC/MS/MS method was used to determine the concentration of the drug in the plasma of the mice after tail vein injection and gavage of the reference compound 1, Example 5 and Example 6 compounds at different times. To study the pharmacokinetic characteristics of the compound of the present invention in mice.

2. Experimental program

2.1 Experimental drugs and animals

Reference compound 1, compound 5 and compound 6 of the present invention; 54 healthy adult male ICR mice, 31.3~35.6g, divided into 6 groups, A~F groups, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Animal quality certificate number: 11400700310546.

2.2 Drug preparation and administration

2.2.1 Preparation of intravenous (IV-A) drug delivery

Weigh an appropriate amount of experimental drugs, add DMSO: Solutol HS-15: Saline=5: 10: 85 (v/v/v), vortex to mix, filter with Nylon filter membrane (0.45 μm), and pipette 100μL×2 is used for concentration determination, the concentration of the prepared solution is 0.2mg/mL, and it is stored at 2~8℃.

2.2.2 Preparation of intragastric administration (IG-B)

Weigh an appropriate amount of experimental drug, add 0.5% sodium carboxymethyl cellulose (CMC-Na), ultrasonic wave to dissolve, use a pipette to draw 100μL×2 for concentration determination, the concentration of the prepared solution is 0.3mg/mL, 2 Store at ~8℃.

2.2.3 Administration

54 healthy adult male ICR mice, 31.3~35.6g, were divided into 6 groups, A~F group. After fasting overnight, group A, group C and group E were administered via tail vein injection, and the dose was 1mg /kg, the administration volume is 5mL/kg; Groups B, D and F are administered by intragastric administration, the dosage is 3mg/kg, and the administration volume is 10mL/kg.

2.3 Operation

0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours before intravenous administration and after administration or 0.25 hours after administration by gavage, For 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours, 80μL of blood was collected from the orbital vein, placed in an EDTA-K2 anticoagulant tube, centrifuged at 1500g for 10 minutes, at -40 to -20°C Store and eat 4 hours after administration. LC-MS/MS method was used to determine the content of the test compound in the plasma of ICR male mice after tail vein injection and intragastric administration of different compounds. Based on blood drug concentration data at different time points, WinNonlin was used to calculate pharmacokinetic parameters.

3. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the present invention are shown in Table 6 and Table 7.

Conclusion: Compared with reference compound 1, intragastric administration of compound 5 and compound 6 of the present invention to mice has higher maximum plasma concentration and area under the drug-time curve, and has better pharmacokinetic properties.

Conclusion: Compared with reference compound 1, intravenous injection of compound 5 and compound 6 of the present invention in mice has a higher area under the drug-time curve and better pharmacokinetic properties.

Claims (47)

A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: R ^{1 is} selected from a hydrogen atom, an alkyl group or -C(O)R ⁵ , wherein the alkyl group is optionally further selected from halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic group,- C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ is substituted by a substituent; R ^{2 is} selected from alkyl, wherein the alkyl is further substituted by one or more halogens; R ^{3 is the} same or different, each independently selected from a hydrogen atom, an alkane Group, alkoxy, hydroxyl, cyano, nitro, halogen, cycloalkyl, heterocyclyl, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ , where alkyl, alkoxy, cycloalkyl or heterocyclyl optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ^8, -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O) R ¹⁰ is substituted by substituents; R ^{4 is} selected from aryl or heteroaryl, wherein aryl or heteroaryl is optionally further substituted by one or more selected from alkyl, alkoxy, hydroxyl, cyano, nitro , Halogen, cycloalkyl, heterocyclyl, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ substituents; wherein the alkyl group or alkoxy group is optionally further substituted with one or more halogens; R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein alkyl, alkoxy Group, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl , Aryl, heteroaryl, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S (O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ; alternatively, R ⁶ and R ⁷ together with the N atom to which they are connected form a 4- to 8-membered heterocyclic group, of which 4 The ~8-membered heterocyclic ring contains one or more N, O or S(O) _n , and the 4- to 8-membered heterocyclic ring is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkane Group, alkoxy group, cycloalkyl group, heterocyclic group , Aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O) _n NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ; R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, Heterocyclyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkane Group, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate substituent; m is selected from 1, 2, 3 or 4; and n is selected from 0, 1 or 2. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 1 of the scope of the patent application, wherein R ^{1 is} selected from an alkyl group or -C(O)R ⁵ , wherein the alkyl group is any is further selected from substituted with one or more substituents selected from halo, hydroxy, alkoxy, cycloalkyl, ^{heterocyclyl, -C (O) R 5,} -OC (O) R 5, -C (O) oR 5, - NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O) _n NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ is substituted. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 2 of the scope of patent application, wherein R ^{1 is} selected from C _1-4 alkyl groups, wherein C _1-4 alkyl groups are any Optionally further substituted by one or more C _1-6 alkoxy groups. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 3 of the scope of the patent application, wherein the C _1-6 alkoxy group is a methoxy group. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 1 of the scope of the patent application, which are the compounds of general formula (II) or their stereoisomers or tautomers Structure or its pharmaceutically acceptable salt,

Wherein: R ^{3 is} selected from hydrogen atom, alkyl group, alkoxy group, hydroxyl group, cyano group, nitro group, halogen, cycloalkyl group, heterocyclic group, -C(O)R ⁵ , -OC(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -S(O)nNR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ , where alkyl, alkoxy Group, cycloalkyl or heterocyclic group is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -S(O)nNR ⁹ R ¹⁰ Or -NR ⁹ C(O)R ¹⁰ is substituted; and R ¹ , R ² , R ⁴ to R ¹⁰ and n are defined as described in any one of items 1-4 in the scope of the patent application. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 1 of the scope of patent application, wherein: R ^{2 is} selected from C _1-4 alkyl, wherein C _1-4 alkyl It is further substituted by one or more halogens. The compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 6 of the scope of the patent application, wherein the halogen is fluorine, chlorine or bromine. The compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in item 7 of the scope of the patent application, wherein the halogen is fluorine. The compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in item 6 of the scope of the patent application, wherein R ² is trifluoroethyl. The compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application, wherein: R ^{3 is} selected from a hydrogen atom, a C _1-4 alkyl group or a halogen. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 10 of the scope of patent application, wherein the C _1-4 alkyl group is methyl or ethyl. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 10 of the scope of the patent application, wherein the halogen is fluorine, chlorine or bromine. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 1 of the scope of the patent application, wherein: R ^{4 is} selected from phenyl or benzothienyl, wherein phenyl or benzo The thienyl group is optionally further substituted with one or more substituents selected from halogen, C _1-4 alkyl or C _1-6 alkoxy; wherein C _1-4 alkyl or C _1-6 alkoxy is either Optionally further substituted by one or more halogens. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 13 of the scope of patent application, wherein the C _1-4 alkyl group is methyl or ethyl. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 13 of the scope of patent application, wherein halogen is fluorine, chlorine or bromine. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 14 of the scope of the patent application, wherein the halogen is fluorine. The compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in item 1 of the scope of the patent application, wherein: R ^{1 is} selected from a hydrogen atom or a C _1-4 alkyl group, wherein C _{1- 4} Alkyl is optionally further substituted by one or more C _1-6 alkoxy; R ^{2 is} selected from C _1-4 alkyl, wherein C _1-4 alkyl is further substituted by one or more selected from fluorine, chlorine Or bromine halogen; R ^{3 is} selected from hydrogen atom, C _1-4 alkyl or halogen, wherein C _1-4 alkyl is optionally further substituted with one or more halogens; and R ^{4 is} selected from phenyl or Benzothienyl, wherein phenyl or benzothienyl is optionally further substituted with one or more substituents selected from halogen, C _1-4 alkyl or C _1-6 alkoxy; wherein C _1-4 The alkyl group or C _1-6 alkoxy group is optionally further substituted with one or more halogens. The compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 17 of the scope of the patent application, wherein the C _1-6 alkoxy group is a methoxy group. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof according to item 17 of the scope of the patent application, wherein R ^{3 is} selected from a hydrogen atom, a C _1-4 alkyl group or a halogen, wherein C _{1 The -4} alkyl group is optionally further substituted with one or more halogens, which are fluorine, chlorine or bromine. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof according to item 17 of the scope of patent application, wherein R ^{4 is} selected from phenyl or benzothienyl, wherein phenyl or benzothiophene The group is optionally further substituted with one or more substituents selected from halogen, C _1-4 alkyl or C _1-6 alkoxy; wherein C _1-4 alkyl or C _1-6 alkoxy optionally Further substituted by one or more halogens; the halogen is fluorine, chlorine or bromine. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof according to item 20 of the scope of the patent application, wherein the halogen is fluorine. The compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 1 of the scope of patent application, wherein the compound is:

A method for preparing the compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof according to any one of items 1 to 4 of the scope of patent application, which comprises:

The compound of the general formula (IA) is reacted with the compound of the general formula (IB) to obtain the compound of the general formula (I); wherein: R ¹ to R ⁴ and m are defined as described in any one of items 1-4 in the scope of the patent application. A method for preparing a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 5 of the scope of patent application, which comprises:

The compound of the general formula (IIA) is reacted with the compound of the general formula (IB) to obtain the compound of the general formula (II); wherein: R ¹ to R ⁴ are defined as described in item 5 of the scope of patent application. An intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

Among them: the definitions of R ¹ ~R ³ and m are as described in any one of items 1-4 in the scope of the patent application. The intermediate compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof as described in item 25 of the scope of the patent application is the compound of general formula (IIA) or its stereoisomers, Tautomers or pharmaceutically acceptable salts thereof,

Among them: the definition of R ¹ ~R ³ is as described in item 25 of the scope of patent application. The intermediate compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 25 of the scope of patent application, wherein the compound is:

A preparation method of the intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 25 of the scope of patent application, which comprises: 1) When R ¹ When it is not a hydrogen atom:

A compound of general formula (Ia) and a compound of general formula (Ib) are subjected to condensation reaction under heating conditions to obtain a compound of general formula (Ic); a compound of general formula (Ic) is reacted with a compound of general formula (Id) to obtain general formula (IA) ); wherein: X is halogen; Ra is an alkyl group; and R ¹ to R ³ and m are defined as described in item 25 of the scope of patent application, and R ^{1 is} not H; and 2) when When R ¹ is a hydrogen atom:

The compound of the general formula (Ia) and the compound of the general formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of the general formula (Ic); the compound of the general formula (Ic) is reacted with the compound of the general formula (Ie) to obtain the general formula ( If) compound; formula (If) compound in the presence of trifluoroacetic acid, to give the intermediate compound of formula (IA); wherein: X is halogen; R ¹ is a hydrogen atom; R ^a is alkyl; R ^b Is an alkyl group; and the definitions of R ² , R ³ and m are as described in item 25 of the scope of patent application. A method for preparing an intermediate compound of general formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 26 of the scope of patent application, which comprises: 1) When R ¹ When it is not a hydrogen atom:

A compound of general formula (Ia) and a compound of general formula (IIa) are subjected to condensation reaction under heating conditions to obtain a compound of general formula (IIb); a compound of general formula (IIb) is reacted with a compound of general formula (Id) to obtain general formula (IIA) ) the intermediate compound; wherein: X is halogen; R ^a is alkyl; and R ¹ ~ R ³ is defined as in the range of 26 patent, and R1 is not H; and 2) when R ¹ is When hydrogen atom:

A compound of general formula (Ia) and a compound of general formula (IIa) are subjected to condensation reaction under heating conditions to obtain a compound of general formula (IIb); a compound of general formula (IIb) is reacted with a compound of general formula (Ie) to obtain general formula (IIc) ); and compounds of formula (IIc) in the presence of trifluoroacetic acid, of general formula (IIA) of the intermediate compound; wherein: X is halogen; R ¹ is a hydrogen atom; R ^a is alkyl; R ^b is alkyl The definition of R ² and R ³ is as described in item 26 of the scope of patent application. A pharmaceutical composition containing an effective dose of The compound according to any one of items 1-22 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients, or combinations thereof. A compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof according to any one of items 1-22 of the scope of patent application, or a pharmaceutical composition according to item 30 of the scope of patent application Use in preparing medicines for treating diseases mediated by c-KIT or mutant c-KIT. The use as described in item 31 of the scope of patent application, wherein the disease mediated by c-KIT or mutant c-KIT is gastrointestinal stromal tumor, systemic mastocytosis, acute myelogenous leukemia, ovarian cancer, Melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia. The use described in item 31 of the scope of patent application, wherein the disease mediated by c-KIT or mutant c-KIT is gastrointestinal stromal tumor, systemic mastocytosis, glioblastoma multiforme and Acute myelogenous leukemia. The use according to item 31 of the scope of patent application, wherein the diseases mediated by c-KIT or mutant c-KIT are gastrointestinal stromal tumors, glioblastoma multiforme, and systemic mastocytosis. The use as described in item 31 of the scope of patent application, wherein the mutation of the mutant c-KIT is located in exon 9, 11, 13, 14, 17 and/or 18, or 816, 670, 560 And/or the 654th amino acid residue. The use described in item 35 of the scope of patent application, wherein the amino acid residue at position 816 is mutated to D816V or D816H. The use described in item 35 of the scope of patent application, wherein the amino acid residue at position 670 is mutated to T670I. The use as described in item 35 of the scope of patent application, wherein the 560th amino acid residue is mutated to V560G. The use described in item 35 of the scope of patent application, wherein the amino acid residue at position 654 is mutated to V654A. A compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof according to any one of items 1-22 of the scope of patent application, or a pharmaceutical composition according to item 30 of the scope of patent application Use in the preparation of c-KIT inhibitors. A compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof according to any one of items 1-22 of the scope of patent application, or a pharmaceutical composition according to item 30 of the scope of patent application Use in preparing medicines for treating diseases mediated by mutant or wild-type PDFGRα. The use described in item 41 of the scope of patent application, wherein the disease mediated by mutant or wild-type PDFGRα is gastrointestinal stromal tumor, systemic mastocytosis, acute myelogenous leukemia, ovarian cancer, melanoma, Cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia. The use described in item 41 of the scope of patent application, wherein the disease mediated by mutant or wild-type PDFGRα is gastrointestinal stromal tumor, systemic mastocytosis, glioblastoma multiforme, and acute myeloid leukemia. The use described in item 41 of the scope of patent application, wherein the disease mediated by mutant or wild-type PDFGRα is gastrointestinal stromal tumor, glioblastoma multiforme and systemic mastocytosis. The use as described in item 41 of the scope of patent application, wherein the mutation of the mutated PDFGRα is located at exon 18 and/or the 842th amino acid residue. The use described in item 45 of the scope of patent application, wherein the mutation at the 842th amino acid residue is D842V mutation. A compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof according to any one of items 1-22 of the scope of patent application, or a pharmaceutical composition according to item 30 of the scope of patent application Use in the preparation of PDFGRα inhibitors.