TW201914999A - 1,2-dihydro-1,6-naphthyridine derivative, preparation method therefor, and application thereof in medicine - Google Patents

Abstract

A 1,2-dihydro-1,6-naphthyridine derivative, a preparation method therefor, and an application thereof in medicine. Specifically provided are a 1,2-dihydro-1,6-naphthyridine derivative as represented by formula (I), a preparation method therefor, pharmaceutically acceptable salts thereof, and application thereof as therapeutic agents, particularly c-KIT inhibitors, wherein the definitions of the substituents in the formula (I) are the same as the definitions in the description.

Description

1,2-dihydro-1,6-naphthyridine derivatives, preparation methods thereof, pharmaceutical compositions and uses thereof in medicine

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

c-KIT (also known as KIT, CD117, and stem cell factor receptors) is a 145 kDa transmembrane tyrosine kinase protein that acts 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). Protein tyrosine kinase phosphorylation of tyrosine is particularly important in cell signaling and can mediate major cellular processes such as signals of proliferation, survival, differentiation, apoptosis, connection, invasion and migration. The c-KIT mutation usually appears in the DNA (exon 11) encoding the proximal membrane domain. They also appear at lower frequencies in exons 7, 8, 9, 11, 13, 14, 17, and 18. The mutation makes c-KIT function independent of activation by SCF, resulting in high cell division rate and possible genomic instability. The function-increasing mutation of c-KIT gene and the expression of constitutively phosphorylated c-KIT can be found in most gastrointestinal stromal tumors (GIST), mastocytosis and acute myeloid leukemia. It has 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 seen in germ cell tumors of gastrointestinal stromal tumors, acute myeloid leukemia, melanoma, breast tumors, cervical tumors, glioblastoma multiforme, ovarian tumors, seminoma or asexual cell tumors , Teratoma, mast cell leukemia and other tissues have been found, its protein expression concentration is closely related to the occurrence and development of tumors. 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 that the incidence rate is 0.66 to 2.20 per 100,000. GIST is extremely insensitive to traditional chemotherapy, the effectiveness of chemotherapy drugs is less than 5%, and the median survival rate during progression is only about 18 months. Even if the tumor is completely removed, the 5-year survival rate of GIST is only 35% -65%, the recurrence and metastasis rate within 2 years is 40% -50%, and as many as 15% -50% of patients at first diagnosis have metastasis. Studies have found that the functional activation mutations of the transmembrane tyrosine kinase receptor c-KIT on the stem cell factor surface and the platelet-derived growth factor receptor PDGFRα gene are the key to the development of GIST. Platelet-derived growth factor receptor (PDGF-R) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. PDGF subunits PDGFα and PDGFβ are important regulators regulating cell proliferation, cell differentiation, cell growth, development and many diseases, including cancer.

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

In order to overcome the shortcomings of the conventional technology, the object of the present invention is to provide a new class of 1,2-dihydro-1,6-naphthyridine derivatives represented by the general formula (I), or their stereoisomers Compounds, tautomers or pharmaceutically acceptable salts thereof. The compounds of the present invention have a large structural difference from the compounds specifically disclosed in the prior art, and can be treated or prevented by adjusting the activities of c-KIT and PDGFα. Diseases such as stromal tumors, acute myeloid leukemia, and systemic mast cell hyperplasia.

The compound represented by the general formula (I) of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

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 one or more of halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic, -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 substituted by the substituent of -NR ⁶ C (O) R ⁷ ;

R ^{2 is} selected from an alkyl group, wherein the alkyl group is further substituted with one or more halogens;

R ^{3 is the} same or different, and is independently 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 said alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further selected from one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, hetero Cyclic, 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;

R ^{4 is} selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further selected by one or more selected from alkyl, alkoxy, hydroxyl, cyano, nitro, halogen, cycloalkane 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 substituents; wherein the alkyl or alkoxy group is optionally further substituted with one or more halogens;

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 from 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 substituents;

Alternatively, R ⁶ and R ⁷ together with the attached N atom form a 4-8 member heterocyclic group, wherein the 4-8 member heterocyclic ring contains one or more N, O or S (O) _n , and 4 ～ The 8-membered heterocyclic ring is optionally further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, = 0, -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 substituted by the substituent of -NR ⁹ C (O) R ¹⁰ ;

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group The radical or heteroaryl is optionally further selected from one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, or carboxy Substituted by the substituent of the ester group;

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 the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of the general formula (II) or its stereo Isomers, tautomers or pharmaceutically acceptable salts thereof,

among them:

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 alkyl, The alkoxy, cycloalkyl or heterocyclic group is optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -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;

The definitions of R ¹ , R ² , R ⁴ to R ¹⁰ and n are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^{1 is} selected from a hydrogen atom or a C _1-4 alkyl group, wherein the C _1-4 alkyl group is optionally further substituted with one or more C _1-6 alkoxy groups; wherein the C _{1-6 group is} The alkoxy group is preferably a methoxy group.

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^{2 is} selected from C _1-4 alkyl, wherein the C _1-4 alkyl is further substituted with 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 the general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is trifluoroethyl.

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt 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 mentioned therein is preferably fluorine, chlorine or bromine.

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^{4 is} selected from phenyl or benzothienyl, wherein the phenyl or benzothienyl is optionally further one or more selected from halogen, C _1-4 alkyl or C _1-6 alkoxy Substituted by a substituent;

Wherein the C _1-4 alkyl or C _1-6 alkoxy is optionally further substituted with one or more halogens;

Wherein the C _1-4 alkyl is preferably methyl or ethyl; and

The halogen mentioned therein is preferably fluorine, chlorine or bromine; more preferably fluorine.

In a preferred embodiment of the present invention, a compound of the general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^{1 is} selected from a hydrogen atom or an alkyl group, preferably a C _1-4 alkyl group, wherein the alkyl group is optionally further substituted with one or more C _1-6 alkoxy groups; wherein the C _{1- 6} alkoxy is preferably methoxy.

R ^{2 is} selected from alkyl, wherein the alkyl is further substituted with one or more halogens; preferably the alkyl is C _1-4 alkyl, more preferably ethyl; 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 C _1-4 alkyl, more preferably methyl or ethyl Radical; and the halogen is preferably fluorine, chlorine or bromine.

R ^{4 is} selected from phenyl or benzothienyl, wherein the phenyl or benzothienyl is optionally further substituted with one or more substituents selected from halogen, alkyl or alkoxy; wherein The alkyl group or alkoxy group 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 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 the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The method includes:

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 ~ R ⁴ and m 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, pyridine, N-methylpyrazine, 4-dimethylpyridine, It is preferably 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 present invention provides a method for preparing a compound of the general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The method includes:

The compound of general formula (IIA) and the compound of general formula (IB) are reacted under basic conditions to obtain the compound of general formula (II);

Wherein: R ¹ ~ R ⁴ are as defined 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, pyridine, N-methylpyrazine, 4-dimethylpyridine, Preferably 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.

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

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

The present invention provides an intermediate compound according to general formula (IA) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is an intermediate compound according to general formula (IIA) or its stereo Isomers, tautomers or pharmaceutically acceptable salts thereof,

Wherein: R ¹ ~ R ³ are as defined 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 the general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The method includes:

The compound of formula (Ia) and the compound of formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of formula (Ic); the compound of formula (Ic) and the compound of formula (Id) are reacted under heating conditions, The intermediate compound of general formula (IA) is obtained;

among them:

X is halogen;

R ^a is alkyl; and

The definitions of R ¹ to R ³ and m are as described in the general formula (IA), and R ^{1 is} not a hydrogen atom.

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

The compound of formula (Ia) and the compound of formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of formula (Ic); the compound of formula (Ic) and the compound of formula (Ie) are subjected to condensation under heating conditions The reaction gives a compound of general formula (If); the compound of general formula (If) is reacted in the presence of trifluoroacetic acid to obtain an intermediate compound of general formula (IA);

among them:

X is halogen;

R ¹ is a hydrogen atom;

R ^a is alkyl; R ^b is alkyl; and

The definitions of R ² , R ³ and m are as described in the general formula (IA).

The present invention provides a method for preparing an intermediate compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof according to general formula (IIA). The method includes:

The compound of formula (Ia) and the compound of formula (IIa) are subjected to condensation reaction under heating conditions to obtain the compound of formula (IIb); the compound of formula (IIb) and the compound of formula (Id) are reacted under heating conditions, The intermediate compound of general formula (IIA) is obtained;

among them:

X is halogen;

R ^a is alkyl; and

The definitions of R ¹ to R ³ are as described in the general formula (IIA), and R ^{1 is} not a hydrogen atom.

The present invention provides a method for preparing an intermediate compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof according to general formula (IIA). The method includes:

The compound of formula (Ia) and the compound of formula (IIa) are subjected to condensation reaction under heating conditions to obtain the compound of formula (IIb); the compound of formula (IIb) and the compound of formula (Ie) are subjected to condensation reaction under heating conditions To obtain a compound of general formula (IIc); a compound of general formula (IIc) is reacted in the presence of trifluoroacetic acid to obtain an intermediate compound of general formula (IIA);

among them:

X is halogen;

R ¹ is a hydrogen atom;

R ^a is alkyl; R ^b is alkyl; and

The definitions of R ² and R ³ are as described in the general formula (IIA).

Furthermore, the present invention provides a pharmaceutical composition containing an effective dose of the compound of the general formula (I) or (II) or its stereoisomer, tautomer or its pharmacological use Salts, 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 stereoisomer, tautomer or its pharmaceutically acceptable Salt, or a pharmaceutical composition thereof.

The present invention provides a compound of the general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation for treatment by c-KIT or mutation Use of a c-KIT-mediated disease in medicine, wherein the disease mediated by c-KIT or mutated c-KIT is preferably gastrointestinal stromal tumor, systemic mast cell hyperplasia, 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 myeloid leukemia, the best are gastrointestinal stromal tumors, glioblastoma multiforme and systemic mast cell hyperplasia; preferably the mutant c -KIT mutations are located in exons 9, 11, 13, 14, 17, and / or 18, or at positions 816, 670, 560, and / or 654 amino acid residues, where the The mutation at amino acid residue 816 is D816V or D816H; the mutation at amino acid residue 670 is T670I; the mutation at amino acid residue 560 is V560G; the mutation is The mutation at amino acid residue 654 is preferably V654A.

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

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

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 The use of PDFGRα-mediated diseases in medicine, wherein the disease mediated by mutant or wild-type PDFGRα is preferably gastrointestinal stromal tumor, systemic mast cell hyperplasia, acute myeloid leukemia, ovarian cancer, Melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; gastrointestinal stromal tumor, systemic mast cell hyperplasia, and more Glioblastoma and acute myeloid leukemia, preferably gastrointestinal stromal tumors, glioblastoma multiforme and systemic mast cell hyperplasia; preferably the mutation of the mutant PDFGRα is located in exon 18 And / or at amino acid residue 842, wherein the mutation at amino acid residue 842 is preferably the D842V mutation.

The present invention provides a method for treating diseases mediated by c-KIT or mutated c-KIT, which includes administering to a patient a therapeutically effective dose of a compound of the general formula (I) or (II) or a stereoisomer thereof, Tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, wherein the diseases mediated by c-KIT or mutated c-KIT are preferably gastrointestinal stromal tumors, systemic mast cell hyperplasia , Acute myeloid leukemia, ovarian cancer, melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; preferably gastrointestinal stromal tumor , Systemic mast cell hyperplasia, glioblastoma multiforme and acute myeloid leukemia, preferably gastrointestinal stromal tumors, glioblastoma multiforme and systemic mast cell hyperplasia; mutations described therein Of c-KIT mutations are located at exons 9, 11, 13, 14, 17, and / or 18, or amino acid residues at positions 816, 670, 560, and / or 654, wherein 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; wherein The mutation at amino acid residue 654 of V654A is better.

The present invention provides a method for treating a disease mediated by PDFGRα or mutant PDFGRα, which includes administering to a patient a therapeutically effective dose of the compound of formula (I) or (II) or its stereoisomers, tautomers Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease mediated by PDFGRα or mutant PDFGRα is preferably gastrointestinal stromal tumor, systemic mast cell hyperplasia, acute myeloid 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 myeloid leukemia, preferably gastrointestinal stromal tumors, glioblastoma multiforme and systemic mastocytosis; wherein the mutation of the mutated PDFGRα is located in exon 18 And / or at amino acid residue 842, wherein the mutation at amino acid residue 842 is preferably the D842V mutation.

Detailed description of the invention

Unless stated to the contrary, some terms used in the specification and patent application scope of the present invention are defined as follows:

"Alkyl" when taken as a group or part of a group refers to a C ₁ -C ₂₀ linear or branched aliphatic hydrocarbon group. It is preferably C ₁ -C ₁₀ alkyl, and more preferably C ₁ -C ₆ alkyl. 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. The alkyl group may be substituted or unsubstituted.

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

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

"Cycloalkyl" means a saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic ring, but none of the aromatic systems has a completely conjugated π electron. It is preferably C ₃ -C ₁₂ cycloalkyl, more preferably C ₃ -C ₈ cycloalkyl, and most preferably C ₃ -C ₆ cycloalkyl. Examples of monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl and the like are preferably cyclopropyl and cyclohexenyl.

"Spirocyclic group" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and the single rings share a carbon atom (called a spiro atom) with each other. One or more rings may contain One or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into monospiro, bispiro or polyspirocycloalkyl, preferably monospiro and dispirocycloalkyl, 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 cyclic structures sharing a pair of carbon atoms with each other. One or more rings may contain one or more double bonds, but There is no aromatic system with a completely conjugated π electron, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic condensed cyclic alkyl groups, preferably bicyclic or tricyclic, more preferably 5 members / 5 members or 5 members / 6 members bicyclic alkyl groups. 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 tetradecylhydrophenanthrenyl.

"Bridge ring group" refers to 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms with each other, a full-carbon polycyclic group, one or more rings may contain one or more A double bond, but none of the rings has a completely conjugated π electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided 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 can be fused to an aryl, heteroaryl or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetralin Group, benzocycloheptyl, etc. The cycloalkyl group can be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups in which one or more ring-forming atoms are heteroatoms, such as oxygen, Nitrogen and sulfur atoms, including single ring, condensed ring, bridge ring and spiro ring. It preferably has a monocyclic ring of 5 to 7 members or a bicyclic or tricyclic ring of 7 to 10 members, 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, pyridine , 2-oxo-pyridinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, pyrazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl and Pyrazinyl. The heterocyclic group may be substituted or unsubstituted.

"Spiroheterocyclic group" refers to a polycyclic group of 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 completely conjugated π-electron aromatic system, wherein 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, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl groups are classified into monospiro heterocyclic groups, bispiro heterocyclic groups or polyspiro heterocyclic groups, preferably monospiro heterocyclic groups and dispiro heterocyclic groups . 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 group. 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-oxo Heterospiro [3.5] nonyl and 5-oxaspiro [2.4] heptyl.

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing 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 a hetero atom of S (O) _n (where n is selected from 0, 1, or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, and 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 members / 5 members or 5 members / 6 members bicyclic fused heterocyclic . Non-limiting examples of "fused heterocyclic groups" 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.

"Bridge heterocyclic group" refers to a polycyclic group of 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may be An aromatic system containing one or more double bonds, but none of the rings has a completely conjugated π electron, 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, and more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, pyridone or polycyclic bridge heterocyclic groups according to the number of constituent rings, 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 Ring [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, where the rings can be linked 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. The aryl group may be substituted or unsubstituted. The "aryl group" may 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, benzo 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 to an aryl, heterocyclyl 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 the group (alkyl-O-). Among them, alkyl refers to relevant definitions herein. C ₁ -C ₆ alkoxy groups are preferred. Examples 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" means fluorine, chlorine, bromine and iodine.

"Amino" refers to -NH ₂ .

"Cyano" means -CN.

"Nitro" refers to -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

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

"Carboxylic acid ester group" means -C (O) O-alkyl or -C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

"DMSO" means dimethyl sulfoxide.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, 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 at their possible chemical positions, and those with ordinary knowledge in the art can determine (via experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

"Substitute" or "substituted" in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy , Alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, 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 from 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 substituents;

Alternatively, R ⁶ and R ⁷ together with the connected N atom form a 4-8 member heterocyclic group, wherein the 4-8 member heterocyclic ring contains one or more N, O, S (O) _n atoms, and 4 The ~ 8 membered heterocyclic ring is optionally further selected from 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 is substituted.

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group The radical or heteroaryl is optionally further selected from one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, or carboxy Substituted by an ester group substituent; and

n is selected from 0, 1, or 2.

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

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically pharmaceutically acceptable salt or prodrug thereof with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients Form agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert 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 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to the general formula (I) of the present invention includes the following steps:

The compound of formula (Ia) and the compound of formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of formula (Ic); the compound of formula (Ic) and the compound of formula (Id) are reacted under heating conditions to obtain The compound of 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);

among them:

X is halogen;

R ^a is alkyl; and

The definitions of R ¹ to R ⁴ and m are as described in the general formula (I), and R ^{1 is} not a hydrogen atom.

The preparation method of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to the general formula (I) of the present invention includes the following steps:

The compound of formula (Ic) and the compound of formula (Ie) are subjected to condensation reaction under heating conditions to obtain the compound of formula (If); the compound of formula (If) is reacted in the presence of trifluoroacetic acid to obtain the formula (IA) ) Intermediate compounds; reacting compounds of general formula (IA) with compounds of general formula (IB) under basic conditions to obtain compounds of general formula (I);

among them:

X is halogen;

R ¹ is a hydrogen atom;

R ^b is alkyl; and

The definition of R ² to R ⁴ is as described 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, pyridine, N-methylpyrazine, 4-dimethylpyridine, It is preferably 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 preparation method of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to the general formula (II) of the present invention includes the following steps:

The compound of formula (Ia) and the compound of formula (IIa) are subjected to condensation reaction under heating conditions to obtain the compound of formula (IIb); the compound of formula (IIb) and the compound of formula (Id) are reacted under heating conditions, The compound of general formula (IIA) is obtained; the compound of general formula (IIA) and the compound of general formula (IB) are reacted under basic conditions to obtain the compound of general formula (II);

among them:

X is halogen;

R ^a is alkyl; and

The definitions of R ¹ to R ⁴ are as described 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, pyridine, N-methylpyrazine, 4-dimethylpyridine, Preferably 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 preparation method of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to the general formula (II) 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 conditions 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 middle of general formula (IIA) Compound; the compound of formula (IIA) and the compound of formula (IB) are reacted under basic conditions to obtain the compound of formula (II);

among them:

X is halogen;

R ¹ is a hydrogen atom;

R ^b is alkyl; and

The definition of R ² to R ⁴ is 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.

Examples

The examples show the preparation of representative compounds represented by formula ( I ) and related structural identification data. It must be noted that the following examples are for illustrating the present invention rather than limiting the present invention. ^{The 1} H NMR spectrum is measured with a Bruker instrument (400 MHz), and the chemical shift is expressed in ppm. Use tetramethylsilane internal standard (0.00ppm). ¹ H NMR representation method: s = single peak, d = doublet, t = triplet, m = multiplet, br = widened, dd = doublet doublet, dt = doublet doublet. If the coupling constant is provided, the unit is Hz.

Mass spectrometry is measured by LC / MS instrument, and the ionization method can be ESI or APCI.

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

The specifications used for the silica gel plates are 0.15mm ~ 0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ~ 0.5mm.

Column chromatography generally uses Yantai Yellow Sea silicone 200 ~ 300 mesh silicone 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, and commercially available materials and reagents are not further purified For direct use, unless otherwise instructed, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd. to purchase.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO- d ₆ : deuterated dimethyl sulfoxide.

Argon means that the reaction bottle 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, silica gel column chromatography eluent system and thin layer chromatography are used, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: Dichloromethane: ethyl acetate; where the volume ratio of the solvent varies according to the polarity of the compound, a small amount of acidic or basic reagents can also be added for adjustment, 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

Combine ethyl 4,6-dichloronicotinate 1a (10.1 g, 45.9 mmol), 2,2,2-trifluoroethylamine (15.5 g, 157 mmol) and N, N-diisopropylethylamine (17.8 g, 138 mmol) was dissolved in 200 mL of dimethyl adipate and reacted at 100 ° C for 8 hours. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotinate 1b (4 g, 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 ethyl 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotinate 1b (4 g, 14.18 mmol) in 50 mL of tetrahydrofuran and add tetrahydrogen at -50 ° C in portions Aluminum lithium (1.89 g, 51 mmol), slowly warmed to 0 ° C, and reacted at 0 ° C for 1.5 hours. At 0 ° C, 20 mL of 10% sodium hydroxide solution was slowly added dropwise to quench the reaction, filtered, the filtrate was extracted with ethyl acetate (30 mL), the aqueous layer was separated, and the organic phase was washed with saturated sodium chloride solution (30 mL × 2) , Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6-chloro-4-((2,2,2-trifluoroethyl) amino) pyridin-3-yl) methanol 1c (3.4 g, yellow solid ), Yield: 100%.

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

third step

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

Combine (6-chloro-4-((2,2,2-trifluoroethyl) amino) pyridin-3-yl) methanol 1c (3.4 g, 14.18 mmol) and activated manganese dioxide (18.5 g, 212.7 mmol) Dissolved in 52 mL of dichloromethane and stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue 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-naphthyridine-2 (1H) -one

Combine 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotin 1d (1 g, 4.2 mmol), 2- (5-amino-2-chloro-4-fluorophenyl) Ethyl acetate 1e (970 mg, 4.2 mmol, prepared according to published patent application WO2013184119), potassium carbonate (1.74 g, 12.6 mmol) dissolved in 70 mL N, N-dimethylformamide and toluene (V: V = 2: 5) The mixed solvent was reacted at 150 ° C for 12 hours. Add 100 mL of ethyl acetate, wash with water (100 mL × 2) and saturated sodium chloride solution (100 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Method (eluent: System A) purification to obtain 3- (5-amino-2-chloro-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1 , 6-Naphthyridine-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

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

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

The 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

3- (5-Amino-2-chloro-4-fluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 1g (100 mg, 0.25 mmol), phenyl isocyanate 1h (33 mg, 0.28 mmol, prepared according to published patent application WO2005113626) and triethylamine (126 mg, 1.25 mmol) dissolved in 2 In mL of dichloromethane, react at room temperature overnight. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: 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 (20 mg, white solid ), Yield: 18%.

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

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

3- (5-Amino-2-chloro-4-fluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 1g (100 mg, 0.25 mmol), 1-fluoro-3-isocyanate phenyl 2a (51 mg, 0.375 mmol) and triethylamine (75 mg, 0.75 mmol) dissolved in 2 mL of dichloromethane In methane, react overnight at room temperature. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: 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 ( 13 mg, white solid), yield: 10%.

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (s, 1H), 8.80 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.87 (s, 1H), 7.58 (d, J = 11.2 Hz, 1H), 7.48 (d, J = 10.8 Hz, 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 = 4.8 Hz, 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

Combine 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotinaldehyde 1d (1 g, 4.2 mmol), 2- (5-amino-4-fluoro-2-methylphenyl ) Ethyl acetate 3a (890 mg, 4.2 mmol, prepared according to the published patent application patent WO2013184119), potassium carbonate (1.74 g, 12.6 mmol) dissolved in 70 mL N, N-dimethylformamide and toluene (V : V = 2: 5), react at 150 ℃ for 8 hours. 50 mL of ethyl acetate was added, washed sequentially with water (50 mL × 2) and saturated sodium chloride solution (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was subjected to a silica gel column Chromatography (eluent: System A) purification to obtain 3- (5-amino-4-fluoro-2-methylphenyl) -7-chloro-1- (2,2,2-trifluoroethyl ) -1,6-naphthyridine-2 (1H) -one 3b (620 mg, 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

3- (5-Amino-4-fluoro-2-methylphenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -A solution of ketone 3b (620 mg, 1.61 mmol) and methylamine in tetrahydrofuran (6 mL, 12 mmol) was dissolved in 36 mL 1,4-dioxane, and reacted in a sealed tube at 100 ° C for 48 hours. It was concentrated under reduced pressure, and the resulting residue 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-naphthyridine-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

3- (5-Amino-4-fluoro-2-methylphenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine- 2 (1H) -one 3c (183 mg, 0.48 mmol), 1-fluoro-3-isocyanate phenyl 2a (198 mg, 1.44 mmol) and triethylamine (243 mg, 2.41 mmol) dissolved in 20 mL tetrahydrofuran At room temperature, react overnight. It was concentrated under reduced pressure, and the resulting 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 (400 MHz, DMSO- d ₆ ) δ 9.25 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 7.95 (d, J = 8.4 Hz, 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 = 7.6 Hz, 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

3- (5-Amino-4-fluoro-2-methylphenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine- 2 (1H) -one 3c (183 mg, 0.48 mmol), phenyl 1-fluoro-4-isocyanate 4a (198 mg, 1.44 mmol) and triethylamine (243 mg, 2.41 mmol) dissolved in 20 mL of tetrahydrofuran At room temperature, react overnight. After concentration under reduced pressure, the resulting 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 (400 MHz, DMSO- d ₆ ) δ 9.07 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.95 (d, J = 8.4 Hz, 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 = 4.8 Hz, 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-naphthyridine-2 (1H) -one

Combine 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotinic acid 1d (300 mg, 1.26 mmol), 2- (5-amino-2,4-difluorophenyl) acetic acid Ethyl ester 5a (271.7 mg, 1.26 mmol, prepared according to published patent application patent WO2013184119) and potassium carbonate (522 mg, 3.78 mmol) dissolved in 28 mL of N, N-dimethylformamide and toluene (V: V = 2: 5) The mixed solvent was reacted at 150 ° C for 8 hours. 50 mL of ethyl acetate was added, washed sequentially with water (50 mL × 2) and saturated sodium chloride solution (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column Chromatography (eluent: System A) purification to obtain 3- (5-amino-2,4-difluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl)- 1,6-naphthyridine-2 (1H) -one 5b (237 mg, light 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

3- (5-Amino-2,4-difluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one A solution of 5b (237 mg, 0.61 mmol) and methylamine in tetrahydrofuran (3 mL, 6 mmol) was dissolved in 20 mL 1,4-dioxane and reacted in a sealed tube at 100 ° C for 12 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 3- (5-amino-2,4-difluorophenyl) -7- (methylamino)- 1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 5c (168 mg, light yellow solid), yield: 72%.

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

¹ H NMR (400 MHz, 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 = 8.0 Hz, 1H), 6.34 (s, 1H), 5.11-5.09 (m, 2H), 5.04 (s, 2H), 2.85 (d, J = 4.0 Hz, 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

3- (5-Amino-2,4-difluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 ( 1H) -one 5c (168 mg, 0.44 mmol), phenyl 1-fluoro-3-isocyanate 2a (90 mg, 0.66 mmol) and triethylamine (727 mg, 7.2 mmol) dissolved in 10 mL dichloromethane At room temperature, react overnight. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: 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, light yellow solid), yield: 2%.

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

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

3- (5-Amino-2,4-difluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 ( 1H) -one 5c (300 mg, 0.78 mmol), 1-fluoro-4-isocyanate phenyl 4a (321 mg, 2.34 mmol) and triethylamine (394 mg, 3.9 mmol) were dissolved in 20 mL of tetrahydrofuran, Reaction at room temperature overnight. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: 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 (400 MHz, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.18 (t, J = 8.4 Hz, 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-naphthyridine-2 (1H) -one

Combine 6-chloro-4-((2,2,2-trifluoroethyl) amino) nicotinaldehyde 1d (600 mg, 2.52 mmol), 2- (5-amino-2-bromo-4-fluorophenyl) Ethyl acetate 7a (698 mg, 2.52 mmol, prepared according to published patent application WO2013184119) and potassium carbonate (1.04 g, 7.56 mmol) were dissolved in 70 mL of N, N-dimethylformamide and toluene (V: V = 2: 5) The mixed solvent was reacted at 150 ° C for 12 hours. 100 mL of ethyl acetate was added, washed with water (100 mL × 2), saturated sodium chloride solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography Method (eluent: System A) purification to obtain 3- (5-amino-2-bromo-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 7b (660 mg, light 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

3- (5-Amino-2-bromo-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H)- A solution of ketone 7b (160 mg, 0.35 mmol) and methylamine in tetrahydrofuran (1.5 mL, 3 mmol) was dissolved in 5 mL of 1,4-dioxane, and reacted in a sealed tube at 100 ° C for 8 hours. After concentration under reduced pressure, the resulting 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-naphthyridine-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

3- (5-Amino-2-bromo-4-fluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -ketone 7c (114 mg, 0.26 mmol), phenyl isocyanate 1h (34 mg, 0.28 mmol) and triethylamine (130 mg, 1.28 mmol) were dissolved in 20 mL of toluene and dichloromethane (V: V = 1: 1) in the mixed solution, react at room temperature overnight. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 1- (4-bromo-2-fluoro-5- (7- (methylamino) -2-oxo Generation-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 (400 MHz, DMSO- d ₆ ) δ 9.16 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.22-7.20 (m, 1H), 6.99 ( t, J = 7.2 Hz, 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

3-isocyanatobenzo [b] thiophene

Dissolve benzo [b] thiophene-3-carboxylic acid 8a (500 mg, 2.8 mmol) and triethylamine (319 mg, 3.2 mmol) in 10 mL of toluene, and stir at room temperature until 8a is completely dissolved. Diphenyl azide phosphate (847 mg, 3.1 mmol) was added, and the reaction was carried out at 50 ° C for 1 hour, and the reaction was continued at 100 ° C for 0.5 hour. Concentrate under reduced pressure to give the crude product 3-isocyanatobenzo [b] thiophene 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

3- (5-Amino-4-fluoro-2-methylphenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine- 2 (1H) -one 3c (183 mg, 0.48 mmol), 3-isocyanatobenzo [b] thiophene 8b (252 mg, 1.44 mmol) and triethylamine (243 mg, 2.41 mmol) dissolved in 20 mL In tetrahydrofuran, react overnight at room temperature. It was 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 Yl-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 (400 MHz, DMSO- d ₆ ) δ 9.42 (s, 1H), 8.86 (s, 1H), 8.46 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.51 (t, J = 6.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 12 Hz, 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

3- (5-Amino-2,4-difluorophenyl) -7- (methylamino) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 ( 1H) -ketone 5c (200 mg, 0.52 mmol), 3-isocyanatobenzo [b] thiophene 8b (91 mg, 0.52 mmol) and triethylamine (157 mg, 1.56 mmol) dissolved in 5 mL of tetrahydrofuran And react overnight at room temperature. It was concentrated under reduced pressure, and the resulting residue 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 Base) urea 9 (50 mg, white solid), yield: 17%.

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

¹ H NMR (400 MHz, 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 = 8.0 Hz, 1H), 7.71 (s, 1H), 7.51 (t, J = 7.6 Hz, 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 = 4.8 Hz, 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-naphthyridine-2 (1H) -one

3- (5-Amino-2-bromo-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H)- Ketone 7b (340 mg, 0.76 mmol), 2-methoxyethylamine (568 mg, 7.57 mmol) and 1,8-diazabicycloundec-7-ene (DBU) (230 mg, 1.51 mmol ) Dissolved in 7 mL N-methylpyrrolidone, microwave reaction at 180 ℃ for 1.5 hours. 70 mL of water was added, extracted with dichloromethane (100 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was used Silica gel column chromatography (eluent: System A) was purified to obtain 3- (5-amino-2-bromo-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1 -(2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 10a (370 mg, 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

3- (5-Amino-2-bromo-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 10a (100 mg, 0.21 mmol), phenyl 1-fluoro-3-isocyanate 2a (42 mg, 0.31 mmol) and triethylamine (62 mg, 0.62 mmol ) Dissolve in 3 mL of dichloromethane and react overnight at room temperature. It was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing agent: 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 (400 MHz, DMSO- d ₆ ) δ 9.36 (s, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 10.4 Hz, 1H), 7.48 (d, J = 12.4 Hz, 1H), 7.31 (q, J = 8.4 Hz, 1H), 7.27-7.23 (m, 1H), 7.08 ( d, J = 8.0 Hz, 1H), 6.81 (t, J = 8.8 Hz, 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

3- (5-Amino-2-bromo-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 10a (100 mg, 0.21 mmol), phenyl 1-fluoro-4-isocyanate 4a (42 mg, 0.31 mmol) and triethylamine (62 mg, 0.62 mmol ) Dissolve in 3 mL of dichloromethane and react overnight at room temperature. It was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developing agent: 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 (400 MHz, DMSO- d ₆ ) δ 9.21 (s, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.46-7.43 (m, 2H), 7.25-7.24 (m, 1H), 7.13 (t, J = 8.8 Hz, 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-naphthyridine-2 (1H) -one

3- (5-Amino-2-chloro-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H)- Ketone 1f (400 mg, 1 mmol), 2-methoxyethylamine (750 mg, 10 mmol) and 1,8-diazabicycloundec-7-ene (DBU) (304 mg, 2 mmol ) Dissolved in 8 mL N-methylpyrrolidone, microwave reaction at 180 ℃ for 1 hour. Add 100 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (eluent: System A ) Purification to give 3- (5-amino-2-chloro-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl ) -1,6-naphthyridine-2 (1H) -one 12a (400 mg, 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

3- (5-Amino-2-chloro-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 12a (70 mg, 0.16 mmol), phenyl 1-fluoro-3-isocyanate 2a (26 mg, 0.19 mmol) and triethylamine (48 mg, 0.47 mmol ) Dissolve in 3 mL of dichloromethane and react overnight at room temperature. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: 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 (400 MHz, DMSO- d ₆ ) δ 9.36 (s, 1H), 8.80 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.58 (d, J = 10.8 Hz, 1H), 7.50-7.43 (m, 2H), 7.31 (q, J = 6.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 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

3- (5-Amino-2-chloro-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 12a (100 mg, 0.225 mmol), phenyl 1-fluoro-4-isocyanate 4a (37 mg, 0.27 mmol) and triethylamine (68 mg, 0.675 mmol ) Dissolve in 3 mL of dichloromethane and react overnight at room temperature. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: 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 (400 MHz, DMSO- d ₆ ) δ 9.15 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.57 (d, J = 11.2 Hz, 1H), 7.46-7.43 (m, 2H), 7.25-7.23 (m, 1H), 7.13 (d, J = 8.8 Hz, 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

3- (5-Amino-2-chloro-4-fluorophenyl) -7-((2-methoxyethyl) amino) -1- (2,2,2-trifluoroethyl) -1 , 6-naphthyridine-2 (1H) -one 12a (100 mg, 0.225 mmol), 1-isocyanate-4- (trifluoromethyl) phenyl ester 14a (50 mg, 0.27 mmol) and triethylamine ( 68 mg, 0.675 mmol) was dissolved in 3 mL of dichloromethane and reacted at room temperature overnight. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: 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 (400 MHz, DMSO- d ₆ ) δ 9.67 (s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.64 (s, 4H), 7.59 (d, J = 11.2 Hz, 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-naphthyridine-2 (1H) -one

3- (5-Amino-2-chloro-4-fluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H)- Ketone 1f (202 mg, 0.4 mmol), (R) -1-methoxypropan-2-amine (223 mg, 2.5 mmol) and 1,8-diazabicycloundec-7-ene (DBU ) (152 mg, 1 mmol) was dissolved in 4 mL of N-methylpyrrolidone and reacted in a microwave at 180 ° C for 1.5 hours. Add 40 mL of water, extract with dichloromethane (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (eluent: System A ) Purification to give (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 (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

( 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 (100 mg, 0.22 mmol), phenyl 1-fluoro-3-isocyanate 2a (45 mg, 0.33 mmol) and triethyl The amine (66 mg, 0.65 mmol) was dissolved in 2 mL of dichloromethane and reacted overnight at room temperature. It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: 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 (400 MHz, DMSO- d ₆ ) δ 9.38 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.58 (d, J = 10.8 Hz, 1H), 7.48 (d, J = 11.6 Hz, 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 = 7.2 Hz, 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 -Naphthyridine-2 (1H) -one

3- (5-Amino-2,4-difluorophenyl) -7-chloro-1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 5b (500 mg, 1.28 mmol) was dissolved in 5 mL 4-methoxybenzylamine 16a and reacted at 130 ° C overnight. After the reaction was completed, it was cooled to room temperature, 10 mL of a mixed solvent of ethyl acetate and water (V: V = 1: 1) was added, and stirred at room temperature for 30 minutes. Extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (Eluent: System A) Purification to obtain 3- (5-amino-2,4-difluorophenyl) -7-((4-methoxybenzyl) amino) -1- (2,2, 2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 16b (375 mg, light 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-naphthyridine-2 (1H) -one

3- (5-Amino-2,4-difluorophenyl) -7-((4-methoxybenzyl) amino) -1- (2,2,2-trifluoroethyl) -1, 6-naphthyridine-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 was completed, it was cooled to room temperature, concentrated under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added at 0 ° C, extracted with ethyl acetate (30 mL × 2), and the organic phases were combined and saturated sodium chloride solution ( 30 mL), washed with anhydrous sodium sulfate, filtered, concentrated under pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 7-amino-3- (5-amino-2 , 4-difluorophenyl) -1- (2,2,2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 16c (200 mg, light 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 (40.4 mg, 0.4 mmol) in 1 mL of tetrahydrofuran and add 7-amino-3- (5-amino-2,4-difluorophenyl) -1- (2,2, 2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 16c (50 mg, 0.1 mmol), then 1-fluoro-4-isocyanate phenyl ester 4a (13.7 mg, 0.1 mmol) at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue 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, light yellow solid) , Yield: 15%.

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.10 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.10 (t, J = 12.0 Hz, 1H), 7.94 (s, 1H), 7.47-7.37 (m, 3H), 7.12 (t, J = 8.0 Hz, 2H), 6.78 (s, 2H), 6.42 (s, 1H), 5.01 (d, J = 8.0 Hz, 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 (54.6 mg, 0.54 mmol) in 3 mL of tetrahydrofuran and add 7-amino-3- (5-amino-2,4-difluorophenyl) -1- (2,2, 2-trifluoroethyl) -1,6-naphthyridine-2 (1H) -one 16c (100 mg, 0.27 mmol), then 1-fluoro-3-isocyanate phenyl ester 2a (40.76 mg, 0.29 mmol) and react overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue 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), Yield: 41%.

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

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

Biological evaluation

Test case 1 3. The compound of the present invention c-KIT [D816V] Kinase activity assay

The following method was used to determine the degree of inhibition of the kinase activity of recombinant human c-KIT [D816V] (D816V 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) by measuring protein-mediated biotinylation The degree of phosphorylation of the peptides reflects the compound's ability to inhibit protein kinase activity. For detailed experiment operation, please refer to the kit manual. Recombinant human c-KIT [D816V] protein kinase was purchased from Carna bioscience (Japan, catalog number c-KIT [D816V] # 08-505).

The experimental procedure is briefly described as follows: the test compound (compounds listed in Table 1) is first dissolved in DMSO to prepare a storage solution, and then is gradually diluted with the buffer provided in the kit, the final test compound in the reaction system The concentration range is 10 μM ~ 0.1 nM. The concentration of the ATP solution (Biotech Engineering (Shanghai) Co., Ltd., # A600311) used in the test is the pre-determined concentration of ATP Km corresponding to each kinase, of which c-KIT [D816V] has an ATP Km value of 30 μM. The reaction was performed in a 384-well microplate. 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. Then, the ATP solution and the biotinylated peptide receptor were added to the reaction solution. Solution, and after shaking incubation at room temperature for 50 minutes, add anti-phosphorylated tyrosine antibody conjugated with europium compound and streptavidin conjugated with modified allophycocyanin XL665 to the reaction , And continue shaking for 1 hour at room temperature. After the incubation, the fluorescence intensity values of each well at the excitation wavelength of 304 nm, emission wavelengths of 620 nm and 665 nm were measured in a microplate reader in TF-FRET mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and a nonlinear regression analysis of the compound concentration log-inhibition rate was performed by GraphPad Prism 5 software to obtain the compound The IC ₅₀ value is shown in Table 1.

Table 1 IC ₅₀ values of compounds of the present invention for c-KIT [D816V] inhibition

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 the compounds prepared in Example 31, Example 59 and Example 15 disclosed in WO2013184119; the specific structure is as follows:

For the preparation method and structure identification, please refer to Example 31, Example 59 and Example 15 of WO2013184119 respectively;

The preparation method of Reference Compound 4 was prepared by referring to Example 15 of WO2013184119, and the structure was identified as follows:

MS m / z (ESI): 468.8 [M + 1];

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.07 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.12 (t, J = 12.0 Hz, 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 = 4.0 Hz, 2H), 2.88 (d, J = 8.0 Hz, 3H ), 1.23 (t, J = 4.0 Hz, 3H).

Test case 2 3. The compound of the present invention c-KIT [T670I] with c-KIT [V560G / D816V] Kinase activity assay

The following method was 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.

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) by measuring protein-mediated biotinylation The degree of phosphorylation of the polypeptide is reflected by the compound's ability to inhibit protein kinase activity. For detailed experiment operation, please refer to the kit manual. Recombinant human c-KIT [T670I] protein kinase and c-KIT [V560G / D816V] were purchased from Carna bioscience (Japan, article number 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 as a storage solution, and then it is gradient diluted with the buffer provided in the kit, and the final concentration of the test compound in the reaction system The range is 10 μM ~ 0.1 nM. The concentration of the ATP solution (Biotechnology (Shanghai) Co., Ltd., # A600311) used in the test is the ATP Km value concentration corresponding to each kinase determined in advance, and the ATP Km value concentration of c-KIT [T670I] is 30 μM, c-KIT [V560G / D816V] ATP Km value concentration is 10 μM. The reaction is carried out in a 384-well microtiter plate. First, the test compound and the test protein (c-KIT [T670I] 0.66 ng or c-KIT [V560G / D816V] 0.03 ng) are added to the empty well at room temperature Incubate for 5 minutes, then add ATP solution and biotinylated peptide substrate solution to the reaction solution, and after shaking incubation at room temperature for 50 minutes, add anti-phosphorylated tyramine coupled with europium compound to the reaction The acid antibody and streptavidin conjugated with modified allophycocyanin XL665 were incubated with shaking at room temperature for 1 hour. After the incubation, the fluorescence intensity values of each well at the excitation wavelength of 304 nm, emission wavelengths of 620 nm and 665 nm were measured in a microplate reader in TF-FRET mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and a nonlinear regression analysis of the compound concentration log-inhibition rate was performed by GraphPad Prism 5 software to obtain the compound The IC ₅₀ value is shown in Table 2.

Table 2 IC ₅₀ values of compounds of the present invention against c-KIT [T670I] and c-KIT [V560G / D816V]

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

Test case 3 3. The compound of the present invention PDFGRα [D842V] Kinase activity assay

The following method was used to determine the inhibitory effect of the representative compounds 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) by measuring protein-mediated biotinylation The degree of phosphorylation of the peptides reflects the compound's ability to inhibit protein kinase activity. For detailed experiment operation, please refer to the kit manual. Recombinant human-derived PDGFRα [D842V] protein kinase was purchased from Carna bioscience (Japan, article number PDFGRα [D842V] # 08-506).

The experimental procedure is briefly described as follows: the test compound is first dissolved in DMSO to prepare as a storage solution, and then diluted with the buffer provided in the kit, the final concentration range of the test compound in the reaction system is 10 μM-0.1 nM . The concentration of the ATP solution (Biotech Engineering (Shanghai) Co., Ltd., # A600311) used in the test is the pre-determined ATP Km value concentration of 30 μM. The reaction was performed in a 384-well microplate. 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. Then, the ATP solution and the biotinylated peptide receptor were added to the reaction solution. Solution, and after shaking incubation at room temperature for 50 minutes, add anti-phosphorylated tyrosine antibody conjugated with europium compound and streptavidin conjugated with modified allophycocyanin XL665 to the reaction , And continue shaking for 1 hour at room temperature. After the incubation, the fluorescence intensity values of each well at the excitation wavelength of 304 nm, emission wavelengths of 620 nm and 665 nm were measured in a microplate reader in TF-FRET mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), and a nonlinear regression analysis of the compound concentration log-inhibition rate was performed by GraphPad Prism 5 software to obtain the compound The IC ₅₀ value is shown in Table 3.

Table 3 This application represents the IC ₅₀ values of compounds for the inhibition of PDGFRα [D842V]

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

Test case 4 3. The compound of the present invention has an effect on mouse mast cell tumor P815 Activity determination

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

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 is gradually diluted with the corresponding cell culture medium to prepare a test sample. The final concentration range of the compound is 30 μM ~ 0.01 nM. Tumor cells in the logarithmic growth phase were inoculated into a 96-well cell culture dish at a density of 1000 cells / well. After overnight in a 5% CO ₂ incubator at 37 ° C, the cells were continuously cultured for 48 hours after adding a test compound sample. After the incubation, add 10 μL of CCK-8 detection solution to each well and incubate at 37 ° C for 1 to 2 hours. Then read the absorbance value of each well of the sample at 450 nm on a microplate reader. By comparing the absorbance values of the control group (0.3% DMSO), the percentage inhibition rate of the compound at each concentration point was calculated, and then a non-linear regression analysis was performed in the GraphPad Prism 5 software with the logarithm of the compound concentration-inhibition rate to obtain the compound inhibitory cells The IC ₅₀ values for proliferation are shown in Table 4.

Table 4 IC ₅₀ values of compounds of the present invention for inhibiting the activity of mouse mast cell tumor

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

Test case 5 Pharmacokinetic test of the compound of the present invention

1. Summary

Using SD rats as test animals, the concentration of the drug in the plasma at different times after the reference compound 1 and the compound 6 of the present invention were measured by intragastric administration of the rats by LC / MS / MS method was studied. Pharmacokinetic characteristics.

2. Experimental scheme

2.1 Experimental drugs and animals

Reference compound 1 and compound 6 of the present invention;

Six healthy adult male SD rats were divided into 3 groups and purchased from Cyper-Bikai Experimental Animal Co., Ltd.

2.2 Drug preparation and administration

Weigh an appropriate amount of experimental drug, add 0.5% sodium carboxymethylcellulose (CMC-Na), sonicate to dissolve, pipette 100 μL for concentration determination, and configure the solution concentration to 0.3 mg / mL.

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

2.3 Operation

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

3. Results of pharmacokinetic parameters

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

Table 5 Pharmacokinetic data table of the compounds of the present invention

Conclusion: Compared with Reference Compound 1, Compound 6 of the present invention has a higher blood drug concentration and area under the drug-time curve, and at the same time has a longer half-life, and has better pharmacokinetic properties.

Test case 6 、 Preferred compounds of the present invention ICR Mouse pharmacokinetic test

1. Summary

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

2. Experimental scheme

2.1 Experimental drugs and animals

Reference compound 1, compound 5 and compound 6 of the present invention;

54 healthy adult ICR male mice, 31.3 ~ 35.6 g, were divided into 6 groups, A ~ F group, purchased from Beijing Viton Lihua Experimental Animal Technology Co., Ltd. Animal product quality certificate number: 11400700310546.

2.2 Drug preparation and administration

2.2.1 Preparation of intravenous (IV-A) preparations

Weigh an appropriate amount of experimental drug, 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 up 100 μL × 2 is used for concentration determination. The concentration of the prepared solution is 0.2 mg / mL and stored at 2 ~ 8 ° C.

2.2.2 Preparation of intragastric (IG-B) administration preparation

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

2.2.3 Administration

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

2.3 Operation

Before intravenous administration and after administration 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours or before intragastric administration and 0.25 hours after administration, 80 hours of blood was collected via the orbital vein at 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours, placed in an EDTA-K2 anticoagulation tube, and centrifuged at 1500 g for 10 minutes at -40 to -20 Store at ℃ and eat 4 hours after administration. The content of the test compound in the plasma of ICR male mice was determined by LC-MS / MS after injection of different compounds via tail vein and intragastric administration. Based on the blood concentration data at different time points, WinNonlin was used to calculate the 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.

Table 6 Pharmacokinetic data table of intragastric administration of the compound of the present invention in mice

Conclusion: Compared with reference compound 1, mice given compound 5 and compound 6 of the present invention by gavage have a higher maximum blood drug concentration and area under the curve, and have better pharmacokinetic properties.

Table 7 Pharmacokinetic data table of the compound of the present invention for intravenous administration in mice

Conclusion: Compared with reference compound 1, mice given compound 5 and compound 6 of the present invention by intravenous injection have a higher area under the curve and have better pharmacokinetic properties.

no.

no.

Claims (20)

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 one or more of halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic,- 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 an alkyl group, wherein the alkyl group is further substituted by one or more halogens; R ^{3 is the} same or different, and is independently selected from a hydrogen atom, an alkyl group 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 alkyl, alkoxy, cycloalkyl or heterocyclic Optionally further 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 by a substituent; R ^{4 is} selected from aryl or heteroaryl, wherein aryl or heteroaryl is optionally further selected from 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 alkyl or alkoxy is optionally further substituted with one or more halogens; 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 Group, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from 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 attached N atom form a 4-8 member heterocyclic group, of which 4 ～ 8 membered heterocyclic ring contains one or more N, O or S (O) _n , and the 4 ～ 8 membered heterocyclic ring is optionally further selected by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl Base, alkoxy, naphthenic Group, heterocyclic group, aryl group, heteroaryl group, = 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 substituents; R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group , Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, 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, carboxy, or carboxylate substituents; 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 patent application scope, wherein R ^{1 is} selected from alkyl or -C (O) R ⁵ , wherein alkyl is One or more selected from halogen, 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 substituent; preferably, R ^{1 is} selected from C _1-4 alkyl, wherein C _1-4 alkyl is optionally further substituted with one or more C _1-6 alkoxy groups, wherein C _1-6 alkoxy is preferably methoxy. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof as described in item 1 or item 2 of the scope of patent application is a compound or stereoisomer of the general formula (II) , 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) nNR ⁶ R ⁷ or -NR ⁶ C (O) R ⁷ , wherein alkyl, alkoxy The radical, cycloalkyl or heterocyclyl is optionally further selected from one or more of 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 substituents; and R ¹ , R ² , R ⁴ ~ R ¹⁰ and n are defined as described in the first or second patent application. The compound or any of its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 3, wherein: R ^{2 is} selected from C _1-4 alkyl Wherein C _1-4 alkyl is further substituted with one or more halogens; wherein halogen is preferably fluorine, chlorine or bromine; more preferably fluorine; R ^{2 is} preferably trifluoroethyl. The compound or any of its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 3, wherein: R ^{3 is} selected from a hydrogen atom, C _{1- 4} alkyl or halogen; wherein C _1-4 alkyl is preferably methyl or ethyl; and wherein halogen is preferably fluorine, chlorine or bromine. The compound or any of its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in any one of the first to third patent claims, wherein: R ^{4 is} selected from phenyl or benzothiophene 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 alkyl or C _1-6 alkoxy is optionally further substituted with one or more halogens; wherein C _1-4 alkyl is preferably methyl or ethyl; and wherein halogen is preferably fluorine, chlorine or bromine; more preferably fluorine. The compound or any of its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 3, wherein: R ^{1 is} selected from a hydrogen atom or C _1-4 Alkyl, wherein C _1-4 alkyl is optionally further substituted with one or more C _1-6 alkoxy; the C _1-6 alkoxy is preferably methoxy; R ^{2 is} selected from C _{1 -4} alkyl, wherein C _1-4 alkyl is further substituted with one or more halogens selected from fluorine, chlorine or bromine; R ^{3 is} selected from a hydrogen atom, C _1-4 alkyl or halogen, wherein C _{1- 4} alkyl is optionally further substituted with one or more halogens, preferably halogen is fluorine, chlorine or bromine; and R ^{4 is} selected from phenyl or benzothienyl, wherein phenyl or benzothienyl is optional Is further substituted by 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 optionally further substituted by Or more than one halogen; and the halogen is preferably fluorine, chlorine or bromine; more preferably fluorine. The compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 1 or item 2 of the patent application scope, wherein the compound is: A method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 1 or 2 of the scope of patent application, which includes: 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: the definitions of R ¹ to R ⁴ and m are as described in item 1 or item 2 of the patent application scope. A method for preparing a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 3 of the patent application scope includes: 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: the definitions of R ¹ to R ⁴ are as described in item 3 of the patent application scope. An intermediate compound of the general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, Among them: R ¹ ~ R ³ and m are defined as described in item 1 or item 2 of the patent scope. The intermediate compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in Item 11 of the patent application scope are the compounds or stereoisomers of the general formula (IIA), Tautomers or their pharmaceutically acceptable salts, Among them: The definition of R ¹ ~ R ³ is as described in item 11 of the patent application scope. The intermediate compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 11 of the patent application scope, wherein the compound is: A method for preparing an intermediate compound of general formula (IA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 11 of the patent application scope, which includes: 1) When R ¹ When not a hydrogen atom: The compound of formula (Ia) and the compound of formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of formula (Ic); the compound of formula (Ic) is reacted with the compound of formula (Id) to obtain the formula (IA) ); Wherein: X is halogen; Ra is alkyl; and R ¹ ~ R ³ and m are defined as described in item 11 of the patent application scope, and R ^{1 is} not H; and 2) when When R ¹ is a hydrogen atom: The compound of formula (Ia) and the compound of formula (Ib) are subjected to condensation reaction under heating conditions to obtain the compound of formula (Ic); the compound of formula (Ic) is reacted with the compound of formula (Ie) to obtain the formula (I If) compound; the compound of general formula (If) is reacted in the presence of trifluoroacetic acid to obtain an intermediate compound of general formula (IA); wherein: X is halogen; R ¹ is a hydrogen atom; R ^a is alkyl; R ^b Is alkyl; and the definitions of R ² , R ³ and m are as described in item 11 of the patent application scope. A method for preparing an intermediate compound of general formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in item 12 of the patent application scope, which includes: 1) When R ¹ When not a hydrogen atom: The compound of the general formula (Ia) and the compound of the general formula (IIa) are subjected to condensation reaction under heating conditions to obtain the compound of the general formula (IIb); the compound of the general formula (IIb) is reacted with the compound of the general formula (Id) to obtain the general formula (IIA) ) Intermediate compounds; wherein: X is halogen; R ^a is alkyl; and R ¹ to R ³ are as defined in item 12 of the patent application scope, and R ¹ is not H; and 2) When R ¹ is When hydrogen atom: The compound of the general formula (Ia) and the compound of the general formula (IIa) are subjected to condensation reaction under heating conditions to obtain the compound of the general formula (IIb); the compound of the general formula (IIb) is reacted with the compound of the general formula (Ie) to obtain the general formula (IIc) ) Compounds; compounds of general formula (IIc) are reacted in the presence of trifluoroacetic acid to obtain intermediate compounds of general formula (IIA); 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 12 of the patent application scope. A pharmaceutical composition containing an effective dose of the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 8 Pharmaceutical carriers, excipients or combinations thereof. A compound as described in any one of items 1 to 8 of the patent application range or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof or a drug as described in item 16 of the patent application range Use of the composition in the preparation of a medicament for the treatment of diseases mediated by c-KIT or mutated c-KIT, wherein the diseases mediated by c-KIT or mutated c-KIT are preferably gastrointestinal stromal tumors, Systemic mastocytosis, acute myeloid leukemia, ovarian cancer, melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; better Gastrointestinal stromal tumors, systemic mast cell hyperplasia, glioblastoma multiforme and acute myeloid leukemia; best for gastrointestinal stromal tumors, glioblastoma multiforme and systemic mast cell hyperplasia ; Preferably, the mutant c-KIT mutation is located in exons 9, 11, 13, 14, 17, and / or 18, or amino acid residues at position 816, 670, 560, and / or 654 Where the mutation at amino acid residue 816 is better D816V or D816H; where the mutation at amino acid residue 670 is better T670I; where the mutation at amino acid residue 560 is better V560G; where the amino acid residue at position 654 V654A mutation is better. A compound as described in any one of items 1 to 8 of the patent application range or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof or a drug as described in item 16 of the patent application range Use of the composition in the preparation of c-KIT inhibitors. A compound as described in any one of items 1 to 8 of the patent application range or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or as described in item 16 of the patent application range Use of a pharmaceutical composition in the preparation of a medicament for treating a disease mediated by mutant or wild-type PDFGRα, wherein the disease mediated by mutant or wild-type PDFGRα is preferably gastrointestinal stromal tumor, systemic mast cell hyperplasia Disease, acute myeloid leukemia, ovarian cancer, melanoma, cervical cancer, seminoma, dysgerminoma, glioblastoma multiforme, teratoma, mast cell leukemia; more preferably gastrointestinal stromal Tumors, systemic mastocytosis, glioblastoma multiforme, and acute myeloid leukemia; gastrointestinal stromal tumors, glioblastoma multiforme, and systemic mast cell hyperplasia; the mutation is preferred The mutation of PDFGRα is located at exon 18 and / or amino acid residue 842, of which the mutation at amino acid residue 842 is preferably the D842V mutation. A compound as described in any one of items 1 to 8 of the patent application range or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or as described in item 16 of the patent application range Use of the pharmaceutical composition in the preparation of PDFGRα inhibitors.