TW201912645A - Pyrrolotriazine derivative, preparation method and use thereof - Google Patents

Abstract

Disclosed are a pyrrolotriazine derivative, a preparation method and use thereof. Specifically, disclosed are the pyrrolotriazine derivative of formula (I), a pharmaceutically acceptable salt thereof, a preparation method and use thereof as a therapeutic agent, particularly as a c-KIT inhibitor, wherein the definition of each substituent in the formula (I) is the same as defined in the description.

Description

Pyrrolotriazine derivative, preparation method thereof and use thereof

The present application relates to novel pyrrolotriazine derivatives, processes for their preparation and pharmaceutical compositions comprising such derivatives and their use as therapeutic agents, in particular as c-KIT inhibitors.

c-KIT (also known as KIT, CD117 and stem cell factor receptor) 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 the c-KIT receptor and its ligand is a stem cell factor. The receptor has tyrosine protein kinase activity and binding to the ligand SCF results in autophosphorylation of c-KIT and its association with a receptor such as phospholipid inositol 3-kinase (PI3K). Phosphorylation of tyrosine by protein tyrosine kinases is particularly important in cell signaling and can mediate signals of major cellular processes such as proliferation, survival, differentiation, apoptosis, connectivity, invasion and migration. c-KIT mutations are commonly found in DNA encoding the membrane proximal domain (exon 11). They also appear in exons 7, 8, 9, 13, 14, 17 and 18 at a lower frequency. Mutations make c-KIT function independent of activation by SCF, resulting in high cell division rates and possible genomic instability. Functionally increased mutations in the c-KIT gene and expression of constitutive phosphorylation 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 of c-KIT mutations and related drugs are mainly imatinib, sunitinib, dasatinib and PKC412.

c-KIT has been used in gastrointestinal stromal tumors, acute myeloid leukemia, systemic mastocytosis, melanoma, breast adenoma, ovarian tumor, cervical cancer, seminoma, dysplasia, teratoma, It has been found in tissues such as mast cell leukemia that its protein expression level is closely related to the occurrence and development of tumors. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal origin of the gastrointestinal tract. According to the current GIST diagnostic criteria, epidemiological studies show an incidence of 0.66-2.20/100,000. GIST is extremely insensitive to traditional chemotherapy, with less than 5% effective chemotherapy drugs and a median survival rate of only about 18 months. Even with complete tumor resection, the 5-year survival rate of GIST is only 35%-65%, and the recurrence and metastasis rate is 40%-50% within 2 years. Up to 15%-50% of patients in the first diagnosis have metastasis. It was found that the transmembrane tyrosine kinase receptor c-KIT on the surface of stem cell factor and the functional activating mutation of the platelet-derived growth factor receptor PDGFRα gene are the key to the development of GIST. The platelet-derived growth factor receptor (PDGF-R) is a cell surface tyrosine kinase receptor that is a member of the platelet-derived growth factor (PDGF) family. The PDGF subunits PDGF-A and PDGF-B are important regulators of cell proliferation, cell differentiation, cell growth, development, and many diseases including cancer.

With the clinical application of the first-generation inhibitor, Imatinib, the acquired resistance of imatinib has 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. Currently in clinical phase III c-KIT inhibitor drugs include ripretinib developed by Decifera and Avapritinib by Blueprint. A series of c-KIT inhibitor patents have also been published, including WO2014039714, WO2014100620 and WO2015134536A1. 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 to continue. Research and development of new c-KIT inhibitors.

In order to overcome the deficiencies of the prior art, one of the objects of the present application is to provide a novel pyrrolotriazine derivative of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present application have large structural differences from the compounds disclosed in the prior art, and diseases such as gastrointestinal stromal tumors and systemic mastocytosis can be treated or prevented by modulating c-KIT activity.

a compound of the formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (I)

among them:

E is a hydrogen atom or ;

Ring A is selected from cycloalkyl, heterocyclic, aryl and/or heteroaryl; preferably aryl; more preferably phenyl;

W and Q are each independently selected from C and/or N, but the two are not C at the same time; W and Q are preferably N;

D is selected from a chemical bond, -(alkylene)-, -(alkenylene)-, -(alkynylene)-, -(cycloalkylene)-, -(heterocyclylene)-, -C( O)-, -O-, -S-, -S(O)-, -SO ₂ -, -NR ⁶ -, -O-(alkylene)-, -(alkylene)-O-, - NR ⁶ -C(O)-, -C(O)-NR ⁶ -, -(alkylene)-NR ⁶ -, -NR ⁶ -(alkylene)-, -NR ⁶ -C(O)- (alkylene)-, -C(O)-NR ⁶ -(alkylene)-, -NR ⁶ -SO ₂ -, -SO ₂ -NR ⁶ -, -NR ⁶ -SO ₂ -(alkylene And/or -SO ₂ -NR ⁶ -(alkylene)-; wherein the alkylene, alkenylene, cycloalkylene or heterocyclylene group is further further selected from one or more selected from the group consisting of hydroxyl groups , halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C( Substituting the substituents of O) R ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ ;

R ¹ and R ³ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a hydroxyl group, a cyano group, a nitro group, a halogen, and/or —NR ⁶ R ⁷ , wherein the alkane The base, alkoxy, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens; R ¹ and R ^{3 are} preferably a hydrogen atom;

R ² and R ⁵ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a hydroxyl group, a cyano group, a nitro group, a halogen group, a heterocyclic group, an aryl group, a heteroaryl group, and -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ , Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S Substituting (O) a substituent of _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ ;

R ^{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further isolated by one or a plurality of selected from the group consisting of halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁸ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , Substituted with a substituent of -C(O)R ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ ;

R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of 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 and/or a heteroaryl group. Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC Substituting (O) a substituent of R ¹¹ , —S(O) _p NR ⁹ R ¹⁰ and/or —NR ⁹ C(O)R ¹⁰ ;

Alternatively, R ⁶ and R ⁷ together with the N atom to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) _p atoms, and Optionally, the 4-8 membered heterocyclic ring is further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , =O, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -S(O) _p Substituted by a substituent of NR ⁹ R ¹⁰ and/or -NR ⁹ C(O)R ¹⁰ ;

R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, The aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and / or substituted with a substituent of a carboxylate group;

m is selected from 1, 2, 3, 4 and/or 5;

n is selected from 1, 2, 3 and/or 4;

p is selected from 0, 1 and/or 2.

According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

D is -(alkylene)-; preferably methylene;

Wherein the alkylene group is further substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyl group, a halogen, and/or -NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are as defined in formula (I).

According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (II)

among them:

R ^a is a hydrogen atom or an alkyl group; preferably a C _1-6 alkyl group, more preferably a methyl group;

R ^{b is} selected from the group consisting of hydroxyl, halogen and/or -NR ⁶ R ⁷ ;

R ¹ -R ⁷ , m and n are as defined in formula (I).

According to a preferred embodiment of the present application, the compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (III)

among them:

R ^{b is} selected from the group consisting of hydroxyl, halogen and/or -NR ⁶ R ⁷ ;

R ¹ -R ⁷ , m and n are as defined in formula (I).

According to a preferred embodiment of the present application, the compound of the formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (IV)

among them:

R ^{b is} selected from the group consisting of hydroxyl, halogen and/or -NR ⁶ R ⁷ ;

R ¹ -R ⁷ , m and n are as defined in formula (I).

According to a preferred embodiment of the present application, the compound of the formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (V)

among them:

R ^{b is} selected from the group consisting of hydroxyl, halogen and/or -NR ⁶ R ⁷ ;

R ¹ -R ⁷ , m and n are as defined in formula (I).

According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof An acceptable salt wherein each R ² is a hydrogen atom.

According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:

R ⁴ is heteroaryl, preferably pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl, more preferably pyrazolyl, wherein the pyrrole Or a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrimidinyl group or a pyridyl group, optionally further selected from one or more selected from the group consisting of C _1-6 alkyl groups, 4-6 membered heterocyclic groups Substituted with a substituent of /C(O)R ⁸ ;

R ⁸ is a C _1-6 alkyl group.

According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:

R ⁴ is a tetrahydropyridinyl group, wherein the tetrahydropyridinyl group is further further selected from one or more selected from the group consisting of C _1-6 alkyl, 4-6 membered heterocyclic, and/or -C(O)R ⁸ Substituted by a substituent;

R ⁸ is a C _1-6 alkyl group;

Wherein the tetrahydropyridyl group is preferably .

According to a preferred embodiment of the present application, the compound of formula (I), (II), (III), (IV) or (V), or a stereoisomer, tautomer thereof or pharmaceutically thereof thereof Acceptable salts, where:

R ^{5 is} selected from a hydrogen atom, a halogen, an alkyl group and/or an alkoxy group;

The halogen is preferably F or Cl;

The alkyl group is preferably a C _1-6 alkyl group; more preferably a methyl group;

The alkoxy group is preferably a C _1-6 alkoxy group; more preferably a methoxy group.

According to a preferred embodiment of the present application, the compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^a is a hydrogen atom or an alkyl group; preferably a C _1-6 alkyl group, more preferably a methyl group;

R ^{b is} selected from the group consisting of hydroxyl, halogen and/or -NR ⁶ R ⁷ ;

R ¹ , R ² and R ³ are each independently a hydrogen atom or a C _1-6 alkyl group;

R ⁴ is a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is further optionally further selected from one or more selected from C _1-6 alkyl, 3-8 membered cycloalkyl, 4-6 Heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, -OR ⁸ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O) Substituted by a substituent of R ⁸ , -S(O) _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ ;

R ^{5 is} selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and/or a C _1-6 alkoxy group;

R ⁶ and R ⁷ are each independently a hydrogen atom or a C _1-6 alkyl group;

R ⁸ is a C _1-6 alkyl group;

m is selected from 1, 2, 3, 4 and/or 5;

n is selected from 1, 2, 3 and/or 4;

p is selected from 0, 1 and/or 2.

Specific compounds of the present application include, but are not limited to Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.

The present application provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein the compound of the formula (IIA) or a salt thereof is reacted with an R ⁴ -substituted boronic acid ester or boric acid to obtain a compound of the formula (II);

among them:

The R ⁴ substituted boronate is preferably: ;

X ¹ is halogen, preferably Br;

R ¹ -R ⁵ , R ^a , R ^b , m and n are as defined in formula (II).

The present application further provides a process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein the compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to obtain a compound of the formula (II);

among them:

The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;

R ^a is an alkyl group;

R ^b is a hydroxyl group;

R ¹ -R ⁵ , m and n are as defined in formula (II).

The present application provides an additional process for the preparation of a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein the compound of formula (IIC) is reacted under acidic conditions to provide a compound of formula (II);

among them:

R ^a is an alkyl group;

R ^b is -NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are a hydrogen atom;

R ^f is -NH-S(O)R ^e ;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ⁵ , m and n are as defined in formula (II).

Further, the application provides the preparation of a compound of the formula (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

among them:

X ¹ is halogen, preferably Br;

R ¹ -R ³ , R ⁵ , R ^a , R ^b , m and n are as defined in the formula (II).

According to a preferred embodiment of the present application, wherein the compound of the formula (IIA) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof is of the formula (IIIA), (IVA) Or a compound of (VA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

X ¹ is halogen, preferably Br;

R ¹ -R ³ , R ⁵ , R ^b , m and n are as defined in formula (II).

Specific compounds of the formula (IIA) of the present application include, but are not limited to Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.

The application provides a compound of the formula (IIB) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein R ¹ -R ⁵ , m and n are as defined in formula (II).

Specific compounds of the compounds of formula (IIB) include, but are not limited to: Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.

The application provides a compound of the formula (IIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

R ^a is an alkyl group;

R ^f is -NH-S(O)R ^e ;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ⁵ , m and n are as defined in formula (II).

Specific compounds of the compound of formula (IIC) include, but are not limited to Or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof.

The present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein a compound of the formula (IIj) or a salt thereof is reacted with a Grignard reagent to give a compound of the formula (IIA);

among them:

The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;

R ^a is an alkyl group;

R ^b is a hydroxyl group;

X ¹ is halogen, preferably Br;

R ¹ -R ³ , R ⁵ , m and n are as defined in the formula (IIA).

The present application provides a process for the preparation of a compound of formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) has a configuration of ( S ) form or ( R ) form; preferably ( S ) form; a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm); a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);

among them:

The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;

X ¹ is a halogen, preferably Br;

R ^a is an alkyl group;

R ^b is -NR ⁶ R ⁷ ; R ⁶ and R ⁷ are a hydrogen atom;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ³ , R ⁵ , m and n are as defined in the formula (IIA).

The present application provides a process for the preparation of a compound of formula (IIB), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

Wherein the compound of the formula (IIp) is reacted with a compound of the formula (IIs) under basic conditions to give a compound of the formula (IIB);

among them:

X ² is a halogen, preferably Cl or Br;

R ¹ -R ⁵ , m and n are as defined in formula (IIB).

The present application provides a process for the preparation of a compound of formula (IIC), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the reaction shown below:

The compound of the formula (IIm) or a salt thereof is reacted with an R ⁴ -substituted boronic acid ester or boric acid to give a compound of the formula (IIC);

among them:

The R ⁴ substituted boronate is preferably: ;

X ¹ is a halogen, preferably Br;

R ^a is an alkyl group;

R ^f is -NH-S(O)R ^e ;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ⁵ , m and n are as defined in formula (IIC).

Further, the application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.

The application provides a method of inhibiting c-KIT comprising the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or Its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.

The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof Or a pharmaceutical composition thereof for use in the manufacture of a medicament for treating a disease caused by c-KIT or a mutant c-KIT vector, wherein the disease of the c-KIT or the mutant c-KIT vector is preferably selected from the group consisting of Stromal tumor, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; More preferably selected from gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation c-KIT is mutated Located at exon 9, 11, 13, 14, 17, and/or 18, and/or at amino acid residue 816, and/or at amino acid residue 670; wherein the amino acid residue at position 816 The mutation at the base is preferably D816V or D816H, wherein the mutation at the amino acid residue at position 670 is preferably T670I.

The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof Or the use of the pharmaceutical composition thereof for the preparation of a c-KIT inhibitor.

The application provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof Or a pharmaceutical composition thereof for use in the manufacture of a medicament for treating a disease caused by a mutated or wild-type PDFGRα vector, wherein the disease of the PDFGRα or the mutant PDFGRα vector is preferably selected from the group consisting of a gastrointestinal stromal tumor, a system Severe mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; better selected from the gastrointestinal tract Stromal tumors, systemic mastocytosis, and/or acute myeloid leukemia, preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGRα is located in exon 18 and/or At position 842, the amino acid residue at position 842 is preferably a D842V mutation.

The application provides a method of treating a disease mediated by c-KIT or a mutant c-KIT comprising administering to a patient a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula ( a compound of V), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease of the c-KIT or the mutant c-KIT vector is preferably selected from the group consisting of Stromal tumor, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; More preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mastocytosis and/or acute myeloid leukemia, preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of c-KIT The mutation is at position 9, 11, 13, 14, 17, and/or 18 of the exon, and/or at amino acid residue 816, and/or at amino acid residue 670, wherein the amino acid residue at position 816 The mutation at the residue is preferably D816V or D816H; wherein the mutation at the amino acid residue at position 670 is preferably T670I.

The application provides a method of treating a disease caused by PDFGRα or a mutant PDFGRα vector, comprising administering to a patient a therapeutically effective amount of the formula (I), formula (II), formula (III), formula (IV) or formula (V) a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease of the PDFGRα or the mutant PDFGRα vector is preferably selected from the group consisting of gastrointestinal stromal tumors, systemic Mast cell hyperplasia, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma and/or mast cell leukemia; more preferably selected from the gastrointestinal tract A stromal tumor, systemic mastocytosis, and/or acute myeloid leukemia, preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGRα is located in exon 18 and/or The amino acid residue at position 842; wherein the mutation at the amino acid residue at position 842 is preferably a D842V mutation.

Detailed description of the invention

Unless otherwise stated, some of the terms used in this specification and the scope of the patent application are defined as follows:

When "alkyl" as a group or part of a group is meant to include C ₁ -C ₂₀ linear or branched saturated aliphatic hydrocarbon groups having chain. For example, C ₁ -C ₂₀ means 1 to 20 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms , 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms. It is preferably a C ₁ -C ₁₀ alkyl group, more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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 can be substituted or unsubstituted.

"Alkylene" is a divalent alkyl group as defined above. It is preferably a C ₁ -C ₁₀ alkylene group, more preferably a C ₁ -C ₆ alkylene group. For example, C ₁ -C ₁₀ means 1 to 10 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, , i-propyl and so on. The alkylene group may be substituted or unsubstituted.

"Alkenyl" refers to an aliphatic hydrocarbon group containing at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group can be optionally substituted or unsubstituted. The alkenyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.

"Alkenylene" refers to a divalent alkenyl group as defined above. For example, "vinylidene" means the group -CH=CH-. Preferred is a C ₂ -C ₁₀ alkenylene group, more preferably a C ₂ -C ₆ alkenylene group, most preferably a C ₂ -C ₄ alkenylene group. Examples of alkenylene groups include, but are not limited to, ethenylene, i2-propenyl, sub-1, 2- or 3-butenyl, and the like. The alkenylene group may be substituted or unsubstituted. The alkenylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, either straight or branched. Preferred is a C ₂ -C ₁₀ alkynyl group, more preferably a C ₂ -C ₆ alkynyl group, most preferably a C ₂ -C ₄ alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted. An alkynyl group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atom, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 Carbon atom or 20 carbon atoms.

"Alkynylene" means a divalent alkynyl group as defined above, preferably a C ₂ -C ₁₀ alkynylene group, more preferably a C ₂ -C ₆ alkynylene group, most preferably C ₂ -C ₄ Alkynylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propylene-1-propynyl, 2-propynyl, sub-1, 2- or 3-butynyl, and the like. The alkynylene group may be substituted or unsubstituted. The alkynylene group may contain 2 to 20 carbon atoms, for example, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 Carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 One carbon atom or 20 carbon atoms.

"Cycloalkyl" refers to a saturated ("cycloalkyl") or partially saturated monocyclic, fused, bridged, and spiro carbon ring, but none of the rings have a fully conjugated π-electron aromatic system. Preferred is a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.

"Cycloalkylene" is a divalent cycloalkyl group as defined above. Preferred is a C ₃ -C ₁₂ cycloalkylene group, more preferably a C ₃ -C ₈ cycloalkylene group, most preferably a C ₃ -C ₆ cycloalkylene group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. A cycloalkylene group can be substituted or unsubstituted.

"Spirocyclyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), one or more of which may contain One or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. The spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, depending on the number of common spiro atoms between the ring and the ring. 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.

"Fused ring group" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures that share a carbon atom with each other, one or more of which may contain one or more double bonds, However, none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or a 5-membered/6-membered bicycloalkyl group. 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, Decalinyl or tetradecafluorophenanyl.

"Bridge ring group" means 5 to 18 members, containing two or more cyclic structures, sharing two carbon-polycyclic groups which are not directly bonded to each other, and one or more of the rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring. 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 Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted.

"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, acridine , 2-oxo-acridinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, pyridazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Pyridazinyl. The heterocyclic group may be substituted or unsubstituted. The heterocyclic group may contain 3 to 14 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) atoms.

"Spiroheterocyclyl" means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and one or more of the rings may contain one or more a double bond, but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and/or S(O) _p (where p is selected from 0, 1, and/or 2 1, 2, 3 or 4 heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. The spiroheterocyclyl group is classified into a monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl. Spiroheterocyclyl groups may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, 13, four, fifteen, fifteen , 16, 17, or 18) atoms.

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more of which may contain one or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen and/or S(O) _p (where p is selected from 0, 1 and/or 2) heteroatoms, the remaining ring atoms For carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 membered bicyclic fused heterocyclic group. . Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine. The fused heterocyclic group may contain from 3 to 18 (eg, three, four, five, six, seven, eight, nine, ten, eleven, twelve, threeteen, fourteen, fifteen, 15 , 16, 17, or 18) atoms.

"Bridge heterocyclyl" refers to a polycyclic group of 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two atoms which are not directly bonded to each other, one or more rings thereof An aromatic system which may contain one or more double bonds, but none of which has a fully conjugated π-electron, wherein one or more ring atoms are selected from nitrogen, oxygen and/or S(O) _p (where p is selected from 0 a hetero atom of 1, 1 and/or 2), the remaining ring atoms being carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. The bridge heterocyclic group may contain 3 to 18 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, or 18) atoms.

"Heterocyclylene" means a divalent heterocyclic group as described above. It preferably has a 5- to 7-membered monocyclic heterocyclic group or a 7 to 10 membered bicyclic heterocyclic group or a tricyclic heterocyclic group, which may contain 1, 2, 3 or 4 selected from nitrogen, oxygen and/or sulfur. The atom in it. The heterocyclylene group may be substituted or unsubstituted.

"Aryl" means a carbocyclic aromatic system comprising one, two or more rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferably aryl groups are phenyl and naphthyl groups, most preferably phenyl groups. The aryl group may contain from 6 to 10 carbon atoms, for example, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. The aryl group can be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to: with .

"Heteroaryl" means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 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, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, oxazolyl, benzisothiazolyl, benzene And oxazolyl and benzoisoxazolyl. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can contain from 6 to 10 (eg, 6, 7, 8, 9, or 10) atoms. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to: with .

"Alkoxy" means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C ₁ -C ₆ are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo and iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

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

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

"Boc" refers to a tert-butoxycarbonyl group.

"DMSO" refers to dimethyl hydrazine.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

As used herein, "substituted" or "substituted", unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy. , alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, -OR ⁸ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C (O) R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ and/or -NR ⁶ C(O)R ⁷ ;

R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of 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 and/or a heteroaryl group. Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , cycloalkyl, heterocyclic, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC Substituting (O) a substituent of R ¹¹ , -S(O) _P NR ⁹ R ¹⁰ and/or -NR ⁹ C(O)R ¹⁰ ;

Alternatively, R ⁶ and R ⁷ together with the attached N atom form a 4-8 membered heterocyclic group wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) _p atoms, and 4 The 8-membered heterocyclic ring is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =0, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -S(O) _p NR ⁹ R ¹⁰ and / Or substituted with a substituent of -NR ⁹ C(O)R ¹⁰ ;

R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and/or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, The aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid And/or substituted with a substituent of a carboxylic acid ester;

p is selected from 0, 1 and/or 2.

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

"Pharmaceutical composition" means a mixture comprising a compound of the present application, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

Method for synthesizing the compound of the present invention

For the purposes of this application, the present application employs the following technical means.

The preparation method of the compound of the formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:

Reaction of a compound of formula (IIA) or a salt thereof with an R ⁴ -substituted boronic acid ester or boric acid to provide a compound of formula (II);

among them:

The R ⁴ substituted boronate is preferably: ;

X ¹ is halogen, preferably Br;

R ¹ -R ⁵ , R ^a , R ^b , m and n are as defined in formula (II).

An additional method of preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, of the present application, comprising the steps of:

The compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to give a compound of the formula (II);

R ^a is an alkyl group;

R ^b is a hydroxyl group;

R ¹ -R ⁵ , m and n are as defined in formula (II).

Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprises the following steps:

The compound of the formula (IIC) is reacted under acidic conditions to give a compound of the formula (II);

among them:

R ^a is an alkyl group;

R ^b is an amino group;

R ^f is -NH-S(O)R ^e ;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ⁵ , m and n are as defined in formula (II).

The preparation method of the compound of the formula (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound of formula (IIa) is subjected to a Suzuki coupling reaction with a compound of formula (IIb) to give a compound of formula (IIc); the compound of formula (IIc) is hydrolyzed to give a compound of formula (IId); under basic conditions, The compound of (IId) is subjected to a condensation reaction in the presence of a condensing agent to obtain a compound of the formula (IIe); the compound of the formula (IIe) is deprotected to give a compound of the formula (IIf); and under basic conditions, the compound of the formula (IIf) The compound is subjected to a substitution reaction with a compound of the formula (IIg) to give a compound of the formula (IIh); the compound of the formula (IIh) is further reacted with a Grignard reagent (IIi) to give a compound of the formula (IIj); a compound of the formula (IIj) Reacting with a Grignard reagent to obtain a compound of formula (IIA);

among them:

X ¹ is a halogen, preferably Br;

X ² -X ³ are each independently halogen, preferably Cl or Br;

R ^a is an alkyl group;

R ^b is a hydroxyl group;

R ^c is an amino protecting group, preferably a tert-butoxycarbonyl group;

R ^d is an alkyl group, preferably a methyl group or an ethyl group;

R ¹ -R ³ , R ⁵ , m and n are as defined in the formula (IIA).

Another method for preparing a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to the present application, comprises the steps of:

The compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIq); the compound of the formula (IIq) is deprotected to give a compound of the formula (IIr); under basic conditions, the formula (IIr) Substituting a compound with a compound of formula (IIg) to give a compound of formula (IIj); a compound of formula (IIj) is reacted with a Grignard reagent to provide a compound of formula (IIA);

among them:

X ¹ is a halogen, preferably Br;

X ² is a halogen, preferably Cl or Br;

R ^a is an alkyl group;

R ^b is a hydroxyl group;

R ^c is an amino protecting group, preferably a tert-butoxycarbonyl group;

R ¹ -R ³ , R ⁵ , m and n are as defined in the formula (IIA).

An additional method of preparing a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, of the present application, comprising the steps of:

A compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) is of the ( S ) form or the ( R ) form; preferably ( S ) form; and the formula (IIk) is obtained. a compound of formula (IIk) is reacted with a Grignard reagent to give a compound of formula (IIm); a compound of formula (IIm) is reacted under acidic conditions to provide a compound of formula (IIA);

among them:

The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide;

X ¹ is a halogen, preferably Br;

R ^a is an alkyl group;

R ^b is -NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are a hydrogen atom;

R ^e is an alkyl group, preferably a tert-butyl group;

R ¹ -R ³ , R ⁵ , m and n are as defined in the formula (IIA).

The preparation method of the compound of the formula (IIB) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound of the formula (IIe) is reacted with a Grignard reagent (IIi) to give a compound of the formula (IIn); the compound of the formula (IIn) is deprotected to give a compound of the formula (IIp); under basic conditions, the formula (IIp) Substituting a compound with a compound of formula (IIs) to give a compound of formula (IIB);

among them:

X ² is a halogen, preferably Cl or Br;

R ^c is an amino protecting group, preferably a tert-butoxycarbonyl group;

R ¹ -R ⁵ , m and n are as defined in formula (IIB).

Another method for preparing a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, comprises the following steps:

The compound of the formula (IIm) or a salt thereof is reacted with an R ⁴ -substituted boronic acid ester or boric acid to obtain a compound of the formula (IIC); and the compound of the formula (IIC) is reacted under acidic conditions to give a compound of the formula (II);

among them:

The R ⁴ -substituted boronate is preferably: ;

X ¹ is a halogen, preferably Br;

R ^a is an alkyl group;

R ^f is -NH-S(O)R ^e ;

R ^e is an alkyl group, preferably a tert-butyl group;

The definitions of R ¹ -R ⁵ , m and n are as described in (IIC).

Further, the compound of the formula (II), when R ^{b is} selected from different substituents, can be converted between the groups, in particular, the compound of the formula (II-2) or the compound of the formula (II-2) or A method of preparing a pharmaceutically acceptable salt, comprising the steps of:

Reaction of a compound of formula (II-1) with N,N-diethyl-1,1,1-trifluoro-λ ⁴ -sulfonamide to give a compound of formula (II-2);

among them:

R ^b1 is a hydroxyl group;

R ^b2 is F;

R ¹ -R ⁵ , R ^a , m and n are as defined in formula (II).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, acridine, N-methylpyridazine and/or 4-dimethylamine. Pyridine, preferably diisopropylethylamine and triethylamine; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and/or potassium hydride, preferably cesium carbonate and potassium carbonate.

Condensing reagents include, but are not limited to, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, bis(2-oxo-3- Oxazolidinylphosphinium chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, o-benzotriazole-N,N,N'N' Tetramethyluronium borate (TBTU), preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

Coupling reagents include, but are not limited to: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) Dipalladium or tri-tert-butylphosphine palladium is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

The Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide.

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The examples give the preparation of representative compounds represented by formula (I) and related structural identification data. It is to be noted that the following examples are intended to illustrate the invention and not to limit the invention.

^{The 1} H NMR spectrum was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. Tetramethyl decane internal standard (0.00 ppm) was used. ¹ H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, its unit is Hz.

Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet. The specification of the tannin sheet used for thin layer chromatography (TLC) is 0.15mm-0.2mm. The specification for thin layer chromatography separation and purification is 0.4. Mm-0.5mm.

Column chromatography generally uses Yantai Huanghai Silicone 200-300 mesh gelatin as a carrier.

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

CD ₃ OD: Deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl hydrazine.

The argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.

There is no particular description in the examples, and the solution in the reaction means an aqueous solution.

The compound is purified by a silica gel chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate systems; B: dichloromethane and methanol systems; Dichloromethane and ethyl acetate; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and it may be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.

Example 1 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine

6-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1a (4.8 g, 22.43 mmol) was dissolved in 100 mL of phosphorus oxychloride at 130 ° C Reaction for 3 hours. The organic layer was extracted with dichloromethane (100 mL×3), and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. The sodium was dried and concentrated under reduced pressure to give 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b (5.15 g, brown solid).

Second step 2-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid ethyl ester

Ethyl 2-chloropyrimidine-5-carboxylate 1c (1.9g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron under argon Heterocyclic pentane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1d (3.4 g, 11.00 mmol), [1,1'-bis(diphenylphosphino) Ferrocene] palladium dichloride (1.5 g, 1.20 mmol), cesium carbonate (6.6 g, 20.00 mmol) dissolved in 66 mL of 1,4-dioxane/water (V/V = 10/1). The reaction was carried out at 60 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate (150 mL), and then washed with water (30 mL×2) and saturated aqueous sodium chloride (30 mL). Purification by chromatography (eluent: A system) to give ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e (1.5 g, white solid), yield: 54.2%.

Step 3 2-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid

Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e (1.5 g, 5.42 mmol) was dissolved in 15 mL of THF. 10 mL of 1 M aqueous sodium hydroxide solution was added dropwise, and the mixture was reacted at room temperature for 5 hours. The tetrahydrofuran was concentrated under reduced pressure, and 20 mL of water was added, and the pH was adjusted to about 2-3 with a 1 M aqueous hydrochloric acid solution, and a white solid product was precipitated in large portions, filtered and dried to give crude 2-(1-(tert-butoxycarbonyl)-1. 2,3,6-Tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f (1.21 g, pale yellow solid), yield: 89.6%.

The fourth step 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

2-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f (1.21 g, 4.86 mmol) was dissolved in 50 mL dichloromethane , N,N-diisopropylethylamine (3.13 g, 24.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea Fluorophosphate (3.79 g, 9.72 mmol) and N,O-dimethylhydroxylamine hydrochloride (711 mg, 7.29 mmol) were reacted for 6 hours at room temperature. The reaction mixture was diluted with 150 mL of dichloromethane and washed with water (20 mL×2), 1M aqueous hydrochloric acid (20 mL), saturated aqueous sodium hydrogen carbonate (20 mL) and saturated aqueous sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. EtOAcjjjjjjjj Pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (1.18 g, white solid), yield: 83.1%. MS m/z (ESI): 292.9 [M-55]

Step 5 4-(5-(4-Fluorobenzylidinyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (under argon) 1.18 g, 3.39 mmol) was dissolved in 15 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and 4-fluorophenylmagnesium bromide (13.6 mL, 1 M/THF) was added dropwise, and reacted at room temperature for 4 hours. . The reaction mixture was quenched with aq. EtOAc EtOAc (EtOAc)EtOAc. Concentration by pressure, the residue obtained is purified by silica gel column chromatography (eluent: A system) to give 4-(5-(4-fluorobenzylidenyl)pyrimidin-2-yl)-3,6- Hydrogenpyridine-1(2H)-tert-butyl formate 1h (0.88 g, white solid), yield: 69.3%. MS m/z (ESI): 327.9 [M-55]

Step 6 (4-Fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone

Dissolve 4-(5-(4-fluorobenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1h (880 mg, 2.36 mmol) in 10 In mL of dichloromethane, 2 mL of trifluoroacetic acid was added and reacted at room temperature for 2 hours. Concentration under reduced pressure gave (4-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i (667 mg, brown oil) , used directly in the next step, yield: 100%. MS m/z (ESI): 283.9 [M+1]

Step 7 (2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(4-fluorophenyl)methanone

(4-Fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i (667 mg, 2.36 mmol) dissolved in 15 mL of dichloro N,N-diisopropylethylamine (1.2 g, 9.44 mmol) was added dropwise to methane, and stirred at room temperature for 5 minutes, then 6-bromo-4-chloropyrrolo[2,1-f][1, 2,4] Triazine 1b (657 mg, 2.83 mmol) was reacted at room temperature for 12 hours. The organic layer was washed with water (10 mL), 1M aqueous hydrochloric acid (10 mL) and saturated aqueous sodium chloride (20 mL). Drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (2-(1-(6-bromopyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (205 mg, White solid), Yield: 17.7%. MS m/z (ESI): 480.8 [M+1]

Step 8 1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)-yl)-1-(4-fluorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (200 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in ice water bath. Methylmagnesium bromide (4.2 mL, 1 M/THF) was reacted for 3 hours at room temperature. The reaction was quenched by the addition of 10 mL of a saturated aqueous solution of ammonium chloride at 0 ° C. The THF was evaporated under reduced pressure. The residue was diluted with 50 mL of ethyl acetate. Washed with a saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and evaporated evaporated. (1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5 -yl)-1-(4-fluorophenyl)ethan-1-ol 1k (180 mg, white solid), yield: 87.1%. MS m/z (ESI): 494.8 [M+1]

The ninth step 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (180 mg, 0.36 mmol), 1-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (151 mg, 0.73 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride (51 mg, 0.07 mmol), potassium carbonate (100 mg, 0.73 mmol) dissolved in 16.5 mL 1,4-dioxane/water (V/V=10/1 In the reaction, the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with water (10 mL × 2) and brine (30 mL). Purification by chromatography (eluent: A system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)e-1- Alcohol 1 (136.8 mg, white solid), yield: 92.4%. MS m/z (ESI): 496.9 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H), 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 ( s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).

Example 2 and Example 3 ( S )-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[ 2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 2 ( R )-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3

First step ( S )-1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 2 ( R )-1 -(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4 Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3

1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2 , 4] triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 1 (136.8 mg, 0.27 mmol) further by use Supercritical fluid chromatography (SFC), separation by high performance liquid chromatography and chiral column chiral isomers (chiralPak AS, 250 × 30 mm ID, 5 μm; 60 mL/min; flow The phase A is CO ₂ and the mobile phase B is methanol (0.1% NH ₃ .H ₂ O)), and ( S )-1-(4-fluorophenyl)-1-(2-(1-() 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 2 (44.3 mg, white solid), yield: 32.4%, 98.7% ee, retention time: 4.39 min; ( R )-1-( 4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]3 Pyrazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 3 (60.75 mg, white solid), yield: 44.4%, 100.0 % ee, retention time: 5.75 min.

Compound 2

MS m/z (ESI): 496.9 [M+1]

1H NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H) , 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 (s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).

Compound 3

MS m/z (ESI): 497.0 [M+1]

1H NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.44-7.40 (m, 2H) , 7.32 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.76 (s, 2H), 4.20 (d, J = 4.0 Hz, 2H), 3.96 (s, 3H), 2.96 (s, 2H), 2.01 (s, 3H).

Example 4 1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 (2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one

The first step is 1-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 (2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (200 mg, 0.40 mmol), 1-(4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 4a (201 mg, 0.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59 mg, 0.08 mmol) and potassium carbonate (110 mg, 0.80 mmol) dissolved in 11 mL 1,4 In a dioxane/water (V/V = 10/1), the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with water (20 mL×2) and brine (20 mL). Purification by chromatography (eluent: A system) to give 1-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl) -3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1 (2H)-yl)ethan-1-one 4 (123.8 mg, white solid), yield: 57.5%. MS m/z (ESI): 539.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H) , 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s, 2H) ), 4.18-4.08 (m, 4H), 3.77 (s, 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).

Example 5 and Example 6 (S)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3 ,6-Dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1 (2H) -yl)ethan-1-one 5(R)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl) -3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1 ( 2H)-yl)ethan-1-one 6

First step (S)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-di Hydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl) 1-ketone 5 (R)-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6 -dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl ) ethyl-1-ketone 6

1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1 (2H) )-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 4 ( 123 mg, 0.23 mmol) Further resolution by high-performance liquid chromatography and chiral column chiral isomers by supercritical fluid chromatography (SFC) (chiral Pak AS, 250 × 30 mm ID) , 5 μm; 60 mL/min; mobile phase A is CO ₂ and mobile phase B is methanol (0.1% NH ₃ .H ₂ O)), and ( S )-1-(4-(4-(4) is obtained. -(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1- f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-yl)ethan-1-one 5 (47.77 mg, white solid), yield: 38.8 %, 100% ee, retention time: 7.45 min; ( R )-1-(4-(4-(4-(5-(1-(4-fluorophenyl)-1-hydroxyethyl)pyrimidine-2) -yl)-3,6-dihydropyridine-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine -1(2H)-yl)ethan-1-one 6 (55.06 mg, white solid), yield: 44.8%, 100% ee, retention time: 11.83 min.

Compound 5 MS m/z (ESI): 539.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s , 2H), 4.18-4.08 (m, 4H), 3.77 (s, 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).

Compound 6 MS m / z (ESI) : 539.9 [M + 1] 1 H NMR (400 MHz, CDCl 3) δ 8.66 (s, 2H), 7.81 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.34 (s, 1H), 7.19 (t, J = 4.0 Hz, 2H), 6.74 (s, 1H), 6.05-5.98 (m, 1H), 5.23 (s , 2H), 4.18-4.08 (m, 4H), 3.77 (s, 1H), 3.61 (s, 1H), 2.88 (s, 2H), 2.51-2.46 (m, 2H), 2.08 (d, J = 4.4 Hz, 3H), 1.93 (s, 3H).

Example 7 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol

First Step 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (494 mg, 0.30 mmol), 1-ethyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (135 mg, 0.60 mmol), [1,1'-bis(diphenyl) Phosphine (ferrocenyl) ferrocene] palladium dichloride (44 mg, 0.06 mmol) and potassium carbonate (83 mg, 0.60 mmol) dissolved in 11 mL 1,4-dioxane/water (V/V=10/ In 1), the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with water (20 mL×2) and brine (20 mL). Purification by chromatography (eluent: A system) gave 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)e-1- Alcohol 7 (46 mg, white solid), yield: 9.3%. MS m/z (ESI): 510.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 2H), 7.91 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H) , 7.54 (s, 1H), 7.35 (q, J = 4.0 Hz, 2H), 7.24 (s, 1H), 6.98 (t, J = 8.0 Hz, 2H), 6.80 (s, 1H), 4.69 (s, 2H), 4.17-4.12 (m, 4H), 2.90 (s, 2H), 1.93 (s, 3H), 1.47 (d, J = 8.0 Hz, 3H).

Example 8 1-(4-Chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 , 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide

4-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (14.0 g, 40.0 mmol Dissolved in 140 mL of dichloromethane, added with 36 mL of trifluoroacetic acid, and reacted at room temperature for 1 h. Concentration under reduced pressure gave crude N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide 8a (9.94 g, brown oil Form), directly used in the next reaction, yield: 100%.

The second step 2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- -N-methoxy-N-methylpyrimidine-5-carboxamide

Dissolving N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide 8a (9.94 g, 40.1 mmol) in 100 mL N,N-diisopropylethylamine (31.03 g, 240.5 mmol) was added dropwise to dichloromethane, and stirred at room temperature for 5 min, then 6-bromo-4-chloropyrrolo[2,1-f][ 1,2,4]triazine 1b (9.72 g, 42.1 mmol) was reacted at room temperature for 3 hours. Dichloromethane was evaporated under reduced pressure, and 100 mL of isopropyl alcohol was added and left overnight. The product was precipitated, filtered, and the filter cake was washed with isopropyl alcohol (50 mL×2) and petroleum ether (50 mL×2) and then dried to give 2-(1-(6-bromopyrrolo[2,1-f] ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (10.97 g, milky white solid), yield: 62%. MS m/z (ESI): 443.1 [M+1]

The third step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(4-chlorophenyl)methanone

2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection -4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.8 g, 4.06 mmol) was dissolved in 50 mL of THF, and the mixture was cooled to 0 ° C with ice water bath. 4-Chlorophenylmagnesium bromide (20.2 mL, 1 M/THF) was added dropwise and allowed to react at room temperature for 0.5 hour. The reaction was quenched with 50 mL of water. EtOAc (EtOAc m. The residue was dried over anhydrous sodium sulfate and evaporated and evaporated.]]]]]]]]]]] ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-chlorophenyl)methanone 8c (1.5 g, pale yellow solid), yield: 75%.

The fourth step 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-chlorophenyl)methanone 8c (1.5 g, 3.02 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. Methylmagnesium bromide (24.2 mL, 1 M/THF) was reacted at room temperature for 0.5 h. The reaction was quenched by the addition of 50 mL of ice water at 0 ° C, and the mixture was evaporated to dryness, and the residue was evaporated to ethyl ether (60 mL × 3). The organic layer was dried over anhydrous sodium sulfate (MgSO4) f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl) -1-Alcohol 8d (1.2 g, white solid), Yield: 76.8%.

Step 5 1-(4-Chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethan-1-ol 8d (600 mg, 1.17 mmol), 1-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (366 mg, 1.76 mmol), [1,1'-bis(diphenylphosphine) Base ferrocene] palladium dichloride (171.3 mg, 0.23 mmol), potassium carbonate (323 mg, 2.34 mmol) dissolved in 12 mL 1,4-dioxane/water (V/V = 10/1) The reaction was carried out at 90 ° C for 5 hours. The reaction mixture was diluted with water (30 mL × 2) and brine (40 mL). Purification by chromatography (eluent: C system) to give 1-(4-chlorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)e-1- Alcohol 8 (256 mg, white solid), yield: 42.7%. MS m/z (ESI): 512.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 2H), 7.88 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H) , 7.57 (s, 1H), 7.45-7.28 (m, 5H), 6.84 (s, 1H), 4.74 (s, 2H), 4.20 (t, J = 8.0 Hz, 2H), 3.94 (s, 3H), 2.95 (s, 2H), 2.00 (s, 3H).

Example 9 1-(4-Chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

The first step is 1-(4-chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-chlorophenyl)ethan-1-ol 8d (200 mg, 0.39 mmol), 1-ethyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (174 mg, 0.78 mmol), [1,1'-bis(diphenylphosphine) Base ferrocene] palladium dichloride (57.1 mg, 0.078 mmol) and potassium carbonate (108 mg, 0.78 mmol) dissolved in 11 mL of 1,4-dioxane/water (V /V = 10/1) The reaction was carried out at 90 ° C for 5 hours. The reaction mixture was diluted with water (25 mL×2) and brine (30 mL). Purification by chromatography (eluent: C system) to give 1-(4-chlorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)e-1- Alcohol 9 (52 mg, white solid), yield: 25.4%. MS m/z (ESI): 526.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 2H), 7.90 (s, 1H), 7.71 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.62 (s, 1H), 7.39-7.26 (m, 5H), 6.85 (s, 1H), 4.75 (s, 2H), 4.25-4.20 (m, 4H), 2.96 (s , 2H), 2.00 (s, 3H), 1.55 (t, J = 7.2 Hz, 3H).

Example 10 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol

First step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(p-tolyl)methanone

2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection 4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (800 mg, 1.8 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath. 4-Methylphenylmagnesium bromide (7.2 mL, 1 M/THF) was added dropwise and allowed to react at room temperature for 0.5 hour. The reaction was quenched with 5 mL of EtOAc EtOAc EtOAc. The organic layer was washed with an aqueous solution and dried over anhydrous sodium sulfate (MgSO4). , 1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(p-tolyl)methanone 10a (680 mg, yellow solid), yield: 79%.

The second step 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(p-tolyl)methanone 10a (680 mg, 1.43 mmol) was dissolved in 15 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C with ice-water bath. Magnesium bromide (14.4 mL, 1 M/THF) was reacted at room temperature for 0.5 h. The reaction was quenched by the addition of 5 mL of saturated ammonium chloride at 0 ° C. The mixture was evaporated to dryness and evaporated to ethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: C system) to give 1-(2-(1-(6) -Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1 -(p-tolyl)ethan-1-ol 10b (401 mg, yellow solid), yield: 56.9%.

The third step 1-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10b (150 mg, 0.31 mmol), 1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (127.3 mg, 0.62 mmol), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (45.4 mg, 0.06 mmol) and potassium carbonate (85.6 mg, 0.62 mmol) dissolved in 11 mL of 1,4-dioxane/water (V /V = 10/1), 90° C reacted for 5 hours. The reaction mixture was diluted with water (40 mL×2) and brine (40 mL). Chromatography (eluent: C system) to give 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10 (18 mg, white solid), Yield: 11.8%. MS m/z (ESI): 493.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ (s, 2 H), 7.94 (s, 1 H), 7.72 (s, 2 H), 7.56 (s , 1 H), 7.31 (d, J = 8.0 Hz, 3 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.92 (s, 1 H), 4.78 (s, 2 H), 4.24 (s , 2 H), 3.96 (s, 3 H), 3.00 (s, 2 H), 2.35 (s, 3 H), 2.00 (s, 3 H).

Example 11 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol

First Step 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetra Hydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 10b (150 mg, 0.31 mmol), 1-ethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (137.6 mg, 0.62 mmol), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (45.4 mg, 0.06 mmol) and potassium carbonate (85.6 mg, 0.62 mmol) dissolved in 11 mL of 1,4-dioxane/water (V/V=10/1), 90 The reaction was carried out at ° C for 5 hours. The reaction mixture was diluted with water (40 mL × 2) and brine (40 mL). Purification by chromatography (eluent: C system) to give 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(p-tolyl)ethan-1-ol 11 (26 mg, white solid), yield: 16.5%. MS m/z (ESI): 507.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ (s, 2 H), 7.92 (s, 1 H), 7.71 (d, J = 6.8 Hz, 2 H ), 7. 62 (s, 1 H), 7.31 (d, J = 8.4 Hz, 3 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.88(s, 1 H), 4.76 (s, 2 H), 4.25-4.19 (m, 4H), 2.98 (s, 2 H), 2.35 (s, 3 H), 1.99 (s, 3 H), 1.54 (t, J = 7.6 Hz, 3 H).

Example 12 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

The first step is 1-(4-fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-propyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 12a (151 mg, 0.60 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL 1,4-dioxane/water (V/V=10/1 In the reaction, the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with water (20 mL×2) and brine (20 mL). Purification by chromatography (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-propyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)e-1- Alcohol 12 (30 mg, white solid), yield: 19.1%. MS m/z (ESI): 525.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 2H), 7.76 (s, 1H), 7.56 (s, 2H), 7.50 (s, 1H), 7.35-7.32 (m, 2H), 7.20 (s, 1H), 6.95 (t, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.63 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 4.00 (t, J = 6.8 Hz, 2H), 2.85 (s, 2H), 1.90 (s, 3H), 1.83 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.6 Hz, 3H).

Example 13 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

first step

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine 13a (135 mg, 0.60 mmol), [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL 1,4-dioxane/water (V/V = 10/1), the reaction was carried out at 90 ° C for 4 hours. The reaction mixture was diluted with water (20 mL×2) and brine (20 mL). Purification by chromatography (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1,2,3,6-tetra) Hydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5 -yl)ethan-1-ol 13 (25 mg, gray solid), yield: 16.3%. MS m/z (ESI): 512.0 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.81 (s, 2H), 7.83 (d, J = 16.0 Hz, 2H), 7.53-7.49 (m, 2H ), 7.26 (s, 1H), 7.16 (t, J = 8.4 Hz, 3H), 6.23 (s, 1H), 6.18 (s, 1H), 4.72 (s, 2H), 4.14 (t, J = 5.6 Hz) , 2H), 3.01 (s, 2H), 2.79 (s, 2H), 2.57-2.56 (m, 2H), 2.50-2.48 (m, 2H), 2.28 (s, 3H), 1.90 (s, 3H).

Example 14 1-(4-Fluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step (oxetan-3-yl)p-toluenesulfonate

Oxetane-3-alcohol 14a (2.0 g, 27.0 mmol), triethylamine (10.9 g, 108.0 mmol) and 4-dimethylaminopyridine (330 mg, 2.7 mmol) were dissolved in 20 mL dichloromethane. p-Toluenesulfonic acid (10.3 g, 54.0 mmol) was added and the reaction was carried out for 12 hours at room temperature. The organic layer was extracted with water (25 mL×3) and saturated aqueous sodium chloride (25 mL×1). Drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel chromatography (eluent: A system) to give (oxetane-3-yl)p-toluenesulfonate 14b (3.2 g, white solid), Yield: 51.9%.

Second step 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole

(Oxetane-3-yl)p-toluenesulfonate 14b (1.4 g, 6.1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-di Oxoborolan-2-yl)-1H-pyrazole 14c (1.0 g, 5.2 mmol) and cesium carbonate (5.0 g, 15.5 mmol) were dissolved in 20 mL of acetonitrile and allowed to react at room temperature for 3 hours. The organic layer was extracted with water (30 mL×3) and saturated aqueous sodium chloride (30 mL×1). The organic layer was dried (MgSO4) , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (482 mg, white solid), yield: 37.4%.

The third step is 1-(4-fluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol 1k (150 mg, 0.30 mmol), 1-(oxetan-3-yl) -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (150 mg, 0.60 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and cesium carbonate (195.6 mg, 0.60 mmol) dissolved in 11 mL 1,4-dioxane In the ring/water (V/V = 10/1), the reaction was carried out at 100 ° C for 4.5 hours. The reaction mixture was diluted with 50 mL of EtOAc. EtOAc (EtOAc)EtOAc. Purification by gel column chromatography (eluent: C system) to give 1-(4-fluorophenyl)-1-(2-(1-(6-(1-(oxetane-3-yl)) -1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl Pyrimidine-5-yl)ethan-1-ol 14 (10 mg, white solid), yield: 6.2%. MS m/z (ESI): 538.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.82 (s, 2H), 8.34 (s, 1H), 8.01 (d, J = 11.2 Hz, 2H), 7.88 (s, 1H), 7.53-7.49 (m, 2H), 7.32 (s, 1H), 7.27 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 6.19 (s, 1H), 5.58 (t, J = 6.8 Hz, 1H), 4.98-4.89 (m, 4H), 4.74 (s, 2H), 4.16 (s, 2H), 2.82 (s, 2H), 1.90 (s, 3H).

Example 15 1-(4-Methoxyphenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step (1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-(3H)-one

6-Bromopyrrolo[2,1-F][1,2,4]triazin-4(1H)-one 1a (8.00 g, 37.38 mmol), 1-methyl-4- under argon (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (15.56 g, 74.76 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (2.74 g, 3.74 mmol) and cesium carbonate (36.54 g, 112.14 mmol) dissolved in 150 mL of 1,4-dioxane/ethanol/water ( In V/V/V = 10/4/1), the reaction was carried out at 120 ° C for 6 hours. The organic layer was extracted with water (100 mL×3) and saturated aqueous sodium chloride (100 mL×1). Drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (1-methyl-1H-pyrazol-4-yl)pyrrolo[2 , 1-f][1,2,4]triazin-4-(3H)-one 15a (3.23 g, yellow solid), yield: 40.2%.

Step 2 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-(3H)-one 15a (3.23 g, 15.02 mmol) Dissolved in 100 mL of phosphorus oxychloride and reacted at 130 ° C for 3 hours. The organic layer was extracted with dichloromethane (100 mL×3), and the organic phase was washed with 100 mL of saturated aqueous sodium chloride. Drying, concentration under reduced pressure, and the residue obtained is purified by silica gel column chromatography (eluent: B system) to give 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrole. [2, 1-f][1,2,4]triazine 15b (1.52 g, yellow solid), yield: 43.2%.

The third step (4-methoxyphenyl) magnesium bromide

Under the protection of argon, magnesium swarf (294 mg, 12.1 mmol) and 1 iodine were dissolved in 10 mL of tetrahydrofuran, and 1-bromo-4-methoxybenzene 15c (4.5 g, 24.2 mmol) was dissolved in 2 mL of tetrahydrofuran. 0.2 mL of the solution was added dropwise to the above reaction solution, and the bottom of the reaction bottle was blown with a blower to initiate a reaction, and then the remaining 1-bromo-4-methoxybenzene solution was slowly added dropwise to the reaction solution, and kept. The reaction was slightly refluxed, and the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (4-methoxyphenyl)magnesium bromide 15d (12 mL, EtOAc m.

The fourth step 4-(5-(4-methoxybenzimidyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (under argon) 500 mg, 1.4 mmol) dissolved in 10 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and (4-methoxyphenyl)magnesium bromide 15d (8.6 mL, 1M/THF) was added dropwise. The reaction was carried out for 1 hour under temperature. The reaction was quenched with 50 mL of aq. EtOAc EtOAc. Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography (eluent: A system) to give 4-(5-(4-methoxybenzylidenyl)pyrimidin-2-yl)-3 , 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 15e (228 mg, white solid), yield: 40%.

Step 5 (4-Methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone

Dissolve 4-(5-(4-methoxybenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 15e (169 mg, 0.43 mmol) In 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (4-methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15f (126 mg, brown oil ), yield: 100%, used directly in the next step.

The sixth step (4-methoxyphenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-12,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)methanone

(4-Methoxyphenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15f (126 mg, 0.43 mmol) and 4-chloro -6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 15b (100 mg, 0.43 mmol) dissolved in 5 mL dichloromethane Then, N,N-diisopropylethylamine (332 mg, 2.57 mmol) was added, and the mixture was reacted at room temperature for 12 hours. The organic layer was concentrated under reduced pressure, and 15 mL of isopropyl alcohol was added and stirred for 10 minutes to precipitate a solid product which was filtered, and the filter cake was washed with isopropyl alcohol (5 mL × 2) and dried to give (4-methoxyphenyl) (2-( 1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-12,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15 g (180 mg, white solid), yield: 85%. MS m/z (ESI): 492.9 [M+1]

Step 7 1-(4-Methoxyphenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

(4-methoxyphenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1] under argon , 2,4]triazin-4-yl)-12,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 15g (180 mg, 0.34 mmol), dissolved in 8 mL of tetrahydrofuran The reaction liquid was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (2.9 mL, 1 M / THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched with 50 mL of aq. EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography (eluent: A system) to give 1-(4-methoxyphenyl)-1-(2-(1-(6-) 1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine- 4-yl)pyrimidin-5-yl)ethan-1-ol 15 (31.9 mg, pale yellow solid), yield: 18.7%. MS m/z (ESI): 509.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 2H), 7.91 (s, 1H), 7.70 (d, J = 6.4 Hz, 2H) , 7.58 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.30 (s, 1H), 6.89 (s, 1H), 6.87 (s, 2H), 4.76 (s, 2H), 4.21 ( t, J = 1.4 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 2.97 (s, 2H), 1.99 (s, 3H).

Example 16 1-(3,4-Difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

first step

(3,4-difluorophenyl)magnesium bromide

Under argon protection, magnesium swarf (294 mg, 12.1 mmol) and 1 iodine were dissolved in 10 mL of tetrahydrofuran, and 4-bromo-1,2-difluorobenzene 16a (3.9 g, 20.4 mmol) was dissolved in 2 mL. In tetrahydrofuran, 0.2 mL was added dropwise to the above reaction solution, and the bottom of the reaction bottle was blown with a blower to initiate a reaction, and then the remaining 4-bromo-1,2-difluorobenzene solution was slowly added dropwise to the reaction solution. The reaction was kept at a slight reflux, and the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (3,4-difluorophenyl)magnesium bromide 16b (12 mL, m.j.

Step 2 4-(5-(3,4-Difluorobenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (under argon) 800 mg, 2.30 mmol) was dissolved in 15 mL of tetrahydrofuran, the reaction solution was cooled to 0 ° C in an ice water bath, and (3,4-difluorophenyl)magnesium bromide 16b (6.8 mL, 1 M/THF) was added dropwise. The reaction was carried out for 1 hour at room temperature. The reaction was quenched with 50 mL of aq. EtOAc EtOAc. Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography (eluent: A system) to give 4-(5-(3,4-difluorobenthyl)pyrimidin-2-yl)- 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 16c (670 mg, white solid), yield: 72.8%. MS m/z (ESI): 345.9 [M-55]

The third step (3,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone

4-(5-(3,4-Difluorobenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 16c (570 mg, 1.43 mmol) Dissolved in 12 mL of dichloromethane, added with 3 mL of trifluoroacetic acid, and reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (3,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 16d (492 mg, yellow oil Shape), yield: 100%, used directly in the next step.

The fourth step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(3,4-difluorophenyl)methanone

(3,4-Difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 16d (508 mg, 1.89 mmol) and 6- Methyl bromo-4-chloropyrrolo[2,1-f][1,2,4]triazinecarboxylate 1b (414 mg, 1.77 mmol) was dissolved in 25 mL of dichloromethane, then N,N- Isopropylethylamine (1.31 mg, 10.12 mmol) was reacted for 4 hours at room temperature. Concentrate under reduced pressure, add 25 mL of isopropanol and stir for 10 minutes to precipitate a solid product, which was filtered. The filter cake was washed with isopropyl alcohol (10 mL×2) and petroleum ether (10 mL×2) and then dried to give (2) -(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine- 5-yl)(3,4-difluorophenyl)methanone 16e (666 mg, brown solid), yield: 79.4%. MS m/z (ESI): 496.7 [M+1]

Step 5 (2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(3,4-difluorophenyl)methanone 16e (666 mg, 1.34 mmol) was dissolved in 25 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in ice water bath Methylmagnesium bromide (10.7 mL, 1 M/THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched with 50 mL of aq. EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: A system) to give (2-(1-(6-bromopyrrolo[2,1-f][1,2, 4] Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (580 mg, white solid), yield: 85%.

Step 6 1-(3,4-Difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (150 mg, 0.29 mmol), 1-methyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (122 mg, 0.59 mmol), [1,1'-bis(diphenyl Phosphinyl)ferrocene]palladium dichloride (43 mg, 0.06 mmol) and potassium carbonate (121 mg, 0.88 mmol) dissolved in 6.6 mL of 1,4-dioxane/water (V/V=10/ In 1), the reaction was carried out at 100 ° C for 4 hours. The reaction mixture was diluted with water (10 mL × 2) and brine (30 mL). Purification by chromatography (eluent: A system) to give 1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazole-4) -yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl) -1-Alcohol 16 (64.1 mg, white solid), yield: 42.5%. MS m/z (ESI): 514.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 2H), 7.90 (s, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.32-7.29 (m, 2H), 7.16-7.13 (m, 2H), 6.87 (s, 1H), 4.76 (s, 2H), 4.21 (t, J =1.4 Hz , 2H), 3.95 (s, 3H), 2.96 (s, 2H), 2.00 (s, 3H).

Example 17 1-(3,4-Difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

The first step is 1-(3,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)-1-(3,4-difluorophenyl)ethan-1-ol 16f (150 mg, 0.29 mmol), 1-ethyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (130 mg, 0.59 mmol), [1,1'-bis(diphenyl) Phosphinyl)ferrocene]palladium dichloride (43 mg, 0.06 mmol) and potassium carbonate (121 mg, 0.88 mmol) dissolved in 6.6 mL of 1,4-dioxane/water (V/V=10/ In 1), the reaction was carried out at 100 ° C for 4 hours. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to give 1-(3,4-difluorophenyl)-1-(2-(1-(6-) 1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine- 4-yl)pyrimidin-5-yl)ethan-1-ol 17 (12.0 mg, pale yellow solid), yield: 8%. MS m/z (ESI): 529.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) 8.66 (s, 2H), 7.84 (s, 1H), 7.63 (d, J = 3.6 Hz, 2H), 7.55 (s, 1H), 7.26-7.24 (m, 2H), 7.09-7.06 (m, 2H), 6.81 (m, 1H), 4.70 (s, 2H), 4.18-4.12 (m, \ 4H), 2.90 (s, 2H), 1.93 (s, 3H), 1.47 (t, J = 8.0 Hz, 3H).

Example 18 1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step (2,4-difluorophenyl)magnesium bromide

Magnesium turnings (374 mg, 15.6 mmol) and one iodine were dissolved in 10 mL of dry tetrahydrofuran under argon. 1-Bromo-2,4-difluorobenzene 18a (2.3 g, 12.0 mmol) was dissolved in 2 mL of dry tetrahydrofuran, then 0.4 mL was added dropwise to the above reaction solution, and the bottom of the reaction flask was heated with a hair dryer to initiate a reaction. . The remaining 1-bromo-2,4-difluorobenzene in tetrahydrofuran was slowly added to keep the reaction solution slightly boiling. After the dropwise addition, the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (2,4-difluorophenyl)magnesium bromide 18b (12 mL, 1M / THF, pale yellow liquid) was obtained.

The second step 4-(5-(2,4-difluorobenzimidyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (under argon) 1.0 g, 2.87 mmol) was dissolved in 10 mL of dry tetrahydrofuran. The reaction solution was cooled to 0 ° C with ice-water bath, and (2,4-difluorophenyl)magnesium bromide 18b (11.5 mL, 1M/THF) was slowly added dropwise. ), reacted at 30 ° C for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) Purification by silica gel column chromatography (eluent: A system) to give 4-(5-(2,4-difluorobenzimidyl)pyrimidin-2-yl)-3,6-dihydropyridine- 1(2H)-tert-butyl formate 18c (612 mg, pale yellow solid), yield: 53%. MS m/z (ESI): 345.9 [M-55]

The third step (2,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone

4-(5-(2,4-Difluorobenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 18c (612 mg, 1.5 mmol) Dissolved in 16 mL of dichloromethane, added with 4 mL of trifluoroacetic acid, and reacted at room temperature for 0.5 hour. Concentration under reduced pressure gave (2,4-difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 18d (461 mg, yellow liquid ), yield: 100%.

The fourth step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone

(2,4-Difluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 18d (461 mg, 1.53 mmol) and 6- Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b (390 mg, 1.9 mmol) was dissolved in 10 mL of dichloromethane and N,N-diisopropyl Amine (1.2 g, 9.2 mmol) was reacted for 12 hours at room temperature. Concentrated under reduced pressure, 20 mL of isopropanol was added, and stirred at room temperature for 10 minutes to precipitate a solid product, which was filtered, and the filter cake was washed with isopropyl alcohol (10 mL×2), petroleum ether (10 mL×2), and dried. , (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4- (A)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (687 mg, yellow solid), yield: 90.5%. MS m/z (ESI): 496.8 [M+1]

Step 5 1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (320 mg, 0.65 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to 0 ° C in ice water bath Methylmagnesium bromide (5.2 mL, 1 M/THF) was slowly added dropwise and allowed to react at room temperature for 0.5 hour. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) Purification by gel column chromatography (eluent: A system) gave 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazine-4 -yl)-1,2,3,6-tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (310 mg, white solid ), yield: 94%. MS m/z (ESI): 512.8 [M+1]

Step 6 1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-methyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (89.4 mg, 0.43 mmol), [1,1'-double (diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (232 mg, 0.66 mmol) dissolved in 11 mL 1,4-dioxane/water (V/V In =10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was extracted with ethyl acetate (50 mL×3). The organic phase was washed with 100 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated. Column chromatography (eluent: A system) was purified to give 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazole)- 4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl) Ethyl-1-alcohol 18 (22.1 mg, white solid), yield: 20%. MS m/z (ESI): 514.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.75 (s, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.86-7.75 (m, 2H), 7.28 (d, J = 7.5 Hz, 2H), 7.20-7.09 (m, 2H), 6.33 (s, 1H), 4.75 (s, 2H) , 4.16 (t, J = 5.3 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 1.92 (s, 3H).

Example 19 1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

The first step is 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-ethyl-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (95 mg, 0.43 mmol), [1,1'-double (diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (210 mg, 0.65 mmol) dissolved in 11 mL 1,4-dioxane/water (V/V In =10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was extracted with ethyl acetate (50 mL×3). The organic phase was washed with 100 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated. Column chromatography (eluent: A system) was purified to give 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazole)- 4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl) Ethyl-1-alcohol 19 (16.7 mg, white solid), yield: 15%. MS m/z (ESI): 529.3 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 2H), 7.84 (s, 1H), 7.64-7.58 (m, 3H), 7.55 ( s, 1H), 7.25 (s, 1H), 6.91-6.86 (m, 1H), 6.82-6.6.79 (m, 1H), 6.74-6.69 (m, 1H), 4.70 (s, 2H), 4.18- 4.14 (m, 4H), 2.90 (s, 2H), 1.95 (s, 3H), 1.47 (t, J = 4.0 Hz, 3H).

Example 20 1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-(1-oxobutan-3-yl)-1H-pyrazol-4-yl) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)ethyl-1 -alcohol

First step 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)ethyl-1 -alcohol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)-4-yl)-1-(2,4-difluorophenyl)ethan-1-ol 18f (110 mg, 0.22 mmol), 1-(oxetane-3 -yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14d (108 mg, 0.43 mmol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol) and cesium carbonate (210 mg, 0.65 mmol) dissolved in 11 mL 1,4-di In the hexacyclohexane/water (V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was concentrated under reduced pressure. (oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3 , 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 20 (9.2 mg, white solid), yield: 8%. MS m/z (ESI): 556.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 2H), 7.90 (s, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.71-7.68 (m, 2H), 7.32 (s, 1H), 6.96 (t, J = 6.8 Hz, 1H), 6.87 (s, 1H), 6.78 (t, J = 4.8 Hz, 1H), 5.48-5.52 (m, 1H), 5.11 (s, 2H), 5.10 (s, 2H), 4.75 (s, 2H), 4.21 (s, 2H), 2.96 (s, 2H), 2.02 (s, 3H) .

Example 21 1-(4-Chloro-3-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

First step (4-chloro-3-fluorophenyl) magnesium bromide

Magnesium turnings (374 mg, 15.6 mmol) and one iodine were dissolved in 10 mL of dry tetrahydrofuran under argon. 4-bromo-1-chloro-2-fluorobenzene 21a (2.5 g, 12.0 mmol) was dissolved in 2 mL of tetrahydrofuran, and then 0.4 mL was added dropwise to the above reaction solution, and the bottom of the reaction bottle was blown with a hair dryer, and the mixture was heated. reaction. The remaining 4-bromo-1-chloro-2-fluorobenzene in tetrahydrofuran solution was slowly added to keep the reaction solution slightly boiling. After the dropwise addition, the reaction was carried out for 1 hour at room temperature. After completion of the reaction, (4-chloro-3-fluorophenyl)magnesium bromide 21b (12 mL, 1M / THF, brownish liquid) was obtained.

Step 2 4-(5-(4-Chloro-3-fluorobenzhydryl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-(5-(Methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1 g (under argon) 1.0 g, 2.87 mmol) was dissolved in 20 mL of dry tetrahydrofuran. The reaction solution was cooled to 0 ° C with ice-water bath, and (4-chloro-3-fluorophenyl)magnesium bromide 21b (10.0 mL, 1 M/) was slowly added dropwise. THF), reacted at room temperature for 0.5 hours. The reaction was quenched with EtOAc EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent: A) to give 4-(5-(4-chloro-3-fluorobenzhydryl)pyrimidin-2-yl)-3,6-dihydro Pyridine-1(2H)-tert-butyl formate 21c (878 mg, pale yellow solid), yield: 67%. MS m/z (ESI): 361.9 [M-55]

The third step (4-chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone

4-(5-(4-Chloro-3-fluorobenzylidenyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 21c (878 mg, 2.1 mmol Dissolved in 20 mL of dichloromethane, added with 5 mL of trifluoroacetic acid, and reacted at room temperature for 3 hours. Concentration under reduced pressure gave (4-chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21d (487 mg, brown Liquid), yield: 75%. MS m/z (ESI): 317.9 [M+1]

The fourth step (4-chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)methanone

(4-Chloro-3-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21d (487 mg, 0.77 mmol) and 4 -Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 15b (98 mg, 0.43 mmol) dissolved in 20 mL N,N-diisopropylethylamine (3.9 g, 30.2 mmol) was added to dichloromethane, and the mixture was reacted at room temperature for 12 hours. The organic layer was washed with 100 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Purification by column chromatography (eluent: A system) to give (4-chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21e ( 128 mg, brown solid), yield: 57%.

Step 5 1-(4-Chloro-3-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol

(4-Chloro-3-fluorophenyl)(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] under argon [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 21e (128 mg, 0.24 mmol) dissolved in 10 In a solution of THF, the reaction solution was cooled to 0 ° C in an ice-water bath, and methyl magnesium bromide (2.0 mL, 1 M/THF) was slowly added dropwise, and reacted at room temperature for 0.5 hour. The reaction was quenched with 50 mL of aq. EtOAc EtOAc EtOAc (EtOAc m. Drying with sodium, concentrating under reduced pressure, and the residue was purified by silica gel chromatography (eluent: A) to give 1-(4-chloro-3-fluorophenyl)-1-(2-(1-(6) -(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro Pyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 21 (7 mg, white solid), yield: 6%. MS m/z (ESI): 530.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H) ), 7.84 (s, 1H), 7.57-7.51 (m, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.27 (s, 2H), 6.36 (s, 1H), 4.74 (s, 2H) , 4.16 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.81 (s, 2H), 1.92 (s, 3H).

Example 22 ( S )-1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine

First step ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (300 mg, 0.63 mmol), ( S )-tert-butylsulfinamide 22a (213 mg, 1.76 mmol) and Tetraethoxytitanium (317 mg, 1.39 mmol) was dissolved in 10 mL of dry tetrahydrofuran and allowed to react at 80 ° C for 16 hours. After cooling to room temperature, 50 mL of water was added, and ethyl acetate (50 mL×3) was evaporated. The organic phase was combined and evaporated. Purification by silica gel column chromatography (eluent: A system) gives ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]3 Pyrazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)ylidene)-2-methylpropane-2-sulfin Indole 22b (133 mg, yellow solid), yield: 36%. MS m/z (ESI): 581.8 [M+1]

The second step is N-(( S )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Under the protection of argon, ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 22b (133 mg, 0.23 mmol) The solution was dissolved in 5 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (1.6 mL, 1 M / THF) was slowly added dropwise, and reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) Purification by gel column chromatography (eluent: A system) gave N-(( S )1-(2-(1-(6-bromopyrrolo[2,1-f][1,2, 4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methyl Propane-2-sulfinamide 22c (100 mg, yellow solid), yield: 73%. MS m/z (ESI): 597.8 [M+1]

The third step ( S ) - 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride

N-(( S )1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 22c (100 mg, 0.17 mmol) A solution of methanolic hydrochloric acid (1.5 mL, 4 M) was added dropwise to 1.5 mL of methanol, and the mixture was reacted at room temperature for 1 hour. Concentration under reduced pressure gave ( S ) - 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3 ,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride crude product 22d (95 mg, brown solid), yield: 100 %. MS m/z (ESI): 493.8 [M+1]

The fourth step ( S ) - 1-(4-fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-amine

Under an argon atmosphere, the (S) - 1- (2- ( 1- (6- bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-yl) -1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine hydrochloride 22d (95 mg, 0.17 mmol), 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (69 mg, 0.33 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.033 mmol) and cesium carbonate (272 mg, 0.84 mmol) dissolved in 11 mL 1,4-dioxane/ In water (V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. Concentrated residue was purified by silica gel column chromatography (eluent: C system) under reduced pressure, to give (S) - 1- (4- fluorophenyl) -1- (2- (1- (6- (1 -methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)ethyl-1-amine 22 (28.6 mg, EtOAc). MS m/z (ESI): 596.0 [M+1] ¹ H NMR (400 MHz, DMSO) δ 9.40 (s, 2H), 8.80 (s, 2H), 8.07 (s, 1H), 8.00 (s, 1H) ), 7.89 (s, 1H), 7.84 (s, 1H), 7.49-7.45 (m, 2H), 7.37-7.29 (m, 4H), 4.77 (s, 2H), 4.18 (t, J = 4.0 Hz, 2H), 3.86 (s, 3H), 2.84 (s, 2H), 2.51 (s, 3H).

Example 23 4-(4-(5-(1-Fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl) -6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

First step 4-(4-(5-(1-fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-yl) -6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

1-(4-Fluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] under argon ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 1 (1.0 g, 2.0 mmol Dissolved in 20 mL of tetrahydrofuran, cooled to -78 ° C, added N,N-diethyl-1,1,1-trifluoro-λ ⁴ -sulfonamide 23a (487.5 mg, 3.0 mmol), slowly warmed to The reaction was carried out at 0 ° C for 2 hours at 0 ° C. The reaction was quenched by the addition of 50 mL of a saturated aqueous solution of ammonium chloride at -78 °C. The reaction mixture was diluted with water (30 mL×3) and brine (20 mL). Chromatography (eluent: B system) to give 4-(4-(5-(1-fluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6- Dihydropyridine-1(2H)-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine 23 (201 Mg, white solid), Yield: 36%. MS m/z (ESI): 499.3 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 8.05 (s, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.51 (dd, J = 8.8, 5.4 Hz, 2H), 7.33 (s, 1H), 7.30 -7.20 (m, 3H), 4.76 (s, 2H) , 4.17 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 2.14 (d, J = 23.7 Hz, 3H).

Example 24 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol

First step (2, 6-difluorophenyl) magnesium bromide

Under argon protection, magnesium chips (520 mg, 22.0 mmol) and 1 iodine were dissolved in 15 mL of tetrahydrofuran, and 1 mL of 2-bromo-1,3-difluorobenzene 24a (3.86 g, 20.0 mmol) was dissolved. 5 mL of tetrahydrofuran solution, the reaction was initiated by heating, then the remaining 2-bromo-1,3-difluorobenzene 24a (2.0 mL, 16.89 mmol) in tetrahydrofuran solution was added slowly, and the reaction was kept at slight reflux. Reaction for 1 hour. After completion of the reaction, (2,6-difluorophenyl)magnesium bromide 24b (20 mL, light brown solution, 1.0 M/THF) was obtained.

The second step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(2,6-difluorophenyl)methanone

2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection 4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.0 g, 2.26 mmol) was dissolved in 20 mL of tetrahydrofuran, and (2,6-difluorophenyl) was added dropwise. Magnesium bromide 24b (9.05 mL, 1.0 M/THF) was reacted for 3 hours at room temperature. The reaction was quenched with EtOAc (EtOAc) (EtOAc) Drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (2-(1-(6-bromopyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,6-difluorophenyl)methanone 24c ( 168 mg, yellow solid), yield: 15.6%. MS m/z (ESI): 496.8 [M+1]

The third step 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,6-difluorophenyl)methanone 24c (180 mg, 0.36 mmol) was dissolved in 5 mL of tetrahydrofuran and the reaction was cooled to 0 ° C Methylmagnesium bromide (0.72 mL, 1 M/THF) was added dropwise, and the mixture was reacted at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc m. Drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 1-(2-(6-bromopyrrolo[2,1-f ][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl) Ethyl-1-alcohol 24d (60 mg, off-white solid), yield: 32.3%. MS m/z (ESI): 512.8 [M+1]

The fourth step 1-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6-difluorophenyl)ethan-1-ol 24d (60 mg, 0.116 mmol), 1-methyl-4-(4) ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (48 mg, 0.232 mmol), [1,1'-double ( Diphenylphosphino)ferrocene]palladium dichloride (8.49 mg, 0.0012 mmol) and cesium carbonate (75.6 mg, 0.232 mmol) in a mixed solvent of 5.5 mL of 1,4-dioxane neutralized water ( In V/V = 10/1), the mixture was heated to 100 ° C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography (eluent: C) to give 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2] ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,6- Difluorophenyl)ethan-1-ol 24 (12.0 mg, white solid), yield: 20%. MS m/z (ESI): 514.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.76 (s, 2H), 8.05 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.06- 7.00 (m, 2H), 6.39 (s , 1H), 4.74 (s, 2H), 4.17 (t, J = 5.3 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 1.96 (s, 3H).

Example 25 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol

First step (2,4,6-trifluorophenyl)magnesium bromide

Under the protection of argon, magnesium turnings (541 mg, 22.54 mmol) and 1 iodine were dissolved in 20 mL of tetrahydrofuran, and 2-bromo-1,3,5-trifluorobenzene 25a (0.67 mL, 5.65) was added to the above solution. Ment), and blow the bottom of the reaction bottle with a blower to initiate the reaction, then slowly add 2-bromo-1,3,5-trifluorobenzene 25a (2.0 mL, 16.89 mmol), and keep the reaction slightly refluxed, add, room The reaction was carried out for 1 hour under temperature. After completion of the reaction, (2,4,6-trifluorophenyl)magnesium bromide 25b (22.6 mL, pale yellow solution, 1.0 M/THF) was obtained.

The second step (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine-4 -yl)pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone

2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine under argon protection -4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide 8b (1.8 g, 4.06 mmol) was dissolved in 50 mL of THF, and the mixture was cooled to 0 ° C with ice water bath. (2,4,6-Trifluorophenyl)magnesium bromide 25b (16.2 mL, 1.0 M/THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Purification by silica gel column chromatography (eluent: A system) to give (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl) -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone 25c (708 mg, pale yellow solid), yield: 35%.

The third step 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridine 4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4,6-trifluorophenyl)methanone 25c (350 mg, 0.68 mmol) dissolved in 30 mL of tetrahydrofuran, cooled to 0 with ice-water bath At ° C, methylmagnesium bromide (7.0 mL, 1 M/THF) was added dropwise, and the mixture was reacted at room temperature for 0.5 hour. The reaction was quenched by the addition of 40 mL of EtOAc EtOAc. Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography (eluent: A system) to give 1-(2-(6-bromopyrrolo[2,1-f][1, 2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)-1-(2,4,6-trifluorophenyl) -1-ol 25d (708 mg, pale yellow solid), yield: 38.0%. MS m/z (ESI): 530.9 [M+1]

The fourth step 1-(1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol 25d (90 mg, 0.169 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (212.2 mg, 1.02 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.041 mmol) and cesium carbonate (300 mg, 0.921 mmol) dissolved in 20 mL of 1,4-dioxane (0.1 mL) Water), reacted at 100 ° C for 6 hours. The reaction mixture was diluted with water (30 mL × 2) and brine (40 mL). Chromatography (eluent: A system) to give 1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl Ethyl-1-alcohol 25 (15.8 mg, white solid), yield: 17.2%. MS m/z (ESI): 532.8 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.78 (s, 2H), 8.06 (s, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 17.6 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.13 (t, J = 9.6 Hz, 2H), 6.44 (s, 1H), 4.75 (s, 2H), 4.17 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 2.83 (s, 2H), 1.94 (s, 3H).

Example 26 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol

First Step 1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4- -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol

Under the protection of argon, 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl)ethan-1-ol 25d (90 mg, 0.175 mmol), 1-ethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (250 mg, 1.13 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.041 mmol) and cesium carbonate (300 mg, 0.921 mmol) dissolved in 15.0 mL of 1,4-dioxane (add 0.5 mL water), reacted at 100 ° C for 6 hours. The reaction mixture was diluted with water (30 mL × 2) and brine (40 mL). Purification by chromatography (eluent: A system) gave 1-(2-(1-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4,6-trifluorophenyl Ethyl-1-ol 26 (13.5 mg, white solid), yield: 15.2%. MS m/z (ESI): 546.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.78 (s, 2H), 8.12 (s, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.28 (d, J = 6.8 Hz, 2H), 7.13 (t, J = 9.6 Hz, 2H), 6.44 (s, 1H), 4.75 (s, 2H) ), 4.24-4.09 (m, 4H), 2.84 (s, 2H), 1.93 (s, 3H), 1.41 (t, J = 7.4 Hz, 3H).

Example 27 (R) - 1- (2,4- difluorophenyl) -1- (2- (1- (6- (l-methyl -1H- pyrazol-4-yl) pyrrolo [2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

First step ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methylene)-2-methylpropane-2-sulfinamide

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (500 mg, 1.05 mmol), ( S )-tert-butylsulfinamide 22a (380 mg, 3.14 Methyl) and tetraethoxytitanium (0.55 mL, 2.63 mmol, 4.8 M/THF) were dissolved in 15 mL of tetrahydrofuran and reacted at 80 ° C for 16 hours. After cooling to room temperature, 50 mL of water was added, and ethyl acetate (50 mL×3) was evaporated. The organic phase was combined and evaporated. Purification by silica gel column chromatography (eluent: A system) gives ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]3 Pyrazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene-2-methylpropane-2 - sulfinamide 27a (492 mg, yellow solid), yield: 78%. MS m/z (ESI): 600.7 [M+1]

The second step N-(( R )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Under the protection of argon, ( S )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 27a (492 mg, 0.82 mmol) was dissolved in 15 mL of tetrahydrofuran, and the reaction mixture was cooled to 0 ° C in an ice water bath, and methyl magnesium bromide (4.1 mL, 1 M/THF) was slowly added dropwise, and reacted at room temperature for 40 minutes. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) Purification by gel column chromatography (eluent: A system) gave N-(( R )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2 ,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)- 2-methylpropane-2-sulfinamide 27b (389 mg, yellow solid), yield: 77%. MS m/z (ESI): 616.8 [M+1]

The third step ( R ) - 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride

N-(( R )-1-(2-(1-(6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 27b (389 mg, 0.63 mmol) was dissolved in 6 mL of methanol, and a solution of hydrochloric acid in methanol (6 mL, 4M) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Concentrated under reduced pressure, to give (R) - 1- (2- ( 1- (6- bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-yl) -1,2,3,4 ,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (369 mg, brown solid) 100%. MS m/z (ESI): 511.8 [M+1]

The fourth step ( R ) - 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

Under protective gas, the (R) - 1- (2- ( 1- (6- bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-yl) -1,2,3,4 ,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (150 mg, 0.17 mmol), 1-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l (122 mg, 0.586 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43 mg, 0.0586 mmol) and cesium carbonate (477 mg, 1.465 mmol) dissolved in 11 mL 1,4-dioxane In a ring/water (V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was washed with 100 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. column chromatography (eluent: C system) to give (R) - 1- (2,4- difluorophenyl) -1- (2- (1- (6- (1-methyl -1H -pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine- 5-yl)ethyl-1-amine 27 (17.8 mg, white solid), yield: 12%. MS m/z (ESI): 513.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.71 (s, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.91-7.77 (m , 3H), 7.27 (s, 2H), 7.13 (dd, J = 23.8, 9.0 Hz, 2H), 4.74 (s, 2H), 4.16 (s, 2H), 3.86 (s, 3H), 2.82 (s, 4H), 1.79 (s, 3H).

Example 28 (R) - 1- (2,4- difluorophenyl) -1- (2- (1- (6- (1-ethyl--1H- pyrazol-4-yl) pyrrolo [2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

First step ( R ) - 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

Under an argon atmosphere, the (R) - 1- (2- ( 1- (6- bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-yl) -1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (120 mg, 0.235 mmol), 1- Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a (105 mg, 0.47 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35 mg, 0.047 mmol) and cesium carbonate (383 mg, 1.17 mmol) dissolved in 11 mL 1,4-dioxane In a six ring/water (V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was washed with 100 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. column chromatography (eluent: C system) to give (R) - 1- (2,4- difluorophenyl) -1- (2- (1- (6- (1-ethyl -1H -pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine- 5-yl)ethyl-1-amine 28 (9.8 mg, pale yellow solid), yield: mp. MS m/z (ESI): 527.9 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.71 (s, 2H), 8.11 (s, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.87 (s, 1H), 7.86-7.76 (m, 2H), 7.27 (s, 2H), 7.14 (dt, J = 18.5, 8.9 Hz, 2H), 4.74 (s, 2H), 4.26-4.03 (m, 4H), 2.82 (s, 2H), 2.67 (s, 2H), 1.79 (s, 3H), 1.41 (dd, J = 9.9, 4.7 Hz, 3H).

Example 29 (R) - 1- (2- (1- (6- (1H- pyrazol-4-yl) pyrrolo [2,1-f] [1,2,4] triazin-4-yl -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine

First step ( R ) - 1-(2-(1-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine

Under an argon atmosphere, the (R) - 1- (2- ( 1- (6- bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-yl) -1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethan-1-amine hydrochloride 27c (140 mg, 0.274 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 29a (137 mg, 0.548 mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.0548 mmol) and cesium carbonate (446 mg, 1.37 mmol) dissolved in 11 mL of 1,4-dioxane/water ( In V/V = 10/1), the reaction was carried out at 100 ° C for 5 hours. The organic layer was washed with 100 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. column chromatography (eluent: C system) to give (R) - 1- (2- ( 1- (6- (1H- pyrazol-4-yl) pyrrolo [2,1-f] [ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl) 1-amine 29 (20 mg, white solid), yield: 13%. MS m/z (ESI): 500.3 [M+1] ¹ H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 8.71 (s, 2H), 8.12 (s, 1H), 8.01 (s, 1H) ), 7.95-7.77 (m, 3H), 7.28 (d, J = 9.8 Hz, 2H), 7.13 (dd, J = 24.1, 8.9 Hz, 2H), 4.75 (s, 2H), 4.17 (s, 2H) , 2.82 (s, 2H), 2.71 (s, 2H), 1.79 (s, 3H).

Example 30 and Example 31 (S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)) Pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)e-1- Alcohol 30 (R)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31

First step (S)-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2 , 1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 30 (R )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31

1-(2,4-Difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 18 (3.55 g, 6.8 mmol) further Resolution by high performance liquid chromatography and chiral column chiral isomers by supercritical fluid chromatography (SFC) (chiral Pak IC, 300 × 50 mm ID, 1 μm; 200 mL / Min; mobile phase A is CO ₂ and mobile phase B is EtOH (0.1% NH ₃ .H ₂ O) for resolution to obtain ( S )-1-(2,4-difluorophenyl)-1-(2) -(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethan-l-ol 30 (1.53 g, yellow solid), yield: 43.1%, 98.1% ee, retention time: 7.99 min; (R )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f] [1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethan-1-ol 31 (1.50 g, yellow solid) Yield: 42.3%, 100% ee, retention time: 6.72 min.

Compound 30 MS m/z (ESI): 515.3 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.74 (s, 2H), 8.06 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H ), 7.88 (s, 1H), 7.83 (d, J = 5.1 Hz, 2H), 7.27 (d, J = 7.1 Hz, 2H), 7.18-7.10 (m, 2H), 6.33 (s, 1H), 4.74 (s, 2H), 4.16 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 2.82 (s, 2H), 1.91 (s, 3H).

Compound 31 MS m/z (ESI): 515.3 [M+1] ¹ H NMR (400 MHz, DMSO) δ 8.74 (s, 2H), 8.05 (s, 1H), 7.98 (d, J = 1.5 Hz, 1H ), 7.88 (s, 1H), 7.83 (d, J = 5.0 Hz, 2H), 7.31-7.25 (m, 2H), 7.19-7.09 (m, 2H), 6.33 (s, 1H), 4.74 (s, 2H), 4.16 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 2.82 (s, 2H), 1.91 (s, 3H).

Example 32 (S) - 1- (2,4- difluorophenyl) -1- (2- (1- (6- (l-methyl -1H- pyrazol-4-yl) pyrrolo [2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

The first step ( R )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methylene)-2-methylpropane-2-sulfinamide

Under the protection of argon, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro) Pyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)methanone 18e (8 g, 16 mmol), ( R )-tert-butylsulfinamide 32a (4.5 g, 32 Methyl) and tetraethoxytitanium (9.2 mL, 43.8 mmol, 4.8 M/THF) were dissolved in 60 mL of tetrahydrofuran and reacted at 80 ° C for 10 hours. After cooling to room temperature, 100 mL of water was added, and ethyl acetate (100 mL×3) was added. The organic phase was combined, and the organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate Purification by gel column chromatography (eluent: A system) gave ( R )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4 Triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-ylpyrimidin-5-yl)(2,4-difluorophenyl)ylidene-2-methylpropane -2-sulfinamide 32b (4.7 g, off-white solid), yield: 51%. MS m/z (ESI): 599.7 [M+1]

The second step is N-(( S )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Under the protection of argon, ( R )-N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2 ,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(2,4-difluorophenyl)ylidene)-2-methylpropane-2-sulfinamide 32b (4.7 g, 8.1 mmol) Dissolve in 15 mL of tetrahydrofuran, cool the reaction solution to -40 ° C -50 ° C, slowly add methyl magnesium bromide (24.3 mL, 1 M / THF), add, the reaction solution is maintained at -40 The reaction was carried out at ±5 ° C for 1.5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Agent: A system) purified to give N-(( S )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl) -1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfin Guanidine 32c (3.33 g, foamy solid), yield: 69%. MS m/z (ESI): 615.7 [M+1]

The third step N-(( S )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrole) And [2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2 -methylpropane-2-sulfinamide

N-(( S )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 32c (1.23 g, 2.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1l ( 832 mg, 4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.2 mmol) and cesium carbonate (1.95 g, 6 mmol) dissolved in 13.2 mL The reaction was carried out at 100 ° C for 2.5 hours in 1,4-dioxane and water (V: V = 10:1). To give N - ((S) -1- ( 2,4- difluorophenyl) -1- (2- (1: concentrated residue was purified by silica gel column chromatography (A eluent system) under reduced pressure, -(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide 32d (1 g, yellow oil), yield: 81.3%. MS m/z (ESI): 618.0 [M+1]

The fourth step ( S ) - 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

N-(( S )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[ 2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-yl The propane-2-sulfinamide 32d (1 g, 1.62 mmol) was dissolved in 20 mL of methanol, and concentrated hydrochloric acid (845 mg, 8.1 mmol) was added dropwise at 0 ° C, and allowed to react at room temperature for 2 hours. The pH was adjusted to pH=7 with 2 N sodium hydroxide solution, concentrated under reduced pressure, and then 30 mL of water was added to adjust to pH = 10, ethyl acetate (70 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate and filtered. 1- (2,4-difluorophenyl) -1- (2- (1- (6 - to give (S): concentrated residue was purified by silica gel column chromatography (C eluant system) under reduced pressure, -(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro Pyridin-4-yl)pyrimidin-5-yl)ethan-1-amine 32 (528 mg, yellow solid), yield: 63.5%. MS m/z (ESI): 513.9 [M+1] ¹ H NMR (400 MHz, DMSO- d 6) δ 8.71 (s, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.90- 7.80 (m, 3H), 7.27 (s, 2H), 7.20-7.07 (m, 2H), 4.74 (s, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.86 (s, 3H), 2.82 (s, 2H), 1.79 (s, 3H).

(S) 33 Example - 1- (2,4-difluorophenyl) -1- (2- (1- (6- (1-ethyl--1H- pyrazol-4-yl) pyrrolo [2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine N-(( S )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methyl Propane-2-sulfinamide

N-(( S )-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3, 6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 32c (1.23 g, 2.0 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 7a ( 890 mg, 4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (146 mg, 0.2 mmol) and cesium carbonate (1.95 g, 6 mmol) dissolved in 13.2 mL The reaction was carried out at 100 ° C for 2.5 hours in 1,4-dioxane and water (V: V = 10:1). To give N - ((S) -1- ( 2,4- difluorophenyl) -1- (2- (1: concentrated residue was purified by silica gel column chromatography (A eluent system) under reduced pressure, -(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6 -tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide 33a (0.8 g, yellow oil), yield: 63.5%. MS m/z (ESI): 632.0 [M+1]

The second step ( S ) - 1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2 ,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl-1-amine

N-(( S )-1-(2,4-difluorophenyl)-1-(2-(1-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[ 2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-yl The propane-2-sulfinamide 33a (0.8 g, 1.27 mmol) was dissolved in 16 mL of methanol, and concentrated hydrochloric acid (662 mg, 6.35 mmol) was added dropwise at 0 ° C and allowed to react at room temperature for 2 hours. The pH was adjusted to pH=7 with 2 N sodium hydroxide solution, concentrated under reduced pressure, and then 30 mL of water was added to adjust to pH = 10, ethyl acetate (70 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate and filtered. 1- (2,4-difluorophenyl) -1- (2- (1- (6 - to give (S): concentrated residue was purified by silica gel column chromatography (C eluant system) under reduced pressure, -(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydro Pyridin-4-yl)pyrimidin-5-yl)ethan-1-amine 33 (525 mg, yellow solid), yield: 78.6%. MS m/z (ESI): 527.9 [M+1] ¹ H NMR (400 MHz, DMSO- d 6) δ 8.71 (s, 2H), 8.11 (s, 1H), 7.89 (s, 1H), 7.88- 7.82 (m, 3H), 7.27 (s, 2H), 7.20-7.07 (m, 2H), 4.74 (s, 2H), 4.19-4.10 (m, 4H), 2.82 (s, 2H), 1.79 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H).

Biological assessment

Test Example 1: Determination of c-KIT [WT], c-KIT [D816V], PDGFRα [D842V] kinase activity by the compounds of the present application

The following method was used to determine the kinase activity of recombinant compounds of the present application against recombinant human c-KIT [WT] (wild type), c-KIT [D816V] (D816V mutation) and PDGFRα [D842V] (D842V mutation) under in vitro conditions. Inhibition.

This method uses Cisbio's HTRF® KinEASE-TK tyrosine kinase kit (Cat. No. 62TK0PEB), which is based on time-resolved fluorescence energy resonance transfer (TF-FRET) by measuring the biotinylation of protein mediators. The degree of phosphorylation of the polypeptide is reflected by the inhibition of the protein kinase activity by the compound. For detailed experimental procedures, refer to the kit instructions. Recombinant human c-KIT [WT], c-KIT [D816V] and PDGFRα [D842V] protein kinases were purchased from Carna bioscience (Japan, article number c-KIT[WT] #08-156, c-KIT[D816V] #08-505, PDFGRα[D842V] #08-506).

The experimental procedure is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted with the buffer provided in the kit, and the final concentration of the test compound in the reaction system ranges from 10 μM to 0.1 nM. . The concentration of the ATP solution used in the test (Biotech (Shanghai) Co., Ltd., #A600311) was determined by pre-determined ATP Km concentration for each kinase, where c-KIT[WT], c-KIT[D816V] The ATP Km values corresponding to PDGFRα [D842V] were 100 μM, 30 μM, and 30 μM, respectively. The reaction was carried out in a 384-well microplate, and the test compound and 0.66 ng of the test protein were first added to the well, and cultured at room temperature for 5 minutes, and then the ATP solution and the biotinylated polypeptide were added to the reaction solution. After the solution was incubated for 50 minutes at room temperature with shaking, an anti-phosphotyrosine antibody conjugated with a lanthanide compound and a streptavidin conjugated with modified phycocyanin XL665 were added to the reaction. And continue to shake culture for 1 hour at room temperature. After the completion of the culture, the fluorescence intensity values of the respective wells at an excitation wavelength of 304 nm and emission wavelengths of 620 nM and 665 nM were measured in a TF-FRET mode by a microplate reader. The percentage inhibition of the compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the nonlinear regression analysis was performed by using GraphPad Prism 5 software as the compound concentration-inhibition rate. The IC ₅₀ values of the compounds are shown in Tables 1-1 and 1-2.

Table 1-1 This application represents the IC ₅₀ value of compound inhibition for c-KIT [D816V]

Conclusion: The representative compounds of the present application have a good inhibitory effect on c-KIT [D816V], and the inhibitory effect is superior to Avapritinib.

Wherein: The structure of Avapritinib is as follows, and is prepared according to the published patent application WO 2015057873. Avapritinib

Table ₅₀ value of the present application IC 1-2 Representative compounds of c-KIT [WT] and PDGFRα [D842V] inhibition

Conclusion: Representative compound 31 of the present application has a good inhibitory effect on both c-KIT [WT] and PDGFRα [D842V].

Test Example 2: Determination of P815 activity in mouse mastocytoma by the compound of the present application

The following method was used to determine the effect of the representative compound of the present application on tumor cell proliferation by using a Cell Counting Kit-8 kit (Dojindo, Toray Chemical). For c-KIT [D816V], mouse mastocytoma P815 (purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was used for culture.

The experimental method is briefly described as follows: The test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted with the corresponding medium of the cells to prepare a test sample, and the final concentration of the compound ranges from 30 μM to 0.01 nM. The tumor cells in the logarithmic growth phase were seeded at a density of 1000 cells/well into a 96-well cell culture plate, and after overnight at 37 ° C in a 5% CO ₂ incubator, the test compound samples were added and the cells were further cultured for 48 hours. After the completion of the culture, 10 μL of CCK-8 test solution was added to each well, and cultured at 37 ° C for 1-2 hours, and then the absorbance values of the respective wells at 450 nM were read on a microplate reader. The percentage inhibition of the compound at each concentration point was calculated by comparison with the absorbance values of the control group (0.3% DMSO), followed by nonlinear regression analysis of the logarithm-inhibition rate of the compound concentration in the GraphPad Prism 5 software to obtain a compound inhibiting cell. The IC ₅₀ values for proliferation are shown in Table 2.

Table 2 IC ₅₀ values of representative compounds of the present application for inhibition of mouse mastocytoma activity

Conclusion: The representative compounds of the present application have a significant inhibitory effect on the proliferation of mouse mastocytoma P815.

Test Example 3: Effect of the compounds of the present application on human hERG ion channels stably expressed in HEK293 cells

3.1 cells

hERG ion channel is stably expressed in HEK293 cells.

3.2 Test equipment

Patch clamp instrument: patch clamp -505B

Micro-manipulation instrument: MP-225

Drawn electrode instrument: PC-10 (Narishige, Japan)

3.3 drug preparation

The final concentrations of the test compounds were prepared on the same day and re-dissolved in the extracellular fluid.

The extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl ₂ , 1.8; MgCl _2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.

The intracellular fluid (mM) was: K Aspartate, 130; MgCl ₂ , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).

3.4 Compound test

The compounds were all perfused using a perfusion system using their own gravity. Test at least two cells per concentration. After the current is stable (or 5 minutes), the change in current magnitude before and after the compound is compared to calculate the blocking effect of the compound.

3.5 positive control

The positive control Cisapride concentration was selected based on its sensitivity to cell sensitivity, and the concentration of about 90% blocking rate was the optimal concentration of the positive control. When the Cisapride was tested at 100 nM, the blocking rate was about 90%, so the positive control Cisapride was set at 100 nM. The method is the same as the test compound.

3.6 Electrophysiology

The cells were transferred to a perfusion tank and perfused with extracellular fluid. The intracellular fluid (mM) was: K Aspartate, 130; MgCl ₂ , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). The intracellular fluid was stored in small portions in a -80 degree refrigerator and thawed on the day of the experiment. The electrodes were drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered using one-fifth of the sampling frequency.

3.7 Test process and results

The cells were clamped at –80 mV, then depolarized to 40 mV with a square wave lasting 4 seconds, and then hyperpolarized to -40 mV with a square wave lasting 2 seconds to obtain the hERG tail current (see Figure 1). This procedure is repeated every 20 seconds. The hERG tail current is a pure hERG current. The maximum current induced by the second square wave is detected. After it is stabilized, the test compound is perfused, and when the reaction is stable, the blocking strength is calculated. The specific IC _{50 is} shown in Table 3. See Figure 1 for details.

Table 3: Representative compounds of the present application IC ₅₀ values of inhibition of the hERG potassium ion channel

Conclusion: The compound of Example 31 of the present application has less inhibitory activity on hERG potassium channel and lower cardiotoxicity than Avapritinib.

Test Example 4: This application represents a pharmacokinetic test of a compound

1. Summary

SD rats were used as test animals, and the drug concentration in plasma was determined by LC/MS/MS method after intragastric administration of Avapritinib, Example 2, Example 27 and Example 31. The pharmacokinetic profile of the claimed compound in rats.

2. Experimental plan

2.2 Drug configuration and drug delivery

Weigh the appropriate amount of experimental drug, add 0.5% CMC-Na, sonicate to the solution, and pipette 100 μL for concentration determination. The concentration of the solution is 0.3 mg/mL.

Four healthy male Sprague-Dawley rats were divided into 12 groups and were intragastrically administered overnight after fasting. The dose was 3 mg/kg.

2.3 Sample Collection

0.15 mL of blood was collected from the neck before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in heparinized tubes at 5500 rpm. Centrifuge for 10 minutes, store at -20 ° C, and eat 4 hours after administration.

2.4 Sample Processing

For plasma samples:

Take 20 μL of the sample, add a solution of internal standard (IS) (containing verapamil 5 ng·mL ^-1 and glibenclamide 50 ng·mL ^-1 ) in 200 μL of acetonitrile, and vortex for 10 minutes. Centrifuge at 3700 rpm for 18 minutes, then take 70 μL of the supernatant and add it to 70 μL of water, vortex for 10 minutes, and take 3 μL of the supernatant to the LC-MS/MS system. Analyze.

For dose sample:

The sample to be administered was diluted with a mixed solvent of methanol and water (4:1, v/v) to a concentration of 1 μg·mL ^-1 , and 20 μL of the diluted sample and the internal standard solution (100 ng·mL ^{-1 ) were taken.} Add 200 μL of acetonitrile solution (containing IS solution) and 220 μL of water, then vortex and mix, and take 3 μL of the supernatant to the LC-MS/MS system for analysis.

3. Pharmacokinetic parameter results

The pharmacokinetic parameters of the representative compounds of the present application are shown in Table 4.

Table 4 Rat pharmacokinetic data sheet representing the compound

Conclusion: In the rat pharmacokinetic test, the present application represents the highest blood concentration of Compound 2, Compound 27 and Compound 31 in vivo, which is superior to Avapritinib and has good pharmacokinetic properties.

Test Example 5: Pharmacokinetics in beagle dogs

1. Summary

The Beagle was used as the test animal, and the drug concentration in plasma was determined by LC/MS/MS method after the administration of Avapritinib and the compound of Example 31 by beagle dogs. The representative compound of the present application was analyzed in Beagle. Pharmacokinetic characteristics in vivo.

2. Experimental plan

2.1 experimental drugs

Avapritinib and compound 31;

Oral administration vehicle: DMSO/0.5% CMC-Na (5:95, v/v)

2.2 Animals

Take the Beagle 6 animals, the animal room is well ventilated, equipped with air conditioning, the temperature is maintained at 16-26 ° C, the humidity is maintained at 40% -70%. The light and dark lighting is 12 hours each, and each dog is independently raised and can eat and drink freely.

2.3 Animal dose

Oral administration, drug concentration 0.6 mg/mL; 3 male beagle dogs per group

The day before the experiment, the Beagle was fasted overnight. On the day of the experiment, after weighing the body weight, the theoretical administration volume of each dog was calculated according to the following formula. The test solution should be ready for use on the day of the test. The actual dose of each dog and the collection time of the plasma sample are detailed in the corresponding table. Beagle dogs can resume eating after 4 hours of administration, and they can drink freely during the experiment.

2.4 sample collection and processing

Before the administration and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after the administration, 0.5 mL of blood was collected from the jugular vein, and centrifuged at 4 ° C for 5 minutes to separate the plasma. Store at -20 ° C for testing.

Take 25 ul of Beagle plasma samples, add 25 μl of internal standard, 225 μl of methanol, vortex for 2 minutes, centrifuge at 12000 rpm for 10 minutes at 4 ° C, and take the supernatant for LC-MS/MS analysis.

2.5 pharmacokinetic analysis

The pharmacokinetic parameters were calculated using Phoenix WinNonlin® 7.0 based on the drug's blood concentration data, providing the AUC _inf , Cmax and T1/2 parameters and their mean and standard deviation.

2.6 pharmacokinetic results are shown in Table 5.

Table 5: Beagle pharmacokinetic parameters

Conclusion: In the Beagle pharmacokinetic test, compared with Avapritinib, Compound 31 of this application has a larger maximum plasma concentration, a drug-time curve area and a longer half-life, and has better pharmacokinetic properties. .

no

Figure 1 is a voltage program diagram of whole cell patch clamp in the hERG potassium channel test in Test Example 3.

Claims (30)

A compound of formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: (I) where: E is a hydrogen atom or Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably aryl; more preferably phenyl; W and Q are each independently selected from C or N, but the two are not C; W and Q are preferably N; D is selected from the group consisting of a chemical bond, an -alkylene-, -alkenylene-, -alkynylene-,-cycloalkylene-,-heterocyclylene-, -C ( O)-, -O-, -S-, -S(O)-, -SO ₂ -, -NR ⁶ -, -O-alkylene-, -alkylene-O-, -NR ⁶ -C (O)-, -C(O)-NR ⁶ -, -alkylene-NR ⁶ -, -NR ⁶ -alkylene-, -NR ⁶ -C(O)-alkylene-, -C( O)-NR ⁶ -alkylene-, -NR ⁶ -SO ₂ -, -SO ₂ -NR ⁶ -, -NR ⁶ -SO ₂ -alkylene- or -SO ₂ -NR ⁶ -alkylene- Wherein the alkylene, alkenylene, cycloalkylene or heterocyclylene group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl , heterocyclic group, aryl, heteroaryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S(O) _p Substituted with a substituent of NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; R ¹ and R ³ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a hydroxyl group, Cyano, nitro, halogen or -NR ⁶ R ⁷ Wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens; R ¹ and R ^{3 are} preferably a hydrogen atom; R ² and R ⁵ are each independently selected from Hydrogen atom, alkyl group, alkoxy group, cycloalkyl group, hydroxyl group, cyano group, nitro group, halogen, heterocyclic group, aryl group, heteroaryl group, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ , wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S(O) _p NR ⁶ R ⁷ or -NR ⁶ C Substituting (O) a substituent of R ⁷ ; R ^{4 is} selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or hetero The aryl group is optionally further further selected from one or more selected from the group consisting of halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁸ , -NR ⁶ R ⁷ , -C (O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ Substituting a substituent of -S(O) _p NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; R ⁶ , R ⁷ and R ⁸ 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 optional Further one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ⁹ R ¹⁰ , -C(O )NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -S(O) _p NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ Substituting a substituent; or R ⁶ and R ⁷ together with the N atom to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic ring contains one or more N, O, S(O) _{a p} atom, and the 4-8 membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, =O, -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -S(O Substituted by a substituent of _p NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ; R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Further selected from one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate groups Substituted; m is selected from 1, 2, 3, 4 or 5; n is selected from 1, 2, 3 or 4; and p is selected from 0, 1 or 2. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: D is -alkylene-; preferably methylene; The alkylene group is further substituted with a substituent selected from an alkyl group, a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; and R ⁶ and R ⁷ are as defined in the first item of the patent application. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof: (II) wherein: R ^a is a hydrogen atom or an alkyl group; preferably a C _1-6 alkyl group, more preferably a methyl group; R ^{b is} selected from a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; and R ^{1 -} R ⁷ The definitions of m, n and n are as described in item 1 of the patent application. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof: (III) wherein: R ^{b is} selected from the group consisting of a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; and R ^{1 -} R ⁷ , m and n are as defined in the first item of the patent application. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof: (IV) wherein: R ^{b is} selected from the group consisting of a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; and R ^{1 -} R ⁷ , m and n are as defined in the first item of the patent application. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (V) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof: (V) wherein: R ^{b is} selected from the group consisting of a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; and R ^{1 -} R ⁷ , m and n are as defined in the first item of the patent application. The compound according to any one of claims 1 to 6, wherein the R ² is a hydrogen atom, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ⁴ is heteroaryl, preferably Is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl or pyridyl, more preferably pyrazolyl, wherein the pyrrolyl, pyrazolyl, imidazolyl, oxazole Further, the isoxazolyl, thiazolyl, pyrimidinyl or pyridyl group is further further substituted by one or more substituents selected from C _1-6 alkyl, 4-6 membered heterocyclic or -C(O)R ⁸ Substituted; and R ⁸ is C _1-6 alkyl. The compound of any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ⁴ is a tetrahydropyridyl group, wherein The tetrahydropyridyl group is optionally further substituted by one or more substituents selected from C _1-6 alkyl, 4-6 membered heterocyclic or -C(O)R ⁸ ; R ⁸ is C _1-6 An alkyl group; and wherein the tetrahydropyridyl group is preferably . The compound of any one of claims 1 to 6 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ^{5 is} selected from the group consisting of a hydrogen atom, a halogen, An alkyl group or an alkoxy group; the halogen is preferably F or Cl; the alkyl group is preferably a C _1-6 alkyl group; more preferably a methyl group; and the alkoxy group is preferably a C _1-6 alkoxy group. More preferably, it is a methoxy group. The compound of claim 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ^a is a hydrogen atom or an alkyl group; preferably a C _1-6 alkane More preferably a methyl group; R ^{b is} selected from a hydroxyl group, a halogen or -NR ⁶ R ⁷ ; R ¹ , R ² and R ³ are each independently a hydrogen atom or a C _1-6 alkyl group; R ⁴ is a heteroaryl group. Or a heterocyclic group, wherein the heteroaryl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of C _1-6 alkyl, 3-8 membered cycloalkyl, 4-6 membered heterocyclic, 6-membered aromatic Base, 5-6 membered heteroaryl, -OR ⁸ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ⁸ , -OC(O)R ⁸ , -S(O Substituted by a substituent of _p NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; R ^{5 is} selected from a hydrogen atom, a halogen, a C _1-6 alkyl group or a C _1-6 alkoxy group; R ⁶ and R ^{7 is} each independently a hydrogen atom or a C _1-6 alkyl group; R ⁸ is a C _1-6 alkyl group; m is selected from 1, 2, 3, 4 or 5; n is selected from 1, 2, 3 or 4; p is selected from 0, 1 or 2. The compound of claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is: or . A process for the preparation of a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3 of the patent application, which comprises the reaction shown below: Wherein the compound of the formula (IIA) or a salt thereof is reacted with an R ⁴ -substituted boronic acid ester or boric acid to give a compound of the formula (II): wherein: the R ⁴ -substituted boronic acid ester is preferably: X ¹ is a halogen, preferably Br; and R ¹ -R ⁵ , R ^a , R ^b , m and n are as defined in the third item of the patent application. A process for the preparation of a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3 of the patent application, which comprises the reaction shown below: Wherein the compound of the formula (IIB) or a salt thereof is reacted with a Grignard reagent to obtain a compound of the formula (II): wherein: the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide; ^a is an alkyl group; R ^b is a hydroxyl group; and R ^{1 -} R ⁵ , m and n are as defined in the third item of the patent application. A process for the preparation of a compound of the formula (II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 3 of the patent application, which comprises the reaction shown below: Wherein formula (IIC) compound under acidic conditions to give the formula (II) compound; wherein: R ^a is alkyl; R ^b is -NR ⁶ R ^7; R ⁶ and R ⁷ is a hydrogen atom; R ^f Is -NH-S(O)R ^e ; R ^e is an alkyl group, preferably a tert-butyl group; and R ¹ -R ⁵ , m and n are as defined in the third item of the patent application. A compound of formula (IIA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: X ¹ is halogen, preferably Br; and R ¹ -R ³ , R ⁵ , R ^a , R ^b , m and n are as defined in the third item of the patent application. A compound according to claim 16 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of the formula (IIIA), (IVA) or (VA) or a stereo Isomer, tautomer or pharmaceutically acceptable salt thereof, Wherein: X ¹ is halogen, preferably Br; and R ¹ -R ³ , R ⁵ , R ^b , m and n are as defined in the third item of the patent application. The compound of claim 16 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is: or . A compound of the formula (IIB): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein R ¹ -R ⁵ , m and n are as defined in the third item of the patent application. The compound of claim 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is: or . A compound of the formula (IIC): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: R ^a is an alkyl group; R ^f is -NH-S(O)R ^e ; R ^e is an alkyl group, preferably a tert-butyl group; and R ¹ -R ⁵ , m and n are as defined in the patent application Said in item 3. A compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to claim 21, which is: or . A process for the preparation of a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 16 of the patent application, which comprises the reaction shown below: Wherein the compound of the formula (IIj) or a salt thereof is reacted with a Grignard reagent to obtain a compound of the formula (IIA); wherein: the Grignard reagent is preferably an alkyl magnesium bromide, more preferably methyl magnesium bromide; ^a is an alkyl group; R ^b is a hydroxyl group; X ¹ is a halogen, preferably Br; and R ^{1 -} R ³ , R ⁵ , m and n are as defined in claim 16 of the patent application. A process for the preparation of a compound of the formula (IIA), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 16 of the patent application, which comprises the reaction shown below: Wherein a compound of the formula (IIj) is reacted with a compound of the formula (IIt), wherein the compound of the formula (IIt) has a configuration of ( S ) form or ( R ) form; preferably ( S ) form; a compound of the formula (IIk) is reacted with a Grignard reagent to give a compound of the formula (IIm); the compound of the formula (IIm) is reacted under acidic conditions to give a compound of the formula (IIA): wherein: the Grignard reagent Preferred is an alkyl magnesium bromide, more preferably methyl magnesium bromide; X ¹ is a halogen, preferably Br; R ^a is an alkyl group; R ^b is -NR ⁶ R ⁷ ; R ⁶ and R ⁷ are hydrogen Atom; R ^e is an alkyl group, preferably a tert-butyl group; and R ¹ -R ³ , R ⁵ , m and n are as defined in claim 16 of the patent application. A process for the preparation of a compound of the formula (IIB), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 19 of the patent application, which comprises the reaction shown below: Wherein the compound of the formula (IIp) is reacted with a compound of the formula (IIs) under basic conditions to give a compound of the formula (IIB): wherein: X ² is a halogen, preferably Cl or Br; and R ¹ -R The definitions of ⁵ , m and n are as described in item 19 of the patent application. A process for the preparation of a compound of the formula (IIC), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, according to claim 21 of the patent application, which comprises the reaction shown below: The compound of the formula (IIm) or a salt thereof is reacted with an R ⁴ -substituted boronic acid ester or boric acid to give a compound of the formula (IIC): wherein: the R ⁴ -substituted boronic acid ester is preferably: X ¹ is halogen, preferably Br; R ^a is alkyl; R ^f is -NH-S(O)R ^e ; R ^e is alkyl, preferably tert-butyl; and R ¹ -R ⁵ , The definitions of m and n are as described in item 21 of the patent application. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof Salts, as well as pharmaceutically acceptable carriers, excipients or combinations thereof. A compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, or as described in claim 27 Use of a pharmaceutical composition for the preparation of a medicament for the treatment of a disease caused by c-KIT or a mutant c-KIT vector, wherein the disease of the c-KIT or the mutant c-KIT vector is preferably selected from the gastrointestinal tract Tumor, systemic mastocytosis, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma or mast cell leukemia; more preferably selected from Gastrointestinal stromal tumor, systemic mastocytosis or acute myeloid leukemia, most preferably gastrointestinal stromal tumor or systemic mastocytosis; wherein the mutation of c-KIT is located in exon 9, 11, 13, 14, 17 and/or 18, or amino acid residue 816 and / or amino acid residue 670; wherein the mutation at amino acid residue 816 is preferably D816V or D816H, wherein The mutation at amino acid residue 670 is preferably T670I. A compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, or as described in claim 27 Use of a pharmaceutical composition for the preparation of a c-KIT inhibitor. A compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, or as described in claim 27 Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of a disease caused by a mutated or wild-type PDFGRα vector, wherein the PDFGRα or the mutated PDFGRα vector is preferably selected from the group consisting of gastrointestinal stromal tumors, systemic mast cells Hyperplasia, acute myeloid leukemia, ovarian cancer, breast cancer, melanoma, cervical cancer, seminoma, dysgerminoma, teratoma or mast cell leukemia; more preferably selected from gastrointestinal stromal tumors, Systemic mastocytosis or acute myeloid leukemia, most preferably gastrointestinal stromal tumors and systemic mastocytosis; wherein the mutation of PDFGRα is located in exon 18 and/or 842 amino acid residues At the base, wherein the mutation at the amino acid residue at position 842 is preferably a D842V mutation.