WO2019080723A1

WO2019080723A1 - Polysubstituted pyridone derivative, preparation method therefor and medical use thereof

Info

Publication number: WO2019080723A1
Application number: PCT/CN2018/109969
Authority: WO
Inventors: 段茂圣; 刘佳乐; 田世鸿; 戴权; 熊艳林
Original assignee: 北京越之康泰生物医药科技有限公司
Priority date: 2017-10-26
Filing date: 2018-10-12
Publication date: 2019-05-02
Also published as: CN110520416B; CN110520416A

Abstract

The present invention relates to a polysubstituted pyridone derivative, a preparation method therefor and a medical use thereof. In particular, involved are a polysubstituted pyridone derivative as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use of same as an Axl/c-MET inhibitor in the treatment of cancers, wherein the definitions of each group in general formula (I) are the same as those in the description.

Description

Multi-substituted pyridone derivative, preparation method thereof and medical use thereof

Technical field

The present invention relates to a polysubstituted pyridone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an Axl/c-MET inhibitor, particularly in the treatment of cancer.

Background technique

Receptor tyrosine kinases (RTKs) are multidomain transmembrane proteins that function as sensors for extracellular receptor ligands in cells. When the ligand binds to the receptor, the receptor is dimerized on the surface of the cell membrane and activates the kinase domain within the membrane, resulting in phosphorylation of tyrosine and further activation of a cascade of signaling pathways downstream. To date, nearly 60 receptor tyrosine kinases have been found in the human genome, which extensively regulate the cellular metabolic processes, including survival, growth, differentiation, proliferation, adhesion, and death.

The TAM family of receptor tyrosine kinases has three members, Axl, Mer, and Tyro-3, which regulate a variety of cytological responses including cell survival, differentiation, migration, and adhesion. Studies have shown that the signaling of receptor TAM also controls vascular smooth muscle homeostasis, platelet function, microthrombus stability and erythrocyte formation. The receptor TAM also plays a key role in immunity and inflammation. It promotes phagocytosis of apoptotic cells and stimulates the differentiation of NK cells.

Axl is a member of the TAM family of receptor tyrosine kinases. Among the three members, Axl and Tyro-3 have the most similar gene structure, while Axl and Mer have the most similar tyrosine kinase domain amino acid sequence. Axl is an important regulator of cell survival, proliferation, aggregation, migration and adhesion. Axl is widely expressed in cells and organs such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney. In the study of many cancer cells, the Axl gene in hematopoietic cells, mesenchymal cells and endothelial cells is overexpressed or ectopically expressed. Overexpression of Axl is particularly prominent in all types of leukemia and most solid tumors. Moreover, Axl is more highly expressed in metastatic or malignant tumors than normal tissues or primary tumors, and its high expression is closely related to poor clinical treatment.

A growing body of evidence suggests that Axl is involved in drug resistance caused by different mechanisms in a variety of tumor cells, and overexpression of Axl kinase has become an important marker of cancer drug resistance in cancer patients. Inhibition of Axl receptor tyrosine kinase can reduce the activation of pro-survival signals of tumor cells, block tumor invasion, and increase the sensitivity of targeted drug therapy and chemoradiotherapy. Therefore, Axl is an effective target for cancer treatment.

Although several tyrosine kinase inhibitors, such as Cabozinidinib, Foretinib, Merestinib, Crizotinib, etc., contain Axl kinase inhibitor activity, they are multi-target molecules, Not selective. The only clinical candidate for Axl selectivity in the world is BGB324, which is undergoing multiple clinical phase II trials. Therefore, there is currently no new drug for Axl inhibitors for patients.

c-MET is a member of the transmembrane tyrosine kinase receptor (RTKs) family with autonomous phosphorylation activity. The c-MET receptor contains a tyrosine residue that regulates the activity of the enzyme in the tyrosine kinase catalytic domain of the cell, forming a docking site for several signaling proteins, which in turn leads to a biological response. c-MET was first isolated from cell lines derived from human osteosarcoma, primarily on epithelial cells. During embryonic development and adulthood, many organ epithelial cells express c-MET receptors on the surface, including liver, pancreas, prostate, kidney, muscle, and bone marrow.

HGF is the only ligand for c-MET. When c-MET binds to it, it triggers receptor dimerization, thereby activating tyrosine kinase in the c-MET cytoplasmic protein kinase domain, causing autophosphorylation of c-MET carboxy terminal tyrosine (Tyrl349, Tyrl356) Chemical. c-MET activates the recruitment of the adaptor proteins Gabl and Grb2, activates Shp2, Ras and ERK/MAPK, and multiple effector proteins in the cytoplasm are recruited to the phosphorylated carboxy terminus and rapidly phosphorylated, resulting in activation of multiple signaling pathways within the cell, such as PI3K/AKT, Ras-Rac/Rho, MAPK and STAT3 pathways promote various biological functions such as cell deformation, proliferation, anti-apoptosis, cell separation, exercise and invasion.

The normal HGF/c-MET signaling pathway participates in various physiological processes in different cells and different stages of cell differentiation, such as controlling cell migration during embryonic development and repairing after tissue damage. However, abnormal c-MET disorders include overexpression, sustained activation of constituent kinases, gene amplification, by HGF paracrine and autocrine activation, c-MET mutations, and subsequent changes. Abnormal HGF/c-MET signaling pathway plays a very important role in tumorigenesis and can induce tumor growth, invasion, drug resistance and survival. Therefore, effective inhibition of HGF/c-MET signaling pathways in tumor cells will have a significant effect on a variety of cancers.

Therefore, the present inventors have developed new AxL/c-MET inhibitors. It can be used alone or in combination with other active drugs, providing a broad prospect for the treatment of cancer.

Summary of the invention

The inventors have deliberately studied and designed a series of polysubstituted pyridone derivatives, and intensive studies have shown that such compounds can be used as effective Axl/c-MET inhibitors. It can be used alone or in combination with other active drugs for the treatment of cancer, in particular solid tumors or hematological tumors with high expression of Axl/c-MET.

Accordingly, the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,

among them,

W and V are each independently selected from CH, CF or N;

R ^{a is} selected from -OR ¹ , -SR ¹ or -NR ¹ R ² ;

R ¹ and R ² are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

Alternatively, when R ^a is -NR ¹ R ² , R ¹ and R ² together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;

R ^{3 is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;

Alternatively, R ^a and R ³ together with ^a carbonyl group attached to R ^a and a nitrogen atom bonded to R ³ form a heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, and nitro Substituting one or more groups of cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Alternatively, when R ^a is -NR ¹ R ² , R ¹ and R ² together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R ^{3 is} bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, said The nitrogen heterocycle is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;

R ^{4 is} selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Alternatively, when R ⁴ is aryl or heteroaryl, R ^{a is} bonded to R ⁴ to form a heterocyclic ring fused to R ⁴ , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R ^{5 is} selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or OR ⁶ , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, The aryl and heteroaryl are optionally further substituted with one or more groups selected from the group Q;

Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR ^b , -O(CH ₂ ) _m OR ^b , -OC(O)R ^b , -C(O)OR ^b , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O)R ^b , -S(O) ₂ R ^b , -S(O)NR ^b R ^c , -NR ^b R ^c , -S(O) ₂ NR ^b Substituting one or more groups of R ^c , -NHS(O)R ^b , -NHS(O) ₂ R ^b ;

R ^{6 is} selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^b , -O(CH ₂ ) _m OR ^b , -OC(O)R ^b , -C(O)OR ^b , -C(O)NR ^b R ^c , -NHC(O)R ^b , -S(O)R ^b , -S(O) ₂ R ^b , -S(O)NR ^b R ^c , -NR ^b R ^c , -S(O) ₂ NR ^b R ^c , -NHS(O)R ^b , -NHS(O) ₂ R ^b Substituting multiple groups;

R ^b and R ^c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;

Or R ^b and R ^c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R ^{7 is} selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

m is an integer from 1 to 6;

n is an integer from 1 to 4;

Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.

In a preferred embodiment of the invention, the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

R ^{a is} selected from -NR ¹ R ² ;

R ¹ and R ² are as defined by the formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

The nitrogen-containing heterocyclic ring is preferably a 4- to 7-membered nitrogen-containing heterocyclic ring, more preferably the following heterocyclic ring:

R ^{3 is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.

among them,

R ^{a is} selected from -NR ¹ R ² ;

Wherein R ¹ or R ^{2 is} bonded to R ³ to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

The nitrogen-containing heterocyclic ring fused to the pyridone ring is preferably a 6- or 12-membered nitrogen-containing heterocyclic ring, more preferably the following nitrogen-containing heterocyclic ring:

among them,

R ^{a is} selected from -NR ¹ R ² ;

R ¹ and R ² together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R ^{3 is} bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

The fused heterocyclic ring is preferably a 10-12 membered fused heterocyclic ring, more preferably:

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

q is an integer from 1 to 4;

W, V, R ^a , R ³ , R ⁴ , R ⁷ , Q, n are as defined in the general formula (I).

among them,

R ^{4 is} selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

The aryl, heteroaryl, alkynyl group is preferably:

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

R ^{8 is} selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is an integer from 1 to 4;

q is an integer from 1 to 4;

W, V, R ^a , R ³ , R ⁷ , Q, n are as defined in the general formula (I).

In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a mesogen, racemate, enantiomer, diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

Q' is selected from -NR ^b R ^c ;

p is an integer from 1 to 4;

W, V, R ^a , R ³ , R ⁷ , m, n are as defined in the general formula (I).

among them,

Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR ^b , -O(CH ₂ ) _m OR ^b Substituted by one or more groups;

R ^{b is} selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;

m is an integer from 1 to 6.

among them,

R ^{a is} selected from -NR ¹ R ² ;

R ¹ or R ^{2 is} bonded to R ⁴ to form a heterocyclic ring fused to R ⁴ , preferably a 6-membered heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy Substituting one or more groups of an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

among them,

R ⁵ is OR ⁶ or SR ⁶ ;

R ^{6 is} as defined in the general formula (I);

among them,

R ^{6 is} selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR ^b , -O(CH ₂ ) _m OR ^b , -NR ^b R ^c ;

R ^b and R ^c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;

m is an integer from 1 to 6.

among them,

R ^{7 is} selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;

n is 1 or 2.

among them,

R ⁵ is the following group:

Exemplary compounds of the invention include, but are not limited to, the following compounds:

Or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

When R ^a is selected when R ² -NR ^1,

Amine transesterification of NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) directly with R ¹ R ² NH To obtain a compound of the formula (I);

Or NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, and then to R ¹ R ² NH is subjected to amidation reaction to obtain a compound of the formula (I) via a two-step process;

When R ^a is selected from -OR ¹ when ¹ or -SR,

The NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , W, V, n are as defined in the formula (I).

The invention further provides a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pancreatic cancer and stomach cancer.

The present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of an Axl/c-MET inhibitor.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the manufacture of a medicament for treating cancer. The cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer. , cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.

According to a further aspect of the invention there is provided a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, for use in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or sequentially with the compound of formula (I) The cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an Axl/c-MET inhibitor.

The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament for treating cancer; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, Lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.

According to a further aspect of the invention there is provided a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for use in combination with another therapeutically active ingredient, wherein the other therapeutically active ingredient is simultaneously and separately separated from the compound of formula (I) Or used sequentially; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal Cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.

A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof a form, a mixture of diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer And stomach cancer.

A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition therewith, and another therapeutically active ingredient, wherein the other therapeutically active ingredient The compounds shown in I) are used simultaneously, separately or sequentially; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer , skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.

The compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.

The compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base according to a conventional method in the art to which the present invention pertains. The base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.

The pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.

As stated above, the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier. As used herein, the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation. The use of any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; and, depending on the formulator's judgment, coloring may also be present in the composition. Agents, release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants.

The compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.

The pharmaceutical compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixture. In the case of capsules, tablets, and pills, the dosage form can also include a buffer.

Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner. Examples of useful embedding compositions include polymeric materials and waxes.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension. For this purpose any bland fixed oil may be employed, including the prepared mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.

It is well known to those skilled in the art that the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.

It will also be understood that the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply. The particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons. The alkyl group of the atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 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-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.

The term "alkynyl" refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of nitrogen and oxygen. Or a hetero atom of S(O) _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" or "spiroheterocycle" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen. a hetero atom of oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclic" or "fused heterocyclic" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with one or more of the other rings in the system, one or more A ring may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" or "bridge heterocycle" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

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, non-limiting examples of which include:

Wait.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl. The heteroaryl ring may 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 of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "mercapto" refers to -SH.

The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "sulfonic acid group" refers to -S(O) ₂ OH.

The term "sulfonate group" refers to -S (O) ₂ O (alkyl), or -S (O) ₂ O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"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.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically 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.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions.

The general preparation method of the compound of the formula (I) of the present invention is as follows.

When R ^a is -NR ¹ R ² , the compound of the formula (I) is prepared according to the following scheme 1:

plan 1

Step 1: Ethyl acetoacetate and N,N-dimethylformamide dimethyl acetal are directly condensed at room temperature to obtain (Z)-2-((dimethylamino)methylene)-3- Ethyl oxobutyrate (Ia);

Step 2: (Z)-2-((Dimethylamino)methylene)-3-oxobutanoate ethyl ester (Ia) is reacted with strong sodium hydride in anhydrous tetrahydrofuran to form an enol sodium salt intermediate And then undergoing a cyclization reaction with diethyl oxalate to obtain diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib);

Step 3: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and amine (R ³ NH ₂ ) are subjected to an addition-condensation reaction to obtain NR ³ -4-oxo- Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (Ic);

Step 4: NR ³ -1-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ic) is brominated by N-bromosuccinimide (NBS). NR ³ -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) was obtained.

Step 5: NR ³ -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and the corresponding boric acid by Suzuki coupling reaction (potassium carbonate as a base, Pd(dppf)Cl ₂ is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C), and NR ³ -3-R ⁴ -4-oxo-1,4-dihydropyridine-2 is obtained. 5-dicarboxylic acid diethyl ester (Ie);

Step 6: Selective hydrolysis of NR ³ -3-R ⁴ -4-oxo-1,4-dihydropyridine-2,5-dicarboxylate diethyl ester (Ie) under the action of sodium hydroxide to obtain NR ^3-6- (ethoxycarbonyl) -5-R ⁴ -4- oxo-1,4-dihydropyridine-3-carboxylic acid (the If);

Step 7: NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-carboxylic acid (If) with aromatic amine (Ih) via HATU and N , N-diisopropylethylamine (DIPEA) was subjected to amidation to give NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3- Aromatic amide (Ig);

Step 8: NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) can be directly amine with R ¹ R ² NH Transesterification to obtain a compound of the formula (I); or a two-step process of amidation with a pre-ester group followed by amidation with R ¹ R ² NH to give a compound of the formula (I).

R ^a is selected from -OR ¹ or -SR ¹ when, (I) a compound of formula 2 was prepared according to the following scheme:

Scenario 2

Step 1: Alkaline hydrolysis of ester groups by NaOH with NR ³ -6-(ethoxycarbonyl)-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-aramidamide (Ig) NR ³ -6-carboxy-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig');

Step 2: NR ³ -6-carboxy-5-R ⁴ -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig') is reacted with an alcohol or a thiol under the action of EDCI. a compound of formula (I).

When R ⁴ forms a heterocyclic ring with R ¹ or R ² together with a nitrogen atom or an oxygen atom or a sulfur atom to which it is bonded, the compound of the formula is further prepared by the following scheme 3:

Option 3

Step 1: NR ³ -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and substituted aryl boronic acid in Pd(dppf)Cl ₂ and Suzuki coupling under the action of K ₂ CO ₃ , while the substituent amino group, hydroxyl group or sulfhydryl group on the aryl group is cyclized with the ortho ester group to obtain cyclized NR ³ -4-oxo-1,4-di Hydropyridine-5-carboxylate ethyl ester (Ii);

Step 2: Cyclized NR ³ -4-oxo-1,4-dihydropyridine-5-carboxylate ethyl ester (Ii) is hydrolyzed under basic conditions (NaOH) to give cyclized NR ³ -4-oxyl Des-1,4-dihydropyridin-5-carboxylic acid (Ij);

Step 3: Cyclization of NR ³ -4-oxo-1,4-dihydropyridine-5-carboxylic acid (Ij) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine (DIPEA) The amidation reaction is carried out to obtain a compound of the formula (I').

When R ¹ or R ² forms a heterocyclic ring with R ³ and the nitrogen or oxygen atom or sulfur atom to which it is attached, the compound of the formula is further prepared by the following scheme 4:

Option 4

Step 1: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) with an amino group (-NH ₂ ) at one end and an amine with PG-X by addition-condensation Reaction to give N-substituted-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik);

Step 2: N-substituted 4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik) is deprotected and then cyclized with an ortho ester group to obtain a cyclization reaction. Cyclolated ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il);

Step 3: Cyclization of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il) by bromination of NBS to give cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Im);

Step 4: Cyclization of ethyl 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylate (Im) with the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl ₂ is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C) to obtain a cyclized 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (In );

Step 5: The cyclized 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester intermediate (In) is hydrolyzed under basic conditions (NaOH) to give a cyclized 3- R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io);

Step 6: Cyclized 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io) with aromatic amine (Ih) via HATU and N,N-diisopropyl B The amine (DIPEA) is subjected to an amidation reaction to give a compound of the formula (I").

When R ^a is -NR ¹ R ² , R ¹ and R ² together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R ³ together with the nitrogen-containing heterocyclic ring and the nitrogen atom to which it is bonded further form a fused heterocyclic ring Further preparing a compound of the formula by the following scheme 5:

Option 5

Step 1: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and aminoacetaldehyde dimethylacetal are obtained by addition-condensation reaction to obtain 1-(2,2-dimethoxy Ethyl ethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip);

Step 2: 1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip) with amino alcohol, amino mercaptan Or the diamine is first subjected to a aldehyde condensation reaction of methanol, and then cyclized with an ortho ester group to obtain a fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq);

Step 3: The fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq) is brominated by NBS to give the cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Ir);

Step 4: 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Ir) and the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl ₂ as catalyst , dioxane / water is a mixed solvent, the reaction temperature is 80 ° C), to give 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Is);

Step 5: Ethyl 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylate (Is) is hydrolyzed under basic conditions (NaOH) to give cyclized 3-R ⁴ -4- Oxo-1,4-dihydropyridine-5-carboxylic acid (It);

Step 6: Cyclized 3-R ⁴ -4-oxo-1,4-dihydropyridine-5-carboxylic acid (It) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine ( DIPEA) is subjected to an amidation reaction to give a compound of the formula (I"').

DRAWINGS

Figure 1. Growth curve of tumor volume in treated and control mice in the EBC-1 non-small cell lung cancer model.

Figure 2. Plot of body weight versus treatment time in treatment and control mice in the EBC-1 non-small cell lung cancer model.

Detailed ways

The compounds of the invention and their preparation are further understood by the examples which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to be within the scope of the invention as described and claimed herein.

The compounds of the present invention are prepared using convenient starting materials and common preparatory procedures. The present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.

In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation" (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.

The separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods. The specific method of use can be referred to the examples described in the present invention. Of course, other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift is given in units of 10 ^-6 (ppm). The NMR was determined by using a Brukerdps300 type nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl. Silane (TMS).

The MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).

The liquid phase was prepared using a Waters 2545 High Performance Liquid Chromatograph (Waters 2489 UV/visible Detector, 2767 Sample MGR, Unitary C18, 5 μm 20 mm x 250 mm) (manufacturer: Waters)

Microwave reaction using Initiator + EU type microwave reactor (manufacturer: Biotage)

Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm～0.5. Mm.

Column chromatography generally uses Qingdao Ocean Silicone 100-200 mesh and 200-300 mesh silica gel as carriers.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform. Methylene chloride, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, and the like. Unless otherwise stated in the examples, the solution means an aqueous solution.

The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78 ° C and 200 ° C. The reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

Purification Compounds The column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid In the ester system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention.

Abbreviations

μL=microliter;

μM=micromolar;

NMR = nuclear magnetic resonance;

Boc=tert-butoxycarbonyl

Br=wide peak

d=double peak

δ=chemical shift

°C=degree Celsius

Dd=double peak

DIPEA=diisopropylethylamine

DMF=N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DCM = dichloromethane

EA=ethyl acetate

HPLC = high performance liquid phase

Hz=hertz

IC ₅₀ = concentration that inhibits 50% activity

J = coupling constant (Hz)

m=multiple peak

M+H ⁺ = parent compound mass + one proton

Mg=mg

mL=ml

Mmmol = millimolar

MS=MS

nM=Namol

NBS=N-bromosuccinimide

PE = petroleum ether

Ppm = per million points

s=single peak

t=triple peak

TEA = triethylamine

TBDPS=tert-butyldiphenyl silicon

TFA = trifluoroacetic acid

THF = tetrahydrofuran

PREPARATIVE EXAMPLE 1: 6-(Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate a Preparation

Step 1: Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (a1)

Ethyl acetoacetate (18 g, 138.31 mmol) was added to a reaction flask containing N,N-dimethylformamide dimethyl acetal (16.48 g, 138.31 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate. . (26.5 g, red oil, yield: 100%).

LC-MS (ESI): m / z 186.2 [M + H +].

Step 2: Preparation of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (a2)

Ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (2.2 g, 11.89 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (25 mL). The reaction solution was cooled to 0 ° C, and sodium hydride (618 mg, 15.46 mmol, 60%) was slowly added with stirring, and the mixture was stirred for 30 minutes. Additional diethyl oxalate (1.91 g, 13.08 mmol) was added, added, heated to reflux and stirring was continued for 2 h. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with EtOAc EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) Solid, yield: 70.1%).

LC-MS (ESI): m / z 241.1 [M + H +].

Step 3: Preparation of diethyl 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a3)

To a reaction flask containing ethanol (40 mL) was added 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (4.5 g, 18.75 mmol), and the mixture was cooled to 0 ° C and then added dropwise with stirring. Aqueous methylamine (3.14 mL, 22.50 mmol, 33%) was added and then warmed to room temperature and stirring was continued for one hour. After the reaction was completed, the reaction mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography chromatography (eluent _{DCM: CH 3 OH / 10:} 1) by silica gel column chromatography to give methyl-4-oxo-1,4-dihydro-pyridine-2,5- Diethyl carboxylate (4.0 g, yellow solid, yield: 84.0%).

LC-MS (ESI): m / z 253.3 [M + H +].

Step 4: Preparation of 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4)

Add 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (4 g, 15.81 mmol) and N-bromo in a reaction flask containing DMF (40 mL) Succinimide (NBS) (5.63 g, 31.62 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 3-bromo-1-methyl-4-oxo-1,4-dihydro-2 , diethyl 5-dicarboxylate (3.8 g, yellow solid, yield: 72.4%).

LC-MS (ESI): m / z 332.1 / 334.1 [M + H +].

Step 5: Preparation of diethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a5)

3-bromo-1-methyl-4-oxo-1,4-dihydrogen was added to the reaction flask containing (50 mL) of a mixture of 1,4-dioxane and water (4:1) at room temperature. Diethyl pyridine-2,5-dicarboxylate (3.8 g, 11.44 mmol), p-fluorophenylboronic acid (1.92 g, 13.73 mmol), potassium carbonate (4.74 g, 34.32 mmol), Pd(dppf)Cl ₂ .DCM (934 mg, 1.14 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL×3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 3- (4-fluorophenyl) -1-methyl-4-oxo-1,4 Dihydropyridine-2,5-dicarboxylic acid diethyl ester (3.2 g, yellow solid, yield: 80.6%).

LC-MS (ESI): m / z 347.3 [M + H +].

Step 6: Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a)

3-(4-Fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester was added to a reaction flask containing (40 mL) of ethanol ( 3.2 g, 9.22 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (10 mL, 11.06 mmol) After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of solid 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) (2.3 g, white solid, yield: 78.1%).

LC-MS (ESI): m / z 320.1 [M + H +].

Preparation Example 2: 5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate b), 5-(4-fluorobenzene) -1 -cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate b1), 5-(4-fluorophenyl)-1-cyclobutyl-4-oxo Des-1,4-dihydropyridine-3-carboxylic acid (intermediate b2) and 5-(4-fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3- Preparation of formic acid (intermediate b3)

In the same manner as in Preparation Example 1, except that isopropylamine, cyclopropylamine, cyclobutylamine and t-butylamine were respectively used in place of the aqueous methylamine solution, respectively:

5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) (gray solid, four-step yield: 38.3%); MS (ESI): m/z 348.3 [M+H ⁺ ].

5-(4-Fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b1) (gray solid, four-step yield: 70.8%); MS (ESI): m / z 346.3 [m + H +].

5-(4-Fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b2) (gray solid, four-step yield: 80.9%); MS (ESI): m / z 360.1 [m + H +].

5-(4-Fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b3) (gray solid, four-step yield: 4.1%); MS (ESI): m / z 362.1 [m + H +].

Preparation Example 3: 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Preparation of formic acid (intermediate c)

5-(4-fluorophenyl)-4 was obtained in the same manner as in Preparation Example 1, except that (tetrahydro-2H-pyran-4-yl)methanamine (Shanghai Pide) was used instead of the aqueous methylamine solution. -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (c) (white solid, four-step yield: 36.8%)

LC-MS (ESI): m / z 403.3 [M + H +].

Preparation Example 4: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4 Preparation of diazepane-8-carboxylic acid (intermediate d)

Step 1:1-(Preparation of 3-((tert-Butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (d1)

Add 4-oxo-4hydro-pyran-2,5-dicarboxylate (a2) (3.0 g, 12.5 mmol) and N-tert-butoxycarbonyl to a round bottom flask containing ethanol (50 mL) at room temperature. - 1,3-propanediamine (2.2 g, 12.6 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Ethyl dihydropyridine-2,5-dicarboxylate (2.5 g, yellow oil, yield: 50%).

LC-MS (ESI): m / z 397.2 [M + H +].

Step 2: Preparation of 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (d2)

Add 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate B to a reaction flask containing dichloromethane (10 mL) Ester (2.5 g, 6.3 mmol) and dioxane hydrochloride (10 mL, 4M). After stirring at room temperature for 30 minutes, the reaction mixture was evaporated. (2.0 g, white solid, yield: 95%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 297.2 [M + H +].

Step 3: 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid Preparation of ester (d3)

Add 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (2.0) in a round bottom flask containing ethanol (20 mL) at room temperature. g, 6.0 mmol) and triethylamine (1.0 g, 12.1 mmol). The mixture was warmed to 80 ° C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: 1,2-a][1,4]Diazepane-8-carboxylic acid ethyl ester (1.5 g, yellow oil, yield: 99%).

LC-MS (ESI): m / z 251.2 [M + H +].

Step 4: 10-Bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- Preparation of 8-carboxylic acid ethyl ester (d4)

Add 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4 to a round bottom flask containing DMF (15 mL) at room temperature. Ethyl diazepane-8-carboxylate (1.5 g, 5.98 mmol) was added dropwise with stirring EtOAc (EtOAc,EtOAc. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH: EtOAc: : : : : : : : : : : : : : : : : : : : : : : : Ethyl pyrido[1,2-a][1,4]diazepane-8-carboxylate (1.1 g, yellow solid, yield: 55.7%).

LC-MS (ESI): m / z 329.1 / 331.1 [M + H +].

Step 5: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azacycloheptane-8-carboxylic acid ethyl ester (d5)

Add 10-bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1] to a round bottom flask containing acetonitrile (12 mL) and water (3 mL) at room temperature. , 2-a][1,4]Diazepane-8-carboxylic acid ethyl ester (1.1 g, 3.32 mmol), 4-fluorophenylboronic acid (693 mg, 4.98 mmol), potassium carbonate (1.37 g, 9.96 mmol) And [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (270 mg, 0.33 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Ethyl 5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (800 mg, white solid, yield: 69.8%).

LC-MS (ESI): m / z 345.2 [M + H +].

Step 6: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxylic acid (d)

Add 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9- to a round bottom flask containing ethanol (8 mL) and water (2 mL) at room temperature. Ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (800 mg, mmol) and lithium hydroxide monohydrate (160 mg, 3.48 mmol). The mixture was warmed to 60 ° C and stirred for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridine [ 1,2-a][1,4]diazepane-8-carboxylic acid (800 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 317.1 [M + H +].

Preparation Example 5: 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxylic acid (intermediate e)

In the same manner as in Preparation Example 4, except that 4-methylbenzeneboronic acid (Shanghai Pide) was used instead of 4-fluorophenylboronic acid, 1,9-dioxo-10-(p-tolyl)-1 was obtained. 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e) (gray solid, two-step yield: 64.3% ).

LC-MS (ESI): m / z 313.2 [M + H +].

Preparation Example 6: 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a] Preparation of [1,4]diazepane-8-carboxylic acid (intermediate f)

Step 1: Preparation of 2-((tert-butyldiphenylsilyl)oxy)propane-1,3-diamine (f1)

1,3-Diamino-2-hydroxypropane (4 g, 44.4 mmol) and imidazole (6.1 g, 88.8 mmol) were added to a round bottom flask containing DMF (30 mL) at room temperature. The mixture was cooled to 0 ° C, and a solution of TBDPSCl in DMF (30 mL, 88.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 12.4 g, yellow oil, yield 85.1%).

LC-MS (ESI): m / z 329.3 [M + H +].

Step 2: 4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- Preparation of a][1,4]diazepane-8-carboxylic acid ethyl ester (f2)

To a round bottom flask containing ethanol (10 mL) was added 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (370 mg, 1.54 mmol), 2- ((un) Butyldiphenylsilyl)oxy)propane-1,3-diamine (608 mg, 1.85 mmol) and triethylamine (1.2 g, 9.24 mmol). The mixture was warmed to 80 ° C and stirred for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: -1,2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (350 mg, yellow oil, yield : 53.2%).

LC-MS (ESI): m / z 505.2 [M + H +].

Step 3: 10-Bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ Preparation of 1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (f3)

4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5 was added to a round bottom flask containing DMF (5 mL) at room temperature. , 9-Hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (250 mg, 0.49 mmol), bromine (0.04 ml, 1.5) Mm). After the addition was completed, the mixture was stirred overnight, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut -Ethoxy-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (200 mg, yellow oil Yield: 69.0%).

LC-MS (ESI): m / z 583.2 / 585.2 [M + H +].

Step 4: 4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Preparation of ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (f4)

Add 10-bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo- in a round bottom flask containing acetonitrile (4 mL) and water (1 mL) at room temperature. 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (270 mg, 0.46 mmol), p-fluorobenzene Boric acid (100 mg, 0.70 mmol), potassium carbonate (200 mg, 1.38 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol) . Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1,1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid Ethyl ester (200 mg, white solid, yield: 73.2%).

LC-MS (ESI): m / z 599.3 [M + H +].

Step 5: 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1 , 4] Preparation of diazepane-8-carboxylic acid (f)

4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1 was added to a round bottom flask containing ethanol (mL) and water (mL) at room temperature. Ethyl 9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (200 mg, 0.33 mmol) and lithium hydroxide monohydrate (10 mg, 0.37 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9- Hydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (190 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 333.2 [M + H +].

Preparation Example 7: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a Preparation of :1',2'-d]pyrazine-3-carboxylic acid (intermediate g)

Step 1: 1 - ((1-(tert-Butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester ( Preparation of g1)

Add 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (1.5 g, 6.25 mmol) and 1-tert-butyl at room temperature in a round bottom flask containing ethanol (20 mL). Oxycarbonyl-2-aminomethylpiperidine (1.68 g, 7.50 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut - Oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.4 g, yellow oil, yield: 88.4%).

LC-MS (ESI): m / z 437.4 [M + H +].

Step 2: 3-Bromo-1-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl Preparation of ester (g2)

Add 1-((1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydrogen to a round bottom flask containing DMF (25 mL) at rt. Diethyl pyridine-2,5-dicarboxylate (2.4 g, 5.50 mmol) and NBS (1.96 g, 10.9 mmol) were stirred overnight. After the reaction mixture was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjj Carbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.3 g, yellow oil, yield: 80.0%)

LC-MS (ESI): m / z 515.2 / 517.2 [M + H +].

Step 3: Preparation of 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester hydrochloride (g3)

3-bromo-1-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4 was added to a reaction flask containing dichloromethane (20 mL) at room temperature. Dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.3 g, 4.4 mmol) and dioxane hydrochloride (10 mL, 4 M) were stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5- Diethyl formate hydrochloride (2.0 g, white solid, yield: 100%) was used for the next step without purification.

LC-MS (ESI): m / z 415.2 / 417.2 [M + H +].

Step 4: 1-Bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d Preparation of pyrazine-3-carboxylic acid ethyl ester (g4)

Add 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2 to a reaction vial containing DMF (20 mL) and water (10 mL). , 5-dicarboxylic acid diethyl ester hydrochloride (2.0g, 4.3mmol) and NaHCO ₃ (2.16g, 25.75mmol), and stirred for 30 minutes. After the reaction was completed, the reaction mixture was extracted with dichloromethane (30 mL×3), and the organic phase was combined. The organic phase was concentrated under reduced pressure to give the crude product 1-bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a: 1 ',2'-d]pyrazine-3-carboxylic acid ethyl ester (1.2 g, white solid, yield: 75.8%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 369.1 / 371.1 [M + H +].

Step 5: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid ethyl ester (g5)

Add 1-bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrogen to a round bottom flask containing acetonitrile (12 mL) and water (3 mL) at rt. Dipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), p-fluorophenylboronic acid (670 mg, 4.79 mmol), potassium carbonate (1.32 g) , 9.57 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (233 mg, mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C, and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut , 8, 9, 10, 12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (890 mg, white solid, yield: 70.2%).

LC-MS (ESI): m / z 385.2 [M + H +].

Step 6: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid (g)

Add 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9 to a round bottom flask containing ethanol (8 mL) and water (2 mL) at room temperature. 10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (800 mg, 2.08 mmol) and lithium hydroxide monohydrate (91 mg, 2.2 mmol) . The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to give crude product 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyridine. And [1,2-a:1',2'-d]pyrazine-3-carboxylic acid (800 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 357.2 [M + H +].

PREPARATIVE EXAMPLE 8: 6-(4-Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrole And [1,2-D]pyrazine-8-carboxylic acid (intermediate h) preparation

In the same manner as in Preparation Example 7, except that 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Shanghai Angji) was used instead of 1-tert-butoxycarbonyl-2-aminomethylpiperidine. , 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[ 1,2-D]pyrazine-8-carboxylic acid (h) (grey solid, 21.5% yield in six steps).

LC-MS (ESI): m / z 343.2 [M + H +].

Preparation Example 9: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-c][1,4]oxazine-9-carboxylic acid (intermediate j)

Step 1: Preparation of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (j1-1)

Morpholine-3-carboxylic acid (3.0 g, 22.9 mmol) and potassium carbonate (15.8 g, 114.4 mmol) were added to a round bottom flask containing acetone (20 mL) and water (10 mL). Boc ₂ O (7.5 g, 34.4 mmol) was slowly added dropwise with stirring, and the mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc : 34.1%).

LC-MS (ESI): m / z 232.1 [M + H +].

Step 2: Preparation of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (j1-2)

4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acid (1.8 g, 7.78 mmol), ammonium chloride (1.26 g, 23.3 mmol), HOBT was added to a round bottom flask containing DMF (40 mL) at room temperature. (3.15 g, 23.3 mmol), EDCI (2.24 g, 11.67 mmol) and DIPEA (4.52 g, 35.01 mmol). The mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj 21.1%).

LC-MS (ESI): m / z 231.1 [M + H +].

Step 3: Preparation of 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1)

A solution of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (380 mg, 1.65 mmol) and borane in THF (1.7 mL, 4.95 mmol) was obtained from THF (4 mL). The mixture was heated to reflux and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then the reaction was quenched by dropwise addition of methanol. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 300 mg, yellow oil, yield: 84.1%).

LC-MS (ESI): m / z 217.1 [M + H +].

The remaining steps were carried out in the same manner as in Preparation Example 7, except that 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1) was used instead of 1-tert-butoxycarbonyl-2-aminomethylpiperidine. 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5] Pyrazino[2,1-c][1,4]oxazine-9-carboxylic acid (j) (grey solid, yield of 18.3% in six steps).

LC-MS (ESI): m / z 359.4 [M + H +].

PREPARATIVE EXAMPLE 10: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k)

Preparation of Step 1:1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k1)

Add 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (5 g, 20.8 mmol) and aminoacetaldehyde in a round bottom flask containing ethanol (50 mL) at room temperature. Methanol (3.3 g, 31.39 mmol). The mixture was warmed to 80 ° C and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dihydropyridine-2,5-dicarboxylic acid diethyl ester (3.4 g, yellow oil, yield: 50.0%).

LC-MS (ESI): m / z 382.3 [M + H +].

Step 2: Preparation of 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k2)

Add 1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid to a round bottom flask containing DMF (100 mL) at room temperature. Ethyl ester (10 g, 30.55 mmol) and NBS (6.0 g, 33.7 mmol). The mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Diethyl 4-dihydropyridine-2,5-dicarboxylate (8.8 g, yellow oil, yield: 71.1%).

LC-MS (ESI): m / z 406.1 / 408.1 [M + H +].

Step 3: 7-Bromo-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2 ,1-b][1,3] Preparation of Oxazine-9-carboxylic Acid Ethyl Ester (k3)

3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5 was added to a round bottom flask containing acetonitrile (80 mL) at room temperature. Diethyldicarboxylate (6.0 g, 14.78 mmol), acetic acid (24 mL) and methanesulfonic acid (8 mL). The mixture was warmed to 70 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, triethylamine (25 mL) and 3-aminopropan-1-ol (2.7 g, 35.95 mmol) were added, and the mixture was heated to reflux and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1:10) to give 7-bromo-6,8-dioxo-3,4,6,8,12,12a-s Hydrogen-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (3.6g, yellow oil, Rate: 65.8%).

LC-MS (ESI): m / z 371.1 / 373.1 [M + H +].

Step 4: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-B][1,3]oxazine-9-carboxylic acid ethyl ester (k4)

Add 7-bromo-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine to a round bottom flask containing acetonitrile (8 mL) and water (2 mL) at room temperature And [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (800 mg, 2.2 mmol), 4-fluorophenylboronic acid (452 mg) , 3.2 mmol), potassium carbonate (900 mg, 6.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (176 mg, 0.22 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut , 12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (830 mg, White solid, yield: 97.7%).

LC-MS (ESI): m / z 387.2 [M + H +].

Step 5: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k)

Add 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a- to a round bottom flask containing ethanol (10 mL) and water (2 mL) at room temperature. Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (830 mg, 2.15 mmol) and one Lithium hydroxide hydrate (128 mg, 2.80 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude product 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k) (830 mg, pale yellow solid, yield: 100.0 %). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 359.4M + H +].

PREPARATIVE EXAMPLE 11: 6,8-Dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate l)

In the same manner as in Preparation Example 10, except that 4-methylbenzeneboronic acid was used in place of 4-fluorophenylboronic acid, 6,8-dioxo-7-(p-tolyl)-3,4,6,8 was obtained. ,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (l) (grey solid , two-step yield 70.3%).

LC-MS (ESI): m / z 355.2 [M + H +].

PREPARATIVE EXAMPLE 12: 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate m)

In the same manner as in Preparation Example 10, except that (6-methylpyridin-3-yl)boronic acid was used instead of 4-fluorophenylboronic acid, 7-(6-methylpyridin-3-yl)-6,8 was obtained. -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Oxazine-9-carboxylic acid (m) (grey solid, two-step yield: 36.2%).

LC-MS (ESI): m / z 356.2 [M + H +].

PREPARATIVE EXAMPLE 13: 7-(5-Methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate n)

In the same manner as in Preparation Example 10 except that (5-methylthiophen-2-yl)boronic acid was used instead of 4-fluorophenylboronic acid, 7-(5-methylthiophen-2-yl)-6,8 was obtained. -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Oxazine-9-carboxylic acid (n) (grey solid, two-step yield: 26.5%).

LC-MS (ESI): m / z 361.2 [M + H +].

PREPARATIVE EXAMPLE 14: 6-(4-Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridinium[ Preparation of 1,2-d]pyrazine-8-carboxylic acid (intermediate o)

In the same manner as in Preparation Example 10 except that 2-aminoethyl-1-ol was used in place of 3-aminopropan-1-ol, 6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (gray solid, three-step Rate: 53.2%).

LC-MS (ESI): m / z 345.1 [M + H +].

PREPARATIVE EXAMPLE 15: 6-(4-Tolyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridin[1] ,2-d]Preparation of pyrazine-8-carboxylic acid (intermediate p)

In the same manner as in Preparation Example 14, except that 4-methylbenzeneboronic acid was used in place of 4-fluorophenylboronic acid, 6-(4-methylphenyl)-5,7-dioxo-2,3,5 was obtained. 7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) (grey solid, two-step yield: 73.5%).

LC-MS (ESI): m / z 341.1 [M + H +].

PREPARATIVE EXAMPLE 16: (3R)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate q)

In the same manner as in Preparation Example 10, except that (R)-2-aminopropan-1-ol was used in place of 3-aminopropan-1-ol, (3R)-6-(4-fluorophenyl)- 3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Carboxylic acid (q) (grey solid, three-step yield: 54.2%).

LC-MS (ESI): m / z 359.2 [M + H +].

PREPARATIVE EXAMPLE 17: (3S)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate r)

In the same manner as in Preparation Example 10, except that (S)-2-aminopropan-1-ol was used instead of 3-aminopropan-1-ol, (3S)-6-(4-fluorophenyl)- 3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Carboxylic acid (r) (grey solid, three-step yield: 51.7%).

LC-MS (ESI): m / z 359.2 [M + H +].

PREPARATIVE EXAMPLE 18: (4R)-7-(4-Fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine And [1', 2': 4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate s)

In the same manner as in Preparation Example 10, except that (R)-3-aminobutan-1-ol was used instead of 3-aminopropan-1-ol, (4R)-7-(4-fluorophenyl)- 4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1 -b][1,3]oxazine-9-carboxylic acid (s) (gray solid, three-step yield: 49.1%).

LC-MS (ESI): m / z 373.2 [M + H +].

PREPARATIVE EXAMPLE 19: 9-(4-Fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7- Preparation of carboxylic acid (intermediate t)

In the same manner as in Preparation Example 4, except that N-tert-butoxycarbonyl-1,2-ethanediamine was used instead of N-tert-butoxycarbonyl-1,3-propanediamine to obtain 9-(4-fluoro Phenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (t) (gray solid, six steps) Yield: 38.7%).

LC-MS (ESI): m / z 303.2 [M + H +].

PREPARATIVE EXAMPLE 20: 4-(4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid Preparation of tert-butyl ester (intermediate u)

Step 1: Preparation of 3-bromo-5-iodopyridin-2-amine (u1)

5-iodopyridin-2-amine (5.0 g, 22.73 mmol) and NBS (4.0 g, 22.73 mmol) were added to a reaction flask containing acetonitrile (100 mL). The reaction mixture was stirred at 50 <0>C for 12 h then cooled to EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj .

LC-MS (ESI): m / z 299.3 / 301.3 [M + H +].

Step 2: Preparation of tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u2)

3-bromo-5-iodopyridin-2-amine (2.5 g, 8.36 mmol), 4- in a reaction flask containing (50 mL) a mixture of toluene, ethanol and water (2:2:1) at room temperature (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-Butyl ester (Beijing coupling, 3.78 g, 10.03 mmol), sodium carbonate (2.66 g, 25.08 mmol), Pd(PPh ₃ ) ₄ (483 mg, 0.42 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction was completed, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc) to afford 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazole- Tert-butyl ester of 1-yl)piperidine-1-carboxylate (2.8 g, yellow solid, yield: 79.4%).

LC-MS (ESI): m / z 422.2 / 424.3 [M + H +].

Step 3: 4-(4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl Preparation of ester (u)

4-(4-(6-Amino-5-bromopyridin-3-yl) was added to a reaction flask containing (40 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature. -1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g, 6.64 mmol), 4-amino-2-fluorobenzeneboronic acid pinacol ester (Shanghai Bide, 1.88 g, 7.96 mmol) ), potassium carbonate (2.75 g, 19.92 mmol), Pd(dppf)Cl ₂ .DCM (538 mg, 0.66 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: Tert-butyl 3-methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate u) (2.3 g, yellow solid, yield: 77.1%).

LC-MS (ESI): m / z 453.4 [M + H +].

PREPARATIVE EXAMPLE 21 Preparation of 3-(4-Amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate v)

The same procedure as in Preparation Example 20 was employed except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H was used. -pyrazole (Beijing coupling) instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- tert-Butyl 1-phenyl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridine-2 - Amine (v) (yellow solid, two-step yield: 68.8%).

LC-MS (ESI): m / z 298.3 [M + H +].

PREPARATIVE EXAMPLE 22: 3-(4-Amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridine-2 - Preparation of an amine (intermediate w)

The same procedure as in Preparation Example 20 was employed except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-di was used. Oxaborane-2-yl)-1H-pyrazole (Beijing coupling) instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Tert-butyl ester of 2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-) 2H-Pyr-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (w) (yellow solid, two-step yield: 72.3%).

LC-MS (ESI): m / z 354.3 [M + H +].

Preparation Example 23: Preparation of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate x)

The same procedure as in Preparation Example 20 was carried out except that (3,4-dimethoxyphenyl)boronic acid (Beijing coupling) was used instead of 4-(4-(4,4,5,5-tetramethyl-1, Tert-butyl 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl) -5-(3,4-Dimethoxyphenyl)pyridin-2-amine (x) (yellow solid, two-step yield: 79.1%).

LC-MS (ESI): m / z 340.2 [M + H +].

Preparation Example 24: 4-(4-(6-Amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine- Preparation of 1-butylic acid tert-butyl ester (intermediate y)

Prepared in the same manner as in Preparation Example 20 except that 4-amino-2,5-difluorophenylboronic acid pinacol ester (Shanghai Bied) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester. 4-(4-(6-Amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl Ester (y) (yellow solid, one step yield: 63.4%).

LC-MS (ESI): m / z 471.4 [M + H +].

Preparation Example 25: 3-(4-Aminophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (middle Preparation of body z)

In the same manner as in Preparation Example 22, except that 4-aminophenylboronic acid pinacol ester (Beijing coupling) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester to obtain 3-(4-aminophenyl). -5-(4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (z) (yellow solid, two-step yield: 72.3%) .

LC-MS (ESI): m / z 336.3 [M + H +].

PREPARATIVE EXAMPLE 26 Preparation of 3-(4-Aminophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate aa)

In the same manner as in Preparation Example 23, except that 4-aminophenylboronic acid pinacol ester (Beijing coupling) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester to obtain 3-(4-aminophenyl). -5-(3,4-Dimethoxyphenyl)pyridin-2-amine (aa) (yellow solid, two-step yield: 79.1%).

LC-MS (ESI): m / z 322.4 [M + H +].

Preparation Example 28: 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl) Preparation of pyridin-2-amine (intermediate bb)

Step 1: Preparation of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolan (bb1)

4-bromo-2-methoxyphenol (2 g, 9.85 mmol), acetone glycerol (1.95 g, 14.77 mmol), triphenylphosphine (diphenylphosphine) was added to a reaction flask containing anhydrous tetrahydrofuran solution (25 mL) at room temperature. 3.1 g, 11.82 mmol) and diisopropyl azodicarboxylate (2.39 g, 11.82 mmol). It was sealed, replaced with nitrogen three times, and the mixture was stirred and stirred under reflux overnight. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, and extracted with dichloromethane (30mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc: 1:1) to give 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2- Dimethyl-1,3-dioxolane (2.5 g, yellow oil, yield: 80.1%).

Step 2: Preparation of 3-(4-bromo-2-methoxyphenoxy)propane-1,2-diol (bb2)

Add 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-di in a reaction flask containing acetic acid (15 mL) and water (15 mL) Oxolane (2.5 g, 7.88 mmol). The mixture was heated to 60 ° C and stirred for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced vacuo. The organic layer was washed with aq. The residue was purified by silica gel column chromatography eluting elut elut elut (2.1 g, yellow oil, yield: 96.3%).

LC-MS (ESI): m / z 277.1 / 279.1 [M + H +].

Step 3: Preparation of 2-((4-bromo-2-methoxyphenoxy)methyl)-1,4-dioxane (bb3)

3-(4-Bromo-2-methoxyphenoxy)propane-1,2-diol (2.1 g, 7.58 mmol) was added sequentially to a reaction flask containing 1,2-dibromoethane (30 mL). Tetrabutylammonium bromide (488 mg, 1.52 mmol) and 50% (w/w) sodium hydroxide solution (30 mL). After heating the mixture to 55 ° C and stirring for 6 hours, additional 1,2-dibromoethane (30 mL) and 50% (w/w) sodium hydroxide solution (30 mL) were added and stirring was continued at this temperature overnight. . After the reaction solution was cooled to room temperature, it was diluted with water and extracted with dichloromethane (100 mL x 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dioxane (1.7 g, yellow solid, yield: 73.9%).

LC-MS (ESI): m / z 303.1 / 305.1 [M + H +].

Step 4: 2-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaborane (bb4)

2-((4-Bromo-2-methoxyphenoxy)methyl)-1 was added to a reaction flask containing 1,4-dioxane (30 mL) and water (7.5 mL) at room temperature. 1,4-dioxane (1.7g, 5.6mmol), with boronic acid pinacol ester (2.8g, 11.2mmol), sodium acetate (1.37mg, 16.8mmol) and _{Pd (dppf) Cl 2 (457mg} , 0.56mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred for 2 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) -Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. (1.83 g, pale yellow oil, yield: 93.3%).

LC-MS (ESI): m / z 351.2 [M / M + H +].

Step 5: Preparation of 3-(4-amino-2-fluorophenyl)-5-bromopyridin-2-amine (bb5)

Add 5-bromo-3-iodopyridin-2-amine (1 g, 3.36 mmol), 4-amino- to a reaction flask containing 1,4-dioxane (10 mL) and water (2.5 mL) at room temperature. 2-fluorophenyl boronic acid pinacol ester (954mg, 4.03mmol), potassium carbonate (1.39g, 10.06mmol) and _{_{Pd (PPh 3) 4 (392mg}} , 0.34mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjj Yellow solid, yield: 92.8%).

LC-MS (ESI): m / z282.0 / 284.0 [M + H +].

Step 6: 5-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridine Preparation of 2-amine (bb)

3-(4-Amino-2-fluorophenyl)-5-bromopyridin-2-amine was added to a reaction flask containing 1,4-dioxane (6 mL) and water (1.5 mL) at room temperature. Bb5) (250 mg, 0.88 mmol), 2-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborane (bb4) (371 mg, 1.06 mmol), cesium carbonate (860 mg, 2.64 mmol), and Pd(PPh ₃ ) ₄ (104 mg, 0.09 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut -Methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridin-2-amine (bb) (140 mg, yellow solid, yield: 37.1%).

LC-MS (ESI): m / z 426.3 [M + H +].

Preparation Example 28: 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolan ( Preparation of intermediate cc)

Step 1: Preparation of 2-(4-bromo-2-methoxyphenoxy)ethan-1-ol (cc1)

4-bromo-2-methoxyphenol (5 g, 24.63 mmol), 2-bromoethanol (6.15 g, 49.26 mmol) and potassium carbonate (10.19 g, 73.89 mmol) were added to a reaction flask containing DMF (60 mL). The mixture was heated to 110 ° C and stirred for 20 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by silica gel column chromatography (EtOAc: EtOAc/EtOAc) Colorless oil, yield: 95.4%).

LC-MS (ESI): m / z 246.0 / 248.0 [M + H +].

Step 2: 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolane (cc) Preparation

2-(4-Bromo-2-methoxyphenoxy)ethan-1-ol (5.5 g, 22.3 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (60 mL). The mixture was cooled to 0 ° C, sodium hydride (3.56 g, 89.2 mmol, 60%) was added and stirred for 30 minutes, then 2,2-dimethyl-1,3-dioxo-p-toluenesulfonate was added. A solution of the cyclo-4-methyl ester in tetrahydrofuran (8.3 g, 29 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hr. After the reaction was completed, water was evaporated, and ethyl acetate (80 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc / 1:1) to give 4-((2-(4-bromo-2-methoxyphenoxy)ethoxy) 2,2-Dimethyl-1,3-dioxolane (cc) (4.6 g, colorless oil, yield: 57.2%).

LC-MS (ESI): m / z 361.1 / 363.0 [M / M + H +].

Preparation Example 29: 5-(4-(2-((1,4-dioxan-2-yl)methoxy)ethoxy)-3-methoxyphenyl)-3-(4- Preparation of amino-2-fluorophenyl)pyridin-2-amine (intermediate dd)

In the same manner as in Preparation Example 27 except that 4-((2-(4-bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1, 3-Dioxolane (cc) instead of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (bb1) To give 5-(4-(2-((1,4-dioxan-2-yl)methoxy)ethoxy)-3-methoxyphenyl)-3-(4-amino-) 2-fluorophenyl)pyridin-2-amine (dd) (yellow solid, four-step yield: 33.8%).

LC-MS (ESI): m / z 470.4 [M + H +].

PREPARATIVE EXAMPLE 30: 3-(4-Amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-2-amine (Intermediate Preparation of ee)

Step 1: Preparation of 4-(2-(4-bromo-2-methoxyphenoxy)ethyl)morpholine (ee1-1)

4-bromo-2-methoxyphenol (6.5 g, 32.34 mmol), 4-(2-chloroethyl)morpholine (5.3 g, 35.57 mmol), potassium carbonate were added to a reaction flask containing DMF (20 mL). (11.2 g, 80.85 mmol). The mixture was warmed to 80 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and ethyl acetate (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAcqqq elut elut elut elut elut 8.9 g, yellow solid, yield: 88.2%).

LC-MS (ESI): m / z 316.1 / 318.2 [M + H +].

Step 2: 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) Preparation of ethyl)ethyl)morpholine (ee1)

4-(2-(4-Bromo-2-methoxyphenoxy)ethyl)morpholine was added to a reaction flask containing 1,4-dioxane (12 mL) and water (3 mL) at room temperature (1 g, 3.16 mmol), pinacol borate (1.22 g, 4.75 mmol), sodium acetate (1.29 g, 9.48 mmol) and Pd(dppf)Cl ₂ .DCM (261 mg, 0.32 mmol). Sealed, replaced with nitrogen three times, heated to 95 ° C and stirred for 12 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate and ethyl acetate (30 mL, The organic phase was washed with brine, dried over anhydrous sodium sulfate -(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (ee1) (700 mg, yellow solid, yield: 60.99%).

LC-MS (ESI): m/z 363.4 [M+H ⁺ ]

The remaining steps were carried out in the same manner as in Preparation Example 20 except that 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclo), cyclopentan-2-yl)phenoxy)ethyl)morpholine (ee1) tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(3-methyl Oxy-4-(2-morpholinoethoxy)phenyl)pyridin-2-amine (Intermediate L1) (yellow solid, two-step yield: 58.9%).

LC-MS (ESI): m / z 438.4 [M + H +].

PREPARATIVE EXAMPLE 31 Preparation of 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (Intermediate ff)

Step 1: Preparation of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (ff1)

4-Chloro-6,7-dimethoxyquinoline (2.0 g, 8.94 mmol) and 2-fluoro-4-nitrophenol (2.81 g) were added to a reaction flask containing diphenyl ether (38 mL) at room temperature. , 17.88 mmol). The mixture was heated to 140 ° C and stirred for 10 hours. After the reaction mixture was cooled to room temperature, a white solid was precipitated. The reaction solution was filtered, and the filter cake was washed with diethyl ether. The solid was collected to give 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (ff1) (3.0 g, white solid , yield: 97.55%).

LC-MS (ESI): m / z 345.2 [M + H +].

Step 2: Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff)

4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (3.0 g, 8.72) was added to a reaction flask containing ethanol (30 mL) and water (10 mL) at room temperature. Methyl), iron powder (2.44 g, 43.6 mmol) and ammonium chloride (4.67 g, 87.2 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Fluoroaniline (ff) (2.6 g, gray solid, yield: 95.0%).

LC-MS (ESI): m / z315.2 [M + H +].

Preparation Example 32: Preparation of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (Intermediate gg)

Step 1: Preparation of 4-((6-chloropyridazin-3-yl)oxy)-6,7-dimethoxyquinoline (gg1)

Add 6,7-dimethoxyquinolin-4-ol (500 mg, 2.44 mmol), 3,6-dichloropyridazine (436 mg, 2.92 mmol) and a reaction flask containing DMF (100 mL) at room temperature. Potassium carbonate (1.0 g, 3.0 mmol). The mixture was warmed to 140 ° C and stirred for 2 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc: EtOAc) Base quinoline (gg1) (137 mg, white solid, yield: 17.6%).

LC-MS (ESI): m / z 318.0 / 320.1 [M + H +].

Step 2: Preparation of N-(2,4-dimethoxybenzyl)-6-((6,7-dimethylquinolin-4-yl)oxy)pyridazin-3-amine (gg2)

4-((6-chloropyridazin-3-yl)oxy)-6,7-dimethoxyquinoline (1.0 g, 3.14 mmol) was added to a microwave tube containing toluene (15 mL) at room temperature. (2,4-Dimethoxyphenyl)methylamine (10.5 g, 62.9 mmol), cesium carbonate (3.1 g, 9.43 mmol), Pd ₂ (dba) ₃ (576 mg, 0.63) and xantphose (728 mg, 1.26 mmol) ). It was sealed, replaced with nitrogen three times, placed in a microwave reactor and warmed to 130 ° C and stirred for 1 hour. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Benzyl quinolin-4-yl)oxy)pyridazin-3-amine (700 mg, white solid, yield: 49.8%).

LC-MS (ESI): m / z 449.2 [M + H +].

Step 3: Preparation of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg)

Add N-(2,4-dimethoxybenzyl)-6-((6,7-dimethylquinolin-4-yl)oxy)anthracene to a reaction flask containing trifluoroacetic acid (10 mL) Pyrazin-3-amine (700 mg, 1.56 mmol). The mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with methylene chloride. The residue was purified by EtOAc EtOAc EtOAcEtOAc 3-amine (gg) (400 mg, white solid, yield: 86.0%).

LC-MS (ESI): m / z 299.2 [M + H +].

Preparation example 33: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (intermediate hh)

Step 1: 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-methoxybenzene Preparation of methyl formate (hh1)

Methyl 4-amino-2-methoxybenzoate (5 g, 27.6 mmol) was added to a reaction flask containing isopropyl alcohol (100 mL) at room temperature. The mixture was warmed to 50 ° C and stirred for 10 minutes, then added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Shanghai Bi De , 5.13 g, 27.6 mmol). The mixture was further heated to 80 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the solid was collected to give 4-((((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl))methyl Methyl amino)-2-methoxybenzoate (8 g, brown solid, yield: 86.5%).

LC-MS (ESI): m / z 336.3 [M + H +].

Step 2: Preparation of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (hh2)

Add 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-)ylene to the reaction flask containing diphenyl ether (100 mL) at room temperature Methyl)amino)-2-methoxybenzoic acid methyl ester (8 g, 23.9 mmol). The mixture was warmed to 200 ° C and stirred for 8 hours. The reaction mixture was cooled to room temperature, filtered, and solid was collected to give 4-hydroxyl. Methyl-7-methoxyquinoline-6-carboxylate (5.2 g, brown solid, yield: 93.4%).

LC-MS (ESI): m / z 234.1 [M + H +].

Step 3: Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (hh3)

Methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (1 g, 4.29 mmol) and DMF (0.1 mL) were added to a reaction flask containing thionyl chloride (20 mL). The mixture was heated to reflux and stirred for 3 hours. After the reaction mixture was cooled to room temperature, concentrated. The residue was diluted with methylene chloride (30 mL). The crude product 4-chloro-7-methoxyquinoline-6-carboxylic acid methyl ester (1.0 g, brown solid, yield: 92.8%) was obtained.

LC-MS (ESI): m / z 237.1 / 239.1 [M + H +].

Step 4: Preparation of 4-chloro-7-methoxyquinolin-6-carboxamide (hh4)

Methyl 4-chloro-7-methoxyquinoline-6-carboxylate (1 g, 3.98 mmol) and aqueous ammonia (33.0%, 5 mL) were added to a reaction flask containing THF (10 mL). The mixture was heated to 80 ° C and stirred overnight. After the reaction mixture was cooled to room temperature, filtered, and the solid was collected to give 4-chloro-7-methoxyquinoline-6-carboxamide (600 mg, brown solid, yield : 63.9%).

LC-MS (ESI): m / z 236.2 / 238.2 [M + H +].

Step 5: Preparation of 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinolin-6-carboxamide (hh5)

4-Chloro-7-methoxyquinoline-6-carboxamide (600 mg, 2.39 mmol) and 2-fluoro-4-nitrophenol (750 mg) were added to a reaction flask containing diphenyl ether (10 mL) at room temperature. , 4.78 mmol). The mixture was heated to 140 ° C and stirred for 10 hours. After the reaction mixture was cooled to room temperature, a white solid was precipitated. The reaction mixture was filtered, and the solid was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj .

LC-MS (ESI): m / z 358.2 [M + H +].

Step 6: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh)

Add 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (800 mg, in a reaction flask containing ethanol (15 mL) and water (5 mL) at room temperature. 2.24 mmol), iron powder (627 mg, 11.2 mmol) and ammonium chloride (1.3 g, 22.7 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc elut elut Formamide (600 mg, gray solid, yield: 81.7%).

LC-MS (ESI): m / z 328.3 [M + H +].

Preparation Example 34: Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (Intermediate ii)

Step 1: Preparation of 4-(4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (ii1)

4-Chloro-7-azaindole (500 mg, 3.28 mmol), 4-nitrophenol (638 mg, 4.58 mmol) and DIPEA (1.27 g, 9.83 mmol) were added to a reaction flask containing NMP (10 mL). The mixture was heated to 200 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by EtOAcqqq elut elut elut elut elut elut 300 mg, yellow solid, yield: 35.8%).

LC-MS (ESI): m / z 256.2 [M + H +].

Step 2: Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (ii)

Add 4-(4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.17 mmol), zinc powder to a reaction flask containing methanol (4 mL) and tetrahydrofuran (4 mL). 230 mg, 3.52 mmol) and ammonium chloride (625 mg, 11.7 mmol). The mixture was stirred at room temperature overnight. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 80 mg, yellow solid, yield: 30.4%).

LC-MS (ESI): m / z 226.1 [M + H +].

PREPARATIVE EXAMPLE 35 Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline (Intermediate jj)

4-((1H-pyrrolo[2,3-b]pyridin-4-yl) was obtained in the same manner as in Preparation Example 36 except that 2-fluoro 4-nitrophenol was used instead of 4-nitrophenol. Oxy)-3-fluoroaniline (yellow solid, two-step yield: 23.5%).

LC-MS (ESI): m / z 244.2 [M + H +].

PREPARATIVE EXAMPLE 36 Preparation of 4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (Intermediate kk)

4- (6) was obtained in the same manner as in Preparation Example 31 except that 4-chloro-6,7-dimethoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinoline. , 7-Dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (yellow solid, two-step yield: 88.6%).

LC-MS (ESI): m / z 306.3 [M + H +].

PREPARATIVE EXAMPLE 37 Preparation of 4-((6,7-Dimethoxyquinazolin-4-yl)oxy)phenylamine (Intermediate 11)

In the same manner as in Preparation Example 36, except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-((6,7-dimethoxyquinazolin-4-yl)oxy was obtained. Aniline (yellow solid, two-step yield: 85.7%).

LC-MS (ESI): m / z 298.3 [M + H +].

Preparation Example 38: Preparation of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Intermediate mm)

In the same manner as in Preparation Example 31, except that 4-chloropyridin-2-amine was used instead of 4-chloro-6,7-dimethoxyquinoline, 4-(4-amino-2-fluorophenoxyl) was obtained. Pyridin-2-amine (yellow solid, two-step yield: 43.5%).

LC-MS (ESI): m / z 220.2 [M + H +].

PREPARATIVE EXAMPLE 39 Preparation of 4-(4-Amino-2-phenoxy)pyridin-2-amine (Intermediate nn)

In the same manner as in Preparation Example 38 except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-(4-amino-2-phenoxy)pyridin-2-amine (yellow) was obtained. Solid, two-step yield: 39.5%).

LC-MS (ESI): m / z 202.1 [M + H +].

PREPARATIVE EXAMPLE 40: Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate oo)

Step 1: Preparation of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinazoline (oo1)

Add 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), 2-fluoro-4-nitrophenol (1.57 mg) to a reaction flask containing NMP (35 mL). , 9.98 mmol) and DIPEA (2.6 g, 20.0 mmol). The mixture was heated to 180 ° C and stirred for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut elut -Methoxyquinazoline (2.1 g, yellow solid, yield: 76.5%).

LC-MS (ESI): m / z 422.2 [M + H +].

Step 2: Preparation of 4-(2-fluoro-4-nitrophenyl)-6-methylquinazolin-7-ol (oo2)

Add 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinazoline (2.1 g, 4.99) to a reaction flask containing trifluoroacetic acid (25 mL). Mm). The mixture was stirred at room temperature overnight, and after the reaction was completed, the mixture was concentrated. The residue was diluted with methylene chloride. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Alcohol (1.4 g, white solid, yield: 91.6%).

LC-MS (ESI): m / z 332.2 [M + H +].

Step 3: Preparation of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinazoline (oo3)

Add 4-(2-fluoro-4-nitrophenyl)-6-methylquinazolin-7-ol (350 mg, 1.13 mmol), 1-bromo-2- in a reaction flask containing DMF (8 mL) Methoxyethane (235 mg, 1.69 mmol), potassium carbonate (400 mg, 2.81 mmol). The mixture was warmed to 80 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc EtOAc(EtOAc 2-methoxyethoxy)quinazoline (340 mg, yellow solid, yield: 77.3%).

LC-MS (ESI): m / z 390.3 [M + H +].

Step 4: Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (oo)

4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyB) was added to a reaction flask containing ethanol (30 mL) and water (10 mL) at room temperature Oxy) quinazoline (340 mg, 0.87 mmol), iron powder (243 mg, 4.35 mmol) and ammonium chloride (460 mg, 8.7 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Quinazolin-4-yl)oxy)aniline (280 mg, gray solid, yield: 89.7%).

LC-MS (ESI): m / z 360.2 [M + H +].

PREPARATIVE EXAMPLE 41: 4-((6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate pp)

In the same manner as in Preparation Example 40, except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-((6-methoxy-7-(2-methoxyethoxy) was obtained. Base quinazolin-4-yl)oxy)aniline (yellow solid, four-step yield: 27.8%).

LC-MS (ESI): m / z 342.3 [M + H +].

PREPARATIVE EXAMPLE 42: 4-(2-((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1 -Preparation of tert-butyl formate (intermediate qq)

4-(2) was obtained in the same manner as in Preparation Example 40 except that 1-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 1-bromo-2-methoxyethane. -((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (yellow solid, Two-step yield: 63.7%).

LC-MS (ESI): m / z 514.4 [M + H +].

PREPARATIVE EXAMPLE 43: 4-(2-((4-(4-Aminophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl Preparation of ester (intermediate rr)

In the same manner as in Preparation Example 42, except that 4-nitrophenol was used in place of 2-fluoro-4-nitrophenol, 4-(2-(4-(4-aminophenoxy)-6-) was obtained. Tert-Butyl methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate (yellow solid, four-step yield: 23.4%).

LC-MS (ESI): m / z 496.4 [M + H +].

PREPARATIVE EXAMPLE 44: Preparation of 4-((6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate ss)

In the same manner as in Preparation Example 43, except that 4-(2-chloroethyl)morpholine was used instead of 4-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester to give 4-(( 6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (yellow solid, two-step yield: 70.2%).

LC-MS (ESI): m / z 394.3 [M + H +].

Preparation Example 45: Preparation of 3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)aniline (tt)

In the same manner as in Preparation Example 42, except that 4-(2-chloroethyl)morpholine was used instead of 4-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester to give 3-fluoro- 4-((6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (yellow solid, two-step yield: 63.2%).

LC-MS (ESI): m / z 415.3 [M + H +].

Example 1: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)

Step 1: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a Preparation

Add 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- to a reaction flask containing DMF (10 mL) Carboxylic acid (a) (150 mg, 0.47 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl Piperidine-1-carboxylic acid tert-butyl ester (u) (235 mg, 0.52 mmol), HATU (268 mg, 0.705 mmol) and DIPEA (182 mg, 1.41 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with brine, dried over anhydrous sodium sulfate (4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro Ethyl phenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a) (230 mg, yellow solid , yield: 65.0%).

LC-MS (ESI): m / z 754.4 [M + H +].

Step 2: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Of 3-(fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b)

Add 5-((4-(2-amino)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-) to a reaction flask containing ethanol (8 mL) at room temperature Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di Ethyl hydropyridine-2-carboxylate (230 mg, 0.31 mmol), lithium hydroxide monohydrate (17 mg, 0.40 mmol) and water (2 mL). The mixture was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give crude 5--(4-(2-amino-5-(1-(1-(t-butoxycarbonyl))piperidine. 4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2-carboxylic acid (1b) (220 mg, gray solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 726.3 [M + H +].

Step 3: 4-(4-(6-Amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di) Preparation of tert-butyl ester (1c) of hydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

In a reaction flask containing DMF (3 mL) was added 5-((4-(2-amino-5-(1-(1-(tert-butoxycarbonyl))piperidin-4-yl)-1H-pyrazole- 4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine- 2-carboxylic acid (70 mg, 0.10 mmol), ammonium chloride (26 mg, 0.5 mmol), tripyrrolidinylphosphonium bromide (93 mg, 0.2 mmol) and DIPEA (52 mg, 0.4 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazole- Tert-butyl ester of 1-yl)piperidine-1-carboxylate (1c) (30 mg, yellow solid, yield: 42.9%)

LC-MS (ESI): m / z725.3 [M + H +].

Step 4: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of -3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)

Add 4-(4-(6-amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl))-1-methyl-4-) to a reaction flask containing DCM (3 mL) Oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol) and a solution of 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N ⁵ -(4-(2-amino-5-(1-(piperidin-4-yl)) -1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydrogen Pyridine-2,5-dimethylformamide (1) (10 mg, white solid, 41.7%).

LC-MS (ESI): m / z 625.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.95 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.27-8.20 (m, 2H), 8.14 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz) , 1H), 7.39–7.31 (m, 3H), 7.27–7.21 (m, 2H), 5.53 (s, 2H), 4.29–4.22 (m, 1H), 3.87 (s, 3H), 3.16 (d, J) =12.7 Hz, 2H), 2.81 - 2.72 (m, 2H), 2.05 (d, J = 12.1 Hz, 2H), 1.91 (tt, J = 12.3, 6.2 Hz, 2H).

Example 2: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-N ² ,1 -dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (2)

In the same manner as in Example 1, except that methylamine hydrochloride was used instead of ammonium chloride, N ⁵ -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-N ² ,1 dimethyl-4-oxo-1,4-dihydro Pyridine-2,5-dimethylformamide (2) (white solid, two-step yield: 22.3%).

LC-MS (ESI): m / z 639.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.94 (s, 1H), 8.82 (d, J = 6.9Hz, 1H), 8.73 (q, J = 4.8Hz, 1H), 8.31 (s, 1H) , 8.26 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 7.94 - 7.88 (m, 1H), 7.83 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.49–7.28 (m, 4H), 7.24 (t, J=8.8 Hz, 2H), 5.54 (s, 2H), 4.25–4.30 (m, 4H), 3.82 (s, 3H), 3.18 (d) , J = 11.9 Hz, 2H), 2.79 (t, J = 12.2 Hz, 2H), 2.14 - 1.86 (m, 4H).

Example 3: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of -N ² -cyclopropyl-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (3)

In the same manner as in Example 1, except that a cyclopropylamine was used in place of ammonium chloride, N ⁵ -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyridyl) was obtained. Zin-4-yl)pyridin-3-yl)-3-fluorophenyl)-N ² -cyclopropyl-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4 - Dihydropyridine-2,5-dimethylformamide (3) (white solid, two-step yield: 25.6%).

LC-MS (ESI): m / z 665.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.93 (s, 1H), 8.89-8.80 (m, 2H), 8.33 (s, 1H), 8.26 (d, J = 2.2Hz, 1H), 8.15 ( s, 1H), 7.89 (d, J = 11.9 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.47 - 7.32 (m, 2H), 7.27 (p, J = 8.6 Hz, 4H), 5.54 (s, 2H), 4.28 (d, J = 11.3 Hz, 2H), 3.20 (d, J = 12.0 Hz, 2H), 2.82 (t, J = 12.2) Hz, 2H), 2.09 (d, J = 13.8 Hz, 2H), 1.96 (p, J = 11.9, 10.4 Hz, 2H), 0.54 (d, J = 7.2 Hz, 2H), 0.01 (d, J = 7.3 Hz, 2H).

Example 4: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of 5-(4-fluorophenyl)-1-methyl-6-(morpholin-4-carbonyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (4)

In the same manner as in Example 1, except that morpholine was used instead of ammonium chloride, N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazole-4) was obtained. -yl)pyridin-3-yl)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl-6-(morpholin-4-carbonyl)-4-oxo-1, 4-Dihydropyridine-3-carboxamide (4) (white solid, two-step yield: 28.6%).

LC-MS (ESI): m / z 695.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.91 (s, 1H), 8.83 (d, J = 6.9Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 2.3Hz, 1H) , 8.15 (s, 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.83 (d, J = 4.6 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.47 - 7.26 ( m,6H),5.55(s,2H),4.30(td,J=11.0,5.3Hz,1H),3.81(s,3H),3.59–3.54(m,2H),3.43–3.30(m,4H) , 3.23 - 3.17 (m, 2H), 3.01 (dd, J = 18.4, 8.9 Hz, 2H), 2.84 - 2.79 (m, 2H), 2.13 - 1.93 (m, 4H).

Example 5: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(azetidin-1-carbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (5) Preparation

In the same manner as in Example 1, except that aziridine hydrochloride was used instead of ammonium chloride, N-(4-(2-amino-5-(1-(piperidin-4-yl)-) was obtained. 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(azetidin-1-carbonyl)-5-(4-fluorophenyl)-1-methyl 4-Oxo-1,4-dihydropyridine-3-carboxamide (5) (white solid, two-step yield: 24.1%).

LC-MS (ESI): m / z 665.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.89 (s, 1H), 8.82 (d, J = 7.1Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 2.3Hz, 1H) , 8.14 (s, 1H), 7.89 (dd, J = 12.2, 1.9 Hz, 1H), 7.83 (d, J = 4.9 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.50 - 7.14 ( m,6H),5.55(s,2H),4.33–4.23(m,1H),3.98(dd,J=9.2,6.6Hz,2H),3.85(s,3H),3.50(d,J=6.8Hz , 2H), 3.18 (d, J = 12.3 Hz, 2H), 2.79 (t, J = 12.0 Hz, 2H), 2.18 - 1.84 (m, 6H).

Example 6: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (6)

In the same manner as in Example 1, except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N ⁵ -(4- (2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl) 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (6) (white solid, four-step yield: 13.5%).

LC-MS (ESI): m / z 663.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.95 (s, 1H), 8.77 (s, 1H), 8.31 (d, J = 2.9Hz, 2H), 8.26 (d, J = 2.3Hz, 1H) , 8.14 (s, 1H), 8.04 (s, 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.81 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.43 ( Dd, J = 8.4, 2.0 Hz, 1H), 7.36 (ddd, J = 10.1, 5.9, 2.9 Hz, 3H), 7.24 (t, J = 9.0 Hz, 2H), 5.54 (s, 2H), 4.51 (q) , J = 6.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.16 (d, J = 12.5 Hz, 2H), 2.82 - 2.74 (m, 2H), 2.05 (d, J = 11.9 Hz, 2H) , 1.96–1.86 (m, 2H), 1.56 (d, J = 6.6 Hz, 6H).

Example 7: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl )-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-di Preparation of formamide (7)

The same procedure as in Example 1 was carried out except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N ⁵ -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 , 5-dimethylformamide (7) (white solid, four-step yield: 11.2%).

LC-MS (ESI): m / z 709.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.90 (s, 1H), 8.78 (d, J = 6.9Hz, 1H), 8.27-8.24 (m, 2H), 8.14 (s, 1H), 8.00 ( s, 1H), 7.92 - 7.80 (m, 2H), 7.55 (d, J = 2.4 Hz, 1H), 7.45 - 7.19 (m, 7H), 5.54 (s, 2H), 4.29 (q, J = 13.1, 11.2 Hz, 1H), 3.94–3.86 (m, 2H), 3.28–3.08 (m, 5H), 2.79 (t, J = 12.1 Hz, 2H), 2.49 (s, 4H), 2.07 (d, J = 13.2) Hz, 2H), 1.51–1.28 (m, 4H).

Example 8: N ⁵ -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl )-3-(4-fluorophenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of -2,5-dimethylformamide (8)

In the same manner as in Example 7, except that methylamine hydrochloride was used instead of ammonium chloride, N ⁵ -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (8) (white solid, two-step yield: 22.3%).

LC-MS (ESI): m / z 723.4 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 8.88 - 8.67 (m, 2H), 8.38 - 8.23 (m, 2H), 8.15 (s, 1H), 7.95 - 7.74 (m) , 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.49 - 7.15 (m, 6H), 5.55 (s, 2H), 4.33 - 4.20 (m, 1H), 4.07 (d, J = 7.3 Hz, 2H), 3.94–3.82 (m, 2H), 3.35–3.10 (m, 4H), 2.84–2.73 (m, 2H), 2.48 (d, J = 4.8 Hz, 4H), 2.15–1.86 (m, 5H) , 1.46 (d, J = 12.4 Hz, 2H), 1.31 (dd, J = 12.2, 4.2 Hz, 1H).

Example 9: N ⁵ -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N ² -methyl-4-oxo- Preparation of 1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2,5-dimethylamide (9)

Step 1: 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9a) preparation

Add 4-oxo-4hydro-pyran-2,5-dicarboxylate (a2) (300 mg, 1.25 mmol) and (tetrahydro-2H-pyridyl) to a round bottom flask containing ethanol (4 mL) at room temperature. Methyl-4-yl)methylamine (173 mg, 1.5 mmol). The mixture was warmed to 80 ° C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (9a) (300 mg, yellow solid, yield: 71.2%).

LC-MS (ESI): m / z 338.3 [M + H +].

Step 2: 3-Bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester Preparation of (9b)

Add 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxyl to a reaction vial containing DMF (5 mL) Diethyl acid (9a) (300 mg, 0.89 mmol) and N-bromosuccinimide (317 mg, 1.78 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 3-bromo-4-oxo-1 - ((tetrahydro-pyran-4 -2H- Methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9b) (320 mg, yellow solid, yield: 86.0%).

LC-MS (ESI): m / z 416.2 / 418.2 [M + H +].

Step 3: 5-Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 - Preparation of formic acid (9c)

3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 was added to a reaction flask containing (9 mL) of ethanol. Diethyl 5-dicarboxylate (9b) (1.0 g, 2.39 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (3 mL, 2.87 mmol) was added dropwise with stirring, and the mixture was warmed to room temperature and stirring was continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of the solid to give 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydro Pyridine-3-carboxylic acid (9c) (600 mg, white solid, yield: 64.4%).

LC-MS (ESI): m / z 304.1 / 306.1 [M + H +].

Step 4: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo Preparation of ethyl 1-((tetrahydro-2H-pyran-2-yl)-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (9d)

Add 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 to a reaction vial containing DMF (10 mL) , 4-dihydropyridine-3-carboxylic acid (9c) (100 mg, 0.26 mmol), 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridine-2 -Amine (aa) (99 mg, 0.31 mmol), HATU (146 mg, 0.39 mmol) and DIPEA (99 mg, 0.77 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with brine, dried over anhydrous sodium sulfate (4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((four Ethyl 2-H-pyran-2-yl)-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (9d) (160 mg,yield:yield: 89.1%).

LC-MS (ESI), m / z 691.3 / 693.4 [M / M + H +].

Step 5: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of ethyl (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylate (9e)

Add 5-((4-(2-amino-5-(3,4-dimethyl)) to the reaction flask containing (5 mL) 1,4-dioxane and water mixture (4:1) at room temperature Oxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-2-yl)-4-yl)- Ethyl 4-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9d) (120 mg, 0.17 mmol), p-methylphenylboronic acid (35 mg, 0.25 mmol), potassium carbonate (70 mg, 0.51 mmol), Pd ( Dppf) Cl ₂ .DCM (14 mg, 0.017 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 5 - ((4- (2-amino-5- (3,4-dimethoxybenzene Pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1 Ethyl 4-dihydropyridine-2-carboxylate (9e) (100 mg, yellow solid, yield: 83.4%).

LC-MS (ESI), m / z 703.4 [M / M + H +].

Step 6: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f)

Add 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamate to a reaction flask containing ethanol (2 mL) at room temperature Acyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9e) (100 mg, 0.14 mmol), lithium hydroxide monohydrate (10 mg, 0.21 mmol) and water (0.5 mL). The reaction solution was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give the crude product 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridine) 3-yl)phenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-di Hydropyridine-2-carboxylic acid (9f) (100 mg, gray solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI), m / z 675.4 [M / M + H +].

Step 7: N ⁵ -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N ² -methyl-4-oxo-1 Preparation of ((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2,5-dimethylformamide (9)

Add 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)amino) to a round bottom flask containing DMF (3 mL) at room temperature Formyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f (50 mg, 0.074 mmol), methylamine hydrochloride (14 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), EDCI (42 mg, 0.22 mmol) and DIPEA (57 mg, 0.44 mmol). The mixture was stirred at this temperature overnight, and after the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N ⁵ -(2-(2-amino-5-(3,4-dimethoxyphenyl) Pyridin-3-yl)phenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)- 1,4-Dihydropyridine-2,5-dimethylformamide (9) (6 mg, white solid, yield: 11.2%).

LC-MS (ESI), m / z 688.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.76 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.80 (d, J = 8.3Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.19 (s, 6H), 6.99 (d, J = 8.3 Hz, 1H), 5.66 (s, 2H), 4.05 (d, J = 7.4 Hz, 2H), 3.87 (d, J = 10.6 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.24 (s, 1H), 2.47 (d, J = 4.6 Hz, 3H) , 2.35 (s, 3H), 1.46 (d, J = 13.2 Hz, 2H).

Example 10: N ⁵ -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-(1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10)

In the same manner as in Example 6, except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N ⁵ -(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl) 1-Isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10) (white solid, three-step yield: 17.5%).

LC-MS (ESI), m / z 640.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 8.77 (s, 1H), 8.29 (d, J = 2.4 Hz, 2H), 8.04 (s, 1H), 7.91 (dd, J=12.5, 1.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.52–7.32 (m, 4H), 7.29–7.18 (m, 2H), 7.18–7.06 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 4.50 (p, J = 6.6 Hz, 1H), 3.79 (d, J = 20.5 Hz, 6H), 1.56 (d, J = 6.6 Hz) , 6H).

Example 11: N ⁵ -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (11)

The same procedure as in Example 10 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- The carboxylic acid (a) is substituted for 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) to obtain N ⁵ -(4- (2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2,5-dimethylformamide (11) (white solid, three-step yield: 18.8%).

LC-MS (ESI), m / z 612.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.95 (s, 1H), 8.83 (s, 1H), 8.29 (d, J = 2.4Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 12.4, 1.8 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.52 - 7.32 (m, 4H), 7.28 - 7.20 (m, 2H), 7.17 - 7.08 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 3.87 (s, 3H), 3.79 (d, J = 20.5 Hz, 6H).

Example 12: N ⁵ -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (12)

The same procedure as in Example 11 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) was used. Instead of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x), N ⁵ -(4-(2-amino) was obtained. -5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo代-1,4-Dihydropyridine-2,5-dimethylformamide (12) (white solid, three-step yield: 20.6%).

LC-MS (ESI), m / z 570.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.95 (s, 1H), 8.83 (s, 1H), 8.23 (dd, J = 6.6,2.2Hz, 2H), 8.09 (s, 1H), 8.02 ( s, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H) ), 7.39 - 7.31 (m, 3H), 7.28 - 7.21 (m, 2H), 5.53 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H).

Example 13: N ⁵ -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (13)

In the same manner as in Example 12 except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N ⁵ -(4- (2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl 4-Oxo-1,4-dihydropyridine-2,5-dimethylformamide (13) (white solid, three-step yield: 22.4%).

LC-MS (ESI), m / z 598.3 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 8.77 (s, 1H), 8.41 - 8.21 (m, 2H), 8.06 (d, J = 18.2 Hz, 2H), 7.90 ( Dd, J = 12.3, 2.0 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.47 - 7.20 (m, 5H), 5.53 (s, 2H), 4.50 (p , J = 6.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 1.77 - 1.16 (m, 9H).

Example 14: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepine Preparation of heptane-8-carboxamide (14)

Step 1: 4-(4-(6-Amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 ,9-Hexidopyrido[1,2-α][1,4]diazepane-8-formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl Preparation of piperidine-1-carboxylic acid tert-butyl ester (14a)

Add 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- to a reaction flask containing DMF (4 mL). a][1,4]diazepane-8-carboxylic acid (d) (45 mg, 0.14 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)) tert-Butyl pyridine-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u) (50 mg, 0.11 mmol), HATU (63 mg, 0.17 mmol) and DIPEA (43 mg, 0.33 mmol) . The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1: 20) to afford 4-(4-(6-amino-5-(2-fluoro-4-(10-(4-) Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepan-8- Formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 14a) (40 mg, yellow solid, yield: 48.2%) .

LC-MS (ESI): m / z 751.3 [M / M + H +].

Step 2: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepine Preparation of heptane-8-carboxamide (14)

Add 4-(4-(6-amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1) to a reaction flask containing DCM (3 mL) , 2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamido)phenyl)pyridin-3-yl)- 1H-Pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (14a) (40 mg, 0.05 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-Hexidopyrido[1,2-α][1,4]diazepane-8-carboxamide (14) (11 mg, white solid, 31.9%).

LC-MS (ESI): m / z 651.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.97 (s, 1H), 8.86 (s, 1H), 8.70 (t, J = 6.6 Hz, 2H), 8.31 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.01–7.91 (m, 2H), 7.83 (s, 1H), 7.51–7.38 (m, 2H), 7.36–7.18 (m, 4H), 6.40 (s, 2H), 4.66 (d, J = 12.3 Hz, 1H), 4.53 - 4.42 (m, 1H), 4.05 (d, J = 15.9 Hz, 1H), 3.40 (s, 2H), 3.09 (d, J = 11.6 Hz, 2H), 2.27 - 1.98 (m, 6H), 1.24 (s, 2H).

Example 15: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluoro Phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4] Preparation of diazepane-8-carboxamide (15)

The same procedure as in Example 14 was employed except that 4-(4-(6-amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazole-1 was used. -yl)piperidine-1-carboxylic acid tert-butyl ester (y) in place of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazole -1-yl)piperidine-1-carboxylic acid tert-butyl ester (u) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazole-4) -yl)pyridin-3-yl)-2,5-difluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9- Hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (15) (white solid, two-step yield: 36.3%).

LC-MS (ESI): m / z 669.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.24 (s, 1H), 8.88 (s, 1H), 8.68 (s, 1H), 8.51-8.39 (m, 1H), 8.28 (s, 1H), 8.15(s,1H), 7.86(s,1H), 7.58(s,1H), 7.37(d,J=6.7Hz,1H),7.35–7.15(m,4H),5.71(s,2H),4.73 – 4.35 (m, 3H), 4.12–4.00 (m, 1H), 3.65–3.36 (m, 4H), 3.05 (s, 2H), 2.18 (s, 6H).

Example 16: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-C][1,4]oxazine-9-carboxamide (16)

The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-c][1,4]oxazine-9-carboxylic acid (j) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4 -(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-7-(4-fluorobenzene ,6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyrazino[2,1-C [1,4]oxazine-9-carboxamide (16) (white solid, two-step yield: 26.7%).

LC-MS (ESI): m / z 693.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 8.95 - 8.86 (m, 1H), 8.78 (s, 2H), 8.26 (s, 2H), 7.95 (s, 3H), 7.48(s,1H), 7.42 (d, J=8.2Hz, 1H), 7.16(s,2H), 6.75–6.52(m,2H), 4.65(s,1H),4.52–4.44(m,1H) , 4.13 (d, J = 6.6 Hz, 2H), 3.97 (s, 3H), 3.46 (s, 2H), 3.31 - 3.28 (m, 2H), 3.13 - 3.06 (m, 2H), 2.94 - 2.80 (m , 2H), 2.20 (s, 4H).

Example 17: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-b][1,3]oxazine-9-carboxamide (17)

The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4 -(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-7-(4-fluorobenzene ,6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b [1,3]oxazine-9-carboxamide (17) (white solid, two-step yield: 29.3%).

LC-MS (ESI): m / z 693.4 [M / M + H +].

1H NMR (400MHz, DMSO-d ₆ ) δ 12.79 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.32–8.17 (m, 2H), 7.98–7.89 (m, 2H) , 7.79 (s, 1H), 7.53 - 7.34 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 7.11 (dd, J = 8.7, 5.8 Hz, 2H), 6.30 (s, 2H), 5.30 (t, J = 4.0 Hz, 1H), 4.73 - 4.50 (m, 2H), 4.46 (dq, J = 10.1, 5.2, 4.2 Hz, 1H), 4.23 (dd, J = 13.2, 4.4 Hz, 1H) , 4.14–3.96 (m, 1H), 3.88 (td, J=11.7, 2.8 Hz, 1H), 3.16–3.04 (m, 3H), 2.50 (s, 1H), 2.38–1.83 (m, 4H), 1.75 –1.62 (m, 1H), 1.58 (d, J = 13.1 Hz, 1H), 1.31 - 1.14 (m, 1H).

Example 18: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (18)

The same procedure as in Example 14 was carried out except that 6,8-dioxy-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 was used. ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 10-(4-fluorophenyl)-1,9-dioxo-1 , 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), N-(4-(2) -amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7- (p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3 Oxazine-9-carboxamide (18) (white solid, two-step yield: 19.8%).

LC-MS (ESI): m / z 689.3 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 8.89 (s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 7.92 - 7.73 ( m, 2H), 7.54 (d, J = 2.3 Hz, 1H), 7.48 - 7.30 (m, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.95 (s, 2H), 5.54 (s, 2H) ), 5.28 (t, J = 4.0 Hz, 1H), 4.72 - 4.43 (m, 2H), 4.31 - 4.02 (m, 3H), 3.91 - 3.80 (m, 1H), 3.09 (d, J = 11.6 Hz, 3H), 2.72–2.60 (m, 2H), 2.51 (s, 2H), 2.36 (s, 3H), 2.01 (d, J = 11.9 Hz, 2H), 1.84 (qd, J = 12.1, 4.0 Hz, 2H) ), 1.73–1.49 (m, 1H).

Example 19: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of alkane-8-carboxamide (19)

The same procedure as in Example 14 was carried out except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a] was used. [1,4]diazepane-8-carboxylic acid (e) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexa Hydrogen pyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4-(2-amino-5-(1-(piperidine)- 4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3, 4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (19) (white solid, two-step yield: 26.4%).

LC-MS (ESI): m / z 647.3 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.0.3 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.14 ( s, 1H), 7.89 (d, J = 12.7 Hz, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.39 (dt, J = 16.4, 8.3 Hz, 2H), 7.16 (dd, J =19.3, 7.9 Hz, 4H), 5.55 (s, 2H), 4.63 (s, 1H), 4.26 (s, 2H), 4.05 (s, 2H), 3.16 (d, J = 11.4 Hz, 2H), 2.77 (s, 2H), 2.34 (s, 3H), 2.23 - 1.84 (m, 6H).

Example 20: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4 Preparation of diazepane-8-carboxamide (20)

The same procedure as in Example 14 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(4-(2-amino-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1, 9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (20) (white solid, Two-step yield: 12.4%).

LC-MS (ESI): m / z 667.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.09-12.99 (m, 1H), 9.01-8.86 (m, 2H), 8.85-8.77 (m, 1H), 8.38 (s, 1H), 8.30-8.18 (m, 1H), 8.05 (s, 2H), 7.58–7.44 (m, 2H), 7.22 (s, 4H), 5.83–5.59 (m, 2H), 5.39–5.23 (m, 1H), 4.58–4.41 (m, 2H), 4.34–4.24 (m, 2H), 3.13–3.06 (m, 2H), 2.96–2.86 (m, 1H), 2.34–2.10 (m, 4H), 0.84–0.71 (m, 4H) .

Example 21: (4R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (21)

The same procedure as in Example 14 was employed except that (4R)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (s) in place of 10-(4-fluorobenzene) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ( d), (4R)-N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1 ', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (21) (white solid, two-step yield: 12.4%).

LC-MS (ESI): m / z 707.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.78 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.90 ( d, J = 12.5 Hz, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17 ( s, 3H), 5.55 (s, 2H), 5.46 (s, 1H), 4.73 (d, J = 10.3 Hz, 1H), 4.52 (d, J = 25.2 Hz, 2H), 4.31 - 4.23 (m, 1H) ), 3.99 (s, 1H), 3.18 (s, 2H), 2.78 (s, 2H), 1.98 (d, J = 49.3 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H).

Example 22: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -9-(4-Fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (22 Preparation

The same procedure as in Example 14 was carried out except that 9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a was used. Pyrazin-7-carboxylic acid (t) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1,2 -a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-9-(4-fluorophenyl)-1,8-dioxo 1,3,4,8-tetrahydro-2H - Pyrido[1,2-a]pyrazine-7-carboxamide (22) (white solid, two-step yield: 36.8%).

LC-MS (ESI): m / z 637.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.93 (s, 1H), 8.86 (s, 1H), 8.77 (s, 1H), 8.28 (d, J = 18.0Hz, 2H), 8.15 (s, 1H), 7.90 (d, J = 12.3 Hz, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.49 - 7.33 (m, 2H), 7.26 - 7.07 (m, 4H), 5.55 (s , 2H), 4.46 (s, 2H), 4.27 (s, 1H), 3.61 (s, 2H), 3.47 - 3.40 (m, 1H), 3.18 (d, J = 12.2 Hz, 2H), 2.80 (d, J = 12.0 Hz, 2H), 1.99 (d, J = 49.9 Hz, 4H).

Example 23: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (23)

The same procedure as in Example 14 was carried out except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2 -a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), to obtain N-(4-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (23) (white solid, two-step Rate: 22.8%).

LC-MS (ESI): m / z 679.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.78 (s, 1H), 8.88 (s, 1H), 8.37-8.23 (m, 2H), 8.15 (s, 1H), 7.96-7.76 (m, 2H ), 7.56 (s, 1H), 7.53 - 7.34 (m, 2H), 7.20 (s, 3H), 5.56 (s, 2H), 4.96 (d, J = 8.9 Hz, 1H), 4.33 (dd, J = 18.0, 9.7 Hz, 2H), 4.16 (dd, J = 14.1, 8.1 Hz, 2H), 3.74 - 3.61 (m, 2H), 3.50 - 3.40 (m, 2H), 3.20 (d, J = 12.5 Hz, 2H) ), 2.82 (t, J = 11.2 Hz, 2H), 2.18 - 1.87 (m, 4H).

Example 24: (3R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- Preparation of a] pyrido[1,2-d]pyrazine-8-carboxamide (24)

The same procedure as in Example 14 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) in place of 10-(4-fluorophenyl)-1,9-dioxo- 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), (3R)-N- (4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d Pyrazine-8-carboxamide (24) (white solid, two-step yield: 20.5%).

LC-MS (ESI): m / z 693.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.78 (s, 1H), 8.88 (s, 1H), 8.37-8.23 (m, 2H), 8.15 (s, 1H), 7.96-7.76 (m, 2H ), 7.56 (s, 1H), 7.53 - 7.34 (m, 2H), 7.20 (s, 3H), 5.56 (s, 2H), 4.96 (d, J = 8.9 Hz, 1H), 4.33 (dd, J = 18.0, 9.7 Hz, 2H), 4.16 (dd, J = 14.1, 8.1 Hz, 2H), 3.74 - 3.61 (m, 2H), 3.50 - 3.40 (m, 1H), 3.20 (d, J = 12.5 Hz, 2H) ), 2.82 (t, J = 11.2 Hz, 2H), 2.18 - 1.87 (m, 4H), 1.21 (t, J = 9.9 Hz, 3H).

Example 25: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl) )-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide Preparation of (25)

The same procedure as in Example 23 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 (white solid, one step yield: 40.2%).

LC-MS (ESI): m / z 666.2 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.76 (s, 1H), 8.87 (d, J = 9.0Hz, 1H), 8.29 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 12.2, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.28 - 7.02 (m, 6H), 6.97 (d, J = 8.4 Hz, 1H), 5.66(s, 2H), 5.46 (dd, J = 10.0, 3.5 Hz, 1H), 4.97 (dt, J = 12.4, 3.4 Hz, 1H), 4.27 - 4.12 (m, 2H), 4.08 - 3.98 (m, 1H), 3.85 - 3.74 (m, 6H), 3.67 (dt, J = 11.2, 7.4 Hz, 1H), 3.47 (dd, J = 6.7, 4.2 Hz, 1H).

Example 26: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide ( Preparation of 26)

The same procedure as in Example 14 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)- 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (26) (white solid, one step yield: 43.2%).

LC-MS (ESI): m / z 638.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.95 (s, 1H), 8.85 (s, 1H), 8.67 (t, J = 6.5Hz, 1H), 8.29 (d, J = 2.4Hz, 1H) , 7.89 (dd, J = 12.3, 1.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.29 (ddd, J = 9.0, 5.7, 2.7 Hz, 2H ), 7.25 - 7.05 (m, 4H), 6.98 (d, J = 8.3 Hz, 1H), 5.66 (s, 2H), 4.65 (d, J = 9.9 Hz, 1H), 4.06 (s, 1H), 3.79 (d, J = 20.3 Hz, 6H), 2.09 (d, J = 47.6 Hz, 4H).

Example 27: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(pair Of -tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (27)

The same procedure as in Example 19 was carried out except that 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (aa) was used instead of 4-( 4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), made N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(p-tolyl) -1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (27) (white solid, one step Rate: 37.9%).

LC-MS (ESI): m / z 616.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.88 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.19 - 7.13 (m, 4H), 6.99 (d, J = 8.3 Hz, 1H), 5.67 ( s, 2H), 4.63 (s, 1H), 4.14 - 3.98 (m, 1H), 3.80 (d, J = 22.3 Hz, 6H), 2.34 (s, 3H), 2.02 (s, 2H).

Example 28: (3R)-N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl) )-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine Preparation of -8-carboxamide (28)

The same procedure as in Example 27 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Instead of 1,9-dioxo-10-(p-tolyl)-1, hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3R)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (28) (white solid, One step yield: 26.8%).

LC-MS (ESI): m / z 662.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.64 (s, 1H), 8.87 (s, 1H), 8.33 (d, J = 58.4Hz, 2H), 7.81 (d, J = 8.2Hz, 2H) , 7.67–7.37 (m, 3H), 7.41–6.95 (m, 6H), 5.66 (s, 2H), 5.55 (d, J = 6.6 Hz, 1H), 4.95 (d, J = 9.2 Hz, 1H), 4.40–4.30 (m, 1H), 4.15 (t, J = 10.6 Hz, 2H), 3.80 (d, J = 22.0 Hz, 6H), 3.70–3.61 (m, 1H), 1.21 (t, J = 10.0 Hz) , 3H).

Example 29: (3S)-N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl) )-3-methyl-5,7-dioxo 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine- Preparation of 8-formamide (29)

The same procedure as in Example 28 was employed except that (3S)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (r) in place of 1,9-dioxo-10-(p-tolyl)-1, 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3S)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (29) (white solid, One step yield: 25.3%).

LC-MS (ESI): m / z 662.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.64 (s, 1H), 8.87 (s, 1H), 8.25 (s, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.65-7.48 ( m, 3H), 7.36 - 7.08 (m, 5H), 6.99 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 5.55 (d, J = 6.5 Hz, 1H), 4.95 (d, J = 8.9 Hz, 1H), 4.40 - 4.25 (m, 1H), 4.25 - 4.05 (m, 2H), 3.80 (d, J = 22.0 Hz, 6H), 3.71 - 3.58 (m, 1H), 1.20 (d, J = 6.2 Hz, 3H).

Example 30: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (30)

Step 1: Preparation of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate 30a)

3-bromo-5-(3,4-dimethoxyphenyl)pyridine was added to a reaction flask containing (10 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature. 2-Amine (prepared according to Example 30 of WO2013115280, page 130) (500 mg, 1.62 mmol), 4-amino-2,5-difluorophenylboronic acid pinacol ester (619 mg, 2.43 mmol), potassium carbonate (671 mg, 4.86 mmol), Pd(dppf)Cl ₂ .DCM (130 mg, 0.16 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was diluted with water (20mL), ethyl acetate (20mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc: EtOAc) Methoxyphenyl)pyridin-2-amine (Intermediate 30a) (400 mg, yellow solid, yield: 69.1%).

LC-MS (ESI): m/z 358.2 [M/M+H ⁺ ]

Step 2: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluoro Phenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8- Preparation of formamide (30)

Add 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2] to a reaction flask containing DMF (4 mL). -a] Pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (45 mg, 0.13 mmol), 3-(4-amino-2,5-difluorophenyl)-5-(3 4-Dimethoxyphenyl)pyridin-2-amine (30a) (57 mg, 0.16 mmol), HATU (63 mg, 0.17 mmol) and DIPEA (50 mg, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,,,,,,,,,,,, (4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluorophenyl)-5 ,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (30) (16 mg, white solid, yield: 18.0%).

LC-MS (ESI): m / z 684.2 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.06 (s, 1H), 8.91 (s, 1H), 8.44 (dd, J = 11.6,6.5Hz, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (dd, J = 11.1, 6.7 Hz, 1H), 7.33 - 7.03 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.80(s, 2H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.99 (dd, J = 12.4, 3.7 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.03 (q, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.67 (dt, J = 11.0, 7.4 Hz, 1H), 3.46 (td, J = 6.7, 3.3 Hz, 1H).

Example 31: N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (31)

The same procedure as in Example 30 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) Instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (30a), N-(4-(2) was obtained. -amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo Generation-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (31) (white solid, one step Yield: 31.2%).

LC-MS (ESI): m / z 624.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.76 (s, 1H), 8.88 (s, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.08 (s, 1H), 7.89 (dd, J = 12.3, 2.1 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (t, J = 8.4) Hz, 1H), 7.19 (s, 4H), 5.53 (s, 2H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.4, 3.7 Hz, 1H), 4.32 - 3.97 (m, 5H), 3.67 (dt, J = 11.0, 7.3 Hz, 1H), 3.46 (ddd, J = 11.0, 6.7, 4.1 Hz, 1H), 1.38 (t, J = 7.3 Hz, 3H).

Example 32: N-(4-(2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-di Oxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide Preparation of (32)

The same procedure as in Example 31 was employed except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a] was used. [1,4]diazepane-8-carboxylic acid (e) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-six N-(4-(2-amino-5-(1-methyl)-hydrocarbazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) -1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5, 9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (32) (white solid, one step yield: 33.7%).

LC-MS (ESI): m / z 592.3 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.89 ( d, J = 12.2 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.40 (dt, J = 16.3, 8.2 Hz, 2H), 7.16 (dd, J = 19.1, 7.9 Hz, 4H) ), 5.58 (s, 2H), 4.63 (s, 1H), 4.11 (dd, J = 14.5, 7.3 Hz, 2H), 3.34 (s, 2H), 2.97 (s, 1H), 2.34 (s, 3H) , 2.10 (d, J = 47.9 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H).

Example 33: N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-di Oxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b Preparation of [1,3]oxazine-9-carboxamide (33)

The same procedure as in Example 31 was employed except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4) -(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7-(p-toluene -3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine -9-carboxamide (33) (white solid, one step yield: 26.7%).

LC-MS (ESI): m / z 634.2 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.82 (s, 1H), 8.89 (s, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J = 12.3, 1.9 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.49 - 7.29 (m, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 6.2 Hz, 2H), 5.54 (s, 2H), 5.34 - 5.24 (m, 1H), 4.74 - 4.52 (m, 2H), 4.27 - 4.17 (m, 1H), 4.15 - 4.02 ( m,3H), 3.87 (dd, J = 12.9, 10.1 Hz, 1H), 3.09 (dd, J = 12.6, 3.5 Hz, 1H), 2.36 (s, 3H), 1.78 - 1.47 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.32 - 1.17 (m, 1H).

Example 34: N-(4-(2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4- Fluorophenyl)-4-hydroxy-1-,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of heptane-8-carboxamide (34)

The same procedure as in Example 31 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7 ,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4-(2-amino-5) -(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1-,9-di Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (34) (white solid, one step Yield: 18.9%).

LC-MS (ESI): m / z 612.3 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.88 (s, 1H), 8.73 (d, J = 26.7 Hz, 2H), 8.26 (d, J = 6.6 Hz, 2H) , 7.97 (dd, J = 29.7, 17.5 Hz, 3H), 7.55 - 7.42 (m, 2H), 7.34 - 7.19 (m, 4H), 7.16 - 6.85 (m, 2H), 5.74 - 5.63 (m, 1H) , 4.76–4.61 (m, 1H), 4.41 (s, 1H), 4.29 (d, J = 13.2 Hz, 2H), 4.13 (q, J = 7.3 Hz, 2H), 2.90 (s, 1H), 1.39 ( t, J = 7.2 Hz, 3H).

Example 35: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazacyclocycle Preparation of heptane-8-carboxamide (35)

The same procedure as in Example 32 was employed except that 3-(4-aminophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridine was used. 2-Amine (z) in place of 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl)-1, 9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8 - Formamide (35) (white solid, one step yield: 23.8%).

LC-MS (ESI): m / z 630.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.88 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.27-8.19 (m, 3H), 7.88-7.75 (m, 3H ), 7.58 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.16 (dd, J = 18.6, 7.9 Hz, 4H), 5.55 (s, 2H), 4.63 (s, 1H), 4.37 (s, 1H), 4.05 (s, 1H), 3.96 (d, J = 11.4 Hz, 2H), 3.48 (t, J = 10.5 Hz, 3H), 3.34 (s, 1H), 2.34 (s, 3H) , 2.17–1.89 (m, 6H).

Example 36: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of diazepane-8-carboxamide (36)

The same procedure as in Example 35 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4 was used. -yl)pyridin-2-amine (w) instead of 3-(4-amino-2-methylphenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4 -yl)pyridin-2-amine (z) to give N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4- Pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyridyl[1 , 2-a][1,4]diazepane-8-carboxamide (36) (white solid, one step yield: 28.7%).

LC-MS (ESI): m / z 648.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.0.3 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.89 ( d, J = 12.1 Hz, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.48 - 7.33 (m, 2H), 7.16 (dd, J = 19.2, 7.9 Hz, 4H), 5.55 (s , 2H), 4.71 - 4.60 (m, 1H), 4.36 (s, 1H), 4.11 - 4.01 (m, 1H), 3.96 (d, J = 11.7 Hz, 2H), 3.47 (t, J = 10.3 Hz, 4H), 2.34 (s, 3H), 2.20–1.89 (m, 6H).

Example 37: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(6-methylpyridin-3-yl)-6,8-dioxo 3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37)

The same procedure as in Example 36 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) instead of 1,9-dioxo-10-(pair Tolyl-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), to give N- (4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4, 5] Pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37) (white solid, one step yield: 19.4%).

LC-MS (ESI): m / z 691.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.71 (s, 1H), 8.93 (s, 1H), 8.30-8.03 (m, 3H), 7.94-7.70 (m, 2H), 7.54 (d, J =2.3Hz,1H), 7.48–7.33(m,3H), 7.25(d,J=7.9Hz,1H),5.55(s,2H),5.30(s,1H),4.74–4.52(m,2H) , 4.43–4.15 (m, 2H), 4.05 (d, J = 16.4 Hz, 1H), 4.01–3.77 (m, 3H), 3.47 (td, J=11.5, 2.6 Hz, 5H), 3.17–3.00 (m) , 1H), 2.15–1.76 (m, 4H), 1.76–1.49 (m, 2H).

Example 38: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of cycloheptane-8-carboxamide (38)

The same procedure as in Example 14 was employed except that 3-(4-amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine- 2-amine (ee) instead of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 - tert-butyl formate (u) to give N-(4-(2-amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl) 3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]diazepane-8-carboxamide (38) (white solid, one step yield: 21.3%).

LC-MS (ESI): m / z 737.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.99 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 7.92 (d, J = 12.3Hz, 1H), 7.74 (s, 1H), 7.44 (q, J = 8.7, 8.3 Hz, 2H), 7.25 (ddd, J = 27.1, 16.2, 8.5 Hz, 6H), 7.10 (d, J = 8.3 Hz, 1H) ), 6.05 (s, 2H), 4.66 (d, J = 11.9 Hz, 1H), 4.35 (s, 2H), 4.06 (s, 1H), 3.86 (s, 7H), 3.47 (s, 6H), 2.10 (d, J = 48.5 Hz, 4H).

Example 39: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (39)

The same procedure as in Example 38 was employed except for 7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine. And [1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (n) instead of 10-(4-fluorophenyl)-1,9 -Dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), N -(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-7-( 5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a hexahydro-2H-pyrido[1',2':4,5]pyrazine And [2,1-b][1,3]oxazine-9-carboxamide (39) (white solid, one step yield: 17.5%).

LC-MS (ESI): m / z 781.3 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.73 (s, 1H), 8.87 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.90 (d, J = 11.7Hz, 1H) , 7.60 (d, J = 2.4 Hz, 1H), 7.51 - 7.33 (m, 2H), 7.21 - 6.94 (m, 3H), 6.74 (d, J = 3.5 Hz, 1H), 6.60 (d, J = 3.5) Hz, 1H), 5.68 (s, 2H), 5.29 (t, J = 4.0 Hz, 1H), 4.63 (ddd, J = 45.8, 14.0, 4.0 Hz, 2H), 4.28 (d, J = 13.3 Hz, 1H) ), 4.08 (t, J = 5.9 Hz, 3H), 3.82 (s, 3H), 3.58 (t, J = 4.7 Hz, 4H), 3.34 (s, 9H), 2.69 (t, J = 5.9 Hz, 2H) ), 1.79–1.55 (m, 2H).

Example 40: N-(4-(5-(4-(2-((1,4-dioxo)-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro Preparation of oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40)

In the same manner as in Example 30 except that 5-(4-(2-((1,4-dioxo-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 3-(4-Amino-2-fluorophenyl)pyridin-2-amine (dd) instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxy Phenyl)pyridin-2-amine (30a) to give N-(4-(5-(4-(2-(4-1,4-dioxan-2-yl)methoxy)ethoxy) 3-methoxyphenyl)-2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40) (white solid, one step yield: 26.7% ).

LC-MS (ESI): m / z 796.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.76 (s, 1H), 8.89 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.33 - 7.03 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H) ), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.4, 3.6 Hz, 1H), 4.28 - 3.96 (m, 5H), 3.82 (s, 3H), 3.77 - 3.38 ( m, 13H).

Example 41: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -5,7-dioxo-6-(p-tolyl)-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d] Preparation of pyrazine-8-carboxamide (41)

The same procedure as in Example 38 was carried out except that 6-(4-methylphenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a ] Pyrido[1,2-d]pyrazine-8-carboxylic acid (p) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(3-methoxy) 4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-5,7-dioxo-6-(p-tolyl)-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (41) (white solid, one step yield: 19.4%) .

LC-MS (ESI): m / z 761.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.84 (s, 1H), 8.87 (s, 1H), 8.41-8.14 (m, 2H), 7.89 (d, J = 12.5Hz, 1H), 7.60 ( s, 1H), 7.53–7.36 (m, 2H), 7.22–6.93 (m, 6H), 5.67 (s, 2H), 5.47 (d, J = 6.6 Hz, 1H), 4.97 (d, J = 8.9 Hz) , 1H), 4.28–3.97 (m, 5H), 3.82 (s, 3H), 3.72–3.53 (m, 5H), 3.45 (s, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.35 ( s, 3H).

Example 42: N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino-pyridine-3 -yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2 -a]Preparation of pyrido[1,2-d]pyrazine-8-carboxamide (42)

In the same manner as in Example 30 except that 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino- 2-fluorophenyl)pyridin-2-amine (bb) in place of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridine-2- Amine (30a) to give N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino- Pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ 3,2-a] Pyrido[1,2-d]pyrazine-8-carboxamide (42) (white solid, one step yield: 30.2%).

LC-MS (ESI): m / z 752.4 [M / M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.76 (s, 1H), 8.89 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.34 - 7.02 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.67 (s, 2H) ), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.3, 3.6 Hz, 1H), 4.26 - 4.11 (m, 2H), 4.08 - 3.40 (m, 15H).

Example 43: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (43)

The same procedure as in Example 41 was carried out except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-methylphenyl)-5,7-dioxo-2, 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) to give N-(4-( 2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7 -(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1, 3] Oxazine-9-carboxamide (43) (white solid, one step yield: 22.7%).

LC-MS (ESI): m / z 775.4 [M / M + H +].

Example 44: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)

Step 1: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-((four Preparation of hydrogen-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)

Add 5-((4-(2-amino-5-(3,4-)) to the reaction flask containing (2.5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. Methoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-2-yl)-4-yl) Methyl)-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9d) (60 mg, 0.09 mmol), (2-aminophenyl)boronic acid (18 mg, 0.14 mmol), potassium carbonate (35 mg, 0.26 mmol) ), Pd(dppf)Cl ₂ .DCM (8 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) Pyridin-3-yl)phenyl)-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo [f][1,7]naphthyridine-2-carboxamide (15 mg, white solid, yield: 25.3%).

LC-MS (ESI): m / z 658.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.67 (s, 1H), 12.48 (s, 1H), 9.91 (d, J = 8.6Hz, 1H), 8.90 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.70 - 7.52 (m, 4H), 7.45 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.69 (s, 2H), 5.03 ( d, J = 7.0 Hz, 2H), 3.81 (d, J = 24.0 Hz, 7H), 3.24 - 3.18 (m, 2H), 2.07 (s, 2H), 1.48 - 1.30 (m, 4H).

Example 45: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1 , 7] Preparation of naphthyridine-2-carboxamide (45)

Step 1: 5-Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 - Preparation of formic acid (45a)

3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 was added to a reaction flask containing (9 mL) of ethanol. Diethyl 5-dicarboxylate (9b, 1.0 g, 2.39 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (3 mL, 2.87 mmol) was added dropwise with stirring, and the mixture was warmed to room temperature and stirring was continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of the solid to give 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydro Pyridine-3-carboxylic acid (600 mg, white solid, yield: 64.4%).

LC-MS (ESI): m / z 388.0 [M / M + H +].

Step 2: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- 3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of ethyl-2-carboxylate (45b)

Add 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 to a reaction vial containing DMF (10 mL) , 4-dihydropyridine-3-carboxylic acid (45a) (100 mg, 0.26 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)- tert-Butyl 1H-pyrazol-1-yl)piperidine-1-carboxylate (u) (140 mg, 0.31 mmol), HATU (146 mg, 0.39 mmol) and DIPEA (99 mg, 0.77 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-(four Ethyl hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (170 mg, yellow solid, yield: 79.6%).

LC-MS (ESI): m / z 822.3 / 824.2 [M / M + H +].

Step 3: 4-(4-(6-Amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)) [Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazole- Preparation of tert-butyl ester of 1-yl) piperidine-1-carboxylate (45c)

Add 5-((4-(2-amino-5-(1-(1-)) to the reaction flask containing (5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. tert-Butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-bromo-4-oxo- Ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (45b) (170 mg, 0.20 mmol), 2-amino-4- fluorobenzene boronic acid (46.5mg, 0.30mmol), potassium carbonate (83mg, 0.60mmol), Pd ( dppf) Cl 2 .DCM (16mg, 0.02mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 4- (4- (6-amino-5- (2-fluoro-4- (8-fluoro [1,7] of -1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f] Naphthyridine-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (45c) (100 mg, yellow solid, yield: 62.0%).

LC-MS (ESI): m / z 807.4 [M / M + H +].

Step 4: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 8-fluoro-1,5--dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1 , 7] Preparation of naphthyridine-2-carboxamide (45)

In a reaction flask containing DCM (3 mL) was added 4-(4-(6-amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-)- [1,7]naphthyridin-2-carboxamido)phenyl)pyridine-3-(2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f] tert-Butyl ester of -1H-pyrazol-1-yl)piperidine-l-carboxylate (45c) (50 mg, 0.06 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-8-fluoro-1,5--dioxo-4-((tetrahydro-2H-pyran-4- Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (45) (15 mg, white solid, 35.4%).

LC-MS (ESI): m / z 707.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.73 (s, 1H), 9.99 (dd, J = 9.3,6.5Hz, 1H), 8.91 (s, 1H), 8.38 (s, 1H), 8.28 ( d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J = 12.2, 2.0 Hz, 1H), 7.83 (s, 1H), 7.62 - 7.49 (m, 2H), 7.42 (t , J = 8.4 Hz, 1H), 7.22 (ddt, J = 12.5, 6.6, 2.8 Hz, 2H), 5.57 (s, 2H), 5.00 (d, J = 7.0 Hz, 2H), 4.28 - 4.15 (m, 1H), 3.87–3.79 (m, 2H), 3.26–3.06 (m, 4H), 2.71 (t, J = 12.2 Hz, 2H), 2.11–1.79 (m, 6H), 1.38 (q, J = 12.6 Hz) , 4H).

Example 46: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of 8-fluoro-4-methyl-1,5-dioxo-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridine-2-carboxamide (46)

In the same manner as in Example 45, except that 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4) was used instead of 3-bromo. 4-Oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9b), obtained N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-8-fluoro 4-methyl-1,5-dioxo-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (46) (white solid, four steps Yield: 7.3%).

LC-MS (ESI): m / z 623.3 [M / M + H +].

Example 47: N ⁵ -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl )-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-di Preparation of formamide (47)

Step 1: 5-((6-Bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) Of ethyl-methyl)dihydropyridine-2-carboxylate (47a)

Add 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- to a reaction flask containing DMF (20 mL) Dihydropyridine-3-carboxylic acid (c) (1.28 g, 3.2 mmol), 6-bromopyridazin-3-amine (660 mg, 3.8 mmol), HATU (2.4 g, 6.3 mmol) and DIPEA (1.63 g, 12.6 mmol) ). The mixture was stirred at room temperature for 24 hours. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Ethyl phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)dihydropyridine-2-carboxylate (Intermediate 47a) (1.3 g, yellow oil , yield: 72.8%).

LC-MS (ESI): m / z 559.1 / 561.1 [M / M + H +].

Step 2: 5-((6-Bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) Of -yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (47b)

Add 5-((6-bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo- in a reaction vial containing tert-butanol (40 mL) at room temperature. Ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)dihydropyridine-2-carboxylate (47a) (1.3 g, 2.3 mmol), lithium hydroxide monohydrate (387 mg, 6.9 Methyl) and water (0.5 mL). The mixture was warmed to 60 ° C and stirred for 3 hours. After the reaction was completed, then concentrated under reduced pressure to remove t-butanol (25 mL). The residue was acidified to pH 2-3 with 1M aqueous hydrochloric acid, filtered, and then evaporated to give 5-((6-bromopyrazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (47b) (700 mg, white solid, yield: 57.1% ).

LC-MS (ESI): m / z 531.1 / 533.1 [M / M + H +].

Step 3: N ⁵ -(6-Bromopyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)- Preparation of 1,4-dihydropyridine-2,5-dimethylformamide (47c)

Add 5-((6-bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-(4) to a reaction vial containing DMF (5 mL) Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (300 mg, 0.56 mmol), ammonium chloride (91 mg, 1.69 mmol), tripyrrolidinyl bromide Phosphorus hexafluorophosphate (394 mg, 0.85 mmol) and DIPEA (364 mg, 2.82 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent MeOH: DCM = 1: 10) , to give N ⁵ - (6- bromo-3-yl) -3- (4-fluorophenyl) - 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (240 mg, yellow solid, yield: 80.0 %).

LC-MS (ESI): m / z 530.1 / 532.1 [M / M + H +].

Step 4: Preparation of (2-amino-5-bromopyridin-3-yl)boronic acid (47d)

2-Amino-3-iodo-5-bromopyridine (2.5 g, 8.36 mmol) and diboronic acid pinacol (3.2 g) were added to a reaction flask containing (25 mL) 1,4-dioxane at room temperature. 12.5 mmol), potassium acetate (2.46 g, 25.0 mmol), Pd ₂ (dba) ₃ (1.53 g, 1.67 mmol) and tricyclohexylphosphine (234 mg, 0.83 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (30mL), ethyl acetate (30mL×3), and the organic phase was combined. The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on a silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give (2-amino-5-bromo-3-yl) boronic acid (47d) (1.5g, yellow Solid, yield: 83.4%).

LC-MS (ESI): m / z 217.0 / 219.0 [M / M + H +].

Step 5: N ⁵ -(6-(2-Amino-5-bromopyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (47e)

(2-Amino-5-bromopyridin-3-yl)boronic acid (47d) (245 mg, 1.13 mmol), N was added to a reaction flask containing (5 mL) mixture of DMF and water (4:1) at room temperature. ^5- (6-Bromopyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 , 4-dihydro-pyridine-2,5-dicarboxamide (47c) (240mg, 0.45mmol) , sodium carbonate (144mg, 1.35mmol), and _{_{Pd (PPh 3) 4 (104mg}} , 0.09mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 20 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (15 mL) and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 5:} 1), to give N ⁵ - (6- (2- amino-5-bromo-3-yl) pyridazine - 3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2, 5-Dimethylamide (47e) (90 mg, yellow solid, yield: 32.0%).

LC-MS (ESI): m / z 622.2 / 624.2 [M / M + H +].

Step 6: 4-(4-(6-Amino-5-(6-(6-carbamoyl-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-py)喃-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine- Preparation of 1-carboxylic acid tert-butyl ester (47f)

Add N ⁵ -(6-(2-amino-5-bromopyridine-3-) to a reaction flask containing (2.5 mL) a mixture of 1-4-dioxane and water (4:1) at room temperature. Pyridazine-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Hydropyridine-2,5-dimethylformamide (intermediate 47e) (90 mg, 0.14 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclohexane) tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (136 mg, 0.36 mmol), cesium carbonate (140 mg, 0.14 mmol) and Pd(dppf)Cl ₂ . DCM (24 mg, 0.03 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 40 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 5:} 1), to give 4- (4- (6-amino-5- (6- (6-carbamoyl- -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazine tert-Butyl -3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 47f) (76 mg, yellow solid, yield: 66.6%).

LC-MS (ESI): m / z 793.4 [M + H +].

Step 7: N ⁵ -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethyl Preparation of amide (47)

Add 4-(4-(6-amino-5-(6-(6-carbamoyl-5-(4-fluorophenyl)-4-oxo-1-) to a reaction flask containing DCM (3 mL) ((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazole tert-Butyl ester of 1-yl)piperidine-l-carboxylate (47f) (76 mg, 0.095 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, acetonitrile / water (0.1% formic acid): 10% to 100%) to yield N ⁵ - (6- (2- amino-5- (l- (piperidin-4-yl) -1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (47) (15.7 mg, white solid, 23.8%).

LC-MS (ESI): m / z 693.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.57 (s, 1H), 8.84 (s, 1H), 8.63 (d, J = 9.5Hz, 1H), 8.48 (d, J = 9.6Hz, 1H) , 8.42–8.18 (m, 5H), 8.01 (s, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.37 (dt, J = 8.3, 4.2 Hz, 4H), 7.29–7.15 (m, 2H) ), 4.58–4.21 (m, 1H), 4.13 (d, J=7.4 Hz, 2H), 4.01–3.77 (m, 2H), 3.40–2.99 (m, 4H), 2.92–2.66 (m, 2H), 2.24 - 2.03 (m, 3H), 1.95 (dt, J = 12.9, 9.3 Hz, 2H), 1.47 (d, J = 12.3 Hz, 2H), 1.34 (qd, J = 12.1, 4.4 Hz, 2H).

Example 48: N ⁵ -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl )-3-(4-fluorophenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of -2,5-dimethylformamide (48)

In the same manner as in Example 47, except that methylamine hydrochloride was used instead of ammonium chloride, N ⁵ -(6-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (48) (white solid, four-step yield: 10.2%).

LC-MS (ESI): m / z 707.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.56 (s, 1H), 8.84 (s, 1H), 8.75 (q, J = 4.7Hz, 1H), 8.63 (d, J = 9.5Hz, 1H) , 8.48 (d, J = 9.6 Hz, 1H), 8.42 - 8.25 (m, 2H), 8.29 - 8.16 (m, 2H), 7.93 (s, 1H), 7.35 (td, J = 5.6, 2.4 Hz, 4H ), 7.28–7.09 (m, 2H), 4.08 (d, J = 7.3 Hz, 2H), 3.92–3.81 (m, 2H), 3.28–3.12 (m, 4H), 2.80 (t, J = 12.0 Hz, 2H), 2.50 - 2.45 (m, 5H), 2.09 (d, J = 13.2 Hz, 3H), 1.99 - 1.90 (m, 1H), 1.52 - 1.15 (m, 4H).

Example 49: N ⁵ -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl Preparation of 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (49)

The same procedure as in Example 47 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) in place of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -carboxylic acid (c) to give N ⁵ -(6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazine 3-yl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (49) (white solid, six steps Yield: 3.1%).

LC-MS (ESI): m / z 609.4 [M + H +].

Example 50: 5-((6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)pyridin-3-yl Preparation of ethyl carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (50)

The same procedure as in Example 47 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) in place of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -carboxylic acid (c) to give 5-((6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)pyridine -3-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester (50) (white solid , 5 steps yield: 6.3%).

LC-MS (ESI): m / z 638.4 [M + H +].

Example 51: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (51)

Step 1: N-(6-Bromopyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrocaine Preparation of oxazo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a)

Add 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2] to a reaction flask containing DMF (3 mL). -a] Pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (80 mg, 0.24 mmol), 6-bromopyridazin-3-amine (80 mg, 0.48 mmol), HATU (176 mg, 0.48) Methyl) and DIPEA (120 mg, 0.96 mmol). The mixture was stirred at room temperature for 12 hr. EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut ,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a) (70 mg, yellow oil, yield: 58.1%).

LC-MS (ESI): m / z 500.0 / 502.0 [M + H +].

Step 2: N-(6-(2-Amino-5-bromopyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2, Preparation of 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (51b)

(2-Amino-5-bromopyridin-3-yl)boronic acid (47d) (61 mg, 0.28 mmol) was added to a reaction flask containing (2.5 mL) a mixture of DMF and water (4:1). N-(6-Bromopyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ 3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a) (70 mg, 0.14 mmol), sodium carbonate (45 mg, 0.42 mmol) and Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 20 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 5:} 1), to give N- (6- (2- amino-5-bromo-3-yl) pyridazin-3 -yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridin[1 , 2-d] pyrazine-8-carboxamide (51b) (30 mg, yellow solid, yield: 36.2%).

LC-MS (ESI): m / z 592.1 / 594.1 [M + H +].

Step 3: 4-(4-(6-Amino-5-(6-(6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-six Hydrocarbazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazole-1- Preparation of tert-butyl ester of piperidine-1-carboxylate (51c)

Add N-(6-(2-amino-5-bromopyridin-3-yl) to a reaction flask containing (2.5 mL) a mixture of 1-4-dioxane and water (4:1) at room temperature. Pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2-a Pyrido[1,2-d]pyrazine-8-carboxamide (51b) (30 mg, 0.05 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.06 mmol), cesium carbonate (50 mg, 0.15 mmol) and Pd ( Dppf) Cl ₂ .DCM (5 mg, 0.005 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 40 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 5:} 1), to give 4- (4- (6-amino-5- (6- (6- (4-Fluorophenyl -5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8- Amido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (51c) (10 mg, yellow solid, yield: 26.3% ).

LC-MS (ESI): m / z 763.4 [M + H +].

Step 4: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)- 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d Preparation of pyrazine-8-carboxamide (51)

Add 4-(4-(6-amino-5-(6-(6-(4-fluorophenyl)-5,7-dioxo-2,3,5) to a reaction flask containing DCM (3 mL) ,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamido)pyridazin-3-yl)pyridin-3-yl) -1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (51c) (10 mg, 0.01 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11 , 11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (51) (2.3 mg, white solid, 34.7%).

LC-MS (ESI): m / z 663.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.60 - 13.51 (m, 1H), 9.33 - 9.25 (m, 1H), 9.03 - 8.98 (m, 1H), 8.95 (s, 1H), 8.87 - 8.78 (m, 1H), 8.76–8.66 (m, 1H), 8.64–8.54 (m, 2H), 8.45 (s, 2H), 8.08 (s, 2H), 7.18 (d, J = 7.5 Hz, 3H), 5.54–5.46 (m, 1H), 5.36–5.26 (m, 1H), 5.05–4.98 (m, 1H), 4.60–4.48 (m, 2H), 4.27–4.17 (m, 2H), 4.11–4.01 (m) , 2H), 3.86–3.80 (m, 1H), 3.19–3.06 (m, 3H), 2.30–2.11 (m, 4H).

Example 52: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of cycloheptane-8-carboxamide (52)

The same procedure as in Example 51 was employed except that 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- a][1,4]diazepane-8-carboxylic acid (d) instead of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a - hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) to give N-(6-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo- 1,2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (52) (white solid, 4-step yield :4.3%).

LC-MS (ESI): m / z 635.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.62 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.62 (d, J = 9.5Hz, 1H), 8.45 (d, J = 9.7 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.25 - 8.18 (m, 2H), 7.92 (s, 1H), 7.31 (dd, J = 8.5 , 5.6 Hz, 3H), 7.22 (t, J = 9.0 Hz, 2H), 4.65 (s, 1H), 4.27 (s, 1H), 4.07 (s, 1H), 3.34 (s, 2H), 3.16 (d) , J = 12.6 Hz, 2H), 2.75 (t, J = 11.1 Hz, 2H), 1.98 (dd, J = 67.0, 10.3 Hz, 6H).

Example 53: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl) -1,9-dioxo-1,2-,3,4,5,9-hexahydropyrido[1,2-D][1,4]diazepane-8-carboxamide Preparation of (53)

The same procedure as in Example 52 was employed except that 3,4-dimethoxyphenylboronic acid was used in place of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclo). tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give N-(6-(2-amino-5-(3,4-dimethoxy) Phenyl) pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo-1,2-,3,4,5,9-six Hydropyrido[1,2-D][1,4]diazepane-8-carboxamide (53) (white solid, three-step yield: 7.8%).

LC-MS (ESI): m / z 622.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.78 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.35 (d, J = 2.1Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.18 - 7.12 (m, 2H), 6.95 (d, J = 8.3 Hz, 2H), 5.68 ( s, 2H), 4.53 (s, 2H), 4.15 - 3.99 (m, 2H), 3.77 (d, J = 22.3 Hz, 6H), 2.12 (s, 2H).

Example 54: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-1-(4-fluorophenyl) -2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3 -formamide (54) preparation

The same procedure as in Example 53 was carried out except that 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyridine was used. [1,2-a:1',2'-d]pyrazine-3-carboxylic acid (g) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(6-(2-amino-5-( 3,4-Dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7 ,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxamide (54) (white solid, three-step yield: 6.5%) ).

LC-MS (ESI): m / z 662.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.69 (s, 1H), 8.82 (s, 1H), 8.43 (d, J = 58.4Hz, 2H), 7.86 (d, J = 8.2Hz, 2H) , 7.77–7.30 (m, 3H), 7.21–6.98 (m, 4H), 5.68 (s, 2H), 4.30–4.21 (m, 1H), 4.13 (t, J = 10.6 Hz, 2H), 3.70 (d) , J = 22.0 Hz, 6H), 3.60 - 3.51 (m, 2H), 1.29 - 1.15 (t, J = 10.0 Hz, 6H).

Example 55: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-7-(4-fluorophenyl )-6,8-dioxo-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b Preparation of [1,3]oxazine-9-carboxamide (55)

The same procedure as in Example 53 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(6 -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-7-(4-fluorophenyl)-6,8-dioxo Generation-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine -9-carboxamide (55) (white solid, three-step yield: 9.3%).

LC-MS (ESI): m / z 664.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.74 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 58.4Hz, 2H), 7.83 (d, J = 8.2Hz, 2H) , 7.67–7.36 (m, 3H), 7.40–6.94 (m, 4H), 5.68 (s, 2H), 5.57 (d, J = 6.6 Hz, 1H), 4.96 (d, J = 9.2 Hz, 1H), 4.41–4.33(m,1H), 4.17(t,J=10.6Hz,2H),3.81(d,J=22.0Hz,6H),3.71–3.66(m,2H),1.20(t,J=10.0Hz , 2H).

Example 56: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl -5,7-dioxo-1,2,3,4-5,7,11,11a hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-D]pyrazine Preparation of -8-formamide (56)

The same procedure as in Example 53 was employed except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1] was used. ,2-a]pyrrolo[1,2-D]pyrazine-8-carboxylic acid (h) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(6-(2-amino-5-( 3,4-Dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-1,2,3,4 -5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-D]pyrazine-8-carboxamide (56) (white solid, three-step yield : 6.1%).

LC-MS (ESI): m / z 648.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.61 (s, 1H), 8.88 (s, 1H), 8.43 (d, J = 58.4Hz, 2H), 7.72 (d, J = 8.2Hz, 2H) , 7.69–7.36 (m, 3H), 7.30–6.85 (m, 4H), 5.66 (s, 2H), 4.40–4.30 (m, 1H), 4.15 (t, J = 10.6 Hz, 2H), 3.80 (d) , J = 22.0 Hz, 6H), 3.70 - 3.61 (m, 2H), 1.21 (t, J = 10.0 Hz, 4H).

Example 57: N-(2'-Amino-5'-(3,4-dimethoxyphenyl)-[3,3'-bipyridyl]-6-yl)-7-(6-methyl Pyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2 , 1-b][1,3] Preparation of Oxazine-9-carboxamide (57)

The same procedure as in Example 53 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) and 2-amino-5bromopyridine are substituted for 10-( 4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- 8-carboxylic acid (d) and 2-amino-5-bromopyridazine to obtain N-(2'-amino-5'-(3,4-dimethoxyphenyl)-[3,3'-linked Pyridyl]-6-yl)-7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridinium[ 1', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (57) (white solid, three-step yield: 9.7%).

LC-MS (ESI): m / z 660.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.84 (s, 1H), 8.95 (s, 1H), 8.46 (d, J = 2.3Hz, 1H), 8.37 (d, J = 8.6Hz, 1H) , 8.29 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.00 (dd, J = 8.6, 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.83 (s, 2H), 5.32 (d, J = 11.4 Hz, 1H), 4.75 - 4.55 (m, 2H), 4.24 (d, J = 13.3 Hz, 1H), 4.07 ( s, 1H), 3.87 (t, J = 11.8 Hz, 1H), 3.80 (d, J = 21.9 Hz, 6H), 3.25 - 2.97 (m, 1H), 2.52 (s, 3H), 1.79 - 1.53 (m , 2H).

Example 58: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (58)

Step 1: 5-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Preparation of ethyl 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (intermediate 58a)

Add 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- to a reaction flask containing DMF (30 mL) Carboxylic acid (a) (800 mg, 2.51 mmol), 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) (790 mg, 2.51 mmol), HATU (1.43 g, 3.77 mmol) and DIPEA (973 mg, 7.53 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1:1) to give 5-((6,7-dimethoxyquinolin-4-yl)oxy. Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (58a) (1.4 g, yellow solid, yield: 90.4%).

LC-MS (ESI): m / z 616.3 [M + H +].

Step 2: 5-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Preparation of 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (58b).

Add 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl) to a reaction flask containing ethanol (16 mL) at room temperature Ethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1.4 g, 2.27 mmol), lithium hydroxide monohydrate (150 mg, 3.57 mmol) and water (4 mL). The mixture was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give crude 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (58b) (1.4 g, Gray solid, yield: 100%). It was used directly in the next reaction without purification.

LC-MS (ESI): m / z 588.3 [M + H +].

Step 3: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl Preparation of keto-4-oxo-1,4-dihydropyridine 2.5-carboxamide (58)

Add 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3 to a reaction flask containing DMF (3 mL) -(4-Fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (70 mg, 0.12 mmol), ammonium chloride (26 mg, 0.48 mmol), tripyrrole Alkyl bromide hexafluorophosphate (84 mg, 0.18 mmol) and DIPEA (62 mg, 0.48 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative HPLC (C18, acetonitrile / water (0.1% formic acid): 10% to 100%) to afford ^{N 5 - (4 - ((} 6,7- dimethoxy-quinolin-4-yl) oxy 3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine 2.5-carboxamide (58b) (30 mg, white solid, 42.9%).

LC-MS (ESI): m / z 587.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.99 (s, 1H), 8.83 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.24 (s, 1H), 8.05 (dd, J = 13.0, 2.4 Hz, 2H), 7.57 - 7.49 (m, 2H), 7.48 - 7.41 (m, 2H), 7.35 (dd, J = 8.5, 5.7 Hz, 2H), 7.25 (t, J = 8.8 Hz) , 2H), 6.49 (d, J = 5.2 Hz, 1H), 3.96 (s, 6H), 3.88 (s, 3H).

Example 59: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N ² Preparation of 1-dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (59)

In the same manner as in Example 58, except that methylamine hydrochloride was used in place of ammonium chloride, N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-N ² -1-dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (59) White solid, one step yield: 23.7%).

LC-MS (ESI): m / z 601.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.98 (s, 1H), 8.83 (s, 1H), 8.73 (q, J = 4.7Hz, 1H), 8.49 (d, J = 5.2Hz, 1H) , 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.58 - 7.40 (m, 4H), 7.38 - 7.18 (m, 4H), 6.49 (d, J = 5.2 Hz, 1H), 3.96 (s, 6H) ), 3.83 (s, 3H), 2.52 (s, 3H).

Example 60: 6-(Azetidine-1-formyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl Preparation of 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (60)

In the same manner as in Example 58, except that azaetidine hydrochloride was used in place of ammonium chloride, N ⁶ -(azetidin-1-yl)-N-(4-((6) was obtained. ,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di Hydropyridine-3-carboxamide (60) (white solid, one step yield: 32.6%).

LC-MS (ESI): m / z 627.4 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.57–7.38 (m, 6H), 7.31 (t, J = 8.7 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 4.01 (d, J = 9.6 Hz, 1H), 3.96 ( s,6H),3.86(s,3H),3.58–3.49(m,2H), 2.15(d,J=9.6Hz,1H),2.08–1.94(m,1H),1.85(d,J=10.6Hz , 1H).

Example 61: N-cyclopropyl-N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluoro Preparation of Phenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-5-dimethylamide (61)

N-cyclopropyl-N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl) was obtained in the same manner as in Example 58 except that instead of ammonium chloride. )oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylamide (61) (white solid, one step yield: 27.8%).

LC-MS (ESI): m / z 627.4 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.83 (d, J = 3.5 Hz, 2H), 8.49 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.56–7.41 (m, 4H), 7.33–7.21 (m, 4H), 6.48 (d, J=5.3 Hz, 1H), 3.96 (s, 6H), 3.85 (s, 3H) ), 2.01 (q, J = 7.3 Hz, 1H), 0.54 (d, J = 7.3 Hz, 2H), 0.03 (d, J = 6.9 Hz, 2H).

Example 62: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl Preparation of keto-6-(morpholine-4-formyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (62)

In the same manner as in Example 58, except that morpholino was used in place of ammonium chloride, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorol was obtained. Phenyl)-5-(4-fluorophenyl)-1-methyl-6-(morpholine-4-formyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (62 ) (white solid, one step yield: 30.4%).

LC-MS (ESI): m / z 657.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.94 (s, 1H), 8.84 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.05 (dd, J = 12.9,2.3Hz, 1H), 7.57–7.27 (m, 8H), 6.50 (d, J=5.2 Hz, 1H), 3.96 (s, 6H), 3.81 (s, 3H), 3.56 (dd, J = 10.9, 5.2 Hz, 2H) ), 3.32–3.26 (m, 2H), 3.07–2.76 (m, 4H).

Example 63: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-4- Preparation of oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxamide (63)

The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxamide (63) (white solid, three Step yield: 24.5%).

LC-MS (ESI): m / z 671.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.93 (s, 1H), 8.78 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.27 (d, J = 14.5Hz, 1H) , 8.15–7.90 (m, 2H), 7.55–7.30 (m, 6H), 7.24 (t, J = 8.9 Hz, 2H), 6.48 (d, J = 5.2 Hz, 1H), 4.12 (d, J = 7.3) Hz, 2H), 3.95 (d, J = 1.6 Hz, 6H), 3.88 (dd, J = 11.7, 3.8 Hz, 2H), 3.21 (s, 1H), 2.49 (s, 2H), 1.49 - 1.28 (m) , 4H).

Example 64: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N ² -Methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (64)

In the same manner as in Example 63, except that methylamine hydrochloride was used instead of ammonium chloride, N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-N ² -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2,5-dimethylformamide (64) (white solid, one step yield: 30.2%).

LC-MS (ESI): m / z 685.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.91 (s, 1H), 8.78 (s, 1H), 8.71 (q, J = 4.6Hz, 1H), 8.49 (d, J = 5.2Hz, 1H) , 8.17–7.97 (m, 1H), 7.59–7.18 (m, 8H), 6.48 (dd, J=5.3, 1.1 Hz, 1H), 4.07 (d, J=7.2 Hz, 2H), 3.95 (d, J) =1.6 Hz,6H), 3.90–3.81 (m, 2H), 3.24 (d, J=2.2 Hz, 1H), 2.51 (s, 3H), 2.48 (d, J = 4.7 Hz, 2H), 1.54–1.17 (m, 4H).

Example 65: N ² -cyclopropyl-N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4- Preparation of fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (65)

In the same manner as in Example 63, except that cyclopropylamine was used in place of ammonium chloride, N ² -cyclopropyl-N ⁵ -(4-((6,7-dimethoxyquinolin-4-) was obtained. (yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2,5-dimethylformamide (65) (white solid, one step yield: 29.8%).

LC-MS (ESI): m / z 711.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.90 (s, 1H), 8.91-8.70 (m, 2H), 8.48 (d, J = 5.2Hz, 1H), 8.05 (dd, J = 12.9,2.4 Hz, 1H), 7.59–7.37 (m, 4H), 7.35–7.13 (m, 4H), 6.48 (dd, J=5.2, 1.1 Hz, 1H), 4.09 (d, J=7.3 Hz, 2H), 4.05 –3.77(m,8H), 3.24 (dd, J=12.6, 10.4 Hz, 2H), 2.50–2.40 (m, 3H), 1.52–1.08 (m, 5H), 0.53 (d, J=7.2 Hz, 2H) ).

Example 66: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (66)

The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N ⁵ -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (66) (white solid, three-step yield: 23.4%).

LC-MS (ESI): m / z 615.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.97 (s, 1H), 8.77 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.35-8.28 (m, 1H), 8.06 ( Dd, J = 13.0, 2.4 Hz, 2H), 7.55 - 7.40 (m, 4H), 7.35 (ddd, J = 8.7, 5.6, 2.6 Hz, 2H), 7.29 - 7.20 (m, 2H), 6.49 (d, J = 5.1 Hz, 1H), 4.50 (p, J = 6.6 Hz, 1H), 3.95 (d, J = 1.7 Hz, 6H), 1.56 (d, J = 6.6 Hz, 6H).

Example 67: 5-((6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl) Preparation of ethyl 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (67)

The same procedure as in the preparation of 58a in Step 1 of Example 58 was used except that 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg) was used instead of 4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give 5-((6-(6,7-dimethoxyquinoline)- 4-yl)oxy)pyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate Ethyl acetate (67) (white solid, one step yield: 21.1%).

LC-MS (ESI): m / z 600.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ13.38 (s, 1H), 8.87 (s, 1H), 8.70 (d, J = 9.5Hz, 1H), 8.61 (d, J = 5.1Hz, 1H) , 7.81 (d, J = 9.5 Hz, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.32 - 7.25 (m, 4H), 7.01 (d, J = 5.1 Hz, 1H), 4.12 ( q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.88 (d, J = 6.7 Hz, 6H), 0.93 (t, J = 7.1 Hz, 3H).

Example 68: N ⁵ -(4-((6-carbamoyl-7methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)- Preparation of 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (68)

The same procedure as in Example 66 was employed except that 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh) was used instead of 4-((6,7- Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N ⁵ -(4-((6-carbamoyl-7-methoxyquinolin-4-yl) )oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylamide (68) ) (white solid, three-step yield: 30.2%).

LC-MS (ESI): m / z 628.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.99 (s, 1H), 8.77 (s, 1H), 8.68 (t, J = 2.6Hz, 2H), 8.31 (s, 1H), 8.12-8.03 ( m, 2H), 7.91–7.84 (m, 1H), 7.74 (s, 1H), 7.56–7.46 (m, 3H), 7.40–7.32 (m, 2H), 7.28–7.21 (m, 2H), 6.54 ( Dd, J = 5.2, 1.2 Hz, 1H), 4.50 (q, J = 6.6 Hz, 1H), 4.04 (s, 3H), 1.56 (d, J = 6.6 Hz, 6H).

Example 69: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-10-(4-fluorophenyl)-1,9 -Preparation of dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (69)

The same procedure as in Example 58 except that 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a was used. ][1,4]diazepane-8-carboxylic acid (d) instead of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1 , 4-dihydropyridine-3-carboxylic acid (a), to give N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Heptane-8-carboxamide (69) (white solid, one step yield: 34.6%).

LC-MS (ESI): m / z 613.2 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.68 (t, J = 6.6 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.04 (dd, J = 12.9, 2.4 Hz, 1H), 7.63 - 7.35 (m, 4H), 7.25 (dddd, J = 30.7, 8.9, 6.2, 1.9 Hz, 4H), 6.49 (dd, J = 5.2, 1.1 Hz, 1H), 3.95 (d, J = 1.3 Hz, 6H), 3.33 (s, 4H), 2.09 (d, J = 45.0 Hz, 2H).

Example 70: 10-(4-Fluorophenyl)-N-(4-((6-methoxy-7-(2-morpholinethyl)quinazolin-4-yl)oxy)phenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( Preparation of 70)

In the same manner as in Example 69 except that 4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (ss) was used instead of 4-( (6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give 10-(4-fluorophenyl)-N-(4-((6-A) Oxy-7-(2-morpholinoethyl)quinazolin-4-yl)oxy)phenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydro Pyrido[1,2-a][1,4]diazepane-8-carboxamide (70) (white solid, one step yield: 26.7%).

LC-MS (ESI): m / z 695.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.79 (s, 1H), 8.83 (s, 1H), 8.66 (t, J = 6.5Hz, 1H), 8.54 (s, 1H), 7.82-7.77 ( m, 2H), 7.56 (s, 1H), 7.42 (s, 1H), 7.29 (dq, J = 8.0, 2.7, 2.2 Hz, 4H), 7.21 (t, J = 9.0 Hz, 2H), 4.70 - 4.60 (m, 1H), 4.32 (t, J = 5.8 Hz, 2H), 4.07 (d, J = 18.6 Hz, 1H), 3.97 (s, 3H), 3.62 - 3.57 (m, 4H), 2.80 (t, J = 5.7 Hz, 2H), 2.28 - 1.91 (m, 4H).

Example 71: N-(6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9 -Preparation of dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (71)

In the same manner as in Example 69 except that 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg) was used instead of 4-((6,7-) Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N-(6-(6,7-dimethoxyquinolin-4-yl)oxy) Pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]Diazepane-8-carboxamide (71) (white solid, one step yield: 15.6%).

LC-MS (ESI): m / z 597.3 [M + H +].

Example 72: N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4 Of 5,9-hexahydropyrido[1,2-A][1,4]diazepane-8-carboxamide (72)

The same procedure as in Example 71 was carried out except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]Diazepane-8-carboxylic acid (e) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydro Pyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), and 4-(4-amino-2-phenoxy)pyridin-2-amine (nn ) and 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg), respectively, to obtain N-(4-((2-aminopyridine-4) -yl)oxy)phenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-A][ 1,4]diazepane-8-carboxamide (72) (white solid, one step yield: 2.7.1%).

LC-MS (ESI): m / z 496.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.84 (s, 1H), 8.81 (s, 1H), 8.60 (t, J = 6.6Hz, 1H), 7.79 (dd, J = 15.6,7.3Hz, 3H), 7.25–7.06 (m, 6H), 6.19 (dd, J=6.0, 2.2 Hz, 1H), 6.06 (s, 2H), 5.85 (d, J=2.2 Hz, 1H), 4.63 (dd, J =14.4, 6.1 Hz, 1H), 4.04 (s, 1H), 2.33 (s, 3H), 2.15 (s, 1H), 2.00-2.03 (m, 1H), 1.09-1.24 (m, 1H), 0.81 0.86 (m, 1H).

Example 73: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7 -Preparation of dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (73)

The same procedure as in Example 69 was used except for 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2- a] pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5, 9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4-((6,7-dimethoxyquine) Phenyl-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrocaine Zoxao[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (73) (white solid, one step yield: 40.3%).

LC-MS (ESI): m / z 641.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.80 (s, 1H), 8.88 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.04 (dd, J = 12.9,2.4Hz, 1H), 7.54 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 16.1, 7.0 Hz, 2H), 7.19 (s, 4H), 6.48 (d, J = 5.1 Hz, 1H), 5.46 ( Dd, J = 10.0, 3.5 Hz, 1H), 4.99 (d, J = 8.9 Hz, 1H), 4.28 - 4.10 (m, 2H), 4.10 - 3.84 (m, 7H), 3.67 (dd, J = 18.5, 7.5 Hz, 1H), 3.47 (d, J = 4.3 Hz, 1H).

Example 74: N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (74 Preparation

In the same manner as in Example 73 except that 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh) was used instead of 4-((6,7-di) Methoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy) 3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- a] Pyrido[1,2-d]pyrazine-8-carboxamide (74) (white solid, one step yield: 32.6%).

LC-MS (ESI): m / z 654.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.81 (s, 1H), 8.89 (s, 1H), 8.68 (d, J = 4.9Hz, 2H), 8.06 (dd, J = 12.9,2.4Hz, 1H), 7.90–7.85 (m, 1H), 7.74 (s, 1H), 7.60–7.53 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H), 7.19 (s, 4H), 6.54 (dd) , J = 5.2, 1.1 Hz, 1H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.99 (dd, J = 12.3, 3.7 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.19 - 4.13 (m, 1H), 4.04 (s, 4H), 3.70 - 3.63 (m, 1H), 3.49 - 3.43 (m, 1H).

Example 75: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8 -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Preparation of oxazine-9-carboxamide (75)

The same procedure as in Example 73 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo 3,4,6,8,12,12a hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 6-(4-fluorophenyl)-5,7-dioxo-2 , 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), to obtain N-(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4, 6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (75 (white solid, one step yield: 40.2%).

LC-MS (ESI): m / z 655.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.78 (s, 1H), 8.90 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.04 (d, J = 15.3Hz, 1H) , 7.61 - 7.33 (m, 4H), 7.29 - 6.98 (m, 4H), 6.48 (d, J = 5.0 Hz, 1H), 5.29 (s, 1H), 4.65 (d, J = 32.4 Hz, 2H), 4.14 (d, J = 58.2 Hz, 2H), 3.95 (d, J = 1.5 Hz, 7H), 3.10 (s, 1H), 1.59 (s, 2H).

Example 76: N-(3-Fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-7- (4-fluorophenyl)-6,8-dioxo-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (76)

The same procedure as in Example 75 was employed except for 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (o Instead of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-(3-fluoro-4-((6-methoxy) 7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4 -,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (76) (white solid, one step yield: 31.2%).

LC-MS (ESI): m / z 700.3 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.52–7.37 (m, 3H), 7.22–6.98 (m, 4H), 5.29 (t, J=4.1 Hz, 1H), 4.64 (ddd, J=44.4, 14.1, 4.1 Hz, 2H) , 4.39 - 4.15 (m, 3H), 4.11 - 3.66 (m, 7H), 3.35 (s, 3H), 3.10 (td, J = 12.8, 3.5 Hz, 1H), 1.75 - 1.47 (m, 2H).

Example 77: N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6 , 8-dioxo-3,4,6-,8,12,12a hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1, 3] Preparation of oxazine-9-carboxamide (77)

In the same manner as in Example 75 except that 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline (ii) was used instead of 3-fluoro-4-( (6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (oo) to give N-(4-((1H-pyrrolo[2] ,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6-,8,12 , 12a hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (77) (white solid, one step Yield: 21.7%).

LC-MS (ESI): m / z 584.3 [M + H +].

1H NMR (400MHz, DMSO-d6) δ 12.74 (s, 1H), 11.78 (s, 1H), 8.90 (s, 1H), 8.11 - 7.95 (m, 2H), 7.48 (dt, J = 8.9, 1.7 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.21 - 7.03 (m, 4H), 6.38 (d, J = 5.4 Hz, 1H), 6.25 (dd, J = 3.5, 1.9 Hz, 1H), 5.28 (t, J = 4.1 Hz, 1H), 4.70 (dd, J = 14.1, 3.7 Hz, 1H), 4.59 (dd, J = 14.1, 4.4 Hz, 1H), 4.22 (d, J = 12.1 Hz, 1H) , 4.09–4.02 (m, 1H), 3.86 (td, J=11.7, 2.8 Hz, 1H), 3.10 (td, J=12.8, 3.5 Hz, 1H), 1.68 (dq, J=12.2, 7.4, 6.1 Hz) , 1H), 1.57 (d, J = 12.9 Hz, 1H).

Example 78: 10-(4-Fluorophenyl)-N-(4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy) Phenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-A Preparation of amide (78)

In the same manner as in Example 69, except that 4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (pp) was used instead of 4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), 10-(4-fluorophenyl)-N-(4-((6-) Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (78) (white solid, one step yield: 30.6%).

LC-MS (ESI): m / z 640.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.80 (s, 1H), 8.84 (s, 1H), 8.67 (t, J = 6.5Hz, 1H), 8.55 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.58 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J = 8.6, 6.2 Hz, 4H), 7.22 (t, J = 8.7 Hz, 2H), 4.66 ( d, J = 10.4 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H), 4.08 (d, J = 11.8 Hz, 1H), 3.99 (s, 3H), 3.84 - 3.74 (m, 2H), 3.36 (s, 5H), 2.16 (s, 1H), 2.04 (s, 1H).

Example 79: N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6, 8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3 Preparation of Oxazine-9-carboxamide (79)

In the same manner as in Example 75, except for 4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (kk) instead of 4-((6,7-) Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy) )-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (79) (white solid, one step yield: 28.2%).

LC-MS (ESI): m / z 656.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.51–7.39 (m, 3H), 7.21–7.07 (m, 4H), 5.29 (t, J=4.1 Hz, 1H), 4.70 (dd, J=14.1, 3.7 Hz, 1H), 4.59 (dd, J = 14.1, 4.4 Hz, 1H), 4.23 (dd, J = 13.7, 4.4 Hz, 1H), 4.07 (dd, J = 11.2, 4.5 Hz, 1H), 3.99 (d, J = 5.8 Hz, 6H), 3.86 (td, J = 11.7, 2.7 Hz, 1H), 3.10 (td, J = 12.8, 3.5 Hz, 1H), 1.80 - 1.54 (m, 2H).

Example 80: N-3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4 -fluorophenyl)-6,8-dioxo-3,4-6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2, Preparation of 1-b][1,3]oxazine-9-carboxamide (80)

The same procedure as in Example 75 was employed except that 3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)aniline (tt) Instead of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-3-fluoro-4-((6-methoxy)- 7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4-6, 8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (80) White solid, one step yield: 24.7%).

LC-MS (ESI): m / z 755.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.53–7.37 (m, 3H), 7.29–6.99 (m, 4H), 5.29 (t, J=4.0 Hz, 1H), 4.73–4.52 (m, 2H), 4.33 (t, J= 5.8 Hz, 2H), 4.25–4.17 (m, 1H), 4.11–4.02 (m, 1H), 3.98 (s, 3H), 3.93–3.77 (m, 1H), 3.61–3.57 (m, 5H), 3.11 – 2.99 (m, 1H), 2.80 (t, J = 5.7 Hz, 2H), 2.53 (d, J = 3.5 Hz, 3H), 1.75 - 1.52 (m, 2H).

Example 81: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-9-(4-fluorophenyl)-1,8 -Preparation of dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (81)

The same procedure as in Example 69 was carried out except that 9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a] Pyrazin-7-carboxylic acid (t) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- a][1,4]diazepan-8-carboxylic acid (d) to obtain N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3 -fluorophenyl)-9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7 - Formamide (81) (white solid, one step yield: 34.9%).

LC-MS (ESI): m / z 599.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.91 (s, 1H), 8.81 (s, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 13.0 Hz, 1H), 7.59 (s, 2H), 7.53 - 7.45 (m, 2H), 7.29 - 7.17 (m, 4H), 6.55 (d, J = 5.1 Hz, 1H), 4.52 (s, 2H) ), 4.01 (d, J = 1.3 Hz, 6H), 3.67 (s, 2H).

Example 82: N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3 ,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-A Preparation of amide (82)

In the same manner as in Example 80, except for 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (mm) instead of 4-((6-methoxy-7-(2-morpholine) Ethoxy)quinazolin-4-yl)oxy)aniline (ss) to give N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-7 -(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine [2,1-b][1,3]oxazine-9-carboxamide (82) (white solid, one step yield: 30.8%).

LC-MS (ESI): m / z 560.2 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.71 (s, 1H), 8.89 (s, 1H), 7.97 (dd, J = 12.9,2.5Hz, 1H), 7.79 (d, J = 5.9Hz, 1H), 7.46 (dt, J = 8.5, 2.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.23 - 7.01 (m, 4H), 6.16 (dd, J = 5.8, 2.3 Hz, 1H) ), 5.94 (s, 2H), 5.79 (d, J = 2.3 Hz, 1H), 5.28 (t, J = 4.0 Hz, 1H), 4.69 (dd, J = 14.1, 3.7 Hz, 1H), 4.58 (dd , J = 14.1, 4.4 Hz, 1H), 4.27 - 4.18 (m, 1H), 4.07 (dd, J = 11.1, 4.5 Hz, 1H), 3.86 (td, J = 11.8, 2.7 Hz, 1H), 3.10 ( Td, J = 12.7, 3.5 Hz, 1H), 1.68 (d, J = 10.9 Hz, 1H), 1.57 (d, J = 13.3 Hz, 1H).

Example 83: N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo Preparation of 1,3,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (83)

In the same manner as in Example 78 except that 4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenylamine (11) was used instead of 4-((6-methoxy-7-). (2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (pp) to give N-(4-((6,7-dimethoxyquinazolin-4-yl) Oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][ 1,4]diazepane-8-carboxamide (83) (white solid, one step yield: 29.4%).

LC-MS (ESI): m / z 596.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.80 (s, 1H), 8.85 (s, 1H), 8.66 (d, J = 7.1Hz, 1H), 8.56 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.40 (s, 1H), 7.31 (d, J = 8.4 Hz, 4H), 7.22 (t, J = 8.7 Hz, 2H), 4.66 (d, J = 13.3 Hz, 1H), 4.07 (s, 1H), 3.99 (d, J = 5.7 Hz, 6H), 2.06 (d, J = 25.5 Hz, 4H).

Example 84: N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-di Preparation of oxo-1,2,3,4-,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (84)

In the same manner as in Example 78 except that 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (ii) was substituted for 4-((6-methoxy-7) -(2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (pp) to give N-(4-((1H-pyrrolo[2,3-b]pyridine-4) -yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4-,5,9-hexahydropyrido[1,2- a] [1,4]diazepane-8-carboxamide (84) (white solid, one step yield: 26.7%).

LC-MS (ESI): m / z 524.4 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.79 (s, 1H), 11.74 (s, 1H), 8.84 (s, 1H), 8.67 (t, J = 6.6Hz, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.36 (t, J = 3.0 Hz, 1H), 7.29 (dd, J = 8.4, 5.6 Hz, 2H), 7.21 (dd, J = 10.7, 8.7 Hz, 4H), 6.43 (d, J = 5.5 Hz, 1H), 6.22 (t, J = 2.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.05 (d, J = 11.7 Hz, 1H), 3.34 - 3.40 (m, 1H), 2.15 (s, 1H), 2.06 - 1.97 (m, 1H).

Example 85: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)benzene -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85)

Step 1: 4-(2-((4-(2-fluoro-4-)-4-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamido)phenoxy)-6- Preparation of tert-butyl oxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate (85a)

Add 4-(2-(4-(4-amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)B to a reaction flask containing DMF (5 mL) Tert-butyl piperazine-1-carboxylate (qq) (80 mg, 0.16 mmol), 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a - hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k) (57 mg, 0.16 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: )-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxazine-9-carboxamido)phenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (85a) (80 mg, yellow solid, yield: 58.6%).

LC-MS (ESI): m / z 854.4 [M / M + H +].

Step 2: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl) )-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85)

Add 4-(2-(4-)-fluoro-4-(7-(4-fluorophenyl)-6,8-dioxo-3,4 to a reaction flask containing DCM (3 mL). 6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide) Benzyloxy-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (85a) (80 mg, 0.09 mmol) and 1,4-dihydrochloride Oxycyclohexane solution (1.5 mL, 4 M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Pyrazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8 ,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85) (16.8 Mg, white solid, 27.8%).

LC-MS (ESI): m / z 754.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ8.90 (s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.52–7.39 (m, 3H), 7.21–7.07 (m, 4H), 5.29 (t, J=4.0 Hz, 1H), 4.72–4.57 (m, 2H), 4.32 (t, J= 5.7 Hz, 2H), 4.26 - 4.20 (m, 1H), 4.06 (d, J = 4.4 Hz, 1H), 3.98 (s, 3H), 3.86 (d, J = 2.8 Hz, 1H), 3.14 - 3.07 ( m, 1H), 2.83 (dt, J = 19.4, 5.3 Hz, 6H), 2.56 (t, J = 4.7 Hz, 4H), 1.71 - 1.54 (m, 2H).

Example 86: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)benzene Base)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxamide (86)

The same procedure as in Example 85 was employed except for 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a. ][1,4]diazepane-8-carboxylic acid (d) instead of 7-(4-fluorophenyl)-6,8-dioxo 3,4,6,8,12,12a hexahydro -2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k) to give N-(3-fluoro- 4-((6-Methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( 86) (white solid, two-step yield: 17.8%).

LC-MS (ESI): m / z 712.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.96 (s, 1H), 8.86 (s, 1H), 8.69 (t, J = 6.6Hz, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.06–7.94 (m, 1H), 7.58 (s, 1H), 7.52–7.42 (m, 3H), 7.35–7.18 (m, 4H), 4.66 (d, J=12.0 Hz, 1H), 4.33 (t, J = 5.7 Hz, 2H), 4.06 (s, 1H), 3.99 (s, 3H), 3.33 (s, 2H), 2.83 (dt, J = 15.8, 5.3 Hz, 6H), 2.56 (s, 4H), 2.16 (s, 1H), 2.09 - 1.99 (m, 1H).

Example 87: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-1,5-dioxo-4 -((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (87) preparation

Step 1: 3-Bromo-5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-oxo- Preparation of ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (87a)

Add 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) (70 mg, 0.22 mmol), 5-- to a reaction flask containing DMF (5 mL) Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (45a) (85 mg, 0.22 mmol), HATU (125 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol). The mixture was stirred at room temperature for half an hour. After the reaction was completed, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Ethyl)-3-fluorophenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 2-carboxylate (87a) (120 mg, yellow solid, yield: 79.8%).

LC-MS (ESI): m / z 683.2 / 684.2 [M / M + H +].

Step 2: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-1,5-dioxo-4- Preparation of ((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (87)

Add 3-bromo-5-((4-((6,7-dimethoxy)) to the reaction flask containing (2.5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. Benzyl quinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2-carboxylic acid ethyl ester (87a) (50 mg, 0.07 mmol), 2-amino-4-fluorobenzeneboronic acid (17 mg, 0.11 mmol), potassium carbonate (30 mg, 0.21 mmol), Pd (dppf) )Cl ₂ .DCM (8 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: EtOAc 3-fluorophenyl)-8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydro Benzo[f][1,7]naphthyridin-2-carboxamide (87) (15 mg, yellow solid, yield: 32.0%).

LC-MS (ESI): m / z 669.4 [M / M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.72 (s, 1H), 12.57 (s, 1H), 9.96 (dd, J = 9.4,6.5Hz, 1H), 8.88 (s, 1H), 8.50 ( d, J = 5.3 Hz, 1H), 8.11 (dd, J = 12.8, 2.4 Hz, 1H), 7.60 (dt, J = 9.0, 1.7 Hz, 1H), 7.54 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.24 - 7.16 (m, 2H), 6.51 (dd, J = 5.3, 1.1 Hz, 1H), 4.99 (d, J = 7.0 Hz, 2H), 3.96 (d, J = 2.1 Hz, 6H), 3.87 - 3.79 (m, 2H), 3.22 - 3.17 (m, 2H), 2.07 (s, 1H), 1.44 - 1.31 (m, 4H).

Example 88: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-4-methyl-1,5- Preparation of Dioxo-1,4,5,6-tetrahydrobenzo[F][1,7]naphthyridine-2-carboxamide (88)

In the same manner as in Example 87, except that 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4) was used instead of 5-bromo- 6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (45a), made N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-4-methyl-1,5-dioxo -1,4,5,6-Tetrahydrobenzo[F][1,7]naphthyridin-2-carboxamide (88) (2.5 mg, white solid, yield: 3.6%).

LC-MS (ESI): m / z 585.3 [M / M + H +].

Example 89: N-(3-Fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluoro Phenyl)-1,9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide ( Preparation of 89)

Step 1: Preparation of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (89a)

4-Chloro-7-azaindole (1.53 g, 10.03 mmol), 2-fluoro-4-nitrophenol (2.36 g, 15.04 mmol) and DIPEA (3.9 g) were added to a reaction flask containing NMP (15 mL). , 30.09mmol). The mixture was heated to 200 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut b] Pyridine (89a) (1.0 g, yellow solid, yield: 36.4%).

LC-MS (ESI): m / z 274.1 [M / M + H +].

Step 2: Preparation of 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine (89b)

Add 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (89a) (1.0 g, 3.65 mmol) to a reaction flask containing DMF (15 mL). N-iodosuccinimide (NIS) (985 mg, 4.38 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent _{DCM: CH 3 OH / 10:} 1), to give 4- (2-fluoro-4-nitrophenoxy) -3-iodo -1H- pyrrole And [2,3-b]pyridine (89b) (940 mg, yellow oil, yield: 64.7%).

LC-MS (ESI): m / z 400.0 [M / M + H +].

Step 3: Preparation of 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89c)

Add 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine (89b) (940 mg, 2.37) to a reaction flask containing DCM (15 mL) Methyl), Boc ₂ O (777 mg, 3.56 mmol), DMAP (43 mg, 0.15 mmol) and triethylamine (919 mg, 7.11 mmol). The mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) 2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89c) (620 mg, yellow solid, yield: 52.4%).

LC-MS (ESI): m / z 500.0 [M / M + H +].

Step 4: Preparation of 3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (89d)

4-(2-Fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b] was added to a reaction flask containing ethanol (8 mL) and water (2 mL) at room temperature. tert-Butyl pyridine-1-carboxylate (89c) (300 mg, 0.60 mmol), iron powder (168 mg, 3.0 mmol) and ammonium chloride (321 mg, 6.0 mmol). The reaction solution was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 4-yl)oxy)aniline (89d) (100 mg, yellow solid, yield: 45.0%).

LC-MS (ESI): m / z 370.0 [M / M + H +].

Step 5: N-(3-Fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( Preparation of 89e)

In a reaction flask containing DMF (5 mL), 3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)aniline (89d) (100 mg, 0.27 mmol), 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Diazepane-8-carboxylic acid (d) (100 mg, 0.32 mmol), HATU (153 mg, 0.40 mmol) and DIPEA (104 mg, 0.81 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9-hexahydropyridyl[1, 2-a][1,4]diazepane-8-carboxamide (89e) (100 mg, yellow solid, yield: 53.9%).

LC-MS (ESI): m / z 668.1 [M / M + H +].

Step 6: 4-(2-Fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1, 2-a][1,4]diazepane-8-carboxamido)phenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl Preparation of ester (89f)

Add N-(3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)- in a reaction flask containing DCM (2 mL) 10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Alkano-8-carboxamide (89e) (40 mg, 0.06 mmol), Boc ₂ O (20 mg, 0.09 mmol), DMAP (1 mg, 0.01 mmol) and triethylamine (18 mg, 0.18 mmol). The mixture was stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxamido)phenoxy)-3 - Iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89f) (30 mg, white solid, yield: 63.5%).

LC-MS (ESI): m / z 768.1 [M / M + H +].

Step 7: N-(3-Fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorobenzene) 1,1,9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (89 Preparation

4-(2-Fluoro-4-(10-(4-fluorophenyl)-1) was added to a reaction flask containing (3.3 mL) a mixture of ethanol, toluene and water (5:5:1) at room temperature. 9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-formylamino)phenoxy -3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89f) (30 mg, 0.04 mmol), phenylboronic acid (6 mg, 0.06 mmol), sodium carbonate (12 mg, 0.12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (7 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N-(3-fluoro-4-((3-phenyl-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9 hexahydropyridyl[1, 2-α][1,4]diazepane-8-carboxamide (89) (6 mg, white solid, yield: 24.3%).

LC-MS (ESI): m / z 618.3 [M / M + H +].

Example 90: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of cyclopropyl-4-oxo-1,4-dihydropyridine-2.5-dicarboxamide (90)

The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b1) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N ⁵ -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (90) (white solid, three-step yield: 52%).

LC-MS (ESI): m / z613.7 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.12 (s, 1H), 8.04 (dd, J = 12.9, 2.4 Hz, 1H), 7.97 (s, 1H), 7.54 - 7.49 (m, 2H), 7.47 - 7.40 (m, 2H), 7.36 - 7.31 (m, 2H), 7.28 - 7.22 (m, 2H), 6.48 (d, J = 5.1 Hz, 1H), 3.95 (d, J = 1.6 Hz, 6H), 2.02 - 1.96 (m, 1H), 1.26 (s, 2H), 1.09 (d, J = 7.1) Hz, 2H).

Example 91: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of cyclobutyl-4-oxo-1,4-dihydropyridine 2.5-dimethylformamide (91)

The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b2) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N ⁵ -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (91) (white solid, three-step yield: 16.4%).

LC-MS (ESI): m / z 627.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 8.78 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 8.06 (dd, J = 12.9, 2.4 Hz, 1H), 7.98 (s, 1H), 7.51 (d, J = 13.1 Hz, 2H), 7.48 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 7.28 - 7.18 ( m, 2H), 6.49 (dd, J = 5.2, 1.0 Hz, 1H), 4.80 (t, J = 8.2 Hz, 1H), 3.95 (d, J = 1.5 Hz, 6H), 2.69 - 2.52 (m, 2H) ), 2.46–2.35 (m, 2H), 1.86–1.71 (m, 2H).

Example 92: 1-(tert-butyl)-5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3- Preparation of ethyl (4-fluorophenyl)-4-carbonyl-1,4-dihydropyridine-2-carboxylate (92)

The same procedure as in the synthesis 58a of Example 58 was used except that 5-(4-fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b3) was used instead. 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give 1-( tert-Butyl)-5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Ethyl 4-carbonyl-1,4-dihydropyridine-2-carboxylate (92) (white solid, yield: 77.4%).

LC-MS (ESI): m / z658.3 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.99 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.9, 2.4 Hz, 1H) ), 7.58–7.39 (m, 4H), 7.26 (dt, J = 11.4, 7.5 Hz, 4H), 6.49 (dd, J = 5.3, 1.0 Hz, 1H), 3.95 (d, J = 2.2 Hz, 6H) , 3.91 (t, J = 7.1 Hz, 2H), 1.73 (s, 9H), 0.83 (t, J = 7.1 Hz, 3H).

Example 93: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N ² -Preparation of methyl-d ₃ -1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (93)

N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3 was obtained in the same manner as in Example 58 except that instead of ammonium chloride. -fluorophenyl)-3-(4-fluorophenyl)-N ² -methyl-d ₃ -1-methyl-4-oxo-1,4-dihydropyridine-2,5-diformamide (93) (white solid, 40 mg, yield: 32%).

LC-MS (ESI): m / z 604.26 [M + H +].

^{1 H NMR (400MHz, DMSO-} d 6) δ12.97 (s, 1H) δ8.82 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.05 (dd , J = 13.0, 2.4 Hz, 1H), 7.56 - 7.40 (m, 4H), 7.32 (ddd, J = 8.7, 5.6, 2.6 Hz, 2H), 7.27 - 7.19 (m, 2H), 6.48 (dd, J = 5.3, 1.1 Hz, 1H), 3.95 (d, J = 1.1 Hz, 6H), 3.82 (s, 3H).

Example 94: N ⁵ -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of isopropyl-N ² -methyl-d ₃ -4-oxo-1,4-dihydropyridin-2,5-dimethylformamide (94)

The same procedure as in Example 58 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3 was used. -carboxylic acid (b) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) And using m-methylamine instead of ammonium chloride to obtain N ⁵ -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3- (4-fluorophenyl)-1-isopropyl-N ² -methyl-d ₃ -4-oxo-1,4-dihydropyridin-2,5-dimethylformamide (94) (white solid, 15 mg, yield: 38%).

LC-MS (ESI): m / z 632.37 [M + H +].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (s, 1H), 8.76 (d, J = 5.4 Hz, 2H), 8.49 (d, J = 5.3 Hz, 1H), 8.06 (dd, J = 12.9, 2.4 Hz, 1H), 7.54 - 7.40 (m, 4H), 7.36 - 7.30 (m, 2H), 7.27 - 7.20 (m, 2H), 6.49 (dd, J = 5.3, 1.1 Hz, 1H), 4.40 (q, J = 6.6 Hz, 1H), 3.95 (d, J = 1.7 Hz, 6H), 1.53 (d, J = 6.6 Hz, 6H).

Example 95: N ⁵ -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-N ² =methyl-d3-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (95)

N ⁵ -(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)) was obtained in the same manner as in Example 12 except that instead of ammonium chloride. Pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-N ² -methyl-d3-4-oxo-1,4-dihydropyridine -2,5-dimethylformamide (95) (white solid, 19 mg, yield: 30%)

LC-MS (ESI): m/z 615.36 [M+H ⁺ ]

^{1 H NMR (400MHz, DMSO-} d6) δ12.93 (s, 1H), 8.77 (s, 1H), 8.74 (s, 1H), 8.24 (d, J = 2.4Hz, 1H), 8.10-8.07 (m , 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (ddd, J = 8.5, 5.5, 2.6 Hz, 2H), 7.23 (t, J = 9.0 Hz, 2H), 5.53 (s, 2H), 4.39 (p, J = 6.6 Hz, 1H), 4.11 (q, J = 7.3 Hz, 2H), 1.53 (d, J = 6.6 Hz, 6H), 1.38 (t, J = 7.3 Hz, 3H) .

Biological evaluation

Test Example 1: c-MET kinase Axl and inhibition of enzyme activity (IC ₅₀₎ evaluation test

In this experiment, the Mobility shift assay was used to test the inhibitory activity of the compound at the ATP concentration of the corresponding kinase Km. The reference substance was staurosporine and cabozantinib.

The concentration of the test compound was started from 10 μM and diluted 10-fold. The test results (IC ₅₀ ) are the average of two independent experiments.

Laboratory supplies:

Kinase Axl (Carna, Cat. No. 08-107, Lot. No. 06 CBS-3408), kinase cMET (Carna, Cat. No. 08-151, Lot. No. 10 CBS-1118M), substrate peptide FAM-P2 (GL Biochem, Cat. No. 112394, Lot. No. P131014-XP112394), substrate peptide FAM-P22 (GL Biochem, Cat. No 112393, Lot. No. P130408-ZB112393), ATP (Sigma, Cat. No.) A7699-1G, CAS No. 987-65-5), DMSO (Sigma, Cat. No. D2650, Lot. No. 474382), EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4) , Brij-35, 96-well plates (Corning, Cat. No. 3365, Lot. No. 22008026), 384-well plates (Corning, Cat. No. 3573, Lot. No. 12608008), Staurosporine (MCE) , Cat. No. HY-15141, Lot. No. 19340), Cabotinib (City of Vietnam, synthesized by reference patent WO 201101763A1)

Experimental steps:

1) Buffer formulation: 50 mM HEPES, pH 7.5, 0.00015% Brij-35.

2) Control product cabozantini and test sample formulation: Cabbolinib and the compound of the present invention were formulated in a gradient concentration in 100% DMSO and diluted to 10% DMSO with the above buffer, and added to a 384-well plate. For example, when the initial concentration of the compound is 10 uM, it is made into 500 uM with 100% DMSO, and diluted in 10 concentrations, and then diluted 10-fold with buffer to prepare an intermediate dilution of the compound containing 10% DMSO, and transferred 5 ul to 384 wells. board.

3) Axl and c-METase were diluted to the optimal concentration with the following buffers: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT. Transfer 10 ul to 384 well plates and incubate with compound for 10-15 minutes.

4) The substrate was diluted to the optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 10 mM MgCl ₂ , adenosine triphosphate at Km. The reaction was initiated by adding 10 ul to a 384-well plate and reacted at 28 ° C for 1 hour.

The reaction concentrations of the respective reagents in the test experiment are shown in Table 1 below.

Table 1

5) The conversion rate was read with a Caliper Reader, and the inhibition rate was calculated as the average of the two tests.

6) Fit the IC ₅₀ with XL-fit software.

The inhibitory activities of the compounds of the present invention against Axl and c-MET kinase are shown in Table 2 below.

Table 2: IC ₅₀ values of the compounds of the present invention and Axl kinase activity of c-MET inhibition

As apparent from the above Table 2, the compounds of the present invention are effective in inhibiting the activities of Axl and MET kinase. Some of the inventive compounds exhibited higher activity inhibition ability than the positive control drug cabozantinib.

Test Example 2: CellTiter-Glo (CTG) method for measuring the activity inhibition ability of the compound of the present invention on cell line EBC-1

Experimental reagents and consumables

1) Fetal bovine serum FBS (GBICO, Cat#10099-141, Lot#1828728)

2)

Luminescent Cell Viability Assay (Promega, Cat#G7573, Lot#0000249676)

3) 96-hole transparent flat black panel (

Cat#3603, Lot#)

4) MEM medium (Hyclone, Cat#SH30024.01, Lot#AC10232463)

5) NEAA (Gibco, Cat#11140-050, Lot#1872982)

6) Reference substance: cabozantini (Vietnamese, according to patent WO201101763A1 synthesis)

7) Cells

Cell name Cell type Medium

EBC-1 lung MEM+0.01mM NEAA+10%FBS

The selected cells were cultured at 37 ° C, 5% CO ₂ , 95% humidity.

instrument

1) Multi-function microplate reader, Molecular Devices, spectraMax M3.

2) CO ₂ incubator, Thermo Scientific, Model 311 Series.

3) Biological safety cabinet, Dong Lian Ha Er, BSC-1100-L II A2.

4) Inverted microscope, Olympus, CKX41.

5) Refrigerator, Haier, BCD-190TMPK.

Cell viability and IC ₅₀ determination

Day 1: Cell culture and inoculation

1) Harvest cells in logarithmic growth phase and perform cell counting using a cell counter. Cell viability was measured by trypan blue exclusion to ensure cell viability was above 90%.

2) Adjust the cell concentration by diluting with complete medium, and add 90 μl of the cell suspension to a 96-well plate (Day 0 plate and test plate) to bring the cell density to the specified concentration: 700 cells/well.

3) Cells in 96-well plates were incubated overnight at 37 ° C, 5% CO ₂ , 95% humidity.

Day 0: T0 reading board

4) 10 μl of the culture solution was added to the T0 plate.

5) Melting CTG reagents (ie

Luminescent Cell Viability Assay Reagent, Promega, Cat# G7573) and equilibrate the cell plates to room temperature for 30 minutes.

6) Add an equal volume of CTG solution to each well.

7) The cells were lysed by shaking for 2 minutes on an orbital shaker.

8) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal.

9) Read the cold light value with a multi-function microplate reader.

Day 0: Dosing

10) Sample dilution: The compound of the present invention and the control product, cabozantinib, were dissolved in DMSO and subjected to gradient dilution to obtain a 10-fold solution.

11) Loading: 10 μl of the drug solution was added to each well of a 96-well plate in which cells were seeded, and three duplicate wells were set for each cell concentration. The highest concentration of the test compound and the control on the cells was 5 μM, 9 concentrations, and 5 fold dilution.

12) Culture: The cells in the 96-well plate that had been loaded were further cultured at 37 ° C, 5% CO ₂ , 95% humidity for 6 days, and subjected to CTG detection analysis.

Day 6: End reading board

13) Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

14) Add an equal volume of CTG solution to each well.

15) The cells were lysed by shaking for 2 minutes on an orbital shaker.

16) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal.

17) Read the luminescence value with a multi-function microplate reader.

data processing

Data was analyzed using GraphPad Prism 7.0 software, using a nonlinear regression curve fit data S derived dose - response curves, _IC50 values calculated therefrom IC.

Cell viability (%) = (Lum _{test compound -} Lum _{culture control} ) / (Lum _{cell control -} Lum _{culture control} ) × 100%

The activity inhibitory ability of the compound of the present invention on the cell line EBC-1 is shown in Table 3 below.

Table 3: Activity inhibition ability (IC ₅₀ value) of the compound of the present invention on cell line EBC-1

As apparent from the above Table 3, the compound of the present invention can effectively inhibit the activity of EBC-1 cells. The compounds of the invention exhibited a more potent inhibitory capacity than the positive control drug cabozantinib. At the same time, since EBC-1 is a c-MET driven lung cancer cell line, the activity of the compounds of the present invention on EBC-1 cells further validates their inhibition of c-MET kinase targets.

Test Example 3: Inhibition of Axl phosphorylation in cell lines NCI-H1299 and A549 by the compounds of the present invention, respectively

NCI-H1299 and A549 are lung cancer cell lines with high expression of Axl. The inhibition of the phosphorylation of Axl (Tyr702) by NCI-H1299 and A549 by the compounds of the present invention (p-Axl) was tested by Western blot.

Experimental Materials:

Cell line:

Tumor cells were cultured in a medium containing 10% FBS and placed in an incubator at 37 ° C, 5% CO 2 and 95% humidity. The serum used was purchased from GIBCO.

Experimental reagents:

1. cOmplete, EDTA-free Protease Inhibitor Cocktail (Roche-4693132001, Sigma)

2.PhosSTOPTM (Roche-4906845001, Sigma)

3. Recombinant human Gas6 protein (885-GSB-050, R&D)

4.Axl (C89E7) rabbit mAb (8661S, Cell Signaling Technology)

5. Phosphine-Axl (Tyr702) (D12B2) rabbit mAb (5724S, Cell Signaling Technology)

6. Anti-rabbit IgG, HRP-linked antibody (7074, Cell Signaling Technology)

7. Trypan blue staining solution (0.4%) (C0040, Solarbio)

8. RIPA cell lysis and extraction buffer (89901, Thermo);

9. NuPAGE sample reduction reagent (10×) (Thermo, Cat#NP0009);

10. NuPAGE loading buffer solution (4×) (Thermo, Cat# NP0008).

equipment:

1.CO2 incubator: Thermo Scientific, Model 311Series;

2. Biological safety cabinet: Dong Lian Ha Er, BSC-1100-L II A2;

3. Inverted microscope: Olympus, CKX41;

4. Refrigerator: Haier, BCD-190TMPK;

5.Mini Gel Tank: A25977, Invitrogen;

6.BlotTM2 Dry Blotting System: IB21001, Invitrogen;

7. Blood count board: MH0096, Meilun Biological.

experimental method:

1. Collect cells in logarithmic growth phase and perform cell counting using a hemocytometer (MH0096, Meilun Bio). Cell viability was determined by trypan blue exclusion, ensuring that the viability of each cell line used in the experiment was above 90%.

2. Dilute the concentration of NCI-H1299 cells to 1×10 6 cells/ml with RPMI1640+10% FBS medium, and dilute the A549 cell concentration to 1×10 6 cells/ml with F12K+10% FBS medium.

3. Add 1 ml of the diluted cell suspension to a 6-well plate. 0.8 ml of RPMI1640 + 10% FBS medium was added to the wells containing NCI-H1299 cells, and 0.8 ml of F12K + 10% FBS medium was added to the wells containing A549 cells.

4. After the cells were attached for 24 hours, the medium was changed to serum-free medium.

5. After 24 hours, the experimental group was added with 200 μL of a 10× concentration of the test compound to give a final concentration of 100 nM. The compound dilution process is as follows:

a. The test compound was formulated into a DMSO 10 mM stock solution.

b. Dilute 2 μL of 10 mM stock solution to 100 μM working solution using 198 μL of DMSO.

c. Dilute 5 μL of 100 μM working solution to 1 μM working solution using 495 μL of PBS.

d. The experimental group was added with 200 μL of a 10× concentration of the test compound, and 200 μL of PBS containing 1% DMSO was added to the control group.

6. After the compound was treated for 2 hours, a defined concentration of Gas6 (for NCI-H1299, Gas6 concentration of 100 ng/ml; for A549, Gas6 concentration of 200 ng/ml) was added. Incubation time: NCI-H1299: 10 min; A549: 30 min.

7. Lysis cells:

a. Discard the supernatant from the cell culture plate and wash the cells once with PBS.

b. Add 100 μL of RIPA lysate to each well.

c. Ice bath for 30 min.

8. Receive samples:

a. The lysed cells were transferred to a 1.5 mL EP tube and centrifuged at 13,000 rpm for 15 min at 4 °C.

b. Take 65 μL of the sample supernatant and mix well with 10 μL of NuPAGE sample reducing reagent (10×) and 25 μL of NuPAGE loading buffer solution (4×).

c. The sample was placed in a boiling water bath for 10 min, then cooled in an ice bath and centrifuged for later use.

9. Western blot analysis of Axl, p-Axl (Tyr702), GADPH expression levels:

a. Use the Quantity One software to read each strip of grayscale values.

b. The p-Axl level was calibrated by Axl, and the control group was taken as 1, and the inhibition rate of each group was calculated. The calculation formula is:

Compound inhibition rate (%) of p-Axl level = 100-100* (experimental group p-Axl volume / experimental group Axl volume) / (control group p-Axl volume / control group Axl volume)).

Experimental results:

The inhibitory effects of the compounds of the present invention on pAxl phosphorylation in the cell lines NCI-H1299 and A549 are shown in Table 4 below.

Table 4: Percentage inhibition of pAxl phosphorylation in cell lines NCI-H1299 and A549, respectively, of the compounds of the invention

Conclusion: It can be seen from Table 4 above that the compound of the present invention can effectively inhibit the phosphorylation of NCI-H1299 and A549Axl (Tyr702), and the inhibition rate is as high as 100%. The high inhibitory effect of the compounds of the invention on Axl kinase activity was further verified.

Test Example 4: Activity inhibition ability of the compound of the present invention on Ba/F3Ax1 cells

Test method: using Promega

The Luminescent Cell Viability Assay kit was used to evaluate the inhibitory activity of the compound on Ba/F3Axl cell proliferation.

Instruments: Molecular Devices' Spectramax M3 multi-function microplate reader, Thermo Scientific's Model 311Series CO ₂ incubator, Thermo Scientific's Model 1300Series A2 biosafety cabinet, Olympus' CKX41SF inverted microscope, Countstar's IC1000 cell counter , SIEMENS KK25E76TI refrigerator, its Lin Bell company's QB-9001 microplate fast oscillator.

Test material: fetal bovine serum FBS (Thermo Fisher, article number #10099-141, batch number #1966174C),

Fluorescent cell survival test reagent (Promega, Cat. #G7572, Lot #0000310975), 96-well clear flat-bottomed black-wall cell culture plate (Thermo Fisher, Inc. ##207365), RPMI1640 medium (GE company, Cat. #SH30809 .01, Lot #AD17321266), Murine IL-3 (PeproTech, Cat. #213-13, Lot #120948), rhGas6 (R&D Systems, Inc. #885-GSB, Lot #DFGX0417081), reference bemcentinib (alias BGB324) , Shanghai Bi De Pharmaceutical Technology Co., Ltd., Item No. #BD559084 Batch #AQU341), Ba/F3Axl cells (constructed by Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., complete medium is RPMI1640+10%FBS+100ng/mL rhGas6 The culture conditions were 37 ° C, 5% CO 2 , 95% humidity, the growth doubling time was about 20 hours, and the passage ratio was 1:10; refer to Oncogene.2009; 28:3442–3455, Oncotarget.FASEB J.2017; (4): 1382–1397).

Test procedure: When the Ba/F3Axl cells were resuscitated, the cell cryotubes were rapidly shaken in a 37 ° C water bath to melt in 1 minute. The melted cell suspension was mixed with RPMI1640 medium containing 10% FBS, centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cell pellet was resuspended in 5 mL of complete medium, placed in a cell culture flask having a bottom area of 25 cm ² , and cultured in a cell incubator at 37 ° C, 95% humidity, and 5% CO ₂ . Cell passage was performed at a cell density of 2 x 106 viable cells/mL. When the cells are passaged, the old cell suspension is directly blown evenly, and then 1/10 (ie, 0.5 mL) of the cell suspension is retained, 4.5 mL of new complete medium is added, and after being evenly blown, the cell bottle is placed in a cell culture flask and culture is continued. . Cell plating was performed when the cell confluence rate reached 2 x 106 viable cells/mL again. When the cells were plated, refer to the cell passage method, and retain 1/10 (ie 0.5 mL) cell suspension to continue the culture. Place the remaining cell suspension in a 15 mL centrifuge tube, discard the supernatant, and resuspend the cells in 5 mL of complete medium. . Using the trypan blue exclusion method, Countstar's IC1000 cell counter was used to measure cell viability to ensure cell viability was above 90%. A complete cell medium was used to prepare a cell suspension with a density of 5.56 x 104 viable cells/mL, and 90 μL of the cell suspension was added to a 96-well cell culture plate to prepare cells in the cell culture plate (Day 0 plate and test plate). The density is 5000 living cells/well. A control group containing no cells, no compound, and only complete medium was set, and a control group containing no compound and containing cells was set. The cell plates were placed in a cell culture incubator overnight. When a compound was added, the compound of the present invention and the control bemcentinib were dissolved in DMSO, and subjected to gradient dilution to obtain a 10-fold solution. 10 μL of the above solution was added to the corresponding cell culture plate so that the initial concentration of the compound was 100 nM, the dilution ratio of the adjacent concentration was 3.16 times, and the DMSO content in the cell culture plate was 0.1%. The cell plates were placed in a cell culture incubator for further 72 hours. Melt CellTiter-Glo reagent during testing (ie

Fluorescent cell survival test reagent, Promega, Cat. #G7572, Lot #0000310975), and the cell plate was allowed to equilibrate to room temperature for 30 minutes, add 100 μL of CellTiter-Glo to each well of the cell plate, at its Linbell QB Vibrate for 5 minutes on a -9001 microplate fast shaker to allow the cells to fully lyse. Place the cell plate at room temperature for 20 minutes to stabilize the cold light signal. Scan the luminescence value of each well at full wavelength with Molecular Devices' Spectramax M3 multi-plate reader. .

Test sample: Example compound and bemcentinib (positive control compound)

Data analysis: Cell viability under various concentrations of compounds was calculated using the following formula:

Cell viability (%) = (Lum test drug - Lum culture control) / (Lum cell control - Lum culture control) × 100%,

Lum refers to the luminescence value of each hole of the test plate read by the multi-function microplate reader.

Example 66 and Example ₅₀ inhibiting activity IC 93 value pair of Ba / F3Axl cell proliferation embodiment of 0.16nM and 0.18nM respectively. Reference Sample bemcentinib of Ba / F3Axl cell proliferation inhibiting activity IC ₅₀ value of 26.9nM. The compounds of the invention exhibit higher cell proliferation inhibitory activity than the control.

Test Example 5: In vivo antitumor activity test of the compound of the present invention in model mouse tumor cell xenograft test

3×106 cells of human non-small cell lung cancer tumor cell line EBC-1 (ATCC) were inoculated subcutaneously into BALB/c-nude model mice (Beijing Vitonda, female, 10). When the tumor was grown subcutaneously to 107 mm ³ in mice, the mice were orally administered test samples.

The mice were divided into a negative vehicle control group, a compound group of the present invention (Example 66) (100 mg/kg), and 5 mice each. It is administered twice daily for four weeks. The tumor growth volume was recorded. Antitumor efficacy is assessed based on the growth curve of the tumor in the treatment and relative tumor volume. The tumor inhibition rate (TGI) is calculated by the following formula:

Relative tumor inhibition rate TGI (%): TGI = 1 - T / C (%). T/C% is the relative tumor proliferation rate, that is, the percentage of tumor volume or tumor weight relative to the treatment group and the control group at a certain time point. T and C are the relative tumor volumes (RTV) of the treatment group and the control group at a specific time point, respectively.

Figure 1 is a graph showing the growth curve of tumor volume in a treatment group and a control group in an EBC-1 non-small cell lung cancer model. Figure 2 is a graph showing the changes in body weight of the treatment group and the control group as a function of treatment time in the EBC-1 non-small cell lung cancer model. As can be seen from Fig. 1, the compound of the present invention can effectively inhibit the growth of tumor cells in model mice, and the tumor inhibition rate (TGI) is as high as 98%. Also, as shown in Fig. 2, the tumor-bearing mice showed no significant change in body weight during the experiment, indicating that the compounds of the present invention have good safety and tolerability.

In vivo experiments in animals have demonstrated that the compounds of the present invention highly inhibit the growth of cancer cells in vivo, and therefore, the compounds of the present invention have broad application prospects in the treatment of diseases associated with cancer-driven genes such as c-MET or Axl, particularly in the treatment of cancer. .

Claims

a compound of the formula (I) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them,

W and V are each independently selected from CH, CF or N;

R a is selected from -OR 1 , -SR 1 or -NR 1 R 2 ;

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;

Alternatively, R a and R 3 together with a carbonyl group attached to R a and a nitrogen atom bonded to R 3 form a heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, and nitro Substituting one or more groups of cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, said thick The heterocyclic ring is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;

R 4 is selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Alternatively, when R 4 is aryl or heteroaryl, R a is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R 5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocyclic aryl or OR 6 , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic And an aryl group and a heteroaryl group are optionally further substituted with one or more groups selected from the group Q;

Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;

R 6 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b R c , -NHS(O)R b , -NHS(O) 2 R b Substituting multiple groups;

R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;

Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R 7 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

m is an integer from 1 to 6;

n is an integer from 1 to 4;

Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,

among them,

R a is selected from -NR 1 R 2 ;

R 1 and R 2 are as defined in claim 1.
The compound of the formula (I) according to claim 1 or 2, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or Medicinal salt,

among them,

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,

among them,

R a is selected from -NR 1 R 2 ;

Wherein R 1 or R 2 is bonded to R 3 to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,

among them,

R a is selected from -NR 1 R 2 ;

R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
The compound of the formula (I) according to any one of claims 1 to 5, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a meso form thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

q is an integer from 1 to 4;

W, V, R a , R 3 , R 4 , R 7 , Q, n are as defined in claim 1.
The compound of the formula (I) according to any one of claims 1 to 6, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,

among them,

R 4 is selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, One or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group are substituted.
The compound of the formula (I) according to any one of claims 1 to 7, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is an integer from 1 to 4;

q is an integer from 1 to 4;

W, V, R a , R 3 , R 7 , Q, n are as defined in claim 1.
The compound of the formula (I) according to any one of claims 1 to 8, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a meso form thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,

among them,

Y is selected from CH or N;

R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;

Q' is selected from -NR b R c ;

R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;

Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

p is an integer from 1 to 4;

W, V, R a , R 3 , R 7 , m, n are as defined in claim 1.
The compound of the formula (I) according to any one of claims 1 to 9, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,

among them,

Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR b , -O(CH 2 ) m OR b Substituted by one or more groups;

R b is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;

m is an integer from 1 to 6.
The compound of the formula (I) according to any one of claims 8 to 10, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,

among them,

R a is selected from -NR 1 R 2 ;

R 1 or R 2 is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo Substituting one or more groups of a group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
The compound of the formula (I) according to any one of claims 1 to 11, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,

among them,

R 5 is OR 6 or SR 6 ;

R 6 is as defined in claim 1.
The compound of the formula (I) according to claim 12, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof With salt,

among them,

R 6 is selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR b , -O(CH 2 ) m OR b , -NR b R c ;

R b and R c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;

Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

m is an integer from 1 to 6.
The compound of the formula (I) according to any one of claims 1 to 13, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,

among them,

R 7 is selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;

n is 1 or 2.
The compound of the formula (I) according to any one of claims 1 to 14, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
a method for producing a compound represented by the formula (I) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, It includes the following steps:

When R a is selected when R 2 -NR 1,

Amine transesterification of NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) directly with R 1 R 2 NH To obtain a compound of the formula (I);

Alternatively, NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, followed by R 1 R 2 NH is subjected to amidation reaction to obtain a compound of the formula (I) via two steps;

When R a is selected from -OR 1 when 1 or -SR,

The NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);

Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in claim 1.
A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 15, or a mesogen, a racemate, an enantiomer thereof, a non-pair thereof An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition according to claim 17, which further comprises another therapeutically active ingredient, preferably another therapeutically active ingredient, which is preferably a drug for treating cancer, such as rectal cancer, intestinal cancer, pancreatic cancer, breast Cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, Lung cancer, breast cancer, pancreatic cancer and stomach cancer.
The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 or 18, in the manufacture of an Axl/c-MET inhibitor.
The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 or 18, for the manufacture of a medicament for the treatment of cancer.
The use according to claim 20, wherein the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer , head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or separately from the compound of formula (I) Used sequentially; the cancer rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.