HK1190142B

HK1190142B - Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof

Info

Publication number: HK1190142B
Application number: HK14103101.4A
Authority: HK
Inventors: Frank Wu; Yan Zhang
Original assignee: 山东轩竹医药科技有限公司
Priority date: 2011-06-04
Filing date: 2012-06-04
Publication date: 2018-06-22

Description

Pyridinonaphthyridine PI3K and mTOR dual inhibitor and preparation and application thereof

Technical Field

The invention relates to a pyridonaphthyridine compound with a PI3K and mTOR dual-inhibition effect, pharmaceutically acceptable salts thereof, stereoisomers thereof and deuterons thereof, a preparation method thereof, a pharmaceutical composition and a pharmaceutical preparation containing the compound, and application of the compound in treating and/or preventing proliferative diseases and preparing medicaments for treating and/or preventing the proliferative diseases.

Background

The tumor is a new organism formed by abnormal gene expression and abnormal cell proliferation caused by the change of cell genetic material under the action of various tumorigenic factors. The tumor cells lose the normal growth regulation function, have the autonomous or relatively autonomous growth capacity, can continue to grow even after the tumorigenic factors disappear, and consume a large amount of nutrient substances of the human body. If the cancer cells are discovered and treated untimely, the cancer cells can also be transferred to all parts of the whole body to grow and reproduce, and release a plurality of toxins, so that the human body is emaciated, anaemic, and the functions of organs are damaged or even killed.

The method for treating tumors mainly comprises three aspects: drug therapy, surgical therapy and radiation therapy. Because the operation treatment and the radiation treatment are difficult to completely eradicate the tumor and have no obvious effect on middle and late-stage tumor patients, the position of the drug treatment in the tumor treatment is more and more obvious. The traditional antitumor drugs cannot distinguish tumor cells from normal tissue cells, and often cause serious side effects. The targeted medicine takes cancer cells as specific targets, can accurately act on tumors, greatly improves the treatment level, and reduces the adverse reaction rate, for example, the median survival time of advanced colorectal cancer is increased by 66.7%, and the treatment effective rate of advanced breast cancer is improved by 71.3%.

Due to the accelerated development of targeted antitumor drugs by many pharmaceutical companies and the strong market demand for this class of antitumor drugs, molecular targeted drugs have become the fastest growing unit in the global antitumor drug market. The PI3K pathway is the most frequently mutated site in human cancer cells, and can cause cell proliferation, activation and signal amplification. Phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) are important kinases of the PI3K signaling pathway.

Phosphatidylinositol 3 kinase (PI3K) is a member of the lipid kinase family and regulates cellular metabolism and growth by phosphorylation of phosphatidylalcohols at the 3-position to produce phosphatidylinositol triphosphate (PIP 3). The second messenger for this lipid, PIP3, allows P13K to bind downstream effector (especially Akt) pairs, leading to membrane recruitment and phosphorylation, cell proliferation, activation. Therefore, inhibition of phosphatidylinositol 3 kinase can affect PI3K pathway, thereby inhibiting cancer cell proliferation and activation.

mTOR is a serine/threonine protein kinase present in the cytosol, belongs to the phosphoinositide kinase-related protein kinase family, and exists in vivo as two complexes, mTORC1 (the target of action of rapamycin) and mTORC2 (not inhibited by rapamycin). mTOR is a cellular signal transduction protein that regulates tumor cell response to nutrients and growth factors, and controls blood supply to tumors through action on vascular endothelial growth factor. mTOR inhibitors starve cancer cells and reduce tumor volume by inhibiting the action of mTOR.

At present, PI3K and mTOR dual inhibitors are developed, but most of the compounds have poor drug potency and no drug is available on the market. Journal of Medicinal Chemistry (2011), 54(5), 1473-.

In conclusion, finding a compound which has double inhibitory effects on PI3K and mTOR, good activity, high selectivity and good pharmacokinetic properties has become a hotspot of current research on antitumor drugs.

The inventor discovers a pyridonaphthyridine compound with double inhibition effects on PI3K and mTOR when developing a medicament with excellent anti-tumor effect.

Disclosure of Invention

Accordingly, the present invention provides compounds represented by the following general formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof, and deuterions thereof:

wherein:

x is O;

R¹is hydrogen, or is unsubstituted or substituted by 1 to 3R⁸Substituted C_1-6Alkyl radical, C_2-6An alkenyl group,C_2-6Alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl, 7-12 membered spirocyclic or 7-12 membered bridged cyclic;

R²is hydrogen, or is unsubstituted or substituted by 1 to 3R^8’Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl, 7-12 membered spirocyclic or 7-12 membered bridged cyclic;

R³and R⁴Each independently selected from the group consisting of: hydrogen, halogen, cyano, amino, hydroxy, sulfonyl, -SO₂C_1-6Alkyl, and C unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxyl group and/or carboxyl group_1-6Alkyl and C_1-6An alkoxy group;

R⁵selected from the group consisting of: hydrogen, cyano, amino, sulfonyl, -SO₂C_1-6Alkyl, and C unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxyl group and/or carboxyl group_1-6Alkyl and C_1-6An alkoxy group;

R⁶and R⁷Each independently selected from the group consisting of: hydrogen, hydroxy, halogen, amino, and C unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy and/or carboxy_1-6Alkyl and C_1-6An alkoxy group;

R⁸and R^8’Each independently selected from the group consisting of:

(1) hydroxy, halogen, amino, cyano, - (CH)₂)_nNR^aR^b，-(CH₂)_nC(O)R^c，-(CH₂)_nS(O)_mR^c，-(CH₂)_nS(O)_mNR^aR^b，-(CH₂)_nNR^aS(O)_mR^c，-(CH₂)_nC(O)(CH₂)_nNR^aR^b，-(CH₂)_nOC(O)R^c，-(CH₂)_nNR^aC(O)R^cAnd- (CH)₂)_nNR^aC(O)NR^aR^b，

(2) C unsubstituted or substituted by 1 to 3 substituents selected from cyano, halogen and/or hydroxy_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and C_1-6Alkoxy radical, and

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Alkoxy, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^b、-(CH₂)_nS(O)_mR^c’、-(CH₂)_nS(O)_mNR^aR^b、-(CH₂)_nNR^aS(O)_mR^c’、-(CH₂)_nOC(O)R^c’、-(CH₂)_nNR^aC(O)R^c’And/or- (CH)₂)_nNR^aC(O)NR^aR^b3-14 membered cycloalkyl, 6-14 membered aryl and 3-14 membered heterocyclyl substituted with the substituents of (a);

wherein

R^aAnd R^bEach independently selected from hydrogen, or C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-6An alkyl group;

R^cis C which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, cyano and/or trifluoromethyl_1-6Alkyl or C_1-6An alkoxy group;

R^c’is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-6Alkyl radical, C_1-6Alkoxy radical, 3-an 8 membered monocyclic cycloalkyl or 3-8 membered monocyclic heterocyclyl;

m is 0, 1 or 2; and

n is 0 to 4.

The invention also provides a pharmaceutical composition containing the compound shown in the general formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or deuterons thereof.

The invention also provides a pharmaceutical preparation containing the compound of the general formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or deuterons thereof and a medicinal carrier.

The invention also provides the compound of the general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, and a pharmaceutical composition containing the compound of the general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, which can be used as a medicament for treating proliferative diseases.

The invention also provides application of the compound of the general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof and a pharmaceutical composition containing the compound of the general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof in preparation of drugs for treating proliferative diseases.

The present invention also provides a method for treating proliferative diseases, comprising the step of administering to a subject in need thereof an effective amount of said compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deutero-derivative thereof, or a pharmaceutical composition containing said compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deutero-derivative thereof.

The invention also provides said compounds of general formula (I), namely the formulaA process for the preparation of a compound, said process comprising the steps of:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶And R⁷Hal is as defined above¹、Hal²And Hal³Represents halogen, each independently selected from F, Cl, Br and I, and Hal¹、Hal²And Hal³May be the same or different; alk represents lower alkyl, e.g. "C_1-6Alkyl radical ", preferably" C_1-4Alkyl "more preferably ethyl; "anhydride" is preferably an organic anhydride selected from, for example, but not limited to, acetic anhydride, propionic anhydride, preferably acetic anhydride;

1. preparation of intermediate 1

Heating and refluxing the raw materials 1 and 2 in an alcohol organic solvent in the presence of alkali to react until the raw materials disappear, thus obtaining an intermediate 1;

2. preparation of intermediate 2

Reacting the intermediate 1 with a reducing agent in an alcohol organic solvent, decompressing to remove the solvent, adding water into the reaction mixture, extracting with a halogenated hydrocarbon organic solvent, concentrating an organic phase, adding an oxidizing agent into the organic phase, and stirring for reaction to obtain an intermediate 2';

3. preparation of intermediate 2

Under the protection of nitrogen, the intermediate 2' is reacted with a Grignard reagent R⁶-Mg-Hal³Reacting, and oxidizing to obtain an intermediate 2;

4. preparation of intermediate 3

The method comprises the following steps: in a sealed container, reacting the intermediate 2 and the raw material 3 in an alcohol organic solvent in the presence of inorganic base at 110-180 ℃ to obtain an intermediate 3; or

The method 2 comprises the following steps: dissolving the intermediate 2 in an aprotic polar organic solvent and the raw material 3', and reacting in a microwave reactor until the raw material disappears to obtain an intermediate 3;

and

5. preparation of Compounds of formula (I)

Dissolving the intermediate 3 and the raw material 4 in an organic solvent, and carrying out reflux reaction under the protection of nitrogen in the presence of a catalyst and alkali to obtain a compound shown in a formula (I);

when necessary, a functional group to be protected, for example, a hydroxyl group, an amino group or the like, may be protected, and thereafter the protecting group may be removed by a conventional method.

In the above-mentioned preparation method, the first step,

the "alcoholic organic solvent" is selected from, for example, but not limited to, methanol, ethanol, isopropanol, tert-butanol, etc., preferably ethanol, tert-butanol;

the "organic solvent" is selected from "alcohol organic solvents", "aromatic hydrocarbon organic solvents" or mixtures thereof, including but not limited to, for example, benzene, toluene, xylene, etc., preferably toluene;

the "halogenated hydrocarbon organic solvent" is selected from, for example, but not limited to, chlorobenzene, dichlorobenzene, methyl chloride, dichloromethane, and the like, preferably dichloromethane;

the "base" includes organic bases and inorganic bases, preferably inorganic bases, selected from, for example, but not limited to, potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like, preferably potassium carbonate and sodium carbonate; such organic bases include, but are not limited to, for example, triethylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, sodium ethoxide, pyridine, dimethylaminopyridine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and the like;

the "aprotic polar organic solvent" is selected from, for example, but not limited to, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc., preferably N, N-dimethylacetamide;

the "reducing agent" is preferably a metal hydride selected from, for example, but not limited to, sodium borohydride, lithium aluminum hydride, diborane, and the like, preferably sodium borohydride;

the "oxidizing agent" is preferably a higher valent compound containing a variable valent element selected from, for example, but not limited to, potassium permanganate, potassium chlorate, manganese dioxide, ferric trichloride, and the like, preferably manganese dioxide; and

the "catalyst" is selected from, for example, but not limited to, a nickel catalyst, a palladium catalyst, a platinum catalyst, a metal hydride catalyst, and the like, preferably a palladium catalyst such as palladium on carbon, palladium chloride, tetrakis (triphenylphosphine) palladium, and the like.

In a preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1 to 3R⁸Substituted 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl, 7-12 membered spirocyclyl, or 7-12 membered bridged cyclyl, wherein R⁸Selected from the group consisting of:

(1) hydroxy, halogen, amino, cyano, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c、-(CH₂)_nS(O)_mR^c、-(CH₂)_nS(O)_mNR^aR^b、-(CH₂)_nNR^aS(O)_mR^c、-(CH₂)_nC(O)(CH₂)_nNR^aR^b、-(CH₂)_nOC(O)R^c、-(CH₂)_nNR^aC(O)R^cAnd- (CH)₂)_nNR^aC(O)NR^aR^b，

(2) C unsubstituted or substituted by 1 to 3 substituents selected from cyano, halogen and/or hydroxy_1-6Alkyl and C_1-6Alkoxy radical, and

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, C_1-6Alkoxy, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^b、-(CH₂)_nS(O)_mR^c’、-(CH₂)_nS(O)_mNR^aR^b、-(CH₂)_nNR^aS(O)_mR^c’、-(CH₂)_nOC(O)R^c’、-(CH₂)_nNR^aC(O)R^c’And/or- (CH)₂)_nNR^aC(O)NR^aR^b3-8 membered monocyclic cycloalkyl, 6-14 membered aryl and 3-8 membered monocyclic heterocyclyl substituted with the substituent(s) of (a),

wherein

R^aAnd R^bEach independently selected from hydrogen, or C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-6An alkyl group, a carboxyl group,

R^cis C which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, cyano and/or trifluoromethyl_1-6Alkyl or C_1-6An alkoxy group,

R^c’is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-6Alkyl and C_1-6An alkoxy group,

m is 0, 1 or 2, and

n is 0, 1, 2 or 3.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1 to 3R⁸A substituted 3-8 membered monocyclic cycloalkyl, 6-14 membered aryl or 3-8 membered monocyclic heterocyclyl, wherein R is⁸Selected from the group consisting of:

(1) Hydroxy, halogen, amino, cyano, - (CH)₂)_nC(O)R^cAnd- (CH)₂)_nS(O)_mR^cWherein R is^cIs C which is unsubstituted or substituted by hydroxy, halogen, cyano or trifluoromethyl_1-4Alkyl or C_1-4An alkoxy group,

(2) c unsubstituted or substituted by cyano, hydroxy or 1-3 halogens_1-4Alkyl and C_1-4Alkoxy radical, and

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, C_1-4Alkoxy, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^bAnd/or- (CH)₂)_nS(O)_mR^c’A 5-8 membered heteromonocyclic group substituted with the substituent(s) of (1), wherein R^aAnd R^bEach independently selected from hydrogen, or C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-4Alkyl radical, R^c’Is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-4Alkyl or C_1-4An alkoxy group,

m is 0, 1 or 2, and

n is 0, 1, 2 or 3.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1 to 3R⁸Substituted 6-10 membered aryl or 3-8 membered saturated heteromonocyclic group or 5-6 membered aromatic heteromonocyclic group, wherein R⁸Selected from the group consisting of:

(1) hydroxy, halogen, amino, cyano and-C (O) R^cWherein R is^cIs C which is unsubstituted or substituted by hydroxy, halogen, cyano or trifluoromethyl_1-4Alkyl or C_1-4An alkoxy group,

(2) unsubstituted or substituted by cyano radicalsHydroxy or 1-3 halogen substituted C_1-4Alkyl and C_1-4Alkoxy radical, and

(3) unsubstituted or substituted by 1-3 substituents selected from cyano, trifluoromethyl, halogen, C (O) R^c’and/or-S (O)₂R^c’A 5-6 membered heteromonocyclic group substituted with the substituent(s) of (1), wherein R^c’Is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-4Alkyl or C_1-4An alkoxy group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1 to 3R⁸Substituted 6-10 membered aryl or 5-6 membered heteromonocyclic group, wherein R⁸Is (1) amino or-C (O) R^c，R^cIs unsubstituted or hydroxy-or halogen-substituted C_1-4Alkyl, (2) C unsubstituted or substituted by cyano or 1-3 halogens_1-4Alkyl or C_1-4Alkoxy, or (3) a 5-6 membered heteromonocyclic group which is unsubstituted or substituted with cyano or trifluoromethyl.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1 to 3R⁸Substituted phenyl, naphthyl or 5-6 membered saturated mono heterocyclic group, wherein R⁸Is composed of

(1) Amino or-C (O) R^c，R^cIs unsubstituted or hydroxy-or halogen-substituted C_1-4An alkyl group, a carboxyl group,

(2) c unsubstituted or substituted by cyano or 1-3 fluorine_1-4Alkyl or C_1-4Alkoxy radical, or

(3) Piperazinyl or piperidinyl which is unsubstituted or substituted by cyano or trifluoromethyl.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R¹Is unsubstituted or substituted by 1-2R⁸Substituted phenyl, piperidinyl or piperazinyl, R⁸Comprises the following steps:

(1) amino or-C(O)R^c，R^cIs unsubstituted or hydroxy-substituted C_1-2An alkyl group, a carboxyl group,

(2) c unsubstituted or substituted by cyano or by three fluorine radicals_1-2Alkyl, or

In a preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1 to 3R^8’A substituted 3-14 membered cycloalkyl, 6-14 membered aryl or 3-14 membered heterocyclyl, wherein R^8’Selected from the group consisting of:

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^b、-(CH₂)_nS(O)_mR^c’、-(CH₂)_nS(O)_mNR^aR^b、-(CH₂)_nNR^aS(O)_mR^c’、-(CH₂)_nOC(O)R^c’、-(CH₂)_nNR^aC(O)R^c’And/or- (CH)₂)_nNR^aC(O)NR^aR^bIs/are as follows

3-8 membered monocyclic cycloalkyl, 6-14 membered aryl and 3-8 membered monocyclic heterocyclyl substituted with substituents; wherein

R^c’is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-6Alkyl or C_1-6An alkoxy group;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1 to 3R^8’Substituted 6-14 membered aryl or 5-10 membered heterocyclyl, wherein R^8’Selected from the group consisting of:

(1) hydroxy, halogen, cyano, amino, - (CH)₂)_nC(O)R^c，-(CH₂)_nNR^aR^b，-(CH₂)_nS(O)_mR^c，-(CH₂)_nS(O)_mNR^aR^b，-(CH₂)_nNR^aS(O)_mR^c，-(CH₂)_nC(O)(CH₂)_nNR^aR^b，-(CH₂)_nOC(O)R^c，-(CH₂)_nNR^aC(O)R^cAnd- (CH)₂)_nNR^aC(O)NR^aR^b，

(2) C unsubstituted or substituted by 1 to 3 substituents selected from cyano, halogen and/or hydroxy_1-4Alkyl and C_1-4Alkoxy radical, and

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_nNR^aR^b、-(CH₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^b、-(CH₂)_nS(O)_mR^c’、-(CH₂)_nS(O)_mNR^aR^b、-(CH₂)_nNR^aS(O)_mR^c’、-(CH₂)_nOC(O)R^c’、-(CH₂)_nNR^aC(O)R^c’And/or- (CH)₂)_nNR^aC(O)NR^aR^bA 5-8 membered heteromonocyclic group substituted with the substituent(s);

R^aand R^bEach independently hydrogen, or C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy and/or halogen_1-4An alkyl group;

R^cis C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-4Alkyl or C_1-4An alkoxy group;

R^c’is C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy and/or halogen_1-4Alkyl or C_1-4An alkoxy group;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

In a further aspect of the invention, compounds of the general formula (I)In a preferred embodiment of step (ii), R²Is unsubstituted or substituted by 1 to 3R^8’A substituted 6-10 membered aryl, a 5-6 membered partially saturated heteromonocyclic group, a 5-6 membered aromatic heteromonocyclic group or a 9-10 membered fused heterocyclic group, wherein R^8’Comprises the following steps:

(1) hydroxy, halogen, cyano, amino, - (CH)₂)_nNR^aC(O)R^cOr- (CH)₂)_nS(O)_mR^cWherein R is^aIs hydrogen or C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy and/or halogen_1-4Alkyl radical, R^cIs C which is unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, halogen and/or cyano_1-4Alkyl or C_1-4Alkoxy, m is 0, 1 or 2; and n is 0, 1, 2 or 3;

(2) c unsubstituted or substituted by 1 to 3 substituents selected from cyano, halogen and/or hydroxy_1-4Alkyl or C_1-4An alkoxy group; or

(3) Unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted 5-6 membered heteromonocyclic group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1 to 3R^8’Substituted 6-10 membered aryl or 5-10 membered heterocyclyl, wherein R^8’Is (1) hydroxy, halogen, amino, cyano, -NHC (O) R^cor-S (O)_mR^cWherein m is 0, 1 or 2, R^cIs C_1-4Alkyl, (2) C unsubstituted or substituted by hydroxy or 1-3 halogens_1-4Alkyl or C_1-4Alkoxy, or (3) unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted 5-6 membered heteromonocyclic group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1 to 3R^8’Substituted 6-10 membered aryl, 5-6 membered partially saturated heteromonocyclic group, 5-6 membered aromatic monocyclic groupHeterocyclic group or 9-to 10-membered fused heterocyclic group, wherein R^8’Is (1) hydroxy, halogen, amino, cyano, -NHC (O) R^cor-S (O)_mR^cWherein m is 0, 1 or 2, R^cIs C_1-4Alkyl, (2) C unsubstituted or substituted by hydroxy or 1-3 halogens_1-4Alkyl or C_1-4Alkoxy, or (3) unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted 5-6 membered heteromonocyclic group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1 to 3R^8’Substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and mixtures thereof,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, indazolyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridine, dihydropyrrolopyridine or pyrazolopyridyl, wherein R^8’Comprises the following steps:

(1) hydroxy, halogen, amino, cyano, -NHC (O) R^cor-S (O)_mR^cWherein m is 0 or 2, R^cIs C_1-4An alkyl group, a carboxyl group,

(2) c unsubstituted or substituted by hydroxy or 1-3 fluorine_1-4Alkyl or C_1-4Alkoxy radical, or

(3) Unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted pyridyl, piperidyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrrolidinyl, or morpholinyl.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R²Is unsubstituted or substituted by 1-2R^8’Substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and mixtures thereof,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyrrolopyridine, dihydropyrrolopyridine or indolyl, wherein R^8’Comprises the following steps:

(1) halogen, amino, cyano, -NHC (O) R^cor-S (O)_mR^cWherein m is 0 or 2, R^cIs C_1-4An alkyl group, a carboxyl group,

(2) c unsubstituted or substituted by hydroxy or by three fluorine radicals_1-4Alkyl or C_1-4Alkoxy radical, or

(3) Unsubstituted or substituted by C_1-4Alkyl-substituted piperazinyl, pyrazolyl, piperidinyl, morpholinyl, and piperazinyl,

Pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl or pyrrolidinyl.

In a preferred embodiment of the compounds of the general formula (I) according to the invention, R³And R⁴Each independently selected from the group consisting of: hydrogen, halogen, cyano, amino, hydroxy, and C unsubstituted or substituted by hydroxy or 1 to 3 halogen atoms_1-6Alkyl and C_1-6An alkoxy group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R³And R⁴Each independently selected from the group consisting of: hydrogen, halogen, cyano, amino, hydroxy, trifluoromethyl and trifluoromethoxy.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R³And R⁴Each is hydrogen.

In a preferred embodiment of the compounds of the general formula (I) according to the inventionIn the scheme, R⁵Is hydrogen, cyano, amino, or C unsubstituted or substituted by hydroxy, carboxy or 1 to 3 halogen atoms_1-6Alkyl or C_1-6An alkoxy group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R⁵Is hydrogen.

In a preferred embodiment of the compounds of the general formula (I) according to the invention, R⁶And R⁷Each independently selected from the group consisting of: hydrogen, hydroxy, halogen, amino, and C unsubstituted or substituted by hydroxy or 1 to 3 halogen atoms_1-6Alkyl and C_1-6An alkoxy group.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention, R⁶And R⁷Each independently is hydrogen or C_1-4An alkyl group.

In another preferred embodiment of the compounds of general formula (I) according to the invention,

R¹is unsubstituted or substituted by 1 to 3R⁸Substituted 3-14 membered cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl, 7-12 membered spirocyclic or 7-12 membered bridged cyclic;

R²is unsubstituted or substituted by 1 to 3R^8’A substituted 3-14 membered cycloalkyl, 6-14 membered aryl or 3-14 membered heterocyclyl;

R³and R⁴Each independently selected from the group consisting of: hydrogen, halogen, cyano, amino, hydroxy, trifluoromethyl and trifluoromethoxy;

R⁵is hydrogen, cyano or amino;

R⁶and R⁷Each independently selected from the group consisting of: hydrogen, hydroxy, halogen, amino, and C_1-6An alkyl group;

R⁸and R^8’Each independently selected from the group consisting of:

(1) hydroxy, halogen, amino, cyano, - (CH)₂)_nC(O)R^c，-(CH₂)_nNR^aR^b，-(CH₂)_nS(O)_mR^c，-(CH₂)_nS(O)_mNR^aR^b，-(CH₂)_nNR^aS(O)_mR^c，-(CH₂)_nC(O)(CH₂)_nNR^aR^b，-(CH₂)_nOC(O)R^c，-(CH₂)_nNR^aC(O)R^cAnd- (CH)₂)_nNR^aC(O)NR^aR^b，

R^cis C which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of hydroxy, halogen, cyano and/or trifluoromethyl_1-6Alkyl and C_1-6An alkoxy group;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

R¹is unsubstituted or substituted by 1 to 3R⁸A substituted 3-8 membered monocyclic cycloalkyl, 6-14 membered aryl or 3-8 membered monocyclic heterocyclyl;

R²is unsubstituted or substituted by 1 to 3R^8’A substituted 3-8 membered monocyclic cycloalkyl, 6-14 membered aryl or 5-10 membered heterocyclyl;

R³、R⁴and R⁵Are each hydrogen;

R⁶and R⁷Each independently is hydrogen or C_1-4An alkyl group;

R⁸selected from the group consisting of:

(1) hydroxy, halogen, cyano, amino, and- (CH)₂)_nC(O)R^c，

(3) unsubstituted or substituted by 1 to 3 substituents selected from cyano, trifluoromethyl, halogen, - (CH)₂)_nC(O)R^c’、-(CH₂)_nC(O)(CH₂)_nNR^aR^bAnd/or- (CH)₂)_nS(O)_mR^c’Is gotA substituted 5-8 membered saturated heteromonocyclic group;

R^8’selected from the group consisting of:

R^aand R^bEach independently hydrogen, or unsubstituted or substituted with 1 to 3 substituents selected from hydroxy and/or halogenC_1-4An alkyl group;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

In a further preferred embodiment of the compounds of the general formula (I) according to the invention:

R¹is unsubstituted or substituted by 1 to 3R⁸A substituted 6-10 membered aryl, 3-8 membered saturated heteromonocyclic group or 5-6 membered aromatic heteromonocyclic group;

R²is unsubstituted or substituted by 1 to 3R^8’Substituted 6-10 membered aryl, 5-6 membered partially saturated heteromonocyclic group, 5-6 membered aromatic heteromonocyclic group or 9-10 membered fused heterocyclic group;

R³、R⁴and R⁵Are each hydrogen;

R⁶and R⁷Each independently is hydrogen or C_1-4An alkyl group;

R⁸is composed of

(1) Hydroxy, halogen, cyano, amino or-C (O) R^c，

(2) C unsubstituted or substituted by 1 to 3 substituents selected from cyano, halogen and/or hydroxy_1-4Alkyl or C_1-4Alkoxy radical, or

(3) Unsubstituted or substituted by 1-3 substituents selected from cyano, trifluoromethyl, halogen, -C (O) R^c’、-C(O)(CH₂)_nNR^aR^band/or-S (O)₂R^c’5-6 membered saturated heteromonocyclic group substituted with the substituent(s)；

R^8’Is composed of

(1) Hydroxy, halogen, cyano, amino, - (CH)₂)_nNR^aC(O)R^cOr- (CH)₂)_nS(O)_mR^c，

(3) Unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted 5-6 membered heteromonocyclic group;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

R¹is unsubstituted or substituted by 1 to 3R⁸Substituted phenyl, naphthyl or 5-8 membered saturated mono heterocyclyl;

R²is unsubstituted or substituted by 1 to 3R^8’Substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and mixtures thereof,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, indazolyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridine, dihydropyrrolopyridine, or pyrazolopyridyl;

R³、R⁴and R⁵Each is hydrogen;

R⁶and R⁷Each independently hydrogen or methyl;

R⁸is composed of

(3) Piperazinyl or piperidinyl which is unsubstituted or substituted by cyano or trifluoromethyl;

R^8’is composed of

In a further preferred embodiment of the compounds of the general formula (I) according to the invention,

R¹is unsubstituted or substituted by 1-2R⁸Substituted phenyl, piperidinyl or piperazinyl;

R²is unsubstituted or substituted by 1-2R^8’Substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and mixtures thereof,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyrrolopyridine, dihydropyrrolopyridine, or indolyl;

R³、R⁴and R⁵Each is hydrogen;

R⁶and R⁷Each independently hydrogen or methyl;

R⁸is composed of

(1) Amino or-C (O) R^c，R^cIs unsubstituted or hydroxy-substituted C_1-4An alkyl group, a carboxyl group,

(2) c unsubstituted or substituted by cyano or by three fluorine radicals_1-4Alkyl, or

R^8’is composed of

(3) Unsubstituted or substituted by C_1-4Alkyl-substituted piperazinyl, pyrazolyl, piperidinyl, morpholinyl, pyrimidinyl, pyridazinylAn oxazinyl group, a pyrazinyl group, a pyrrolyl group or a pyrrolidinyl group.

Preferred compounds of the invention include the following compounds and pharmaceutically acceptable salts thereof as well as their stereoisomers and their deuterions:

in the present invention, the term "halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present invention, the term "C_1-6Alkyl "refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example," C_1-4Alkyl group "," C_2-5Alkyl group "," C_1-3Alkyl groups "and the like; examples include, but are not limited toFor example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.

In the present invention, the term "C_2-6The alkenyl group means a linear, branched or cyclic hydrocarbon group having 2 to 6 carbon atoms and containing a double bond, and includes, for example, "C_2-4Alkenyl group "," C_2-5Alkenyl group "," C_2-3Alkenyl group ", C_3-6Cycloalkenyl groups and the like; examples thereof include, but are not limited to, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, and the like, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-2-pentenyl, 3-methyl-1-pentenyl, 3-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-2-pentenyl, 3, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, methyl-2-pentenyl, methyl-3-pentenyl, methyl-2-butenyl, 1, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1,3-two methyl 2-butene radical, 1, 3-two methyl 2-butene radical, 2-two methyl 3-butene radical, 2, 3-two methyl 1-butene radical, 2, 3-two methyl 2-butene radical, 2, 3-two methyl 3-butene radical, 3-two methyl 1-butene radical, 3-two methyl 2-butene radical, 1-ethyl-1-butene radical, 1-ethyl-2-butene radical, 1-ethyl-3-butene radical, 2-ethyl-1-butene radical, 2-ethyl-2-butene radical, 2-ethyl-3-butene radical, 2-ethyl-1-butene radical, 1, 1, 2-trimethyl-2-propenyl group, 1-ethyl-1-methyl-2-propenyl group, 1-ethyl-2-methyl-1-propenyl group, 1-ethyl-2-methyl-2-propenyl group, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like. Said "C_3-6Cycloalkenyl "examples thereof include, but are not limited to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, and the like.

In the present invention, the term "C_2-6Alkynyl refers to a straight or branched chain hydrocarbon group of 2-6 carbon atoms containing a triple bond, including, for example, "C_2-4Alkynyl group "," C_2-5Alkynyl group "," C_2-3Alkynyl, etc.; examples thereof include, but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.

In the present invention, the term "C_1-6Alkoxy "means" C_1-6alkyl-O- "group, wherein C_1-6Alkyl is as defined above and includes, for example, "C_1-4Alkoxy group "," C_2-5Alkoxy radical“C_1-3Alkoxy "and the like; examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like.

In the present invention, the term "3-14 membered cycloalkyl" means a cycloalkyl group having 3-14 carbon atoms, which includes, for example, "3-12 membered cycloalkyl", "5-10 membered cycloalkyl", "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "5-8 membered cycloalkyl", and the like; also included are "3-8 membered monocyclic cycloalkyl" and "6-14 membered fused ring cycloalkyl".

The "3-8 membered monocyclic cycloalkyl" means a monocyclic cycloalkyl group having 3-8 carbon atoms, and includes, for example, "3-6 membered monocyclic cycloalkyl", "5-8 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl" and the like; examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.; the 3-8 membered monocyclic cycloalkyl may be further substituted by C_1-6Alkyl substitutions include, but are not limited to, methylcyclopropyl, dimethylcyclopropane, methylcyclobutyl, dimethylcyclobutane, methylcyclopentyl, dimethylcyclopentanyl, methylcyclohexyl, dimethylcyclohexanyl, and the like.

The "6-to 14-membered fused ring cycloalkyl" refers to a fused ring alkyl group in which the fused ring is formed by two or more ring structures sharing two adjacent carbon atoms with each other, and includes, for example, "6-to 12-membered fused ring cycloalkyl", "8-to 12-membered fused ring cycloalkyl", "7-to 10-membered fused ring cycloalkyl", and the like; examples include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl and the like.

In the present invention, the term "6-14 membered aryl" means an aromatic group having 6 to 14 carbon atoms, and includes, for example, "6-10 membered aryl" and the like; also included are "6-8 membered monocyclic aryl" and "8-14 membered fused ring aryl".

The "6-to 8-membered monocyclic aryl" includes, for example, phenyl, cyclooctatetraenyl and the like.

The "8-to 14-membered fused ring aryl" means a fused ring group having 8 to 14 carbon atoms and at least one ring being an aromatic ring, which is formed by two or more ring structures sharing two adjacent carbon atoms with each other, and includes a fused ring aryl having 10 to 14-membered rings all of which are aromatic rings, such as naphthyl, phenanthryl and the like, and also includes a fused ring aryl having 8 to 14-membered rings some of which are aromatic rings, such as benzo 3-to 8-membered monocyclic cycloalkyl, benzo C_3-6Cycloalkenyl group and the like, and specific examples thereof include, but are not limited to, for example, 2, 3-dihydro-1H-indenyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like.

In the present invention, the term "7-to 12-membered bridged cyclic group" means an alicyclic hydrocarbon group containing 7 to 12 ring atoms, which are formed by any two rings sharing two atoms not directly connected, and which may be all carbon atoms or contain a hetero atom selected from nitrogen, oxygen, sulfur and the like. The "7-to 12-membered bridged ring group" includes "7-to 12-membered saturated bridged ring group" and "7-to 12-membered unsaturated bridged ring group".

The "7-to 12-membered saturated bridged ring group" means that all rings in the bridged ring group are saturated cyclic groups, and includes, for example, "7-to 10-membered saturated bridged ring group", "7-to 8-membered saturated bridged ring group", etc.; specific examples thereof include, but are not limited to, groups such as the following bridged rings:etc.; 7-to 8-membered saturated bridged ring groups are preferred.

Said "7-12 Yuan BuSaturated bridge ring group "means a cyclic group in which at least one ring of the bridge ring group is unsaturated, and includes, for example," 7-to 10-membered unsaturated bridge ring group "," 7-to 8-membered unsaturated bridge ring group ", and the like; specific examples thereof include, but are not limited to, groups such as the following bridged rings:etc.; preferably 7-to 8-membered unsaturated bridged ring groups.

In the present invention, the term "7-12-membered spirocyclic group" means a type of alicyclic hydrocarbon group containing 7 to 12 ring atoms formed by at least two rings sharing one atom, the ring atoms may be all carbon atoms or contain a hetero atom selected from nitrogen, oxygen, sulfur and the like, and includes, for example, "7-11-membered spirocyclic group", "8-11-membered spirocyclic group", "9-10-membered spirocyclic group" and the like, and also "7-12-membered saturated spirocyclic group" and "7-12-membered unsaturated spirocyclic group".

The "7-12 membered saturated spiro ring group" means that all rings in the spiro ring group are saturated rings; these include, for example, "7-to 11-membered saturated spiro ring group", "8-to 11-membered saturated spiro ring group", "9-to 10-membered saturated spiro ring group", etc.; specific examples thereof include, but are not limited to, groups such as the following spiro rings:

and the like.

The "7-to 12-membered unsaturated spiro ring group" means a ring in which at least one ring is unsaturated, and includes, for example, "7-to 11-membered unsaturated spiro ring group", "8-to 11-membered unsaturated spiro ring group", "9-to 10-membered unsaturated spiro ring group", and the like; specific examples thereof include, but are not limited to, groups such as the following spiro rings:and the like.

In the present invention, the term "3-14-membered heterocyclic group" means a cyclic group containing 3 to 14 ring atoms (wherein at least one hetero atom is contained), and includes, for example, "3-8-membered heterocyclic group", "4-12-membered heterocyclic group", "5-10-membered heterocyclic group", "5-8-membered heterocyclic group", "5-6-membered heterocyclic group", etc., and also "3-8-membered monocyclic heterocyclic group" and "6-14-membered fused heterocyclic group", said hetero atom being selected from nitrogen, oxygen and sulfur, etc.

The "3-to 8-membered heteromonocyclic group" means a monocyclic heterocyclic group having 3 to 8 ring atoms (wherein at least one hetero atom is contained), and includes, for example, "5-to 8-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", etc., and also includes "5-to 8-membered aromatic heteromonocyclic group", "3-to 8-membered partially saturated heteromonocyclic group" and "3-to 8-membered saturated heteromonocyclic group".

The "5-to 8-membered aromatic heteromonocyclic group" means an aromatic heteroatom-containing cyclic group, and includes, for example, "5-to 6-membered aromatic heteromonocyclic group", "5-to 7-membered aromatic heteromonocyclic group", etc.; specific examples thereof include, but are not limited to, for example, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl,Azolyl group,Oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-An oxazinyl group, 4H-1,2-oxazinyl, 6H-1, 2-Oxazinyl, 4H-1, 3-Oxazinyl, 6H-1, 3-Oxazinyl, 4H-1, 4-Azinyl, pyridazinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 4, 5-tetrazinyl, oxepitrienyl, thiepintrienyl, azepintrienyl, 1, 3-diazepitrienyl, and azepinatetraenyl, and the like.

The "3-to 8-membered partially saturated heteromonocyclic group" means a heteromonocyclic group having a double bond, and includes, for example, "5-to 8-membered partially saturated heteromonocyclic group", "5-to 6-membered partially saturated heteromonocyclic group", etc.; specific examples thereof include, but are not limited to, for example, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-Oxazine groups, and the like.

The "3-to 8-membered saturated heteromonocyclic group" means a heteromonocyclic group having all saturated bonds, and includes, for example, "5-to 8-membered saturated heteromonocyclic group", "5-to 6-membered saturated heteromonocyclic group", "3-to 6-membered saturated heteromonocyclic group", etc.; specific examples thereof include, but are not limited to, for example, aziridinyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, 1, 4-dioxanyl, 1, 3-dithiacyclohexane, morpholinyl, piperazinyl, and the like.

The "6-to 14-membered fused heterocyclic group" means a fused heterocyclic group having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by linking two or more ring structures sharing two adjacent atoms with each other, and includes, for example, "8-to 12-membered fused heterocyclic group", "7-to 10-membered fused heterocyclic group", "9-to 12-membered fused heterocyclic group" and the like, and also "8-to 14-membered aromatic fused heterocyclic group", "6-to 14-membered partially saturated fused heterocyclic group" and "6-to 14-membered saturated fused heterocyclic group".

The "8-to 14-membered aromatic fused heterocyclic group" means a fused heterocyclic group in which all rings are aromatic rings, and includes, for example, "8-to 12-membered aromatic fused heterocyclic group", "9-to 10-membered aromatic fused heterocyclic group", "10-to 14-membered aromatic fused heterocyclic group" and the like, such as fused heterocyclic group formed by benzo 5-to 8-membered aromatic heteromonocyclic group, fused heterocyclic group formed by 5-to 8-membered aromatic heteromonocyclic group and the like; specific examples thereof include, but are not limited to, for example: benzofuranyl, benzisofuranyl, benzothienyl, indolyl, benzoOxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, pyridopyrazolyl, pyridopyrrolyl, pyrimidopyrazolyl, pyrimidopyrrolyl, pyridazinopyrazolyl, pyridazinopyrrolyl, acridinyl, phenanthridinyl, benzopyrazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl and the like.

The "6-to 14-membered partially saturated fused heterocyclic group" means a fused heterocyclic group containing at least one partially saturated ring or aromatic ring, such as a group formed by a benzo 3-8-membered partially saturated monoheterocyclic group, a 6-14-membered fused heterocyclic group formed by a 3-8-membered partially saturated monoheterocyclic group and a 3-8-membered partially saturated monoheterocyclic group, etc., a 6-14-membered fused heterocyclic group formed by a 3-8-membered partially saturated monoheterocyclic group and a 3-8-membered monocyclic cycloalkyl group, a fused heterocyclic group formed by a 5-6-membered aromatic monoheterocyclic group and a 3-8-membered partially saturated monoheterocyclic group, etc.; specific examples thereof include, but are not limited to, for example: 1, 3-dihydrobenzofuranyl, benzo [ d ] [1.3] dioxolyl, isoindolinyl, chromanyl, 1, 2, 3, 4-tetrahydropyrrolo [3, 4-c ] pyrrolyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, dihydropyrrolopyridazinyl, tetrahydropyrrolopyridinyl, tetrahydropyrrolopyrimidinyl, tetrahydropyrrolopyridazinyl and the like.

The "6-14 membered saturated fused heterocyclic group" means a fused heterocyclic group in which all rings are saturated, such as a 6-14 membered fused heterocyclic group formed by a 3-8 membered saturated heteromonocyclic group and a 3-8 membered saturated heteromonocyclic group, a 6-14 membered fused heterocyclic group formed by a 3-8 membered saturated monocyclic cycloalkyl group and a 3-8 membered saturated heteromonocyclic group, and the like; specific examples thereof include, but are not limited to, for example: cyclobutane four pyrrolidine base, cyclopentane four pyrrolidine base, azetidine imidazole alkyl.

In one embodiment of the process for the preparation of the compounds of formula (I) according to the invention, R⁶Compounds of formula (I) ═ H can be prepared using specific methods such as those described in the following schemes:

wherein R is¹、R²、R³、R⁴、R⁵And R⁷Hal is as defined above¹And Hal²Represents halogen, each independently selected from F, Cl, Br and I, and Hal¹And Hal²May be the same or different; alk represents lower alkyl, e.g. "C_1-6Alkyl radical ", preferably" C_1-4Alkyl "more preferably ethyl; "anhydride" is preferably an organic anhydride selected from, for example, but not limited to, acetic anhydride, propionic anhydride, and the like, preferably acetic anhydride;

1. preparation of intermediate 1

Dissolving the raw materials 1 and 2 in an alcoholic organic solvent (including but not limited to, for example, methanol, ethanol, isopropanol or tert-butanol, etc., preferably ethanol and tert-butanol), adding a base (including an organic base and an inorganic base, preferably an inorganic base, including but not limited to, for example, potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate, etc., preferably potassium carbonate and sodium carbonate) to the system, and heating, refluxing and stirring to react until the raw materials disappear to obtain an intermediate 1;

2. preparation of intermediate 2

The intermediate 1 is added to an alcoholic organic solvent (including but not limited to, for example, methanol, ethanol, isopropanol, tert-butanol, etc.), and a reducing agent (preferably a metal hydride, including but not limited to, for example, sodium borohydride, lithium aluminum hydride, diborane, etc.) is added to perform a reduction reaction. Removing the solvent under reduced pressure, adding water, extracting with halogenated hydrocarbon organic solvent (including but not limited to chlorobenzene, dichlorobenzene, chloromethane or dichloromethane, etc.), drying the organic phase with neutral drying agent (selected from but not limited to anhydrous calcium sulfate, anhydrous sodium sulfate or anhydrous magnesium sulfate, etc., preferably anhydrous sodium sulfate), concentrating, adding oxidant (selected from but not limited to potassium permanganate, potassium chlorate, manganese dioxide or ferric trichloride, etc.) in batches into the obtained concentrated solution, and stirring for reaction to obtain intermediate 2';

3. preparation of intermediate 3

The method comprises the following steps: adding an inorganic base (selected from, for example, but not limited to, potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate and the like) into a solution of the intermediate 2' and the raw material 3 dissolved in an alcoholic organic solvent (selected from, for example, but not limited to, methanol, ethanol, isopropanol, tert-butanol and the like) in a sealed container, and reacting at 130-160 ℃ to obtain an intermediate 3; or

The method 2 comprises the following steps: dissolving the intermediate 2 'in an aprotic polar organic solvent (selected from, but not limited to, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like) and the raw material 3', and reacting in a microwave reactor until the raw material disappears to obtain an intermediate 3;

and

4. preparation of formula (I')

Dissolving the intermediate 3' and the raw material 4 in an organic solvent [ selected from an "alcohol organic solvent (including but not limited to, for example, methanol, ethanol, isopropanol, tert-butanol, etc.)," an "aromatic hydrocarbon organic solvent (including but not limited to, for example, benzene, toluene, xylene, etc.)" or a mixture thereof ], adding a catalyst (selected from, for example, but not limited to, a nickel catalyst, a palladium catalyst, a platinum catalyst, a metal hydride catalyst, etc.) and a solution of a base (for example, potassium hydroxide, sodium hydroxide, zinc hydroxide, calcium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.) to the system, and refluxing under the protection of nitrogen to obtain a compound of formula (I);

"pharmaceutically acceptable salts" of the compounds of formula (I) according to the invention refer to the acidic functions (e.g., -COOH, -OH, SO) present in the compounds of formula (I)₃H, etc.) with suitable inorganic or organic cations (bases), including salts with alkali metals such as sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc., ammonium salts, and salts with nitrogen-containing organic bases, including, but not limited to, for example, trimethylamine, triethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- β -phenethylamine, 1-diphenylhydroxymethylamine, N' -dibenzylethylenediamine, etc., and salts of basic functions present in the compounds of formula (I) (e.g., -NH2, etc.) with suitable inorganic or organic anions (acids), including salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, etc., with organic carboxylic acidsSalts formed, such as tartrates, formates, acetates, lactates, citrates, trichloroacetates, trifluoroacetates, and the like, with sulfonic acids, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, naphthalenesulfonates, and the like.

"stereoisomers" of the compounds of formula (I) of the present invention refers to all stereoisomers produced when asymmetric carbon atoms, carbon-carbon double bonds, etc. exist in the compounds of formula (I), including enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof, which are included in the scope of the present invention.

The invention comprises the "deuterons" of the compounds of formula (I), and the deuterons formed when a hydrogen atom in the compound is partially or fully replaced by deuterium (symbol D) which is an isotope thereof also fall within the scope of the invention.

The compounds of general formula (I) and pharmaceutically acceptable salts thereof, and stereoisomers and deuterated forms thereof, of the present invention can be administered to a mammal, such as a human, by oral, parenteral (intravenous, intramuscular, subcutaneous, rectal, etc.), pulmonary, topical, etc. administration. The daily dose of the compound of the present invention may be about 20mg to 500mg, preferably 50mg to 300 mg.

The compound of formula (I), pharmaceutically acceptable salt thereof, stereoisomer thereof or deutero-substitute thereof can be mixed with one or more medicinal carriers to prepare pharmaceutically acceptable medicinal preparations, and the pharmaceutically acceptable medicinal preparations are administered to patients needing the treatment by oral administration, parenteral administration and the like.

For oral administration, the compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deutero-derivative thereof of the present invention may be mixed with a conventional filler, binder, disintegrant, lubricant and/or diluent, etc. to prepare a conventional solid preparation such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation, such as oral solution, oral suspension, syrup, etc.; for parenteral administration, it can be formulated into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives, or adding appropriate additives such as osmotic pressure regulator, pH regulator, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending agent, etc. according to the properties of the medicine.

The compounds of formula (I), their pharmaceutically acceptable salts, their stereoisomers or their deuterons of the invention can be used for the treatment and/or prevention of proliferative diseases and can be used in combination or in combination with one or more other therapeutic agents, in particular antineoplastic agents and immunosuppressants. The antineoplastic and immunosuppressive agents are selected from the group consisting of antimetabolites including, but not limited to, capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitors including, but not limited to, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; antibodies, including but not limited to herceptin, bevacizumab; mitotic inhibitors including, but not limited to, paclitaxel, vinorelbine, docetaxel, doxorubicin; antineoplastic hormones including, but not limited to, letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; alkylating agents including, but not limited to, cyclophosphamide, mechlorethamine, melphalan, cinchonine, carmustine; platinoids including but not limited to carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors including, but not limited to, topotecan, camptothecin, topotecan, irinotecan; immunosuppressive species including but not limited to everolimus, sirolimus, and temazepride; purine analogs, including but not limited to 6-mercaptopurine, 6-thioguanine, azathioprine; antibiotics, including but not limited to, rhzomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; platinum complexes including, but not limited to, cisplatin, carboplatin; adrenocortical suppressants, including but not limited to aminoglutethimide and the like. The components to be administered in combination or combination may be administered simultaneously or separately in sequential order, in the same formulation or in separate and distinct formulations.

The invention also relates to application of the compound shown in the formula (I), pharmaceutically acceptable salts thereof, stereoisomers thereof or deuterons thereof in preparing medicines for treating and/or preventing proliferative diseases.

The proliferative disease includes cancer selected from brain tumor, lung cancer, non-small cell lung cancer, squamous cell, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, non-hodgkin's lymphoma, glioma, glioblastoma multiforme, gliosarcoma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma, astrocytoma, Neuroblastoma, sarcoma, etc.; the non-cancerous proliferative disease is selected from, for example, benign hyperplasia of the skin or prostate, and the like.

Experiments prove that the compound is a PI3K and mTOR dual inhibitor, has excellent antitumor effect and excellent treatment effect on proliferative diseases; and has good pharmacokinetic properties.

Detailed Description

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.

I. Preparation examples of Compounds of the present invention

(I) Preparation of 4, 6-dichloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (raw material)

Referring to the method of WO2010/038165 a1, the preparation process is as follows:

preparation of 1.6-bromopyridin-3-amine

Iron powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL) were added to a solution of 2-bromo-5-nitropyridine (64g, 0.317mol) in ethanol (1L) in this order, the mixture was reacted under reflux for 5h, the reaction mixture was cooled, filtered, the filtrate was concentrated and adjusted to pH 7-8 with sodium bicarbonate solution, filtered again, the filtrate was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 40.5g of the title compound as a pale yellow solid in 74.4% yield.

Preparation of 2.2- ((6-bromopyridin-3-ylamino) methylene) malonic acid diethyl ester

6-bromopyridin-3-amine (74g, 0.43mol) and diethyl ethoxymethylenemalonate (100mL) were added to 680mL ethanol, heated under reflux for 5h, the reaction mixture was cooled to precipitate a solid, which was filtered with suction and washed with petroleum ether to give 125.4g of the title compound as a pale yellow solid in 85.2% yield.

Preparation of 3, 6-bromo-4-hydroxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester

To boiling diphenyl ether (214mL) was added diethyl (2- ((6-bromopyridin-3-ylamino) methylene) malonate (40g, 0.117mol) portionwise over 5 minutes, heated under reflux for 45 minutes, TLC (ethyl acetate: petroleum ether ═ 1: 3) showed disappearance of the starting material, the reaction mixture was cooled, poured into petroleum ether, a solid precipitated, and suction filtered to give 24.6g of the title compound as an earthy yellow solid in 71.2% yield.

Preparation of 4, 6-dichloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester

Ethyl 6-bromo-4-hydroxy-1, 5-naphthyridine-3-carboxylate (49.8g, 0.168mmol) and N, N-dimethylaniline (8mL) were added to phosphorus oxychloride (400mL), heated under reflux for 3h, the reaction mixture was cooled, the phosphorus oxychloride was evaporated under reduced pressure, the resulting residue was poured into ice water, adjusted to pH ca.8 with sodium bicarbonate solution, then extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 3: 1) to give 20.2g of the title compound as a pale yellow solid with a yield of 44.5%.

(II) preparation of the Compounds of the invention

Example 1: 2- (6-Aminopyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]Naphthalene Preparation of pyridin-9 (10H) -one (Compound 1)

Preparation of 1, 5-naphthyridine-3-carboxylic acid ethyl ester 6-chloro-4- (3- (trifluoromethyl) anilino) -1

Ethyl 4, 6-dichloro-1, 5-naphthyridine-3-carboxylate (2.70g, 10.0mmol) and 3-trifluoromethylaniline (1.77g, 11.0mmol) were dissolved in t-butanol (50mL), potassium carbonate (4.15g, 30.0mmol) was added to the system, the reaction was stirred under reflux for 3 hours, and TLC (ethyl acetate: petroleum ether ═ 1: 3) showed disappearance of the starting materials. Suction filtration, washing of the filter cake with dichloromethane, discarding of the filter cake, combining the washings with the filtrate, concentration under reduced pressure to give a solid which is recrystallized from ether to give 3.7g of the title compound as a pale yellow solid in 93.5% yield.

Preparation of 6-chloro-4- (3- (trifluoromethyl) anilino) -1, 5-naphthyridine-3-aldehyde

Ethyl 4- (3-trifluoromethylanilino) -6-chloro-1, 5-naphthyridine-3-carboxylate (2.5g, 6.3mmol) was added to ethanol (80mL), sodium borohydride (0.95g, 25.1mmol) was added to the system in divided portions, stirring was performed at room temperature for 24 hours, ethanol was evaporated under reduced pressure, 20mL of water was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentration under reduced pressure was performed to obtain 1.3g of a crude product, which was dissolved in dichloromethane (20mL), manganese dioxide (9.6g, 110.5mmol) was added to the obtained solution in divided portions, and the reaction was stirred at room temperature for 8 hours. Filtration, washing of the filter cake with dichloromethane, discarding of the filter cake, combining the washings with the filtrate, concentration under reduced pressure gave a solid which was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 2: 1) to give 1.1g of the title compound in 49.7% yield over two steps.

Preparation of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To a solution of 6-chloro-4- (3- (trifluoromethyl) anilino) -1, 5-naphthyridine-3-carboxaldehyde (1.0g, 2.84mmol) and ethyl 2- (diethoxyphosphoryl) acetate (1.78g, 7.98mmol) in t-butanol (70mL) was added potassium carbonate (2.36g, 17.1mmol) in a 250mL closed pot (sealed pot), reacted at 160 ℃ for 36 hours, the reaction mixture was cooled, suction filtered, the cake was washed with dichloromethane, the cake was discarded, the washing solution was combined with the filtrate, and concentrated under reduced pressure to give a solid, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 3: 1) to give 0.56g of the title compound in 52.5% yield.

Preparation of 2- (6-aminopyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (418mg, 1.11mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (368mg, 1.67mmol) were dissolved in toluene (40mL) and ethanol (10mL), and tetrakis (triphenylphosphine) palladium (12mg) and 2N sodium carbonate solution (2mL) were added to the system. The reaction was refluxed for 12 hours under a nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, the organic layer was concentrated under reduced pressure and dissolved in dichloromethane, and the resulting solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 3: 1) to give 248mg of the title compound in 51.5% yield.

The molecular formula is as follows: c₂₃H₁₄F₃N₅O molecular weight: 433.1 mass spectrum (M + 1): 434

¹H NMR(d₆-DMSO，400MHz)：9.14(1H，s)，8.33(2H，d)，8.22-8.10(2H，m)，7.87-7.79(2H，m)，7.72(1H，t)，7.65-7.55(1H，m)，6.95(1H，d)，6.80(1H，d)，6.40(2H，s)，6.27(1H，d)。

Referring to the preparation method of example 1 (Compound 1), Compound 3, i.e., Compound 1, can be prepared

(R) -2- (6-Aminopyridin-3-yl) -10- (1- (2-hydroxypropionyl) piperidin-4-yl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

The molecular formula is as follows: c₂₄H₂₄N₆O₃Molecular weight: 444.19 Mass Spectrometry (M + H): 445.

referring to the preparation method of example 1 (Compound 1), Compound 4, i.e., Compound 1, can also be prepared

(R) -10- (1- (2-hydroxypropionyl) piperidin-4-yl) -2- (6-methoxypyridin-3-yl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

the molecular formula is as follows: c₂₅H₂₅N₅O₄Molecular weight: 459.19 Mass Spectrometry (M + H): 460.

example 2: 2- (6-methoxypyridin-3-yl) -10- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) pyridine And [3, 2-c ]][1，5]Preparation of naphthyridin-9 (10H) -one (Compound 2)

Preparation of methyl 4- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (trifluoromethyl) aniline) -6-chloro-1, 5-naphthyridine-3-carboxylate

Ethyl 4, 6-dichloro-1, 5-naphthyridine-3-carboxylate (0.5g, 1.84mmol) and tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (0.766g, 2.22mmol) were dissolved in a mixed solution of dichloromethane (5mL) and tert-butanol (5mL), potassium carbonate (0.612g, 4.43mmol) was added to the system, and the reaction was stirred at room temperature for 24 hours. Suction filtration, washing of the filter cake with dichloromethane, discarding of the filter cake, combining the washings with the filtrate, concentration under reduced pressure gave a solid which was recrystallized from ether to give 0.73g of the title compound as a pale yellow solid in 70.1% yield.

Preparation of tert-butyl 4- (4- (6-chloro-3- (hydroxymethyl) -1, 5-naphthyridin-4-ylamino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Methyl 4- (4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (trifluoromethyl) aniline) -6-chloro-1, 5-naphthyridine-3-carboxylate (0.565g, 1.0mmol) was added to ethanol (10mL), to the system was added sodium borohydride (0.228g, 6mmol) in portions, stirred at room temperature for 18 hours, ethanol was removed under reduced pressure, 10mL of water was added, the resulting mixture was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude title compound was used directly in the next step as a solid.

Preparation of tert-butyl 4- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Crude tert-butyl 4- (4- (6-chloro-3- (hydroxymethyl) -1, 5-naphthyridin-4-ylamino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (1mmol) obtained in the above step was dissolved in dichloromethane (10mL), manganese dioxide (2.14g, 24.6mmol) was added to the resulting solution, and the reaction was stirred at room temperature for 3 h. Filtration and washing of the filter cake with dichloromethane were carried out, the filter cake was discarded, the washings were combined with the filtrate and concentrated under reduced pressure to give a solid which was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 2: 1) to give 0.33g of the title compound in a two-step yield of 61.6%.

Preparation of tert-butyl 4- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

To a solution of tert-butyl alcohol (125mL) to which were added tert-butyl 4- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (2.5g, 4.66mmol) and ethyl 2- (diethoxyphosphoryl) acetate (2.93g, 13.1mmol) in a 250mL closed tank was added potassium carbonate (3.87g, 28.0mmol), reacted at 160 ℃ for 36h, the reaction mixture was cooled, suction filtered, the filter cake was washed with dichloromethane, the filter cake was discarded, the washing solution was combined with the filtrate, and concentrated under reduced pressure to give a solid, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 3: 1) to give 145mg of the title compound in 5.6% yield.

Preparation of tert-butyl 4- (4- (2- (6-methoxypyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (4- (2- (6-methoxypyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (145mg, 0.26mmol) and 6-methoxy-3-pyridineboronic acid (40mg, 0.26mmol) were dissolved in toluene (8mL) and ethanol (2mL), and tetrakis (triphenylphosphine) palladium (3mg) and 2N sodium carbonate solution (0.12mL) were added to the system. The reaction was refluxed for 4 hours under a nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, an organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 3: 1) to give 72mg of the title compound in 43.8% yield.

Preparation of 2- (6-methoxypyridin-3-yl) -10- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

Tert-butyl 4- (4- (2- (6-methoxypyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (72mg, 0.114mmol) was dissolved in dichloromethane (8mL), hydrogen chloride gas was introduced into the system for half an hour to precipitate a solid, the solid was filtered under suction, the solid was washed with dichloromethane and diethyl ether in this order, the solid was dissolved in water and then adjusted to pH 9 with 1N sodium hydroxide solution, followed by extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 54mg of the title compound as a solid in 88.6% yield.

The molecular formula is as follows: c₂₈H₂₃F₃N₆O₂Molecular weight: 532.18 Mass Spectrometry (M + H): 532.9

¹H NMR(CDCl₃，400MHz)：.9.04(1H，s)，8.43(1H，d)，8.14(1H，d)，8.03(1H，d)，7.95(1H，d)，7.59(1H，d)，7.47-7.38(3H，m)，7.01(1H，d)，6.72(1H，d)，3.97(3H，s)，3.05(6H，br s)，2.98-2.89(2H，m)。

Example 3: 2-methyl-2- (4- (9-oxo-2- (quinolin-3-yl) pyrido [3, 2-c)][1，5]Naphthyridine-10 (9H) Preparation of (Yl) phenyl) propionitrile (Compound 5)

Preparation of methyl 6-chloro-4- (4- (2- (cyanopropyl-2-yl) anilino) -1, 5-naphthyridine-3-carboxylate

Ethyl 4, 6-dichloro-1, 5-naphthyridine-3-carboxylate (5.0g, 18.4mmol) and 2- (4-aminophenyl) -2-methylpropanenitrile (2.96g, 18.5mmol) were dissolved in 1, 4-dioxane (80mL), the reaction was stirred under reflux for 4 hours, the reaction mixture was cooled, concentrated under reduced pressure, the resulting solid was dissolved in dichloromethane, washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6.54g of the title compound as a pale yellow solid in 90.2% yield.

Preparation of 2- (4- (6-chloro-3- (hydroxymethyl) -1, 5-naphthyridin-4-ylamino) phenyl) -2-methylpropanenitrile

Ethyl 6-chloro-4- (4- (2- (cyanopropyl-2-yl) anilino) -1, 5-naphthyridine-3-carboxylate (6.54g, 16.6mmol) was added to ethanol (200mL), sodium borohydride (6.27g, 166mmol) was added to the system in portions, stirred at room temperature for 24 hours, the ethanol was removed under reduced pressure, the solution pH was adjusted to neutral with 1N dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 5.8g of the crude title compound as a solid was used directly in the next step.

Preparation of 2- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) phenyl) -2-methylpropanenitrile

About 5.8g of the crude 2- (4- (6-chloro-3- (hydroxymethyl) -1, 5-naphthyridin-4-ylamino) phenyl) -2-methylpropanenitrile obtained in the above step was dissolved in dichloromethane (80mL), and manganese dioxide (46.2g, 0.53mol) was added to the resulting solution in portions and the reaction was stirred at room temperature for 30 hours. Filtration and washing of the filter cake with dichloromethane were carried out, the filter cake was discarded, the washings were combined with the filtrate and concentrated under reduced pressure to give a solid which was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 2: 1) to give 2.3g of the title compound in 39.5% yield over two steps.

Preparation of 2- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile

2- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) phenyl) -2-methylpropanenitrile (1.0g, 2.85mmol), ethyl 2- (diethoxyphosphoryl) acetate (1.8g, 8.03mmol), tert-butanol (70mL) and potassium carbonate (1.85g, 13.4mmol) were sequentially added to a 250mL stuffer jar, reacted at 160 ℃ for 48h, the reaction mixture was cooled, suction filtered, the cake was washed with dichloromethane, the cake was discarded, the washing solution was combined with the filtrate, and concentrated under reduced pressure to give a solid, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 1) to give 0.31g of the title compound in 29.0% yield.

Preparation of 2-methyl-2- (4- (9-oxo-2- (quinolin-3-yl) pyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) propionitrile

2- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile (310mg, 0.827mmol) and quinolin-3-ylboronic acid (159mg, 0.919mmol) were dissolved in toluene (21mL) and ethanol (7mL), and tetrakis (triphenylphosphine) palladium (10mg) and a 2N sodium carbonate solution (1.2mL) were added to the system. The reaction was refluxed for 8 hours under a nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, an organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 1) to obtain 108mg of the title compound with a yield of 27.9%.

The molecular formula is as follows: c₃₀H₂₁N₅O molecular weight: 467.17 Mass Spectrometry (M + H): 467.9

¹H-NMR(d₆-DMSO，400MHz)：9.25(1H，s)，8.76(1H，d)，8.55(1H，d)，8.46(1H，d)，8.41-8.33(2H，m)，8.04(1H，d)，7.99(1H，d)，7.85-7.77(1H，m)，7.69-7.58(3H，m)，7.43(2H，d)，6.99(1H，d)，1.60(6H，s)。

Example 4: 2- (6-Aminopyridin-3-yl) -10- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) pyrido [3，2-c][1，5]Naphthyridin-9 (10H) -one (Compound 6) hydrochloride

Tert-butyl 4- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (524mg, 0.98mmol) was dissolved in 9mL of N, N-dimethylacetamide and 6mL of acetic anhydride, reacted in a microwave reactor at 160 ℃ for 40 minutes, the reaction mixture was cooled, most of the solvent was removed under reduced pressure and purified by silica gel column chromatography (ethyl acetate) to give 505mg of the title compound as a white solid in 91.8% yield.

Preparation of tert-butyl 4- (4- (2- (6-aminopyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (4- (2- (6-methoxypyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (302mg, 0.54mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (240mg, 1.09mmol) were dissolved in toluene (6mL) and ethanol (2mL), and tetrakis (triphenylphosphine) palladium (13mg) and 2N sodium carbonate solution (1.6mL) were added to the system. The reaction was refluxed for 4 hours under a nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, an organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 1) to obtain 312mg of the title compound with a yield of 93.5%.

Preparation of 2- (6-aminopyridin-3-yl) -10- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one hydrochloride

Tert-butyl 4- (4- (2- (6-aminopyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (312mg, 0.505mmol) was dissolved in dichloromethane (8mL), hydrogen chloride gas was introduced into the system for half an hour to precipitate a solid, which was then filtered with suction and washed with dichloromethane and ether in this order to give 271mg of the title compound as a white solid in 96.8% yield.

The molecular formula is as follows: c₂₇H₂₃ClF₃N₇O molecular weight: 553.16 Mass Spectrometry (M-HCl + H): 518.0

¹H-NMR(D₂O，400MHz)：9.06(1H，s)，8.28-8.19(2H，m)，8.04(1H，s)，7.88(1H，d)，7.51(1H，s)，7.38(1H，d)，7.22(1H，d)，7.05-6.93(2H，m)，6.74(1H，d)，3.32(4H，br s)，3.22-3.10(2H，m)，2.88-2.78(2H，m)。

Example 5: 2- (4- (2- (6-aminopyridin-3-yl) -9-oxopyrido [3, 2-c)][1，5]Naphthyridine-10 (9H) Preparation of (E) -yl) phenyl) -2-methylpropanenitrile (Compound 7)

2- (4- (6-chloro-3-formyl-1, 5-naphthyridin-4-ylamino) phenyl) -2-methylpropanenitrile (1.3g, 3.71mmol) was dissolved in 12mL of N, N-dimethylacetamide and 8mL of acetic anhydride, reacted at 160 ℃ for 60 minutes in a microwave reactor, the reaction mixture was cooled, most of the solvent was removed under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate) to give 1.1g of the title compound as a white solid in 79.0% yield.

2- (4- (2- (6-Aminopyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile

2- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile (400mg, 1.07mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (282mg, 1.28mmol) were dissolved in toluene (21mL) and ethanol (7mL), and tetrakis (triphenylphosphine) palladium (12mg) and 2N sodium carbonate solution (1.6mL) were added to the system. The reaction was refluxed for 8 hours under a nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, an organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 1) to obtain 61mg of the title compound with a yield of 13.2%.

The molecular formula is as follows: c₂₆H₂₀N₆O molecular weight: 432.17 Mass Spectrometry (M + H): 433.0

¹H-NMR(d₆-DMSO，400MHz)：9.11(1H，s)，8.35-8.26(2H，m)，8.10(1H，d)，7.96(1H，s)，7.60(2H，d)，7.34(2H，d)，7.24(1H，d)，6.92(1H，d)，6.39-6.27(3H，m)，1.74(6H，s)。

Example 6: 2- (4- (2- (6-methoxypyridin-3-yl) -9-oxopyrido [3, 2-c)][1，5]Naphthyridine-10 (9H) Preparation of (E) -yl) phenyl) -2-methylpropanenitrile (Compound 12)

The procedure was carried out in exactly the same manner as in example 1, but using 2- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile (200mg, 0.534mmol) and 6-methoxy-3-pyridineboronic acid (100mg, 0.654mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, to give 182mg of the title compound in a yield of 76.2%.

The molecular formula is as follows: c₂₇H₂₁N₅O₂Molecular weight: 447.17 Mass Spectrometry (M + H): 448.2

¹H-NMR(d₆-DMSO，400MHz)：9.18(1H，s)，8.42(1H，d)，，8.33(1H，d)，8.21(1H，d)7.85(1H，d)，7.79(1H，dd)，7.63(2H，d)，7.37(2H，d)，6.95(1H，d)，6.78(1H，d)，3.91(3H，s)，1.75(6H，s)。

Example 7: 2- (2-aminopyrimidin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]Naphthalene Preparation of pyridin-9 (10H) -one (Compound 13)

6-chloro-4- (3- (trifluoromethyl) anilino) -1, 5-naphthyridine-3-carboxaldehyde (0.600g, 1.71mmol) was dissolved in 10mL of LN, N-dimethylacetamide and 6mL of acetic anhydride, reacted in a microwave reactor at 160 ℃ for 40 minutes, the reaction mixture was cooled, most of the solvent was removed under reduced pressure and purified by silica gel column chromatography (ethyl acetate) to give 0.580g of the title compound as a white solid in 90.1% yield.

Preparation of 2- (2-aminopyrimidin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

The procedure was specifically the same as in example 1, except for using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (300mg, 0.799mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyrimidin-2-amine (213mg, 0.963mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, 148mg of the title compound are obtained in 42.7% yield.

The molecular formula is as follows: c₂₂H₁₃F₃N₆O molecular weight: 434.11 Mass Spectrometry (M + H): 434.9

¹H-NMR(d₆-DMSO，400MHz)：9.14(1H，s)，8.41-8.29(2H，m)，8.15(1H，d)，7.98(2H，s)，7.82-7.70(3H，m)，7.69-7.63(1H，m)，7.03(2H，s)，6.94(1H，d)。

Example 8: 2- (2-methoxypyrimidin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5] Preparation of naphthyridin-9 (10H) -one (Compound 14)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (180mg, 0.479mmol) and 2-methoxypyrimidin-5-ylboronic acid (89mg, 0.578mmol) with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, to give 165mg of the title compound in 76.6% yield.

The molecular formula is as follows: c₂₃H₁₄F₃N₅O₂Molecular weight: 449.11 Mass Spectrometry (M + H): 450.2

¹H-NMR(d₆-DMSO，400MHz)：9.25(1H，s)，8.50(1H，d)，8.37(1H，d)，8.33(2H，s)，8.30(1H，d)，7.85(1H，s)，7.82(1H，d)，7.74(1H，t)，7.66(1H，d)，7.00(1H，d)，3.96(3H，s)。

Example 9: n- (5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c)][1， 5]Preparation of naphthyridin-2-yl) pyridin-2-yl) acetamide (Compound 15)

Preparation of N- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) acetamide

To a solution of 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (300mg, 1.36mmol) in dichloromethane (15mL) were added dimethylaminopyridine (17mg, 0.139mmol), triethylamine (0.21mL, 1.50mmol) and acetic anhydride (153mg, 1.50mmol) in that order, and the reaction was stirred at room temperature for a period of time. Then, the mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 225mg of the title compound in a yield of 63.1%.

Preparation of N- (5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) pyridin-2-yl) acetamide

To N- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) acetamide (225mg, 0.858mmol) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (300mg, 0.799mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (1.3 mL). The reaction mixture was cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 160mg of the title compound in 42.2% yield.

The molecular formula is as follows: c₂₅H₁₆F₃N₅O₂Molecular weight: 475.13 Mass Spectrometry (M + H): 476.2

¹H-NMR(d₆-DMSO，400MHz)：10.65(1H，s)，9.23(1H，s)，8.46(1H，d)，8.37(1H，d)，8.34(1H，d)，8.32(1H，d)，7.98(1H，d)，7.86(1H，s)，7.80(1H，d)，7.74(1H，t)，7.66(1H，d)，7.31(1H，dd)，6.98(1H，d)，2.12(3H，s)。

Example 10: 5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c)][1，5] Preparation of naphthyridin-2-yl) -2-cyanopyridine (Compound 16)

In particular, the procedure was carried out in the same manner as in example 9, preparation step 2 of Compound 15 except that 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-cyanopyridine (138mg, 0.60mmol) were used in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and N- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) acetamide, respectively, 128mg of the title compound are obtained in 57.8% yield.

The molecular formula is as follows: c₂₄H₁₂F₃N₅O molecular weight: 443.1 Mass Spectrometry (M + H): 444.1

¹H-NMR(d₆-DMSO，400MHz)：9.27(1H，s)，8.55(1H，d)，8.49(1H，d)，8.40(1H，d)，8.37(1H，d)，7.97(1H，d)，7.89(1H，d)，7.81(1H，s)，7.77(1H，t)，7.71-7.62(2H，m)，7.00(1H，d)。

Example 11: 2- (1H-pyrrolo [ 2.3-b)]Pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]preparation of naphthyridin-9 (10H) -one (Compound 17)

Preparation of tert-butyl 3- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) -1H-pyrrolo [2, 3-b ] pyridine-1-carboxylate

2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (137mg, 0.365mmol) and tert-butyl 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2, 3-b ] pyridine-1-carboxylate (151mg, 0.439mmol) were dissolved in toluene (6mL) and ethanol (2mL), and tetrakis (triphenylphosphine) palladium (10mg) and 2N sodium carbonate solution (0.5mL) were added to the system. The reaction was refluxed for 6 hours under nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, and the organic layer was separated, concentrated under reduced pressure, dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 193mg of the title compound in 95.2% yield.

Preparation of 2- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

Tert-butyl 3- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) -1H-pyrrolo [2, 3-b ] pyridine-1-carboxylate (193mg, 0.347mmol) obtained in the above step was dissolved in methylene chloride (10mL), and hydrogen chloride gas was introduced into the system for half an hour, precipitating solid, filtering, washing the obtained solid with dichloromethane and diethyl ether, dissolving in water, adjusting pH to 9 with 1N sodium hydroxide solution, then, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction-filtered, concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain 44mg of the title compound in 27.7% yield.

The molecular formula is as follows: c₂₅H₁₄F₃N₅O molecular weight: 457.12 Mass Spectrometry (M + H): 458.2

¹H-NMR(d₆-DMSO，400MHz)：12.16(1H，s)，9.15(1H，s)，8.39(1H，d)，8.35(1H，d)，8.31-8.24(2H，m)，8.18(1H，d)，7.83(1H，s)，7.77-7.65(3H，m)，7.17(1H，dd)，6.96(1H，d)，6.73(1H，s)。

Example 12: 2- (6- (hydroxymethyl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 18)

Preparation of (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) methanol

To 1, 4-dioxane (20mL) was added (5-bromopyridin-2-yl) methanol (376mg, 2.0mmol), bis (pinacolato) borate (762mg, 3.0mmol), potassium acetate (504mg, 5.14mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (20mg) in that order, the reaction was stirred at 90 ℃ for 12 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without treatment.

Preparation of 2- (6- (hydroxymethyl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step ((5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) methanol) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (315mg, 0.84mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (3.0 mL). The reaction mixture was cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 189mg of the title compound with a yield of 50.0%.

The molecular formula is as follows: c₂₄H₁₅F₃N₄O₂Molecular weight: 448.11 Mass Spectrometry (M + H): 449.2

¹H-NMR(d₆-DMSO，400MHz)：9.24(1H，s)，8.58(1H，d)，8.49(1H，d)，8.38(1H，d)，8.35(1H，d)，7.89-7.83(2H，m)，7.73(1H，t)，7.65(1H，d)，7.35(1H，d)，7.25(1H，dd)，6.99(1H，d)，5.51(1H，t)，4.58(2H，d)。

Example 13: 2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3，2-c][1，5]Preparation of naphthyridin-9 (10H) -one (Compound 19)

1.1 preparation of- (5-bromopyridin-2-yl) -4-methylpiperazine

2, 5-dibromopyridine (2.00g, 8.44mmol) and 1-methylpiperazine (3.00mL) were stirred at 110 ℃ for two hours, excess 1-methylpiperazine was evaporated under reduced pressure in vacuo, a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the organic solvent was removed under reduced pressure to give the title compound g as a 1.45 brown solid in 67.1% yield.

Preparation of 1-methyl-4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine

To 1, 4-dioxane (20mL) was added 1- (5-bromopyridin-2-yl) -4-methylpiperazine (0.67g, 2.62mmol), bis-pinacolato borate (1.00g, 3.94mmol), potassium acetate (0.65g, 6.63mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15mg) in that order, the reaction was stirred at 90 ℃ for 12 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without treatment.

Preparation of 2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step (1-methyl-4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (0.68g, 1.81mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (3.9 mL). The resulting mixture was reacted at 90 ℃ for 16 hours under nitrogen atmosphere, cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 518mg of the title compound in 55.6% yield.

The molecular formula is as follows: c₂₈H₂₃F₃N₆O molecular weight: 516.19 Mass Spectrometry (M + H): 517.3

¹H-NMR(CDCl₃，400MHz)：8.99(1H，s)，8.35(1H，d)，8.33(1H，d)，8.02(1H，d)，7.94(1H，d)，7.76(1H，d)，7.69(1H，s)，7.63(1H，t)，7.42(1H，d)，6.99(1H，d)，6.94(1H，dd)，6.46(1H，d)，3.75-3.67(4H，m)，2.64-2.56(4H，m)，2.40(3H，s)。

Example 14: 2- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]preparation of naphthyridin-9 (10H) -one (Compound 20)

Preparation of 1.5-bromo-2- (1H-pyrazol-1-yl) pyridine

Pyrazole (2.05g, 30.1mmol) was added in portions to a solution of 60% sodium hydride (1.20g, 30.0mmol) in N, N-dimethylformamide (40mL), and the mixture was stirred at room temperature for reaction for one hour, then 2.5-dibromopyridine (4.75g, 20.1mmol) was added to the reaction system, and the reaction mixture was stirred at 100 ℃ for reaction for 2 hours, and the reaction mixture was cooled and poured into ice water to precipitate a solid, which was then filtered with suction, and the solid was dried under vacuum and recrystallized from N-hexane to obtain 3.31g of the title compound as a brown solid with a yield of 73.6%.

Preparation of 2- (1H-pyrazol-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

To 1, 4-dioxane (20mL) was added 5-bromo-2- (1H-pyrazol-1-yl) pyridine (0.45g, 2.01mmol), bis-pinacolato borate (0.76g, 2.99mmol), potassium acetate (0.51g, 5.20mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15mg) in that order, the reaction mixture was stirred at 90 ℃ for 5 hours under nitrogen protection, and was used in the next step without treatment after cooling.

Preparation of 2- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step (2- (1H-pyrazol-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (300mg, 0.799mmol), tetrakis (triphenylphosphine) palladium (15mg), and a 2N sodium carbonate solution (3 mL). The reaction mixture was cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 291mg of the title compound with a yield of 75.2%.

The molecular formula is as follows: c₂₆H₁₅F₃N₆O molecular weight: 484.13 Mass Spectrometry (M + H): 485.2

¹H-NMR(d₆-DMSO，400MHz)：9.24(1H，s)，8.62(1H，d)，8.54(1H，d)，8.50(1H，d)，8.38(1H，d)，8.36(1H，d)，7.93(1H，d)，7.91-7.87(2H，m)，7.79-7.72(2H，m)，7.65(1H，d)，7.38(1H，dd)，6.99(1H，d)，6.62(1H，t)。

Example 15: 2- (4- (2- (2-methoxypyrimidin-5-yl) -9-oxopyrido [3, 2-c)][1，5]Naphthyridine-10 (9H) Preparation of (E) -yl) phenyl) -2-methylpropanenitrile (Compound 21)

The procedure was carried out in exactly the same manner as in example 1, except for using 2- (4- (2-chloro-9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile (166mg, 0.443mmol) and 2-methoxypyrimidin-5-ylboronic acid in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, to obtain 157mg of the title compound in 79.0% yield.

The molecular formula is as follows: c₂₆H₂₀N₆O₂Molecular weight: 448.16 Mass Spectrometry (M + H): 449.2

¹H-NMR(d₆-DMSO，400MHz)：9.19(1H，s)，8.45(1H，d)，，8.37(2H，s)，8.32(1H，d)，8.27(1H，d)，7.63(2H，d)，7.37(2H，d)，6.96(1H，d)，3.96(3H，s)，1.78(6H，s)。

Example 16: 2- (6- (methylsulfonyl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2- c][1，5]Preparation of naphthyridin-9 (10H) -one (Compound 22)

1.5 preparation of bromo-2- (methylthio) pyridine

2.5-dibromopyridine (3.0g, 12.66mmol) is dissolved in N, N-dimethylformamide (20mL), sodium thiomethoxide (1.1g, 15.69mmol) is added to the solution, the reaction is stirred in an ice bath under nitrogen for 16h, the reaction mixture is poured into water (150mL), a solid is precipitated and filtered off with suction, and the solid obtained is dried to yield 2.5g of crude title compound as a white solid which is used directly in the next step.

Preparation of 5-bromo-2- (methylsulfonyl) pyridine

2.5g of the crude 5-bromo-2- (methylthio) pyridine obtained in the above step was dissolved in a mixed solution of isopropanol (10mL) and water (5mL), oxone complex salt (15.7g, 25.5mmol) was added, the mixture was stirred at room temperature overnight, and the filtrate was concentrated and dissolved in ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain 0.43g of the title compound as a white solid, with a yield of 14.4% in two steps.

Preparation of 2- (methylsulfonyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

To 1, 4-dioxane (20mL) was added 5-bromo-2- (methylsulfonyl) pyridine (0.200g, 0.847mmol), bis-pinacolato borate (433mg, 1.71mmol), potassium acetate (167mg, 1.70mmol), and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (50mg) in that order, the reaction was stirred at 90 ℃ for 5 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without treatment.

Preparation of 2- (6- (methylsulfonyl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step (i.e., 2- (methylsulfonyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (319mg, 0.85mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (1.3 mL). The reaction mixture was cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 58mg of the title compound with a yield of 13.7%.

The molecular formula is as follows: c₂₄H₁₅F₃N₄O₃S molecular weight: 496.08 Mass Spectrometry (M + H): 497.1

¹H-NMR(d₆-DMSO，400MHz)：9.35(1H，s)，8.74(1H，d)，8.63(1H，d)，8.50(1H，d)，8.44(1H，d)，7.99-7.89(3H，m)，7.82(1H，t)，7.73(1H，d)，7.68(1H，dd)，7.07(1H，d)，3.36(3H，s)。

Example 17: 2- (6-methoxypyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1， 5]Preparation of naphthyridin-9 (10H) -one (Compound 23)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (100mg, 0.266mmol) and 6-methoxy-3-pyridineboronic acid, respectively, to give 82mg of the title compound in 68.8% yield.

The molecular formula is as follows: c₂₄H₁₅F₃N₄O₂Molecular weight: 448.11 Mass Spectrometry (M + H): 449.1

¹H-NMR(d₆-DMSO，400MHz)：9.22(1H，s)，8.45(1H，d)，8.39-8.34(2H，m)，8.29(1H，d)，7.92-7.84(2H，m)，7.74(1H，t)，7.63(1H，d)，7.10(1H，dd)，6.99(1H，d)，6.66(1H，d)，3.90(3H，s)。

Example 18: 2- (6-Morpholinopyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1， 5]Preparation of naphthyridin-9 (10H) -one (Compound 24)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (150mg, 0.399mmol) and 6-morpholinopyridin-3-ylboronic acid (100mg, 0.481mmol) with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine, respectively, to give 78mg of the title compound in 38.8% yield.

The molecular formula is as follows: c₂₇H₂₀F₃N₅O₂Molecular weight: 503.16 Mass Spectrometry (M + H): 504.2

¹H-NMR(d₆-DMSO，400MHz)：9.16(1H，s)，8.37(1H，d)，8.34(1H，d)，8.28(1H，d)，8.22(1H，d)，7.90(1H，d)，7.84(1H，s)，7.73(1H，t)，7.62(1H，d)，7.00(1H，dd)，6.97(1H，s)，6.62(1H，d)，3.71(4H，t)，3.53(4H，t)。

Example 19: 2- (5-methoxypyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1， 5]Preparation of naphthyridin-9 (10H) -one (Compound 25)

The procedure was specifically the same as in example 1, except for replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (150mg, 0.399mmol) and 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -pyridine (113mg, 0.48mmol), 87mg of the title compound are obtained in 48.6% yield.

¹H-NMR(d₆-DMSO，400MHz)：9.26(1H，s)，8.51(1H，d)，8.37(1H，d)，8.35(1H，d)，8.31(1H，d)，7.85-7.75(3H，m)，7.74-7.63(2H，m)，7.24(1H，s)，6.99(1H，d)，3.89(3H，s)。

Example 20: 2- (2-methoxypyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyridine [3, 2-c][1，5] Preparation of naphthyridin-9 (10H) -one (Compound 26)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (150mg, 0.399mmol) and 2-methoxypyridin-3-yl boronic acid (74mg, 0.484mmol), respectively, to give 107mg of the title compound in 59.9% yield.

¹H-NMR(d₆-DMSO，400MHz)：9.25(1H，s)，8.43(1H，d)，8.37(1H，d)，8.24(1H，d)，8.20(1H，dd)，7.82(1H，s)，7.74(1H，d)，7.65(1H，t)，7.60(1H，d)，6.98(1H，d)，6.84(1H，dd)，6.72(1H，dd)，3.90(3H，s)。

Example 21: 10- (3- (trifluoromethyl) phenyl) -2- (6- (trifluoromethyl) pyridin-3-yl) pyrido [3, 2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 27)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (150mg, 0.399mmol) and 6- (trifluoromethyl) pyridin-3-ylboronic acid (92mg, 0.482mmol) for 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, to give 102mg of the title compound in 52.6% yield.

The molecular formula is as follows: c₂₄H₁₂F₆N₄O molecular weight: 486.09 Mass Spectrometry (M + H): 487.1

¹H-NMR(d₆-DMSO，400MHz)：9.29(1H，s)，8.66(1H，s)，8.57(1H，d)，8.42(1H，d)，8.38(1H，d)，7.88(1H，d)，7.85-7.75(3H，m)，7.69(1H，d)，7.59(1H，d)，7.01(1H，d)。

Example 22: 2- (6-methylpyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5] Preparation of naphthyridin-9 (10H) -one (Compound 28)

The procedure was carried out in exactly the same manner as in example 1, but using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (225mg, 0.599mmol) and 6-methylpyridin-3-ylboronic acid (99mg, 0.723mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine, respectively, to give 160mg of the title compound in 61.8% yield.

The molecular formula is as follows: c₂₄H₁₅F₃N₄O molecular weight: 432.12 Mass Spectrometry (M + H): 433.2

¹H-NMR(CDCl₃，400MHz)：9.06(1H，s)，8.61(1H，s)，8.46(1H，d)，8.05(1H，d)，8.03(1H，d)，7.76(1H，d)，7.66(1H，d)，7.63(1H，s)，7.47(1H，d)，7.07-7.00(3H，m)，2.60(3H，s)。

Example 23: 2- (3, 5-dimethyliso) Azol-4-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 29)

The procedure was carried out in the same manner as in step 4 of example 1, except that 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] was used][1，5]Naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 3, 5-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -iso-propylAzole (134mg, 0.575mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c, respectively][1，5]Naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine gave 112mg of the title compound in 51.4% yield.

The molecular formula is as follows: c₂₃H₁₅F₃N₄O₂Molecular weight: 436.11 Mass Spectrometry (M + H): 437.1

¹H-NMR(d₆-DMSO，400MHz)：9.26(1H，s)，8.45(1H，d)，8.37(1H，d)，7.76(1H，d)，7.65-7.55(3H，m)，7.50(1H，d)，7.00(1H，d)，2.11(3H，s)，1.89(3H，s)。

Example 24: 2- (5-Fluoropyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]Naphthalene Preparation of pyridin-9 (10H) -one (Compound 30)

The procedure was carried out in exactly the same manner as in example 1, but using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (200mg, 0.53mmol) and 5-fluoropyridin-3-yl boronic acid (90mg, 0.64mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine, respectively, to give 162mg of the title compound in 69.8% yield.

The molecular formula is as follows: c₂₃H₁₂F₄N₄O molecular weight: 436.09 Mass Spectrometry (M + H): 437.1

¹H-NMR(d₆-DMSO，400MHz)：9.29(1H，s)，8.61(1H，d)，8.55(1H，d)，8.50(1H，t)，8.42(1H，d)，8.39(1H，d)，7.87(1H，s)，7.81(1H，d)，7.75(1H，t)，7.69(1H，d)，7.14(1H，dt)，7.01(1H，d)。

Example 25: 10- (3- (trifluoromethyl) phenyl-2- (5- (trifluoromethyl) pyridin-3-yl) pyrido [3, 2-c)] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 31)

Preparation of 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) pyridine

To 1, 4-dioxane (20mL) was added 3-bromo-5-trifluoromethylpyridine (273mg, 1.21mmol), bis-pinacolato borate (460mg, 1.81mmol), potassium acetate (300mg, 3.06mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15mg) in that order, the reaction was stirred at 90 ℃ for 12 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without further treatment.

Preparation of 10- (3- (trifluoromethyl) phenyl-2- (5- (trifluoromethyl) pyridin-3-yl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) pyridine), 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (300mg, 0.799mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (1.8mL) were added. The resulting mixture was reacted at 90 ℃ for 16 hours under nitrogen atmosphere, cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain 72mg of the title compound in 18.5% yield.

¹H-NMR(d₆-DMSO，400MHz)：9.29(1H，s)，9.00(1H，s)，8.55(1H，d)，8.44(1H，d)，8.41-8.36(2H，m)，8.12(1H，s)，7.78(1H，s)，7.76-7.71(3H，m)，7.01(1H，d)。

Example 26: 2- (1-methyl-1H-pyrazol-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 32)

The procedure was specifically the same as in example 1, except for using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole (127mg, 0.61mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, 105mg of the title compound are obtained in 49.8% yield.

The molecular formula is as follows: c₂₂H₁₄F₃N₅O molecular weight: 421.12 Mass Spectrometry (M + H): 422.1

¹H-NMR(d₆-DMSO，400MHz)：9.27(1H，s)，8.48(1H，d)，8.38(1H，d)，7.95(1H，d)，7.74(1H，s)，7.64-7.55(3H，m)，7.35(1H，d)，7.00(1H，d)，6.05(1H，d)，3.58(3H，s)。

Example 27: 2- (thiazol-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]Naphthyridine-9 (10H) Preparation of (Compound 33)

The procedure was specifically identical to example 1, step 4, but replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -thiazole (125mg, 0.59mmol) with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, to give 71mg of the title compound, the yield thereof was found to be 33.6%.

The molecular formula is as follows: c₂₁H₁₁F₃N₄Molecular weight of OS: 424.06 Mass Spectrometry (M + H): 425.1

¹H-NMR(d₆-DMSO，400MHz)：9.22(1H，s)，9.10(1H，s)，8.46(1H，d)，8.37(1H，s)，8.35(1H，d)，8.28(1H，d)，7.85-7.80(2H，m)，7.75(1H，t)，7.59(1H，d)，6.97(1H，d)。

Example 28: 3-methyl-5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2- c][1，5]Preparation of naphthyridin-2-yl) -2-cyanopyridine (Compound 34)

Preparation of 1.5-bromo-3-methyl-2-cyanopyridine

To a solution of 2, 5-dibromo-3-methylpyridine (5.0g, 19.9mmol) in N, N-dimethylformamide (20mL) was added cuprous cyanide (1.8g, 20.0 mmol). The reaction was stirred at 120 ℃ for 12 hours, the reaction mixture was cooled, water was added thereto, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 2.4g of the title compound as a white solid in a yield of 61.3%.

Preparation of 3-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-cyanopyridine

To 1, 4-dioxane (20mL) was added 5-bromo-3-methyl-2-cyanopyridine (390mg, 1.98mmol), bis (pinacolato) borate (754mg, 2.97mmol), potassium acetate (493mg, 5.03mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (20mg) in that order, the reaction was stirred at 90 ℃ for 12 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without treatment.

Preparation of 3-methyl-5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) -2-cyanopyridine

To the cooled reaction solution of the above step (3-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-cyanopyridine) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (500mg, 1.33mmol), tetrakis (triphenylphosphine) palladium (15mg) and 2N sodium carbonate solution (3.0 mL). The reaction mixture was cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give 192mg of the title compound with a yield of 31.6%.

The molecular formula is as follows: c₂₅H₁₄F₃N₅O molecular weight: 457.12 Mass Spectrometry (M + H): 458.1

¹H-NMR(d₆-DMSO，400MHz)：9.30(1H，s)，8.58(1H，d)，8.40(1H，d)，8.38(1H，d)，8.20(1H，d)，7.87(1H，d)，7.82-7.72(4H，m)，7.02(1H，d)，2.52(3H，s)。

Example 29: 5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c)][1，5] Preparation of naphthyridin-2-yl) -3-cyanopyridine (Compound 35)

2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (200mg, 0.532mmol) and 5-cyanopyridin-3-ylboronic acid (95mg, 0.642mmol) were dissolved in 1, 4-dioxane (12mL), and tetrakis (triphenylphosphine) palladium (10mg), 2N sodium carbonate solution (0.9mL) were added to the system. The reaction was refluxed for 6 hours under nitrogen atmosphere, and the reaction mixture was cooled to room temperature, filtered, and the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain 186mg of the title compound in 78.8% yield.

The molecular formula is as follows: c₂₄H₁₂F₃N₅O molecular weight: 443.10 Mass Spectrometry (M + H): 444.10

¹H-NMR(d₆-DMSO，400MHz)：9.29(1H，s)，9.05(1H，d)，8.70(1H，d)，8.57(1H，d)，8.44(1H，d)，8.39(1H，d)，7.89-7.74(5H，m)，7.02(1H，d)。

Example 30: 2- (6- (pyrrolidin-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]preparation of naphthyridin-9 (10H) -one (Compound 36)

The procedure was specifically the same as in example 1, but using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 2- (pyrrol-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -pyridine (165mg, 0.602mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, 198mg of the title compound are obtained in 81.2% yield.

The molecular formula is as follows: c₂₇H₂₀F₃N₅O molecular weight: 487.16 Mass Spectrometry (M + H): 488.2

¹H-NMR(d₆-DMSO，400MHz)：9.13(1H，s)，8.36-8.33(2H，m)，8.32(1H，s)，8.19(1H，d)，7.90-7.83(2H，m)，7.71(1H，t)，7.59(1H，d)，6.95(1H，d)，6.85(1H，dd)，6.21(1H，d)，3.46-3.38(4H，m)，1.99-1.93(4H，m)。

Example 31: 2- (1-methyl-1H-pyrazol-4-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 37)

The procedure was specifically the same as in example 1, but using 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (188mg, 0.50mmol) and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole (125mg, 0.60mmol) in place of 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-amine, respectively, 163mg of the title compound were obtained in 77.4% yield.

The molecular formula is as follows: c₂₂H₁₄F₃N₅O molecular weight: 421.12 Mass Spectrometry (M + H): 422.2

¹H-NMR(d₆-DMSO，400MHz)：9.12(1H，s)，8.36-8.28(2H，m)，7.97-7.89(2H，m)，7.84(1H，s)，7.76(1H，t)，7.60(1H，d)，7.43(1H，s)，7.25(1H，s)，6.94(1H，d)，3.79(3H，s)。

Example 32: 2- (6- (methylthio) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido[3，2-c] [1，5]Preparation of naphthyridin-9 (10H) -one (Compound 38)

Preparation of 2- (methylthio) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

To 1, 4-dioxane (20mL) was added 5-bromo-2- (methylthio) pyridine (326mg, 1.60mmol), bis-pinacolato borate (608mg, 2.39mmol), potassium acetate (402mg, 4.08mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (35mg) in that order, the reaction was stirred at 90 ℃ for 12 hours under nitrogen protection, and the reaction mixture was cooled and used in the next step without treatment.

Preparation of 2- (6- (methylthio) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one

To the cooled reaction solution of the above step (i.e., 2- (methylthio) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine) were added 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (300mg, 0.799mmol), tetrakis (triphenylphosphine) palladium (15mg), and 2N sodium carbonate solution (2.4 mL). The resulting mixture was reacted at 90 ℃ for 16 hours under nitrogen protection, cooled to room temperature, filtered, the organic layer was separated, concentrated under reduced pressure and dissolved in dichloromethane, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain 153mg of the title compound with a yield of 41.3%.

The molecular formula is as follows: c₂₄H₁₅F₃N₄Molecular weight of OS: 464.09 Mass Spectrometry (M + H): 465.1

¹H-NMR(d₆-DMSO，400MHz)：9.24(1H，s)，8.50(1H，d)，8.48(1H，d)，8.37(1H，d)，8.34(1H，d)，7.90(1H，d)，7.87(1H，s)，7.74(1H，t)，7.64(1H，d)，7.18-7.09(2H，m)，6.99(1H，d)，2.56(3H，s)。

Example 33: 2- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c][1，5]preparation of naphthyridin-9 (10H) -one (Compound 39)

The procedure was specifically the same as in example 1, except for replacing 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) 1H-pyrrolo [2, 3-b ] pyridine (117mg, 0.479mmol) with 2-chloro-10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one (150mg, 0.399mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine, respectively, 94mg of the title compound are obtained in 51.6% yield.

¹H-NMR(d₆-DMSO，400MHz)：11.83(1H，s)，9.21(1H，s)，8.45(1H，d)，8.38(1H，d)，8.36(1H，d)，8.26(1H，d)，7.90(1H，d)，7.87(1H，s)，7.78(1H，t)，7.70(1H，d)，7.53(1H，d)，7.52(1H，t)，6.98(1H，d)，6.51(1H，dd)。

In vitro enzymology and determination of the antitumor Activity of the Compounds of the invention

The advantageous effects of the compounds of the present invention are further illustrated below by in vitro enzymology and antitumor experiments of the compounds of the present invention, and other compounds of the present invention have the same advantageous effects as the compounds of the present invention exemplified in the experiments, but it should not be understood that the compounds of the present invention have only the following advantageous effects.

Experimental example 1 in vitro enzymatic inhibitory Activity of the Compound of the present invention

Test article

The compounds of the present invention: the compound is prepared by self-preparation, and the chemical name and the structural formula of the compound are shown in preparation examples of each compound.

mTOR (mammalian target of rapamycin) enzymatic experimental method

1. Reagent final concentration and compound formulation

1.1mTOR (2.5nM) kinase solution, substrate ULight-4E-BP1peptide 50nM, ATP 10.8 uM;

1.24 fold kinase solution, 2 fold substrate and ATP solution;

1.3 test Compound 1mM stock solution (100-fold final concentration in DMSO).

2. Experimental procedure

2.1 test compound 1mM, diluted with DMSO 4-fold gradient, then diluted 25-fold with kinase buffer;

2.2384 well plates were loaded with 2.5 μ L of serially diluted compounds per well;

2.3 Add 2.5. mu.L of 4-fold kinase solution per well;

2.4 Add 2.5. mu.L of substrate/ATP solution per well;

2.5 incubation for 60 min;

2.6 Envision read data Lance signal (665 nM).

3. Data processing

% inhibition ═ Lance signal-min)/(max-min). times.100

Where "max" is the DMSO control with enzyme but no compound and "min" is the control without kinase.

The inputs were plotted in GraphPad prism5.0 to generate curves and IC 50.

PI3K α enzyme experiment method

1. Reagent final concentration and compound formulation

1.1 PI3K alpha (1.65nM) kinase solution, substrate PIP 250. mu.M, ATP 25. mu.M;

1.24 fold kinase solution, 2 fold substrate and ATP solution;

1.3 test Compound 1mM stock solution (100-fold final concentration in DMSO).

2. Experimental procedure

2.3 Add 2.5. mu.L of 4-fold kinase solution per well;

2.4 Add 2.5. mu.L of substrate/ATP solution per well;

2.5 incubation for 60 min;

2.6 Envision read data Lance signal (665 nM).

3. Data processing

% inhibition ═ sample RLU-min)/(max-min). times.100

Where "max" is a control without kinase and "min" is a DMSO control with enzyme without compound.

The inputs were plotted in GraphPad prism5.0 to generate curves and IC 50.

Results of the experiment

See table 1 below.

TABLE 1In vitro enzymatic Activity (IC) of Compounds of the invention₅₀)

Conclusion of the experiment

As can be seen from Table 1, the compounds of the present invention have very good inhibitory activity against both PI3K α and mTOR enzymes in vitro.

Experimental example 2 in vitro cytological inhibitory Activity of Compounds of the invention

Test article

Control drug: torin-2, the structural formula of which is described in the "background" section above, is synthesized by reference to the literature method journal medical Chemistry (2011), 54(5), 1473-yl 1480, "Discovery of 9- (6-Aminopyridin-3-yl) -1- (3- (trifluoromethyl) phenyl) benzol [ H ] [1, 6] naphthyridin-2(1H) -one (in 2) as a potential, selective, and organic available mammalian target of rapamycin (mTOR) inhibitor for cancer" synthesis; and

the compounds of the present invention: the chemical name and the structure of the compound are shown in the preparation examples of each compound.

Positive control drug: paclitaxel

Experimental methods

1. Reagent and compound formulation: preparing PBS, XTT detection working solution, paclitaxel stock solution and gradient dilution solution, and test compound stock solution and gradient dilution solution;

2. cell culture: recovering cells, carrying out passage and freezing;

3. cell plating: preparing cell suspension, adding the cell suspension into 96-well plate at 37 deg.C and 5% CO per well₂Culturing in a cell culture box overnight;

4. and (3) drug treatment: adding the drug into cell culture plate, adding CO₂Culturing for 72 hours in a cell culture box;

XTT method detectionCell viability: adding XTT working solution in CO₂Placing the cell culture box for 2 hours, and placing the cell culture box into an enzyme-labeling instrument to read the light absorption of 450 nm;

6. data processing

1) Percent inhibition ═ 100% (solvent control well reading-compound well reading)/(solvent control well reading-positive control well reading);

2) inputting GraphPad prism5.0 to plot to obtain curves and IC₅₀；

Results of the experiment

See table 2 below.

TABLE 2 in vitro cytological Activity of Compounds of the invention (IC50)TABLE 2 ₅₀

Test article	U87MG cells (nM)	A549 cells (nM)
			Torin-2	12.4	14.7
Compound 1	8.9	11.9
			Compound 7	29.3	-
Compound 13	26.4	-
			Compound 15	12.7	20.2
Compound 39	8.4	6.8

Conclusion of the experiment

As shown in Table 2, the compounds of the present invention were effective in inhibiting the proliferation of U87MG and A549 cells, and had comparable activity to that of the control drug Torin-2.

Experimental example 3 rat in vivo pharmacokinetic experiment of the Compound of the present invention

Test animal

Male SD rats, each test substance, used 3 rats per administration, weighing 200-.

Test article

Control drug: torin-2, dissolving with 5% of NMP, 40% of PEG400 and 55% of sterile water for injection;

the compounds of the present invention: compound 16 was dissolved with 5% NMP + 60% PEG400+ 35% sterile water for injection, and the remaining compounds were dissolved with 5% NMP + 40% PEG400+ 55% sterile water for injection.

Experimental methods

Administration of drugsThe test article administration and dosage are shown in table 3 below.

TABLE 3Test substance administration mode and dosage

Blood sampling0h before administration (pre-drug), 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration, about 100. mu.L of whole blood was taken at each time point, plasma was separated by centrifugation at 8000rpm for 6 minutes in a high speed centrifuge, and the plasma was frozen at-80 ℃ in a refrigerator.

Plasma sample analysisTreating plasma sample by liquid-liquid extraction, taking 20 μ L of plasma, vortexing at 1500 rpm for 10min, then centrifugating at 12000 rpm for 5 min, taking 400 μ L of supernatant, blow-drying under nitrogen, and re-dissolving with 200 μ L of methanol and water (1: 1, V/V); LC-MS/MS analysis.

Results of the experiment

See table 4 below.

TABLE 4Results of rat PK evaluation of Compounds of the invention (dose see Table 3)

T_1/2Represents the half-life

AUC_lastArea under curve when representing drug_0→t

F% represents absolute bioavailability

Conclusion of the experiment

As can be seen from Table 4, AUC of the compounds of the present invention, whether administered intravenously or orally_lastAUC significantly higher than control drug_lastThe compound of the invention is shown to have good pharmacokinetic property and excellent drug forming property.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuteride thereof:

wherein:

x is O;

R¹is unsubstituted or substituted by 1 to 3R⁸Substituted phenyl;

R²is not coveredSubstituted or substituted by 1-3R^8’A substituted 5-10 membered heterocyclyl;

R³、R⁴and R⁵Each is hydrogen;

R⁶and R⁷Each independently is hydrogen or C_1-4An alkyl group;

R⁸is composed of

(1) Hydroxy, halogen, cyano, amino or-C (O) R^c，

(3) Unsubstituted or substituted by 1-3 substituents selected from cyano, trifluoromethyl, halogen, -C (O) R^c’、-C(O)(CH₂)_nNR^aR^band/or-S (O)₂R^c’A 5-6 membered saturated heteromonocyclic group substituted with the substituent(s);

R^8’is composed of

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterio thereof, wherein

R¹Is unsubstituted or substituted by 1 to 3R⁸Substituted phenyl, wherein R⁸Is (1) amino or-C (O) R^c，R^cIs unsubstituted or hydroxy-or halogen-substituted C_1-4Alkyl, (2) C unsubstituted or substituted by cyano or 1-3 halogens_1-4Alkyl or C_1-4Alkoxy, or (3) 5-6 membered heteromonocyclic group which is unsubstituted or substituted by cyano or trifluoromethyl; and/or

R²Is unsubstituted or substituted by 1 to 3R^8’Substituted 5-6 membered aromatic heteromonocyclic group or 9-10 membered fused heterocyclic group, wherein R^8’Is (1) hydroxy, halogen, amino, cyano, -NHC (O) R^cor-S (O)_mR^cWherein m is 0, 1 or 2, R^cIs C_1-4Alkyl, (2) C unsubstituted or substituted by hydroxy or 1-3 halogens_1-4Alkyl or C_1-4Alkoxy, or (3) unsubstituted or substituted by cyano, trifluoromethyl, halogen, C_1-4Alkyl or C_1-4Alkoxy-substituted 5-6 membered heteromonocyclic group.

3. The compound of claim 2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterio thereof, wherein

R¹Is unsubstituted or substituted by 1-2R⁸Substituted phenyl;

R²is unsubstituted or substituted by 1-2R^8’Substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and mixtures thereof,Azolyl radical, isoAzolyl, thiazoleA group, isothiazolyl, quinolinyl, isoquinolinyl, pyrrolopyridine, dihydropyrrolopyridine, or indolyl group;

R⁸is composed of

R^8’is composed of

(3) Unsubstituted or substituted by C_1-4Alkyl-substituted piperazinyl, pyrazolyl, piperidinyl, morpholinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl or pyrrolidinyl.

4. The compound of claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterate thereof, selected from the group consisting of:

2- (6-aminopyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (4- (2- (6-aminopyridin-3-yl) -9-oxopyrido [3, 2-c ] [1, 5] naphthyridin-10 (9H) -yl) phenyl) -2-methylpropanenitrile,

2- (2-aminopyrimidin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (2-methoxypyrimidin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

n- (5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) pyridin-2-yl) acetamide,

5- (9-oxo-10- (3- (trifluoromethyl) phenyl) -9, 10-dihydropyrido [3, 2-c ] [1, 5] naphthyridin-2-yl) -2-cyanopyridine,

2- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (6- (hydroxymethyl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (6- (1H-pyrazol-1-yl) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one,

2- (6- (methylthio) pyridin-3-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one, and

2- (1H-pyrrolo [2, 3-b ] pyridin-5-yl) -10- (3- (trifluoromethyl) phenyl) pyrido [3, 2-c ] [1, 5] naphthyridin-9 (10H) -one.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuteride thereof.

6. The composition of claim 5 further comprising one or more antineoplastic and/or immunosuppressive agents selected from the group consisting of capecitabine, gemcitabine, pemetrexed disodium; a growth factor inhibitor selected from the group consisting of pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; is an antibody selected from herceptin and bevacizumab; is mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, and doxorubicin; is an antitumor hormone selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; is an alkylating agent selected from cyclophosphamide, mechlorethamine, melphalan, cremastin and carmustine; is a metal platinum group selected from carboplatin, cisplatin and oxaliplatin; is a topoisomerase inhibitor selected from topotecan, irinotecan; is selected from everolimus, sirolimus and anticancer drugs; is purine analog selected from 6-mercaptopurine, 6-thioguanine, azathioprine; is an antibiotic selected from the group consisting of rhzomorph D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; is a platinum complex selected from cisplatin and carboplatin; is an adrenocortical inhibitor selected from aminoglutethimide.

7. A pharmaceutical preparation comprising the compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deutero-derivative thereof and one or more pharmaceutically acceptable carriers, which is in any clinically or pharmaceutically acceptable dosage form.

8. Use of a compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deutero-derivative thereof, for the manufacture of a medicament for the treatment and/or prevention of a proliferative disease.

9. Use of a pharmaceutical composition comprising a compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deutero thereof, in the manufacture of a medicament for the treatment of a proliferative disease.

10. The use of claim 8 or 9, wherein the proliferative disease is a cancer or a non-cancerous proliferative disease selected from brain tumor, lung cancer, non-small cell lung cancer, squamous cell, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumors, non-hodgkin's lymphoma, glioma, glioblastoma multiforme, gliosarcoma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, histiocytoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, Glioblastoma, astrocytoma, neuroblastoma, sarcoma; the non-cancerous proliferative disease is selected from benign hyperplasia of the skin or prostate.

11. A process for the preparation of a compound of general formula (I) according to claim 1, comprising the steps of:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶And R⁷Hal is as defined above¹、Hal²And Hal³Represents halogen, each independently selected from F, Cl, Br and I, and Hal¹、Hal²And Hal³May be the same or different; alk represents lower alkyl; "anhydride" is an organic anhydride;

1. preparation of intermediate 1

2. preparation of intermediate 2

3. preparation of intermediate 2

4. preparation of intermediate 3

and

5. preparation of Compounds of formula (I)

when necessary, the functional group to be protected may be protected, and thereafter the protecting group may be removed by a conventional method.