CN104418853B - Substituted naphthyridines-2-ketonic compound, preparation method, purposes and pharmaceutical composition - Google Patents

Abstract

The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, a preparation method, an application and a pharmaceutical composition. Wherein the compound shown in formula I is as follows: The compound represented by formula I of the present invention has more excellent anticancer or tumor effect, and can simultaneously inhibit multiple kinases present in cells and on the cell surface, including PI3‑K kinase and mTOR kinase, so it has a more potent anticancer effect. Cancer or tumor effect. The pharmaceutical composition of the present invention can be used for treating brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer , colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, sarcoma, osteosarcoma, and rhabdoid myoma.

Description

Substituted naphthyridin-2-one compound, preparation method, use and pharmaceutical composition

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a substituted naphthyridin-2-one compound, a preparation method, an application and a pharmaceutical composition.

Background technique

The research and development of anticancer drugs is a very challenging and significant field in today's life sciences. In recent years, with the rapid development of molecular biology and the further understanding of the occurrence, development and mechanism of cancer, the signal transduction in malignant tumor cells, the regulation of cell cycle, the induction of apoptosis, angiogenesis and the relationship between cells and cells Various basic processes such as the interaction of the extracellular matrix are being gradually elucidated. Therefore, it has become one of the important fields of current drug research and development to find and discover new anti-tumor drugs with high efficiency, low toxicity and strong specificity that selectively act on specific targets, and a new field of anti-cancer drugs-molecular targeted drugs.

Molecularly targeted drugs refer to the therapeutic mode of inhibiting tumor growth at the molecular level by targeting receptors in the process of cell carcinogenesis or key enzymes in the transduction process. It targets the characteristic molecules of tumor cells, and reduces the toxic and side effects on normal cells while exerting anti-tumor effects.

Phosphoinositide 3-kinase (PI3-K) catalyzes the synthesis of phosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P2 and PI(3,4,5)P3(PIP3) . Under the appropriate cellular environment, these three lipids control a variety of physiological processes including cell growth, survival, differentiation and chemotaxis. The major PI3-kinase isoform in cancer is the class I PI3-Kα consisting of a catalytic subunit (p110α) and a regulatory subunit (p85). Several components of the PI3-K/Akt/PTEN pathway are involved in tumorigenesis, play an important role in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis, and motility, and are important contributors to diseases such as cancer, diabetes, and An important component of the molecular mechanisms of diseases such as immune inflammation.

Therefore, PI3-Kα is an attractive and promising target for the development of cancer drugs, which will inhibit the proliferation of cancer cells and avoid the damage of cytotoxic agents to the body and the resistance of cancer cells to cytotoxic agents. However, the existing PI3-Kα inhibitors have the disadvantages of high toxicity and side effects and low therapeutic effect in clinical trials. Therefore, it is urgent to develop new PI3-Kα inhibitors, which can be used as cancer therapeutic drugs in the field of cancer treatment.

Contents of the invention

In order to solve the above-mentioned problems in the prior art, the present invention provides a substituted naphthyridin-2-one compound, a preparation method, an application and a pharmaceutical composition.

Specifically, the present invention provides:

(1) A compound represented by formula I or a pharmaceutically acceptable salt thereof:

in,

R ₁ is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, or C ₃ -C ₁₀ heterocycloalkyl, wherein said C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ Heterocycloalkyl is optionally substituted by -OR ₂ , wherein R ₂ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ hydroxyalkyl; and

R ₃ is selected from hydrogen, or -NHSO ₂ R ₄ , wherein R ₄ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ aryl or C ₅ -C ₁₀ hetero Aryl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ aryl or C ₅ -C ₁₀ heteroaryl is optionally replaced by one or more R ₅ Substituted, each R ₅ is independently selected from halogen, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy.

(2) The compound represented by formula I or a pharmaceutically acceptable salt thereof according to (1), wherein R ₁ is a group as shown below:

Wherein, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₄ alkyl; preferably selected from hydrogen or methyl.

(3) The compound represented by formula I according to (1) or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ heterocycloalkyl , which is optionally substituted by -OR ₂ .

(4) The compound represented by formula I according to ( ₁ ) or a pharmaceutically acceptable salt thereof, wherein, preferably, R is selected from cyclopropyl, cyclopentyl, cyclohexyl, or oxetane Hexyl, which is optionally substituted by -OR ₂ .

(5) The compound represented by formula I or a pharmaceutically acceptable salt thereof according to (1), wherein R ₂ is C ₁ -C ₆ hydroxyalkyl; more preferably -CH ₂ -CH ₂ -OH .

(6) The compound represented by formula I or a pharmaceutically acceptable salt thereof according to (1), wherein R ₃ is -NHSO ₂ R ₄ , wherein,

R ₄ is preferably selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₅ -C ₆ aryl or C ₅ -C ₆ heteroaryl, wherein said C ₁ -C ₄ alkyl , C ₃ -C ₅ cycloalkyl, C ₅ -C ₆ aryl or C ₅ -C ₆ heteroaryl are optionally substituted by one or more R ₅ , each of which R ₅ is independently selected from halogen , cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy.

(7) The compound represented by formula I according to (6) or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, aryl or 5-membered heteroaryl, wherein said C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, aryl or 5-membered heteroaryl are optionally substituted by one or more R ₅ , the The above R ₅ are each independently selected from halogen, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; the 5-membered heteroaryl preferably contains a sulfur atom.

(8) The compound represented by formula I according to (6) or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from aryl or 5-membered heteroaryl, the aryl or 5-membered heteroaryl Heteroaryl is optionally substituted by 1-5 R ₅ , preferably substituted by 1-2 R ₅ ; said R ₅ is selected from halogen, cyano, -CF ₃ or C ₁ -C ₄ alkane Oxygen.

(9) The compound represented by formula I or a pharmaceutically acceptable salt thereof according to (6), wherein R ₄ is selected from C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl, wherein The C ₁ -C ₄ alkyl and C ₃ -C ₅ cycloalkyl are optionally substituted by 1-5 R ₅ , more preferably 1-3 R ₅ substituted; the R ₅ is halogen.

(10) The compound represented by formula I or a pharmaceutically acceptable salt thereof according to (1), wherein the compound represented by formula I is selected from the following compounds:

Compound 1:

Compound 2:

Compound 3:

Compound 4:

Compound 5:

Compound 6:

Compound 7:

Compound 8:

Compound 9:

Compound 10:

Compound 11:

Compound 12:

Compound 13:

Compound 14:

Compound 15:

Compound 16:

Compound 17:

Compound 18:

Compound 19:

Compound 20:

Compound 21:

as well as

Compound 22:

(11) The preparation method of the compound shown in formula I according to any one of (1)-(10), which comprises: making the compound shown in formula A and the compound shown in formula B in the presence of palladium catalyst The following reaction takes place, thereby obtaining the compound shown in formula I:

Wherein, R ₁ and R ₃ are as defined in (1); X is halogen, preferably bromine; and R ₈ is or

(12) The method according to (11), wherein the palladium catalyst is bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride.

(13) The method according to (11), wherein the compound represented by formula A is prepared by the following method:

Make the compound shown in formula L and N-halogenated succinimide take place following halogenation reaction, thereby obtain the compound shown in formula A:

(14) The method according to (13), wherein the compound represented by formula L is prepared by the following method:

The following deprotection reaction occurs between the compound shown in formula K and hydroxylamine hydrochloride, so as to obtain the compound shown in formula L:

(15) The method according to (14), wherein the compound represented by formula K is prepared by the following method:

In the presence of potassium tert-butoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene, the compound shown in formula J undergoes the following ring closure reaction to obtain the compound shown in formula K compound of:

(16) The method according to (15), wherein the compound represented by formula J is prepared by the following method:

Make the compound shown in formula H react with ethyl acrylate in the presence of a palladium catalyst as follows to obtain the compound shown in formula J:

Wherein, X is a halogen, preferably bromine; the palladium catalyst is preferably tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphine) base) ferrocene]palladium dichloride, more preferably tetrakis(triphenylphosphine)palladium.

(17) The method according to (16), wherein the compound represented by formula H is prepared by the following method:

The compound shown in formula F and the compound shown in formula G are reacted as follows in the presence of acid-binding agent diisopropylethylamine, thereby obtaining the compound shown in formula H:

Wherein, X is halogen, preferably bromine.

(18) The method according to (17), wherein the compound represented by formula F is prepared by the following method:

Make the compound shown in formula E and iodine take place following iodination reaction in the presence of lithium diisopropylamide group, thereby obtain the compound shown in formula F:

Wherein, X is halogen, preferably bromine.

(19) The method according to (18), wherein the compound represented by formula E is prepared by the following method:

Make the compound shown in formula C and the compound shown in formula D react as follows under the presence of catalyzer p-toluenesulfonic acid, thereby obtain the compound shown in formula E:

Wherein, X is halogen, preferably bromine.

(20) The method according to (11), wherein,

When _R8 is , the compound shown in formula B is prepared by the following method:

The compound represented by formula M and the compound represented by formula N are reacted as follows in the presence of catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, thereby obtaining the compound represented by formula B Compounds shown:

(21) According to any one of (1)-(10), the compound represented by formula I or a pharmaceutically acceptable salt thereof is used for the treatment and/or prevention of PI3-K kinase and/or mTOR kinase Use in medicines that cause disease.

(22) The use according to (21), wherein the PI3-K kinase is PI3-Kα kinase.

(23) The use according to (21), wherein the disease is cancer or tumor.

(24) The use according to (21), wherein the disease is selected from brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small One or more of lung cancer, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, sarcoma, osteosarcoma, and rhabdoid myoma .

(25) A pharmaceutical composition for treating and/or preventing diseases caused by PI3-K kinase and/or mTOR kinase, said pharmaceutical composition comprising any one of (1)-(10) The compound represented by formula I and/or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

Compared with the prior art, the present invention has the following advantages and positive effects:

The present invention provides a new class of naphthyridin-2-one compounds for the first time. Compared with existing compounds, the compound represented by formula I of the present invention has better anti-cancer or tumor effects, and can simultaneously inhibit multiple existing Intracellular and cell surface kinases, including PI3-K kinase and mTOR kinase, thus have comparable or stronger anticancer or tumor effects.

The pharmaceutical composition of the present invention can be used for treating brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer , colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, sarcoma, osteosarcoma, and rhabdoid myoma.

detailed description

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

In the description and claims of the present invention, the compounds are named according to the chemical structural formula. If the naming of the compound is inconsistent with the chemical structural formula when representing the same compound, the chemical structural formula or chemical reaction formula shall prevail.

In the present invention, the "Me" is methyl.

In the present invention, the wavy line in the substituent " " means that the group of the substituent is connected with the group of the main chain (for example, benzene ring) through a chemical bond at the position of the wavy line.

The present inventors have conducted extensive research on compounds with PI3-K kinase inhibitory activity, and unexpectedly found that by replacing the 1-nitrogen atom in the compound shown in formula a with a carbon atom, that is, with a pyrimidopyridine ring, it can The resulting compound has the inhibitory activity of both PI3K and mTOR kinases.

Wherein R is a substituent, which may be the same or different. On the basis of this discovery, the present inventors further screened and optimized the substituent R in order to obtain higher inhibitory activities of the two kinases of PI3K and mTOR, thereby further obtaining the technical solution of the present invention.

Specifically, the present invention provides:

(1) Compounds shown in formula I

The present invention firstly provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

in,

R ₁ is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, or C ₃ -C ₁₀ heterocycloalkyl, wherein said C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ Heterocycloalkyl is optionally substituted by -OR ₂ , wherein R ₂ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ hydroxyalkyl; and

R ₃ is selected from hydrogen, or That is -NHSO ₂ R ₄ , wherein, R ₄ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ aryl or C ₅ -C ₁₀ heteroaryl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ aryl or C ₅ -C ₁₀ heteroaryl are optionally substituted by one or more R ₅ , said Each R ₅ is independently selected from halogen, cyano, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy.

Preferably, R is _a group as shown below:

Wherein, R ₆ and R ₇ are independently selected from hydrogen or C ₁ -C ₄ alkyl; more preferably, R ₆ and R ₇ are independently selected from hydrogen or methyl.

Preferably, R ₁ is selected from C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ heterocycloalkyl, which is optionally substituted by -OR ₂ .

Preferably, R ₁ is selected from cyclopropyl, cyclopentyl, cyclohexyl, or oxanyl, optionally substituted by -OR ₂ .

Preferably, R ₁ is selected from or It is optionally substituted with -OR ₂ .

Preferably, R ₂ is C ₁ -C ₆ hydroxyalkyl. More preferably, R ₂ is -CH ₂ -CH ₂ -OH.

Preferably, _R3 is That is -NHSO ₂ R ₄ .

The present inventors unexpectedly found by analyzing the co-crystal X-ray diffraction pattern of PI3Kγ that the interaction site between 2-methoxypyridine and PI3Kγ receptor is the same as the compound GSK2126458 of GlaxoSmithKline (Knight, S.D.et.al.Discovery of GSK2126458, a highly potent inhibitor of PI3K and themammalian target of rapamycin. ACS Med. Chem. Lett. 2010, 1, 39–43), so the introduction of a sulfonamide substituent at its 3-position can be compatible with the PI3Kγ receptor Lys833 produces hydrogen bonding, thereby enhancing the activity of the compound. In particular, the introduction of 2,4-difluorobenzenesulfonamide at its 3-position interacts with the hydrophobic pocket of PI3K kinase to generate Van der Waals force, which can further enhance the activity of the compound.

Preferably, R ₄ is preferably selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₅ -C ₆ aryl or C ₅ -C ₆ heteroaryl, wherein said C ₁ - C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₅ -C ₆ aryl or C ₅ -C ₆ heteroaryl are optionally substituted by one or more R ₅ , each of which R ₅ is independently is selected from halogen, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy.

More preferably, R ₄ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, aryl or 5-membered heteroaryl, wherein said C ₁ -C ₄ alkyl, C ₃ - C ₅ cycloalkyl, aryl or 5-membered heteroaryl is optionally substituted by one or more R ₅ , each of which R ₅ is independently selected from halogen, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy. More preferably, said 5-membered heteroaryl contains a sulfur atom.

More preferably, R ₄ is selected from aryl or 5-membered heteroaryl, and said aryl or 5-membered heteroaryl is optionally substituted by 1-5 R ₅ , more preferably 1- 2 R ₅ substituted; said R ₅ is selected from halogen, cyano, -CF ₃ or C ₁ -C ₄ alkoxy.

Preferably, R ₄ is selected from C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl, wherein said C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl is optionally replaced by 1 -5 R ₅ substituted, more preferably 1-3 R ₅ substituted; said R ₅ is halogen.

Preferably, the compound shown in formula I is selected from the following compounds:

Compound 1:

Compound 2:

Compound 3:

Compound 4:

Compound 5:

Compound 6:

Compound 7:

Compound 8:

Compound 9:

Compound 10:

Compound 11:

Compound 12:

Compound 13:

Compound 14:

Compound 15:

Compound 16:

Compound 17:

Compound 18:

Compound 19:

Compound 20:

Compound 21:

as well as

Compound 22:

The pharmaceutically acceptable salt of the compound shown in formula I of the present invention is selected from:

a) salts of inorganic and organic acids selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid , 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid ;

b) Salts of organic and inorganic bases selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium cations, aliphatic substituted ammonium cations, and aryl substituted ammonium cations.

(2) The preparation method of the compound shown in formula I:

The present invention secondly provides a kind of preparation method of the compound shown in formula I, it comprises:

Make the compound shown in formula A and the compound shown in formula B react as follows under the presence of palladium catalyst, thereby obtain the compound shown in formula I:

wherein R and _R are as defined in claim ₁ ; X is halogen, preferably bromine; and _R is or

Preferably, the palladium catalyst is bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

Preferably, the compound shown in formula A is prepared by the following method:

Make the compound shown in formula L and N-halogenated succinimide take place following halogenation reaction, thereby obtain the compound shown in formula A:

More preferably, the compound shown in formula L is prepared by the following method:

The following deprotection reaction occurs between the compound shown in formula K and hydroxylamine hydrochloride, so as to obtain the compound shown in formula L:

More preferably, the compound shown in formula K is prepared by the following method:

In the presence of potassium tert-butoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene, the compound shown in formula J undergoes the following ring closure reaction to obtain the compound shown in formula K compound of:

More preferably, the compound shown in formula J is prepared by the following method:

Make the compound shown in formula H react with ethyl acrylate in the presence of a palladium catalyst as follows to obtain the compound shown in formula J:

Wherein, X is a halogen, preferably bromine; more preferably, the palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride, preferably tetrakis(triphenylphosphine)palladium.

More preferably, the compound shown in formula H is prepared by the following method:

The compound shown in formula F and the compound shown in formula G are reacted as follows in the presence of acid-binding agent diisopropylethylamine, thereby obtaining the compound shown in formula H:

Wherein, X is halogen, preferably bromine.

More preferably, the compound shown in formula F is prepared by the following method:

Make the compound shown in formula E and iodine take place following iodination reaction in the presence of lithium diisopropylamide group, thereby obtain the compound shown in formula F:

Wherein, X is halogen, preferably bromine.

More preferably, the compound shown in formula E is prepared by the following method:

Make the compound shown in formula C and the compound shown in formula D react as follows under the presence of catalyzer p-toluenesulfonic acid, thereby obtain the compound shown in formula E:

Wherein, X is halogen, preferably bromine.

In a preferred embodiment of the present invention, the compound shown in formula A is prepared by the following method:

1) The compound shown in formula C and the compound shown in formula D are reacted as follows in the presence of catalyst p-toluenesulfonic acid, so as to obtain the compound shown in formula E:

Wherein, X is halogen, preferably bromine;

2) Make the compound shown in formula E react with iodine as follows in the presence of lithium diisopropylamide to obtain the compound shown in formula F:

Wherein, X is halogen, preferably bromine;

3) The compound represented by formula F and the compound represented by formula G are reacted as follows in the presence of the acid-binding agent diisopropylethylamine, thereby obtaining the compound represented by formula H:

Wherein, X is halogen, preferably bromine;

4) make the following reaction between the compound shown in formula H and ethyl acrylate in the presence of palladium catalyst, so as to obtain the compound shown in formula J:

Wherein, X is a halogen, preferably bromine; more preferably, the palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride, preferably tetrakis(triphenylphosphine)palladium;

5) In the presence of potassium tert-butoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene, the compound represented by formula J undergoes the following ring closure reaction to obtain formula K Compounds shown:

6) The following deprotection reaction occurs between the compound represented by formula K and hydroxylamine hydrochloride to obtain the compound represented by formula L:

;as well as

7) The following halogenation reaction occurs between the compound represented by formula L and N-halogenated succinimide to obtain the compound represented by formula A:

Preferably, when R ₈ is , the compound shown in formula B is prepared by the following method:

The compound represented by formula M and the compound represented by formula N are reacted as follows in the presence of catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, thereby obtaining the compound represented by formula B Compounds shown:

(3) Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof

The present invention again provides the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating and/or preventing diseases caused by PI3-K kinase and/or mTOR kinase.

The compound represented by formula I of the present invention is a multi-kinase inhibitor, which can simultaneously inhibit multiple kinases present in cells and on the cell surface, including: PI3-K kinase and mTOR kinase. More preferably, the PI3-K kinase is PI3-Kα kinase.

Preferably, the disease is cancer or tumor.

Preferably, the disease is selected from brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin Cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, sarcoma, osteosarcoma, and rhabdoid myoma.

(4) A pharmaceutical composition for treating and/or preventing diseases caused by PI3-K kinase and/or mTOR kinase

Finally, the present invention provides a pharmaceutical composition for treating and/or preventing diseases caused by PI3-K kinase and/or mTOR kinase, said pharmaceutical composition comprising a compound represented by formula I and/or its pharmaceutical composition acceptable salts, and pharmaceutically acceptable excipients.

Preferably, the dosage form of the pharmaceutical composition is injection, oral preparation, transdermal absorption or suppository.

The content of the present invention is further explained or illustrated by way of examples below, but these examples should not be construed as limiting the protection scope of the present invention.

In the following examples, unless otherwise specified, all reagents are commercially available, for example, from Bailingwei Technology Co., Ltd., Alpha Aisha (Tianjin) Chemical Co., Ltd. or Beijing Coupling Technology Co., Ltd.

In the following example, the formula for calculating the yield is: yield = product weight × raw material molar mass / (raw material weight × product molar mass).

Example 1: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (Compound 1)

Preparation:

Step 1: Synthesis of 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-2-methylpyridine

A mixture of 2-amino-5-bromo-6-methylpyridine (38.2g, 204mmol), 2,5-hexanedione (36mL, 306mmol), p-toluenesulfonic acid monohydrate (1.94g, 10.2mmol) and A three-necked flask of 380mL toluene was connected with a water separator and a condenser, and the reaction mixture was refluxed for 6h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (500 mL), washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100:1, v/v) to obtain the product as a brown oil (41.4 g, yield 76%).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.17(d, J=8.4Hz, 1H), 7.21(d, J=8.4Hz, 1H), 5.80(s, 2H), 2.60(s, 3H) , 2.06(s, 6H).

Step 2: Synthesis of 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine

Under argon atmosphere, n-butyllithium (69.69mmol, prepared as 2.4M n-hexane solution 29mL) was added dropwise to diisopropylamine (9.83mL, 69.69mmol) in anhydrous tetrahydrofuran (60mL) at -30°C solution, and the reaction mixture was stirred at -30°C for 30 min. After cooling down to -78°C, 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-2-picoline (16.8g, 63.36mmol) was added dropwise in anhydrous tetrahydrofuran (120mL ), and the reaction mixture was stirred at -78 °C for 30 min. A solution of iodine (17.7 g, 69.69 mmol) in anhydrous tetrahydrofuran (120 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water (400 mL), extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=150:1, v/v) to obtain the product as a yellow solid (13.09 g, yield 53%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.84(s, 1H), 5.80(s, 2H), 2.71(s, 3H), 2.08(s, 6H)

Step 3: Synthesis of 3-bromo-N-cyclopentyl-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-amine

In a sealed tube, mix 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine (9.5 g, 24.3 mmol), cyclopentylamine ( 6.21 g, 72.9 mmol), a solution of diisopropylethylamine (9.42 g, 72.9 mmol) in N-methylpyrrolidone (95 mL) was stirred at 160°C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 80:1, then petroleum ether/ethyl acetate = 50:1, v/v) to give the product as a yellow solid (6.0 g, 56% yield ).

¹ H NMR (400MHz, DMSO-d ₆ ) δ6.44(s, 1H), 5.75(s, 2H), 5.66(d, J=7.2Hz, 1H), 3.95-3.91(m, 1H), 2.47( s, 3H), 2.06 (s, 6H), 1.99-1.95 (m, 2H), 1.68-1.55 (m, 6H)

MS(ESI+)m/z348.0[M+H] ⁺

Step 4: (E)-3-(4-(cyclohexylamino)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-3-yl)acrylic acid ethyl Synthesis of esters

In a sealed tube, 3-bromo-N-cyclopentyl-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-amine (7.2 g, 20.67 mmol) and ethyl acrylate (6.6 mL, 62.01 mmol) in triethylamine (70 mL) was bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (2.39 g, 2.067 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 135°C, cooled and concentrated. Water (200 mL) was added, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×2) and saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50:1, then petroleum ether/ethyl acetate=12:1, v/v) to obtain the product as a yellow oil (6.46g, yield 85% ).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.62(d, J=16.4Hz, 1H), 6.40(s, 1H), 6.29(d, J=16.4Hz, 1H), 6.05(d, J= 6.8Hz, 1H), 5.75(s, 2H), 4.21(q, J=7.2Hz, 2H), 3.88-3.84(m, 1H), 2.38(s, 3H), 2.08(s, 6H), 1.91- 1.97(m, 2H), 1.50-1.47(m, 6H), 1.28(t, J=7.2Hz, 3H).

MS(ESI+)m/z368.2[M+H] ⁺

Step 5: Synthesis of 1-cyclopentyl-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-1,6-naphthyridin-2(1H)-one

Under argon atmosphere, (E)-3-(4-(cyclopentylamino)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridine-3- base) ethyl acrylate (279mg, 0.76mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene (568μL, 3.8mmol) and potassium tert-butoxide (43mg, 0.38mmol ) in N,N-dimethylformamide (6 mL) was stirred overnight at 150 °C. After cooling to room temperature, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10:1, then petroleum ether/ethyl acetate = 8:1, v/v) to give the product as a yellow oil (66 mg, 27% yield ).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.14(d, J=9.8Hz, 1H), 7.47(s, 1H), 6.65(d, J=9.7Hz, 1H), 5.83(s, 2H) , 5.48-5.28(m, 1H), 2.74(s, 3H), 2.19-2.04(m, 2H), 2.11(s, 6H), 1.90(dd, J=16.7, 10.2Hz, 4H), 1.73-1.57 (m, 2H).

MS(ESI+)m/z322.1[M+H] ⁺

Step 6: Synthesis of 7-amino-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one

1-cyclopentyl-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-1,6-naphthyridin-2(1H)-one (66mg, 0.21mmol ) and hydroxylamine hydrochloride (73 mg, 1.05 mmol) in ethanol and water (4 mL:0.4 mL) were refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:3, then ethyl acetate/triethylamine = 100:1, v/v) to give the product as a yellow foamy solid (22 mg, The yield was 44%).

MS(ESI+)m/z244.0[M+H] ⁺

Step 7: Synthesis of 7-amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one

N-bromosuccinimide (56mg, 0.315mmol) was added to 7-amino-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (100mg, 0.315 mmol) in a solution of N,N-dimethylformamide (2 mL), and the reaction solution was stirred at room temperature for 1 h. 20 mL of water was added, and the resulting mixture was extracted with ethyl acetate (20 mL×5). The combined organic layer was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (20 mg, yield 76%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.29(s, 1H), 6.50(s, 2H), 6.29(s, 1H), 5.27(p, J=8.8Hz, 1H), 2.19-1.93( m, 4H), 1.92-1.75(m, 2H), 1.73-1.56(m, 2H).

MS(ESI+)m/z321.9[M+H] ⁺

Step 8: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

A solution of 2,4-difluorobenzenesulfonyl chloride (510 mg, 2.4 mmol, 1.2 eq) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature overnight. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (590 mg, yield 78%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.46(s, 1H), 8.13(d, J=2.3Hz, 1H), 7.84-7.70(m, 2H), 7.64-7.51(m, 1H), 7.23(td, J=8.5, 2.0Hz, 1H), 3.61(s, 3H).

Step 9: N-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-3-yl)- Synthesis of 2,4-difluorobenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (576mg, 1.52mmol), anhydrous potassium acetate (300mg, 3.04mmol) and diboronic acid A mixture of nicohol ester (466mg, 1.84mmol) in dioxane (7mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56mg, 0.076 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 3 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (480 mg, yield 74%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18(s, 1H), 8.20(d, J=1.5Hz, 1H), 7.80-7.63(m, 2H), 7.56(dd, J=14.3, 5.5 Hz, 1H), 7.20(t, J=7.5Hz, 1H), 3.61(s, 3H), 1.29(s, 12H).

Step 10: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (90mg, 0.28mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide ( 143 mg, 0.336 mmol) and potassium carbonate (166 mg, 1.2 mmol) in N,N-dimethylformamide and water (3 mL/0.6 mL) were degassed and bis(triphenylphosphine) dichlorinated Palladium (20 mg, 0.028 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:1 then petroleum ether/ethyl acetate = 1:2, v/v) to give the product as a yellow solid (103 mg, 68% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.19(s, 1H), 8.28(d, J=2.4Hz, 1H), 7.94(s, 1H), 7.92(d, J=2.4Hz, 1H) , 7.76-7.70(m, 1H), 7.62-7.52(m, 1H), 7.20(td, J=8.4, 2.4Hz, 1H), 6.44(s, 2H), 6.30(s, 1H), 5.38-5.29 (m, 1H), 3.63(s, 3H), 2.57(s, 3H), 2.18-2.12(m, 2H), 2.08-2.01(m, 2H), 1.90-1.82(m, 2H), 1.71-1.64 (m, 2H)

MS(ESI+)m/z541.9[M+H] ⁺ .

Example 2: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-4-cyanobenzenesulfonamide (compound 2)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-4-cyanobenzenesulfonamide

A solution of 4-cyanobenzenesulfonyl chloride (482 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 4 h. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (699 mg, yield 95%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ10.49(s, 1H), 8.12(d, J=2.3Hz, 1H), 8.07(d, J=8.5Hz, 2H), 7.90(d, J= 8.5Hz, 2H), 7.76(d, J=2.3Hz, 1H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base)-4-cyanobenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-4-cyanobenzenesulfonamide (368mg, 1.0mmol), anhydrous potassium acetate (196mg, 2mmol) and diboronic acid pinacol ester (bis(pinacolato)diboron) (304mg, 1.2mmol) in dioxane (7mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (37 mg, 0.05 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1, v/v) to obtain the product as a yellow solid (360 mg, yield 87%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.22(s, 1H), 8.24(d, J=1.6Hz, 1H), 7.73(d, J=1.6Hz, 1H), 7.30(d, J= 4.0Hz, 1H), 7.21(d, J=4.0Hz, 1H), 3.71(s, 3H), 1.30(s, 12H).

MS(ESI+)m/z333.9[M+H] ⁺

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-4-cyanobenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-cyanobenzenesulfonamide (100mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide-water (5mL:0.20mL) mixture was degassed, and [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (75 mg, yield 71%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.23(s, 1H), 8.26(d, J=2.2Hz, 1H), 8.07(d, J=8.6Hz, 2H), 7.94(s, 1H) , 7.92(d, J=2.2Hz, 1H), 7.91(d, J=8.6Hz, 2H), 6.45(s, 2H), 6.30(s, 1H), 5.40-5.26(m, 1H), 3.60( s, 3H), 2.57(s, 3H), 2.21-2.10(m, 2H), 2.09-1.99(m, 2H), 1.92-1.80(m, 2H), 1.73-1.61(m, 2H).

Example 3: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide (Compound 3)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide

A solution of 4-(trifluoromethyl)benzenesulfonyl chloride (587 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and Pyridine (237 mg, 3 mmol) was dissolved in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 4 h. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (690 mg, yield 84%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.42(s, 1H), 8.11(d, J=2.4Hz, 1H), 7.98(d, J=8.8Hz, 2H), 7.94(d, J= 8.8Hz, 2H), 7.76(d, J=2.4Hz, 1H), 3.54(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of -4-(trifluoromethyl)benzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide (411mg, 1.0mmol), anhydrous potassium acetate (196mg, 2mmol) and biboronic acid A mixture of pinacol ester (304 mg, 1.2 mmol) in dioxane (7 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg , 0.05 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (390 mg, yield 85%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.14(s, 1H), 8.20(d, J=1.6Hz, 1H), 7.96(d, J=8.4Hz, 2H), 7.87(d, J= 8.4Hz, 2H), 7.69(d, J=1.6Hz, 1H), 3.54(s, 3H), 1.29(s, 12H)

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonate A mixture of amide (110mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide-water (5mL:0.20mL) was degassed and [1,1' - Bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=60:1, v/v) to obtain the product as a yellow solid (91 mg, yield 78%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18(s, 1H), 8.26(d, J=2.2Hz, 1H), 8.03-7.90(m, 6H), 6.45(s, 2H), 6.30( s, 1H), 5.41-5.27(m, 1H), 3.57(s, 3H), 2.57(s, 3H), 2.23-2.10(m, 2H), 2.10-1.95(m, 2H), 1.94-1.78( m, 2H), 1.74-1.58 (m, 2H).

Example 4: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide (compound 4)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide

A solution of 2-(trifluoromethyl)benzenesulfonyl chloride (587 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and Pyridine (237 mg, 3 mmol) was dissolved in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 4 h. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (660 mg, yield 80%).

¹ H NMR (400MHz, CD ₃ OD) δ8.07-7.89(m, 3H), 7.88-7.62(m, 3H), 3.69(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of )-2-(trifluoromethyl)benzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide (411mg, 1.0mmol), anhydrous potassium acetate (196mg, 2mmol) and biboronic acid A mixture of pinacol ester (304 mg, 1.2 mmol) in dioxane (7 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg , 0.05 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (349 mg, yield 76%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.96(s, 1H), 8.19(d, J=1.6Hz, 1H), 8.06-7.96(m, 1H), 7.96-7.90(m, 1H), 7.88-7.77(m, 2H), 7.72(d, J=1.6Hz, 1H), 3.56(s, 3H), 1.28(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonate A mixture of amide (110mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide and water (5mL/0.20mL) was degassed and [1,1' - Bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (76 mg, yield 67%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.00(s, 1H), 8.26(d, J=2.2Hz, 1H), 8.05-7.98(m, 2H), 7.92(d, J=2.2Hz, 1H), 7.91(s, 1H), 7.87-7.78(m, 2H), 6.44(s, 2H), 6.30(s, 1H), 5.44-5.22(m, 1H), 3.59(s, 3H), 2.56 (s, 3H), 2.22-2.09(m, 2H), 2.09-1.96(m, 2H), 1.92-1.78(m, 2H), 1.74-1.59(m, 2H).

Example 5: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide (Compound 5)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (588 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and Pyridine (237 mg, 3 mmol) was dissolved in dichloromethane (5 mL) and the reaction mixture was stirred at room temperature overnight. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (320 mg, yield 39%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.43(s, 1H), 8.12(d, J=2.3Hz, 1H), 8.09-8.05(m, 2H), 8.00(d, J=8.0Hz, 1H), 7.82(t, J=8.0Hz, 1H), 7.77(d, J=2.3Hz, 1H), 3.54(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of )-3-(trifluoromethyl)benzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide (270mg, 0.66mmol), anhydrous potassium acetate (130mg, 1.32mmol) and A mixture of pinacol borate (167 mg, 0.79 mmol) in dioxane (6 mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 25mg, 0.033mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1, v/v) to obtain the product as a yellow solid (220 mg, yield 73%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.20(s, 1H), 8.18(d, J=1.7Hz, 1H), 8.05(d, J=7.9Hz, 1H), 8.00(s, 1H) , 7.95(d, J=7.9Hz, 1H), 7.81(t, J=7.9Hz, 1H), 7.71(d, J=1.7Hz, 1H), 3.57(s, 3H), 1.29(s, 12H) .

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonate A mixture of amide (110 mg, 0.24 mmol) and potassium carbonate (83 mg, 0.60 mmol) in N,N-dimethylformamide and water (4 mL: 0.20 mL) was degassed and [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (101 mg, yield 88%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.19(s, 1H), 8.25(d, J=2.1Hz, 1H), 8.11(s, 1H), 8.08-7.97(m, 3H), 7.95( s, 1H), 7.81(t, J=7.8Hz, 1H), 6.45(s, 2H), 6.30(s, 1H), 5.44-5.28(m, 1H), 3.58(s, 3H), 2.57(s , 3H), 2.22-2.10(m, 2H), 2.10-1.99(m, 2H), 1.94-1.79(m, 2H), 1.75-1.58(m, 2H).

Example 6: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-4-fluorobenzenesulfonamide (Compound 6)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

A solution of 4-fluorobenzenesulfonyl chloride (467 mg, 2.4 mmol, 1.2 eq) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine ( 237 mg, 3 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature overnight. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (590 mg, yield 82%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.21(s, 1H), 8.08(d, J=2.3Hz, 1H), 7.82(dd, J=8.9, 5.2Hz, 2H), 7.72(d, J=2.3Hz, 1H), 7.43(t, J=8.9Hz, 2H), 3.63(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base)-4-fluorobenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide (550mg, 1.52mmol), anhydrous potassium acetate (300mg, 3.04mmol) and diboronic acid pinacol ester (466mg, 1.84mmol) in dioxane (7mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56mg, 0.076mmol) Add to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (374 mg, yield 60%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.92(s, 1H), 8.17(d, J=1.6Hz, 1H), 7.82(dd, J=8.9, 5.2Hz, 2H), 7.71(d, J=1.6Hz, 1H), 7.40(t, J=8.9Hz, 2H), 3.61(s, 3H), 1.29(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-4-fluorobenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (103mg, 0.24 mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide-water (4mL:0.20mL) mixture was degassed, and [1,1'-bis(diphenyl phosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (56 mg, yield 53%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.93(s, 1H), 8.23(d, J=2.2Hz, 1H), 7.92(d, J=2.2Hz, 1H), 7.91(s, 1H) , 7.82(dd, J=8.9, 5.2Hz, 2H), 7.41(t, J=8.8Hz, 2H), 6.44(s, 2H), 6.30(s, 1H), 5.41-5.23(m, 1H), 3.65(s, 3H), 2.57(s, 3H), 2.22-2.09(m, 2H), 2.08-2.00(m, 2H), 1.92-1.81(m, 2H), 1.71-1.61(m, 2H).

Example 7: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-2-fluorobenzenesulfonamide (Compound 7)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide

A solution of 2-fluorobenzenesulfonyl chloride (467 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) ) in dichloromethane (5 mL), the reaction mixture was stirred overnight at room temperature. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (588 mg, yield 82%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.40(s, 1H), 8.11(d, J=2.3Hz, 1H), 7.76-7.66(m, 3H), 7.49-7.42(m, 1H), 7.34(td, J=7.8, 1.0Hz, 1H), 3.59(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base)-2-fluorobenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide (580mg, 1.60mmol), anhydrous potassium acetate (315mg, 3.20mmol) and biboronic acid pinacol ester (490mg, 1.92mmol) in dioxane (7mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59mg, 0.08mmol) Add to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1, v/v) to obtain the product as a yellow solid (350 mg, yield 54%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.12(s, 1H), 8.18(d, J=1.7Hz, 1H), 7.72(d, J=1.7Hz, 1H), 7.71-7.60(m, 2H), 7.49-7.40(m, 1H), 7.34-7.25(m, 1H), 3.59(s, 3H), 1.29(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-2-fluorobenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (100mg, 0.30mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-fluorobenzenesulfonamide (148mg, 0.36 mmol) and potassium carbonate (125 mg, 0.90 mmol) in N, N-dimethylformamide and water (5 mL:0.30 mL) were degassed, and [1,1'-bis(diphenylphosphino ) ferrocene] palladium dichloride (22 mg, 0.03 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=50:1, v/v) to obtain the product as a yellow solid (120 mg, yield 76%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.12(s, 1H), 8.25(d, J=2.0Hz, 1H), 7.93(d, J=2.0Hz, 1H), 7.92(s, 1H) , 7.73-7.64(m, 2H), 7.51-7.40(m, 1H), 7.30(t, J=7.6Hz, 1H), 6.44(s, 2H), 6.30(s, 1H), 5.41-5.26(m , 1H), 3.59(s, 3H), 2.57(s, 3H), 2.24-2.10(m, 2H), 2.10-2.00(m, 2H), 1.95-1.77(m, 2H), 1.75-1.59(m , 2H).

MS(ESI+)m/z524.0[M+H] ⁺

Example 8: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-3-fluorobenzenesulfonamide (Compound 8)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-3-fluorobenzenesulfonamide

A solution of 3-fluorobenzenesulfonyl chloride (467 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) ) in dichloromethane (5 mL), the reaction mixture was stirred overnight at room temperature. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (560 mg, yield 74%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.33(s, 1H), 8.10(d, J=2.2Hz, 1H), 7.72(d, J=2.3Hz, 1H), 7.69-7.50(m, 4H), 3.63(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base)-3-fluorobenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-3-fluorobenzenesulfonamide (550mg, 1.52mmol), anhydrous potassium acetate (300mg, 3.04mmol) and biboronic acid pinacol ester (466mg, 1.84mmol) in dioxane (7mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59mg, 0.08mmol) Add to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (400 mg, yield 65%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.06(s, 1H), 8.18(d, J=1.6Hz, 1H), 7.72(d, J=1.6Hz, 1H), 7.67-7.57(m, 1H), 7.56-7.47(m, 3H), 3.62(s, 3H), 1.29(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-3-fluorobenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (81mg, 0.25mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-fluorobenzenesulfonamide (123mg, 0.30 mmol) and potassium carbonate (103 mg, 0.75 mmol) in N, N-dimethylformamide and water (4 mL:0.25 mL) were degassed, and [1,1'-bis(diphenylphosphino ) ferrocene] palladium dichloride (20 mg, 0.025 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=50:1, v/v) to obtain the product as a yellow solid (104 mg, yield 80%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.06(s, 1H), 8.22(d, J=2.0Hz, 1H), 7.94(d, J=2.0Hz, 1H), 7.92(s, 1H) , 7.65-7.48(m, 5H), 6.44(s, 2H), 6.30(s, 1H), 5.41-5.24(m, 1H), 3.65(s, 3H), 2.56(s, 3H), 2.24-2.10 (m, 2H), 2.10-1.96(m, 2H), 1.94-1.78(m, 2H), 1.74-1.58(m, 2H).

Example 9: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-5-chlorothiophene-2-sulfonamide (Compound 9)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-5-chlorothiophene-2-sulfonamide

A solution of 5-chloro-thiophene-2-sulfonyl chloride (521 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred at room temperature for 4 h. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (755 mg, yield 98%).

¹ H NMR (300MHz, CD ₃ OD) δ8.01(d, J=2.1Hz, 1H), 7.88(d, J=2.1Hz, 1H), 7.33(d, J=3.9Hz, 1H), 7.02( d, J=3.9Hz, 1H), 3.79(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of -5-chlorothiophene-2-sulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-5-chlorothiophene-2-sulfonamide (595mg, 1.55mmol), anhydrous potassium acetate (306mg, 3.1mmol) and diboronic acid A mixture of nicohol ester (472mg, 1.86mmol) in dioxane (10mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60mg, 0.08 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (458 mg, yield 69%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.22(s, 1H), 8.24(d, J=1.7Hz, 1H), 7.73(d, J=1.7Hz, 1H), 7.30(d, J= 4.1Hz, 1H), 7.21(d, J=4.1Hz, 1H), 3.71(s, 3H), 1.30(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-5-chlorothiophene-2-sulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-5-chlorothiophene-2-sulfonamide ( 104mg, 0.24mmol) and potassium carbonate (83mg, 0.60mmol) in N, N-dimethylformamide and water (4mL: 0.20mL) mixture degassed, and [1,1'- bis (diphenyl phosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (64 mg, yield 59%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.23(s, 1H), 8.30(d, J=2.1Hz, 1H), 7.97(d, J=2.1Hz, 1H), 7.96(s, 1H) , 7.39(d, J=4.1Hz, 1H), 7.22(d, J=4.1Hz, 1H), 6.44(s, 2H), 6.31(s, 1H), 5.44-5.24(m, 1H), 3.74( s, 3H), 2.58(s, 3H), 2.21-2.11(m, 2H), 2.11-1.99(m, 2H), 1.92-1.80(m, 2H), 1.72-1.60(m, 2H).

Example 10: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -methoxypyridin-3-yl)methanesulfonamide (compound 10)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide

A solution of methanesulfonyl chloride (275mg, 2.4mmol, 1.2eq) in dichloromethane (5mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol) ) in dichloromethane (5 mL), the reaction mixture was stirred overnight at room temperature. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1, v/v) to obtain the product as a yellow solid (498 mg, yield 89%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.49(s, 1H), 8.09(d, J=2.3Hz, 1H), 7.78(d, J=2.3Hz, 1H), 3.91(s, 3H) , 3.10(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Base) Synthesis of Methanesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (490mg, 1.74mmol), anhydrous potassium acetate (315mg, 3.20mmol) and diboronic acid pinacol ester (531mg, 2.09 mmol) in dioxane (10 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (64 mg, 0.087 mmol) was added to the mixture . The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1, v/v) to obtain the product as a yellow solid (410 mg, yield 72%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.25(s, 1H), 8.21(d, J=1.7Hz, 1H), 7.77(d, J=1.7Hz, 1H), 3.94(s, 3H) , 3.01(s, 3H), 1.30(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)methanesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (97mg, 0.30mmol), N-(2-methoxy-5 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (119 mg, 0.36 mmol) and carbonic acid A mixture of potassium (125mg, 0.90mmol) in N,N-dimethylformamide and water (5mL:0.30mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (22 mg, 0.03 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia in methanol = 100:1 then dichloromethane/10% ammonia in methanol = 80:1, v/v) to give the product as a yellow solid (84 mg, yield rate of 64%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.26(s, 1H), 8.26(d, J=2.2Hz, 1H), 7.96(s, 1H), 7.95(d, J=2.1Hz, 1H) , 6.44(s, 2H), 6.29(s, 1H), 5.47-5.29(m, 1H), 3.95(s, 3H), 3.04(s, 3H), 2.57(s, 3H), 2.23-2.11(m , 2H), 2.11-1.97(m, 2H), 1.93-1.77(m, 2H), 1.74-1.56(m, 2H).

Example 11: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)cyclopropanesulfonamide (compound 11)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)cyclopropanesulfonamide

A solution of cyclopropanesulfonyl chloride (338 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in In dichloromethane (5 mL), the reaction mixture was stirred overnight at room temperature. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1, v/v) to obtain the product as a yellow solid (493 mg, yield 81%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.54(s, 1H), 8.10(d, J=2.3Hz, 1H), 7.79(d, J=2.3Hz, 1H), 3.91(s, 3H) , 2.78(s, 1H), 0.99-0.87(m, 4H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- base) synthesis of cyclopropanesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)cyclopropanesulfonamide (485mg, 1.58mmol), anhydrous potassium acetate (311mg, 3.16mmol) and diboronic acid pinacol ester (482mg, 1.90 mmol) in dioxane (8 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60 mg, 0.079 mmol) was added to the mixture middle. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1, v/v) to obtain the product as a yellow solid (510 mg, yield 91%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.28(s, 1H), 8.21(d, J=1.7Hz, 1H), 7.79(d, J=1.7Hz, 1H), 3.94(s, 3H) , 2.70-2.58(m, 1H), 1.30(s, 12H), 0.98-0.79(m, 4H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)cyclopropanesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (60mg, 0.186mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide (80mg, 0.223mmol) and A mixture of potassium carbonate (77mg, 0.558mmol) in N,N-dimethylformamide and water (2.0mL:0.186mL) was degassed and [1,1'-bis(diphenylphosphino)di Ferrocene]palladium dichloride (15 mg, 0.0186 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=50:1, v/v) to obtain the product as a yellow solid (40 mg, yield 46%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s, 1H), 8.26(d, J=2.2Hz, 1H), 7.99(d, J=2.1Hz, 1H), 7.96(s, 1H) , 6.45(s, 2H), 6.29(s, 1H), 5.44-5.33(m, 1H), 3.95(s, 3H), 2.71-2.64(m, 1H), 2.57(s, 3H), 2.22-2.11 (m, 2H), 2.11-2.00(m, 2H), 1.91-1, 80(m, 2H), 1.71-1, 60(m, 2H), 0.97-0.88(m, 4H).

MS(ESI+)m/z470.1[M+H] ⁺ .

Example 12: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-3-chloropropane-1-sulfonamide (compound 12)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-3-chloropropane-1-sulfonamide

A solution of 3-chloropropane-1-sulfonyl chloride (425 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine ( 237 mg, 3 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature overnight. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (402 mg, yield 58%).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.70(s,1H),8.12(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),3.91(s,3H) ,3.75(t,J=6.5Hz,2H),3.29(t,J=7.6Hz,2H),2.23-2.10(m,2H).

Step 2: 3-Chloro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of pyridin-3-yl)propane-1-sulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-3-chloropropane-1-sulfonamide (400mg, 1.16mmol), anhydrous potassium acetate (228mg, 2.32mmol) and diboronic acid A mixture of nicohol ester (325 mg, 1.28 mmol) in dioxane (5 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (42 mg, 0.058 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (308 mg, yield 68%).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.46(s,1H),8.22(d,J=1.6Hz,1H),7.78(d,J=1.6Hz,1H),3.94(s,3H) ,3.74(t,J=6.5Hz,2H),3.26-3.13(m,2H),2.24-2.10(m,2H),1.30(s,12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-3-chloropropane-1-sulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65 mg, 0.20 mmol), 3-chloro-N-(2-methyl Oxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propane-1-sulfonamide ( 94mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide and water (4mL:0.20mL) were degassed and [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (50 mg, yield 50%).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.37(d, J=2.2Hz, 1H), 8.04(d, J=2.2Hz, 1H), 7.98(s, 1H), 6.44(s, 2H) , 6.30(s, 1H), 5.42-5.29(m, 1H), 3.94(s, 3H), 3.74(t, J=6.4Hz, 2H), 3.37(t, J=7.4Hz, 2H), 2.58( s, 3H), 2.48-2.39(m, 2H), 2.24-2.11(m, 2H), 2.08-2.00(m, 2H), 1.90-1.80(m, 2H), 1.72-1.61(m, 2H).

Example 13: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)butane-1-sulfonamide (compound 13)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)butane-1-sulfonamide

A solution of butane-1-sulfonyl chloride (376 mg, 2.4 mmol, 1.2 eq) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature overnight. 25 mL of water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (469 mg, yield 73%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.50(s, 1H), 8.09(d, J=2.3Hz, 1H), 7.77(d, J=2.3Hz, 1H), 3.90(s, 3H) , 3.15(t, J=7.6Hz, 2H), 1.74-1.61(m, 2H), 1.43-1.32(m, 2H), 0.87(t, J=7.4Hz, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base) butane-1-sulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)butane-1-sulfonamide (400mg, 1.24mmol), anhydrous potassium acetate (244mg, 2.48mmol) and diboronic acid pinacol ester (347mg, 1.36mmol) in dioxane (6mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (46mg, 0.062mmol) Add to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (401 mg, yield 87%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s, 1H), 8.20(d, J=1.7Hz, 1H), 7.78(d, J=1.6Hz, 1H), 3.93(s, 3H) , 3.05(t, J=7.4Hz, 2H), 1.75-1.62(m, 2H), 1.43-1.32(m, 2H), 1.30(s, 12H), 0.86(t, J=7.4Hz, 3H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)butane-1-sulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)butane-1-sulfonamide (89mg, 0.24 mmol) and potassium carbonate (83 mg, 0.60 mmol) in N, N-dimethylformamide and water (4 mL:0.20 mL) were degassed, and [1,1'-bis(diphenylphosphino ) ferrocene] palladium dichloride PdCl ₂ (dppf) (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (67 mg, yield 69%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s, 1H), 8.26(d, J=2.2Hz, 1H), 7.96(d, J=2.2Hz, 1H), 7.95(s, 1H) , 6.44(s, 2H), 6.30(s, 1H), 5.43-5.29(m, 1H), 3.94(s, 3H), 3.16-3.02(t, J=7.6Hz, 2H), 2.57(s, 3H ), 2.26-2.10(m, 2H), 2.10-1.97(m, 2H), 1.93-1.78(m, 2H), 1.80-1.58(m, 4H), 1.47-1.32(m, 2H), 0.88(t , J=7.6Hz, 3H).

Example 14: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)benzenesulfonamide (compound 14)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)benzenesulfonamide

A solution of benzenesulfonyl chloride (424 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg, 3 mmol) in 2 Chloromethane (5 mL), the reaction mixture was stirred at room temperature for 4 hr. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1, v/v) to obtain the product as a yellow solid (580 mg, yield 85%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ10.16(s, 1H), 8.05(d, J=2.2Hz, 1H), 7.81-7.38(m, 6H), 3.62(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- base) synthesis of benzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)benzenesulfonamide (580mg, 1.69mmol), anhydrous potassium acetate (332mg, 3.38mmol) and biboronic acid pinacol ester (515mg, 2.03 mmol) in dioxane (10 mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (62 mg, 0.0845 mmol) was added to the mixture . The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=9:1, v/v) to obtain the product as a yellow solid (470 mg, yield 71%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.86(s, 1H), 8.15(d, J=1.3Hz, 1H), 7.77-7.49(m, 6H), 3.60(s, 3H), 1.29( s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of methoxypyridin-3-yl)benzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (94mg, 0.24mmol) and carbonic acid A mixture of potassium (83mg, 0.60mmol) in N,N-dimethylformamide-water (4mL:0.20mL) was degassed and [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (84 mg, yield 83%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.87(s, 1H), 8.21(d, J=2.2Hz, 1H), 7.94(d, J=2.1Hz, 1H), 7.91(s, 1H) , 7.77(dd, J=7.4, 1.4Hz, 2H), 7.64(t, J=7.4Hz, 1H), 7.56(t, J=7.5Hz, 2H), 6.44(s, 2H), 6.31(s, 1H), 5.44-5.25(m, 1H), 3.63(s, 3H), 2.57(s, 3H), 2.27-2.11(m, 2H), 2.11-2.00(m, 2H), 1.98-1.76(m, 2H), 1.77-1.57(m, 2H).

Example 15: N-(5-(7-amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-4-methoxybenzenesulfonamide (compound 15)

Step 1: Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-4-methoxybenzenesulfonamide

A solution of 4-methoxybenzenesulfonyl chloride (496 mg, 2.4 mmol) in dichloromethane (5 mL) was added dropwise to 3-amino-5-bromo-2-methoxypyridine (0.406 g, 2 mmol) and pyridine (237 mg , 3 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 4 h. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1, v/v) to obtain the product as a yellow solid (668 mg, yield 90%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.99(s, 1H), 8.02(d, J=2.4Hz, 1H), 7.70(d, J=9.0Hz, 2H), 7.67(d, J= 2.4Hz, 1H), 7.09(d, J=9.0Hz, 2H), 3.82(s, 3H), 3.67(s, 3H).

Step 2: N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Synthesis of base)-4-methoxybenzenesulfonamide

N-(5-bromo-2-methoxypyridin-3-yl)-4-methoxybenzenesulfonamide (373mg, 1.0mmol), anhydrous potassium acetate (196mg, 2mmol) and diboronic acid pinacol A mixture of ester (304mg, 1.2mmol) in dioxane (7mL) was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (62mg, 0.0845mmol ) are added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1, v/v) to obtain the product as a yellow solid (370 mg, yield 88%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.67(s, 1H), 8.13(d, J=1.6Hz, 1H), 7.72(d, J=1.6Hz, 1H), 7.61(d, J= 9.0Hz, 2H), 7.05(d, J=9.0Hz, 2H), 3.80(s, 3H), 3.65(s, 3H), 1.29(s, 12H).

Step 3: N-(5-(7-Amino-1-cyclopentyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-4-methoxybenzenesulfonamide

7-Amino-3-bromo-1-cyclopentyl-5-methyl-1,6-naphthyridin-2(1H)-one (65mg, 0.20mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (101mg , 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) in N,N-dimethylformamide and water (4mL:0.20mL) were degassed, and [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100° C. for 5 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (84 mg, yield 79%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.68(s, 1H), 8.18(d, J=2.0Hz, 1H), 7.91(d, J=2.0Hz, 1H), 7.88(s, 1H) , 7.71(d, J=8.9Hz, 2H), 7.06(d, J=8.9Hz, 2H), 6.43(s, 2H), 6.30(s, 1H), 5.43-5.22(m, 1H), 3.81( s, 3H), 3.68(s, 3H), 2.56(s, 3H), 2.21-2.10(m, 2H), 2.10-2.00(m, 2H), 1.92-1.80(m, 2H), 1.77-1.56( m, 2H).

Example 16: 7-Amino-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-3-(6-methoxypyridin-3-yl)-5-methyl-1,6 -Naphthyridin-2(1H)-one (compound 16)

Step 1: Synthesis of trans-4-(3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-ylamino)cyclohexanol

In a sealed tube, mix 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine (7.8 g, 20 mmol), trans-4-amino A solution of cyclohexanol (4.6 g, 40 mmol), diisopropylethylamine (7.76 g, 60 mmol) in N-methylpyrrolidone (80 mL) was stirred at 160°C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (400 mL), extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1, then petroleum ether/ethyl acetate = 4:1, v/v) afforded the product as a yellow solid (4.90 g, 65% yield ).

¹ H NMR (400MHz, DMSO-d ₆ ,) δ6.52(s, 1H), 5.75(s, 2H), 5.51(d, J=8.4Hz, 1H), 4.56(d, J=4.0Hz, 1H ), 3.57-3.35(m, 2H), 2.46(s, 3H), 2.05(s, 6H), 1.90-1.73(m, 4H), 1.49-1.27(m, 4H).

MS(ESI+)m/z378.0[M+H] ⁺ .

Step 2: 2-(trans-4-(3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-ylamino)cyclohexyloxy ) Synthesis of ethanol

Sodium hydride (70% dispersion in oil, 686 mg, 20 mmol) was added to trans-4-(3-bromo-6-(2,5-dimethyl-1H-pyrrole-1- yl)-2-methylpyridin-4-ylamino)cyclohexanol (3.78g, 10mmol) in a solution of N,N-dimethylformamide (38mL), and the resulting reaction mixture was heated at 0°C Stirring was continued for 2.5 hours. 1,3,2-Dioxazothiophene-2,2-dioxide (1.86 g, 15 mmol) was added and the resulting reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with methanol (2 mL) and evaporated to dryness under reduced pressure. The residue was diluted with 150 mL of dioxane and 3.78 mL of water. p-Toluenesulfonic acid monohydrate (3.80 g, 20 mmol) was added and the resulting reaction mixture was stirred at 40°C for 3 hours. The reaction mixture was concentrated, diluted with 100 mL of water, and extracted with dichloromethane (50 mL×3). The combined organic layers were washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1, then petroleum ether/ethyl acetate = 3:1, v/v) to give the product as a yellow oil (760 mg, 18% yield ).

¹ H NMR(300MHz,DMSO-d ₆ )δ6.53(s,1H),5.74(s,2H),5.56(d,J=8.4Hz,1H),4.54(t,J=5.4Hz,1H) ,3.59-3.36(m,5H),3.29-3.15(m,1H),2.46(s,3H),2.05(s,6H),1.95-1.85(m,4H),1.55-1.26(m,4H) .

MS(ESI+)m/z422.0[M+H] ⁺

Step 3: (E)-3-(6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-(trans-4-(2-hydroxyethoxy)cyclohexylamino)- Synthesis of ethyl 2-methylpyridin-3-yl)acrylate

In a sealed tube, place 2-(trans-4-(3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-ylamino)cyclo A solution of hexyloxy)ethanol (0.76 g, 1.8 mmol) and ethyl acrylate (575 μL, 5.40 mmol) in triethylamine (15 mL) was bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (0.208 g, 0.18 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 130°C, cooled and concentrated. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:2, v/v) to obtain the product as a yellow oil (770 mg, yield 97%).

¹ H NMR (400MHz,DMSO-d ₆ )δ7.60(d,J=16.0Hz,1H),6.47(s,1H),6.28(d,J=16.0Hz,1H),5.89(d,J= 8.0Hz,1H),5.74(s,2H),4.53(t,J=5.6Hz,1H),4.21(q,J=7.2Hz,2H),3.55-3.36(m,5H),3.25-3.16( m,1H),2.37(s,3H),2.07(s,6H),2.01-1.78(m,4H),1.47-1.30(m,4H),1.28(t,J=7.2Hz,3H).

MS(ESI+)m/z442.1[M+H] ⁺

Step 3: 7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6 Synthesis of -Naphthyridin-2(1H)-one

Under argon atmosphere, (E)-3-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(trans-4-(2-hydroxyethoxy)cyclohexyl Amino)-2-methylpyridin-3-yl)ethyl acrylate (0.77g, 1.74mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene (1.3mL, 8.70 mmol) and potassium tert-butoxide (98 mg, 0.87 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 150°C overnight. After cooling to room temperature, the reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate=1.5:1, then petroleum ether/ethyl acetate=1:1, v/v) gave the product as a yellow oil (0.25 g, yield 36 %).

¹ H NMR (300MHz, DMSO-d ₆ )δ8.12(d, J=9.6Hz, 1H), 6.61(d, J=9.6Hz, 1H), 5.84(s, 2H), 4.53(t, J= 5.2Hz, 1H), 3.55-3.40(m, 5H), 3.35-3.27(m, 1H), 2.73(s, 3H), 2.70-2.55(m, 2H), 2.12(s, 6H), 2.08-1.97 (m, 2H), 1.70-1.40 (m, 4H).

MS(ESI+)m/z396.0[M+H] ⁺

Step 4: Synthesis of 7-amino-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one

7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6-naphthalene A mixture of pyridin-2(1H)-one (250mg, 0.63mmol) and hydroxylamine hydrochloride (218mg, 3.15mmol) in ethanol and water (5mL:0.5mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia in methanol = 20:1, then dichloromethane/10% ammonia in methanol = 15:1, v/v) to give the product as a yellow foam like solid (100mg, yield 50%).

¹ H NMR (300MHz, DMSO-d ₆ )δ7.79(d, J=9.9Hz, 1H), 6.45(s, 1H), 6.28(s, 2H), 6.08(d, J=9.9Hz, 1H) , 4.57(t, J=5.1Hz, 1H), 3.54-3.43(m, 5H), 3.42-3.25(m, 1H), 2.68-2.54(m, 2H), 2.48(s, 3H), 2.18-2.05 (m, 2H), 1.63-1.50(m, 2H), 1.40-1.20(m, 2H).

MS(ESI+)m/z318.1[M+H] ⁺

Step 5: Synthesis of 7-amino-3-bromo-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one

Add N-bromosuccinimide (56mg, 0.315mmol) to 7-amino-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6- A solution of naphthyridin-2(1H)-one (100 mg, 0.315 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was stirred at room temperature for 1 hour. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (20 mL×5). The combined organic layer was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia in methanol = 30:1, then dichloromethane/10% ammonia in methanol = 20:1, v/v) to give the product as a yellow solid (30 mg, Yield 32%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.27(s, 1H), 6.50-6.37(m, 3H), 4.57(s, 1H), 3.55-3.35(m, 6H), 2.62-2.53(m , 2H), 2.49(s, 3H), 2.18-2.08(m, 2H), 1.73-1.67(m, 2H), 1.38-1.25(m, 2H)

MS(ESI+)m/z395.9[M+H] ⁺ .

Step 6: 7-Amino-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-3-(6-methoxypyridin-3-yl)-5-methyl-1,6- Synthesis of Naphthyridin-2(1H)-one

7-amino-3-bromo-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one (30mg, 0.076mmol), 6-methoxypyridin-3-ylboronic acid (17.4mg, 0.115mmol) and potassium carbonate (166mg, 1.20mmol) in N,N-dimethylformamide and water (3mL:0.6mL) The mixture is degassed. Bis(triphenylphosphine)palladium dichloride (11 mg, 0.0152 mmol) was added to the mixture. The resulting reaction mixture was degassed and stirred at 100 °C for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=20:1, v/v) to obtain the product as a yellow solid (29 mg, yield 90%).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.42(d, J=2.4Hz, 1H), 7.99(dd, J=8.4, 2.4Hz, 1H), 7.93(s, 1H), 6.83(d, J=8.4Hz, 1H), 6.48(s, 1H), 6.35(s, 2H), 4.58(s, 1H), 3.88(s, 3H), 3.55-3.45(m, 5H), 3.45-3.30(m , 1H), 2.70-2.57(m, 2H), 2.56(s, 3H), 2.20-2.10(m, 2H), 1.68-1.60(m, 2H), 1.40-1.26(m, 2H)

MS(ESI+)m/z425.0[M+H] ⁺

Example 17: N-(5-(7-amino-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 17)

7-amino-3-bromo-1-(trans-4-(2-hydroxyethoxy)cyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one (79.2mg , 0.2mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 3-yl)-2,4-difluorobenzenesulfonamide (102.3mg, 0.24mmol) and potassium carbonate (138mg, 1.0mmol) in N,N-dimethylformamide and water (2.5mL:0.5mL) The mixture was degassed, and bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=20:1, v/v) to obtain the product as a yellow solid (43 mg, 35% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18(s, 1H), 8.27(d, J=2.4Hz, 1H), 7.93(s, 1H), 7.91(s, 1H), 7.73(td, J=8.4, 6.4Hz, 1H), 7.66-7.49(td, J=10.0, 2.4Hz, 1H), 7.20(td, J=8.4, 2.1Hz, 1H), 6.47(s, 1H), 6.38(s , 2H), 4.58(t, J=4.8Hz, 1H), 3.63(s, 3H), 3.56-3.45(m, 4H), 3.45-3.35(m, 1H), 3.36-3.27(m, 1H), 2.74-2.52(m, 2H), 2.56(s, 3H), 2.15(d, J=10.0Hz, 2H), 1.65(d, J=10.8Hz, 2H), 1.41-1.28(m, 2H).

MS(ESI+)m/z615.90[M+H] ⁺

Example 18: N-(5-(7-amino-1-(trans-4-hydroxycyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 18)

Step 1: (E)-3-(6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-(trans-4-hydroxycyclohexylamino)-2-methylpyridine-3 -Synthesis of ethyl acrylate

In a sealed tube, trans-4-(3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-ylamino)cyclohexanol ( A solution of 4.86 g, 12.85 mmol) and ethyl acrylate (2.73 mL, 25.70 mmol) in triethylamine (97 mL) was bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (1.48 g, 1.285 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 130°C, cooled and concentrated. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:2, v/v) to obtain the product as a yellow oil (3.77 g, yield 74%).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.59(d, J=16.4Hz, 1H), 6.45(s, 1H), 6.28(d, J=16.4Hz, 1H), 5.85(d, J= 8.4Hz, 1H), 5.74(s, 2H), 4.54(d, J=4.0Hz, 1H), 4.21(q, J=7.2Hz, 2H), 3.45-3.35(m, 2H), 2.37(s, 3H), 2.07(s, 6H), 1.88-1.71(m, 4H), 1.45-1.20(m, 4H), 1.28(t, J=7.2Hz, 3H)

MS(ESI+)m/z398.0[M+H] ⁺

Step 2: 7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridine-2(1H )-ketone synthesis

Under argon atmosphere, (E)-3-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(trans-4-hydroxycyclohexylamino)-2-methyl Pyridin-3-yl)ethyl acrylate (3.37g, 8.48mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene DBU (6.4mL, 42.4mmol) and tert-butyl A solution of potassium alkoxide (475 mg, 4.24 mmol) in N,N-dimethylacetamide (35 mL) was stirred at 150 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with 150 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate=1.5:1, then petroleum ether/ethyl acetate=1:1, v/v) gave the product as a yellow oil (1.02 g, yield 31 %).

¹ H NMR (300MHz, DMSO-d ₆ )δ8.11(d, J=9.6Hz, 1H), 7.69-7.49(m, 1H), 6.60(d, J=9.6Hz, 1H), 5.84(s, 2H), 4.60(d, J=3.9Hz, 1H), 3.60-3.40(m, 1H), 2.72(s, 3H), 2.69-2.54(m, 2H), 2.12(s, 6H), 1.95-1.75 (m, 2H), 1.69-1.36 (m, 4H).

MS(ESI+)m/z352.1[M+H] ⁺

Step 3: Synthesis of 7-amino-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one

7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridine-2(1H)- A mixture of ketone (1.01 g, 2.87 mmol) and hydroxylamine hydrochloride (998 mg, 14.35 mmol) in ethanol and water (20 mL:2 mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia in methanol = 50:1, then dichloromethane/10% ammonia in methanol = 40:1, v/v) to give the product as a yellow foam like solid (100mg, yield 50%).

¹ H NMR (300MHz, DMSO-d ₆ )δ7.79(d, J=9.6Hz, 1H), 6.44(s, 1H), 6.30(s, 2H), 6.07(d, J=9.6Hz, 1H) , 4.67(d, J=4.2Hz, 1H), 4.10(q, J=5.1Hz, 1H), 3.66-3.44(m, 1H), 2.74-2.52(m, 2H), 2.47(s, 3H), 2.05-1.86(m, 2H), 1.64-1.45(m, 2H), 1.41-1.20(m, 2H).

MS(ESI+)m/z274.1[M+H] ⁺

Step 4: Synthesis of 7-amino-3-bromo-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one

Add N-bromosuccinimide (228 mg, 1.28 mmol) to 7-amino-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridine-2(1H) - A solution of ketone (538 mg, 1.97 mmol) in N,N-dimethylformamide (10 mL). The reaction solution was stirred at room temperature for 1 hour. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (20 mL×5). The combined organic layer was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=50:1, v/v) to obtain the product as a yellow solid (312 mg, 45% yield).

¹ H NMR (300MHz, DMSO-d ₆ ) δ8.27(s, 1H), 6.45(s, 2H), 5.76(s, 1H), 4.69(d, J=4.2Hz, 1H), 3.62-3.44( m, 1H), 2.66-2.52(m, 2H), 2.49(s, 3H), 2.02-1.90(m, 2H), 1.63-1.50(m, 2H), 1.43-1.25(m, 2H).

MS(ESI+)m/z352.0[M+H] ⁺ .

Step 5: N-(5-(7-amino-1-(trans-4-hydroxycyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3 Synthesis of -yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

7-amino-3-bromo-1-(trans-4-hydroxycyclohexyl)-5-methyl-1,6-naphthyridin-2(1H)-one (100mg, 0.284mmol), N-( 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4 - A mixture of difluorobenzenesulfonamide (145mg, 0.115mmol) and potassium carbonate (276mg, 2mmol) in N,N-dimethylformamide and water (5mL:1mL) was degassed, and bis(triphenyl Phosphine) palladium dichloride (20 mg, 0.0284 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 3 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=60:1, v/v) to obtain the product as a yellow solid (19 mg, yield 12%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18(s, 1H), 8.26(s, 1H), 7.94-7.89(m, 2H), 7.73(td, J=8.8, 6.4Hz, 1H), 7.58(t, J=8.8Hz, 1H), 7.21(td, J=9.2, 2.4Hz, 1H), 6.48(s, 1H), 6.39(s, 2H), 4.69(d, J=4.0Hz, 1H ), 3.63(s, 3H), 2.56(s, 3H), 2.55(m, 2H), 1.98(d, J=8.8Hz, 2H), 1.60(d, J=10.8Hz, 2H), 1.41-1.30 (m, 2H).

MS(ESI+)m/z571.9[M+H] ⁺

Example 19: 7-amino-3-(6-methoxypyridin-3-yl)-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine Synthesis of -2(1H)-one (compound 19)

Step 1: 3-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methyl-4-(tetrahydro-2H-pyran-4-ylamino)pyridine synthesis

In a sealed tube, mix 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine (6.00 g, 15.35 mmol), tetrahydro- A solution of 2H-pyran-4-amine (3.11g, 30.70mmol), diisopropylethylamine (5.95g, 46.05mmol) in N-methyl-2-pyrrolidone (60mL) was heated at 160°C 24 hours. After cooling to room temperature, 300 mL of water was added, and the resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with water (150 mL×2) and brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1, v/v) to obtain the product as a yellow solid (1.52 g, yield 27%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ6.62(s, 1H), 5.75(s, 2H), 5.70(d, J=7.2Hz, 1H), 3.89-3.82(m, 2H), 3.80- 3.72(m, 1H), 3.43(t, J=10.9Hz, 2H), 2.48(s, 3H), 2.05(s, 6H), 1.95-1.85(m, 2H), 1.70-1.56(m, 2H) .

MS(ESI+)m/z364.0[M+H] ⁺ .

Step 2: (E)-3-(6-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-methyl-4-(tetrahydro-2H-pyran-4-ylamino ) Synthesis of pyridin-3-yl) ethyl acrylate

In a sealed tube, 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methyl-4-(tetrahydro-2H-pyran-4-ylamino ) A solution of pyridine (1.71 g, 4.69 mmol) and ethyl acrylate (1.50 mL, 14.07 mmol) in triethylamine (30 mL) was bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (0.542 g, 0.47 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 130°C, cooled and concentrated. 100 mL of water was added, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1, then petroleum ether/ethyl acetate=5:1, v/v) to give the product as a yellow oil (540 mg, yield 30%) .

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.52(d, J=16.4Hz, 1H), 6.40(s, 1H), 6.35(d, J=16.4Hz, 1H), 6.05(d, J= 6.8Hz, 1H), 5.75(s, 2H), 4.21(q, J=7.2Hz, 2H), 3.90-3.77(m, 2H), 3.75-3.62(m, 1H), 3.43(t, J=11.2 Hz, 2H), 2.38(s, 3H), 2.08(s, 6H), 1.84-1.72(m, 2H), 1.65-1.51(m, 2H), 1.28(t, J=7.2Hz, 3H).

MS(ESI+)m/z384.1[M+H] ⁺ .

Step 3: 7-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine Synthesis of -2(1H)-one

Under argon atmosphere, (E)-3-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methyl-4-(tetrahydro-2H-pyran-4 -ylamino)pyridin-3-yl)ethyl acrylate (313 mg, 0.82 mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene (627 μL, 4.1 mmol) and tert A solution of potassium butoxide (46 mg, 0.41 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 150°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1, then petroleum ether/ethyl acetate = 2:1, v/v) to give the product as a yellow oil (72 mg, 26% yield ).

¹ H NMR (400MHz, CDCl ₃ )δ7.94(d, J=9.7Hz, 1H), 7.28(s, 1H), 6.73(d, J=9.7Hz, 1H), 5.96(s, 2H), 5.30 -5.09(m, 1H), 4.19-4.09(m, 2H), 3.55(t, J=11.2Hz, 2H), 3.00-2.84(m, 2H), 2.82(s, 3H), 2.21(s, 6H ), 1.72-1.62(m, 2H).

Step 4: Synthesis of 7-amino-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one

7-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine-2 A mixture of (1H)-ketone (721 mg, 2.14 mmol) and hydroxylamine hydrochloride (743 mg, 10.7 mmol) in ethanol-water (15 mL:1.5 mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia in methanol = 50:1, then dichloromethane/10% ammonia in methanol = 25:1, v/v) to give the crude product as yellow Solid (684 mg, 114% crude yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.82(d, J=9.6Hz, 1H), 6.52(s, 1H), 6.35(s, 2H), 6.10(d, J=9.6Hz, 1H) , 5.20-4.90(m, 1H), 4.01(dd, J=11.2, 4.0Hz, 2H), 3.45(t, J=11.2Hz, 2H), 2.85-2.70(m, 2H), 2.48(s, 3H ), 1.53-1.46(m, 2H).

Step 5: Synthesis of 7-amino-3-bromo-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one

Add N-bromosuccinimide (294 mg, 1.65 mmol) to 7-amino-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine- Crude 2(1H)-ketone (564 mg, 2.18 mmol) was dissolved in N,N-dimethylformamide (17 mL). The reaction solution was stirred at room temperature for 1 h. 100 mL of water was added, and the resulting mixture was extracted with ethyl acetate (50 mL×5). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=25:1, v/v) to obtain the product as a yellow solid (335 mg, yield 46%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ8.30(s, 1H), 6.52(s, 1H), 6.50(s, 2H), 4.90-4.70(m, 1H), 4.01(dd, J=11.2 , 4.1Hz, 2H), 3.45(t, J=11.2Hz, 2H), 2.84-2.65(m, 2H), 2.50(s, 3H), 1.60-1.50(m, 2H).

Step 6: 7-Amino-3-(6-methoxypyridin-3-yl)-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine- 2(1H)-keto

7-Amino-3-bromo-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one (101mg, 0.3mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)- A mixture of 2,4-difluorobenzenesulfonamide (154mg, 0.36mmol) and potassium carbonate (138mg, 1mmol) in N,N-dimethylformamide and water (2.5mL:0.5mL) was degassed, and Bis(triphenylphosphine)palladium dichloride (21 mg, 0.03 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 4 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=30:1, v/v) to obtain the product as a yellow solid (103 mg, yield 68%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.20(s, 1H), 8.27(s, 1H), 7.94(d, J=6.9Hz, 2H), 7.73(dd, J=14.8, 8.4Hz, 1H), 7.58(t, J=8.8Hz, 1H), 7.20(t, J=8.5Hz, 1H), 6.54(s, 1H), 6.45(s, 2H), 5.02-4.89(m, 1H), 4.04(dd, J=11.2, 4.0Hz, 2H), 3.62(s, 3H), 3.47(t, J=11.2Hz, 2H), 2.87-2.74(d, J=9.0Hz, 2H), 2.57(s , 3H), 1.57 (dd, J=11.2, 2.0Hz, 2H).

MS(ESI+)m/z557.9[M+H] ⁺ .

Example 20: 7-amino-3-(6-methoxypyridin-3-yl)-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridine Synthesis of -2(1H)-one (compound 20)

7-Amino-3-bromo-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one (101mg, 0.3mmol), A mixture of pyridine-4-boronic acid (55mg, 0.36mmol) and potassium carbonate (138mg, 1mmol) in N,N-dimethylformamide-water (2.5mL:0.5mL) was degassed and di(triphenyl (phosphine)palladium dichloride (21mg, 0.03mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 4 hours under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=30:1, v/v) to obtain the product as a yellow solid (70 mg, yield 64%).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.43(d, J=2.2Hz, 1H), 8.00(dd, J=8.6, 2.2Hz, 1H), 7.95(s, 1H), 6.84(d, J=8.6Hz, 1H), 6.54(s, 1H), 6.41(s, 2H), 5.03-4.79(m, 1H), 4.02(dd, J=11.2, 4.0Hz, 2H), 3.88(s, 3H ), 3.47(t, J=11.4Hz, 2H), 2.88-2.75(m, 2H), 2.57(s, 3H), 1.57(dd, J=11.2, 2.0Hz, 2H).

MS(ESI+)m/z367.0[M+H] ⁺ .

Example 21: N-(5-(7-amino-1-isopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 Synthesis of -methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 21)

Step 1: Synthesis of 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-N-isopropyl-2-methylpyridin-4-amine

In a sealed tube, mix 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine (15 g, 38.5 mmol) and diisopropylethyl A solution of phenylamine (4.96 g, 38.5 mmol) in isopropylamine (75 mL) was stirred at 160°C for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate (500 mL), washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate = 150:1, then petroleum ether/ethyl acetate = 50:1, v/v) afforded the product as a yellow solid (7.5 g, 61% yield ).

¹ H NMR (400MHz, DMSO-d ₆ ) δ6.44(s, 1H), 5.74(s, 2H), 5.60(d, J=8.3Hz, 1H), 3.87-3.77(m, 1H), 2.47( s, 3H), 2.06(s, 6H), 1.20(d, J=6.3Hz, 6H).

MS(ESI+)m/z322.0[M+H] ⁺ .

Step 2: (E)-3-(6-(2,5-Dimethyl-1H-pyrrol-1-yl-)-4-(isopropylamino)-2-methylpyridin-3-yl) Synthesis of Ethyl Acrylate

In a sealed tube, 3-bromo-N-cyclopentyl-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-amine (7.5 g, 23.4 mmol) and ethyl acrylate (5.0 mL, 46.7 mmol) in triethylamine (55 mL) was bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (1.35 g, 11.68 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 130°C, cooled and concentrated. 200 mL of water was added, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×2) and saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was a yellow oil (8.00 g, 100% yield) which was used directly in the next step without further purification.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.61(d, J=16.2Hz, 1H), 6.40(s, 1H), 6.30(d, J=16.2Hz, 1H), 5.94(d, J= 8.1Hz, 1H), 5.74(s, 2H), 4.22(q, J=7.1Hz, 2H), 3.81-3.70(m, 1H), 2.38(s, 3H), 2.07(s, 6H), 1.28( t, J=7.1Hz, 3H), 1.17(d, J=6.3Hz, 6H).

MS(ESI+)m/z342.1[M+H] ⁺

Step 3: Synthesis of 7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropyl-5-methyl-1,6-naphthyridin-2(1H)-one

Under argon atmosphere, (E)-3-(6-(2,5-dimethyl-1H-pyrrol-1-yl-)-4-(isopropylamino)-2-methylpyridine-3 -yl) ethyl acrylate (8.0g, 23.5mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene (17.5mL, 117.3mmol) and potassium tert-butoxide (1.32 g, 11.75 mmol) in N,N-dimethylacetamide (80 mL) was stirred overnight at 150 °C. After cooling to room temperature, the reaction mixture was diluted with 400 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×2) and saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1, then petroleum ether/ethyl acetate=5:1, v/v) afforded the product as a yellow oil (2.7 g, yield 39 %).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.13(d, J=9.8Hz, 1H), 7.46(s, 1H), 6.63(d, J=9.8Hz, 1H), 5.83(s, 2H) , 5.38-5.17(m, 1H), 2.73(s, 3H), 2.11(s, 6H), 1.51(d, J=6.8Hz, 6H).

Step 4: Synthesis of 7-amino-1-isopropyl-5-methyl-1,6-naphthyridin-2(1H)-one

7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropyl-5-methyl-1,6-naphthyridin-2(1H)-one (2.7g, 9.2 mmol) and hydroxylamine hydrochloride (3.2 g, 4.58 mmol) in ethanol and water (40 mL/4 mL) were refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:3, then ethyl acetate/triethylamine = 100:1, v/v) to give the product as a yellow foamy solid (1.3 g , the yield was 65%).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.80(d, J=9.6Hz, 1H), 6.43(s, 1H), 6.30(s, 2H), 6.09(d, J=9.6Hz, 1H) , 5.32(q, J=7.2Hz, 1H), 2.48(s, 3H), 1.49(d, J=7.2Hz, 6H).

Step 5: Synthesis of 7-amino-3-bromo-1-isopropyl-5-methyl-1,6-naphthyridin-2(1H)-one

Add N-bromosuccinimide (1.14g, 6.41mmol, added in three batches) to 7-amino-1-isopropyl-5-methyl-1,6-naphthyridine-2(1H) - A solution of ketone (1.39 g, 6.41 mmol) in N,N-dimethylformamide (14 mL). The reaction solution was stirred at room temperature for 1 hour. 60 mL of water was added, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate = 3:1, then petroleum ether/ethyl acetate/triethylamine = 50:50:1, v/v) afforded the product as a yellow solid (1.02 g , yield 54%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.15(s, 1H), 6.30(s, 1H), 4.70(br s, 2H), 4.12(q, J=7.2Hz, 1H), 2.60(s, 3H ), 1.60(d, J=7.2Hz, 6H).

MS(ESI+)m/z296.0, 298.0[M+H] ⁺ .

Step 6: N-(5-(7-Amino-1-isopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

7-Amino-3-bromo-1-isopropyl-5-methyl-1,6-naphthyridin-2(1H)-one (100mg, 0.34mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide ( 173mg, 0.41mmol) and potassium carbonate (110mg, 1.02mmol) in N,N-dimethylformamide-water (4mL: 0.34mL, 12:1) was degassed and [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.034 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 5 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (40 mg, yield 23%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.18(s, 1H), 8.28(d, J=1.9Hz, 1H), 7.93(d, J=2.0Hz, 1H), 7.92(s, 1H) , 7.73(dt, J=8.4, 6.5Hz, 1H), 7.63-7.52(m, 1H), 7.27-7.12(m, 1H), 6.45(s, 1H), 6.39(s, 2H), 5.35-5.30 (m, 1H), 3.62(s, 3H), 2.56(s, 2H), 1.53(d, J=7.0Hz, 6H).

MS(ESI+)m/z516.1[M+H] ⁺ .

Example 22: N-(5-(7-amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 22)

Step 1: Synthesis of 3-bromo-N-cyclopropyl-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-amine

In a sealed tube, combine 3-bromo-6-(2,5-methyl-1H-pyrrol-1-yl)-4-iodo-2-methylpyridine (6 g, 15.4 mmol) and DIEA (1.98 g, 15.4 mmol) in cyclopropylamine (30 mL) was stirred at 90°C for 48 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate (200 mL), washed with water (100 mL×2) and saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 150:1 then petroleum ether/ethyl acetate = 50:1, v/v) to give the product as a yellow solid (1.6 g, 33% yield) .

¹ H NMR (400MHz, DMSO-d ₆ ) δ6.63(s, 1H), 6.62(brs, 1H), 5.76(s, 2H), 2.47(s, 3H), 2.09(s, 6H), 2.02- 1.95(m, 1H), 0.83-0.76(m, 2H), 0.61-0.51(m, 2H).

MS(ESI+)m/z320.0[M+H] ⁺ .

Step 2: (E)-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrrol-1-yl-)-2-methylpyridin-3-yl) Synthesis of Ethyl Acrylate

In a sealed tube, 3-bromo-N-cyclopropyl-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-4-amine (1 g, 3.1 mmol ) and ethyl acrylate (0.68 mL, 6.2 mmol) in triethylamine (10 mL) were bubbled with argon for 5 min. Tetrakis(triphenylphosphine)palladium (0.362 g, 0.31 mmol) was added, the mixture was bubbled again with argon for 5 min and the vial was sealed. The reaction solution was stirred overnight at 130°C, cooled and concentrated. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate = 50:1 then petroleum ether/ethyl acetate = 5:1, v/v) gave the product as a yellow oil (0.58 g, 55% yield ).

¹ H NMR (400MHz, CDCl ₃ ) δ7.67(d, J=16.4Hz, 1H), 6.76(s, 1H), 6.24(d, J=16.4Hz, 1H), 5.88(s, 2H), 5.03 (s, 1H), 4.30(q, J=7.1Hz, 2H), 2.48(s, 3H), 2.46-2.39(m, 1H), 2.20(s, 6H), 1.36(t, J=7.1Hz, 3H), 0.92-0.77(m, 2H), 0.63-0.52(m, 2H).

Step 3: Synthesis of 1-cyclopropyl-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-1,6-naphthyridin-2(1H)-one

Under argon atmosphere, (E)-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrrol-1-yl-)-2-methylpyridine-3 -yl) ethyl acrylate (1.08g, 3.2mmol), 1,5-diazabicyclo(5,4,0)undec-5-ene DBU (2.36mL, 15.9mmol) and potassium tert-butoxide ( 0.179 g, 1.6 mmol) in N,N-dimethylacetamide (20 mL) was stirred overnight at 150°C. After cooling to room temperature, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (50 mL×2) and saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1, then petroleum ether/ethyl acetate=2:1, v/v) gave the product as a yellow oil (0.42 g, yield 45 %).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.11(d, J=9.8Hz, 1H), 7.49(s, 1H), 6.61(d, J=9.8Hz, 1H), 5.84(s, 2H) , 3.05-2.91(m, 1H), 2.72(s, 3H), 2.15(s, 6H), 1.35-1.24(m, 2H), 0.83-0.70(m, 2H).

Step 4: Synthesis of 7-amino-1-cyclopropyl-5-methyl-1,6-naphthyridin-2(1H)-one

1-cyclopropyl-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-1,6-naphthyridin-2(1H)-one (0.42g, 1.43 mmol) and hydroxylamine hydrochloride (0.498g, 7.17mmol) in ethanol-water (5mL/0.5mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1:3, then ethyl acetate/triethylamine = 100:1, v/v) to give the product as a yellow foamy solid (273 mg, The yield was 89%).

¹ H NMR (400MHz, DMSO-d ₆ )δ7.79(d, J=9.6Hz, 1H), 6.53(s, 1H), 6.38(s, 2H), 6.06(d, J=9.6Hz, 1H) , 2.80-2.68(m, 1H), 2.46(s, 3H), 1.20-1.15(m, 2H), 0.75-0.62(m, 2H).

Step 5: Synthesis of 7-amino-3-bromo-1-cyclopropyl-5-methyl-1,6-naphthyridin-2(1H)-one

N-bromosuccinimide (181mg, 0.8eq) was added to 7-amino-1-cyclopropyl-5-methyl-1,6-naphthyridin-2(1H)-one (273mg, 1.27 mmol) in a solution of N,N-dimethylformamide (4 mL). The reaction solution was stirred at room temperature for 1 h. 20 mL of water was added, and the resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1, then petroleum ether/ethyl acetate:triethylamine=50:50:1, v/v) to give the product as a yellow solid (200 g, Yield 53%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.26(s, 1H), 6.54(s, 2H), 6.53(s, 1H), 2.92-2.79(m, 1H), 2.48(s, 3H), 1.30- 1.16(m, 2H), 0.77-0.66(m, 2H).

Step 6: N-(5-(7-Amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- Synthesis of Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

7-Amino-3-bromo-1-cyclopropyl-5-methyl-1,6-naphthyridin-2(1H)-one (60mg, 0.205mmol), N-(2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide ( 105mg, 0.246mmol) and potassium carbonate (85mg, 0.615mmol) in N,N-dimethylformamide-water (4mL: 0.3mL) mixture was degassed, and [1,1'-bis(diphenyl phosphino)ferrocene]palladium dichloride (15 mg, 0.021 mmol) was added to the mixture. The resulting reaction mixture was degassed, and reacted at 100° C. in the dark for 5 h under an argon protective atmosphere. After cooling, 30 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/10% ammonia methanol solution=100:1, v/v) to obtain the product as a yellow solid (20 mg, yield 19%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.18(s, 1H), 8.29(d, J=2.2Hz, 1H), 7.93(d, J=2.2Hz, 1H), 7.92(s, 1H) , 7.73(td, J=8.5, 6.4Hz, 1H), 7.66-7.49(m, 1H), 7.20(td, J=8.5, 2.3Hz, 1H), 6.55(s, 1H), 6.49(s, 2H ), 3.62(s, 3H), 2.87-2.80(m, 1H), 2.55(s, 3H), 1.30-1.13(m, 2H), 0.79-0.66(m, 2H).

Example 23 Biochemical detection of PI3K-α activity

The potency of compounds of the invention against PI3K-α was assessed using an in vitro kinase assay. The in vitro activity of PI3K-α was determined by detecting the level of ADP produced in the kinase reaction using the ADP-Glo ^TM Kinase Assay Kit. In the kinase detection experiment, the kinase consumes ATP to generate ADP, the ADP-Glo reagent will terminate the kinase reaction and completely consume the remaining ATP, and finally add the kinase detection reagent to convert ADP into new ATP. The luciferase in the detection reagent can catalyze luciferin with the participation of ATP and _O2 , produce oxidized luciferin, AMP and generate light quanta, thereby converting the chemical signal into a light signal (Luminecence), the intensity of the light signal is related to that of the kinase The amount of ADP produced in the reaction is positively correlated, so that the activity of the kinase PI3K-α can be quantitatively detected. ADP-Glo ^TM Kinase Detection Kit was purchased from Promega.

All detection experiments were performed at room temperature, using Corning3674 white 384-well plates, the kinase PI3K-α was from BPS Biosciences, the kinase substrate was P1P2/PS (Invitrogen), and the optical signal was read using a microplate reader EnVision (PerkinElmer). The detection buffer includes 40mM Tris-HCl (pH7.5), 3mM MgCl ₂ and 0.01%BSA; the kinase PI3K-α is prepared as a kinase reaction solution with a concentration of 4nM using the detection buffer; the substrate reaction solution includes 100uM P1P2/PS and 100uM ATP. The compound was first dissolved and diluted to 2mM in 100% DMSO, and then diluted to 0.05mM with detection buffer. Add 1 μL of the compound with a concentration of 0.05 mM and 2 μL of the kinase reaction solution to the detection plate, mix well, and incubate at room temperature in the dark for 15 minutes; then add 2 μL of the kinase reaction solution, the total reaction volume is 5 μL, and react the reaction mixture at room temperature for 45 minutes in the dark ; Then add 5 μL of ADP-Glo ^TM reagent equal to the volume of the reaction to stop the reaction, mix well and place at room temperature for 40 minutes; finally add 10 μL of kinase detection reagent, place in the dark at room temperature for 30 minutes, and then read the value on the Envision.

Percent inhibition was calculated based on the following formula:

Inhibition percentage=[1-(RLU _compound -RLU _min )/(RLU _max -RLU _min )]×100%

Where RLU _compound is the luminescence reading at a given compound concentration, RLU _min is the luminescence reading without adding kinase, and RLU _max is the luminescence reading without adding the compound. The _IC50 of the compounds was calculated by using the XLfit program in Excel.

The experimental results are shown in Table 1.

Example 24 Biochemical detection of mTOR activity

The potency of compounds against mTOR was assessed using an in vitro kinase assay. The kinase activity of mTOR was determined by measuring the phosphorylation level of the substrate 4E-BP1. In time-resolved energy resonance transfer assays, mTOR kinase phosphorylates the GFP-tagged substrate GFP-4E-BP1, with higher amounts of phosphorylated substrate in excess of the substrate. A Tb-labeled specific antibody Tb-chelate labeled anti-4E-BP1[pT46] can terminate the reaction and induce the resonance transfer of fluorescence energy from Tb to GFP, and the phosphorylation of the 4E-BP1 substrate is proportional to the energy transferred from Tb to GFP to calculate. mTOR TR-FRET Kinase Detection Kit was purchased from Invitrogen.

All detection experiments were carried out at room temperature, using a black 384-well plate with a PE company product number of Greiner784076, the kinase mTOR was from Invitrogen, the kinase substrate was GFP-4E-BP1 (Invitrogen), and read using a microplate reader Envision (Perkin Elmer) fluorescent signal. The detection buffer includes 50mM HEPES, 5mM MgCl ₂ , 0.01%BSA, 1mMDTT, 1mM EGTA and 0.01%Triton X-100; the kinase mTOR is prepared as a kinase reaction solution with a concentration of 0.31ng/μL using the detection buffer; the substrate reaction solution Contains 0.8uM GFP-4E-BP1 and 60uM ATP. The compound was first dissolved and diluted to 1mM in 100% DMSO, and then serially diluted 3 times for a total of 10 concentration points, and then diluted to 100uM with detection buffer. Add 0.5 μL of the compound with a concentration of 100 uM and 2 μL of the kinase reaction solution to the detection plate, mix well, and incubate at room temperature in the dark for 15 minutes; then add 2.5 μL of the kinase reaction solution, the total reaction volume is 5 μL, and react the reaction mixture at room temperature in the dark 40min; then add 5μL TR-FRET detection reagent (including 2nM Tb-chelatelabeled anti-4E-BP1[pT46] and 30mM EDTA) equal to the reaction volume to terminate the reaction, mix well and place in the dark at room temperature for 60min; then in the Envision instrument After excitation at 340nm, read the values under 495nm and 520nm emission light respectively.

Percent inhibition was calculated based on the following formula:

Inhibition percentage=[1-(compound-min)/(max-min)]×100%

Where "compound" is the ratio of fluorescence readings at a given compound concentration, min is the ratio of fluorescence without adding kinase, and max is the ratio of fluorescence without adding compound. The _IC50 of the compounds was calculated by using the XLfit program in Excel.

The experimental results are shown in Table 1 and Table 2.

Table 1 Biological data of PI3K-α

It can be seen from the data in Table 1 that all the compounds of the present invention have obvious inhibitory effects on PI3K. Among them, the IC ₅₀ value of compound 12 was 1.725 μM; the IC ₅₀ value of compounds 3, 4, 14, and 15 reached 100-200 nM; the IC ₅₀ values of the other compounds reached 1-100 nM.

Table 2 Biological data of mTOR

It can be seen from the data in Table 2 that all the compounds of the present invention also have obvious inhibitory effects on mTOR. Among them, the IC ₅₀ values of compounds 11 and 21 reached 100-200nM; the IC ₅₀ values of the other compounds reached 1-100nM.

Claims (16)

1. A compound or a pharmaceutically acceptable salt thereof shown in formula I: in, R ₁ is selected from C ₃ -C ₆ cycloalkyl, or oxanyl, which is optionally substituted by -OR ₂ , wherein R ₂ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ hydroxyalkyl; or R1 is _a group as shown below: Wherein, R ₆ and R ₇ are each independently selected from hydrogen, or C ₁ -C ₄ alkyl; R ₃ is -NHSO ₂ R ₄ , wherein, R ₄ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₆ aryl or 5-membered heteroaryl containing a sulfur atom, wherein said C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₆ aryl or 5-membered heteroaryl containing a sulfur atom are optionally substituted by one or more R ₅ , and each of said R ₅ is independently selected from halogen, cyano , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy. 2. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₆ and R ₇ are selected from methyl. 3. the compound shown in formula I according to claim 1 or its pharmaceutically acceptable salt, wherein, R _Be selected from cyclopropyl, cyclopentyl, cyclohexyl or oxanyl, its optional is replaced by -OR ₂ . 4. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is C ₁ -C ₆ hydroxyalkyl; 5. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ₂ is -CH ₂ -CH ₂ -OH. 6. The compound shown in formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R is selected from C Aryl or a _{5 -} membered heteroaryl containing a sulfur atom, said C ₆ aryl or 5 membered heteroaryl containing a sulfur atom is optionally substituted with 1-5 R ₅ . 7. The compound shown in formula I according to claim 6 or a pharmaceutically acceptable salt thereof, wherein, R ₄ is substituted by 1-2 R ₅ ; said R ₅ is selected from the group consisting of halogen, cyano, -CF ₃ or C ₁ -C ₄ alkoxy. 8. The compound represented by formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from C ₁ -C ₄ alkyl or C ₃ -C ₅ cycloalkyl, wherein said The C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl are optionally substituted by 1-5 R ₅ , 9. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein R ₄ is substituted by 1-3 R ₅ ; 10. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 8 or 9, wherein said R ₅ is halogen. 11. The compound shown in formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, the compound shown in formula I is selected from the following compounds: Compound 1: Compound 2: Compound 3: Compound 4: Compound 5: Compound 6: Compound 7: Compound 8: Compound 9: Compound 10: Compound 11: Compound 12: Compound 13: Compound 14: Compound 15: Compound 16: Compound 17: Compound 18: Compound 19: Compound 20: Compound 21: as well as Compound 22: 12. According to any one of claims 1-11, the compound shown in formula I or a pharmaceutically acceptable salt thereof is used for the treatment and/or prevention of diseases caused by PI3-K kinase and/or mTOR kinase use in medicines. 13. The use according to claim 12, wherein the PI3-K kinase is PI3-Kα kinase. 14. The use according to claim 12, wherein the disease is cancer or tumor. 15. The use according to claim 12, wherein the disease is selected from brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney cancer, acute leukemia, chronic leukemia, non-small cell One or more of lung cancer, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, sarcoma, osteosarcoma, and rhabdoid myoma. 16. A pharmaceutical composition for treating and/or preventing diseases caused by PI3-K kinase and/or mTOR kinase, comprising formula I according to any one of claims 1-11 The compounds shown and/or their pharmaceutically acceptable salts, and pharmaceutically acceptable auxiliary materials.