CN105461711A - Pyrido[1,2-a]pyrimidone analogs as PI3K inhibitors - Google Patents

Abstract

The invention discloses a class of pyrido[1,2-a]pyrimidinone analogues as PI3K inhibitors. Specifically, the invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Pyrido[1,2-a]pyrimidinone analogs as PI3K inhibitors

technical field

The present invention relates to a class of pyrido[1,2-a]pyrimidinone analogs as PI3K inhibitors, in particular, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Background technique

The PI3K pathway is the most frequently mutated place in human cancer cells, which can lead to cell proliferation, activation, and signal amplification.

PI3K kinases (phosphatidylinositol 3-kinases, PI3Ks) belong to the lipid kinase family and can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol. Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of regulatory subunit p85 or p101 and catalytic subunit p110, which catalyzes phosphatidylinositol 4,5-diphosphate (phosphatidylinositol4 , 5-bisphosphate, PIP2) is phosphorylated into phosphatidylinositol 3,4,5-trisphosphate (phosphatidylinositol3,4,5-trisphosphate, PIP3) to activate downstream Akt, etc., which play a role in cell proliferation, survival and metabolism. Key role. Therefore, inhibition of phosphoinositide 3-kinase can affect the PI3K pathway, thereby inhibiting the proliferation and activation of cancer cells.

The tumor suppressor gene PTEN (phosphataseandtensionhomologdeletedonchromosometen) dephosphorylates PIP3 to generate PIP2, thereby realizing the negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting cell apoptosis. The frequent occurrence of PI3K gene mutation and amplification in cancer and the loss of PTEN in cancer all suggest that PI3K is closely related to tumorigenesis.

Contents of the invention

The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

structural unit replace with

E is selected from C _1-6 alkyl, C _3-10 cycloalkyl or heterocycloalkyl optionally substituted by R ₃ ;

Among L and Q, one is selected from -C(R _d1 )(R _d2 )-, -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, -C(=O)O-, -C(=O) -, -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _d8 )C(=O)N(R _d9 )-, the other selected from a single key or -C(R _d1 )(R _d2 )-;

A and T are independently selected from N or C(R _t );

0 or 1 of X, Y, and Z is selected from N, and the rest are selected from C(R _t );

B is selected from -C(R _d1 )(R _d2 )-, -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O ) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C( =S)-, -S(=O)-, -S(=O) ₂ - or -N(R _d8 )C(=O)N(R _d9 )-;

The heteroatoms or heteroatom groups are independently selected from -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ₂ - and/or -N(R _d8 )C(=O)N(R _d9 )-;

m ₁ are independently selected from 0, 1, 2 or 3;

One of R _1-3 selected from The rest are selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , CHO, COOH, or from C _1-10 alkyl or heteroalkyl optionally substituted by R ₀₁ , C _{3- 10} cycloalkyl or heterocycloalkyl, C _1-10 alkyl or heteroalkyl substituted by C _3-10 cycloalkyl or heterocycloalkyl;

D ₁ is selected from single bond, -C(R _d1 )(R _d2 )-, -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, - S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, -C(=O)O-, -C(=O)- , -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _d8 )C(=O)N(R _d9 )-;

D ₂ is selected from -C(R _d1 )(R _d2 )-;

D ₃ is selected from -N(R _d4 )-, -C(=O)N(R _d4 )-, -N(R _d4 )C(=O)-, -N(R _d4 )C(=O)O -, -N(R _d4 )OC(=O)-, -N(R _d4 )C(=O)N(R _d4 )-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-;

R ₄ is selected from H, or selected from C _1-10 alkyl or heteroalkyl, C _3-10 cycloalkyl or heterocycloalkyl optionally substituted by R ₀₁ , substituted by C _3-10 cycloalkyl or heterocycloalkyl C _1-10 alkyl or heteroalkyl;

n is selected from 1, 2, 3, 4, 5 or 6;

Optionally, between any _{two R1s} , between _{Rd1 and Rd2 in} the same _D2 , between _{two D2s} , between R4 and one D2 or between _R4 and _D3 Attached to the same carbon atom or heteroatom to form one or two 3, 4, 5 or 6 membered carbocyclic or heterocyclic rings;

R _t , R _d1 , R _d2 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , CHO, COOH, C(=O)NH ₂ , S(=O)NH _2. S(=O) ₂ NH ₂ , or selected from C _1-10 alkyl or heteroalkyl, C _3-10 cycloalkyl or heterocycloalkyl optionally substituted by R ₀₁ , C _3-10 cycloalkyl Or C _1-10 alkyl or heteroalkyl substituted by heterocycloalkyl;

R _{01 is} selected from F, Cl, Br, I, CN, OH, SH, NH ₂ , CHO, COOH, R ₀₂ ;

R ₀₂ is selected from C _1-10 alkyl, C _1-10 alkylamino, N,N-di(C _1-10 alkyl) amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _{1 -10} alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkoxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkoxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl, 5- 6-membered unsaturated heterocyclic group, 6-12 membered aryl or heteroaryl;

The heteroatoms or heteroatom groups are independently selected from -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C (=S)-, -S(=O)-, -S(=O) ₂ - and/or -N(R _d8 )C(=O)N(R _d9 )-;

R _d3 - _d9 are independently selected from H, OH, NH ₂ , R ₀₂ ;

R ₀₂ is optionally substituted by R ₀₀₁ ;

R ₀₀₁ is selected from F, Cl, Br, I, CN, OH, N(CH ₃ ) ₂ , NH(CH ₃ ), NH ₂ , CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl group, methoxy group, formyl group, methoxycarbonyl group, methylsulfonyl group, methylsulfinyl group;

The numbers of R ₀₁ , R ₀₀₁ , heteroatoms or heteroatom groups are independently selected from 0, 1, 2 or 3, respectively.

In one embodiment of the present invention, the above-mentioned E is selected from C _1-6 alkyl or C _3-6 cycloalkyl substituted by R ₃ , the number of R ₃ is selected from 0, 1, 2 or 3, or E is selected from

in,

0, 1, 2 or 3 of G _1-5 are selected from N, and the rest are selected from C (R ₃ );

G ₆ is selected from -C(R ₃ )(R ₃ )-, -C(=O)N(R _3a )-, -N(R _3a )-, -C(=NR _3a )-, -S(= O) ₂ N(R _3a )-, -S(=O)N(R _3a )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C (=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _3a )C(=O)N(R _3a )-;

0, 1 or 2 of G _7-9 are selected from N, and the rest are selected from C (R ₃ );

0, 1, 2, 3 or 4 of G _10-16 are selected from N, and the rest are selected from C(R ₃ );

G ₁₇ is selected from N or C (R ₃ );

0, 1, 2 or 3 of G _18-22 are selected from -C(=O)N(R _3a )-, -N(R _3a )-, -C(=NR _3a )-, -S(= O) ₂ N(R _3a )-, -S(=O)N(R _3a )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C (=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _3a )C(=O)N(R _3a )-, the rest are selected from -C(R ₃ ) (R ₃ )-;

R _3a is selected from C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 Cycloalkyl, C _3-10 cycloalkylacyl, C _3-10 cycloalkoxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl, 5-6 membered unsaturated hetero Cyclic group, 6-10 membered aryl or heteroaryl;

The remaining variables are as defined in claim 1.

In one version of the present invention, above _- mentioned E is selected from methyl, ethyl, propyl,

In one solution of the present invention, above-mentioned E is selected from

In a solution of the present invention, among the above-mentioned L and Q, one is selected from -S(=O) ₂ NH-, -S(=O) ₂ -, -NH-, -NHC(=O)NH-, and the other selected from single bonds, -CH ₂ -.

In one aspect of the present invention, 0 or 1 of the aforementioned X, Y, and Z is selected from N, and the rest are selected from CH, C(CH ₃ ), C(CF ₃ ), CCl, and CF.

In one solution of the present invention, the above-mentioned A and T are independently selected from N, CH, C(CH ₃ ), C(CF ₃ ), CCl, CF; or, B is selected from NH, N(CH ₃ ) or N (CF ₃ ).

In one solution of the present invention, between any _{two R1s} above, between _{Rd1 and Rd2 in} the same _D2 , between _{two D2s} , between R4 and one D2, or between _R4 and D2 The ring formed between ₃ is selected from:

In one aspect of the present invention, one of the above-mentioned R _1-3 is selected from The rest are selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , CHO, COOH, OR _a , N(R _b )(R _c ), C _1-3 optionally substituted by R _d Alkyl or cyclopropyl;

D ₁ is selected from a single bond, -C(R _e )(R _e )-, -C(=O)N(R _a )-, -N(R _a )-, -C(=NR _a )-, - S(=O) ₂ N(R _a )-, -S(=O)N(R _a )-, -O-, -S-, -C(=O)O-, -C(=O)- , -C(=S)-, -S(=O)-, -S(=O) ₂ - or -N(R _a )C(=O)N(R _a )-;

D ₂ is selected from -C(R _a )(R _a )-;

n is selected from 1, 2, 3, 4, 5 or 6;

R _a , R _b , and R _c are independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl optionally substituted by R _d ;

R _e is selected from H, optionally R _d substituted C _1-6 alkyl or alkoxy, optionally R _d substituted C _3-6 cycloalkyl or cycloalkoxy;

R _d is selected from F, Cl, Br, I, CN, OH, CHO, COOH, CH ₃ , CF ₃ , CH ₃ O, CH ₃ CH ₂ O, and the number of R _d is selected from 0, 1, 2 or 3;

Optionally, between any two R ₁ , between R _a and R _a in the same D ₂ , between two D ₂ , or between R _a and a D ₂ are jointly connected to the same carbon atom or oxygen One or two 3, 4, 5 or 6-membered carbocyclic rings or oxygen heterocyclic rings are formed on the atoms, and the number of oxygen atoms is 1 or 2.

In one solution of the present invention, the ring formed between any _two R1 above, between R _a and R _a in the same D2, between _{two D2s} , _{or between R a and} one D2 It is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and 1,3-dioxetanyl.

In one aspect of the present invention, one of the above-mentioned R _1-3 is selected from The rest are selected from H, F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, propyl, methoxy, ethoxy, methylamino, dimethylamino, halomethyl, halo Ethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl.

In one embodiment of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:

Related definitions:

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

C _{1-10 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ; C _{3-10 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ .

C _1-10 alkyl or heteroalkyl, C _3-10 cyclic or heterocycloalkyl, C _1-10 alkyl or heteroalkyl substituted by C _3-10 cycloalkyl or heterocycloalkyl include but are not limited to:

C _1-10 alkyl, C _1-10 alkylamino, N,N-di(C _1-10 alkyl) amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkoxy Carbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 Cycloalkoxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl;

Methyl, ethyl, n-propyl, isopropyl, -CH ₂ C(CH ₃ )(CH ₃ )(OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropanoyl, benzyloxy radical, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl , Dimethylamino, Diethylamino, Dimethylaminocarbonyl, Diethylaminocarbonyl;

N(CH ₃ ) ₂ ,NH(CH ₃ ),-CH ₂ CF ₃ ,-CH2CH ₂ CF ₃ ,-CH ₂ CH ₂ F,-CH ₂ CH ₂ S(=O) ₂ CH ₃ ,-CH ₂ CH ₂ CN, -CH ₂ CH(OH)(CH3) ₂ ,-CH ₂ CH(F)(CH ₃ ) ₂ ,-CH ₂ CH ₂ F,-CH ₂ CF ₃ ,-CH ₂ CH ₂ CF ₃ ,-CH ₂ CH ₂ NH ₂ ,-CH ₂ CH ₂ OH,-CH ₂ CH ₂ OCH ₃ ,-CH ₂ CH ₂ CH ₂ OCH ₃ ,-CH ₂ CH ₂ N(CH ₃ ) ₂ ,-S(=O) ₂ CH ₃ ,-CH ₂ CH ₂ S(=O) ₂ CH ₃ ,

Phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-oxopentacyclyl, pyrazolyl, 2-pyrazolinyl, Pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4- Thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1,4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3 ,5-trithianyl, 1,3,5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, iso Quinolinyl, cinnolinyl or quinoxalinyl;

Methyl, ethyl, propyl, methoxy, ethoxy, methylamino, dimethylamino, halomethyl, haloethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl , cyclopropyl; and

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in the conventional manner followed by isolation of the parent compound. The parent form of the compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.

"Pharmaceutically acceptable salt" as used herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturin, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

Graphical representations of racemic, ambiscalemicandscalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as amino group) or an acidic functional group (such as carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then step by step known in the art Resolution of diastereomers by crystallization or chromatography followed by recovery of the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.

The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

Alkyl and heteroalkyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl The substituents of those groups) are generally referred to as "alkyl substituents", which may be selected from, but not limited to, one or more of the following groups: -R', -OR', =O, =NR' , =N-OR', -NR'R", -SR', Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R', - CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) ₂ R', -NR ""'-C(NR'R"R"')=NR"", NR""C(NR'R")=NR"', -S(O)R', -S(O) ₂ R' , -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluoro(C ₁ -C ₄ )alkyl, substituted The number of radicals is 0～(2m'+1), wherein m' is the total number of carbon atoms in this type of atomic group. R', R", R"', R"" and R""' are each independently preferably hydrogen, Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted by 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkane Oxy group or aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected, as when there are more than one R', R", R "', R"" and R""' groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6-, or 7- - Yuan ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include carbon A group consisting of an atom bonded to a non-hydrogen group, such as a haloalkyl group (eg -CF ₃ , -CH ₂ CF ₃ ) and an acyl group (eg -C(O)CH ₃ , -C(O)CF ₃ , - C(O _{) CH2OCH3} , etc.).

Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally referred to collectively as "aryl substituents" selected from, for example, -R', -OR', -NR'R", -SR', - Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C (O)R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""'-C(NR'R"R"')=NR"", NR ""C(NR'R")=NR"', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R', - CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluoro(C ₁ -C ₄ )alkoxy and fluoro(C ₁ -C ₄ )alkyl, etc., the number of substituents is 0 to aromatic ring Between the total number of open valences above; wherein R', R", R"', R"" and R""' are independently preferably selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds of the present invention include more than one R group, for example, each R group is independently Optionally, as when more than one R', R", R"', R"" and R""' groups are present each of these groups.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -TC(O)-(CRR')qU-, where T and U are independently selected from From -NR-, -O-, CRR'- or a single bond, q is an integer of 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where A and B are independently selected from –CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is 1 to 4 integer. Optionally, a single bond on the new ring thus formed can be replaced by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where s and d are independently selected from An integer from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl groups.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, etc. Wait.

Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above-mentioned alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C _1-6 alkoxy includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- Pentyloxy. "Cycloalkyl" includes saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl. "Alkenyl" includes hydrocarbon chains in straight or branched configuration in which one or more carbon-carbon double bonds are present at any stable point on the chain, eg, ethenyl and propenyl.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the term "hetero" means a heteroatom or heteroatom group (i.e., a group of atoms containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups of atoms containing these heteroatoms, including, for example, oxygen (O ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C(=O) N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H) _- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The so-called ring includes monocyclic, bicyclic, spiro, fused or bridged rings. The number of atoms on a ring is usually defined as the number of ring members, for example, "5-7 membered ring" refers to 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but excludes phenyl. The term "ring" also includes ring systems comprising at least one ring, wherein each "ring" is independently defined above.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing heteroatoms or heteroatom groups, which may be saturated, partially unsaturated or unsaturated ( aromatic) containing carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein). The heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen positions if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. A preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable aromatic ring of 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic groups, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein). Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycle. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to: acridinyl, aziocinyl, benzimidazolyl, benzofuryl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolyl Azolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, Carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuryl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizyl, indolyl, 3H-indole Indolyl, isatinoyl, isobenzofuryl, pyran, isoindolyl, isoindolinyl, isoindolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, Methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrole Phenyl, phenazine, phenothiazine, benzoxanthyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridine Base, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridimidazole, pyridothiazole, pyridyl, pyrimidinyl, Pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydro Isoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, isothiazolylthienyl, thienyl, thienooxazolyl, thienothiazolyl, thiophene Imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthyl. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched-chain or cyclic Hydrocarbon radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, may be mono-, di- or polysubstituted, may include divalent or polyvalent radicals, have a specified number of carbon atoms (e.g. C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrocarbon group" includes but not limited to aliphatic hydrocarbon group and aromatic hydrocarbon group, said aliphatic hydrocarbon group includes chain and ring, specifically includes but not limited to alkyl, alkenyl, alkynyl, said aromatic hydrocarbon group includes but not limited to 6-12 members Aromatic hydrocarbon groups such as benzene, naphthalene, etc. In some embodiments, the term "alkyl" refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Homologues or isomers of methyl, cyclopropylmethyl, and n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups. Unsaturated alkyl has one or more double or triple bonds, examples of which include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and iso Construct.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term represent stable straight-chain, branched or cyclic hydrocarbon radicals or combinations thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including the position where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to _-CH2 - _CH2 -O- _CH3 , _-CH2 - _CH2 -NH- _CH3 , _-CH2 - _CH2 -N( _CH3 ) _-CH3 , _-CH2 -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , - _CH2 -CH=N- _OCH3 and -CH=CH-N( _CH3 ) _-CH3 . Up to two heteroatoms can be consecutive, eg _-CH2 -NH- _OCH3 .

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively. base group.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concepts (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl , heterocycloalkynyl, etc.) by themselves or in combination with other terms means a cyclized "hydrocarbyl", "heterohydrocarbyl", respectively. Furthermore, in the case of heteroalkyl or heterocycloalkyl (eg, heteroalkyl, heterocycloalkyl), a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofurindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl Azolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isox Azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene Base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents for any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

For convenience, aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (e.g., methylene) has been replaced by, e.g., oxygen Those alkyl groups in which atoms are substituted, such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxyl protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.

All solvents used in the present invention are commercially available and used without further purification. The reaction is generally carried out under an inert nitrogen atmosphere in an anhydrous solvent. Proton NMR data were recorded on a Bruker AvanceIII400 (400MHz) spectrometer, and the chemical shifts were expressed in ppm at the downfield of tetramethylsilane. Mass spectra were measured on an Agilent 1200 series plus 6110 (&1956A). LC/MS or ShimadzuMS contains a DAD: SPD-M20A (LC) and Shimadzu Micromass2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive or negative mode.

The present invention adopts the following abbreviations: aq represents water; HATU represents O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate ; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butylcarbonyl, which is an amine protecting group; HOAc represents acetic acid; NaCNBH ₃ represents sodium cyanoborohydride; rt stands for room temperature; O/N stands for overnight; _THF stands for tetrahydrofuran; Boc2O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; _SOCl2 stands for thionyl chloride ; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF Represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents melting point.

Compounds were manually or The software is named, and the commercially available compounds adopt the supplier catalog name.

detailed description

In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

Process 1:

Reaction conditions: a) tert-butyldimethylsilyl chloride, 1 hydrogen-imidazole; b) 1-tert-butoxy-N, N, N', N'-tetramethyldiaminomethane, heating; c) 2-Amino-5-bromopyridine, acetic acid, heating; d) acetic acid, microwave; e) potassium carbonate, DMF, heating; f) R borolipid (boric acid), 1,1'-bis(diphenylphosphine) Ferrocene Palladium Chloride, Potassium Carbonate, Dioxane, Water, Heat. g) methanesulfonyl chloride, triethylamine, dichloromethane, 0 degrees; h) 4,4-difluoropiperidine, diisopropylethylamine, acetonitrile, heating.

Example 1

N-(5-(3-(2-(4,4-difluoro-1-piperidinyl)ethoxy)-4-oxo-pyrido[1,2-a]pyrimidin-7-yl] -2-methoxypyridine-3-]-2,4-dimethylthiazole-5-sulfonamide

a) 2-((tert-butyldimethylsilyl)oxy) ethyl acetate

Ethyl glycolate (100g, 961mmol) and 1 hydrogen-imidazole (130g, 1.9mol) were dissolved in dichloromethane (1L) and placed in a three-necked round-bottomed flask, and tert-butyldimethylsilyl chloride ( 158g, 1mol), the mixture was stirred at room temperature for 8 hours, washed with water (1L*3), dried over sodium sulfate and concentrated to give the title compound (195g, 93%) as a yellow oil.

1HNMR (400MHz, CDCl ₃ )ppmδ4.14-4.09(m,4H),1.20-1.16(t,3H),0.83(s,9H),0.01(s,6H).

b) (Z)-ethyl 2-((tert-butyldimethylsilyl)oxy)-3-(dimethylamino)acrylate

Ethyl 2-((tert-butyldimethylsilyl)oxy)acetate (96g, 0.44mol) and 1-tert-butoxy-N,N,N',N'-tetramethyldiaminomethane ( 91.9g, 0.53mol) was stirred under reflux for 24 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (80 g, 66.6%) as a yellow oil.

1HNMR (400MHz, CDCl ₃ )ppmδ6.68(s, 1H), 4.13-4.11(q, 2H), 2.96(s, 6H), 1.28-1.24(t, 3H), 0.95(s, 9H), 0.14( s,6H).

c) (Z)-ethyl 3-((5-bromopyridin-2-yl)amino)-2-((tert-butyldimethylsilyl)oxy)acrylate

(Z)-Ethyl 3-((5-bromopyridin-2-yl)amino)-2-((tert-butyldimethylsilyl)oxy)acrylate (80g, 293mmol) and 2-amino -5-bromopyridine (50.6g, 293mmol) was dissolved in acetic acid (800mL), and stirred at 80°C for 2 hours. The mixture was concentrated, the residue was dissolved in ethyl acetate (500 mL), washed with sodium carbonate solution (500 mL) and saturated brine (500 mL), dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (74g, 63.0%).

1HNMR (400MHz, CDCl ₃ )ppmδ8.24(s,1H),7.75-7.72(d,1H),7.63-7.60(d,1H),6.75-6.72(d,1H),6.57-6.54(d,1H ),4.25-4.20(q,2H),1.34-1.30(t,3H),1.02(s,9H),0.22(s,6H).

d) 7-bromo-3-hydroxy-4-hydro-pyrido[1,2-a]pyrimidin-4-one

(Z)-Ethyl 3-((5-bromopyridin-2-yl)amino)-2-((tert-butyldimethylsilyl)oxy)acrylate (2g*34, 169mmol) was dissolved in acetic acid ( 13mL*34), stirred in microwave at 140°C for 4 hours. The mixture was concentrated, the residue was dissolved in ethanol (50 mL*34), and filtered to obtain the title compound (20.4 g, 50%).

1HNMR (400MHz, CDCl ₃ )ppmδ8.98(s,1H),8.14(s,1H),8.00-7.98(d,1H),7.79-7.77(d,1H).

e) 7-bromo-3-(2-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

2-Bromoethanol (933mg, 7.47mmol), 7-bromo-3-hydroxyl-4H-pyrido[1,2-a]pyrimidin-4-one (600mg, 2.49mmol) and potassium carbonate (1.03g, 7.47 mmol) was dissolved in N,N-dimethylformamide (10 mL), stirred and reacted at 110°C for 1 hour under nitrogen protection. LCMS showed the reaction was complete. The reaction solution was concentrated to obtain a crude product. The crude product was used directly in the next step.

f) N-(5-(3-(2-hydroxyethyl)-4-oxo 4H-pyrido[1,2-a]pyrimidin-7-yl)-2-methoxypyridin-3-yl )-2,4-Dimethylthiazole-5-sulfonamide

7-Bromo-3-(2-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (704 mg, 2.49 mmol) was dissolved in dioxane (10 mL) and water (2 mL ), add N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-3-yl )-2,4-dimethylthiazole-5-sulfonamide (1.06g, 2.49mmol), potassium carbonate (687mg, 4.97mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (50mg). The reaction solution was stirred and reacted at 100°C for 3 hours. LCMS showed the reaction was complete. The reaction solution was concentrated by filtration to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the title product (500 mg, 40%) as a white solid.

1HNMR (400MHz, CDCl ₃ )ppmδ9.09(s,1H),8.24(s,1H),8.18(d,1H),8.01(d,1H),7.80-7.67(m,1H),4.28-4.22( m,2H),4.01-3.92(m,5H),2.65(s,3H),2.56(s,3H).

g) 2-((7-(5-(2,4-dimethylthiazole 2,4-dimethylthiazole-5-sulfonamido)-6-methoxypyridin-3-yl)-4- Oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)oxy)ethyl methanesulfonate

N-(5-(3-(2-hydroxyethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-3-yl)-2,4 -Dimethylthiazole-5-sulfonamide (50.00mg, 99.30umol) and triethylamine (20.10mg, 198.60umol) were dissolved in dichloromethane, and methanesulfonyl chloride (13.65mg, 119.16umol) was added at 0°C. The reaction was stirred at 0°C for 1 hour. TLC showed that the reaction was complete, and dichloromethane (10 mL) and water (8 mL) were added to the reaction solution. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (55 mg, 95.2%) as a light yellow solid.

¹ HNMR (400MHz, CDCl ₃ ) ppmδ9.08 (d, J = 1.10Hz, 1H), 8.54 (d, J = 2.43Hz, 1H), 8.21 (s, 1H), 7.67-7.79 (m, 3H), 4.58-4.66(m,2H),4.43-4.50(m,2H),4.01(s,3H),3.17(s,3H),2.74(s,3H),2.46(s,3H).

h) N-(5-(3-(2-(4,4-difluoro-1-piperidinyl)ethoxy)-4-oxo-pyrido[1,2-a]pyrimidine-7- Base]-2-methoxypyridine-3-]-2,4-dimethylthiazole-5-sulfonamide

2-((7-(5-(2,4-dimethylthiazole 2,4-dimethylthiazole-5-sulfonamido)-6-methoxypyridin-3-yl)-4-oxo Substitute-4H-pyrido[1,2-a]pyrimidin-3-yl)oxy)ethyl methanesulfonate (50.00mg, 85.96umol) and 4,4-difluoropiperidine (12.50mg, 103.16umol ) was dissolved in acetonitrile (2 mL), and diisopropylethylamine (22.22 mg, 171.93 umol) was added. Stir the reaction at 50°C for 12 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to give the title product (15.00 mg, 28.77%) as a light yellow solid.

¹ HNMR (400MHz, CD ₃ OD) ppmδ9.11 (d, J = 1.51Hz, 1H), 8.30 (d, J = 2.26Hz, 1H), 8.27 (s, 1H), 8.01-8.11 (m, 2H) ,7.74(d,J=9.29Hz,1H),4.35(t,J=5.40Hz,2H),3.89(s,3H),2.94-2.97(m,2H),2.78(d,J=5.02Hz, 4H),2.64(s,3H),2.49(s,3H),1.98-2.05(m,4H).

With reference to the preparation method of Example 1, the following 5 compounds have also been synthesized:

Process 2:

Reaction conditions: a) 2-morpholine ethanol, dibromotriphenylphosphine, dichloromethane; b) 7-bromo-3-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, carbonic acid Potassium, N,N-dimethylformamide; c) 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridine )-3-amine, 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, potassium carbonate, dioxane, water, heating; d) R group sulfonyl chloride, pyridine.

Example 7

2,4-Dimethyl-N-(2-methoxy-5-(3-(2-morpholineethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine- 4-keto-7-yl)pyridin-3-yl)benzenesulfonamide

a) 4-(2-bromoethyl)morpholine hydrobromide

Under the protection of nitrogen, dibromotriphenylphosphine (15.45 g, 36.59 mmol) was added in portions to a solution of 2-morpholine ethanol (4 g, 30.49 mmol) in dichloromethane (80 mL) at 0°C. The mixture was stirred at 15°C for 18 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with dichloromethane and dried under reduced pressure to obtain a near-white solid (5.1 g, 60.8%).

1HNMR (400MHz, CDCl ₃ )ppmδ4.06(d, J=12.2Hz, 2H), 3.89-3.75(m, 4H), 3.71-3.63(m, 2H), 3.56(d, J=12.5Hz, 2H) ,3.28-3.18(m,2H)

b) 7-bromo-3-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one

Under nitrogen protection, 7-bromo-3-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (1g, 4.15mmol), 4-(2-bromoethyl)morpholine hydrobromide Salt (1.14g, 4.15mmol) and potassium carbonate (1.72g, 12.45mmol) were placed in N,N-dimethylformamide (80mL) and stirred at 120°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to remove N,N-dimethylformamide. Dichloromethane was added to the concentrate and filtered. The filtrate was concentrated to give the product as a brown solid (1.3 g, 88.4%).

¹ HNMR (400MHzCDCl ₃ )ppmδ9.03(d, J＝1.7Hz, 1H), 8.07(s, 1H), 7.51(dd, J＝2.2, 9.5Hz, 1H), 7.45-7.29(m, 1H), 4.24(t, J=5.7Hz, 2H), 3.75-3.56(m, 4H), 2.78(t, J=5.6Hz, 2H), 2.62-2.47(m, 4H)

c) 7-(5-amino-6-methoxypyridin-3-yl)-3-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one

Under nitrogen protection, 7-bromo-3-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (100mg, 0.28mmol), 2-methyl Oxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridin)-3-amine (46mg, 0.31mmol) and potassium carbonate (117mg, 0.85mmol) in dioxane (5mL) was added 1,1'-bis(diphenylphosphine)ferrocenepalladium chloride (8mg, 0.008mmol) and water (1mL). The mixture was stirred at 90° C. for 18 hours under nitrogen protection. After the reaction was completed, the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative TLC and preparative liquid chromatography to give off-white solid (23.82 mg, 22.06%).

1HNMR (400MHz, CDCl ₃ )ppmδ9.13(d, J=1.5Hz, 1H), 8.46(d, J=2.5Hz, 1H), 8.19(s, 1H), 7.86(dd, J=2.5, 8.5Hz ,1H),7.79(dd,J=2.0,9.0Hz,1H),7.72-7.64(m,1H),6.89(d,J=8.5Hz,1H),4.33(t,J=5.5Hz,2H) ,4.01(s,3H),3.82-3.66(m,4H),2.87(t,J=5.8Hz,2H),2.62(br.s.,4H)

d) 2,4-Dimethyl-N-(2-methoxy-5-(3-(2-morpholineethoxy)-4-oxo-4H-pyrido[1,2-a] Pyrimidin-4-one-7-yl)pyridin-3-yl)benzenesulfonamide

7-(5-amino-6-methoxypyridin-3-yl)-3-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (100.00mg, 251.62umol) in pyridine (3mL) was added dropwise with 2-methyl-4-fluorobenzenesulfonyl chloride (61.8mg, 301.94umol). The reaction solution was stirred at 18 degrees for 18 hours. After the reaction, pyridine was distilled off under reduced pressure. The residue was dissolved in dichloromethane and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to give a yellow solid product (23.16mg, 16.11%).

1HNMR (400MHz, CDCl ₃ )ppmδ8.97(s, 1H), 8.16(s, 1H), 8.03(d, J=2.2Hz, 1H), 7.91(d, J=8.1Hz, 1H), 7.82(d ,J=2.0Hz,1H),7.65(d,J=1.0Hz,2H),7.16(d,J=8.1Hz,1H),7.10(s,1H),4.31(t,J=5.6Hz,2H ),3.99(s,3H),3.82-3.66(m,4H),2.86(t,J=5.6Hz,2H),2.64(s,3H),2.61(d,J=4.2Hz,4H),2.33 (s,3H).

The following 13 compounds have also been synthesized with reference to the preparation method of Example 7:

Process 3:

Reaction conditions: a) methanesulfonyl chloride, triethylamine, dichloromethane; b) potassium carbonate, N,N-dimethylformamide; c) N-(2-methoxy-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide, palladium, potassium carbonate , dioxane, water, heat.

Example 21

N-(2-methoxy-5-(4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethoxy)-4H-pyrido[1,2-a] Pyrimidin-7-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide

a) 2-(2-oxopyrrolidin-1-yl) ethyl methanesulfonate

At 0 degrees, into a solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (500.00mg, 3.87mmol) and triethylamine (1.17g, 11.61mmol) in dichloromethane (5mL) Methanesulfonyl chloride (531.97 mg, 4.64 mmol) was added. The reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily crude product (470.00 mg, 58.60%).

1HNMR (400MHz, CDCl ₃ ) δ4.35(t, J=5.1Hz, 2H), 3.62(t, J=5.1Hz, 2H), 3.51(t, J=7.1Hz, 2H), 3.03(s, 3H ), 2.40(t, J＝8.1Hz, 2H), 2.06(quin, J＝7.6Hz, 2H)

b) 7-bromo-3-(2-(2-oxopyrrolidin-1-yl)ethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one

Under nitrogen protection, 7-bromo-3-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (100.00mg, 414.87umol), 2-(2-oxopyrrolidine- A mixture of 1-yl)ethylmethanesulfonate (257.94mg, 1.24mmol) and potassium carbonate (229.36mg, 1.66mmol) in N,N-dimethylformamide (10mL) was stirred at 120°C for 18 hours. After the reaction was completed, the reaction solution was concentrated. The concentrate was purified by silica gel column chromatography to obtain a yellow oily product (210.00 mg, 79.05%, purity: 55%).

1HNMR (400MHz, CDCl ₃ ) δ9.02(d, J=1.7Hz, 1H), 8.03(s, 1H), 7.51(dd, J=2.1, 9.4Hz, 1H), 7.44-7.37(m, 1H) ,4.23(t,J=5.1Hz,2H),3.67(s,2H),3.62(t,J=7.0Hz,2H),2.34(t,J=8.0Hz,2H),2.10-1.86(m, 2H).

c) N-(2-methoxy-5-(4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethoxy)-4H-pyrido[1,2- a] pyrimidin-7-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide

Under nitrogen protection, to the addition of 7-bromo-3-(2-(2-oxopyrrolidin-1-yl)ethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (210.00mg, 327.96umol), N-(2-methoxy-5-(4,4,5,5-t tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1, 1'-Bis(diphenylphosphino)ferrocenepalladium chloride (2.40 mg, 3.28 umol) and water (1 mL). Under nitrogen protection, the mixture was stirred at 90°C for 18 hours. After the reaction was completed, the reaction solution was concentrated. The concentrated residue was purified by preparative thin-layer chromatography to give the title compound (60.07 mg, 30.41%) as a yellow solid.

1HNMR (400MHz, CDCl ₃ ) δ8.98(s, 1H), 8.20-8.06(m, 3H), 7.92(d, J=2.2Hz, 1H), 7.68(d, J=1.1Hz, 2H), 7.58 (s,1H),7.28(d,J=2.4Hz,1H),7.20-7.09(m,1H),4.32(t,J=5.1Hz,2H),4.00(s,3H),3.84-3.65( m,4H),2.42(t,J=8.0Hz,2H),2.08(quin,J=7.6Hz,2H)

The following 15 compounds were also synthesized with reference to the preparation method of Example 21:

Process 4:

Reaction conditions: a) 1,2-dibromoethane, potassium carbonate, DMF, heating; b) 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide, 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, Potassium carbonate, dioxane, water, heating; c) 1H-pyrazole, cesium carbonate, acetonitrile, heating.

Example 37

2,4-Difluoro-N-(2-methoxy-5-(4-oxo-3-(2-pyrazole-1-ethoxy)pyrido[1,2-a]pyrimidine-7 -yl)pyridin-3-yl)benzenesulfonamide

a) 7-bromo-3-(2-bromoethoxy)pyrido[1,2-a]pyrimidin-4-one

7-Bromo-3-hydroxy-pyrido[1,2-a]pyrimidin-4-one (600.00 mg, 2.49 mmol) and 1,2-dibromoethane (1.40 g, 7.47 mmol) were dissolved in DMF ( 10mL), potassium carbonate (1.03g, 7.47mmol) was added. The reaction was stirred at 100°C for 1.5 hours. TLC showed that the reaction was complete, and the reaction solution was cooled to room temperature. Purification by silica gel column chromatography gave the title compound (550.00 mg, 63.5%) as a brown solid.

¹ HNMR (400MHz, CDCl ₃ )ppmδ9.10(s, 1H), 8.20(s, 1H), 7.61(dd, J=9.54, 1.71Hz, 1H), 7.49(d, J=9.54Hz, 1H), 4.49(t, J=6.36Hz, 2H), 3.66(t, J=6.36Hz, 2H).

b) N-(5-(3-(2-bromoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-2-methoxypyridine-3 -yl)-2,4-difluorobenzenesulfonamide

7-Bromo-3-(2-bromoethoxy)pyrido[1,2-a]pyrimidin-4-one (550.00 mg, 1.58 mmol) was dissolved in dioxane (15 mL) and water (2 mL) , under nitrogen protection, add 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyridin-3-yl)benzenesulfonamide (673.67mg, 1.58mmol), potassium carbonate (436.74mg, 3.16mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (117.20mg, 158.00umol). The reaction was stirred at 90°C for 1.5 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title product (250.00 mg, 27.89%) as a light yellow solid.

¹ HNMR (400MHz, CDCl ₃ )ppmδ9.03(s, 1H), 8.24(s, 1H), 8.12(d, J=2.20Hz, 1H), 7.89-7.98(m, 2H), 7.68-7.76(m ,2H),7.32(br.s.,1H),6.99-7.06(m,1H),6.90-6.98(m,1H),4.52(t,J＝6.24Hz,2H),3.98(s,3H) ,3.69(t,J=6.36Hz,2H).

c) 2,4-difluoro-N-(2-methoxy-5-(4-oxo-3-(2-pyrazole-1-ethoxy)pyrido[1,2-a]pyrimidine -7-yl)pyridin-3-yl)benzenesulfonamide

N-(5-(3-(2-bromoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-2-methoxypyridine-3- base)-2,4-difluorobenzenesulfonamide (50.00mg, 88.13umol) and 1H-pyrazole (9.00mg, 132.20umol) were dissolved in acetonitrile (0.5mL), cesium carbonate (57.43mg, 176.26umol) was added . Stir the reaction at 70°C for 2 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to afford the title product (15.00 mg, 30.69%) as a yellow solid.

¹ HNMR (400MHz, CDCl ₃ ) ppmδ9.00 (d, J = 0.98Hz, 1H), 8.11 (d, J = 2.20Hz, 1H), 7.87-7.99 (m, 3H), 7.61-7.73 (m, 3H ),7.49-7.57(m,1H),7.34(br.s.,1H),6.98-7.06(m,1H),6.90-6.98(m,1H),6.26(t,J=1.96Hz,1H) ,4.57(dd,J=10.88,4.28Hz,4H),3.97(s,3H).

The following 3 compounds were also synthesized with reference to the preparation method of Example 37:

Process 5:

Reaction conditions: a) methanesulfonyl chloride, triethylamine, dichloromethane, 0 degrees to room temperature; b) potassium carbonate, DMF, heating; c) R borolipid (boric acid), 1,1'-bis (diphenyl Phosphorus) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; d) hydrochloric acid-ethyl acetate, ethyl acetate, room temperature.

Example 41

2,4-Difluoro-N-(2-methoxy-5-(4-oxo-3-(piperidin-4-oxyl)-4H-pyrido[1,2-a]pyrimidine-7 -yl)pyridin-3-yl)benzenesulfonamide

a) tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Dissolve tert-butyl 4-hydroxypiperidine-1-carboxylate (1g, 4.97mmol) and triethylamine (1g, 9.95mmol) in dichloromethane (4mL), and add methanesulfonyl chloride ( 1 g, 8.72 mmol). After the dropwise addition, the reaction solution was raised to room temperature and stirred for 2 hours. The reaction solution was quenched by pouring into ice water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (1.6 g, crude product) as a red solid.

b) tert-butyl 4-((7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)oxy)piperidine-1-carboxylate

tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (200mg, 0.72mmol), 7-bromo-3-hydroxy-4H-pyrido[1,2-a]pyrimidine- 4-Kone (115mg, 0.48mmol) and potassium carbonate (198mg, 1.43mmol) were dissolved in N,N-dimethylformamide (2mL), and stirred at 120°C for 2 hours under nitrogen protection. Water was added to the reaction solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (170 mg, 84%) as a red solid.

1HNMR (400MHz, CDCl ₃ )ppmδ9.14-9.10(m,1H),8.17(s,1H),7.65-7.59(m,1H),7.53-7.47(m,1H),4.90-4.88(m,1H ),3.85(m,2H),3.71-3.70(m,2H),1.95(s,3H),1.47(s,9H).

c) tert-butyl 4-((7-(5-(2,4-difluorobenzenesulfonamide)-6-methoxypyridin-3-yl)-4-oxo-4H-pyrido[1, 2-a]pyrimidin-3-yl)oxy)piperidine-1-carboxylate

tert-Butyl 4-((7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)oxy)piperidine-1-carboxylate (130mg, 0.3mmol) , 2,4-Difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine -3-yl)benzenesulfonamide (130mg, 0.3mmol), potassium carbonate (85mg, 0.61umol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (22mg, 0.03mmol) were dissolved in in dioxane (2 mL) and water (0.4 mL). The reaction solution was stirred and reacted at 100° C. for 2 hours under a nitrogen-protected microwave condition. The crude product was purified by silica gel column chromatography to give the title compound (80 mg, 30%) as a red oil.

d) 2,4-difluoro-N-(2-methoxy-5-(4-oxo-3-(piperidin-4-oxyl)-4H-pyrido[1,2-a]pyrimidine -7-yl)pyridin-3-yl)benzenesulfonamide hydrochloride

tert-butyl 4-((7-(5-(2,4-difluorobenzenesulfonamide)-6-methoxypyridin-3-yl)-4-oxo-4H-pyrido[1,2 -a] pyrimidin-3-yl)oxy)piperidine-1-carboxylate (28 mg, 0.043 mmol) was dissolved in ethyl acetate (2 mL), and hydrochloric acid/ethyl acetate (15 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered, and the solid was spin-dried to obtain the title product (7.4 mg, 29%) as a brown solid.

1HNMR (400MHz, CD ₃ OD)ppmδ9.24(s,1H),8.47-8.46(m,2H),8.37(s,1H),8.13(s,1H),7.97-7.86(m,2H),7.26 -7.21(m,1H),7.12-7.08(m,1H),4.85-4.84(m,1H),3.86(s,1H),3.55-3.50(m,2H),3.31-3.25(m,2H) ,2.19(s,4H).

The following 3 compounds were also synthesized with reference to the preparation method of Example 41:

Process 6:

Reaction conditions: a) 5-bromo-2-chloro-3-nitropyridine, R alcohol, potassium hydroxide, potassium carbonate, 2-(2-methoxyethoxy)-N,N-bis[2- (2-methoxyethoxy)ethyl]ethylamine, toluene; b) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,3,2-dioxaborane, 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, potassium acetate, dioxygen Hexacyclic, heating; c) Pd/C, methanol; d) 7-bromo-3-chloro-pyrido[1,2-a]pyrimidin-4-one, 1,1'-bis(diphenylphosphine) Ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; e) 2,4-difluorobenzenesulfonyl chloride, pyridine; f) hydrochloric acid/dioxane, dioxane.

Example 45

N-[5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-2-(3-(methylamino)propoxy)pyridine-3 -yl]-2,4-difluoro-benzenesulfonamide

a) Tert-butyl (3-((5-bromo-3-nitropyridin-2-yl)oxy)propyl)(methyl)carbamate

Add 5-bromo-2-chloro-3-nitropyridine (1.8g, 7.58mmol) to the mixture of potassium hydroxide (723mg, 12.89mmol) and potassium carbonate (1.78g, ), (3-hydroxypropyl)(methyl)carbamate tert-butyl ester (1.72g, 9.1mmol) and 2-(2-methoxyethoxy)-N,N-bis[2-(2- Methoxyethoxy)ethyl]ethylamine (245 mg, 0.758 mmol). The mixture was stirred at 15° C. for 18 hours under nitrogen protection. After the reaction, the reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EA=20:1-4:1) to obtain the target compound (1.5 g, 50%) as yellow oil.

1HNMR (400MHz, CDCl ₃ )ppmδ8.40(d, J=2.0Hz, 1H), 8.36(d, J=2.2Hz, 1H), 4.47(t, J=6.1Hz, 2H), 3.40(t, J ＝6.8Hz, 2H), 2.87(s, 3H), 2.03(s, 2H), 1.41(s, 9H)

b) Methyl (3-((3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)pyridin-2-yl )oxy)propyl)tert-butyl carbamate

Under nitrogen protection, (3-((5-bromo-3-nitropyridin-2-yl)oxy)propyl)(methyl)carbamate tert-butyl ester (1.5g, 3.84mmol), 4 ,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-1,3,2-di Add 1,1'-bis(diphenylphosphino)ferrocene chloride to a mixture of oxaborane (1.17g, 4.61mmol) and potassium acetate (1.13g, 11.53mmol) in dioxane (30mL) Palladium (97 mg, 0.11 mmol). The mixture was stirred at 80° C. for 18 hours under nitrogen protection. After the reaction was detected, the reaction solution was filtered, and the filtrate was concentrated and purified by silica gel chromatography to obtain a yellow oily crude product (0.9 g, 53%).

1HNMR (400MHz, CDCl ₃ ) ppm8.65(d, J=1.5Hz, 1H), 8.55(d, J=1.5Hz, 1H), 4.52(t, J=5.7Hz, 2H), 3.41(t, J =6.8Hz,2H),2.87(s,3H),2.04(br.s.,2H),1.41(s,9H),1.33(s,12H).

c) (3-((3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)pyridin-2-yl)oxy) Propyl)(methyl)carbamate tert-butyl ester

Methyl(3-((3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2- To a solution of tert-butyl)carbamate (900mg, 2.06mmol) in methanol (10mL) was added Pd/C (90.00mg). The mixture was stirred at 15° C. for 4 hours under hydrogen atmosphere. After the reaction was detected, the reaction solution was filtered, and the filtrate was concentrated to obtain a yellow oily crude product (870 mg, 95%).

1HNMR (400MHz, CDCl ₃ )ppmδ7.93(s, 1H), 7.21(s, 1H), 4.41(t, J=6.0Hz, 2H), 3.39(br.s., 2H), 2.85(br.s .,3H),2.00(br.s.,2H),1.41(br.s.,9H),1.31(s,12H).

d) (3-((3-amino-5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-2-yl)oxy)propyl )(methyl)carbamate tert-butyl ester

Under nitrogen protection, 7-bromo-3-chloro-pyrido[1,2-a]pyrimidin-4-one (503 mg, 1.94 mmol), (3-((3-amino-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propyl)(methyl)carbamate ( 790mg, 1.94mmol) and sodium carbonate (1M, 4.85mL, 4.85mmol) in dioxane (10mL) mixture was added 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (17mg, 0.019 mmol). The mixture was stirred at 80° C. for 18 hours under nitrogen protection. After the reaction was detected, the reaction solution was filtered, and the filtrate was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (600 mg, 67%) as a yellow solid.

1HNMR (400MHz, CDCl ₃ ) δ9.18(d, J=1.7Hz, 1H), 8.48(s, 1H), 7.97(dd, J=2.1, 9.2Hz, 1H), 7.84-7.66(m, 2H) ,7.13(d,J=1.7Hz,1H),4.45(br.s.,2H),3.43(br.s.,2H),2.88(br.s.,3H),2.05(t,J=6.5 Hz,2H),1.43(s,9H).

e) (3-((5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-3-(2,4-difluorobenzenesulfonamide) Pyridin-2-yl)oxy)propyl)(methyl)carbamate tert-butyl ester

Added (3-((3-amino-5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-2-yl)oxy)propane 2,4-Difluorobenzenesulfonyl chloride (333 mg, 1.57 mmol) was added to a mixture of tert-butyl (methyl)carbamate (600 mg, 1.3 mmol) in pyridine (5 mL). The mixture was reacted at 15 degrees for 18 hours. After the reaction was completed, the reaction solution was concentrated. The residue was dissolved in dichloromethane and washed with water, brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resultant was purified by silica gel chromatography to give the title compound (404 mg, 48%) as a yellow solid.

f) N-[5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-2-(3-(methylamino)propoxy)pyridine -3-yl]-2,4-difluoro-benzenesulfonamide

To (3-((5-(3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-3-(2,4-difluorobenzenesulfonamide)pyridine -2-yl)oxy)propyl)(methyl)carbamate tert-butyl ester (450mg, 0.43mmol) in dioxane (30mL) solution was added hydrochloric acid/dioxane solution (4mL). The mixture was Stir for 3 hours at 15°C. After the reaction was completed, the reaction solution was concentrated. Aqueous sodium bicarbonate solution was added to the concentrated residue. The precipitate was filtered off, sucked dry, and washed with dichloromethane to give the title product (175.56 mg, 75.9%) as a pale yellow solid.

1HNMR (400MHz, DMSO-d ₆ )δ8.81(d, J=1.5Hz, 1H), 8.56(s, 1H), 8.13(dd, J=2.0, 9.3Hz, 1H), 8.02-7.89(m, 1H), 7.85-7.73(m, 2H), 7.47(d, J=2.2Hz, 1H), 7.33-7.21(m, 1H), 7.19-7.09(m, 1H), 4.29(t, J=5.4Hz ,2H),3.20-3.08(m,2H),2.72(s,3H),2.08(m,2H).

The following 5 compounds were also synthesized with reference to the preparation method of Example 45:

Process 7:

Reaction conditions: a) diethyl ethoxymethylene malonate, ethanol, heating; b) phosphorus oxybromide, heating; c) DIBAL-H, tetrahydrofuran, -5-0 degrees; d) manganese dioxide, Dioxane, heating; e) Morpholine, sodium borohydride acetate, acetic acid, methanol, heating; f) N-[2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl]-2,4-dimethyl-5-sulfonamide, 1,1'-bis(diphenylphosphine)dicene Iron Palladium Chloride, Potassium Carbonate, Dioxane, Water, Heat.

Example 51

N-(2-methoxy-5-(3-(morpholinomethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-3-yl)- 2,4-Dimethylthiazole-5-sulfonamide

a) Diethyl 2-(((5-bromopyridin-2-yl)amino)methylene)malonate

2-Amino-5-bromopyridine (1.72g, 9.94mmol) and diethyl ethoxymethylene malonate (4.51g, 20.87mmol) were placed in a round bottom flask, and stirred at 130°C for 2 hours. TLC showed that the reaction was complete. The mixture was cooled to 25°C, filtered, and the filter cake was rinsed with petroleum ether (20 mL*3) to obtain the title compound (3.14 g, 92%) as a white solid.

¹ HNMR (400MHz, CDCl ₃ )ppmδ11.10(d, J=12.47Hz, 1H), 9.06(d, J=12.72Hz, 1H), 8.38(d, J=2.20Hz, 1H), 7.74(dd, J=8.56, 2.45Hz, 1H), 6.76(d, J=8.56Hz, 1H), 4.21-4.34(m, 4H), 1.35(dt, J=16.02, 7.15Hz, 6H).

b) Ethyl 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

Diethyl 2-(((5-bromopyridin-2-yl)amino)methylene)malonate (21.76 g, 63.41 mmol) and phosphorus oxybromide (54.54 g, 190.23 mmol) were placed in a round bottom In the flask, stir and react at 80 degrees for 4 hours. TLC showed that the reaction was complete, and the mixture was cooled to 25°C and slowly added to ice water. Aqueous sodium carbonate solution was added to the mixture to adjust the pH to around 8. Extracted with dichloromethane (300mL*3), washed the organic phase with saturated brine (200mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (18.8g, 99.8%) as a white solid.

¹ HNMR (400MHz, CDCl ₃ ) ppmδ9.36 (d, J = 1.98Hz, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.26, 1.98Hz, 1H), 7.67 (d, J = 9.26 Hz,1H),4.42(q,J=7.06Hz,2H),1.41(t,J=7.06Hz,3H).

c) 7-bromo-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

Dissolve ethyl 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (5.00 g, 16.83 mmol) in tetrahydrofuran (150 mL) in a three-neck round bottom flask , A solution of DIBAL-H (50.49 mmol) in toluene (50 mL) was added dropwise to the above mixture at -5°C. The reaction solution was stirred at 0°C for 2 hours. TLC showed that the reaction was complete, slowly added saturated aqueous ammonium chloride solution to the reaction solution, extracted with ethyl acetate (200mL*3), washed with saturated brine (200mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product . The crude product was purified by silica gel column chromatography to give the title compound (1.1 g, 25.6%) as a brick red solid.

¹ HNMR (400MHz, CDCl ₃ ) ppmδ9.15 (d, J = 1.96Hz, 1H), 8.39 (s, 1H), 7.98 (dd, J = 9.54, 2.20Hz, 1H), 7.59 (d, J = 9.29 Hz,1H),4.64(s,2H).

d) 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde

7-Bromo-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.7g, 2.74mmol) was dissolved in dioxane (15mL) and placed in a 50mL round bottom In the flask, manganese dioxide (2.39 g, 27.44 mmol) was added. Stir and react at 80°C for 3 hours. TLC showed that the reaction was complete, and the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (50mL) and filtered. The filtrate was concentrated to give the title compound (0.6 g, 86.5%) as a yellow solid.

¹ HNMR (400MHz, CDCl ₃ )ppmδ10.38(s, 1H), 9.39(d, J=2.21Hz, 1H), 8.90(s, 1H), 8.06(dd, J=9.26, 2.21Hz, 1H), 7.73(d,J=9.26Hz,1H).

e) 7-bromo-3-(morpholine methyl)-4H-pyrido[1,2-a]pyrimidin-4-one

Dissolve 7-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (88.00mg, 347.75umol) in methanol (4mL) in a 10mL thumb bottle, add morpholine (45.44mg, 521.63umol) and AcOH (41.77mg, 695.51umol). Stir at 50 degrees for 2 hours. Sodium acetate borohydride (294.81 mg, 1.39 mmol) was added to the above reaction solution, and stirring was continued at 50°C for 12 hours. TLC showed that the reaction was complete, and the reaction solution was cooled to room temperature. Purification by silica gel column chromatography gave the title compound (45 mg, 40%) as a yellow solid.

¹ HNMR (400MHz, CDCl ₃ ) ppmδ9.13 (d, J = 1.71Hz, 1H), 8.38 (s, 1H), 7.70 (dd, J = 9.41, 2.08Hz, 1H), 7.49 (d, J = 9.29 Hz,1H),3.68-3.73(m,4H),3.62(s,2H),2.57(br.s.,4H).

f) N-(2-methoxy-5-(3-(morpholine methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-3-yl )-2,4-Dimethylthiazole-5-sulfonamide

7-Bromo-3-(morpholinemethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (60.00mg, 185.09umol) was dissolved in dioxane (3mL) and water (0.5 mL), under nitrogen protection, add N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridin-3-yl]-2,4-dimethylthiazole-5-sulfonamide (86.60mg, 203.60umol), potassium carbonate (51.16mg, 370.18umol) and 1,1'-bis(diphenylphosphine) Ferrocenepalladium chloride (13.54mg, 18.51umol). Stir the reaction at 80°C for 2 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to afford the title product (50.00 mg, 50%) as a yellow solid.

¹ HNMR (400MHz, CDCl ₃ )ppmδ9.23(s, 1H), 8.42(s, 1H), 8.20(d, J=1.76Hz, 1H), 8.06(s, 1H), 7.90(dd, J=9.04 ,1.76Hz,1H),7.77(d,J=9.04Hz,1H),4.00(s,3H),3.76(t,J=4.41Hz,4H),3.65(s,2H),2.66(s,3H ),2.59(s,7H).

The following 1 compound was also synthesized with reference to the preparation method of Example 51:

Process 8:

Conditions: a) malonyl chloride, dichloromethane, room temperature; b) phosphorus oxychloride, reflux; c) N-(2-hydroxypropyl) morpholine, sodium hydrogen, tetrahydrofuran, 0 degrees to room temperature; d) R Borofat (boric acid), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, potassium carbonate, dioxane, water, heating.

Example 53

2-Chloro-4-fluoro-N-(2-methoxy-5-(2-(2-morpholineethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidine- 7-yl)pyridin-3-yl)benzenesulfonamide

a) 7-bromo-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one

2-Amino-5-bromopyridine (1.0g, 5.7mmol) was dissolved in dichloromethane (10mL) and placed in a 50mL round bottom flask, and malonyl chloride (977mg, 6.9mmol) was added dropwise at 0°C. After the dropwise addition, the reaction solution was raised to 15°C, and the reaction was stirred at 15°C for 48 hours. LCMS showed the reaction was complete. The reaction solution was filtered, and the filter cake was rinsed with dichloromethane (20 mL) to obtain the title compound (1.4 g, 100%) as a yellow solid.

b) 7-bromo-2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one

Dissolve 7-bromo-2-hydroxyl-4H-pyrido[1,2-a]pyrimidin-4-one (900mg, 3.73mmol) in phosphorus oxychloride (8mL) and place in a 50mL round bottom flask at 110°C The reaction was stirred for 18 hours. LCMS showed the reaction was complete. The reaction solution was cooled to room temperature, slowly poured into room temperature water (50 mL) to quench, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (300 mg, 31%) as a yellow solid.

1H NMR (400MHz, DMSO-d ₆ )ppmδ8.99(d,1H),8.21(dd,1H),7.65(d,1H),6.56(s,1H).

c) 7-bromo-2-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one

N-(2-hydroxypropyl)morpholine (404mg, 3.08mmol) was dissolved in tetrahydrofuran (5mL) and placed in a 50mL round bottom flask, sodium hydrogen (308mg, 7.71mmol, 60% purity) was added at 0°C, The reaction was stirred for 30 minutes under high temperature, and 7-bromo-2-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (200mg, 770umol) was added dropwise. The reaction solution was raised to 15°C and stirred for 3 hours. TLC showed the reaction was complete. The reaction solution was slowly poured into ice water (50 mL) to quench, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative TLC to give the title compound (40 mg, 14%).

d) 2-chloro-4-fluoro-N-(2-methoxy-5-(2-(2-morpholineethoxy)-4-oxo-4H-pyrido[1,2-a] Pyrimidin-7-yl)pyridin-3-yl)benzenesulfonamide

7-Bromo-2-(2-morpholineethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (70mg, 197umol) was dissolved in dioxane (5mL) and water ( 1mL), add 2-chloro-4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyridin-3-ylbenzenesulfonamide (87mg, 197umol), potassium carbonate (54mg, 395umol) and 1,1'-bis(diphenylphosphine)ferrocenepalladium chloride (7mg). Reaction solution The reaction was stirred at 100°C for 3 hours under the protection of nitrogen. LCMS showed that the reaction was complete. The reaction solution was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain the title product (50 mg, 42%) as a white solid.

1HNMR (400MHz, CDCl ₃ )ppmδ9.08(d,1H),8.14(dd,1H),8.09(d,1H),7.90(d,1H),7.87(dd,1H),7.58(d,2H) ,7.28(d,1H),7.19-7.12(m,1H),5.86(s,1H),4.58-4.48(m,2H),3.99(s,3H),3.76(br.s.,4H), 2.85(br.s.,2H),2.62(br.s.,3H).

Process 9:

Reaction conditions: a) triphosgene, triethylamine, 2,4-dimethyl-5-aminothiazole, 0 degrees; anhydrous dichloromethane, room temperature; b) 1,1'-bis(diphenylphosphine ) ferrocene palladium chloride, potassium acetate, double pinacol borate, anhydrous dioxane, heating; c) 1-(2-methoxy-5-bromopyridin-3-yl)- 3-(2,4-Dimethylthiazol-5-yl)urea, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride, potassium phosphate trihydrate, tetrahydrofuran, water, heating.

Example 54

1-(2,4-Dimethylthiazol-5-yl)-3-(2-methoxy-5-(3-(2-morpholinoethyl)-4-oxo-4H-pyrido [1,2-a]pyrimidin-7-yl)pyridin-3-yl)urea

a) 1-(2-methoxy-5-bromopyridin-3-yl)-3-(2,4-dimethylthiazol-5-yl)urea

2-Methoxy-3-amino-5-bromopyridine (100.00mg, 492.52umol), triethylamine (498.38mg, 4.93mmol) and anhydrous dichloromethane (5mL) were placed in a 10mL three-neck round bottom flask In 0°C, triphosgene (438.47 mg, 1.48 mmol) dichloromethane solution (1 mL) was slowly added dropwise under the protection of nitrogen, and the reaction was stirred at room temperature for 2 hours. 2,4-Dimethyl-5-aminothiazole (162.20mg, 985.04umol) was added at 0°C under nitrogen protection, and the reaction was stirred overnight at room temperature. Liquid phase mass spectrometry showed that the reaction was complete, water (50mL) was added to the mixture, extracted with dichloromethane (50mL*3), the organic phases were combined, washed with saturated brine (50mL*2), dried over anhydrous sodium sulfate, filtered, Concentration and silica gel chromatography gave the title compound (85.00 mg, 48%).

¹ H NMR (400MHz, CD ₃ OD) ppm δ8.57 (d, 1H), 7.82 (d, 1H), 4.02 (s, 3H), 2.56 (s, 3H), 2.26 (s, 3H).

b) (3-(2-morpholinoethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid

7-Bromo-3-(2-morpholinoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (200.00mg, 564.65umol) was placed in a 10mL long-necked round bottom flask, Dissolve in dioxane (3mL) at room temperature, then add double pinacol borate (430.16mg, 1.69mmol), potassium acetate (221.57mg, 2.26mmol), 1,1' - Bis(diphenylphosphino)ferrocenepalladium dichloride (41.32mg, 56.47umol). The mixture was reacted at 100 degrees for 2 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL), extracted with water (20 mL*3), the aqueous phases were combined and concentrated to obtain the title compound (120.00 mg, crude product), which was directly used in the next reaction without purification.

c) 1-(2,4-dimethylthiazol-5-yl)-3-(2-methoxy-5-(3-(2-morpholinoethyl)-4-oxo-4H- Pyrido[1,2-a]pyrimidin-7-yl)pyridin-3-yl)urea

To 3-(2-morpholinoethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid (120.00mg, crude product) tetrahydrofuran (4mL) and water (1mL ) solution was added 1-(2-methoxy-5-bromopyridin-3-yl)-3-(2,4-dimethylthiazol-5-yl)urea (30.00mg, 83.98umol), three Potassium phosphate hydrate (38.68mg, 167.96umol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (5.47mg, 8.40umol), the mixture was reacted at 80°C for 5 hours. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to give the title product (24.00 mg, 52%).

¹ HNMR (400MHz, DMSO-d ₆ )ppmδ8.92(d,1H),8.73(d,1H),8.18(s,1H),8.13(d,1H),8.01–8.03(m,1H),7.66 (d,1H),4.19–4.22(m,2H),4.01(s,3H),3.54–3.56(m,4H),2.67–2.70(m,2H),2.45–2.49(m,7H),2.23 (s,3H).

The following 1 compound was also synthesized with reference to the preparation method of Example 54:

Process 10:

Reaction conditions: a) Thionyl chloride, dichloromethane, room temperature; b) 7-(5-amino-6-methoxypyridin-3-yl)-3-(2-morpholineethoxy)-4H - Pyrido[1,2-a]pyrimidin-4-one, DMF, heating.

Example 56

Nitrogen-(2-methoxy-5-(3-(2-morpholinoethoxy)-4-oxo-4hydropyrido[1,2-a]pyrimidin-7-yl)pyridine-3 -yl)-2,4-dimethylthiazole-5-carboxamide

a) 2,4-Dimethylthiazole-5-carbonyl chloride

2,4-Dimethylthiazole-5-carboxylic acid (50.0mg, 0.318mmol) and dichloromethane (2mL) were placed in a 10mL round bottom flask, and thionyl chloride (378.43mg, 3.18 mmol) was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The mixture was concentrated to obtain the title compound as a black solid, which was directly carried out to the next reaction without further purification.

b) Nitrogen-(2-methoxy-5-(3-(2-morpholinoethoxy)-4-oxo-4hydropyrido[1,2-a]pyrimidin-7-yl)pyridine -3-yl)-2,4-dimethylthiazole-5-carboxamide

2,4-Dimethylthiazole-5-carbonyl chloride (50.0mg, 0.284mmol), 7-(5-amino-6-methoxypyridin-3-yl)-3-(2-morpholinoethyl Oxy)-4hydro-pyrido[1,2-a]pyrimidin-4-one (113.1mg, 0.284mmol), DMF (0.5mL) were placed in a 10mL round bottom flask, stirred at 60°C for 0.5 hours. TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, and purified by preparative thin-layer chromatography to obtain the title compound (10 g, 80%).

1HNMR (400MHz, CD ₃ OD)ppmδ9.19(s,1H),8.82(d,1H),8.35-8.37(m,1H),8.16-8.19(m,1H),7.81(d,1H),4.50 -4.52(m,2H),4.13(s,3H),3.97(s,4H),3.59(s,1H),3.49(s,1H),2.73(d,1H).

The following 1 compound was also synthesized with reference to the preparation method of Example 56:

Process 11:

Reaction conditions: a) triethylamine, diphenylphosphoryl azide, tert-butanol, heating; b) hydrochloric acid-ethyl acetate, room temperature; c) chlorosulfonic acid, heating; d) pyridine, 2,4-dimethyl Ethyl-5-aminothiazole, dioxane, heated; e) sodium nitrite, concentrated hydrochloric acid, ice bath; f) sodium methoxide, methanol, heated; g) bis-inhalyl borate, 1,1' -bis(diphenylphosphino)ferrocenepalladium chloride, potassium acetate, dioxane, heating; h)(3-(2-morpholineethoxy)-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-7-yl)boronic acid, 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, potassium carbonate, dioxane, water, heating.

Example 58

N-(2,4-dimethylthiazol-5-yl)-2-methoxy-5-(3-(2-morpholineethoxy)-4-oxo-4H-4H-pyrido[ 1,2-a]pyrimidin-7-yl)pyridine-3-sulfonamide

a) tert-butyl (2,4-dimethylthiazol-5-yl) carbamate

2,4-dimethylthiazole-5-carboxylic acid (700.00mg, 4.45mmol), diphenylphosphoryl azide (1.65g, 6.00mmol), triethylamine (1.13g, 11.13mmol) and tert-butanol (35mL) was placed in a 100mL round-bottomed single-necked flask, stirred at 85°C for 4 hours. TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, H ₂ O (20mL) was added thereto, extracted three times with ethyl acetate, and the organic phases were combined , dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (900.00 mg, 88.54%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.46 (br.s., 1H), 2.46 (s, 3H), 2.14 (s, 3H), 1.43 (s, 9H).

b) 2,4-Dimethyl-5-aminothiazole hydrochloride

Dissolve tert-butyl (2,4-dimethylthiazol-5-yl) carbamate in hydrochloric acid-ethyl acetate (10 mL), stir at room temperature for 1 hour and then spin dry, and the obtained crude product is beaten with ethyl acetate The title compound (700 mg) was obtained.

¹ HNMR (400MHz, DMSO-d ₆ )δ2.66(s,3H),2.19(s,3H).

c) 2-Amino-5-bromo-3-sulfonylchlorpyridine

Put chlorosulfonic acid (136.18g, 57.80mmol) in a 250mL round-bottomed three-neck flask, cool to -15 degrees, and add 2-amino-5-bromopyridine (10.00g, 57.80mmol) dropwise under nitrogen protection . After the dropwise addition was completed, the temperature was gradually raised to 160° C. in an oil bath, heated and stirred for 5 hours. After the reaction was completed, cool to room temperature, and slowly pour it into ice. After the ice melted, the precipitated solid was filtered and washed with ice water to obtain the title compound (10.00g, 63.72%)

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.27(d, J=2.3Hz, 1H), 8.08(d, J=2.0Hz, 1H).

d) 2-Amino-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide

Place a solution of 2-amino-5-bromo-3-sulfonylchloropyridine (164.90mg, 607.33mmol) in dioxane (3mL) in a 50mL round-bottomed three-necked flask, cool to 0°C, and add pyridine (196.00 mg, 2.48 mmol) and 2,4-dimethyl-5-aminothiazole hydrochloride (100.00 mg, 607.33 mmol). The reaction solution was gradually raised to room temperature and stirred for 2 hours, then heated to 50°C for 1 hour. After the reaction was over, cool to room temperature and dissolve it in a mixed solution of dichloromethane and methanol (dichloromethane:methanol=20:1), stir for 30 minutes and then filter, spin the obtained filtrate to dryness, and use a silica gel column to obtain the crude product. Purification by chromatography afforded the title compound (60.00 mg, 27.20%).

¹ H NMR (400MHz, CD ₃ OD) δ8.27(d, J=2.5Hz, 1H), 7.81(d, J=2.5Hz, 1H), 2.56(s, 3H), 2.06(s, 3H).

e) 2-Chloro-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide

Place 2-amino-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide (100.00mg, 275.29umol) in a 25mL round bottom flask, cool to 0 degree, and concentrated hydrochloric acid (7 mL) was added thereto. Then, an aqueous solution of sodium nitrite (855.00 mg, 12.39 mmol, 1.5 mL) was added dropwise thereto at 0°C. After the dropwise addition, it was raised to room temperature and stirred for 1 hour, filtered, and the pH value of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution. After the obtained solution was spin-dried, it was dissolved in a mixed solution of dichloromethane and methanol (dichloromethane:methanol=10:1), stirred for 30 minutes and then filtered, the obtained filtrate was spin-dried, and the obtained crude product was purified by thin-layer chromatography. The title compound (30.00 mg, 28.48%) was obtained.

¹ HNMR (400MHz, CD ₃ OD) δ8.76(d, J=2.3Hz, 1H), 8.40(d, J=2.5Hz, 1H), 2.55(s, 3H), 2.17(s, 3H).

f) 2-methoxy-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide

A solution containing 2-chloro-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide (30.00mg, 78.39umol) and sodium methoxide (10.00mg, 185.19umol) The methanol solution was placed in a closed microwave tube, heated to 110°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, saturated sodium bicarbonate (5 mL) was added thereto, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the title compound (20.00 mg, 67.45%) .

¹ HNMR (400MHz, CD ₃ OD) δ8.24 (d, J = 2.5Hz, 1H), 8.10 (d, J = 2.5Hz, 1H), 3.97 (s, 3H), 2.44 (s, 3H), 2.06 (s,3H).

g) (3-(2-morpholineethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid

Containing 7-bromo-3-(2-morpholineethoxy)-4H-4-oxopyrido[1,2-a]pyrimidine (80.00mg, 225.86umol), bis-diancol borate (172.06mg, 677.58umol), 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (49.58mg, 67.76umol) and potassium acetate (66.50mg, 677.58umol) in dioxane (3mL ) solution was placed in a 50mL round-bottom single-necked flask, heated to 80°C under nitrogen protection and stirred for 1 hour. After the reaction, water (5 mL) was added thereto, extracted three times with ethyl acetate, the aqueous phase was spin-dried, and the obtained crude product was slurried with a mixed solution of dichloromethane and methanol (dichloromethane:methanol=20:1), and filtered to obtain The title compound (60.00 mg, 83.24%).

¹ HNMR (400MHz, CD ₃ OD) δ9.00(br.s., 1H), 8.23(s, 1H), 8.00(d, J=7.8Hz, 1H), 7.53(d, J=8.3Hz, 1H ), 4.31 (br.s., 2H), 3.73 (br.s., 4H), 2.87 (br.s., 2H), 2.65 (br.s., 4H), 1.22 (s, 4H).

h) N-(2,4-dimethylthiazol-5-yl)-2-methoxy-5-(3-(2-morpholineethoxy)-4-oxo-4H-4H-pyridine And[1,2-a]pyrimidin-7-yl)pyridine-3-sulfonamide

2-Methoxy-5-bromo-N-(2,4-dimethylthiazol-5-yl)pyridine-3-sulfonamide (20.00mg, 52.87umol), (3-(2-morpholine ethyl Oxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid (60.00mg, 188.02umol), 1,1'-bis(diphenylphosphino)ferrocene Palladium chloride (3.87mg, 5.29umol) and potassium carbonate (21.92mg, 158.61umol) were dissolved in dioxane (3mL) and water (0.3mL), under the protection of nitrogen, the reaction solution was heated to 80 degrees and stirred for 1 Hour. After the reaction, the solution was spin-dried, and the obtained crude product was purified by preparative high performance liquid chromatography to obtain the title compound (5.00 mg, 16.51%).

¹ HNMR (400MHz, CD ₃ OD) δ9.14(s, 1H), 8.64(s, 1H), 8.39(d, J=2.5Hz, 1H), 8.26(s, 1H), 8.03(d, J= 11.3Hz, 1H), 7.74(d, J=9.3Hz, 1H), 4.35(t, J=5.4Hz, 2H), 4.10(s, 3H), 3.76-3.69(m, 4H), 2.88(t, J=5.5Hz, 2H), 2.66(br.s., 4H), 2.44(s, 3H), 2.11(s, 3H); MS(ESI) m/z: 573(M+H ⁺ ).

Process 12:

Reaction conditions: a) carbonyldiimidazole, acetonitrile, heating; b) 4-(2-chloroethyl) morpholine, cesium carbonate, dimethyl sulfoxide, heating; c) 2,4-difluoro-N-(2 -Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridin-3-yl)benzenesulfonamide, [1,1' - bis(diphenylphosphino)ferrocene]palladium chloride, potassium carbonate, dioxane, water, heating.

Example 59

2,4-Difluoro-N-(2-methoxy-5-(2-(2-morpholine ethyl)-3-oxo-2,3-dihydro-[1,2,4]tri Azo[4,3-a]pyridin-6-yl)pyrimidin-3-yl)benzenesulfonamide

a) 6-Bromo-[1,2,4]triazol[4,3-a]pyridin-3(2H)-one

5-Bromo-2-hydrazino-1,2-dihydropyridine (5.00g, 26.59mmol) and acetonitrile (100mL) were placed in a 250mL round-bottom single-necked flask, and then carbonyl di Imidazole (4.75 g, 29.29 mmol). The reaction solution was placed at 80°C for 2 hours. The solid precipitated by filtration was then added to acetonitrile (20 mL) for slurry purification, and the title compound (3.90 g, 68.53%) was obtained by filtration.

¹ H NMR (400MHz,DMSO-d ₆ )δ12.63(br.s.,1H),8.07(s,1H),7.28-7.19(m,2H)

b) 6-bromo-2-(2-morpholine ethyl)-[1,2,4]triazol[4,3-a]pyridin-3(2H)-one

Dissolve 6-bromo-[1,2,4]triazol[4,3-a]pyridin-3(2H)-one (1.00 g, 4.67 mmol) in dimethyl sulfoxide (10 mL), add carbonic acid Cesium (3.80g, 11.68mmol) and 4-(2-chloroethyl)morphine (1.40g, 9.34mmol), the resulting solution was stirred at room temperature for 16 hours. After the reaction, filter, add water (10mL) to the filtrate and extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry, the crude product is separated and purified by column chromatography to obtain the title compound (500.00mg, 32.72% )

¹ HNMR (400MHz, DMSO-d ₆ )δ8.14(s,1H),7.38-7.19(m,2H),4.02(t,J=6.5Hz,2H),3.53-3.49(m,4H),2.68 (t,J=6.3Hz,2H),2.41(br.s.,4H).

c) 2,4-difluoro-N-(2-methoxy-5-(2-(2-morpholine ethyl)-3-oxo-2,3-dihydro-[1,2,4 ]triazol[4,3-a]pyridin-6-yl)pyrimidin-3-yl)benzenesulfonamide

6-Bromo-2-(2-morpholine ethyl)-[1,2,4]triazol[4,3-a]pyridin-3(2H)-one (100.00mg, 305.64umol), 2 ,4-Difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranyl-2-yl)-3-pyridine Base] benzenesulfonamide (130.28mg, 305.64umol), potassium carbonate (42.24mg, 305.64umol) and 1,1'- bis (diphenylphosphine) ferrocene palladium chloride (223.64mg, 305.64umol) dissolved in Dioxane (1.5 mL) and water (0.3 mL). Under the condition of nitrogen protection, the above reaction solution was reacted at 80°C for 2 hours. After the reaction, spin to dry, the crude product was purified by preparative high performance liquid chromatography to obtain the title compound (50.00 mg, 29.93%).

¹ HNMR (400MHz, CD ₃ OD) δ7.99-7.92 (m, 1H), 7.84 (s, 1H), 7.75 (d, J = 2.0Hz, 1H), 7.60 (d, J = 2.0Hz, 1H) ,7.50-7.43(m,1H),7.27(d,J=9.5Hz,1H),7.08-6.95(m,2H),4.18(t,J=6.3Hz,2H),3.88(s,3H), 3.71-3.64(m,4H),2.88-2.83(m,2H),2.58(br.s.,4H).

Process 13:

Reaction conditions: a) ethyl formate, sodium hydrogen, ethylene glycol dimethyl ether, heating; b) 5-bromopyridin-2-amine, ammonium acetate, heating; c) phosphorus oxybromide, heating; d) cesium carbonate , acetonitrile, heated; e) R boronic acid (boronic acid ester), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride, potassium carbonate, dioxane, water, heated.

Example 60

2-Chloro-4-fluoro-N-(2-methoxy-5-(3-(2-ethylmorpholine)-4-oxo-4H-pyrido[1,2-a]pyrimidine-7 -yl)pyridin-3-yl)benzenesulfonamide

a) Sodium (E)-(2-oxodihydrofuran-3(2H)-alkenylene)methoxide

Sodium hydrogen (0.93 g, 23.23 mmol) was slowly added in portions to a 500 mL round bottom flask containing ethylene glycol dimethyl ether (96 mL). A solution of dihydrofuran-2(3H)-one (2g, 23.23mmol) and ethyl formate (1.72g, 23.23mmol) in ethylene glycol dimethyl ether (12mL) was added dropwise to the above mixture under stirring, and then Ethanol (0.15 mL) was added. The reaction solution was stirred and reacted at 60°C for 16 hours. The mixture was cooled to 25°C, filtered, and the filter cake was rinsed with ethyl acetate (20 mL*3) to obtain the title compound (2.1 g, 66%) as a yellow-green solid.

1HNMR (400MHz, D ₂ O) ppm δ8.45-8.31(m, 1H), 4.27(t, 2H), 2.71(t, 2H).

b) (E)-3-(((5-bromopyridin-2-yl)amino)methenidene)dihydrofuran-2(3H)-one

(E)-(2-Oxodihydrofuran-3(2H)-alkenylene)sodium methoxide (1.42g, 10.4mmol), 5-bromopyridin-2-amine (1.2g, 6.94mmol) and acetic acid Ammonium (2.67g, 34.68mmol) was placed in a 50mL round bottom flask, and stirred at 120°C for 1 hour. Liquid phase mass spectrometry showed that the reaction was complete, the reaction solution was cooled to room temperature, slowly poured into ice water, a solid precipitated, filtered, and the filter cake was rinsed with water (20mL*3) to obtain the title compound as a crude solid, which was then washed with petroleum ether (30mL ) to give the gray title compound (1.4 g, 75%).

1HNMR (400MHz, CDCl ₃ )ppmδ8.29(d,1H),8.02(d,1H),7.74(dd,1H),6.79(d,1H),4.44(t,2H),2.90(dt,2H) .

c) 7-bromo-3-(2-bromoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

(E)-3-(((5-bromopyridin-2-yl)amino)methenylene)dihydrofuran-2(3H)-one (1.4g, 5.2mmol) and phosphorus oxybromide (6.98 g, 24.35mmol) was placed in a 50mL round-bottomed flask, stirred and reacted at 80°C for 1.5 hours. Liquid phase mass spectrometry showed that the reaction was complete. Cool the reaction solution to room temperature, slowly pour it into ice water, adjust the pH value to 8, extract with dichloromethane (20mL*3), wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Concentration afforded the title compound (1.2 g, 69%) as a yellow solid.

1HNMR (400MHz, CDCl ₃ )ppmδ9.17(d,1H),8.27(s,1H),7.74(dd,1H),7.54(d,1H),3.73(t,2H),3.21(t,2H) .

d) 7-bromo-3-(2-ethylmorpholine)-4H-pyrido[1,2-a]pyrimidin-4-one

7-bromo-3-(2-bromoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.2g, 0.6mmol), morpholine (78.73mg, 0.9mmol) and carbonic acid Cesium (0.59g, 1.81mmol) was placed in a 50mL round-bottomed flask, and stirred at 70°C for 12 hours. Liquid phase mass spectrometry showed that the reaction was complete. Cool the reaction solution to room temperature, add water, extract with dichloromethane (20mL*3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the oily crude title compound, which is used directly Next reaction.

e) 2-chloro-4-fluoro-N-(2-methoxy-5-(3-(2-ethylmorpholine)-4-oxo-4H-pyrido[1,2-a]pyrimidine -7-yl)pyridin-3-yl)benzenesulfonamide

7-Bromo-3-(2-ethylmorpholine)-4H-pyrido[1,2-a]pyrimidin-4-one (0.59 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL ), under nitrogen protection, add 2-chloro-4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl)pyridin-3-yl)benzenesulfonamide (0.59 mmol), potassium carbonate (1.18 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (22 mg). The mixture was placed under microwave reaction conditions at 100°C for 1 hour. Liquid mass spectrometry showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography and preparative high performance liquid chromatography to give the title product.

1HNMR (400MHz, CDCl ₃ )ppmδ9.08(s,1H),8.29(s,1H),8.17-8.09(m,2H),7.94(d,1H),7.85-7.77(m,1H),7.75- 7.68(m,1H),7.28(d,1H),7.18-7.12(m,1H),4.00(s,3H),3.79(br.s.,3H),2.93(br.s.,1H).

Experimental example 1 in vitro enzyme activity test

In all the examples of the present invention, the kinase activity of PI3K (p110α) was tested by the following two testing methods.

method one:

Reaction buffer: HEPES50mM (pH7.0), NaN30.02%, BSA0.01%, Orthovanadate0.1mM, 1%DMSO

Detection buffer: HEPES10mM (pH7.0), BSA0.02%, KF0.16M, EDTA4mM

Reaction enzymes: N-terminal His-tagged human recombinant full-length PI3Kp110α subunit (molecular weight = 128.4kDa) and untagged p85α subunit (molecular weight = 83.6kDa) expressed in insect cells

Substrate for reaction: 10 μM IP2 substrate (PI(4,5)P2)

Reaction conditions: 10 μMPI(4,5)P2 and 10 μM ATP

Reaction steps:

1. Prepare the substrate in a freshly prepared reaction solution.

2. Add the kinase to the substrate reaction solution and mix gently.

3. Use Acoustic technology (Echo550; nanoliterrang) to transfer the compound dissolved in 100% DMSO into the kinase reaction solution and incubate at room temperature for 10 minutes

4. Add appropriate concentration of ATP to the reaction system.

Incubate at 5.30°C for half an hour

6. Add stop solution to stop the reaction.

7. Add detection mix and incubate overnight.

8. Detection using the homogeneous time-resolved fluorescence (HTRF) method. (Excitation wavelength 320nm, measure the ratio of readings at 615nm and 665nm emission wavelength).

Method Two:

ADP-Glo experimental method

Compound dilution:

3-fold serial dilution of the test compound, a total of 10 concentration points (10000nM to 0.5nM).

experimental method:

Transfer 50nL of the compound to the reaction plate (PerkinElmer #6007299), add 3uL enzyme/substrate mixture (0.33nMPI3Kalpha, Millipore#14-602-K/166.5uMPIP2), incubate for 20min, add 2uLATP solution (100uM) to initiate the reaction, room temperature After reacting for 2 hours, add 5uLADP-Glo reagent to terminate the kinase reaction, incubate at room temperature for 60 minutes to completely digest the remaining unreacted ATP, add 10uL kinase detection reagent, incubate at room temperature for 40 minutes, and read the fluorescence on the Envision. PIP2, ATP, ADP-Glo reagent and kinase detection reagent are all from ADP-Glo Kinase Detection Kit (Promega #V1792).

data analysis:

IC50 was calculated by standard 4-parameter fitting method (Model205, XL-fit, iDBS).

In all the examples of the present invention, the kinase activity of mTOR is tested by the following test methods.

Reaction buffer: 20mM Hepes (pH7.5), 10mMMgCl ₂ , 2mMMnCl ₂ , 1mMEGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1mMNa ₃ VO ₄ , 2mMDTT, 2% DMSO.

Reaction enzyme: N-terminal GST-tagged human recombinant mTOR fragment expressed in insect cells (amino acid 1360-2549, molecular weight = 163.9kDa)

Substrate for the reaction: human recombinant full-length 4EBP1 (molecular weight = 13.6kDa) expressed in bacteria with a His-tagged N-terminus

Reaction conditions: 3 μM 4EBP1 and 10 μM ATP

Reaction steps:

1. Add the reaction substrate and other reaction factors to the freshly prepared reaction buffer.

2. Add the kinase to the substrate reaction solution and mix gently.

3. Using Acoustic technology (Echo550; nanoliterrang), the compound dissolved in 100% DMSO was transferred into the kinase reaction solution, and incubated at room temperature for 20 minutes.

4. Add appropriate concentration of ³² P-ATP into the reaction system.

5. Incubate at room temperature for two hours.

6. Use P81 filter-binding method to detect kinase activity.

The experimental results are shown in Table 3:

Table 3 In vitro enzyme activity test results

Note: A≤1nM; 1nM<B≤50nM; 50nM<C≤200nM; 200nM<D; NT means not measured.

Experimental example 2 in vitro cell activity test

Experimental steps and methods:

1. Seed MCF-7 cells into a 96-well plate at a density of 2.5×10 ⁴ per well (the culture medium used must be a complete culture medium containing 10% FBS).

2. On the second day, remove the culture medium in the well, dissolve a certain concentration (preliminary screening) or a series of concentrations (IC ₅₀ test) of the compound in the serum-free culture medium, and add the 96-well plate to culture the cells 2 Hour.

3. Dissolve insulin in serum-free culture medium, add to cells and incubate for 30 minutes, and the final concentration of insulin is 10 micrograms/ml.

4. While waiting for the reaction, prepare the lysate as follows:

a) The Enhancer Solution needs to be taken out of the refrigerator and melted in advance.

b) Dilute the Enhancer Solution (EnhancerSolution) with 5X Lysis Buffer (LysisBuffer) 10 times to prepare a concentrated lysate.

c) Dilute the concentrated lysate 5 times with double distilled water to prepare a lysate.

5. Aspirate the culture medium in the well, and rinse once with PBS quickly.

6. Add 150 microliters of freshly prepared lysate to each well, then shake at room temperature for 10 minutes.

7. After confirming that all cells have been detached, transfer the lysate together with the cell debris to a 1.5 ml tube.

8. Vortex several times to completely mix the lysate and cells, and then centrifuge the mixture at 12000g for 10 minutes at 4°C.

9. Calculate the number of ELISA-one microplate strips needed. Remove the excess microslats from the frame and place back in the storage bag to seal. Before using the microstrips, rinse each well with 200 μl double distilled water to remove preservatives.

10. Add 50 microliters of antibody cocktail to each well. (The antibody mixture is prepared by mixing the medium antibody reagent and the enzyme-labeled antibody reagent in equal proportions. Be careful not to vortex when preparing the antibody mixture)

11. Add 25 microliters of cell lysate to each well of the ELISA-One microplate. Cover the microplate with adhesive parafilm and incubate for 1 hour at room temperature on a microplate shaker.

12. Wash each well 3 times with 150 microliters of 1X wash buffer. After the last wash, the wash buffer in the wells was aspirated. Allow 1X Wash Buffer to sit in the microplate for up to 30 minutes, if desired, to allow time to prepare the substrate mix.

13. The substrate mixture should be prepared as needed. Add 100 microliters of substrate mix to each well, then seal the microplate with foil and incubate on a microplate shaker at room temperature for 10 minutes.

14. Add 10 microliters of stop solution to each well and mix briefly (5-10 seconds) on a microplate shaker.

15. Assemble the corresponding ELISA-One filter set and read the fluorescence signal intensity.

The experimental results are shown in Table 4:

Table 4 In vitro cell activity test results

Note: A≤50nM; 50nM<B≤100nM; 100nM<C≤250nM; D>250nM.

Conclusion: the compound of the present invention has significant inhibitory effect on PI3K, but weaker inhibitory effect on mTOR.

Claims (12)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein,

can form a structural unitIs replaced by

E is selected from optionally substituted with R₃Substituted C_1-6Alkyl radical, C_3-10Cycloalkyl or heterocycloalkyl;

one of L and Q is selected from-C (R)_d1)(R_d2)-、-C(＝O)N(R_d3)-、-N(R_d4)-、-C(＝NR_d5)-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_d8)C(＝O)N(R_d9) -, another is selected from a single bond or-C (R)_d1)(R_d2)-；

A. T is independently selected from N or C (R)_t)；

X, Y, Z wherein 0 or 1 is selected from N and the rest is selected from C (R)_t)；

B is selected from-C (R)_d1)(R_d2)-、-C(＝O)N(R_d3)-、-N(R_d4)-、-C(＝NR_d5)-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_d8)C(＝O)N(R_d9)-；

Each heteroatom or heteroatom group is independently selected from-C (═ O) N (R)_d3)-、-N(R_d4)-、-C(＝NR_d5)-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-and/or-N (R)_d8)C(＝O)N(R_d9)-；

m₁Each independently selected from 0, 1,2 or 3;

R_1-3is selected fromThe rest is selected from H, F, Cl, Br, I, CN, OH, SH, NH₂CHO, COOH, or selected from optionally substituted R₀₁Substituted C_1-10Alkyl or heteroalkyl, C_3-10Cycloalkyl or heterocycloalkyl radical, or_3-10Cycloalkyl-or heterocycloalkyl-substituted C_1-10Alkyl or heteroalkyl;

D₁selected from single bond, -C (R)_d1)(R_d2)-、-C(＝O)N(R_d3)-、-N(R_d4)-、-C(＝NR_d5)-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_d8)C(＝O)N(R_d9)-；

D₂Is selected from-C (R)_d1)(R_d2)-；

D₃Is selected from-N (R)_d4)-、-C(＝O)N(R_d4)-、-N(R_d4)C(＝O)-、-N(R_d4)C(＝O)O-、-N(R_d4)OC(＝O)-、-N(R_d4)C(＝O)N(R_d4)-、-S(＝O)-、-S(＝O)₂-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-；

R₄Selected from H, or selected from optionally substituted by R₀₁Substituted C_1-10Alkyl or heteroalkyl, C_3-10Cycloalkyl or heterocycloalkyl radical, or_3-10Cycloalkyl-or heterocycloalkyl-substituted C_1-10Alkyl or heteroalkyl;

n is selected from 1,2,3, 4,5 or 6;

optionally, any two R₁Same as D₂R in (1)_d1And R_d2Two of D₂R is₄And a D₂Or R is₄And D₃Are connected together to the same carbon atom or heteroatom to form one or two 3,4,5 or 6 membered carbocyclic or heterocyclic rings;

R_t、R_d1、R_d2each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH₂、CHO、COOH、C(＝O)NH₂、S(＝O)NH₂、S(＝O)₂NH₂Or is selected from optionally substituted R₀₁Substituted C_1-10Alkyl or heteroalkyl, C_3-10Cycloalkyl or heterocycloalkyl radical, or_3-10Cycloalkyl-or heterocycloalkyl-substituted C_1-10Alkyl or heteroalkyl;

R₀₁selected from F, Cl, Br, I, CN, OH, SH, NH₂、CHO、COOH、R₀₂；

R₀₂Is selected from C_1-10Alkyl radical, C_1-10Alkylamino, N-di (C)_1-10Alkyl) amino, C_1-10Alkoxy radical, C_1-10Alkanoyl radical, C_1-10Alkoxycarbonyl, C_1-10Alkylsulfonyl radical, C_1-10Alkylsulfinyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkylamino radical, C_3-10Heterocycloalkylamino, C_3-10Cycloalkoxy, C_3-10Cycloalkyl acyl, C_3-10Cycloalkoxycarbonyl, C_3-10Cycloalkylsulfonyl radical, C_3-10Cycloalkylsulfinyl, 5-6 membered unsaturated heterocyclyl, 6-12 membered aryl or heteroaryl;

each heteroatom or heteroatom group is independently selected from-C (═ O) N (R)_d3)-、-N(R_d4)-、-C(＝NR_d5)-、-S(＝O)₂N(R_d6)-、-S(＝O)N(R_d7)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-and/or-N (R)_d8)C(＝O)N(R_d9)-；

R_d3-_d9Each independently selected from H, OH, NH₂、R₀₂；

R₀₂Optionally substituted by R₀₀₁Substitution;

R₀₀₁selected from F, Cl, Br, I, CN, OH, N (CH)₃)₂、NH(CH₃)、NH₂CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methanesulfonyl, methylsulfinyl;

R₀₁、R₀₀₁the number of heteroatoms or groups of heteroatoms is independently selected from 0, 1,2 or 3, respectively.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein E is selected from R₃Substituted C_1-6Alkyl orC_3-6Cycloalkyl radical, R₃Is selected from 0, 1,2 or 3, or E is selected from

Wherein,

G_1～50, 1,2 or 3 of (A) are selected from N, the remainder are selected from C (R)₃)；

G₆Is selected from-C (R)₃)(R₃)-、-C(＝O)N(R_3a)-、-N(R_3a)-、-C(＝NR_3a)-、-S(＝O)₂N(R_3a)-、-S(＝O)N(R_3a)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_3a)C(＝O)N(R_3a)-；

G_7～90, 1 or 2 of (A) are selected from N, the remainder are selected from C (R)₃)；

G_10～160, 1,2,3 or 4 of (A) are selected from N, the remainder are selected from C (R)₃)；

G₁₇Selected from N or C (R)₃)；

G_18～220, 1,2 or 3 of (a) are selected from-C (═ O) N (R)_3a)-、-N(R_3a)-、-C(＝NR_3a)-、-S(＝O)₂N(R_3a)-、-S(＝O)N(R_3a)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_3a)C(＝O)N(R_3a) -, the remainder being selected from-C (R)₃)(R₃)-；

R_3aIs selected from C_1-10Alkyl radical, C_1-10Alkyl acyl radical, C_1-10Alkoxycarbonyl, C_1-10Alkylsulfonyl radical, C_1-10Alkylsulfinyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl acyl, C_3-10Cycloalkoxycarbonyl, C_3-10Cycloalkylsulfonyl radical, C_3-10Cycloalkylsulfinyl, 5-6 membered unsaturated heterocyclyl, 6-10 membered aryl or heteroaryl;

the remaining variables are as defined in claim 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, wherein E is optionally substituted with R₃Substituted methyl, ethyl, propyl,

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein E is selected from

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein one of L and Q is selected from-S (═ O)₂NH-、-S(＝O)₂-, -NH-, -NHC (═ O) NH-, and another is selected from the group consisting of single bonds, -CH₂-。

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein 0 or 1 of X, Y, Z is selected from N and the others are selected from CH and C (CH)₃)、C(CF₃)、CCl、CF。

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein, A, T is independently selected from N, CH、C(CH₃)、C(CF₃) CCl, CF; or B is selected from NH and N (CH)₃) Or N (CF)₃)。

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein any two R₁Same as D₂R in (1)_d1And R_d2Two of D₂R is₄And a D₂Or R is₄And D₃The ring formed between is selected from:

9. a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R_1-3Is selected fromThe rest is selected from H, F, Cl, Br, I, CN, OH, SH, NH₂、CHO、COOH、OR_a、N(R_b)(R_c) Optionally with R_dSubstituted C_1-3Alkyl or cyclopropyl; d₁Selected from single bond, -C (R)_e)(R_e)-、-C(＝O)N(R_a)-、-N(R_a)-、-C(＝NR_a)-、-S(＝O)₂N(R_a)-、-S(＝O)N(R_a)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)₂-or-N (R)_a)C(＝O)N(R_a)-；D₂Is selected from-C (R)_a)(R_a)-；

n is selected from 1,2,3, 4,5 or 6;

R_a、R_b、R_ceach independently selected from H, optionally R_dSubstituted C_1-6Alkyl or C_3-6A cycloalkyl group;

R_eselected from H, optionally R_dSubstituted C_1-6Alkyl or alkoxy radicalsOptionally R_dSubstituted C_3-6Cycloalkyl or cycloalkoxy;

R_dselected from F, Cl, Br, I, CN, OH, NH₂、CHO、COOH、CH₃、CF₃、CH₃O、CH₃CH₂O,R_dThe number of (a) is selected from 0, 1,2 or 3;

optionally, any two R₁Same as D₂R in (1)_aAnd R_aTwo of D₂Or R is_aAnd a D₂Are connected together to the same carbon atom or oxygen atom to form one or two 3,4,5 or 6-membered carbocyclic or heterocyclic oxygen rings in which the number of oxygen atoms is 1 or 2.

10. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 9, wherein any two R are₁Same as D₂R in (1)_aAnd R_aTwo of D₂Or R is_aAnd a D₂The ring formed between them is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, 1, 3-dioxolanyl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10 wherein R_1-3Is selected from The rest is selected from H, F, Cl, Br, I, CN, OH and NH₂Methyl, ethyl, propyl, methoxy, ethoxy, methylamino, dimethylamino, halomethyl, haloethylHalopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from: