TWI812183B - A selective parp1 inhibitor and an application thereof - Google Patents

Abstract

The present disclosure provides a selective PARP1 inhibitor and an application thereof.

Description

A selective PARP1 inhibitor and its application

The present invention relates to a selective PARP1 inhibitor or its stereoisomer and its application in medicine.

PARPs (ploy(ADP-ribose)polymerases) are a type of poly-ADP-ribose polymerase that catalyzes the poly-ADP-ribosylation of a variety of proteins. This process plays important roles in DNA damage repair, transcriptional regulation, and chromatin. Plays an important role in many cellular processes such as reorganization and remodeling. Currently, although multiple PARP1/2 inhibitors have been successfully marketed, side effects such as blood and gastrointestinal tract are still common whether used alone or in combination in clinical practice, resulting in limited clinical application. Therefore, the development of safer and more effective PARP inhibitors is still a clinical issue that needs to be solved. A series of studies have shown that compared with PARP1/2 inhibitors, highly selective PARP1 inhibitors have better efficacy and lower toxicity, which is expected to reduce the potential risks of current clinical PARP drugs, broaden the scope of clinical application, and improve patient outcomes. quality of life.

The purpose of the present invention is to provide a selective PARP1 inhibitor or its stereoisomer, its pharmaceutical composition, and its medical application.

The present invention provides a compound represented by general formula (I) or a stereoisomer thereof: (I)

in:

A is ;

R _a0 is selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, the C _{1- 6} alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally further selected from halogen or C ₁ by one or more _-6 Alkyl substituent substitution;

R _a1 is selected from H, halogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen or C _1-6 alkyl;

L _a1 , L _a2 , and L _a3 are each independently N or CR _L ;

R _L is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

L is selected from -NH-, -CO- or -(CR ₁ R ₂ ) _n -;

R ₁ and R ₂ are each independently selected from H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano. ;

B is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered paracyclic ring, or a 4- to 12-membered bridged ring, and the The 4 to 12 membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b ;

R _b is selected from H, hydroxy, cyano or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from hydroxy, halogen or cyano;

Alternatively, any two R _b can form a 3 to 8 membered ring;

C is ;

_{X 1 , X 2 , and} X ₂ cannot be CH at the same time;

R ₃ and R ₄ are each independently selected from H, halogen, cyano or C _1-6 alkyl;

R _c is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _{1- 6} alkoxy group, C _3-8 cycloalkyl group or C _3-8 heterocycloalkyl group is optionally further substituted by 1 or more selected from D, halogen, hydroxyl, cyano group, NR _c1 R _c2 , C _{1- 6} alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl substituents;

R _c1 and R _c2 are each independently selected from H or C _1-6 alkyl;

n is 1 or 2;

The conditions are:

The compound represented by general formula (I) is not ;

The compound of general formula (I) is optionally further substituted by one or more deuteriums.

The present invention provides a compound or a stereoisomer thereof, and the compound is selected from the group consisting of compounds represented by general formula (II) or a stereoisomer thereof: (II)

in:

R _a0 is selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, the C _{1- 6} alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally further selected from halogen or C ₁ by one or more _-6 Alkyl substituent substitution;

R _a1 is selected from H, halogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen or C _1-6 alkyl;

Z ₁ and Z ₂ are each independently N or CR _L ;

R _L is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

L is selected from -NH-, -CO- or -(CR ₁ R ₂ ) _n -;

R ₁ and R ₂ are each independently selected from H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano. ;

B is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered paracyclic ring, or a 4- to 12-membered bridged ring, and the The 4 to 12 membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b ;

R _b is selected from H, hydroxy, cyano or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from hydroxy, halogen or cyano;

Alternatively, any two R _b can form a 3 to 8 membered ring;

C is ;

_{X 1 , X 2 , and} X ₂ cannot be CH at the same time;

R ₃ and R ₄ are each independently selected from H, halogen, cyano or C _1-6 alkyl;

R _c is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _{1- 6} alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further selected from 1 or more D, halogen, hydroxyl, cyano, NR _c1 R _c2 , C1-6 Substituted with alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl substituents;

R _c1 and R _c2 are each independently selected from H or C _1-6 alkyl;

n is 1 or 2;

The compound of general formula (II) is optionally further substituted by one or more deuterium atoms.

Compounds provided by the invention or their stereoisomers:

in:

A is ;

R _a0 is selected from C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl, said C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl Optionally further substituted by one or more substituents selected from halogen or C _1-6 alkyl;

L _a1 , L _a2 , and L _a3 are each independently N or CR _L ;

R _L is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

L is -(CR ₁ R ₂ ) _n -;

R ₁ and R ₂ are each independently selected from H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano. ;

B is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered paracyclic ring, or a 4- to 12-membered bridged ring, and the The 4 to 12 membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b ;

R _b is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen or cyano;

Alternatively, any two R _b can form a 3 to 8 membered ring;

C is ;

_{X 1 , X 2 , and} X ₂ cannot be CH at the same time;

R ₃ and R ₄ are each independently selected from H, halogen, cyano or C _1-6 alkyl;

R _c is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _{1- 6} alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further substituted by 1 or more selected from D, halogen, hydroxyl, NR _c1 R _c2 , C _1-6 alkyl Or substituted by a substituent of C _3-8 heterocycloalkyl;

R _c1 and R _c2 are each independently selected from H or C _1-6 alkyl;

n is 1 or 2;

The conditions are:

The compound represented by general formula (I) is not ;

The compound is optionally further substituted by one or more deuterium atoms.

The compound or its stereoisomer provided by the invention:

in:

A is ;

R _a0 is selected from C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl, said C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl Optionally further substituted by one or more substituents selected from halogen or C _1-6 alkyl;

L _a1 , L _a2 , and L _a3 are each independently CH or N;

L is -(CR ₁ R ₂ ) _n -;

R ₁ and R ₂ are each independently H or C _1-6 alkyl;

B is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, a 4- to 12-membered paracyclic ring, or a 4- to 12-membered bridged ring, and the The 4 to 12 membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b ;

R _b is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen or cyano;

Alternatively, any two R _b can form a 3 to 8 membered ring;

C is ;

_{X 1 , X 2 , and} X ₂ cannot be CH at the same time;

R ₃ and R ₄ are each independently selected from H, halogen, cyano or C _1-6 alkyl;

R _c is selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the C _1-6 alkyl or C _3-8 cycloalkyl is optionally further selected from 1 or more D , halogen or C _1-6 alkyl substituent substitution;

n is 1 or 2;

The conditions are:

The compound represented by general formula (I) is not ;

The compound is optionally further substituted by one or more deuterium atoms.

The compound or its stereoisomer provided by the present invention is selected from the group consisting of compounds represented by general formula (III) or its stereoisomer: (III)

Ra ₂ is C _1-6 alkyl or C _3-8 cycloalkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen;

R _d is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _{1- 6} alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further substituted by 1 or more substituents selected from D, halogen, hydroxyl or C _1-6 alkyl;

The compound represented by the general formula (III) is optionally further substituted by one or more deuterium atoms.

The compound of the present invention or its stereoisomer, the compound is selected from the compounds represented by the general formula (IV) or its stereoisomer: (IV)

Ra ₃ is C _1-6 alkyl or C _3-8 cycloalkyl;

Re is selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _3-8 heterocycloalkyl, optionally further substituted by 1 or more substituents selected from hydroxyl;

The compound represented by the general formula (IV) is optionally further substituted by one or more deuterium atoms.

The compound or its stereoisomer provided by the invention:

in:

A is ;

R _a0 is a C _1-6 alkyl group, which is optionally further substituted _by one or more substituents selected from halogen;

L _a1 , L _a2 , and L _a3 are each independently CH or N;

L is -(CR ₁ R ₂ )n-;

R ₁ and R ₂ are each independently H or C _1-3 alkyl;

B is ;

C is ;

R _b is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen or cyano;

Alternatively, any two R _b can form a 3 to 8 membered ring;

R _c is H or C _1-6 alkyl;

n is 1 or 2;

m is 0, 1 or 2;

The compound is optionally further substituted by one or more deuterium atoms.

The present invention provides compounds or stereoisomers thereof, and the compounds are selected from:

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

The compound is optionally further substituted by one or more deuterium atoms.

One or more embodiments of the invention provide a pharmaceutical composition comprising:

(1) The compound of the present invention or its stereoisomer;

(2) Optional one or more other active ingredients; and

(3) Pharmaceutically acceptable carriers and/or excipients.

One or more embodiments of the invention provide the use of a compound of the invention or a stereoisomer thereof or a pharmaceutical composition of the invention in the preparation of a medicament for the treatment of cancer.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12C, 13C and 14C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy Hydrogen), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16O, 17O and 18O, sulfur isotopes include 32S, 33S, 34S and 36S, nitrogen isotopes include 14N and 15N, fluorine isotopes include 17F and 19F , the isotopes of chlorine include 35Cl and 37Cl, and the isotopes of bromine include 79Br and 81Br.

"Alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably Alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

"Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" mentioned above.

"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3 to 10-membered monocyclic ring, a 4 to 12-membered bicyclic ring, or a 10 to 20-membered polycyclic ring system, and the ring carbon atoms are preferably 3 to 10 carbon atoms, further 3 to 8 carbon atoms are preferred. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptadienyl, etc. When substituted, it may optionally be further substituted with zero or more substituents.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 A heteroatom selected from N, O or S, preferably a 3 to 8-membered heterocyclyl group. The selectively substituted N and S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be connected to a heteroatom or a carbon atom; "heterocycloalkyl" can be a bridged ring Or spiral ring. Non-limiting examples of "heterocycloalkyl" include oxiethyl, aziridyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4- Dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuran base, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxygen Heterotricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.

"Alkenyl" refers to a straight group containing 1 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds and composed of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably an alkenyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 carbon atoms. An alkenyl group of 8 carbon atoms is further preferred, and an alkenyl group of 2 to 6 carbon atoms is further preferred. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decene-4-yl, and undecayl En-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

"Alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon triple bonds and composed of 2 to 20 carbon atoms, preferably an alkynyl group of 2 to 12 carbon atoms, more preferably An alkynyl group having 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group can optionally be further selected from 0 to 4 F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto , amide group, carbocyclic group or heterocyclic group substituent.

"Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocyclic ring, it can be a monocyclic ring with 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members), a 4 to 12 member (such as 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8-membered heterocyclic groups. The optionally substituted 1 to 4 (such as 1, 2, 3, 4) N and S in the ring of "heterocyclyl" or "heterocycle" can be oxidized into various oxidation states; "heterocyclyl" or "heterocyclyl" "Heterocyclic ring" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocyclic ring" can be a branched ring, a bridged ring or a spiro ring. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "heterocyclyl", "heterocycle", "cycloalkyl" or "heterocycloalkyl" When substituted, it may be optionally further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano , Amino, C1-6 alkylamino, =O, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, -NRq4Rq5, =NRq6, -C(=O) OC1-6 alkyl, -OC(=O)C1-6 alkyl, -C(=O)NRq4Rq5, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-10 aryl, C5-10 Heteroaryl, -C(=O)OC6-10aryl, -OC(=O)C6-10aryl, -OC(=O)C5-10heteroaryl, -C(=O)OC5-10 Heteroaryl, -OC(=O)C3-8heterocycloalkyl, -C(=O)OC3-8heterocycloalkyl, -OC(=O)C3-8cycloalkyl, -C(=O )OC3-8 cycloalkyl, -NHC(=O)C3-8 heterocycloalkyl, -NHC(=O)C6-10 aryl, -NHC(=O)C5-10 heteroaryl, -NHC( Substituents of =O)C3-8 cycloalkyl, -NHC(=O)C3-8 heterocycloalkyl, -NHC(=O)C2-6 alkenyl or -NHC(=O)C2-6 alkynyl Substituted, and the substituents mentioned therein are C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-10 aryl, C5-10 heteroaryl, -NHC(=O)C6-10 aryl, -NHC(=O)C5-10 heteroaryl, -NHC(=O)C3-8 heterocycloalkane The base or -NHC(=O)C3-8 cycloalkyl group is optionally further selected from 1 to 3 OH, F, Cl, Br, I, C1-6 alkyl, C1-6 alkoxy, -NRq4Rq5 or =O substituent; Rq1 is selected from C1-6 alkyl, C1-6 alkoxy or C6-10 aryl; Rq2 and Rq3 are selected from H or C1-6 alkyl; Rq4 and Rq5 are selected from H, C1-6 alkyl, -NH(C=NRq1)NRq2Rq3, -S(=O)2NRq2Rq3, -C(=O)Rq1 or -C(=O)NRq2Rq3, wherein the C1-6 alkyl is optional Further selected from OH, F, Cl, Br, I, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C5-10 heteroaryl, C3-8 cycloalkyl substituted by a substituent of a C3-8 heterocycloalkyl group; or Rq4, Rq5 and N atoms form a 3 to 8-membered heterocyclic ring, and the ring may contain 1 or more selected from N, O or S heteroatoms.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.

"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to be administered.

"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.

"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers and conformational isomers.

"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may but may not occur, and the description includes the circumstances in which the event or condition occurs and the circumstances in which it does not occur. What happened. For example, "heterocyclyl optionally substituted by alkyl" means that the alkyl group may but not necessarily be present. This description includes the case where the heterocyclyl is substituted by an alkyl group, and the case where the heterocyclyl is not substituted by an alkyl group. condition.

The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited to these.

The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR was measured using Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetrahydrofuran. Methylsilane (TMS);

Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS measurement;

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.15 mm-0.20 mm. The specifications used for thin layer chromatography separation and purification products are 0.4 mm. -0.5 mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier. Intermediate 1 2-Fluoro-N-methyl-4-(piperazin-1-yl)benzamide Intermediate 1 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

first step: 4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1c tert-butyl 4- (3-fluoro-4-(methylcarbamoyl) phenyl) piperazine - 1- carboxylate

Dissolve 1a (2 g, 8.62 mmol) and 1b (1.77 g, 9.48 mmol) in 15 mL toluene, then add palladium acetate (194 mg, 0.86 mmol) and 1,1'-binaphthyl-2,2'- Diphenylphosphine (537 mg, 0.86 mmol) was added under nitrogen protection. The reaction system was placed at 120 °C for reaction. After 16 h, the reaction was completed. Add 20 mL of water and ethyl acetate (3×30 mL) for extraction. Three times, the organic phase was collected, concentrated under reduced pressure, and purified by column chromatography (PE:EA=2:1-1:2) to obtain crude product 1c. Step two: 2-Fluoro-N-methyl-4-(piperazin-1-yl)benzamide Intermediate 1 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

Add 1c to 15 mL of 1,4-dioxane solution of hydrochloric acid (4M), stir and react at room temperature for 16 h. After the reaction, filter the reaction system and collect the filter cake to obtain Intermediate 1 (white solid , 1.4 g, yield 69%).

1H NMR (400 MHz, DMSO-d6) δ 9.67 (dr s, 1H), 8.58 (dr s, 1H), 7.81 (t, J = 8.6 Hz, 1H), 7.12-6.93 (m, 2H), 3.60- 3.56(m, 4H), 2.97 (d, J = 2.6 Hz, 3H), 3.12-3.09 (m, 4H).

LCMS m/s=238.30[M+1] .Intermediate 2 7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one intermediate 2 7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)- one

Intermediate 2 was prepared according to the synthesis method of intermediate 14 of patent WO2021013735, m/z (ES+) [M]+ = 267. Intermediate 3 2-fluoro-N-(methyl-d3)-4-(piperazin-1-yl)benzamide intermediate 3 2-fluoro-N-(methyl-d3)-4-(piperazin-1-yl )benzamide

According to the preparation method of Intermediate 1 , Intermediate 3 (white solid, 1.5 g, yield 75%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.54 (dr s, 1H), 7.83 (d, J = 4.8 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H), 6.87 – 6.85 (m, 1H ), 6.83(s, 1H), 3.60 – 3.45 (m, 4H), 3.18 – 3.13 (m, 4H).

LCMS m/s=241.20[M+1] .Intermediate 4 2-fluoro-4-(piperazin-1-yl)benzamide Intermediate 4 2-fluoro-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 4 (white solid, 1.4 g, yield 70%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.85 (dr s, 2H), 7.90 (t, J = 8.9 Hz, 1H), 7.33-7.03 (m, 2H), 6.85(s, 1H), 3.84-3.68 (m, 4H), 3.28-3.19 (m, 4H).

LCMS m/s=224.10[M+1] .Intermediate 5 2-Chloro-N-methyl-4-(piperazin-1-yl)benzamide Intermediate 5 2-chloro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 5 (white solid, 1.5 g, yield 73%) was obtained.

LCMS m/s=254.10[M+1] .Intermediate 6 4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-fluoro-N-methylbenzamide intermediate 6 4-(3,6-diazabicyclo[3.1. 1]heptan-3-yl)-2-fluoro-N-methylbenzamide

According to the preparation method of Intermediate 1 , Intermediate 6 (white solid, 1.4 g, yield 86%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.45 (dr s, 1H), 8.33 (dr s, 1H), 7.62 (t, J = 9.0 Hz, 1H), 6.62-6.59(m, 1H), 6.58 – 6.51 (m, 1H), 3.65-3.62 (m, 2H), 3.45-3.39(m, 2H), 3.31-3.28 (m, 2H), 2.75 (d, J = 4.5 Hz, 3H), 2.58 – 2.52 ( m, 1H), 1.47-1.44 (m, 1H).

LCMS m/s=250.1 [M+1] .Intermediate 7 N-cyclopropyl-2-fluoro-4-(piperazin-1-yl)benzamide Intermediate 7 N-cyclopropyl-2-fluoro-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 7 (brown solid, 1.4 g, yield 81%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.73 (dr s, 1H), 8.69 (dr s, 1H), 7.95 (t, J = 8.4 Hz, 1H), 7.64-7.28 (m, 2H), 3.56- 3.50(m, 4H), 2.81-2.77 (m, 1H), 3.18-3.15 (m, 4H), 0.68-0.64(m, 2H), 0.56-0.51 (m, 2H).

LCMS m/s=264.1[M+1] .Intermediate 8 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 8 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 8 (white solid, 1.2 g, yield 85%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.50 (d, J = 3.1 Hz, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.13 (t, J = 8.7 Hz, 1H), 4.42-4.36 (m, 4H), 3.23-3.18 (m, 4H), 2.75 (d, J = 3.1 Hz, 3H).

LCMS m/s=238.1[M+1] .Intermediate 9 (R)-2-Fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 9

According to the preparation method of Intermediate 1 , Intermediate 9 (white solid, 2.1 g, yield 87%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.07 (dd, J = 7.0, 2.9 Hz, 1H), 7.90 (dd, J = 8.0, 4.6 Hz, 1H), 7.55 (dt, J = 21.6, 9.0 Hz, 2H), 4.25 (t, J = 6.7 Hz, 1H), 3.84-3.77 (m, 2H), 3.76-3.64 (m, 4H), 3.52 (d, J = 4.5 Hz, 4H ), 3.48 (t, J = 6.3 Hz, 2H), 2.12 (dq, J = 12.8, 7.7 Hz, 1H), 1.93-1.81 (m, 1H).

LCMS m/s=294.3[M+1] .Intermediate 10 (S)-2-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 10 (S)-2-fluoro-4-(piperazin-1- yl)-N-(tetrahydrofuran-3-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 10 (white solid, 1.7 g, yield 89%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.06 (dd, J = 7.0, 2.9 Hz, 1H), 7.90 (dd, J = 8.0, 4.6 Hz, 1H), 7.54 (dt, J = 21.6, 9.0 Hz, 2H), 4.24 (t, J = 6.7 Hz, 1H), 3.82-3.74 (m, 2H), 3.77-3.66 (m, 4H), 3.52 (d, J = 4.5 Hz, 4H ), 3.48 (t, J = 6.3 Hz, 2H), 2.11 (dq, J = 12.8, 7.7 Hz, 1H), 1.92-1.80 (m, 1H).

LCMS m/s=294.3[M+1] .Intermediate 11 4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide intermediate 11 4-(3,6-diazabicyclo[3.1. 1]heptan-6-yl)-2-fluoro-N-methylbenzamide

According to the preparation method of Intermediate 1 , Intermediate 11 (white solid, 1.2 g, yield 70%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.46 (dr, 1H), 8.35 (dr, 1H), 7.65 (m, 1H), 6.62 - 6.58 (m, 1H), 6. 43– 6.40 (m, 1H ), 4.38 - 4.33(m, 2H), 3.81 - 3.64 (m, 2H), 3.31- 3.21 (M, 2H), 2.73 (d, 3H), 2.67 - 2.59 (m, 1H), 1.55 (d, J = 8.7 Hz, 1H).

LCMS m/s=250.10[M+1] .Intermediate 12 2-Chloro-6-fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 12 3-2-chloro-6-fluoro-N-methyl-4-(piperazin-1 -yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 12 (yellow solid, 630 mg, yield 83%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.42 (q, J = 4.6 Hz, 1H), 6.91-6.86 (m, 2H), 3.57 – 3.48 (m, 4H), 3.18- 3.05(m, 4H), 2.72 (d, J = 4.6 Hz, 3H).

LCMS m/s=272.1[M+1] Intermediate 13 2,3,5,6-tetrafluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 13 2,3,5,6-tetrafluoro-N-methyl-4-( piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 13 (yellow solid, 91 mg, yield 31%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.69 (q, J = 4.8 Hz, 1H), 3.45-3.43 (m, 2H), 3.20-3.17 (m, 2H), 2.96- 2.94 (m, 4H), 1.43 (d, J =4.8 Hz, 3H).

LCMS m/s=292.1[M+1] .Intermediate 14 3-bromo-2,5,6-trifluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 14 3-bromo-2,5,6-trifluoro-N-methyl -4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 14 (yellow solid, 187 mg, yield 63%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.51 (q, J = 4.8 Hz, 1H), 2.96-2.94 (m, 4H), 2.79-2.76 (m, 4H), 1.43 ( d, J = 4.8 Hz, 3H).

LCMS m/s=352.0[M+1] .Intermediate 15 (S)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide intermediate 15 (S)-2-fluoro-N-methyl-4-(3 -methylpiperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 15 (yellow solid, 480 mg, yield 85%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.85 (q, J = 4.8 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H), 6.90 – 6.81 (m, 2H) , 3.97 – 3.86 (m, 2H), 3.36 – 3.23 (m, 2H), 3.13 – 2.87 (m, 3H), 2.74 (d, J = 4.8 Hz, 3H), 1.30 (d, J = 6.5 Hz, 3H ).

LCMS m/s=252.2[M+1] .Intermediate 16 (R)-2-fluoro-N-methyl-4-(3-methylpiperazin-1-yl)benzamide intermediate 16 (R)-2-fluoro-N-methyl-4-(3 -methylpiperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 16 (yellow solid, 460 mg, yield 81%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.75 (S, 2H), 7.87 (q, J = 4.7 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 6.90 – 6.78 (m, 2H) , 4.76 (d, J = 4.7 Hz, 3H), 3.96-3.87 (m, 2H), 3.33 – 3.13 (m, 3H), 3.02-2.92(m, 2H), 1.31 (d, J = 6.4 Hz, 3H ).

LCMS m/s=252.2[M+1] .Intermediate 17 (S)-4-(3-(cyanomethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide intermediate 17 (S)-4-(3-(cyanomethyl)piperazin -1-yl)-2-fluoro-N-methylbenzamide

According to the preparation method of Intermediate 1 , Intermediate 17 (yellow solid, 1.1 g, yield 85%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.81 (s,1H), 7.88 q, J = 4.5 Hz, 1H), 7.64-7.59 (m, 1H), 6.93 – 6.80 (m, 2H), 4.00 – 3.85 (m, 2H), 3.73-3.69 (m, 2H), 3.39-3.35 (m, 1H), 3.25 – 3.15 (m, 2H), 3.13 (d, J = 6.3 Hz, 2H), 2.75 (d, J = 4.5 Hz, 3H).

LCMS m/s=277.1[M+1] .Intermediate 18 (R)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide intermediate 18 (R)-2-fluoro-4-(3- (hydroxymethyl)piperazin-1-yl)-N-methylbenzamide

According to the preparation method of Intermediate 1 , Intermediate 18 (yellow solid, 210 mg, yield 61%) was obtained.

LCMS m/s=268.1[M+1] .Intermediate 19 (S)-2-fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-N-methylbenzamide intermediate 19 (S)-2-fluoro-4-(3- (hydroxymethyl)piperazin-1-yl)-N-methylbenzamide

According to the preparation method of Intermediate 1 , Intermediate 19 (yellow solid, 240 mg, yield 67%) was obtained.

LCMS m/s=268.1[M+1] .Intermediate 20 2-cyano-N-methyl-4-(piperazin-1-yl)benzamide intermediate 20 2-cyano-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 20 (yellow solid, 920 mg, yield 87%) was obtained.

LCMS m/s=245.1[M+1] .Intermediate 21 3-Fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide intermediate 21 3-fluoro-N-methyl-4-(1,2, 3,6-tetrahydropyridin-4-yl)benzamide

first step: 4-(2-Fluoro-4-(methylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 21b tert-butyl 4- (2-fluoro- 4- (methylcarbamoyl) phenyl) - 3,6- dihydropyridine -1(2H)-carboxylate

Dissolve 8a (500 mg, 2.17 mmol) and 21a (610 mg, 1.98 mmol) in 15 mL of 1,4-dioxane, then add tetrakis(triphenylphosphine)palladium (231 mg, 0.20 mmol), carbonic acid Cesium (968 mg, 2.97 mmol). After the addition is completed, nitrogen is used to protect the reaction system. The reaction system is placed at 120 °C for reaction. After 16 h, the reaction is completed. Add 20 mL of water and ethyl acetate (3 × 30 mL) for extraction three times and collect The organic phase was concentrated under reduced pressure and purified by column chromatography (PE:EA=2:1-1:2) to obtain crude product 21b . Step two: 3-Fluoro-N-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide intermediate 2 1 3-fluoro-N-methyl-4-(1,2 ,3,6-tetrahydropyridin-4-yl)benzamide

Add 21b to 15 mL of 1,4-dioxane solution of hydrochloric acid (4 M), stir and react at room temperature for 16 h, filter after the reaction, and collect the filter cake to obtain intermediate 21 (white solid, 465 mg, yield 84%).

LCMS m/s=235.1[M+1] .Intermediate 22 N-methyl-4-(piperazin-1-yl)benzamide intermediate 22 N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 22 (yellow solid, 1 g, yield 69%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.68 (dr, 1H), 8.46 (d, 1H), 7.78 (d, 2H), 7.00 (d, 2H), 3.51 – 3.38 (m, 4H), 3.23 – 3.20 (m, 4H), 2.74 (d, 3H).

LCMS m/s=220.10[M+1] .Intermediate 23 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 23 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 23 (white solid, 1.8 g, yield 84%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.14-8.04 (m, 1H), 7.44 (dd, J = 13.3, 6.7 Hz, 1H), 7.04 (dd, J = 12.5, 7.1 Hz, 1H), 3.57-3.43 (m, 4H), 3.36 (dd, J = 6.6, 3.7 Hz, 4H), 2.76 (d, J = 4.5 Hz, 3H).

LCMS m/s=256.27[M+1] .Intermediate 24 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 24 2,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 24 (white solid, 1.1 g, yield 86%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.19 (dq, J = 6.2, 3.9 Hz, 1H), 7.39 (td, J = 8.3, 7.8, 2.0 Hz, 1H), 6.97 ( td, J = 8.5, 8.0, 1.8 Hz, 1H), 3.58 (d, J = 11.6 Hz, 2H), 3.37 (d, J = 4.6 Hz, 2H), 3.23 (q, J = 4.7 Hz, 4H), 2.76 (d, J = 4.6 Hz, 3H).

LCMS m/s=256.27[M+1] .Intermediate 25 Nitrogen-(2-(dimethylamino)ethyl)-2-fluoro-4-(piperazin-1-yl)benzamide intermediate 25 N-(2-(dimethylamino)ethyl)-2-fluoro- 4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 25 (white solid, 1.4 g, yield 89%) was obtained.

LCMS m/s=295.37[M+1] .Intermediate 26 2-Fluoro-nitrogen-(oxetan-3-yl)-4-(piperazin-1-yl)benzamide intermediate 26 2-fluoro-N-(oxetan-3-yl)-4 -(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 26 (white solid, 1.1 g, yield 84%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 7.76 – 7.69 (m, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.06 (dd, J = 23.5, 12.7 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 4.52 (d, J = 33.3 Hz, 8H), 4.16 (q, J = 6.4 Hz, 1H), 3.79 – 3.74 (m, 2H), 3.48 ( dd, J = 11.0, 6.5 Hz, 2H).

LCMS m/s=280.32[M+1] .Intermediate 27 2-fluoro-nitrogen-(1-methylazetidin-3-yl)-4-(piperazin-1-yl)benzamide intermediate 27 2-fluoro-N-(1-methylazetidin- 3-yl)-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 27 (white solid, 1.2 g, yield 87%) was obtained.

LCMS m/s=293.36[M+1] .Intermediate 28 2-fluoro-nitrogen-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide intermediate 28 2-fluoro-N-(2-methoxyethyl)-4-(piperazin- 1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 28 (white solid, 1.7 g, yield 83%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.89 – 7.80 (m, 1H), 7.60 (t, J = 8.8 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H) , 6.83 (q, J = 2.2 Hz, 1H), 3.54 (t, J = 5.3 Hz, 4H), 3.41 (qd, J = 8.3, 3.0 Hz, 4H), 3.26 (s, 3H), 3.16 (t, J = 5.1 Hz, 4H).

LCMS m/s=282.33[M+1] .Intermediate 29 2-fluoro-nitrogen-(2-hydroxyethyl)-4-(piperazin-1-yl)benzamide intermediate 29 2-fluoro-N-(2-hydroxyethyl)-4-(piperazin-1- yl)benzamide

According to the preparation method of Intermediate 1, Intermediate 29 (white solid, 1.4 g, yield 81%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.89 – 7.80 (m, 1H), 7.60 (t, J = 8.8 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H) , 6.83 (q, J = 2.2 Hz, 1H), 5.14(s, 1H), 3.54 (t, J = 5.3 Hz, 4H), 3.41 (qd, J = 8.3, 3.0 Hz, 4H), 3.16 (t, J = 5.1 Hz, 4H).

LCMS m/s=268.30[M+1] .Intermediate 30 3-fluoro-nitrogen-(2-methoxyethyl)-4-(piperazin-1-yl)benzamide intermediate 30 3-fluoro-N-(2-methoxyethyl)-4-(piperazin- 1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 30 (white solid, 1.5 g, yield 81%) was obtained.

LCMS m/s=282.15[M+1] .Intermediate 31 3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide intermediate 31 3-fluoro-N-((1s,3s) -3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 31 (white solid, 430 mg, yield 83%) was obtained.

LCMS m/s=294.15[M+1] .Intermediate 32 3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide intermediate 32 3-fluoro-N-((1r,3r) -3-hydroxycyclobutyl)-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 32 (white solid, 370 mg, yield 86%) was obtained.

LCMS m/s=294.15[M+1] .Intermediate 33 3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(piperazin-1-yl)benzamide intermediate 33 3-fluoro-N-(2-hydroxy-2-methylpropyl )-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 33 (white solid, 1.1 g, yield 91%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.30 (t, 1H), 7.73 (q, 1H), 7.70 (d, 1H), 7.15 (t, 1H), 5.09 (s, 1H), 3.36 – 3.30 (m, 4H), 3.27 (s, 2H), 3.23 (d, 4H), 1.08 (s, 6H).

LCMS m/s=296.36[M+1] .Intermediate 34 3-Fluoro-N-methyl-4-(piperidin-4-yl)benzamide Intermediate 34 3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide

first step: 3-Fluoro-N-methyl-4-(piperidin-4-yl)benzamide Intermediate 34 3-fluoro-N-methyl-4-(piperidin-4-yl)benzamide

Intermediate 21 (150 mg, 2.17 mmol), ammonium formate (120 mg, 1.98 mmol), and 10% Pd/C (150 mg) were dissolved in 3 mL of anhydrous methanol, and the reaction system was placed at 80 °C for 5 hours. Filter, collect the filtrate, and concentrate under reduced pressure to obtain intermediate 34 (white solid, 170 mg, yield 82%).

LCMS m/s=237.13[M+1] .Intermediate 35 (S)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide intermediate 35 (S)-3-fluoro-N-(2-hydroxypropyl) -4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 35 (white solid, 1.3 g, yield 94%) was obtained.

LCMS m/s=282.15[M+1] .Intermediate 36 (R)-3-fluoro-N-(2-hydroxypropyl)-4-(piperazin-1-yl)benzamide intermediate 36 (R)-3-fluoro-N-(2-hydroxypropyl) -4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 36 (white solid, 0.9 g, yield 85%) was obtained.

LCMS m/s=282.15[M+1] .Intermediate 37 N-(2-hydroxyethyl)-6-(piperazin-1-yl)nicotinamide intermediate 37 N-(2-hydroxyethyl)-6-(piperazin-1-yl)nicotinamide

According to the preparation method of Intermediate 1 , Intermediate 37 (white solid, 0.8 g, yield 82%) was obtained.

LCMS m/s=251.14[M+1] .Intermediate 38 3-Chloro-N-methyl-4-(piperazin-1-yl)benzamide Intermediate 38 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 38 (white solid, 1.2 g, yield 77%) was obtained.

LCMS m/s=254.10[M+1] .Intermediate 39 4-fluoro-N-((1-hydroxycyclopropyl)methyl)-4-(piperazin-1-yl)benzamide intermediate 39 4-fluoro-N-((1-hydroxycyclopropyl)methyl) -4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 39 (white solid, 0.9 g, yield 85%) was obtained.

LCMS m/s=294.15[M+1] .Intermediate 40 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one intermediate 40 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H) -one

first step: ethyl 6-formyl-5-nitronicotinate 40b ethyl 6-formyl-5-nitronicotinate

Dissolve 6-methyl-5-nitronicotinate ethyl ester 40a (purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., 10 g, 45.6 mmol) and selenium dioxide (7.6 g, 68.4 mmol) in dioxane (100 mL), refluxed at 110°C for 4 h, filtered hot after the reaction, concentrated the filtrate under reduced pressure, and obtained compound 40b (yellow solid, 9.7 g, yield 90%) by column chromatography.

LC-MS m/z (ESI) = 225.10 [M+1]. Step 2: 6-(2-bromo-3-ethoxy-3-oxypropan-1-en-1-yl)-5-nitronicotinate ethyl ester 40c ethyl 6-(2-bromo-3-ethoxy-3- oxoprop-1-en-1-yl)-5-nitronicotinate

Dissolve 2-bromo-2-(diethoxyphosphonate)ethyl acetate (purchased from Shanghai Merrill Chemical Technology Co., Ltd., 20 g, 66.6 mmol) in tetrahydrofuran (100 mL), and slowly add sodium at -78 °C. Hydrogen (1.6 g, 66.6 mmol) was slowly heated to 40 ℃ and reacted for 10 min. Then the temperature was lowered to -78 ℃ and a tetrahydrofuran solution of 40b (9.7 g, 44.4 mmol) was slowly added dropwise. After reacting for 15 min, a saturated aqueous ammonium chloride solution was added. (100 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were concentrated under reduced pressure, and column chromatography gave 40c (yellow solid, 13 g, yield 81%, E/Z=10:3) .

1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, 1H), 9.23 (d, 0.3H), 8.86 (d, 1H), 8.80 (d, 0.3H), 8.61 (s, 1H), 7.89 ( s, 0.3H), 4.46-4.38 (m, 2.6H), 4.34 (q, 2H), 4.16 (q, 0.6H), 1.39-1.34 (m, 3.9H), 1.32 (t, 3H), 1.08 ( t, 0.9H).

LC-MS m/z (ESI) = 373.00 [M+1]. Step 3: 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 40d ethyl 5-amino-6-(2-bromo-3- ethoxy-3-oxoprop-1-en-1-yl)nicotinate

Compound 40c (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL), iron powder (5.8 g, 104.5 mmol) was added, reacted at room temperature for 2 h, then distilled water (100 mL) was added to quench the reaction, ethyl acetate (100 mL×3), the combined organic phases were concentrated under reduced pressure to obtain compound 40d (yellow solid, 10 g, yield 83%).

LC-MS m/z (ESI) = 343.00 [M+1]. Step 4: 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 40e ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine- 3-carboxylate

Compound 40d (10 g, 29.1 mmol) was placed in a reaction bottle, hydrogen bromide acetic acid solution (100 mL) was added under nitrogen protection, reacted at 50°C for 4 h, then concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (100 mL ) to quench the reaction, extract with ethyl acetate (50 mL×3), concentrate under reduced pressure, and obtain compound 40e (yellow solid, 2 g, yield 23%) by column chromatography.

1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.88 (d, 1H), 8.51 (s, 1H), 8.14 (d, 1H), 4.37 (q, 2H), 1.35 (t, 3H).

LC-MS m/z (ESI) = 297.00 [M+1]. Step 5: 7-Cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 40f ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5 -naphthyridine-3-carboxylate

Compound 40e (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane complex (purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd., 328 mg, 0.40 mmol), potassium carbonate (745 mg, 5.4 mmol), cyclopropylboronic acid (Hangzhou Aikang Biotechnology Co., Ltd., 231 mg, 2.7 mmol) dissolved in dioxane (4 mL), refluxed at 110°C After 8 h, water (5 mL) was added to quench, extracted with ethyl acetate (5 mL×3), concentrated under reduced pressure and purified by column chromatography to obtain compound 40f (yellow solid, 270 mg, yield 77%).

1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.85 (d, 1H), 8.12 (d, 1H), 7.46 (s, 1H), 4.36 (q, 2H), 2.25-2.12 ( m, 1H), 1.34 (t, 3H), 1.02 (dt, 2H), 0.90 (dt, 2H).

LC-MS m/z (ESI) = 259.10 [M+1]. Step 6 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one 40g 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

Compound 40f (270 mg, 1 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of lithium aluminum tetrahydride in tetrahydrofuran (purchased from Anaiji Chemical, 2 mL, 2 mmol) was slowly added dropwise in an ice-water bath, and stirred after the dropwise addition. After 10 min, ethyl acetate (1 mL) was added, and the compound was concentrated by column chromatography under reduced pressure to obtain 40 g of compound (yellow solid, 100 mg, yield 44%).

1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.35 (d, 1H), 7.59 (d, 1H), 7.41 (s, 1H), 5.45 (t, 1H), 4.60 (d, 2H), 2.16-2.09 (m, 1H), 0.96 (dt, 2H), 0.82 (dt, 2H).

LC-MS m/z (ESI) = 217.10 [M+1]. Step 7 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one intermediate 40g 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H) -one

Compound 40g (100 mg, 0.46 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 242 mg, 0.92 mmol) were dissolved in dichloromethane (1 mL), and tetrabromide was added under an ice-water bath. A solution of carbon (purchased from Anaiji Chemical, 306 mg, 0.92 mmol) in dichloromethane (0.5 mL) was reacted for 0.5 h. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound intermediate 40 (yellow solid, 100 mg , yield 78%).

LC-MS m/z (ESI) = 279.00 [M+1]. Intermediate 41 (R)-6-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide intermediate 41 (R)-6-(piperazin-1-yl)-N-(tetrahydrofuran-3 -yl)nicotinamide

According to the preparation method of Intermediate 1 , Intermediate 35 (white solid, 0.4 g, yield 87%) was obtained.

LCMS m/s=277.16[M+1] .Intermediate 42 N-methyl-4-(piperazin-1-yl)picolinamide intermediate 42 N-methyl-4-(piperazin-1-yl)picolinamide

According to the preparation method of Intermediate 1 , Intermediate 42 (yellow solid, 500 mg, yield 74%) was obtained.

LCMS m/s=221.28[M+1] .Intermediate 43 N-methyl-5-(piperazin-1-yl)pyrazine-2-carboxamide intermediate 43 N-methyl-5-(piperazin-1-yl)pyrazine-2-carboxamide

According to the preparation method of Intermediate 1 , Intermediate 43 (yellow solid, 1.1 g, yield 72%) was obtained.

LCMS m/s=222.26[M+1] .Intermediate 44 5-fluoro-N-methyl-6-(piperazin-1-yl)nicotinamide intermediate 44 5-fluoro-N-methyl-6-(piperazin-1-yl)nicotinamide

According to the preparation method of Intermediate 1 , Intermediate 44 (yellow solid, 530 mg, yield 78%) was obtained.

LCMS m/s=239.12[M+1] .Intermediate 45 3,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 45 3,5-difluoro-N-methyl-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 45 (white solid, 1.4 g, yield 69%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.60 (q, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 3.46 – 3.36 (m, 4H), 3.20 – 3.11 (m, 4H), 2.76 (d, 3H).

LCMS m/s=256.10[M+1] .Intermediate 46 2-Chloro-5-fluoro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 46 2-chloro-5-fluoro-N-methyl-4-(piperazin-1-yl )benzamide

Intermediate 46 (white solid, 1.5 g, yield 75%) was obtained according to the same method as above.

1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.32 (q, 1H), 7.32 (d, 1H), 7.15 (d, 1H), 3.39 – 3.26 (m, 4H), 3.24 – 3.16 (m, 4H), 2.72 (d, 3H).

LCMS m/s=272.10 [M+1] .Intermediate 47 2,6-dichloro-N-methyl-4-(piperazin-1-yl)benzamide intermediate 47 2,6-dichloro-N-methyl-4-(piperazin-1-yl)benzamide

Following the same method as above, intermediate 47 (white solid, 1.4 g, yield 70%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.39 (q, 1H), 7.06 (s, 2H), 3.55 – 3.45 (m, 4H), 3.18 – 3.09 (m, 4H), 2.72 (d, 3H).

LCMS m/s=288.10[M+1] .Intermediate 48 7-(bromomethyl)-3-methyl-1,5-naphthyridin-2(1H)-one intermediate 48 7-(bromomethyl)-3-methyl-1,5-naphthyridin-2(1H)- one

Intermediate 48 was prepared according to the synthesis method of Intermediate 14 of patent WO2021013735, using triethyl 2-phosphonopropyl ester instead of triethyl 2-butyl propenyl ester, LCMS m/s = 253.10 [M+1]. Intermediate 49 (R)-3-chloro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide intermediate 49 (R)-3-chloro-4-(piperazin-1- yl)-N-(tetrahydrofuran-3-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 49 (white solid, 1.3 g, yield 94%) was obtained.

LCMS m/s=310.7[M+1] .Intermediate 50 3-Chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide intermediate 50 3-chloro-N-((3S, 4R)-4-hydroxytetrahydrofuran-3-yl)-4-(piperazin-1-yl) benzamide

According to the preparation method of Intermediate 1 , Intermediate 50 (white solid, 1.6 g, yield 94%) was obtained.

LCMS m/s=326.1[M+1] .Intermediate 51 3-Chloro-N-(3-methyltetrahydrofuran-3-yl)-4-(piperazin-1-yl)benzamide intermediate 51 3-chloro-N-(3-methyltetrahydrofuran-3-yl) -4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 51 (white solid, 1.1 g, yield 92%) was obtained.

LCMS m/s=324.1[M+1] .Intermediate 52 N-(3-oxazolecyclo[3.1.0]hexan-6-yl)-3-chloro-4-(piperazin-1-yl)benzamide intermediate 52 N-(3-oxabicyclo[3.1 .0]hexan-6-yl)-3-chloro-4-(piperazin-1-yl)benzamide

According to the preparation method of Intermediate 1 , Intermediate 52 (white solid, 1.3 g, yield 91%) was obtained.

LCMS m/s=322.1[M+1] .Example 1 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- N-methylbenzamide compound 1 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)- 2-fluoro-N-methylbenzamide

Intermediate 2 (100 mg, 0.37 mmol) and Intermediate 1 (98 mg, 0.41 mmol) were dissolved in 5 mL acetonitrile, and then N,N-diisopropylethylamine (241.5 mg, 1.9 mmol) was added. The reaction was carried out under nitrogen protection at 70 °C. The reaction was completed after 3 hours. The crude product was obtained by concentrating under reduced pressure and then purified by column chromatography (MeOH:DCM=1:60 to 1:15) to obtain compound 1 (white solid, 50 mg, Yield: 32%).

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.22 (dr s, 1H), 7.75 (s, 1H), 7.62 (s, 1H ), 7.56 (t, J = 9.0 Hz, 1H), 6.82 - 6.72 (m, 2H), 3.64 (s, 2H), 3.29-3.26 (m, 4H), 2.74 (d, J = 4.5 Hz, 3H) , 2.54 - 2.51 (m, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=424.50[M+1] .Example 2 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- N-(methyl-D3)benzamide compound 2 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1 -yl)-2-fluoro-N-(methyl-d3)benzamide

Compound 2 (white solid, 100 mg, yield: 62%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 ( s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.75 (dr s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.56 (t, J = 9.0 Hz, 1H), 6.81 – 6.70 (m, 2H), 3.63 (s, 2H), 3.29 – 3.26 (m, 4H), 2.59 – 2.51 (m, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=427.20[M+1] .Example 3 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzene Formamide compound 3 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-2-fluorobenzamide

Compound 3 (white solid, 5 mg, yield: 7%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.32 (dr s, 1H), 7.20 (dr s, 1H), 6.83 – 6.67 (m, 2H), 3.64 (s, 2H), 3.32-3.27 (m, 4H ), 2.54-2.50 (m, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=410.20[M+1] .Example 4 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-methylbenzamide compound 4 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1 -yl)-N-methylbenzamide

Compound 4 (white solid, 50 mg, yield: 30%) was prepared according to the method of compound 1 .

LCMS m/s=440.20[M+1]. Example 5 4-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1. 1]Heptan-3-yl)-2-fluoro-N-methylbenzamide compound 5 4-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin -3-yl)methyl)- 3,6-diazabicyclo[3.1.1] heptan-3-yl)-2-fluoro-N-methylbenzamide

Compound 5 (white solid, 18 mg, yield: 23%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.53 (s, 1H), 7.90 – 7.53 (m, 4H), 6.76 – 6.47 (m, 2H), 3.88-3.61 (m, 4H ), 3.21-3.12 (m, 4H) 2.77 (s, 3H), 2.62 – 2.51 (m, 3H), 1.29-1.25 (m, 1H), 1.15 (s, 3H).

LCMS m/s=436.20 [M+1]. Example 6 N-cyclopropyl-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl )-2-fluorobenzamide compound 6 N-cyclopropyl-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) methyl)piperazin - 1-yl)-2-fluorobenzamide

Compound 6 (white solid, 18 mg, yield: 6%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.39 (d, J = 1.8 Hz, 1H), 7.85 (s, 1H),

7.75 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 6.81 - 6.70 (m, 2H), 3.63 (s, 2H ), 3.27-3.24 (m, 4H), 2.80-2.77 (m, 1H), 2.56 - 2.55 (m, 6H), 1.17 (t, J = 7.5 Hz, 3H). 0.68-0.65(m, 2H), 0.53-0.50 (m, 2H).

LCMS m/s=450.2[M+1] .Example 7 4-(4-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N -Methyl benzamide compound 7 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-3 -fluoro-N-methylbenzamide

Compound 7 (white solid, 50 mg, yield: 78%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (s, 1H), 8.33 (q, J = 4.1 Hz, 1H), 7.75 (s, 1H), 7.68 – 7.52 (m, 3H), 7.05 (t, J = 8.6 Hz, 1H), 3.65 (s, 2H), 3.14-3.08 (m, 4H), 2.75 (d, J = 4.1 Hz, 3H), 2.59 – 2.55 (m, 4H ), 2.54-2.51 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=424.2[M+1] Example 8 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 2-Fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 8 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Compound 8 (white solid, 40 mg, yield: 82%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.96 (dd, J = 6.7, 3.6 Hz, 1H), 7.75 (s, 1H) , 7.62 (s, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.82-6.69 (m, 2H), 4.40 (d, J = 5.6 Hz, 1H), 3.81 (td, J = 9.5, 6.8 Hz, 2H), 3.73-3.66 (m, 1H), 3.64 (s, 2H), 3.53 (dd, J = 8.8, 4.4 Hz, 1H), 3.28 (s, 4H), 2.54 (d, J = 8.3 Hz , 6H), 2.17-2.06 (m, 1H), 1.87 (dd, J = 12.2, 5.8 Hz, 1H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=480.5[M+1]. Example 9 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 2-Fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 9 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Compound 9 (white solid, 46 mg, yield: 84%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.96 (dd, J = 6.6, 3.5 Hz, 1H), 7.75 (s, 1H) , 7.62 (d, J = 1.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 6.80- 6.70 (m, 2H), 4.39 (d, J = 6.1 Hz, 1H), 3.85-3.77 ( m, 2H), 3.73-3.67 (m, 1H), 3.63 (s, 2H), 3.53 (dd, J = 8.8, 4.4 Hz, 1H), 3.27 (d, J = 5.4 Hz, 4H), 2.59-2.51 (m, 6H), 2.18-2.06 (m, 1H), 1.85 (dq, J = 12.5, 6.2 Hz, 1H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=480.5[M+1] .Example 10 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro -Nitrogen-methylbenzamide compound 10 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl) -3-fluoro-N-methylbenzamide

first step: 6-formyl-5-nitronicotinat 10B ethyl 6-formyl-5-nitronicotinat

Dissolve 6-methyl-5-nitronicotinate ethyl ester compound 10A (purchased from Jiangsu Aikang Biopharmaceutical R&D Co., Ltd., 10 g, 45.6 mmol) and selenium dioxide (7.6 g, 68.4 mmol) in dioxane Ring (100 mL), refluxed at 110°C for 4 h, filtered hot after the reaction, concentrated the filtrate under reduced pressure, and obtained compound 10B (yellow solid, 9.7 g, yield 90%) by column chromatography.

LC-MS m/z (ESI) = 225.10 [M+1]. Step 2: 6-(2-Bromo-3-ethoxy-3-propoxyacid-1-en-1-yl)-5-nitronicotinate ethyl ester 10C ethyl 6-(2-bromo-3-ethoxy-3 -oxoprop-1-en-1-yl)-5-nitronicotinate

Dissolve 2-bromo-2-(diethoxyphosphonate)ethyl acetate (purchased from Shanghai Merrill Chemical Technology Co., Ltd., 20 g, 66.6 mmol) in tetrahydrofuran (100 mL), and slowly add sodium at -78 °C. Hydrogen (1.6 g, 66.6 mmol) was slowly heated to 40 ℃ and reacted for 10 min. Then the temperature was lowered to -78 ℃ and a tetrahydrofuran solution of 10B (9.7 g, 44.4 mmol) was slowly added dropwise. After reacting for 15 min, a saturated aqueous ammonium chloride solution was added ( 100 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were concentrated under reduced pressure, and column chromatography yielded 10C (yellow solid, 13 g, yield 81%, E/Z=10:3).

1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, 1H), 9.23 (d, 0.3H), 8.86 (d, 1H), 8.80 (d, 0.3H), 8.61 (s, 1H), 7.89 ( s, 0.3H), 4.46 – 4.38 (m, 2.6H), 4.34 (q, 2H), 4.16 (q, 0.6H), 1.39 – 1.34 (m, 3.9H), 1.32 (t, 3H), 1.08 ( t, 0.9H).

LC-MS m/z (ESI) = 373.00 [M+1]. Step 3: 5-Amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 10D ethyl 5-amino-6-(2-bromo-3- ethoxy-3-oxoprop-1-en-1-yl)nicotinate

Compound 10C (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL), iron powder (5.8 g, 104.5 mmol) was added, and the reaction was carried out at room temperature for 2 h. Distilled water (100 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) extraction, and the combined organic phases were concentrated under reduced pressure to obtain compound 10D (yellow solid, 10 g, yield 83%).

LC-MS m/z (ESI) = 343.00 [M+1]. Step 4: 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 10E ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine -3-carboxylate

Place compound 10D (10 g, 29.1 mmol) in a reaction bottle, add hydrogen bromide in acetic acid solution (100 mL) under nitrogen protection, react at 50°C for 4 hours, then concentrate under reduced pressure, and saturated aqueous sodium bicarbonate solution (100 mL) ) to quench the reaction, extract with ethyl acetate (50 mL×3), concentrate under reduced pressure, and perform column chromatography to obtain compound 10E (yellow solid, 2 g, yield 23%).

1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.88 (d, 1H), 8.51 (s, 1H), 8.14 (d, 1H), 4.37 (q, 2H), 1.35 (t, 3H).

LC-MS m/z (ESI) = 297.00 [M+1]. Step 5: 7-Cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 10F ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5 -naphthyridine-3-carboxylate

Compound 10E (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd., 328 mg, 0.40 mmol), potassium carbonate (745 mg, 5.4 mmol), cyclopropylboronic acid (Hangzhou Aikang Biotechnology Co., Ltd., 231 mg, 2.7 mmol) dissolved in dioxane (4 mL), refluxed at 110 °C After 8 h, water (5 mL) was added to quench, extracted with ethyl acetate (5 mL×3), and concentrated under reduced pressure and purified by column chromatography to obtain compound 10F (yellow solid, 270 mg, yield 77%).

1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.85 (d, 1H), 8.12 (d, 1H), 7.46 (s, 1H), 4.36 (q, 2H), 2.25 – 2.12 ( m, 1H), 1.34 (t, 3H), 1.02 (dt, 2H), 0.90 (dt, 2H).

LC-MS m/z (ESI) = 259.10 [M+1]. Step 6: 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one 10G 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)- one

Compound 10F (270 mg, 1 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of lithium aluminum tetrahydride in tetrahydrofuran (purchased from Anaiji Chemical, 2 mL, 2 mmol) was slowly added dropwise in an ice-water bath. Stir for 10 min, add ethyl acetate (1 mL), and concentrate under reduced pressure. Compound 10G (yellow solid, 100 mg, yield 44%) was obtained by column chromatography.

1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.35 (d, 1H), 7.59 (d, 1H), 7.41 (s, 1H), 5.45 (t, 1H), 4.60 (d, 2H), 2.16 – 2.09 (m, 1H), 0.96 (dt, 2H), 0.82 (dt, 2H).

LC-MS m/z (ESI) = 217.10 [M+1]. Step 7: 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one 10H 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)- one

Compound 10G (100 mg, 0.46 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 242 mg, 0.92 mmol) were dissolved in dichloromethane (1 mL), and tetrabromide was added under an ice-water bath. A solution of carbon (purchased from Anaiji Chemical, 306 mg, 0.92 mmol) in dichloromethane (0.5 mL) was reacted for 0.5 h. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 10H (yellow solid, 100 mg, product rate 78%).

LC-MS m/z (ESI) = 279.00 [M+1]. Step 8: 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro -Nitrogen-methylbenzamide compound 10 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl) -3-fluoro-N-methylbenzamide

Compound 10H (100 mg, 0.36 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide (93 mg, 0.39 mmol), intermediate 8, N,N-di Isopropylethylamine (230 mg, 1.8 mmol) was dissolved in acetonitrile (4 mL) and reacted at 80 °C for 4 h. The reaction solution was concentrated under reduced pressure and subjected to preparative chromatography to obtain compound 10 (white solid, 40 mg, yield 27% ).

1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.37 (d, 1H), 8.35 – 8.31 (m, 1H), 7.64 – 7.53 (m, 3H), 7.41 (s, 1H), 7.05 (t, 1H), 3.63 (d, 2H), 3.12 – 3.09 (m, 4H), 2.75 (d, 3H), 2.57 – 2.54 (m, 4H), 2.19 – 2.11 (m, 1H), 1.02 – 0.92 (m, 2H), 0.87 – 0.74 (m, 2H).

LC-MS m/z (ESI) = 436.20 [M+1]. Example 11 4-(4-((7-ethyl-2,6-dioxy-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazine-1- ethyl)-3-fluoro-N-methylbenzamide compound 11 4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-methylbenzamide

first step: (5-acetyl-7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acetate methyl ester 11B (5-acetyl-7-ethyl-6- oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl acetate

Compound 11A (1.02 g, 5 mmol; prepared according to the synthesis method of intermediate 13 of patent WO2021013735, LC-MS m/s = 205.1 [M+1]) and acetic anhydride (10.2 g, 100 mmol) were added to a 100mL reaction bottle , stir the reaction in an oil bath at 100 °C for 8 h under a nitrogen atmosphere. TLC monitors the reaction to be complete. The solvent is concentrated under reduced pressure and separated by column chromatography (PE:EA = 5:1) to obtain compound 11B (light yellow solid). , 1.15 g, yield 80%).

LC-MS m/s = 289.1 [M+1]. Step 2: 3-ethyl-7-(hydroxymethyl)-1,5-dihydro-1,5-naphthyridine-2,6-dione 11C 3-ethyl-7-(hydroxymethyl)-1,5-dihydro- 1,5-naphthyridine-2,6-dione

Take a 50 mL reaction bottle, dry it, add compound 11B (1.15 g, 4 mmol) and 10 mL dichloromethane, replace the nitrogen, add m-chloroperoxybenzoic acid (756 mg, 4.4 mmol) in batches under ice-water bath conditions, naturally Return to room temperature and stir for 5 hours. TLC monitors that the reaction is complete. Add saturated sodium bicarbonate aqueous solution (20 mL) and extract with dichloromethane (3 × 20 mL). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the organic matter. Solvent. Add acetic anhydride (10 mL), reflux and stir for 2 hours, then add distilled water (8 mL), continue the reflux and stir reaction for 2 hours, concentrate under reduced pressure to remove the organic solvent, add methanol (20 mL) and potassium carbonate (2.76g, 20 mmol) ), react with stirring at room temperature for 1 h, filter, wash the filter cake with methanol, collect the filtrate, and concentrate under reduced pressure to remove the organic solvent. The crude product is separated by a reversed-phase column to obtain compound 11C (brown solid, 310 mg, yield 35%).

1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 2H), 6.94 (d, 1H), 6.73 (s, 1H), 5.37 (t, 1H), 4.20 (dd, 2H), 2.35 (qd, 2H), 1.08 (t, 3H).

LC-MS m/s = 221.1 [M+1]. Step 3: 3-(bromomethyl)-7-ethyl-1,5-dihydro-1,5-naphthyridine-2,6-dione 11D 3-(bromomethyl)-7-ethyl-1,5-dihydro- 1,5-naphthyridine-2,6-dione

Compound 11C (310 mg, 1.41 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 739 mg, 2.82 mmol) were dissolved in methylene chloride (5 mL), and tetrabromobromide was added under ice-water bath conditions. A solution of carbonic acid (purchased from Anaiji Chemical, 933 mg, 2.82 mmol) in dichloromethane (2 mL) was reacted for 0.5 h. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 11D (yellow solid, 160 mg, Yield 40%).

1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 2H), 6.99 (s, 1H), 6.73 (s, 1H), 3.97 (d, 2H), 2.33 (qd, 2H), 1.08 (t, 3H).

LC-MS m/s = 283.0 [M+1]. Step 4: 4-(4-((7-ethyl-2,6-dioxy-1,2,5,6-tetrahydro-1,5-naphthyridin-3-yl)methyl)piperazine-1- ethyl)-3-fluoro-N-methylbenzamide compound 11 4-(4-((7-ethyl-2,6-dioxo-1,2,5,6-tetrahydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-methylbenzamide

Compound 11D (100 mg, 0.35 mmol), intermediate 8 (93 mg, 0.39 mmol), N,N-diisopropylethylamine (230 mg, 1.8 mmol) were dissolved in acetonitrile (4 mL), 80 °C The reaction was carried out for 4 h, and the reaction solution was concentrated under reduced pressure and subjected to preparative chromatography to obtain compound 11 (white solid, 31 mg, yield 27%).

1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.52 (s, 1H), 8.28 (s, 1H), 7.63 (dd, 1H), 7.31 (dd, 1H), 6.96 – 6.60 ( m, 3H), 4.13 (d, 2H), 3.08 (t, 4H), 2.81 (s, 3H), 2.56 (d, 3H), 2.49 – 2.22 (m, 2H), 1.15 (t, 3H).

LC-MS m/s = 440.2 [M+1]. Example 12 4-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1. 1]Heptan-6-yl)-2-fluoro-nitrogen-methylbenzamide compound 12 4-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin -3-yl)methyl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-fluoro-N-methylbenzamide

Compound 12 (white solid, 50 mg, yield: 47%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.14 (s, 1H), 7.75 - 7.72 (m, 1H), 7.70 (s, 1H), 7.54 (t, 1H), 7.46 ( s, 1H), 6.36 (s, 1H), 6.34 (s, 1H), 4.33 - 4.32(m, 2H), 3.59 (s, 2H), 3.04 -3.01(m, 2H), 2.82 - 2.69 (m, 5H), 2.55 - 2.52(m, 2H), 1.99 - 1.97(m, 1H), 1.23 - 1.21(m, 1H), 1.17 (t, 3H).

LCMS m/s=436.20[M+1] .Example 13 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Fluoro-nitrogen-methylbenzamide compound 13 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl ) piperazin-1-yl)-6-fluoro-N-methylbenzamide

Compound 13 (white solid, 17.7 mg, yield: 42%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (s, 1H), 8.36 (q, J = 4.6 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H) , 6.82 (s, 1H), 6.78-6.76 (m, 1H), 3.62 (s, 2H), 3.28-3.22 (m, 4H), 3.16-3.12 (m, 2H), 2.71 (d, J = 4.6 Hz , 3H), 2.57 – 2.51 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -113.43 (s).

LCMS m/s=458.2[M+1] .Example 14 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,3, 5,6-Tetrafluoro-nitrogen-methylbenzamide compound 14 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-2,3,5,6-tetrafluoro-N-methylbenzamide

Compound 14 (white solid, 6.5 mg, yield: 41%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.68 (d, J = 4.6 Hz, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H) , 3.65 (s, 2H), 3.27-3.22 (s, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.57-2.54 (m, 4H), 2.54 (d, J = 7.4 Hz, 2H), 1.18 (t, J = 7.4 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -144.07 (dd, J = 22.8, 8.3 Hz), -150.60 (dd, J = 22.8, 8.3 Hz).

LCMS m/s=478.2[M+1] .Example 15 4-bromo-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 2,5,6-Trifluoro-N-methylbenzamide compound 15 3-bromo-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-2,5,6-trifluoro-N-methylbenzamide

Compound 15 (white solid, 15.3 mg, yield: 44%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.53 (q, J = 4.6 Hz, 1H), 8.38 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H) , 3.60 (s, 2H), 3.15-3.10 (m, 4H), 3.05-2.99 (m, 4H), 2.77 (d, J = 4.6 Hz, 3H), 2.57 – 2.52 (m, 2H), 1.18 (d , J = 7.4 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -117.65 (d, J = 11.5 Hz), -133.54 (d, J = 25.6 Hz), -143.13 (dd, J = 25.6, 11.5 Hz).

LCMS m/s=538.1[M+1] .Example 16 (S)-4-(4-((7-ethyl-6-carbonyl5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazine-1- ethyl)-2-fluoro-nitrogen-methylbenzamide compound 16 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)- 3-methylpiperazin-1-yl)-2-fluoro-N-methylbenzamide

Following the method of compound 1 , compound 16 (white solid, 43 mg, yield: 46%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.54 (q, J = 4.4 Hz, 1H), 7.95-7.59 (m, 5H), 6.84 (s, 1H), 3.64-3.60 ( m, 4H), 3.18 – 3.12 (m, 4H), 2.95-2.87 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.59 – 2.53 (m, 2H), 1.46 (d, J = 6.5 Hz, 3H), 1.18 (t, J = 8.0 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -111.44.

LCMS m/s=438.2[M+1]. Example 17 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazine- 1-yl)-2-fluoro-nitrogen-methylbenzamide compound 17 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)- 3-methylpiperazin-1-yl)-2-fluoro-N-methylbenzamide

Following the method of compound 1 , compound 17 (white solid, 41 mg, yield: 43%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.40 (d, J = 4.7 Hz, 1H), 7.75 (s, 2H), 7.62 (s, 1H), 7.55 (t, J = 8.9 Hz, 1H), 6.82 – 6.68 (m, 2H), 3.64-3.58 (m, 4H), 3.15 – 3.11 (m, 4H), 2.93-2.84 (m, 1H), 2.74 (d, J = 4.7 Hz , 3H), 2.58 – 2.51 (m, 2H), 1.17 (m, 6H).

19F NMR (377 MHz, DMSO-d6) δ -111.57.

LCMS m/s=438.2[M+1] Example 18 (S)-4-(3-(cyanomethyl)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) Piperazin-1-yl)-2-fluoro-nitrogen-methylbenzamide compound 18 (S)-4-(3-(cyanomethyl)-4-((7-ethyl-6-oxo-5,6 -dihydro-1,5-naphthyridin-3-yl) methyl) piperazin-1-yl)-2-fluoro-N-methylbenzamide

Compound 18 (white solid, 39 mg, yield: 45%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.47 (q, J = 4.4 Hz, 1H), 8.27 (s, 1H), 7.91-7.63 (m, 3H), 6.91-6.83 ( m, 2H), 3.65 (s, 2H), 3.33 – 3.27 (m, 4H), 3.13-3.09 (m, 4H), 2.91-2.86 (m, 1H), 2.73 (d, J = 4.4 Hz, 3H) , 2.59 – 2.53 (m, 2H), 1.17 (t, J = 7.8 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -111.53.

LCMS m/s=463.2[M+1]. Example 19 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl) Piperazin-1-yl)-2-fluoro-nitrogen-methylbenzamide compound 19 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5 -naphthyridin-3-yl)methyl)- 3-(hydroxymethyl)piperazin-1-yl)-2-fluoro-N-methylbenzamide

Following the method of compound 1 , compound 19 (white solid, 42 mg, yield: 43%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.42 (q, J = 4.6 Hz, 1H), 7.76 (s, 2H), 7.65 (s, 1H), 7.57 (t, J = 9.0 Hz, 1H), 6.80 – 6.67 (m, 2H), 4.77 (t, J = 5.2 Hz, 1H), 3.78 – 3.43 (m, 6H), 3.05 – 2.94 (m, 4H), 2.75 (d, J = 4.6 Hz, 3H), 2.70-2.68 (m, 1H), 2.56-2.53 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -111.56.

LCMS m/s=454.2[M+1]. Example 20 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(hydroxymethyl) Piperazin-1-yl)-2-fluoro-nitrogen-methylbenzamide compound 20 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5 -naphthyridin-3-yl)methyl)- 3-(hydroxymethyl) piperazin-1-yl)-2-fluoro-N-methylbenzamide

Following the method of compound 1 , compound 20 (white solid, 46 mg, yield: 45%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.41 (q, J = 4.7 Hz, 1H), 7.75 (s, 2H), 7.64 (s, 1H), 7.57 (t, J = 8.9 Hz, 1H), 6.79 – 6.67 (m, 2H), 4.79 (t, J = 5.2 Hz, 1H), 3.83 – 3.40 (m, 6H), 3.07-2.99(m, 4H), 2.74 (d, J = 4.7 Hz, 3H), 2.71-2.67 (m, 1H), 2.57 – 2.52 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H).

LCMS m/s=454.2[M+1] .Example 21 2-cyano-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) -N-Methylbenzamide compound 21 2-cyano-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) methyl)piperazin- 1-yl)-N-methylbenzamide

Following the method of compound 1 , compound 21 (white solid, 43 mg, yield: 44%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.62 (s, 1H), 8.40 (q, J = 4.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.75 (s, 2H), 7.27 – 7.18 (m, 2H), 3.64 (s, 2H), 3.09-3.87(m, 4H), 2.75 (d, J = 4.7 Hz, 3H), 2.54-2.51 (m, 6H ), 1.18 (t, J = 7.4 Hz, .3H).

LCMS m/s=431.2[M+1].\ Example 22 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridine -4-yl)-3-fluoro-N-methylbenzamide compound 22 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl )methyl)- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-methylbenzamide

Compound 22 (white solid, 39 mg, yield: 46%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.51 (q, J = 4.5 Hz, 1H), 8.41 (s, 1H), 7.75 (s, 1H), 7.70 – 7.57 (m, 3H), 7.49 – 7.41 (m, 1H), 6.08 (s, 1H), 3.71 (s, 2H), 3.14-3.12 (m, 2H), 2.77 (d, J = 4.5, 3H), 2.69-2.64 ( m, 2H), 2.58 – 2.51 (m, 4H), 1.18 (d, J = 7.5, 3H).

19F NMR (377 MHz, DMSO-d6) δ -114.94.

LCMS m/s=421.2[M+1] .Example 23 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl Benzamide compound 23 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-methylbenzamide

Compound 23 (white solid, 100 mg, yield: 70%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, 1H), 8.13 (q, 1H), 7.75 (d, 1H), 7.72 – 7.67 (m, 2H), 7.62 ( d, 1H), 6.97 – 6.90 (m, 2H), 3.64 (s, 2H), 3.27 – 3.24 (m, 4H), 2.73 (d, 3H), 2.57 – 2.52 (m, 6H), 1.18 (t, 3H).

LCMS m/s=406.20[M+1] .Example 24 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-nitrogen-(tetrahydrofuran-3-yl)benzamide compound 24 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

first step: (R)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide 24B (R)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Dissolve compound 24A (2 g, 9.9 mmol) in dichloromethane (20 mL), and add (R)-tetrahydrofuran-3-amine (1.73 g, 19.8 mmol) and HATU (3.5 g, 3.5 g, 14.8 mmol) and triethylamine (2 ml), react at room temperature for 90 min. After the reaction is completed, concentrate under reduced pressure and perform column purification to obtain 24B (yellow solid, 2.1 g, yield 78%).

LC-MS m/z (ESI) = 287.10 [M+1]. Step 2: (R)-4-(2-fluoro-4-((tetrahydrofuran-3-yl)carbamate)phenyl)piperazine-1-carboxylic acid tert-butyl ester 24C tert-butyl (R)-4-(2 -fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl) piperazine-1-carboxylate

Referring to the synthesis method of compound 1c , compound 24C (white solid, 1.8 g, yield 88%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.62(d, 1H), 3.23 – 3.03 (m, 4H), 2.86 - 2.71 (m, 3H), 2.67 – 2.42 (m, 4H), 2.49 – 2.29 (m, 2H), 2.23 (dt, 1H), 1.95 – 1.83 (m, 1H), 1.50 (s, 9H).

LC-MS m/z (ESI) = 394.12 [M+1]. Step 3: (R)-3-fluoro-4-(piperazin-1-yl)-nitrogen-(tetrahydrofuran-3-yl)benzamide 24D (R)-3-fluoro-4-(piperazin-1-yl) -N-(tetrahydrofuran-3-yl)benzamide

Referring to the synthesis method of intermediate 1 , compound 24D (white solid, 1.0 g, yield 81%) was synthesized and isolated.

LC-MS m/z (ESI) = 294.15 [M+1]. Step 4: (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-nitrogen-(tetrahydrofuran-3-yl)benzamide compound 24 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Referring to the synthetic method of compound 1 , compound 24 (white solid, 26 mg, yield 54%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.40 (dd, 1H), 8.00 – 7.48 (m, 5H), 7.05 (t, 1H), 4.41 (dtt, 1H), 3.96 – 3.48 (m, 6H), 3.23 – 3.00 (m, 4H), 2.64 – 2.39 (m, 4H), 2.13 (dtd, 1H), 1.96 – 1.81 (m, 1H), 1.37 – 1.21 (m, 2H), 1.18 (t, 3H) .Example 25 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-nitrogen-(tetrahydrofuran-3-yl)benzamide compound 25 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

first step: (S)-4-bromo-3-fluoro-nitrogen-(tetrahydrofuran-3-yl)benzamide 25A (S)-4-bromo-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Referring to the synthetic method of compound 24B , compound 25A (yellow solid, 2.3 g, yield 82%) was synthesized and isolated.

LC-MS m/z (ESI) = 287.10 [M+1]. Step 2: (S)-4-(2-Fluoro-4-((tetrahydrofuran-3-yl)carbamate)phenyl)piperazine-1-carboxylic acid tert-butyl ester 25B tert-butyl (S)-4-(2 -fluoro-4-((tetrahydrofuran-3-yl)carbamoyl)phenyl) piperazine-1-carboxylate

Referring to the synthesis method of compound 1c , compound 25B (white solid, 2.5 g, yield 89%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.62(d, 1H), 3.23 – 3.03 (m, 4H), 2.86 - 2.71 (m, 3H), 2.67 – 2.42 (m, 4H), 2.49 – 2.29 (m, 2H), 2.23 (dt, 1H), 1.95 – 1.83 (m, 1H), 1.50 (s, 9H).

LC-MS m/z (ESI) = 394.12 [M+1]. Step 3 (S)-3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide 25C (S)-3-fluoro-4-(piperazin-1-yl) -N-(tetrahydrofuran-3-yl)benzamide

Referring to the synthesis method of Intermediate 1 , compound 25C (white solid, 1.6 g, yield 83%) was synthesized and isolated.

LC-MS m/z (ESI) = 294.15 [M+1]. Step 4 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-nitrogen-(tetrahydrofuran-3-yl)benzamide compound 25 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Referring to the synthetic method of compound 1 , compound 25 (white solid, 19 mg, yield 42%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.40 (dd, 1H), 8.00 – 7.48 (m, 5H), 7.05 (t, 1H), 4.41 (dtt, 1H), 3.96 – 3.48 (m, 6H), 3.23 – 3.00 (m, 4H), 2.64 – 2.39 (m, 4H), 2.13 (dtd, 1H), 1.96 – 1.81 (m, 1H), 1.37 – 1.21 (m, 2H), 1.18 (t, 3H) Example 26 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-(2-hydroxyethyl)benzamide compound 26 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin- 1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

first step: 4-bromo-3-fluoro-N-(2-hydroxyethyl)benzamide 26A 4-bromo-3-fluoro-N-(2-hydroxyethyl)benzamide

Referring to the synthetic method of compound 24B, compound 26A (yellow solid, 2.5 g, yield 82%) was synthesized and isolated.

LC-MS m/z (ESI) = 261.98 [M+1]. Step 2: 4-(2-Fluoro-4-((2-hydroxyethyl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 26B tert-butyl 4-(2-fluoro-4-(( 2-hydroxyethyl)carbamoyl)phenyl) piperazine-1-carboxylate

Referring to the synthesis method of compound 1c , compound 26B (white solid, 2.2 g, yield 83%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, 1H), 7.78 (d, 1H), 7.42 – 7.12 (m, 2H), 5.41 (s, 1H), 3.15 (s, 6H), 2.65 – 2.42 (m, 6H), 1.51 (s, 9H).

LC-MS m/z (ESI) = 394.12 [M+1]. Step 3: 3-fluoro-4-(piperazin-1-yl)-nitrogen-(tetrahydrofuran-3-yl)benzamide 26C 3-fluoro-4-(piperazin-1-yl)-N-(tetrahydrofuran-3- yl)benzamide

Referring to the synthesis method of intermediate 1 , compound 26C (white solid, 1.6 g, yield 83%) was synthesized and isolated.

LC-MS m/z (ESI) = 254.12 [M+1]. Step 4: 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-(2-hydroxyethyl)benzamide compound 26 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin- 1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

Referring to the synthetic method of compound 1 , compound 26 (white solid, 19 mg, yield 42%) was synthesized and isolated.

1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H), 8.17 (d, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.42 – 7.14 (m, 2H), 5.25 ( s, 1H), 4.44 (d, 2H), 3.69 (s, 3H), 3.19 (s, 6H), 2.69 – 2.51 (m, 7H), 1.17 (t, 3H). Example 27 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- Nitrogen-(2-hydroxyethyl)benzamide compound 27 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin- 1-yl)-2-fluoro-N-(2-hydroxyethyl)benzamide

Compound 27 (white solid, 42 mg, yield: 74%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 15.3 Hz, 1H), 4.74 (t, J = 5.4 Hz, 1H), 3.63 (d, J = 4.6 Hz, 2H), 3.47 (t, J = 5.6 Hz, 2H), 3.29 (d, J = 4.8 Hz, 8H), 2.54 (d, J = 8.1 Hz, 4H), 1.18 (t, J = 7.4 Hz , 3H).

LCMS m/s=454.52[M+1]. Example 28 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- N-(2-methoxyethyl)benzamide compound 28 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(2-methoxyethyl)benzamide

Compound 28 (white solid, 42 mg, yield: 74%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.57 (t, J = 9.0 Hz, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 6.77 – 6.71 (m, 1H), 3.64 (s, 2H), 3.46 – 3.34 (m, 6H), 3.28 (d, J = 5.4 Hz, 4H), 3.26 (s, 3H), 2.57 – 2.52 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=468.55[M+1] .Example 29 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- Nitrogen-(1-methylazetidin-3-yl)benzamide compound 29 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide

Compound 29 (white solid, 11 mg, yield: 63%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.59 – 8.50 (m, 2H), 7.80 (s, 1H), 7.76 (s, 1H), 7.64 (td, J = 8.9, 2.8 Hz, 1H), 6.95 – 6.84 (m, 2H), 4.85 – 4.71 (m, 1H), 4.53 – 4.29 (m, 4H), 4.09 (d, J = 40.8 Hz, 4H), 3.22 (s, 4H) , 2.88 (dd, J = 7.4, 4.7 Hz, 3H), 2.60 (s, 4H), 1.19 (t, J = 7.4 Hz, 3H).

LCMS m/s=479.57[M+1] .Example 30 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- Nitrogen-(oxoalk-3-yl)benzamide compound 30 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide

Compound 30 (white solid, 17 mg, yield: 64%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.37 (s, 1H), 8.43 (s, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H) , 6.84 – 6.73 (m, 2H), 4.85 (t, J = 5.6 Hz, 1H), 4.42 – 4.21 (m, 2H), 4.18 (q, J = 7.1, 6.3 Hz, 2H), 3.59 (ddt, J = 10.0, 7.4, 3.3 Hz, 4H), 3.45 (d, J = 15.0 Hz, 2H), 3.11 (qd, J = 7.4, 4.1 Hz, 2H), 2.56 (s, 4H), 1.17 (t, J = 7.4 Hz, 3H).

LCMS m/s=466.53[M+1]. Example 31 N-(2-(dimethylamino)ethyl)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) yl)piperazin-1-yl)-2-fluorobenzamide compound 31 N-(2-(dimethylamino)ethyl)-4-(4-((7-ethyl-6-oxo-5,6-dihydro - 1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide

Compound 31 (white solid, 16 mg, yield: 57%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 5.8 Hz, 1H), 7.82 (d, J = 5.2 Hz , 2H), 7.66 (t, J = 8.8 Hz, 1H), 6.93 – 6.85 (m, 2H), 4.76 (s, 2H), 3.78 (d, J = 6.4 Hz, 2H), 3.52 (d, J = 5.7 Hz, 6H), 3.22 (d, J = 5.4 Hz, 4H), 3.08 (s, 6H), 2.59 (t, J = 7.4 Hz, 2H), 1.18 (d, J = 7.3 Hz, 3H).

LCMS m/s=481.59[M+1] .Example 32 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-fluoro- Nitrogen-(oxoalk-3-yl)benzamide compound 32 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-2-fluoro-N-(oxetan-3-yl)benzamide

Compound 32 (white solid, 68 mg, yield: 72%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 8.06 – 7.99 (m, 1H), 7.75 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 13.5, 6.8 Hz, 1H), 6.89 (dd, J = 12.7, 7.1 Hz, 1H), 3.64 (s, 2H), 3.13 (t, J = 4.8 Hz, 4H), 2.75 (d, J = 4.5 Hz, 3H), 2.54 (d, J = 8.5 Hz, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=442.48[M+1] .Example 33 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2,5- Difluoro-nitrogen-methylbenzamide compound 33 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1- yl)-2,5-difluoro-N-methylbenzamide

Compound 33 (white solid, 57 mg, yield: 64%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.06 – 7.99 (m, 1H), 7.75 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 13.5, 6.8 Hz, 1H), 6.89 (dd, J = 12.7, 7.1 Hz, 1H), 3.64 (s, 2H), 3.13 (t, J = 4.8 Hz, 4H), 2.75 (d, J = 4.5 Hz, 3H), 2.54 (d, J = 8.5 Hz, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=442.48[M+1] .Example 34 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-(2-methoxyethyl)benzamide compound 34 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

Compound 34 (white solid, 36 mg, yield: 68%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.43 (t, J = 5.3 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.66 – 7.58 (m, 3H), 7.05 (t, J = 8.7 Hz, 1H), 3.64 (s, 2H), 3.44-3.38 (m, 4H), 3.25 (s, 3H), 3.16 – 3.08 (m, 4H ), 2.60 – 2.52 (m, 6H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=468.23[M+1] .Example 35 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-((1s,3s)-3-hydroxycyclobutyl)benzamide compound 35 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)piperazin-1-yl)- 3-fluoro-N-((1s,3s)-3-hydroxycyclobutyl)benzamide

Compound 35 (white solid, 41 mg, yield: 65%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.67 – 7.60 (m, 3H), 7.04 (t, J = 8.8 Hz, 1H), 5.10 (d, J = 5.5 Hz, 1H), 3.90 – 3.80 (m, 2H), 3.65 (s, 2H), 3.17-3.11 (m, 4H ), 2.59 – 2.52 (m, 6H), 1.92-1.85 (m, 2H), 1.28 – 1.23 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

19F NMR (377 MHz, DMSO-d6) δ -122.18.

LCMS m/s=480.23[M+1] .Example 36 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-((1r,3r)-3-hydroxycyclobutyl)benzamide compound 36 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)piperazin-1-yl)- 3-fluoro-N-((1r,3r)-3-hydroxycyclobutyl)benzamide

Compound 36 (white solid, 44 mg, yield: 68%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.45 (d, J = 6.8 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.64 -7.60 (m, 3H), 7.05 (t, J = 8.7 Hz, 1H), 5.02 (d, J = 5.3 Hz, 1H), 4.45 – 4.26 (m, 2H), 3.65 (s, 2H), 3.19 – 3.08 (m, 4H), 2.58-2.53 (m, 6H), 2.27-2.21 (m, 2H), 2.16-2.09 m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

LCMS m/s=480.23[M+1] .Example 37 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-(2-methoxyethyl)benzamide compound 37 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

Compound 37 (white solid, 32 mg, yield: 84%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.40 (d, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.65 – 7.60 ( m, 2H), 7.06 (t, 1H), 4.56 (s, 1H), 3.65 (s, 2H), 3.22 (d, 2H), 3.11 (d, 4H), 2.61 – 2.51 (m, 6H), 1.18 (t, 3H), 1.07 (s, 6H).

LCMS m/s=482.57[M+1] .Example 38 (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3 -Fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 38 (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

first step: 7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 38A ethyl 7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine -3-carboxylate

Intermediate 10D (1 g, 2.9 mmol) was added to hydrochloric acid-1,4-dioxane solution (10 mL, 4 mol/L) at room temperature, and reacted at 80 °C for 16 hours. After the reaction was completed Filtration gave intermediate 38A (yellow solid, 700 mg, yield 95%).

LC-MS m/z (ESI) = 253.00 [M+1]. Step 2: 3-chloro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one 38B 3-chloro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

Referring to the synthesis method of compound 10G , intermediate 38B (yellow solid, 500 mg, yield 85%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ 12.50 (dr, 1H), 8.45 (d, 1H), 8.27 (d, 1H), 7.68 (d, 1H), 5.53 (dr, 1H), 4.64 (d, 2H).

LC-MS m/z (ESI) = 211.00 [M+1]. Step 3: 7-(bromomethyl)-3-chloro-1,5-naphthyridin-2(1H)-one 38C 7-(bromomethyl)-3-chloro-1,5-naphthyridin-2(1H)-one

Referring to the synthesis method of compound 10H , intermediate 38C (yellow solid, 400 mg, yield 62%) was obtained.

LC-MS m/z (ESI) = 273.00 [M+1]. Step 4: (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3 -Fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 38 (S)-4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Compound 38 (white solid, 20 mg, yield: 20%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.89 (dr, 1H), 8.46 (d, 1H), 8.41 (d, 1H), 7.80 – 7.48 (m, 3H), 7.44 (s, 1H), 6.79 ( d, 1H), 4.42 (dtt, 1H), 3.96 – 3.50 (m, 6H), 3.25 – 3.01 (m, 4H), 2.64 – 2.39 (m, 2H), 2.12 (dtd, 1H), 1.94 – 1.81 ( m, 1H), 1.38 – 1.22 (m, 2H).

LCMS m/s=486.20 [M+1]. Example 39 4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)3-fluoro-N- (2-hydroxyethyl)benzamide compound 39 4-(4-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1- yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

Compound 39 (white solid, 25 mg, yield: 28%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.47 (d, 1H), 8.40 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.58 (d, 1H), 6.75 (d, 1H), 4.74 (t, 1H), 3.63 (d, 2H), 3.47 (t, 2H), 3.29 – 3.18 (m, 6H), 2.54 – 2.48 (m, 4H).

LCMS m/s=460.20 [M+1]. Example 40 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-3-fluoro- N-methylbenzamide compound 40 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperidin-4-yl)- 3-fluoro-N-methylbenzamide

Compound 40 (white solid, 28 mg, yield: 81%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.46 (d, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.68 – 7.51 (m, 3H), 7.44 ( t, 1H), 3.61 (s, 2H), 2.93-2.82 (m, 3H), 2.77 (d, 3H), 2.56-2.52 (m, 2H), 2.14-2.10 (m, 2H), 1.75-1.72 ( m, 4H), 1.18 (t, 3H).

LCMS m/s=423.21[M+1] .Example 41 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-N-(2-hydroxypropyl)benzamide compound 41 (S)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide

Compound 41 (white solid, 42 mg, yield: 77%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 8.32 (t, 1H), 7.75 (d, 1H), 7.65-7.60 (m, 3H), 7.05 ( t, 1H), 4.73 (d, 1H), 3.80 – 3.72 (m, 1H), 3.65 (s, 2H), 3.18-3.14(m, 2H), 3.12-3.10 (m, 4H), 2.60 – 2.52 ( m, 6H), 1.18 (t, 3H), 1.04 (d, 3H).

LCMS m/s=468.23[M+1] .Example 42 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 3-Fluoro-N-(2-hydroxypropyl)benzamide compound 42 (R)-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(2-hydroxypropyl)benzamide

Compound 42 (white solid, 54 mg, yield: 82%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 8.31 (t, 1H), 7.75 (d, 1H), 7.64-7.60 (m, 3H), 7.05 ( t, 1H), 4.73 (d, 1H), 3.80 – 3.71 (m, 1H), 3.65 (s, 2H), 3.18-3.14 (m, 2H), 3.12 -3.10(m, 4H), 2.60 – 2.52 ( m, 6H), 1.18 (t, 3H), 1.04 (d, 3H).

LCMS m/s=468.23[M+1]. Example 43 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2 -Hydroxyethyl)nicotinamide compound 43 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)- N-(2-hydroxyethyl)nicotinamide

Compound 43 (white solid, 44 mg, yield: 73%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 8.31 (t, 1H), 7.75 (d, 1H), 7.64-7.60 (m, 3H), 7.05 ( t, 1H), 4.73 (d, 1H), 3.80 – 3.71 (m, 1H), 3.65 (s, 2H), 3.18-3.14 (m, 2H), 3.12 -3.10(m, 4H), 2.60 – 2.52 ( m, 6H), 1.18 (t, 3H), 1.04 (d, J = 6.2 Hz, 3H).

LCMS m/s=437.22[M+1]. Example 44 4-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-methylbenzamide compound 44 4-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1 -yl)-N-methylbenzamide

Compound 44 (white solid, 49 mg, yield: 88%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.59–8.25 (m, 2H), 7.86 (d, 1H), 7.76 (d, 2H), 7.66–7.57 (m, 1H), 7.18 (d, 1H), 3.66 (s, 2H), 3.05 (s, 4H), 2.75 (d, 3H), 2.64–2.51 (m, 6H), 1.19 (q, 3H).

LCMS m/s=440.18[M+1] .Example 45 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro- N-((1-hydroxycyclopropyl)methyl)benzamide compound 45 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl )methyl) piperazin-1-yl)-3-fluoro-N-((1-hydroxycyclopropyl)methyl)benzamide

Compound 45 (white solid, 37 mg, yield: 71%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.70 (t, 1H), 8.40 (d, 1H), 7.75 (s, 1H), 7.71 – 7.56 (m, 3H), 7.08 ( t, 1H), 4.37 – 3.98 (m, 5H), 3.65 (s, 2H), 3.23 – 3.05 (m, 4H), 2.62 – 2.51 (m, 4H), 2.46 (t, 2H), 1.42 (s, 2H), 0.94 (t, 3H).

LCMS m/s=480.56[M+1]. Example 46 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro -N-(2-methoxyethyl)benzamide compound 46 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl ) piperazin-1-yl)-3-fluoro-N-(2-methoxyethyl)benzamide

Compound 46 (white solid, 34 mg, yield: 65%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.43 (t, 1H), 8.37 (d, 1H), 7.69 – 7.53 (m, 3H), 7.41 (s, 1H), 7.04 ( t, 1H), 3.62 (s, 2H), 3.41 (dd, 4H), 3.25 (s, 3H), 3.10 (t, 4H), 2.55 (t, 4H), 2.13 (tt, 1H), 0.96 (dt , 2H), 0.86 – 0.72 (m, 2H).

LCMS m/s=480.23[M+1] .Example 47 (R)-4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) -3-Fluoro-N-(tetrahydrofuran-3-yl)benzamide compound 47 (R)-4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin -3-yl)methyl) piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

Compound 47 (white solid, 33 mg, yield: 64%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.41 (t, 1H), 8.37 (dd, 1H), 7.65 – 7.51 (m, 3H), 7.41 (s, 1H), 7.04 ( t, 1H), 4.43 (dtt, 1H), 3.92 – 3.44 (m, 3H), 3.21 – 3.00 (m, 4H), 2.64 – 2.39 (m, 3H), 2.13 (dtd, 1H), 1.96 – 1.81 ( m, 1H), 1.33 – 1.20 (m, 2H), 1.15 (t, 3H).0.95 (dt, 2H), 0.85 – 0.70 (m, 2H).

LCMS m/s=492.23[M+1]. Example 48 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro -N-(2-hydroxyethyl)benzamide compound 48 4-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin -1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

Compound 48 (white solid, 31 mg, yield: 62%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.46 – 8.27 (m, 2H), 7.68 – 7.56 (m, 3H), 7.42 (s, 1H), 7.05 (t, 1H), 4.74 (t, 1H), 3.63 (s, 2H), 3.48 (dd, 2H), 3.29 (d, 2H), 2.56 (t, 4H), 2.20 – 2.07 (m, 2H), 1.23 (s, 3H) , 1.02 – 0.90 (m, 2H), 0.87 – 0.74 (m, 2H).

LCMS m/s=466.22[M+1]. Example 49 (R)-6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(tetrahydrofuran-3-yl)nicotinamide compound 49 (R)-6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl ) piperazin-1-yl)-N-(tetrahydrofuran-3-yl)nicotinamide

Compound 49 (white solid, 41 mg, yield: 65%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.60 (d,1H), 8.40 (d, 1H), 8.28 (d, 1H), 7.97 (dd, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 6.84 (d, 1H), 4.47 – 4.38 (m, 1H), 3.86-3.81 (m, 2H), 3.72-3.66 (m, 1H), 3.63 (s, 2H) , 3.61-3.59 (m, 4H), 3.56-3.52 (m, 1H), 2.59 – 2.52 (m, 2H), 2.49-2.47 (m, 4H), 2.19 – 2.07 (m, 1H), 1.94 – 1.83 ( m, 1H), 1.18 (t, 3H).

LCMS m/s=463.24[M+1] .Example 50 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl Pyrazine-2-methamide compound 50 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-methylpyrazine-2-carboxamide

Compound 50 (white solid, 37 mg, yield: 76%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.59 (d, 1H), 8.40 (d, 1H), 8.34 (d, 1H), 8.26 (d, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 3.70 (t, 4H), 3.65 (s, 2H), 2.77 (d, 3H), 2.58 – 2.51 (m, 6H), 1.18 (t, 3H).

LCMS m/s=408.48[M+1] .Example 51 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5-fluoro- N-methylnicotinamide compound 51 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-5 -fluoro-N-methylnicotinamide

Compound 51 (white solid, 31 mg, yield: 67%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 8.52 – 8.32 (m, 3H), 7.92 – 7.52 (m, 4H), 3.59 (d, 6H), 3.17 (d, 2H), 2.76 (d, 3H), 2.52 (s, 4H), 1.18 (t, 3H).

LCMS m/s=404.49[M+1] .Example 52 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3,5- Difluoro-N-methylbenzamide compound 52 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1- yl)-3,5-difluoro-N-methylbenzamide

Compound 52 (white solid, 50 mg, yield: 32%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.45 (q, 1H), 8.39 (d, H), 7.74 (d, 1H), 7.63 (d, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 3.64 (s, 2H), 3.23 - 3.17 (m, 4H), 2.75 (d, 3H), 2.57 - 2.51 (m, 6H), 1.18 (t, 3H).

LCMS m/s=442.20[M+1] .Example 53 2-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 5-Fluoro-N-methylbenzamide compound 53 2-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl ) piperazin-1-yl)-5-fluoro-N-methylbenzamide

Compound 53 (white solid, 40 mg, yield: 45%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (s, 1H), 8.27 – 8.22 (m, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 7.26 ( d, 1H), 7.03 (d, 1H), 3.65 (s, 2H), 3.11 – 3.05 (m, 4H), 2.72 (d, 3H), 2.63 – 2.52 (m, 6H), 1.18 (t, 3H) .

LCMS m/s=458.20[M+1] .Example 54 2,6-Dichloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1- methyl)-N-methylbenzamide compound 54 2,6-dichloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) methyl) piperazin-1-yl)-N-methylbenzamide

Compound 54 (white solid, 15 mg, yield: 14%) was obtained according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.39 (d, 1H), 8.37 – 8.31 (m, 1H), 7.75 (s, 1H), 7.61 (d, 1H), 6.96 ( s, 2H), 3.63 (s, 2H), 3.27 – 3.21 (m, 4H), 2.71 (d, 3H), 2.58 – 2.51 (m, 6H), 1.18 (t, 3H).

LCMS m/s=474.10[M+1] .Example 55 (R) -3-Chloro-4-(4-((7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)-N-(tetrahydrofuran-3-yl)benzamide compound 55 (R)-3-chloro-4-(4-((7-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-(tetrahydrofuran-3-yl)benzamide

Compound 55 (white solid, 36 mg, yield: 67%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.50 (d, 1H), 8.40 (d, 1H), 7.93 (d, 1H), 7.85 – 7.76 (m, 2H), 7.62 ( d, 1H), 7.18 (d, 1H), 4.48 – 4.36 (m, 1H), 3.87 – 3.79 (m, 2H), 3.75 – 3.63 (m, 3H), 3.56 (dd, 1H), 3.06 (s, 4H), 2.58 (s, 4H), 2.13 (d, 3H), 2.09 (d, 1H), 1.94 – 1.85 (m, 1H).

LCMS m/s=482.98[M+1] .Example 56 3-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide compound 56 3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1 ,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide

Compound 56 (white solid, 30 mg, yield: 62%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.55 – 8.30 (m, 2H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.75 (s, 1H), 7.62 ( s, 1H), 7.19 (d, 1H), 5.27 (d, 1H), 4.18 (d, 2H), 3.98 (dd, 1H), 3.89 (dd, 1H), 3.66 (s, 2H), 3.61 (dd , 1H), 3.52 (dd, 1H), 3.06 (s, 4H), 2.58 - 2.50 (m, 6H), 1.18 (t, 3H).

LCMS m/s=512.21[M+1] .Example 57 3-Chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide compound 57 3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1 ,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)benzamide

Compound 57 (white solid, 34 mg, yield: 71%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.56 – 8.31 (m, 2H), 7.91 (d, 1H), 7.80 (dd, 1H), 7.76 (s, 1H), 7.61 ( s, 1H), 7.15 (d, 1H), 4.18 (d, 2H), 3.98 (dd, 1H), 3.89 (dd, 1H), 3.66 (s, 2H), 3.61 (dd, 1H), 3.52 (dd , 1H), 3.06 (s, 4H), 2.58 - 2.50 (m, 6H), 1.39 (s, 3H) 1.18 (t, 3H).

LCMS m/s=510.22[M+1] .Example 58 N-(3-oxazolecyclo[3.1.0]hexan-6-yl)-3-chloro-4-(4-((7-ethyl-6-oxo-5,6-dihydro-1, 5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzamide compound 58 N-(3-oxabicyclo[3.1.0]hexan-6-yl)-3-chloro-4-( 4-((7-ethyl-6-oxo- 5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 58 (white solid, 30 mg, yield: 58%) was prepared according to the method of compound 1 .

1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.50 – 8.37 (m, 2H), 7.86 (d, 1H), 7.81 – 7.70 (m, 2H), 7.62 (s, 1H), 7.19 (d, 1H), 3.85 (d, 2H), 3.72 – 3.52 (m, 4H), 3.06 (s, 4H), 2.69 – 2.53 (m, 7H), 1.90 – 1.83 (m, 2H), 1.18 ( t, 3H).

LCMS m/s=508.20[M+1]. Biological experiments 1. PARP1/PARP2 trapping experimental operations:

1.1 PARP1 trapping experiment:

(1) Use buffer to prepare 4×PARP1 (purchased from BPS Bioscience, Cat. No.: 80501) and Mab anti GST-Tb (purchased from cisbio, Cat. No.: 61GSTTLA) ) mixture, add 4 μL/well of the mixture to a 384-well plate (purchased from Greiner Company, product number: 784075);

(2) Use buffer to prepare 4×DSB DNA probe-1 (purchased from Generay), and add 4 μL/well to the 384-well plate;

(3) Add 4 μL/well inhibitor to the 384-well plate (initial concentration is 10 μM, dilute 10 concentrations at a 1:5 ratio), and incubate at room temperature for 1 hour; (4) Use buffer to prepare 4×NAD (purchased from Sigma Aldrich (Sigma Company), Catalog No.: 10127965001), add 4 μL/well to the 384-well plate, and incubate at room temperature for 10 minutes; (5) The results are detected by TR-FRET, and the curve is fitted using GraphPad 5.0, and the IC50 is calculated. calculate.

1.2 PARP2 trapping experiment:

(1) Use buffer to prepare a 4×PARP2 (purchased from BPS Bioscience Company, Catalog No.: 80502) and Mab anti GST-Tb (purchased from cisbio Company, Catalog No.: 61GSTTLA) mixture, and add it to a 384-well plate (purchased from Greiner Company, (Cat. No.: 784075), add 4 μL of this mixture; (2) Use buffer to prepare 4×PARP2 probe2 (purchased from Generay), and add 4 μL/well to the 384-well plate; (3) Add 4 μL/well to the 384-well plate. Well inhibition (initial concentration is 10 μM, diluted to 10 concentrations at a ratio of 1:5), incubate at room temperature for 45 minutes; (4) Prepare 4×NAD with buffer (purchased from Sigma, Cat. No.: 10127965001), and add to 384-well plate Add 4 μL/well and incubate at room temperature for 10 min; (5) The results are detected by TR-FRET, use GraphPad 5.0 to fit the curve, and calculate IC50.

注：對照例1為J. Med. Chem(2021), 64(19)14498–14512的化合物 25，對照例按照其製備方法製備得到。

Note: Comparative Example 1 is compound 25 of J. Med. Chem (2021), 64(19)14498–14512. The comparative example was prepared according to its preparation method.

Conclusion: The compound of the present invention has significant inhibitory activity against PARP1 trapping, and has good selectivity relative to PARP2 trapping. 2. PARP1 and PARP2 activity inhibition test

The inhibitory activity of the compound on PARP1 and PARP2 was detected by PARP1 Chemiluminescent assay (purchased from BPS Bioscience Company, product number: 80551) and PARP2 Chemiluminescent assay (purchased from BPS Bioscience Company, product number: 80552) respectively. The results were quantified using chemiluminescence. The specific experimental protocol is as follows:

(1) Coat the 96-well plate overnight with 1×histone mixture (50 μL/well);

(2) Coating solution; add Blocking buffer 3 (200 μL) to each well and incubate at room temperature for 90 minutes;

(3) Blocking solution, wash twice with PBST; add 25 μL master mixture (including 2.5 μL 10×PARP buffer, 2.5 μL 10×PARP Assay mixture, 5 μL activated DNA, 15 μL ddH2O), 5 μL inhibitor (inhibitor The initial concentration is 10 μM, diluted to 8 concentrations at a 1:5 ratio), 20 μL enzyme (2 ng/μL); incubate at room temperature for 1 h;

(4) Discard the liquid and wash twice with PBST; add 50 μL of Streptavidin-HRP (diluted 50 times in Blocking buffer 3); incubate at room temperature for 30 minutes;

(5) Discard the liquid and wash 3 times with PBST; add 100 μL ELISA ECL Substrate A/B mix (50 μL each);

(6) For the microplate reader test results, use GraphPad Prism 8 to calculate IC50.

The results show that the compound of the present invention has significant inhibitory activity on PARP1 and has good selectivity relative to PARP2. 3. DLD1 BRCA2-/- cell proliferation inhibition experiment

DLD-1 BRCA2-/- cells (purchased from Horizon Discovery Ltd.) were cultured in 1640 (10% FBS, 1% PS) medium, and the culture conditions were 37°C and 5% CO2. When the cells grow to the logarithmic growth phase, resuspend the cells and dilute them to 15,000 cells/mL with 1640 medium. Use an Echo pipette to add 40 nL of the compound to be tested (final concentrations are 10 μM, 2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, respectively) into each well of a 384-well white plate (PerkinElmer). 0.0256 nM, 0.00512 nM); each concentration gradient was repeated twice, and control group 1 (0.1% DMSO added) and control group 2 (blank medium) were set. Then, 40 μL (600 cells) of cell suspension was added to each well of a 384-well white plate (PerkinElmer) (no cells were added to control group 2).

Place the above 384-well plate in a CO2 incubator (37°C, 5% CO2) and continue culturing for 7 days. Take out the 384-well plate and place it at room temperature for 30 minutes. Add 20 μL of Celltiter Glo detection solution to each well, shake with a plate shaker for 2 minutes, and leave at room temperature for 30 minutes. Chemiluminescence values were measured with a microplate reader (PerkinElmer; EnVision).

GraphPad Prism 8.0 performed curve fitting and IC50 calculations. For the microplate reader test results, IC50 was calculated using GraphPad Prism 8. Compound number DLD1 BRCA2-/- cells IC ₅₀ (nM) Compound 1 7.00 Compound 2 11.00 Compound 8 5.88 Compound 9 10.43 Compound 10 10.00 Compound 11 14.73 Compound 22 33.80 Compound 24 6.84 Compound 25 6.72 Compound 26 22.00 Compound 27 24.00 Compound 28 8.30 Compound 35 19.00 Compound 36 22.18

The results show that the compound of the present invention has a significant inhibitory effect on the proliferation of DLD1 BRCA2-/- cells. 3. MDA-MB-436 cell proliferation inhibition experiment

MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS, 1% PS) at 37 °C and 5% CO2. When the cells grow to the logarithmic growth phase, resuspend in DMEM medium and dilute the cells to 1500 cells/ml. Add 40 μL of the compound to be tested into each well of the 384-well plate (final concentrations are 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM respectively); Make 2 repetitions of each concentration gradient, and set up control group 1 (adding 0.1% DMSO) and control group 2 (blank culture medium). Then 40 μL of cell suspension was added to the 384-well plate (control group 2 did not add cells).

Place the above 384-well plate in an incubator (37 °C, 5% CO2) for continuous culture for 7 days, then take out the 384-well plate and place it at room temperature for 30 minutes. Add 30 µL Celltiter Glo assay kit detection solution to each well, shake with a shaker for 3 minutes, and leave at room temperature for 30 minutes. Chemiluminescence values were measured with a microplate reader (PerkinElmer; EnVision).

The detection results were analyzed using GraphPad Prism 8 for curve fitting and IC50 calculation. Compound number MDA-MB-436 cells IC ₅₀ (nM) Comparative example 2 ＞10000.00 Compound 2 41.31 Compound 7 8.76 Compound 23 5.92 Compound 24 9.29 Compound 25 26.88 Compound 26 27.44 Compound 27 46.9 Compound 34 30.01 Compound 35 18.00 Compound 36 21.35 Compound 41 44.57 Compound 42 42.98 Compound 44 2.43 Compound 45 35.81 Compound 56 13.39 Compound 57 28.98 Compound 58 2.46

Comparative Example 2 was prepared according to the synthesis method of compound 62 of patent WO200905337.

The results show that the compound of the present invention has a significant inhibitory effect on the proliferation of MDA-MB-436 cells.

The specification of the present invention describes specific embodiments in detail. Those skilled in the art should realize that the above embodiments are illustrative and cannot be understood as limitations of the present invention. Under the premise, by making several improvements and modifications to the present invention, the technical solutions obtained through these improvements and modifications also fall within the protection scope of the claims of the present invention.

without

without

Claims (9)

A compound or a stereoisomer thereof, said compound being selected from the group consisting of compounds represented by general formula (II) or a stereoisomer thereof:

Wherein: R _a0 is selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl or C _2-6 alkenyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, or C _2-6 alkenyl is optionally further substituted by 1 or more substituents selected from halogen or C _1-6 alkyl; R _a1 Selected from H or halogen; Z ₁ and Z ₂ are each independently CR _L ; R _L is H; L is selected from -NH-, -CO- or -(CR ₁ R ₂ ) _n -; R ₁ and R ₂ are each independently is independently H; B is a 4- to 12-membered heterocyclic ring, and the 4- to 12-membered heterocyclic ring is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered spirocyclic ring, or a 4- to 12-membered bridged ring, and the 4- to 12-membered heterocyclic ring is The 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b ; R _b is selected from H, hydroxyl, cyano or C _{1 -6} alkyl, the C _1-6 alkyl is optionally further substituted by one or more substituents selected from hydroxyl or cyano; C is

_{; X 1 ,} X _{2 , and} From H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy group, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further selected from 1 or more D, halogen, hydroxyl, NR _c1 R _c2 , C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl substituent substitution; R _c1 and R _c2 are each independently selected from H or C _1-6 alkyl; n is 1; the general formula (II ) compound is optionally further substituted by one or more deuterium atoms. The compound according to claim 1 or its stereoisomer: wherein: R _a0 is selected from C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl, and the C _1-6 Alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl is optionally further substituted by one or more substituents selected from halogen or C _1-6 alkyl; R _L is H; L is - (CR ₁ R ₂ ) _n -; R ₁ and R ₂ are each independently H; B is a 4- to 12-membered heterocycle, and the 4- to 12-membered heterocycle is selected from a 4- to 12-membered monocyclic ring, a 5- to 12-membered heterocycle A spiro ring or a 4- to 12-membered bridged ring. The 4- to 12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S, and may be optionally further substituted by 1 or more R _b Substituted; R _b is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from cyano; C is

_{; X 1 ,} X _{2 , and} group or C _1-6 alkyl; R _c is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further selected from 1 or more D, halogen, hydroxyl, NR _c1 R _c2 , C _1-6 alkyl or C _3-8 heterocycloalkyl substituents are substituted; R _c1 and R _c2 are each independently selected from H or C _1-6 alkyl; n is 1; the compound Optionally further substituted by one or more deuterium atoms. The compound according to claim 1 or 2 or its stereoisomer: wherein: R _a0 is selected from C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl, and the C _{1 -6} alkyl, C _3-8 cycloalkyl or C _2-6 alkenyl is optionally further substituted by 1 or more substituents selected from halogen or C _1-6 alkyl; L is -(CR ₁ R ₂ ) _n -; R ₁ and R ₂ are each independently H; B is a 4 to 12 membered heterocyclic ring, and the 4 to 12 membered heterocyclic ring is selected from a 4 to 12 membered monocyclic ring, a 5 to 12 membered spirocyclic ring, or _{R b} is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from cyano; C is

_{; X 1 ,} X _{2 , and} , cyano or C _1-6 alkyl; R _c is selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, the C _1-6 alkyl or C _3-8 cycloalkyl is optional is further substituted by 1 or more substituents selected from D, halogen or C _1-6 alkyl; n is 1; the compound is optionally further substituted by 1 or more deuterium atoms. The compound according to claim 1 or its stereoisomer, said compound is selected from the group consisting of compounds represented by general formula (III) or its stereoisomer:

Ra ₂ is C _1-6 alkyl or C _3-8 cycloalkyl, and the C _1-6 alkyl is optionally further substituted by one or more substituents selected from halogen; R _d is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl is optionally further substituted by 1 or more substituents selected from D, halogen, hydroxyl or C _1-6 alkyl; the general formula ( The compounds represented by III) are optionally further substituted by one or more deuterium atoms. The compound according to claim 4 or its stereoisomer, said compound is selected from the group consisting of compounds represented by general formula (IV) or its stereoisomer:

Ra ₃ is C _1-6 alkyl or C _3-8 cycloalkyl; R _e is selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _3-8 heterocycloalkyl optionally It is further substituted by one or more substituents selected from hydroxyl groups; the compound represented by the general formula (IV) is optionally further substituted by one or more deuterium atoms. The compound according to claim 1 or its stereoisomer: wherein: R _a0 is a C _1-6 alkyl group, and the C _1-6 alkyl group is optionally further substituted by one or more halogens. Substituted with a base; L is -(CR ₁ R ₂ ) _n -; R ₁ and R ₂ are each independently H; B is

; C is

; R _b is H or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from cyano; R _c is H or C _1-6 alkyl group; n is 1; m is 0, 1 or 2; the compound is optionally further substituted by one or more deuterium atoms. A compound or a stereoisomer thereof, the compound is selected from:

The compound is optionally further substituted by one or more deuterium atoms. A pharmaceutical composition comprising: (1) the compound described in any one of claims 1 to 7 or its stereoisomer; (2) optionally one or more other active ingredients; and ( 3) Pharmaceutically acceptable carriers and/or excipients. The use of a pharmaceutical composition as described in claim 8 or a compound or a stereoisomer thereof as described in any one of claims 1 to 7 in the preparation of anti-tumor drugs.