HETEROARYL DERIVATIVE PARP INHIBITOR AND USE THEREOF

Abstract

Provided are a compound represented by formula (I), a stereoisomer, pharmaceutically acceptable salt, solvate and eutectic or deuterated material thereof, or a pharmaceutical composition comprising same, and a use thereof as a PARP-1 inhibitor in the preparation of a drug for treating related diseases.

Description

TECHNICAL FIELD

The present invention belongs to the field of drugs, and in particular relates to a small molecule compound having a PARP-1 inhibitory activity, or a stereoisomer, pharmaceutically acceptable salt, solvate and eutectic or deuterated material thereof, and the use thereof in the preparation of a drug for treating related diseases.

BACKGROUND ART

Approximately 5% of breast cancer patients are associated with germline mutations in the BRCA1/2 genes (3% in the BRCA1 gene and 2% in the BRCA2 gene). Most breast cancers caused by BRCA1 mutations are triple-negative breast cancers (70%), while BRCA2 mutations are more likely to cause estrogen receptor-positive breast cancers (70%). The BRCA1/2 genes are tumor suppressor genes and play an important role in DNA damage repair, normal cell growth, etc. Mutations in the genes can inhibit the normal repair ability after DNA damage and cause homologous recombination deficiency (HRD), that is, loss of BRCA function or mutation or loss of function in other homologous recombination-related genes, making repair of DNA double-strand breaks impossible through homologous recombination repair (HRR), eventually leading to cancer.

Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated by DNA damage and breakage. As a molecular sensor of DNA damage, it has the function of identifying and binding to the DNA break location, thereby activating and catalyzing the polyADP ribosylation of the receptor protein and participating in the DNA repair process. PARP plays a key role in the process of DNA single-strand base excision and repair. In HRD tumor cells, DNA double-strand breaks cannot be repaired, and PARP inhibitors block the single-strand repair, resulting in a “synthetic lethal” effect, leading to tumor cell death.

PARP inhibitors have a “trapping” effect on the PARP protein, causing the PARP protein that binds to damaged DNA to be trapped on the DNA, directly causing other DNA repair proteins to be unable to bind, eventually leading to cell death. At present, several PARP inhibitors have been successfully developed, such as olaparib, rucapalib and niraparib. However, adverse reactions limit their ability to be used in combination with chemotherapy drugs. This may be related to the lack of selectivity of marketed PARP inhibitors against the PARP family. These side effects include intestinal toxicity caused by tankyrase inhibition and hematological toxicity caused by PARP-2 inhibition. Therefore, it is of great clinical significance to develop highly selective PARP-1 inhibitors and reduce the toxic and side effects associated with non-selective PARP inhibitors.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide a compound that inhibits PARP-1, or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof, and the medical application thereof. The compound has the advantages of good efficacy, low toxic and side effects, high safety, strong selectivity, good pharmacokinetics, high bioavailability, and no inhibition to CYP enzymes.

The present invention relates to a compound represented by formula (I), (II), (III), (IV), (V), (VI), (II-1) or (II-2), or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof,

wherein X is selected from CR^x, C(R^x)₂, O, N or NR^x;Y is selected from N, C or CH; in some embodiments, Y is selected from N or C; in some embodiments, Y is selected from C;represents a single bond or a double bond;v is selected from 1, 2 or 3; in some embodiments, v is selected from 1 or 2; in some embodiments, v is selected from 1;X¹, X² and X³ are each independently selected from N or CR^x; in some embodiments, X¹ is selected from N, and X² and X³ are selected from CR^x; in some embodiments, X¹, X² and X³ are selected from N; in some embodiments, X¹ is selected from N, X² is selected from N, and X³ is selected from CR^x; in some embodiments, X¹ is selected from N, X² is selected from CR^x, and X³ is selected from N; in some embodiments, X¹, X² and X³ are selected from CR^x; in some embodiments, X¹ is selected from CR^x, and X² and X³ are selected from N; in some embodiments, X¹ is selected from CR^x, X² is selected from N, and X³ is selected from CR^x; in some embodiments, X¹ is selected from CR^x, X² is selected from CR^x, and X³ is selected from N;provided that when represents a double bond, and v is selected from 1, X, X¹, X² and X³ are not all selected from CR^x;X⁴ is selected from O or S; in some embodiments, X⁴ is selected from 0; in some embodiments, X⁴ is selected from S;X⁵ is selected from N or CR^x; in some embodiments, X⁵ is selected from N; in some embodiments, X⁵ is selected from CR^x; in some embodiments, X⁵ is selected from CH;each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl); or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, deuterated C_1-4 alkoxy, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-2 alkyl-O—C_1-2 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl, —(CH₂)_r—C_5-7 bicyclic spiro cycloalkyl, —(CH₂)_r-(4- to 6-membered heterocycloalkyl), or —(CH₂)_r-(7- to 9-membered bicyclic spiro heterocycloalkyl); or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H, D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, halo C_1-2 alkyl, deuterated C_1-2 alkyl, C_1-2 alkoxy, —(CH₂)_r—C_3-4 monocyclic cycloalkyl, —(CH₂)_r—C_5-6 bicyclic spiro cycloalkyl, —(CH₂)_r-(4- to 5-membered heterocycloalkyl), or —(CH₂)_r-(7- to 8-membered bicyclic spiro heterocycloalkyl); or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H, D, F, Cl, cyano, hydroxyl, C_1-2 alkyl, halo C_1-2 alkyl, or deuterated C_1-2 alkyl; or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H, D, C_1-2 alkyl, halo C_1-2 alkyl, or deuterated C_1-2 alkyl; or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H or D, or two R^x on the same carbon atom together form ═O; in some embodiments, each R^x is independently selected from H or D; R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2 or 3 groups selected from D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl or C_1-6 alkoxy; in some embodiments, R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-2 alkyl-O—C_1-2 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl, —(CH₂)_r—C_5-7 bicyclic spiro cycloalkyl, —(CH₂)_r-(4- to 6-membered heterocycloalkyl), or —(CH₂)_r-(6- to 9-membered bicyclic spiro heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1, 2 or 3 groups selected from D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl, or C_1-2 alkoxy; in some embodiments, R¹ is selected from F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, C_1-2 alkoxy, C_2-3 alkenyl, C_1-2 alkyl-O—C_1-2 alkyl, —(CH₂)_r—C_3-4 monocyclic cycloalkyl, —(CH₂)_r—C_5-7 bicyclic spiro cycloalkyl, —(CH₂)_r-(4- to 5-membered heterocycloalkyl), or —(CH₂)_r-(6- to 8-membered bicyclic spiro heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1, 2 or 3 groups selected from D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl, or C_1-2 alkoxy; in some embodiments, R¹ is selected from cyano, C_1-2 alkyl, C_2-3 alkenyl, C_1-2 alkyl-O—C_1-2 alkyl, C_3-4 monocyclic cycloalkyl, or 4- to 5-membered heterocycloalkyl, wherein the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1, 2 or 3 groups selected from D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, or C_1-2 alkoxy; in some embodiments, R¹ is selected from cyano, C_1-2 alkyl, C_2-3 alkenyl, C_1-2 alkyl-O—C_1-2 alkyl, or C_3-4 monocyclic cycloalkyl;each r is independently selected from 0, 1, 2 or 3; in some embodiments, each r is independently selected from 0 or 1; in some embodiments, r is selected from 0;R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl-O—C_1-6 alkyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy or C_1-6 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-5 cycloalkyl or 4- to 5-membered heterocycloalkyl;in some embodiments, R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl-O—C_1-2 alkyl, hydroxy C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, deuterated C_1-4 alkoxy or C_1-4 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-5 cycloalkyl or 4- to 5-membered heterocycloalkyl; in some embodiments, R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl-O—C_1-2 alkyl, hydroxy C_1-2 alkyl, C_1-2 alkoxy, halo C₁₂ alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, deuterated C_1-2 alkoxy or C_1-2 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-4 cycloalkyl or 4-membered heterocycloalkyl; in some embodiments, R² and R³ are each independently selected from H, D, F, hydroxyl, halo C_1-2 alkyl, deuterated C_1-2 alkyl or C_1-2 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-4 cycloalkyl; in some embodiments, R² and R³ are each independently selected from H, D, or C_1-2 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-4 cycloalkyl; in some embodiments, R² and R³ are each independently selected from H, D, or C_1-2 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-4 cycloalkyl; in some embodiments, R² and R³ are each independently selected from H or D;each R⁴ is independently selected from D, halogen, cyano, amino, hydroxyl, —SFS, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl or deuterated C_1-6 alkoxy; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O; in some embodiments, each R⁴ is independently selected from D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O; in some embodiments, each R⁴ is independently selected from D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O; in some embodiments, each R⁴ is independently selected from D, F, Cl, methyl, ethyl, methoxy, ethoxy, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —CH₂D, —CHD₂, —CD₃, —CH₂CH₂D, —CH₂CHD₂, —CH₂CD₃, —CHDCH₂D, —CHDCHD₂, —CHDCD₃, —CD₂CH₂D, —CD₂CHD₂, or —CD₂CD₃; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O; each R⁵ is independently selected from D, halogen, cyano, amino, hydroxyl, —SFS, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl or deuterated C_1-6 alkoxy; in some embodiments, each R⁵ is independently selected from D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy; in some embodiments, each R⁵ is independently selected from D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, each R⁵ is independently selected from D, F, Cl, C_1-2 alkyl, halo C_1-2 alkyl, or deuterated C_1-2 alkyl; in some embodiments, each R⁵ is independently selected from D, F, Cl, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —CH₂D, —CHD₂, —CD₃, —CH₂CH₂D, —CH₂CHD₂, —CH₂CD₃, —CHDCH₂D, —CHDCHD₂, —CHDCD₃, —CD₂CH₂D, —CD₂CHD₂, or —CD₂CD₃;q is selected from 0, 1, 2 or 3; in some embodiments, q is selected from 0, 1 or 2; in some embodiments, q is selected from 0 or 1; in some embodiments, q is selected from 0;p is selected from 0, 1, 2 or 3; in some embodiments, p is selected from 0, 1 or 2; in some embodiments, p is selected from 0 or 1; in some embodiments, p is selected from 0; ring B is 5- to 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 5- to 6-membered partially unsaturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6- to 8-membered saturated bridged heterocycle containing 1-4 nitrogen atoms, 5- to 10-membered saturated fused heterocycle containing 1-4 nitrogen atoms, or 5- to 11-membered saturated spiro heterocycle containing 1-4 nitrogen atoms; in some embodiments, ring B is 5-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 7-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 8-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 8-membered saturated fused heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 9-membered saturated fused heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 10-membered saturated fused heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 7-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 8-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 9-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 10-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, or 11-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms; in some embodiments, ring B is 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 7-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 8-membered saturated bridged heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 7-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, 9-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms, or 11-membered saturated spiro heterocycle containing 1, 2, 3 or 4 nitrogen atoms; in some embodiments, ring B is 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms (i.e., containing 1-5 heteroatoms selected from nitrogen, oxygen or sulfur), 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; in some embodiments, ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; in some embodiments, ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2 or 3 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; in some embodiments,

is selected from or

ring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1-3 substituents selected from R_b; in some embodiments, ring A is selected from 8- to 10-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 8- to 10-membered bicyclic fused aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1, 2 or 3 substituents selected from R_b; in some embodiments, ring A is selected from 8-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 9-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 10-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 8-membered bicyclic fused aromatic ring, 9-membered bicyclic fused aromatic ring, or 10-membered bicyclic fused aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1 substituent selected from R_b; in some embodiments, ring A is selected from 8-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 9-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 10-membered bicyclic fused heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 8-membered bicyclic fused aromatic ring, 9-membered bicyclic fused aromatic ring, or 10-membered bicyclic fused aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1 substituent selected from R_b; in some embodiments,

is selected from

in some embodiments,

is selected from

is selected from

in some embodiments,

is selected from

in some embodiments,

is selected from

in some embodiments,

is selected from

in some embodiments,

is selected from

R^5a is selected from cyano, amino, hydroxyl, —SF₅, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; in some embodiments, R^5a is selected from cyano, amino, hydroxyl, —SF₅, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy; in some embodiments, R^5a is selected from cyano, amino, hydroxyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, R^5a is selected from cyano or deuterated C_1-2 alkyl;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; in some embodiments, R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)R^a1, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, halo C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5-membered monocyclic heteroaryl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, 4-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 5-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 4-membered monocyclic cycloalkyl, 5-membered monocyclic cycloalkyl, or 6-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, methyl, ethyl, methoxy, ethoxy, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —OCHF₂, —OCH₂F, —OCF₃, —OCH₂CH₂F, —OCH₂CHF₂, —OCH₂CF₃, —OCHFCH₂F, —OCHFCHF₂, —OCHFCF₃, —OCF₂CH₂F, —OCF₂CHF₂, —OCF₂CF₃, —CH₂D, —CHD₂, —CD₃, —CH₂CH₂D, —CH₂CHD₂, —CH₂CD₃, —CHDCH₂D, —CHDCHD₂, —CHDCD₃, —CD₂CH₂D, —CD₂CHD₂, —CD₂CD₃, —OCHD₂, —OCH₂D, —OCD₃, —OCH₂CH₂D, —OCH₂CHD₂, —OCH₂CD₃, —OCHDCH₂D, —OCHDCHD₂, —OCHDCD₃, —OCD₂CH₂D, —OCD₂CHD₂, or —OCD₂CD₃; R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; in some embodiments, R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, C_1-2 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)R^a1, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, C_1-2 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, R_b is selected from —C(O)N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, or halo C_1-2 alkyl; in some embodiments, R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)R^a1, ═O, D, halogen, cyano, hydroxyl, amino, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, or —CHFCF₃; R_c is selected from —C(O)R^a2, —NHR^a2, —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; or R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; in some embodiments, R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, halo C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; in some embodiments, R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5-membered monocyclic heteroaryl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms, 4-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 5-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heterocycloalkyl containing 1 or 2 nitrogen, oxygen or sulfur atoms, 4-membered monocyclic cycloalkyl, 5-membered monocyclic cycloalkyl, or 6-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, methyl, ethyl, methoxy, ethoxy, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —OCHF₂, —OCH₂F, —OCF₃, —OCH₂CH₂F, —OCH₂CHF₂, —OCH₂CF₃, —OCHFCH₂F, —OCHFCHF₂, —OCHFCF₃, —OCF₂CH₂F, —OCF₂CHF₂, —OCF₂CF₃, —CH₂D, —CHD₂, —CD₃, —CH₂CH₂D, —CH₂CHD₂, —CH₂CD₃, —CHDCH₂D, —CHDCHD₂, —CHDCD₃, —CD₂CH₂D, —CD₂CHD₂, —CD₂CD₃, —OCHD₂, —OCH₂D, —OCD₃, —OCH₂CH₂D, —OCH₂CHD₂, —OCH₂CD₃, —OCHDCH₂D, —OCHDCHD₂, —OCHDCD₃, —OCD₂CH₂D, —OCD₂CHD₂, or —OCD₂CD₃;each R^a1 is independently selected from H, D, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C_1-6 alkyl; or each R^a1 is independently selected from H, D, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl; in some embodiments, each R^a1 is independently selected from H, D, C_1-4 alkyl, C_3-6 monocyclic cycloalkyl, C_5-11 bicyclic spiro cycloalkyl, C_6-8 bicyclic bridged cycloalkyl, C_7-10 bicyclic fused cycloalkyl, 4- to 6-membered heterocycloalkyl, 6- to 9-membered bicyclic spiro heterocycloalkyl, C_6-8 bicyclic bridged heterocycloalkyl, C_7-10 bicyclic fused heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl; in some embodiments, each R^a1 is independently selected from H, C_1-4 alkyl, C_3-6 monocyclic cycloalkyl, C_5-7 bicyclic spiro cycloalkyl, 4- to 6-membered heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, or C_1-2 alkyl; in some embodiments, each R^a1 is independently selected from H, C_1-4 alkyl, C_3-4 monocyclic cycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, or C_1-2 alkyl; in some embodiments, each R^a1 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl,

methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃;each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, C_1-6 alkyl-O—C_3-6 cycloalkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-6 alkyl, deuterated C_1-6 alkyl or phenyl; in some embodiments, each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, C_1-4 alkyl-O—C_3-4 cycloalkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; in some embodiments, each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, C_1-3 alkyl-O—C_3-4 cycloalkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; in some embodiments, each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-6 alkyl, deuterated C_1-6 alkyl, or phenyl; in some embodiments, each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl; in some embodiments, each R^a2 is independently selected from C_3-6 monocyclic cycloalkyl, C_1-4 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, C_5-11 bicyclic spiro cycloalkyl, C_6-8 bicyclic bridged cycloalkyl, C_7-10 bicyclic fused cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 6- to 9-membered bicyclic spiro heterocycloalkyl, C_6-8 bicyclic bridged heterocycloalkyl, C_7-10 bicyclic fused heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-4 alkyl; in some embodiments, each R^a2 is independently selected from C_3-6 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_5-7 bicyclic spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; in some embodiments, each R^a2 is independently selected from C_3-6 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_5-7 bicyclic spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, deuterium, or C_1-2 alkyl; in some embodiments, each R^a2 is independently selected from C_3-4 monocyclic cycloalkyl, —CH₂—C_3-4 monocyclic cycloalkyl, C₆_₉ spiro cycloalkyl, C_5-8 bridged cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; in some embodiments, each R^a2 is independently selected from C_3-4 monocyclic cycloalkyl, —CH₂—C_3-4 monocyclic cycloalkyl, C₆_₉ spiro cycloalkyl, C₅_8 bridged cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, or C_1-2 alkyl; in some embodiments, each R^a2 is independently selected from cyclopropyl, cyclobutyl,

methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CHFCH₂F, —CHFCHF₂, —CHFCF₃, —CF₂CH₂F, —CF₂CHF₂, —CF₂CF₃, —CH₂CH₂CH₂F, —CH₂CH₂CHF₂, —CH₂CH₂CF₃,

in some embodiments, each R^a2 is independently selected from

in some embodiments, each R^a2 is independently selected from cyclopropyl,

alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl; in some embodiments, two R^a2 together with the nitrogen atom to which they are attached form 4-, 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, or C_1-2 alkyl;unless otherwise specified, the above-mentioned heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen or sulfur; in some embodiments, the heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur; the heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur; the heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.

The present invention provides a compound represented by formula (1), or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof, wherein when represents a single bond, and v is selected from 1, X is selected from NH, CH₂ or C═O.

Specifically, the first technical solution of the present invention provides a compound represented by formula (I), or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof,

wherein X is selected from CR^x, C(R^x)₂, O, N or NR^x;Y is selected from N, C or CH;represents a single bond or a double bond;v is selected from 1, 2 or 3;X¹, X² and X³ are each independently selected from N or CR^x; provided that when represents a double bond, and v is selected from 1, X, X¹, X² and X³ are not all selected from CR^x;X⁴ is selected from O or S;X⁵ is independently selected from N or CR^x;each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl); or two R^x on the same carbon atom together form ═O;R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 groups selected from D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl or C_1-6 alkoxy;each r is independently selected from 0, 1, 2 or 3;R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl-O—C_1-6 alkyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy or C_1-6 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-5 cycloalkyl or 4- to 5-membered heterocycloalkyl;R⁴ is selected from D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl or deuterated C_1-6 alkoxy; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O;R⁵ is selected from D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;q is selected from 0, 1, 2 or 3; p is selected from 0, 1, 2 or 3;ring B is 5- to 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 5- to 6-membered partially unsaturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6- to 8-membered saturated bridged heterocycle containing 1-4 nitrogen atoms, 5- to 10-membered saturated fused heterocycle containing 1-4 nitrogen atoms, or 5- to 11-membered saturated spiro heterocycle containing 1-4 nitrogen atoms;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; orring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1-3 substituents selected from R_b; or

is selected from

R^5a is selected from cyano, amino, hydroxyl, —SFS, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_c is selected from —C(O)R^a2, —NHR^a2, —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy; or R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R_a)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;each R^a1 is independently selected from H, D, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C_1-6 alkyl; or each R^a1 is independently selected from H, D, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl;each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl; or each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-6 alkyl, deuterated C_1-6 alkyl, or phenyl; oreach R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkyl-C_3-12 cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, C_1-6 alkyl-O—C_3-6 cycloalkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-6 alkyl, deuterated C_1-6 alkyl or phenyl;alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl;unless otherwise specified, the above-mentioned heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1-5 heteroatoms selected from nitrogen, oxygen or sulfur.

Specifically, the second technical solution of the present invention provides a compound represented by formula (I), or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof,

wherein X is selected from CR^x, C(R^x)₂, O, N or NR^x;Y is selected from N, C or CH; represents a single bond or a double bond;v is selected from 1, 2 or 3;X¹, X² and X³ are each independently selected from N or CR^x;provided that when represents a double bond, and v is selected from 1, X, X¹, X² and X³ are not all selected from CR^x;X⁴ is selected from O or S;X⁵ is independently selected from N or CR^x;each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl); or two R^x on the same carbon atom together form ═O;R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkyl-O—C_1-6 alkyl, —(CH₂)_r—C_3-2 cycloalkyl or —(CH₂)_r-(3- to 12-membered heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 groups selected from D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl or C_1-6 alkoxy;each r is independently selected from 0, 1, 2 or 3;R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-6 alkyl-O—C_1-6 alkyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, deuterated C_1-6 alkoxy or C_1-6 alkyl; or R² and R³ together with the carbon atom to which they are attached form C_3-5 cycloalkyl or 4- to 5-membered heterocycloalkyl;R⁴ is selected from D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl or deuterated C_1-6 alkoxy; or two R⁴ on the same carbon atom together with the carbon atom to which they are attached form ═O;R⁵ is selected from D, halogen, cyano, amino, hydroxyl, —SF₅, C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;q is selected from 0, 1, 2 or 3; p is selected from 0, 1, 2 or 3;ring B is 5- to 6-membered saturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 5- to 6-membered partially unsaturated monocyclic heterocycloalkane containing 1-2 nitrogen atoms, 6- to 8-membered saturated bridged heterocycle containing 1-4 nitrogen atoms, 5- to 10-membered saturated fused heterocycle containing 1-4 nitrogen atoms, or 5- to 11-membered saturated spiro heterocycle containing 1-4 nitrogen atoms;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; orring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1-3 substituents selected from R_b; or

is selected from

R^5a is selected from cyano, amino, hydroxyl, —SF₅, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;R_c is selected from —C(O)N(R^a2)₂, —NR^a1C(O)OR^a1, —C(O)NHR^a2, —NR^a1C(O)N(R^a1)₂, —NR^a1C(O)R^a1, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-6 alkyl, —N(C_1-6 alkyl)₂, C_1-6 alkyl, halo C_1-6 alkyl, C_1-6 alkoxy, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy;each R^a1 is independently selected from H, D, C_1-6 alkyl, C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl;each R^a2 is independently selected from C_3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-6 alkoxy, C_1-6 alkyl-O—C_1-6 alkyl, halo C_1-6 alkyl, halo C_1-6 alkoxy, deuterated C_1-6 alkyl, or deuterated C_1-6 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl;alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-6 alkyl;unless otherwise specified, the above-mentioned heterocycloalkane, heterocycloalkyl, heteroaryl, or heteroaromatic ring contains 1-5 heteroatoms selected from nitrogen, oxygen or sulfur.

The third technical solution of the present invention relates to the compound represented by formula (I), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, having a structure of formula (II), (III), (IV), (V), or (VI):

wherein X is selected from CR^x or N, provided that X, X¹ and X² are not all selected from CR^x; other groups are consistent with those mentioned above.

The fourth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkyl-O—C_1-4 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl or —(CH₂)_r-(4- to 6-membered monocyclic heterocycloalkyl);

R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkyl-O—C_1-4 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl, —(CH₂)_r—C_5-9 spiro cycloalkyl, —(CH₂)_r-(4- to 6-membered monocyclic heterocycloalkyl) or —(CH₂)_r-(5- to 9-membered spiro heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino, hydroxyl, C_1-3 alkyl or C_1-3 alkoxy;R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl-O—C_1-2 alkyl, hydroxy C_1-3 alkyl, C_1-3 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, deuterated C_1-4 alkoxy or C_1-4 alkyl; or R² and R³ together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl;R⁵ is selected from D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R^5a is selected from cyano, amino, hydroxyl, —SF₅, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; orring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1 substituent selected from R_b;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-4 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, C_3-6 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R_c is selected from —C(O)R^a2, —NHR^a2, —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-4 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy; or R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R_a)₂, —S(O)₂N(R_a)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-4 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl; or each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl; oreach R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; oreach R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, C_1-4 alkyl-O—C_3-4 cycloalkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each r is independently selected from 0, 1 or 2;p is selected from 0, 1 or 2;other groups are consistent with those mentioned above.

The fifth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein each R^x is independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkyl-O—C_1-4 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl or —(CH₂)_r-(4- to 6-membered monocyclic heterocycloalkyl);

R¹ is selected from halogen, nitro, cyano, amino, hydroxyl, —SF₅, C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkyl-O—C_1-4 alkyl, —(CH₂)_r—C_3-6 monocyclic cycloalkyl, —(CH₂)_r—C_5-9 spiro cycloalkyl, —(CH₂)_r-(4- to 6-membered monocyclic heterocycloalkyl) or —(CH₂)_r-(5- to 9-membered spiro heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino, hydroxyl, C_1-3 alkyl or C_1-3 alkoxy;R² and R³ are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C_1-2 alkyl-O—C_1-2 alkyl, hydroxy C_1-3 alkyl, C_1-3 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, deuterated C_1-4 alkoxy or C_1-4 alkyl; or R² and R³ together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl;R⁵ is selected from D, halogen, cyano, amino, hydroxyl, C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R^5a is selected from cyano, amino, hydroxyl, —SF₅, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from R_a; orring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1 substituent selected from R_b;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-4 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, C_3-6 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;R_c is selected from —C(O)N(R^a2)₂, —NR^a1C(O)OR^a1, —C(O)NHR^a2, —NR^a1C(O)N(R^a1)₂, —NR^a1C(O)R^a1, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-4 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-4 alkoxy, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy;each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each r is independently selected from 0, 1 or 2;p is selected from 0, 1 or 2;other groups are consistent with those mentioned above.

The sixth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R^x is independently selected from H or D;R¹ is selected from cyano, C_1-2 alkyl, C_2-3 alkenyl, C_1-2 alkyl-O—C_1-2 alkyl or C_3-4 monocyclic cycloalkyl, wherein the alkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino or hydroxyl;R² and R³ are each independently selected from H or D;R⁵ is selected from D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R^5a is selected from cyano, amino, hydroxyl, —SFS, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, halo C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)R^a1, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, C_3-4 monocyclic cycloalkyl, 4- to 5-membered monocyclic heterocycloalkyl, C_1-2 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_c is selected from —C(O)R^a2, —NHR^a2, —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy; or R_c is selected from —C(O)N(R^a2)₂, —C(O)NHR^a2, NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1R^a2, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R_a)₂, —S(O)₂N(R_a)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl; oreach R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; or each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl; oreach R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, C_1-3 alkyl-O—C_3-4 cycloalkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each r is independently selected from 0 or 1;other groups are consistent with those mentioned above.

The seventh technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R^x is independently selected from H or D;R¹ is selected from cyano, C_1-2 alkyl, C_2-3 alkenyl, C_1-2 alkyl-O—C_1-2 alkyl or C_3-4 monocyclic cycloalkyl, wherein the alkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino or hydroxyl;R² and R³ are each independently selected from H or D;R⁵ is selected from D, F, Cl, cyano, amino, hydroxyl, C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R^5a is selected from cyano, amino, hydroxyl, —SFS, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, halo C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_b is selected from —C(O)N(R^a1)₂, —NR^a1C(O)R^a1, ═O, D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-2 alkyl)₂, C_1-2 alkyl, C_3-4 monocyclic cycloalkyl, 4- to 5-membered monocyclic heterocycloalkyl, C_1-2 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-2 alkyl, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;R_c is selected from —C(O)N(R_a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)R^a1, —NR C(O)N(R^a)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC_1-2 alkyl, —N(C_1-4 alkyl)₂, C_1-4 alkyl, halo C_1-4 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;alternatively, two R^a2 together with the nitrogen atom to which they are attached form 4-, 5- or 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C_1-2 alkyl;each r is independently selected from 0 or 1;other groups are consistent with those mentioned above.

The eighth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

is selected from

is selected from

other groups are consistent with those mentioned above.

The ninth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein ring A is selected from the following groups:

the ring A is optionally further substituted with 1 R_b;other groups are consistent with those mentioned above.

The tenth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

is selected from

is selected from

is selected from

is selected from

is selected from

is selected from

is selected from

other groups are consistent with those mentioned above.

The eleventh technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

is selected from

other groups are consistent with those mentioned above.

The twelfth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

is selected from

is selected from

other groups are consistent with those mentioned above.

The thirteenth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

is selected from

other groups are consistent with those mentioned above.

The fourteenth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein R_a is selected from —C(O)N(R^a1)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂,

each R^a1 is independently selected from H, D, C_1-4 alkyl, C_3-4 monocyclic cycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl;other groups are consistent with those mentioned above.

The fifteenth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein R_c is selected from —C(O)N(R^a2)₂, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂, —C(═S)N(R^a1)₂, —S(O)₂N(R^a1)₂,

each R^a2 is independently selected from H, D, C_3-4 monocyclic cycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, or deuterated C_1-4 alkyl;other groups are consistent with those mentioned above.

The sixteenth technical solution of the present invention relates to the compound represented by formula (I), (II), (III), (IV), (V), or (VI), or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein R_c is selected from —C(O)R^a2, —C(O)N(R^a2)₂, —C(O)NHR^a2, —NR^a1C(O)OR^a1, —NR C(O)R^a1, —NR^a1C(O)N(R^a1)₂, —NHR^a2,

each R^a1 is independently selected from H, C_1-4 alkyl, C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, deuterium, or C_1-2 alkyl; each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; or each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, C_1-2 alkyl-C_3-5 monocyclic cycloalkyl, C_1-3 alkyl-O—C_3-4 cycloalkyl, C_5-9 spiro cycloalkyl, C_5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C_1-4 alkoxy, C_1-2 alkyl-O—C_1-2 alkyl, halo C_1-4 alkyl, halo C_1-4 alkoxy, deuterated C_1-4 alkyl, or deuterated C_1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl, or phenyl; other groups are consistent with those mentioned above.

The seventeenth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, having a structure of formula (VI-1):

wherein ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is further substituted with 1 substituent selected from R_a; orring A is selected from 8-, 9- or 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is optionally further substituted with 1-2 substituents selected from R_b;R⁵ is selected from halogen;R_a is selected from —C(O)N(R^a)₂, —C(O)NHR^a2, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1C(O)OR^a1 or —NR^a1C(O)N(R^a1)₂;R_b is selected from C_1-2 alkyl, halo C_1-2 alkyl or =0;each R^a1 is independently selected from H, C_1-2 alkyl, C_3-5 monocyclic cycloalkyl or 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the cycloalkyl or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, C_1-3 alkyl-O—C_3-4 cycloalkyl, C_1-2 alkyl-C_3-5 cycloalkyl or C_5-9 spiro cycloalkyl, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl or phenyl;p is selected from 0 or 1;other groups are consistent with those mentioned above.

The eighteenth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is further substituted with 1 substituent selected from R_a; further, ring A is selected from furan, pyrrole, thiophene, thiazole, imidazole, oxazole, or

wherein the ring is further substituted with 1 substituent selected from R_a;orring A is selected from 8-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 9-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is optionally further substituted with 1-2 substituents selected from R_b; further, ring A is selected from

wherein the heteroaromatic ring is optionally further substituted with 1 or 2 substituents selected from R_b;further, ring A is selected from

R⁵ is selected from F or Cl;R_a is selected from —C(O)N(R^a1)₂, —C(O)NHR^a2, —NR^a1C(O)R^a1, —NR^a1 C(O)R^a2, —NR^a1C(O)OR^a1 or —NR^a1C(O)N(R^a1)₂;R_b is selected from —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, or =O;each R^a1 is independently selected from H, —CH₃, —CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, or —CH₂CH₃;each R^a2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, azetidinyl, azacyclopentyl, azacyclohexyl, —CH₃—O—CH₃, —CH₃—O—CH₂CH₃, —CH₂CH₃—O—CH₃, —CH₂CH₃—O—CH₂CH₃, —CH₃—O-cyclopropyl, —CH₃—O-cyclobutyl, —CH₂CH₃—O-cyclopropyl, —CH₂CH₃—O-cyclobutyl, —CH₂CH₂CH₃—O-cyclopropyl, —CH₂CH₂CH₃—O-cyclobutyl, —CH₃-cyclopropyl, —CH₃-cyclobutyl, —CH₃— cyclopentyl, —CH₂CH₃-cyclopropyl, —CH₂CH₃-cyclobutyl, —CH₂CH₃-cyclopentyl, a spiro ring formed by a three-membered ring and a three-membered ring, a spiro ring formed by a three-membered ring and a four-membered ring, a spiro ring formed by a three-membered ring and a five-membered ring, a spiro ring formed by a three-membered ring and a six-membered ring, a spiro ring formed by a four-membered ring and a four-membered ring, a spiro ring formed by a four-membered ring and a five-membered ring, a spiro ring formed by a four-membered ring and a six-membered ring, a spiro ring formed by a five-membered ring and a five-membered ring, or a spiro ring formed by a five-membered ring and a six-membered ring, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, or spiro ring is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, —CH₂CH₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;p is selected from 0 or 1;other groups are consistent with those mentioned above.

The nineteenth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein ring A is selected from 8-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 9-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is optionally further substituted with 1-2 substituents selected from R_b;

R⁵ is selected from F or Cl;R_b is selected from —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, or =O;p is selected from 0 or 1;other groups are consistent with those mentioned above.

The twentieth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein ring A is selected from 9-membered bicyclic heteroaromatic ring containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the heteroaromatic ring is optionally further substituted with 1-2 substituents selected from R_b;

R⁵ is selected from F or Cl;R_b is selected from —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, or =0;p is selected from 0 or 1;other groups are consistent with those mentioned above.

The twenty-first technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, having a structure of formula (II-1), (II-2), (II-3), or (II-4):

The twenty-second technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R_c is selected from —C(O)NHR^a2, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂ or 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, wherein the heteroaryl is optionally further substituted with 1-2 groups selected from D, F, Cl, cyano, hydroxyl, amino, C_1-2 alkyl, halo C_1-2 alkyl, C_1-2 alkoxy, halo C_1-2 alkoxy, deuterated C_1-2 alkyl, or deuterated C_1-2 alkoxy;each R⁵ is independently selected from D, F, Cl, cyano, C_1-2 alkyl, halo C_1-2 alkyl or deuterated C_1-2 alkyl;p is selected from 0 or 1;each R^a1 is independently selected from H, C_1-2 alkyl, C_3-5 monocyclic cycloalkyl or 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the cycloalkyl or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 6-membered monocyclic heterocycloalkyl, C_1-2 alkyl-O—C_1-2 alkyl, C_1-3 alkyl-O—C_3-4 cycloalkyl, C_1-2 alkyl-C_3-5 cycloalkyl, C_5-9 spiro cycloalkyl or C_5-9 bridged cycloalkyl, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, deuterated C_1-2 alkyl or phenyl;other groups are consistent with those mentioned above.

The twenty-third technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R_c is selected from —C(O)NHR^a2, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1C(O)OR^a1, —NR^a1C(O)N(R^a1)₂, 5-membered monocyclic heteroaryl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms (such as pyrrolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, or

or 6-membered monocyclic heteroaryl containing 1, 2, 3 or 4 nitrogen, oxygen or sulfur atoms (such as pyridine, pyrimidine, or pyridazine), wherein the heteroaryl is optionally further substituted with 1-2 groups selected from D, F, Cl, cyano, hydroxyl, amino, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, methoxy, ethoxy, —O—CF₃, —O—CHF₂, —O—CH₂F, —O—CH₂CF₃, —O—CH₂CHF₂, —O—CH₂CH₂F, —O—CHFCH₃—, O—CF₂CH₃, O—CF₂CH₂F, O—CF₂CHF₂, O—CF₂CF₃, —O—CHFCF₃—, —O—CHFCHF₂—, O—CHFCH₂F, —O—CCl₃, —O—CHCl₂, —O—CH₂Cl, —O—CH₂CCl₃, —O—CH₂CHCl₂, —O—CH₂CH₂Cl, —O—CHClCH₃—, O—CCl₂CH₃, O—CCl₂CH₂Cl, O—CCl₂CHCl₂, O—CCl₂CCl₃, —O—CHClCCl₃—, —O—CHClCHCl₂—, O—CHClCH₂Cl, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, —CD₂-CD₃, or —O—CD₃, —O—CHD₂, —O—CH₂D, —O—CH₂CD₃, —O—CH₂CHD₂, —O—CH₂CH₂D, —O—CHDCH₃—, —O—CD₂CH₃, —O—CD₂CH₂D, —O—CD₂CHD₂, —O—CD₂CD₃, —O—CHDCD₃-, —O—CHDCHD₂-, or —O—CHDCH₂D;each R⁵ is independently selected from D, F, Cl, cyano, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;p is selected from 0 or 1;each R^a1 is independently selected from H, —CH₃, —CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms (such as pyrrolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, or

or 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, or —CH₂CH₃;each R^a2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms (such as pyrrolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, or

6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, azetidinyl, azacyclopentyl, azacyclohexyl, —CH₃—O—CH₃, —CH₃—O—CH₂CH₃, —CH₂CH₃—O—CH₃, —CH₂CH₃—O—CH₂CH₃, —CH₃—O-cyclopropyl, —CH₃—O-cyclobutyl, —CH₂CH₃—O-cyclopropyl, —CH₂CH₃—O-cyclobutyl, —CH₂CH₂CH₃—O-cyclopropyl, —CH₂CH₂CH₃—O-cyclobutyl, —CH₃-cyclopropyl, —CH₃-cyclobutyl, —CH₃— cyclopentyl, —CH₂CH₃-cyclopropyl, —CH₂CH₃-cyclobutyl, —CH₂CH₃-cyclopentyl, a spiro ring formed by a three-membered ring and a three-membered ring, a spiro ring formed by a three-membered ring and a four-membered ring, a spiro ring formed by a three-membered ring and a five-membered ring, a spiro ring formed by a three-membered ring and a six-membered ring, a spiro ring formed by a four-membered ring and a four-membered ring, a spiro ring formed by a four-membered ring and a five-membered ring, a spiro ring formed by a four-membered ring and a six-membered ring, a spiro ring formed by a five-membered ring and a five-membered ring, a spiro ring formed by a five-membered ring and a six-membered ring, 5-membered bridged cycloalkyl, 6-membered bridged cycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, or 9-membered bridged cycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, spiro ring, or bridged ring is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, —CH₂CH₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;other groups are consistent with those mentioned above.

The twenty-fourth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate,

or pharmaceutically acceptable salt thereof according to the present invention, wherein R_c is selected from —C(O)NHR^a2, —NR^a1C(O)R^a1, —NR^a1C(O)R^a2, —NR^a1C(O)OR^a1, or —NR^a1C(O)N(R^a1)₂; each R⁵ is independently selected from D, F, Cl, cyano, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃, —CHF—CH₃, —CF₂—CH₃, —CHF—CH₂F, —CHF—CHF₂, —CHF—CF₃, —CF₂—CH₂F, —CF₂—CHF₂, —CF₂—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂—CH₂Cl, —CH₂—CHCl₂, —CH₂—CCl₃, —CHCl—CH₃, —CCl₂—CH₃, —CHCl—CH₂Cl, —CHCl—CHCl₂, —CHCl—CCl₃, —CCl₂—CH₂Cl, —CCl₂—CHCl₂, —CCl₂—CCl₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;p is selected from 0 or 1; in some embodiments, p is selected from 0;each R^a1 is independently selected from H, —CH₃, —CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, or —CH₂CH₃;each R^a2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, azetidinyl, azacyclopentyl, azacyclohexyl, —CH₃—O—CH₃, —CH₃—O—CH₂CH₃, —CH₂CH₃—O—CH₃, —CH₂CH₃—O—CH₂CH₃, —CH₃—O-cyclopropyl, —CH₃—O-cyclobutyl, —CH₂CH₃—O-cyclopropyl, —CH₂CH₃—O-cyclobutyl, —CH₂CH₂CH₃—O-cyclopropyl, —CH₂CH₂CH₃—O-cyclobutyl, —CH₃-cyclopropyl, —CH₃-cyclobutyl, —CH₃— cyclopentyl, —CH₂CH₃-cyclopropyl, —CH₂CH₃-cyclobutyl, —CH₂CH₃-cyclopentyl, a spiro ring formed by a three-membered ring and a three-membered ring, a spiro ring formed by a three-membered ring and a four-membered ring, a spiro ring formed by a three-membered ring and a five-membered ring, a spiro ring formed by a three-membered ring and a six-membered ring, a spiro ring formed by a four-membered ring and a four-membered ring, a spiro ring formed by a four-membered ring and a five-membered ring, a spiro ring formed by a four-membered ring and a six-membered ring, a spiro ring formed by a five-membered ring and a five-membered ring, a spiro ring formed by a five-membered ring and a six-membered ring, 5-membered bridged cycloalkyl, 6-membered bridged cycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, or 9-membered bridged cycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, spiro ring, or bridged ring is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, —CH₂CH₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;other groups are consistent with those mentioned above.

The twenty-fifth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, having a structure of formula (II-1) or (II-2):

other groups are consistent with those mentioned above.

The twenty-sixth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R_c is selected from —C(O)NHR^a2, —NR^a1C(O)R^a1, or —NR^a1C(O)R^a2;each R^a1 is independently selected from H, C_1-2 alkyl, C_3-5 monocyclic cycloalkyl or 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the cycloalkyl or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C_1-2 alkyl;each R^a2 is independently selected from C_3-5 monocyclic cycloalkyl or 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the cycloalkyl or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C_1-2 alkyl, or deuterated C_1-2 alkyl;other groups are consistent with those mentioned above.

The twenty-seventh technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein

R_c is selected from —C(O)NHR^a2, —NR^a1C(O)R^a1, or —NR^a1C(O)R^a2;each R^a1 is independently selected from H, —CH₃, —CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, or —CH₂CH₃;each R^a2 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 5-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, or 6-membered monocyclic heteroaryl containing 1, 2, 3, 4 or 5 nitrogen, oxygen or sulfur atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or heteroaryl is optionally substituted with 1, 2 or 3 substituents selected from F, Cl, deuterium, —CH₃, —CH₂CH₃, —CH₂D, —CHD₂, —CD₃, —CH₂—CH₂D, —CH₂—CHD₂, —CH₂—CD₃, —CHD-CH₃, —CD₂-CH₃, —CHD-CH₂D, —CHD-CHD₂, —CHD-CD₃, —CD₂-CH₂D, —CD₂-CHD₂, or —CD₂-CD₃;other groups are consistent with those mentioned above.

The twenty-eighth technical solution of the present invention relates to the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, wherein the compound is selected from one of the following structures:

Secondly, the present invention also provides a pharmaceutical composition, comprising the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to any one of the preceding first to twenty-eighth technical solutions, and a pharmaceutically acceptable excipient and/or carrier.

Further, the present invention also provides the use of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the preceding embodiments in the preparation of a drug for treating a PARP-1-mediated disease.

Further, the PARP-1-mediated disease includes, but is not limited to cancer.

Further, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, or pancreatic cancer.

The present invention also provides a pharmaceutical composition or pharmaceutical preparation, comprising 1-1440 mg of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to any one of the preceding first to twenty-eighth technical solutions, and a pharmaceutically acceptable excipient and/or carrier.

The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to any one of the preceding first to twenty-eighth technical solutions, and a pharmaceutically acceptable excipient and/or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg; the disease is preferably cancer; and further, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, or pancreatic cancer.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof according to the present invention, and a pharmaceutically acceptable excipient. The pharmaceutical composition can be in a unit preparation form (the amount of the drug substance in the unit preparation is also referred to as the “preparation strength”).

The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof or the pharmaceutical composition according to the present invention. In some embodiments, the mammal according to the present invention comprises humans.

The term “effective amount” or “therapeutically effective amount” according to the present application refers to a sufficient amount of the compound disclosed in the present application that is administered to ameliorate, to some extent, one or more symptoms of a disease or condition (such as cancer) being treated. In some embodiments, the outcome is the reduction and/or remission of signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an “effective amount” in terms of the therapeutic use is an amount of the composition comprising the compound disclosed in the present application that is required to provide clinically significant reduction of the symptoms of the disease. Examples of the therapeutically effective amount include, but are not limited to 1-1440 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg; 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, or 100-200 mg.

In some embodiments, the pharmaceutical composition comprises the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof according to the present invention in an amount including but not limited to 1-1440 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1440 mg.

The present invention also provides a method for treating a disease in a mammal, comprising administering to an individual a therapeutically effective amount of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable excipient and/or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg; the disease is preferably cancer; and further, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, or pancreatic cancer.

The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a drug, i.e., the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable excipient and/or carrier in a daily dose of 1-1440 mg/day, wherein the daily dose can be a single dose or divided doses; in some embodiments, the daily dose includes, but is not limited to 10-1440 mg/day, 20-1440 mg/day, 25-1440 mg/day, 50-1440 mg/day, 75-1440 mg/day, 100-1440 mg/day, 200-1440 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100-1000 mg/day, 200-1000 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, or 200-400 mg/day; in some embodiments, the daily dose includes, but is not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 1200 mg/day, 1400 mg/day, or 1440 mg/day.

The present invention relates to a kit, wherein the kit can comprise a composition in the form of a single dose or multiple doses and comprises the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof according to the present invention, and the amount of the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof according to the present invention is identical to the amount of same in the above-mentioned pharmaceutical composition.

In the present invention, the amount of the compound, or the stereoisomer, deuterated material, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof according to the present invention is calculated in the form of a free base in each case.

Synthetic Route

Patent document WO 2021013735 A1 introduces a method for preparing a PARP-1 inhibitor, and those skilled in the art would have been able to prepare the compounds of the present invention by means of combining the document and known organic synthesis techniques, wherein the starting materials used therein are commercially available chemicals and (or) compounds described in chemical documents. “Commercially available chemicals” are obtained from regular commercial sources, and suppliers include: Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., PharmaBlock Sciences (Nanjing), Inc., WuXi Apptec Co., Ltd., J&K Scientific Co., Ltd., etc.

References and monographs in the art introduce in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation method for reference. The references and monographs include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups”, John Wiley & Sons, in 73 volumes.

Specific and similar reactants can be selectively identified by the indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, wherein the indexes are available in most public libraries or university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, wherein many of standard chemical supply plants (for example, those listed above) provide custom synthesis services. Reference document for the preparation and selection of the pharmaceutically acceptable salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Term

Unless otherwise specified, the terms of the present invention have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen and halogen involved in the groups and compounds of the present invention all comprise isotopes thereof, and are optionally further substituted with one or more of the corresponding isotopes thereof, wherein the isotopes of carbon comprise ¹²C, ¹³C and ¹⁴C; the isotopes of hydrogen comprise protium (H), deuterium (deuterium, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen); the isotopes of oxygen comprise ¹⁶O, ¹⁷O and ¹⁸O; the isotopes of sulfur comprise ³²S, ³³S, ³⁴S and ³⁶S; the isotopes of nitrogen comprise 4N and ¹⁵N; the isotope of fluorine comprises ¹⁹F; the isotopes of chlorine comprise ³⁵Cl and ³⁷Cl; and the isotopes of bromine comprise ⁹Br and ⁸¹Br.

The term “halogen” herein refers to F, Cl, Br, I, or isotopes thereof.

The term “halo” or “substituted with halogen” refers to being substituted with one or more groups selected from F, Cl, Br, I, or isotopes thereof, wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Generally, the circumstances of being substituted with 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen are included.

The term “deuterium” refers to the isotope deuterium of hydrogen (H).

The term “deuterated” or “deuterated material” refers to the case where a hydrogen atom on a group, such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl and alkynyl is substituted with at least one deuterium atom, wherein the upper limit of the number of deuterium substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of deuterium substituents is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.

Group “C_x-y” refers to a group comprising x to y carbon atoms, for example, “C_1-6 alkyl” refers to alkyl comprising 1-6 carbon atoms.

The term “alkyl” refers to a monovalent straight or branched saturated aliphatic hydrocarbon group, usually an alkyl group with 1 to 20 carbon atoms, or an alkyl group with 1 to 8 carbon atoms, or an alkyl group with 1 to 6 carbon atoms, or an alkyl group with 1 to 4 carbon atoms, such as “C_1-6 alkyl”, “C_1-5 alkyl”, “C_1-4 alkyl”, “C_1-3 alkyl”, “C_1-2 alkyl”, “C_2-6 alkyl”, “C_2-5 alkyl”, “C_2-4 alkyl”, “C_2-3 alkyl”, “C_3-6 alkyl”, “C_3-5 alkyl”, “C_3-4 alkyl”, “C_4-6 alkyl”, “C_4-5 alkyl”, and “C_5-6 alkyl”. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The alkyl can be further substituted with any substituent.

The term “alkylene” refers to a bivalent straight or branched saturated alkyl. Examples of alkylene include, but are not limited to, methylene, ethylidene, etc. The alkylene can be optionally further substituted with a substituent.

The term “haloalkyl” refers to an alkyl group in which one or more hydrogens are substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the alkyl group. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit. Generally, the alkyl group is substituted with 1-5 halogen, 1-3 halogen, 1-2 halogen or 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Specific examples include, but are not limited to, —CF₃, —CH₂Cl, —CH₂CF₃, —CCl₂, CF₃, etc.

The term “alkoxy” or “alkyloxy” refers to —O-alkyl, such as —O—C_1-8 alkyl, —O—C_1-6 alkyl, —O—C_1-4 alkyl or —O—C_1-2 alkyl. Non-limiting and specific examples of alkoxy or alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy, cyclobutoxy, etc. The alkoxy may be optionally substituted with a substituent.

The term “haloalkoxy” refers to —O-haloalkyl, such as —O-halo C_1-8 alkyl, —O-halo C_1-6 alkyl, —O-halo C_1-4 alkyl or —O-halo C_1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Non-limiting examples of haloalkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

The term “alkenyl” refers to a straight or branched hydrocarbon group comprising at least one carbon-carbon double bond (C=C) and generally comprises 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and more further such as 2 to 4 carbon atoms. Examples of alkenyl include, but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; and the alkenyl may further be optionally substituted with a substituent.

The term “alkenylene” refers to a straight or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, the alkynylene contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples of alkynylene include ethynylene, and the alkenylene may be optionally substituted with a substituent.

The term “alkynyl” refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C) and generally comprises 2 to 18 carbon atoms; further, alkynyl comprises 2 to 8 carbon atoms; further, alkynyl comprises 2 to 6 carbon atoms, and more further, alkynyl comprises 2 to 4 carbon atoms. Examples of alkynyl include, but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, etc.; and the alkynyl may be optionally substituted with a substituent.

The term “alkynylene” refers to a straight or branched, divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C) and generally comprises 2-6 carbon atoms, and further comprises 2-4 carbon atoms. Non-limiting examples of alkynylene include ethynylene, propynylene, and butynylene, and the alkynylene may be optionally substituted with a substituent.

The term “cycloalkyl” refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. The cycloalkyl may be monocyclic, bicyclic or polycyclic; the bicyclic or polycyclic cycloalkyl may be in the form of a fused ring, a spiro ring, a bridged ring or a combination thereof, and may comprise one or more aromatic rings, but the ring system is non-aromatic as a whole; and the connection site is on a non-aromatic ring. Generally, the cycloalkyl contains 3 to 20 carbon atoms; further, the cycloalkyl contains 3-8 carbon atoms; and still further, the cycloalkyl contains 3-6 carbon atoms; when the cycloalkyl is monocyclic cycloalkyl, the cycloalkyl contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when the cycloalkyl is bicyclic or polycyclic cycloalkyl, the cycloalkyl contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl,

etc., and the cycloalkyl may be optionally substituted with a substituent.

The term “cycloalkylene” refers to a divalent group of cycloalkyl.

The term “aryl” refers to a substituted or unsubstituted aromatic 6- to 15-membered carbocycle, and includes monocyclic aryl and fused aryl. Aryl is preferably a 6- to 10-membered aromatic ring, further preferably a 6- to 9-membered aromatic ring, and further preferably a 6- to 8-membered aromatic ring. Aryl ring can be fused to an aryl ring and a non-aryl ring (such as a heteroaryl, heterocycloalkyl, or cycloalkyl ring), wherein the aryl ring is the connection site. The “x- to y-membered aryl” means that the aryl has a total number of ring atoms of x to y, and can be a phenyl fused non-aromatic ring in which the aromatic ring is the connection site. For example, “7- to 12-membered aryl” represents that the aryl, as the connection site, has a total number of ring atoms of 7-12, e.g., benzocyclobutyl and benzocyclopentyl. Non-limiting examples of aryl include phenyl, naphthyl, anthryl, phenanthryl and

and the aryl may be optionally further substituted with any substituent.

The term “heterocycloalkyl” refers to a saturated or partially unsaturated, non-aromatic carbocycle comprising 1, 2, 3, 4 or 5 heteroatoms selected from N, S, O, P or Si. The heterocycloalkyl may be monocyclic, bicyclic or polycyclic; the bicyclic or polycyclic heterocycloalkyl may be in the form of a bridged ring, a fused ring, a spiro ring or a combination thereof, and may comprise one or more aromatic rings or heteroaromatic rings, but the ring system is non-aromatic as a whole; and the connecting site is on a non-aromatic ring. Usually, the heterocycloalkyl is a 3-20-membered ring. When the heterocycloalkyl is monocyclic heterocycloalkyl, the heterocycloalkyl is usually a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring; when the heterocycloalkyl is bicyclic or polycyclic heterocycloalkyl, the heterocycloalkyl is usually a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. The heteroatoms N, S and P include their oxidation states C═O, N—O, S═O, S(═O)₂, P═O, and P(═O)₂. When heterocycloalkyl is a bicyclic or polycyclic ring, at least one ring contains at least one heteroatom, and the heterocycloalkyl can be a bicyclic or polycyclic ring formed by a ring containing the heteroatom(s) and a ring containing no heteroatom, or a bicyclic or polycyclic ring formed by a ring containing the heteroatom(s) and a ring containing the heteroatom(s). When heterocycloalkyl is connected to other groups, the connection site can be at a heteroatom or a carbon atom. Non-limiting examples of heterocycloalkyl include azetidinyl, morpholinyl, piperazinyl, piperidyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azacyclohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and the heterocycloalkyl may be optionally substituted with a substituent.

The term “heteroaromatic ring” or “heteroaryl”, unless otherwise specified, refers to a substituted or unsubstituted aromatic ring containing 1 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states, which can be monocyclic, bicyclic, or polycyclic, wherein the bicyclic or polycyclic heteroaromatic ring or heteroaryl can be bridged rings, fused rings, spiro rings and combinations thereof. Bicyclic or polycyclic heteroaromatic ring or heteroaryl can be formed by fusion of heteroaryl to aryl, of heteroaryl to heteroaryl, or of heteroaryl to cycloalkyl or heterocycloalkyl, wherein the heteroaryl is the connection site. The “x- to y-membered heteroaryl” means that the heteroaryl has a total number of ring atoms of x to y, which can be 5- to 6-membered heteroaryl, and can also be 5- to 6-membered heteroaryl fused to other rings (e.g., cycloalkyl, heterocycloalkyl, and aromatic rings) in which the heteroaromatic ring is the connection site. For example, “5- to 12-membered heteroaryl” represents that the heteroaryl, as the connection site, has a total number of ring atoms of 5-12, e.g., pyridocyclobutyl and pyridocyclopentyl. Non-limiting examples of heteroaromatic ring or heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl,

etc. The heteroaryl may be optionally substituted with a substituent.

The term “aromatic ring” refers to an aromatic ring system containing or containing no N, S, O, P, Si and other heteroatoms, and its definition includes aryl and heteroaryl. The aromatic ring may be optionally substituted with a substituent.

The term “heterocycle” or “heterocyclyl” refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states, and its meaning includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles and bicyclic spiro heterocycles or combinations thereof. The heterocycle is usually a 3- to 12-membered heterocycle, or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle. Heterocyclyl can be connected to a heteroatom or a carbon atom. Non-limiting examples of heterocyclyl include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl,

etc., and the heterocycle may be optionally substituted with a substituent.

The term “spiro ring” refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between rings, which may contain 0 or at least 1 double or triple bond, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Generally, a spiro ring is a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Generally, a spiro ring is a spiro ring formed by a three-membered ring and a three-membered ring, a three-membered ring and a four-membered ring, a three-membered ring and a five-membered ring, a three-membered ring and a six-membered ring, a four-membered ring and a four-membered ring, a four-membered ring and a five-membered ring, a four-membered ring and a six-membered ring, a five-membered ring and a five-membered ring or a five-membered ring and a six-membered ring. The spiro ring may be spirocyclic, non-limiting examples of which include

and the spiro ring may be optionally substituted with a substituent.

The term “bicyclic spiro cycloalkyl” means that both rings forming the spiro ring are cycloalkyl.

The term “bicyclic spiro heterocycloalkyl” means that at least one of the two rings forming the spiro ring is heterocycloalkyl.

The term “fused ring” refers to a polycyclic group in which the rings share two adjacent ring atoms and one chemical bond, which may contain one or more double or triple bonds, and may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Generally, a fused ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring or a 5- to 10-membered ring. Generally, a fused ring is in the form of a three-membered ring fused a four-membered ring (indicating a fused ring formed by a three-membered ring and a four-membered ring, and either the three-membered ring or the four-membered ring may be possibly used as the basic ring according to the IUPC nomenclature; similarly hereinafter), a three-membered ring fused a five-membered ring, a three-membered ring fused a six-membered ring, a four-membered ring fused a four-membered ring, a four-membered ring fused a five-membered ring, a four-membered ring fused a six-membered ring, a five-membered ring fused a five-membered ring, a five-membered ring fused a six-membered ring, and a six-membered ring fused a six-membered ring. Non-limiting examples of fused ring include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, and

and the fused ring may be optionally substituted with a substituent.

The term “bridged ring” refers to a ring system in which two non-adjacent ring atoms are shared between two rings and a bridged ring may contain 1 or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Generally, the bridged ring has 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged ring include adamantane,

Unless otherwise specified, the term “substitute” or “substituent” refers to any substitution at a position allowed by chemical theory, and the number of substituents conforms to the rules of chemical bonding. Exemplary substituents include, but are not limited to: C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-8 heteroalkyl, C_5-12 aryl, 5- to 12-membered heteroaryl, hydroxyl, C_1-6 alkoxy, C_5-12 aryloxy, thiol, C_1-6 alkylthio, cyano, halogen, C_1-6 alkylthiocarbonyl, C_1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halo C_1-6 alkyl, halo C_1-6 alkoxy, amino, phosphonic acid, —CO₂(C_1-6 alkyl), —OC(═O)(C_1-6 alkyl), —OCO₂(C_1-6 alkyl), —C(═O)NH₂, —C(═O)N(C_1-6 alkyl)₂, —OC(═O)NH(C_1-6 alkyl), —NHC(═O)(C_1-6 alkyl), —N(C_1-6 alkyl)C(═O)(C_1-6 alkyl), —NHCO₂(C_1-6 alkyl), —NHC(═O)N(C_1-6 alkyl)₂, —NHC(═O)NH(C_1-6 alkyl), —NHC(═O)NH₂, —NHSO₂(C_1-6 alkyl), —SO₂N(C_1-6 alkyl)₂, —SO₂NH(C_1-6 alkyl), —SO₂NH₂, —SO₂C_1-6 alkyl, etc.

“” represents the connection site.

The term “optional” or “optionally” refers to that the events or circumstances subsequently described may but not necessarily occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, “alkyl optionally substituted with F” means that the alkyl may but not necessarily be substituted with F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.

The term “pharmaceutically acceptable salt” refers to a salt of the compound of the present invention, which salt maintains the biological effectiveness and characteristics of a free acid or a free base and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.

The term “pharmaceutical composition” represents a mixture of one or more compounds described herein or the stereoisomers, solvates, pharmaceutically acceptable salts or eutectics thereof and other components comprising physiologically/pharmaceutically acceptable carriers and/or excipients.

The term “preparation strength” refers to the weight of the drug substance contained in each vial, tablet or other unit preparation.

The term “carrier” refers to: a system that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human body and the distribution of the drug in the body, control the release rate of the drug and delivery the drug to targeted organs. Non-limiting examples of the carrier include microcapsule, microsphere, nanoparticle, liposome, etc.

The term “excipient” refers to: a substance that is not a therapeutic agent per se, but used as a diluent, adjuvant, adhesive and/or vehicle for addition to a pharmaceutical composition, thereby improving the disposal or storage properties thereof, or allowing to or promoting the formation of a compound or a pharmaceutical composition into a unit dosage form for administration. As is known to those skilled in the art, a pharmaceutically acceptable excipient can provide various functions and can be described as a wetting agent, a buffer, a suspending agent, a lubricant, an emulsifier, a disintegrating agent, an absorbent, a preservative, a surfactant, a colorant, a flavoring agent and a sweetening agent. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starch, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (such as croscarmellose sodium); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter or suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffered solution; (21) polyester, polycarbonate and/or polyanhydride; and (22) other non-toxic compatible substances used in a pharmaceutical preparation.

The term “stereoisomer” refers to an isomer produced as a result of different spatial arrangement of atoms in molecules, including cis-trans isomers, enantiomers and conformational isomers.

The compounds of the present invention also include tautomers thereof, for example, when the present invention describes the left side compound in which the pyrimidine ring is substituted with OH, the right side tautomer compound is also included.

The term “solvate” refers to a substance formed by the compound of the present invention or the salt thereof and a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, the solvate is a hydrate.

The term “eutectic” refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio among various components. The eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the tumor growth curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.

FIG. 2 shows the animal body weight change curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.

DETAILED DESCRIPTION OF EMBODIMENTS

The content of the present invention is described in detail with the following examples. If a specific condition is not indicated in the examples, a conventional condition is used in an experimental method. The listed examples are intended to better illustrate the content of the present invention, but should not be construed as limiting the content of the present invention. According to the above-mentioned content of the invention, those skilled in the art can make unsubstantial modifications and adjustments to the embodiments, which still fall within the protection scope of the present invention.

Detection Method

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in the unit of 10-6 (ppm). NMR is determined with Bruker Avance 111 400 and Bruker Avance 300; the solvents for determination are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD); and the internal standard is tetramethylsilane (TMS);

MS is determined with Agilent 6120B (ESI) and Agilent 6120B (APCI);HPLC is determined with Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as a thin layer chromatography silica plate, and the silica gel plate for the thin layer chromatography (TLC) is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4 mm-0.5 mm;and for the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier.

The abbreviation herein has the following meaning:

RuPhos-Pd-G3: catalyst with CAS No. 1445085-77-7.

Example 1

3-ethyl-7-((4-(2-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 1)

Step 1:

5-Bromo-2-methyl-1,3-dihydroisoindol-1-one (600 mg, 2.65 mmol) and N-Boc-piperazine (593 mg, 3.18 mmol) were dissolved in 1,4-dioxane (10 mL), cesium carbonate (1.73 g, 5.31 mmol) and RuPhos-Pd-G3 (89 mg, 0.11 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. Subsequently, the reaction liquid was quenched with water (15 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 1A (720 mg, 81.9%).

LC-MS (ESI): m/z=332.2, 276.1 [M+H]⁺.

Step 2:

1A (720 mg, 2.17 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 1B hydrochloride (580 mg, crude).

LC-MS (ESI): m/z=232.2 [M+H]⁺.

Step 3:

Ethyl 6-methyl-5-nitronicotinate (10 g, 47.6 mmol) and selenium dioxide (21.14 g, 190.5 mmol) were dissolved in 1,4-dioxane (100 ml), and the mixture was refluxed overnight at 100° C. After the reaction was completed, the reaction liquid was filtered through a funnel lined with diatomaceous earth, the diatomaceous earth was washed with ethyl acetate, the filtrate was concentrated, and the resulting residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether (v/v)=0%-40%), to afford compound 1C (10.104 g, 94.7%).

LCMS(ESI) m/z=225.1 [M+1]⁺.

Step 4:

Sodium hydride (2.695 g, 112.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and stirred at 0° C., and triethyl 2-phosphonobutyrate (28.3 g, 112.3 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 0° C. for 20 min, warmed to 40° C. and stirred for 10 min, and then transferred to a dry ice ethanol bath. Compound 1C (10.48 g, 46.8 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and added dropwise to a reaction flask. The mixture was kept in the dry ice ethanol bath and stirred for 1 h. After the reaction was completed, the reaction liquid was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (200 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether (v/v)=0-10%), to afford compound 1D (11.57 g, 76.8%), a mixture of two isomers.

LC-MS(ESI) m/z=323.1 [M+1]⁺.

Step 5:

Compound 1D (11.57 g, 35.9 mmol) was dissolved in ethanol (50 ml), and 10% palladium on carbon catalyst (1 g) was added. The mixture was subjected to hydrogen replacement three times, stirred overnight at room temperature, and filtered through a funnel lined with diatomaceous earth, and the diatomaceous earth was washed with anhydrous ethanol. The filtrate was concentrated, to the resulting residue was added a solution of hydrogen chloride in dioxane (60 ml, 4M), and the mixture was stirred at room temperature for 1 h and concentrated. To the resulting residue was added ethyl acetate (50 ml), the mixture was stirred and filtered, and the filter cake was washed with ethyl acetate and dried, to afford compound 1E (4.28 g, 42.0%).

¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.62 (d, 1H), 7.75 (s, 1H), 4.38-4.29 (m, 2H), 3.24 (dd, 1H), 2.97 (dd, 1H), 2.62-2.53 (m, 1H), 1.83-1.64 (m, 1H), 1.55-1.35 (m, 1H), 1.33 (dd, 3H), 0.94 (t, 3H).

Step 6:

Compound 1E (4.28 g, 17.3 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (4.309 g, 19.0 mmol) were dissolved in dioxane (86 ml), and the mixture was reacted at 100° C. for 3.5 h at reflux. After the reaction was completed, saturated sodium bicarbonate solution (40 ml) and ethyl acetate (120 ml) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (120 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=0-50%), to afford compound 1F (3.375 g, 79.5%).

LC-MS(ESI) m/z=247.1 [M+1]⁺.

Step 7:

Compound 1F (3.375 g, 13.72 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), and the mixture was stirred at −78° C. Lithium aluminum hydride (1.564 g, 41.16 mmol) was added portionwise, and the mixture was stirred at −78° C. for 20 min and then warmed to −40° C. and stirred for 20 min. After the reaction was completed, 1M hydrochloric acid was added to adjust the system to a neutral pH, the solvent was removed by distillation under reduced pressure, to the resulting residue was added methanol/dichloromethane (1:10, 100 ml) for dissolution, and the mixture was subjected to ultrasonic vibration for 10 min and filtered. The filtrate was collected, the filter cake was redissolved in methanol/dichloromethane (1:10, 100 ml), and this process was repeated 8 times. The filtrate was combined and concentrated, to afford compound 1G (2.8 g, 100%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.37 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 5.44 (t, 1H), 4.61 (d, 2H), 2.57-2.51 (m, 2H), 1.18 (t, 3H).

Step 8:

1G (100 mg, 0.49 mmol) was added to dichloromethane (2.5 mL), DMF (1 mL) was added to assist dissolution, thionyl chloride (350 mg, 2.94 mmol) was added dropwise at 0° C., and the mixture was reacted at room temperature for 1 hour. Upon complete depletion of raw materials monitored by LCMS, the reaction liquid was directly spun to dryness, to afford title compound 1H (109 mg, crude) which was used in the next reaction.

LC-MS (ESI): m/z=223.1, 225.1 [M+H]⁺.

Step 9:

1H (109 mg, 0.49 mmol) and 1B (131 mg, 0.49 mmol) were dissolved in anhydrous acetonitrile (5 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (316 mg, 2.45 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, passed through column (DCM:MeOH (v/v)=1:0-10:1), and separated with a preparative silica gel plate (DCM:MeOH=10:1), to afford compound 1 (39 mg, 19.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.41 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.12-6.93 (m, 2H), 4.33 (s, 2H), 3.65 (s, 2H), 3.30-3.25 (m, 4H), 3.01 (s, 3H), 2.60-2.52 (m, 6H), 1.19 (t, 3H).

LC-MS (ESI): m/z=418.3 [M+H]⁺.

Example 2

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide (Compound 2)

Step 1:

2A (600 mg, 2.76 mmol) and N-Boc-piperazine (618 mg, 3.32 mmol) were dissolved in 1,4-dioxane (10 mL), cesium carbonate (1.8 g, 5.53 mmol) and RuPhos-Pd-G3 (93 mg, 0.11 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. Subsequently, the reaction liquid was quenched with water (15 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 2B (779 mg, 87.7%).

LC-MS (ESI): m/z=323.1, 267.1 [M+H]⁺.

Step 2:

2B (779 mg, 2.42 mmol) was dissolved in methanol (10 mL), methylamine aqueous solution (750 mg, 40%) was added, and the mixture was reacted at room temperature for 4 hours. The suspension was concentrated, saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun to dryness, to afford title compound 2C (760 mg, 97.9%).

LC-MS (ESI): m/z=322.2 [M+H]⁺.

Step 3:

2C (760 mg, 2.37 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for two hours and spun to dryness, to afford title compound 2D (523 mg, crude).

LC-MS (ESI): m/z=222.1 [M+H]⁺.

Step 4:

1H (109 mg, 0.49 mmol) and 2D (127 mg, 0.49 mmol) were dissolved in anhydrous acetonitrile (5 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (316 mg, 2.45 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (DCM:MeOH (v/v)=1:0-10:1), to afford compound 2 (80 mg, 40.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.59 (s, 1H), 8.43-8.38 (m, 1H), 8.32 (q, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 3.70 (s, 4H), 3.65 (s, 2H), 2.77 (d, 3H), 2.60-2.52 (m, 6H), 1.18 (t, 3H).

LC-MS (ESI): m/z=408.2 [M+H]⁺.

Example 3

3-ethyl-7-((4-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 3)

Step 1:

Hydrazine hydrate (694 mg, 13.89 mmol) was added to a solution of 3A (1 g, 4.63 mmol) in methanol (10 mL), and the mixture was heated to reflux for 1 hour. The reaction liquid was concentrated under reduced pressure, and the solid was filtered off, washed with methanol and dried, to afford title compound 3B (880 mg, 88.0%).

LC-MS (ESI): m/z=216.1, 218.1 [M+H]⁺.

Step 2:

3B (880 mg, 4.07 mmol) and triethylamine (1.14 mL, 8.15 mmol) were added to dichloromethane (15 mL), acetic anhydride (0.44 mL, 4.48 mmol) was added dropwise at 25° C., and the reaction liquid was stirred for 1.5 hours. Subsequently, the reaction liquid was poured into ice water, and the solid was filtered off, washed with water and dried, to afford title compound 3C (1 g, 95.1%).

LC-MS (ESI): m/z=257.1, 259.1 [M+H]⁺.

Step 3:

3C (1 g, 3.88 mmol) and triethylamine (3.2 mL, 23.3 mmol) were added to dichloromethane (15 mL), p-toluenesulfonyl chloride (884 mg, 4.65 mmol) was then added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the reaction liquid was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatographic column (EA:PE (v/v)=0: 1-1:0), to afford title compound 3D (810 mg, 87.1%).

LC-MS (ESI): m/z=223.1 [M+H]⁺.

Step 4:

3D (400 mg, 1.67 mmol), benzyl-1-piperazine carbonate (440 mg, 2.00 mmol), cesium carbonate (1.63 g, 5.00 mmol) and RuPhos-Pd-G3 (56 mg, 0.04 mmol) were added to 1,4-dioxane (10 mL), and the mixture was subjected to nitrogen replacement and reacted overnight at 100° C. Upon complete depletion of raw materials monitored by TLC, the reaction liquid was filtered, concentrated, and separated and purified by silica gel chromatographic column (EA:PE (v/v)=0: 1-1:0), to afford title compound 3E (494 mg, 78.2%).

LC-MS(ESI): m/z=380.2 [M+H]⁺.

Step 5:

3E (250 mg, 0.66 mmol) was dissolved in methanol, and palladium on carbon catalyst (10%, 100 mg) was added. The reaction was carried out under hydrogen conditions for 2 hours, and the reaction liquid was filtered and spun to dryness, to afford title compound 3F (160 mg, 99.0%).

Step 6:

1H (50 mg, 0.22 mmol) and 3F (66 mg, 0.27 mmol) were dissolved in anhydrous acetonitrile (5 mL), potassium iodide (4 mg, 0.02 mmol) and DIPEA (144 mg, 1.12 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 3 (56 mg, 57.9%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.45-8.37 (m, 2H), 7.91 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.45 (dd, 1H), 3.66 (s, 2H), 3.45-3.34 (m, 4H), 2.60-2.52 (m, 9H), 1.19 (t, 3H).

LC-MS (ESI): m/z=432.2 [M+H]⁺.

Example 4

N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 4)

Step 1:

3A (2.16 g, 10 mmol) and N-Boc-piperazine (2.03 g, 11 mmol) were dissolved in 1,4-dioxane (100 mL), cesium carbonate (6.5 g, 20 mmol) and RuPhos-Pd-G3 (253 mg, 0.3 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction was terminated, cooled to room temperature, and filtered. The filtrate was collected, and the filter residue was washed with ethyl acetate (20 mL×3). The filtrate was concentrated, a small amount of anhydrous ethanol was added, and the mixture was heated and dissolved. A large amount of petroleum ether was then added, and the mixture was cooled to collect the precipitated crystals, to afford title compound 4A (2.37 g, 73.4%).

LC-MS (ESI): m/z=321.1 [M+H]⁺.

Step 2:

Compound 4A (400 mg, 1.24 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide (30 mg, 1.24 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, water was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to dryness. To the resulting solid was added DMF (10 mL), HATU (565 mg, 1.49 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (2 mL) was added, excess cyclopropylamine was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 4B (309 mg, 71.5%).

LC-MS (ESI): m/z=347.2 [M+H]⁺.

Step 3:

4B (309 mg, 0.89 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 4C (200 mg, crude).

LC-MS (ESI): m/z=247.1 [M+H]⁺.

Step 4:

1H (100 mg, 0.44 mmol) and 4C (200 mg, 0.81 mmol) were dissolved in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 8 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 4 (76 mg, 38.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 3.65 (s, 2H), 3.35-3.31 (m, 4H, overlapped with solvent DMSO peak), 2.90-2.80 (m, 1H), 2.59-2.52 (m, 6H, overlapped with solvent DMSO peak), 1.19 (t, 3H), 0.66 (dd, 2H), 0.63 (q, 2H).

LC-MS (ESI): m/z=433.2 [M+H]⁺.

Example 5

3-ethyl-7-((4-(6-(pyrrolidine-1-carbonyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 5)

Step 1:

Compound 4A (400 mg, 1.24 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide (30 mg, 1.24 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, water was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to dryness. To the remaining solid was added DMF (10 mL), HATU (565 mg, 1.49 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (2 mL) was added, excess pyrrolidine was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 5A (362 mg, 80.5%).

LC-MS (ESI): m/z=361.2 [M+H]⁺.

Step 2:

5A (360 mg, 1 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 5B hydrochloride (243 mg, crude).

LC-MS (ESI): m/z=261.1 [M+H]⁺.

Step 3:

1H (100 mg, 0.44 mmol) and 5B (243 mg, 0.93 mmol) were dissolved in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL, 2.45 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted overnight at 80° C. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 5 (64 mg, 34.6%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.40 (d, 1H), 8.26 (d, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 7.63 (d, 1H), 7.36 (dd, 1H), 3.77-3.68 (m, 2H), 3.65 (s, 2H), 3.47 (t, 2H), 3.32-3.27 (m, 4H), 2.59-2.52 (m, 6H), 1.89-1.75 (m, 4H), 1.18 (t, 3H).

LC-MS (ESI): m/z=447.2 [M+H]⁺.

Example 6

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpicolinamide (Compound 6)

Step 1:

6A (2.34 g, 10 mmol) and N-Boc-piperazine (2.03 g, 11 mmol) were dissolved in 1,4-dioxane (100 mL), cesium carbonate (6.5 g, 20 mmol) and RuPhos-Pd-G3 (253 mg, 0.3 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction was terminated, cooled to room temperature, and filtered. The filtrate was collected, and the filter residue was washed with ethyl acetate (20 mL×3). The filtrate was concentrated, a small amount of anhydrous ethanol was added, and the mixture was heated and dissolved. A large amount of petroleum ether was then added, and the mixture was cooled to collect the precipitated crystals, to afford title compound 6B (1.89 g, 56.5%).

LC-MS (ESI): m/z=340.2 [M+H]⁺.

Step 2:

6B (400 mg, 1.18 mmol) was dissolved in methanol (10 mL), methylamine aqueous solution (0.5 mL, 40%) was added, and the mixture was reacted at room temperature for 4 hours. The system was concentrated, saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun to dryness, to afford title compound 6C (384 mg, 96.7%).

LC-MS (ESI): m/z=339.2 [M+H]⁺.

Step 3:

6C (380 mg, 1.12 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 6D (255 mg, crude).

LC-MS (ESI): m/z=239.1 [M+H]⁺.

Step 4:

1H (100 mg, 0.44 mmol) and 6D (255 mg, 1.07 mmol) were dissolved in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (316 mg, 2.45 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 6 (78 mg, 41.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.40 (d, 1H), 8.25 (q, 1H), 8.13 (t, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 7.21 (dd, 1H), 3.65 (s, 2H), 3.39 (t, 4H), 2.75 (d, 3H), 2.56 (d, 2H), 2.54 (s, 4H), 1.19 (t, 3H).

LC-MS (ESI): m/z=425.3 [M+H]⁺.

Example 7

N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)acetamide (Compound 7)

Step 1:

7A (800 mg, 2.60 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and concentrated under reduced pressure, to afford title compound 7B hydrochloride (602 mg, crude).

LC-MS (ESI): m/z=209.1 [M+H]⁺.

Step 2:

1H (300 mg, 1.34 mmol) and 7B (600 mg, 2.87 mmol) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (15 mg, 0.05 mmol) and DIPEA (1 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 8 hours, at which time a large amount of yellow solid was observed to be generated. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, ethyl acetate (20 mL) was added, and the mixture was subjected to ultrasonic vibration and filtered to collect the filter residue, which was compound 7C (247 mg, 46.7%).

LC-MS (ESI): m/z=395.2 [M+H]⁺.

Step 3:

7C (247 mg, 0.62 mmol) was dissolved in anhydrous methanol (20 mL), palladium on carbon (50 mg, 10%) and hydrazine hydrate (0.5 mL) were added, and the mixture was reacted at 75° C. for 4 hours. After the reaction was completed as monitored by LCMS, the reaction liquid was filtered to remove palladium on carbon and concentrated under reduced pressure, to afford target compound 7D (204 mg, 89.8%).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 4:

Compound 7D (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (10 mL), acetic anhydride (27.5 mg, 0.27 mmol) and two drops of pyridine were added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 7 (81 mg, 72.9%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 10.29 (s, 1H), 8.55 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.46 (dd, 1H), 4.53 (s, 2H), 3.81 (s, 4H), 3.00 (s, 4H), 2.65-2.51 (m, 2H), 2.05 (s, 3H), 1.20 (t, 3H).

LC-MS (ESI): m/z=407.2 [M+H]⁺.

Example 8

methyl(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)carbamate (Compound 8)

Compound 7D (100 mg, 0.27 mmol) was dissolved in methanol (10 mL), (Boc)₂O (70.6 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed as monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 8 (82 mg, 71.3%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.92 (s, 1H), 8.55 (d, 1H), 8.01 (d, 1H), 7.81 (s, 1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.48 (dd, 1H), 4.53 (s, 2H), 3.65 (s, 3H), 3.43 (s, 4H), 3.13 (d, 4H), 2.64-2.53 (m, 2H), 1.20 (t, 3H).

LC-MS (ESI): m/z=423.2 [M+H]⁺.

Example 9

N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (Compound 9)

Cyclopropanecarboxylic acid (86.1 mg, 1 mmol) was dissolved in DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, 7D (240 mg, 0.65 mmol) and DIPEA (420 mg, 3.25 mmol) were added after 30 min, and the mixture was reacted at room temperature for 4 h. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (DCM:MeOH (v/v)=1:0-1:1), to afford title compound 9 (181 mg, 63.7%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.49 (s, 1H), 8.40 (d, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.36 (dd, 1H), 3.64 (s, 2H), 3.14 (t, 4H), 2.56 (m, 4H), 2.54-2.52 (m, 2H), 2.01-1.89 (m, 1H), 1.19 (t, 3H), 0.79 (t, 2H), 0.77-0.70 (m, 2H).

LC-MS (ESI): m/z=433.2 [M+H]⁺.

Example 10

N-cyclobutyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 10)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, excess cyclobutylamine was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 10B (336 mg, 93.3%).

LC-MS (ESI): m/z=361.2 [M+H]⁺.

Step 2:

10B (336 mg, 0.93 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for two hours and spun to dryness, to afford title compound 10C hydrochloride (251 mg, crude).

LC-MS (ESI): m/z=261.2 [M+H]⁺.

Step 3:

1H (150 mg, 0.67 mmol) and 10C (251 mg, 0.85 mmol) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, a product was generated, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 10 (128 mg, 42.8%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.51 (d, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.81 (d, 1H), 7.75 (q, 1H), 7.68-7.60 (m, 1H), 7.39 (dd, 1H), 4.41 (h, 1H), 3.66 (s, 2H), 3.39-3.32 (m, 4H), 2.56 (dd, 4H), 2.54 (d, 2H), 2.22-2.16 (m, 2H), 2.15-2.10 (m, 2H), 1.69-1.58 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=447.2 [M+H]⁺.

Example 11

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1R,2S)-2-fluorocyclopropyl)picolinamide (Compound 11)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, excess 11D was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 11B (312 mg, 85.7%).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 2:

11B (312 mg, 0.86 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 11C hydrochloride (215 mg, crude).

LC-MS (ESI): m/z=265.2 [M+H]⁺.

Step 3:

1H (150 mg, 0.67 mmol) and 11C (215 mg, 0.72 mmol) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 11 (128 mg, 42.8%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.40 (d, 1H), 8.31 (d, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.41 (dd, 1H), 4.90-4.65 (m, 1H), 3.65 (s, 2H), 3.35 (t, 4H), 2.94-2.80 (m, 1H), 2.56 (dd, 4H), 2.54 (d, 2H), 1.29-1.19 (m, 2H), 1.17 (t, 3H), 1.15-1.03 (m, 2H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 12

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-4-fluoro-N-methylpicolinamide (Compound 12)

Step 1:

Methyl 4-aminopyridine-2-carboxylate (1.52 g, 10 mmol) was dissolved in dichloroethane (50 mL), N-bromosuccinimide (1.78 g, 10 mmol) was added under stirring, and the mixture was reacted overnight at room temperature. After the reaction was completed as monitored by LCMS, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to solvent removal, to afford title compound 12A (1.76 g, 76%).

LC-MS (ESI): m/z=231.0/233.0 [M+H]⁺.

Step 2:

To the hydrogen fluoride pyridine solution (50 mL, 65%-70% w/w) in a plastic bottle was added sodium nitrite solid (3.15 g, 46 mmol) in an ice-water bath, 12A (1.76 g, 7.6 mmol) was added under stirring, and the mixture was stirred overnight at 30° C. After the reaction was completed, the reaction liquid was cooled to room temperature, quenched with 200 mL of water, and extracted with dichloromethane (200 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dry the solvent, and separated by silica gel chromatographic column (DCM:MeOH (v/v)=1:0-10:1), to afford title compound 12B (747 mg, 42.1%).

LC-MS (ESI): m/z=233.9/235.9 [M+H]⁺.

Step 3:

12B (747 mg, 3.19 mmol) and N-Boc-piperazine (653 mg, 3.51 mmol) were dissolved in 1,4-dioxane (30 mL), cesium carbonate (2.07 g, 6.38 mmol) and RuPhos-Pd-G3 (86 mg, 0.1 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction was terminated, cooled to room temperature, and filtered. The filtrate was collected, and the filter residue was washed with ethyl acetate (20 mL×3). The filtrate was concentrated, filtered, spun to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 12C (706 mg, 67.2%).

LC-MS (ESI): m/z=340.1 [M+H]⁺.

Step 4:

12C (706 mg, 2.08 mmol) was dissolved in methanol (20 mL), methylamine aqueous solution (1 mL, 40%) was added, and the mixture was reacted at room temperature for 4 hours. The system was concentrated, saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun to dryness, to afford title compound 12D (384 mg, 96.7%).

LC-MS (ESI): m/z=339.2 [M+H]⁺.

Step 5:

12D (338 mg, 1.0 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (2 mL, 4M) was added. The mixture was reacted at room temperature for two hours and spun to dryness, to afford title compound 12E hydrochloride (243 mg, crude).

LC-MS (ESI): m/z=239.1 [M+H]⁺.

Step 6:

1H (100 mg, 0.44 mmol) and 12E (243 mg, 0.89 mmol) were dissolved in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (316 mg, 2.45 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 8 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH (v/v)=1:0-10:1), to afford compound 12 (80 mg, 42.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 8.59 (d, 1H), 8.55-8.53 (m, 1H), 8.36 (d, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.74 (d, 1H), 4.50 (s, 2H), 3.88-3.55 (m, 4H), 3.41-3.13 (m, 4H), 2.81 (d, 3H), 2.62-2.53 (m, 2H), 1.20 (t, 3H).

LC-MS (ESI): m/z=425.2 [M+H]⁺.

Example 13

N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-4-fluoropicolinamide (Compound 13)

Step 1:

Compound 12C (340 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to afford compound 13B (331 mg, 100%).

LC-MS (ESI): m/z=332.2 [M+H]⁺.

Step 2:

Compound 13B (331 mg, 1 mmol) was dispersed in DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, excess cyclopropylamine was finally added, and the mixture was reacted at room temperature for 4 h. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 13C (321 mg, 87.9%).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 3:

13C (321 mg, 0.88 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for two hours and spun to dryness, to afford title compound 13D (275 mg, crude).

LC-MS (ESI): m/z=265.2 [M+H]⁺.

Step 4:

1H (150 mg, 0.67 mmol) and 13D (275 mg, 0.92 mmol) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=1:0-10:1), to afford compound 13 (134 mg, 44.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.53 (d, 1H), 8.47-8.37 (m, 1H), 8.24 (d, 1H), 7.75 (s, 1H), 7.69 (d, 1H), 7.62 (s, 1H), 3.66 (s, 2H), 3.23 (t, 4H), 2.90-2.83 (m, 1H), 2.61-2.56 (m, 4H), 2.54 (d, 2H), 1.18 (t, 3H), 0.72-0.66 (m, 2H), 0.66-0.59 (m, 2H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 14

1-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-3-methylurea (Compound 14)

Step 1:

Compound 14A (558 mg, 2 mmol) was dissolved in DMF (20 mL) under nitrogen protection and cooled in an ice-water bath, sodium hydride (320 mg, 60%) was then added, and the mixture was stirred and reacted for 1 h in the ice bath. Subsequently, carbonyldiimidazole (486 mg, 3 mmol) was added, and the mixture was stirred and reacted for 30 min, at which time the color of the system was observed to become lighter. Excess methylamine tetrahydrofuran solution was finally added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, to the system was added ethyl acetate (100 mL), and the mixture was washed with water (100 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA (v/v)=1:0-1:1), to afford title compound 14B (233 mg, 34.9%).

LC-MS (ESI): m/z=336.2 [M+H]⁺.

Step 2:

14B (233 mg, 0.69 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for two hours and spun to dryness, to afford title compound 14C (175 mg, crude).

LC-MS (ESI): m/z=236.2 [M+H]⁺.

Step 3:

1H (120 mg, 0.54 mmol) and 14C (175 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 14 (104 mg, 45.8%).

¹H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.92 (s, 1H), 8.39 (d, 1H), 7.95-7.85 (m, 1H), 7.81 (d, 1H), 7.74 (s, 1H), 7.62 (d, 1H), 7.39 (dd, 1H), 7.21 (d, 1H), 3.64 (s, 2H), 3.07 (t, 4H), 2.70 (d, 3H), 2.57-2.54 (m, 4H), 2.54-2.51 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=422.2 [M+H]⁺.

Example 15

3-ethyl-7-((4-(2-methylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 15)

Step 1:

Under nitrogen protection, 15A (300 mg, 1.42 mmol), piperazine (610 mg, 7.08 mmol), tris(dibenzylideneacetone)dipalladium (129.6 mg, 0.142 mmol), 2-(di-tert-butylphosphine)biphenyl (63.3 mg, 0.212 mmol) and sodium tert-butoxide (271.7 mg, 2.83 mmol) were all added to a reaction flask, toluene (20 mL) was added, and the mixture was warmed to 110° C. and reacted overnight. After the reaction was completed as monitored by TLC, the reaction liquid was filtered through diatomaceous earth and washed with ethyl acetate. The organic phase was concentrated, and the resulting residue was separated and purified by silica gel column chromatography (dichloromethane:methanol:concentrated ammonia water (v/v/v)=100:10:0.5), to afford compound 15B (270 mg, 87.8%).

LC-MS (ESI): 218.2 [M+H]⁺.

Step 2:

Compound 1H (50 mg, 0.225 mmol), 15B (53.7 mg, 0.247 mmol), N,N-diisopropylethylamine (145 mg, 2.24 mmol), and potassium iodide (3.71 mg, 0.0225 mmol) were all added to a reaction tube, dry acetonitrile (3 mL) was added, and the mixture was warmed to 80° C. and reacted for about 5 hours. After the reaction was completed as monitored by TLC, water (5 mL) was added, and the mixture was extracted with ethyl acetate (3 mL×10). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was separated and purified by preparative HPLC with methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm); 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid; 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.5% ammonium acetate); b. gradient elution, mobile phase A: 5%-50%; c. flow rate: 12 mL/min; d. elution time: 10 min, to afford compound 15 (22 mg, 24.3%).

¹H NMR (400 MHz, CD₃OD): δ 8.59 (s, 1H), 8.49 (d, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.74 (d, 1H), 7.62 (s, 1H), 3.74 (s, 2H), 3.42-3.29 (m, 5H), 2.76-2.62 (m, 5H), 2.41 (s, 3H), 1.27 (t, 3H).

LC-MS (ESI): 404.1 [M+H]⁺.

Example 16

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(piperidin-4-yl)picolinamide (Compound 16)

Step 1:

Intermediate 1H (3.20 g, 14.4 mmol), methyl 5-(piperazin-1-yl)picolinate (4.23 g, 14.4 mmol), potassium iodide (478 mg, 2.88 mmol) and N,N-diisopropylethylamine (12.5 ml, 71.96 mmol) were dissolved in acetonitrile (150 ml), and the mixture was reacted at 80° C. for 2 h at reflux. After the reaction was completed, the reaction liquid was concentrated, and extracted with water (80 ml), dichloromethane (150 ml) and methanol (15 ml). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (150 ml×3). The organic phases were combined and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: methanol:dichloromethane (v/v)=0%-15%), to afford compound 16A (4.24 g, 72.1%).

LCMS m/z=408.2 [M+1]⁺.

Step 2:

Compound 16A (4.24 g, 10.4 mmol) was dissolved in tetrahydrofuran (80 ml) and water (80 ml), lithium hydroxide (750 mg, 31.2 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. After the reaction was completed, 1M hydrochloric acid was added to adjust the system to pH 4-5, the mixture was concentrated, and the resulting residue was purified by C18 column chromatography (eluent: methanol:water containing 0.1% trifluoroacetic acid (v/v)=30%), to afford compound 16B (4.01 g, 100%).

LCMS m/z=394.2 [M+1]⁺.

Step 3:

Compound 16B (1 g, 2.54 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (609 mg, 3.05 mmol) were dissolved in DMF (5 mL), benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (962 mg, 2.54 mmol) and N,N-diisopropylethylamine (1.31 ml, 7.54 mmol) were added, and the mixture was stirred and reacted at room temperature for 1 h. After the reaction was completed, water (10 ml) and ethyl acetate (12 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was separated and purified by silica gel column chromatography (eluent: methanol:dichloromethane (v/v)=0%-15%), to afford product 16C (563 mg, 38.5%).

LCMS m/z=576.3 [M+1]⁺.

Step 4:

Compound 16C (563 mg, 0.98 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, the reaction liquid was concentrated, adjusted to pH >7 with triethylamine, and separated and purified by liquid phase preparative column after concentration (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonia water (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.); to afford title compound 16 (351 mg, yield: 75.5%, retention time: about 6.5 min).

¹H NMR (400 MHz, CD3OD) δ 8.49 (d, 1H), 8.27 (d, 1H), 7.91 (d, 1H), 7.83 (s, 1H), 7.76 (d, 1H), 7.37 (d, 1H), 4.06-3.90 (m, 1H), 3.74 (s, 2H), 3.44-3.37 (m, 4H), 3.22-3.06 (m, 2H), 2.84-2.73 (m, 2H), 2.72-2.55 (m, 6H), 2.10-1.83 (m, 2H), 1.75-1.50 (m, 2H), 1.36-1.20 (m, 3H).

MS M/Z (ESI): m/z=476.2 [M+1]⁺.

Example 17

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-methylpiperidin-4-yl)picolinamide (Compound 17)

Step 1:

Compound 16 (50 mg, 0.11 mmol) and paraformaldehyde (50 mg) were added to methanol (2 mL), 1,2-dichloroethane (2 mL) was then added, three drops of glacial acetic acid were added dropwise, and the mixture was reacted at 60° C. for 12 hours. Subsequently, sodium cyanoborohydride (50 mg, 0.8 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction liquid was spun to dryness, and then separated and purified by liquid phase preparative column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonium bicarbonate (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 17 (30 mg, yield: 58%, retention time: about 8.1 min).

¹H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 8.11 (d, 1H), 7.83 (d, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 3.77-3.67 (m, 1H), 3.65 (s, 2H), 3.35-3.31 (m, 4H), 2.70 (d, 2H), 2.60-2.51 (m, 6H), 2.15 (s, 3H), 2.04-1.89 (m, 2H), 1.79-1.67 (m, 2H), 1.66-1.52 (m, 2H), 1.27-1.11 (m, 3H).

MS M/Z (ESI): m/z=490.3 [M+1]⁺.

Example 18

(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(pyrrolidin-3-yl)picolinamide (Compound 18)

Step 1:

Compound 16B (0.5 g, 1.27 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (283 mg, 1.5 mmol) were dissolved in DMF (5 mL), benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol) and N,N-diisopropylethylamine (330 mg, 2.54 mmol) were added, and the mixture was stirred and reacted at room temperature for 1 h. After the reaction was completed, water (10 ml) and ethyl acetate (10 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, to afford crude product 18A (700 mg, 98%).

LCMS m/z=562.3 [M+1]⁺.

Step 2:

Compound 18A (700 mg, 1.27 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, the reaction liquid was concentrated, adjusted to pH >7 with triethylamine, and separated and purified by liquid phase preparative column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonia water (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 18 (400 mg, yield: 68%, retention time: about 6.6 min).

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.26 (d, 2H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.39 (d, 1H), 4.33 (s, 1H), 3.65 (s, 2H), 3.37-3.31 (m, 4H), 3.06-2.79 (m, 3H), 2.77-2.62 (m, 2H), 2.60-2.52 (m, 6H), 2.04-1.95 (m, 1H), 1.70-1.51 (m, 1H), 1.22-1.14 (m, 3H).

MS M/Z (ESI): m/z=462.2 [M+1]⁺.

Example 19

(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-methylpyrrolidin-3-yl)picolinamide (Compound 19)

Step 1:

Compound 18 (50 mg, 0.11 mmol) and paraformaldehyde (50 mg) were added to methanol (2 mL), 1,2-dichloroethane (2 mL) was then added, three drops of glacial acetic acid were added dropwise, and the mixture was reacted at 60° C. for 12 hours. Subsequently, sodium cyanoborohydride (50 mg, 0.8 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction liquid was spun to dryness, and then separated and purified by liquid phase preparative column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonium acetate (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 19 (32 mg, yield: 58%, retention time: about 8.1 min).

¹H NMR (400 MHz, DMSO-d6) δ8.40 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.82 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (d, 1H), 4.46-4.29 (m, 1H), 3.65 (s, 2H), 3.45-3.24 (m, 4H), 2.71-2.58 (m, 2H), 2.59-2.52 (m, 6H), 2.47-2.41 (m, 1H), 2.35-2.29 (m, 1H), 2.26 (s, 3H), 2.22-2.11 (m, 1H), 1.72-1.61 (m, 1H), 1.22-1.15 (m, 3H).

MS M/Z (ESI): m/z=476.2 [M+1]⁺.

Example 20

(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(pyrrolidin-3-yl)picolinamide (Compound 20)

Step 1:

Compound 16B (0.5 g, 1.27 mmol) and tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (283 mg, 1.5 mmol) were dissolved in DMF (5 mL), benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol) and N,N-diisopropylethylamine (330 mg, 2.54 mmol) were added, and the mixture was stirred and reacted at room temperature for 1 h. After the reaction was completed, water (10 ml) and ethyl acetate (10 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, to afford crude product 20A (700 mg, 98%).

LCMS m/z=562.3 [M+1]⁺.

Step 2:

Compound 20A (700 mg, 1.27 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, the reaction liquid was concentrated, adjusted to pH >7 with triethylamine, and separated and purified by liquid phase preparative column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonia water (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 20 (401 mg, yield: 68%, retention time: about 6.6 min).

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.27 (s, 2H), 7.83 (d, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.40 (d, 1H), 4.32 (s, 1H), 3.65 (s, 2H), 3.38-3.30 (m, 4H), 2.98-2.82 (m, 3H), 2.76-2.59 (m, 2H), 2.58-2.52 (m, 6H), 2.08-1.89 (m, 1H), 1.70-1.57 (m, 1H), 1.21-1.13 (m, 3H).

MS M/Z (ESI): m/z=462.2 [M+1]⁺.

Example 21

(S)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-methylpyrrolidin-3-yl)picolinamide (Compound 21)

Step 1:

Compound 20 (50 mg, 0.11 mmol) and paraformaldehyde (50 mg) were added to methanol (2 mL), 1,2-dichloroethane (2 mL) was then added, three drops of glacial acetic acid were added dropwise, and the mixture was reacted at 60° C. for 12 hours. Subsequently, sodium cyanoborohydride (50 mg, 0.8 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction liquid was spun to dryness, and then separated and purified by liquid phase preparative column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonium acetate (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 21 (33 mg, yield: 58%, retention time: about 8.1 min).

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.82 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 4.46-4.32 (m, 1H), 3.65 (s, 2H), 3.37-3.31 (m, 4H), 2.70-2.59 (m, 2H), 2.59-2.52 (m, 6H), 2.47-2.42 (m, 1H), 2.35-2.28 (m, 1H), 2.26 (s, 3H), 2.22-2.12 (m, 1H), 1.76-1.60 (m, 1H), 1.22-1.14 (m, 3H).

MS M/Z (ESI): m/z=476.2 [M+1]⁺.

Example 22

N-(azetidin-3-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 22)

Step 1:

Compound 16B (1 g, 2.54 mmol) and tert-butyl 3-aminoazetidin-1-carboxylate (525 mg, 3.05 mmol) were dissolved in DMF (5 mL), benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (962 mg, 2.54 mmol) and N,N-diisopropylethylamine (1.31 ml, 7.54 mmol) were added, and the mixture was stirred and reacted at room temperature for 1 h. After the reaction was completed, water (10 ml) and ethyl acetate (12 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was separated and purified by silica gel column chromatography (eluent: methanol:dichloromethane (v/v)=0%-15%), to afford product 22A (500 mg, 36%).

LCMS m/z=548.3 [M+1]⁺.

Step 2:

Compound 22A (500 mg, 0.91 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, the reaction liquid was concentrated, adjusted to pH >7 with triethylamine, and separated and purified by liquid phase preparative column after concentration (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonia water (A) and acetonitrile (B), gradient elution, mobile phase B=5%-50%, elution time: 15 min, flow rate: 12 mL/min, and column temperature: 30° C.), to afford title compound 22 (300 mg, yield: 73%, retention time: about 6.5 min).

¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, 1H), 8.30 (d, 1H), 7.90 (d, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.37 (d, 1H), 3.95-3.90 (m, 1H), 3.88-3.83 (m, 1H), 3.74 (s, 2H), 3.44-3.39 (m, 3H), 3.31-3.30 (m, 4H), 2.75-2.56 (m, 6H), 1.32-1.20 (m, 3H).

MS M/Z (ESI): m/z=448.2 [M+1]⁺.

Example 23

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide (Compound 23)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, 1-methyl-4-aminopyrazole hydrochloride (336 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 23B (351 mg, 90.6%).

LC-MS (ESI): m/z=387.2 [M+H]⁺.

Step 2:

23B (351 mg, 0.90 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 23C (274 mg, crude).

LC-MS (ESI): m/z=287.2 [M+H]⁺.

Step 3:

1H (150 mg, 0.67 mmol) and 23C (274 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH (v/v)=1:0-10:1), to afford compound 23 (141 mg, 48.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 10.55 (s, 1H), 8.56 (d, 1H), 8.39 (d, 1H), 8.04 (s, 1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.79 (d, 1H), 7.71 (s, 1H), 7.53 (dd, 1H), 4.55 (s, 2H), 3.81 (s, 3H), 3.81-3.64 (m, 4H), 3.24-3.04 (m, 4H), 2.62-2.54 (m, 2H), 1.20 (t, 3H).

LC-MS (ESI): m/z=473.2 [M+H]⁺.

Example 24

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide (Compound 24)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, excess 2-methoxyethylamine was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 24B (282 mg, 77.5%).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 2:

24B (282 mg, 0.77 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 24C (225 mg, crude).

LC-MS (ESI): m/z=265.2 [M+H]⁺.

Step 3:

1H (120 mg, 0.54 mmol) and 24C (225 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 24 (91 mg, 37.6%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 8.29 (s, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.65 (s, 2H), 3.47-3.40 (m, 4H), 3.35 (t, 4H), 3.27 (s, 3H), 2.61-2.51 (m, 4H), 2.55-2.50 (m, 2H), 1.19 (t, 3H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 25

N-(3,3-difluorocyclobutyl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 25)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, 3,3-difluorocyclobutylamine (214 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 25B (332 mg, 83.6%).

LC-MS (ESI): m/z=397.2 [M+H]⁺.

Step 2:

25B (332 mg, 0.83 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 25C (275 mg, crude).

LC-MS (ESI): m/z=297.2 [M+H]⁺.

Step 3:

1H (160 mg, 0.72 mmol) and 25C (275 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 25 (114 mg, 23.6%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.91 (d, 1H), 8.41 (d, 1H), 8.27 (s, 1H), 7.83 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 4.36-4.21 (m, 1H), 3.66 (s, 2H), 3.36 (t, 4H), 2.93-2.80 (m, 4H), 2.64-2.55 (m, 4H), 2.55-2.51 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=483.2 [M+H]⁺.

Example 26

N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-3,3-difluorocyclobutane-1-carboxamide (Compound 26)

Step 1:

3,3-Difluorocyclobutane-1-carboxylic acid (214 mg, 2 mmol) was dissolved in DMF (10 mL), HATU (1140 mg, 3 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, 14A (278 mg, 1 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added 50 mL of ethyl acetate, and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 26B (254 mg, 64.1%).

LC-MS (ESI): m/z=397.2 [M+H]⁺.

Step 2:

26B (254 mg, 0.64 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 26C (197 mg, crude).

LC-MS (ESI): m/z=297.2 [M+H]⁺.

Step 3:

• • 1H (120 mg, 0.54 mmol) and 26C (197 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, a product was generated, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH (v/v)=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH (v/v)=1:0-10:1), to afford compound 26 (84 mg, 32.3%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.41 (s, 1H), 8.40 (d, 1H), 8.00 (d, 1H), 7.96 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.64 (s, 2H), 3.26-3.17 (m, 1H), 3.14 (t, 4H), 2.86-2.68 (m, 4H), 2.58-2.54 (m, 4H), 2.54-2.50 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=483.2 [M+H]⁺.

Example 27

3-ethyl-7-((4-(2-methylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 27)

Step 1:

27A (200 mg, 0.94 mmol), piperazine (89 mg, 1.07 mmol), Pd₂(dba)₃ (26 mg, 0.028 mmol), JohnPhos (12.45 mg, 0.028 mmol), sodium tert-butoxide (226 mg, 2.35 mmol) and toluene (10 mL) were added to a reaction flask, and the mixture was stirred at 100° C. under nitrogen protection for 5 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, extracted three times with ethyl acetate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford a crude. The crude was subjected to Flash column chromatography (MeOH:DCM=9%), to afford light brown 27B (119 mg, 0.55 mmol, yield: 58.3%).

Step 2:

27B (119 mg, 0.55 mmol), 1H (122.47 mg, 0.55 mmol), diisopropylethylamine (213 mg, 1.65 mmol), KI (46 mg, 0.28 mmol) and acetonitrile (5 mL) were added to a reaction flask, and the mixture was stirred at 80° C. for 5 h. After the reaction was completed, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm) 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; retention time: 7.0 min, to afford title compound 27 (17 mg, 8%).

LCMS m/z=404.2 [M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.40 (d, 1H), 7.75 (s, 1H), 7.70 (d, 1H), 7.64 (d, 2H), 7.07 (d, 1H), 3.65 (s, 2H), 3.45 (s, 4H), 2.57-2.52 (m, 6H), 2.28 (s, 3H), 1.18 (t, 3H).

Example 28

3-ethyl-7-((4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 28)

Step 1:

28A (200 mg, 0.94 mmol), piperazine (178 mg, 2.07 mmol), Pd₂(dba)₃ (26 mg, 0.028 mmol), JohnPhos (12.45 mg, 0.028 mmol), sodium tert-butoxide (226 mg, 2.35 mmol) and toluene (10 mL) were added to a reaction flask, and the mixture was stirred at 100° C. under nitrogen protection for 5 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, extracted three times with ethyl acetate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford a crude. The crude was subjected to Flash column chromatography (MeOH:DCM=9%), to afford compound 28B (130 mg, 63.7%).

Step 2:

28B (140 mg, 0.64 mmol), 1H (143 mg, 0.64 mmol), diisopropylethylamine (248 mg, 1.92 mmol), potassium iodide (53 mg, 0.32 mmol) and acetonitrile (5 mL) were added to a reaction flask, and the mixture was stirred at 100° C. for 5 h. After the reaction was completed, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; retention time: 7.0 min, to afford title compound 28 (17 mg, 7%).

LCMS m/z=404.2 [M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.53 (d, 1H), 8.41 (d, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H), 4.12 (s, 3H), 3.66 (s, 2H), 3.12 (s, 4H), 2.61 (d, 4H), 2.58-2.52 (m, 2H), 1.18 (t, 3H).

Example 29

7-((4-(6-(1H-1,2,3-triazol-5-yl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2 (1H)-one (Compound 29)

Step 1:

Compound 29A (1.5 g, 8.04 mmol) was dissolved in methanol (30 mL), trimethoxymethane (3.41 g, 32.16 mmol) and p-toluenesulfonic acid (0.028 g, 0.16 mmol) were added, and the mixture was warmed to 75° C. and reacted for 3 h. After the reaction was completed, the reaction system was diluted with ethyl acetate (50 ml). The organic phase was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29B (1.5 g, 80%).

LC-MS (ESI): m/z=232.1[M+1]⁺.

Step 2:

Under nitrogen protection, compound 29B (1.5 g, 6.46 mmol) and benzyl piperazine-1-carboxylate (1.71 g, 7.75 mmol) were dissolved in 1,4-dioxane (30 mL), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (II) (0.27 g, 0.32 mmol) and cesium carbonate (6.31 g, 19.38 mmol) were added, and the mixture was warmed to 100° C. and reacted overnight. After the reaction was completed, the reaction system was diluted with ethyl acetate (50 ml). The organic phase was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29C (1.3 g, 54%).

LC-MS (ESI): m/z=372.3[M+1]⁺.

Step 3:

Compound 29C (1.3 g, 3.50 mmol) was dissolved in tetrahydrofuran (10 mL), 4M hydrochloric acid (0.64 g, 17.57 mmol) was added, and the mixture was warmed to 50° C. and reacted for 5 h. After the reaction was completed, the reaction system was adjusted to pH 6 with sodium bicarbonate and diluted with ethyl acetate (50 ml). The organic phase was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29D (1.1 g, 97%).

LC-MS (ESI): m/z=326.2[M+1]⁺.

Step 4:

Compound 29D (800 mg, 2.46 mmol) was dissolved in methanol (10 mL), dimethyl 1-diazo-2-oxopropylphosphonate (0.71 g, 3.70 mmol) and potassium carbonate (0.68 g, 4.92 mmol) were added, and the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction liquid was filtered, the organic phase was collected and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29E (0.75 g, 95%).

LC-MS (ESI): m/z=322.2[M+1]⁺.

Step 5:

Compound 29E (750 mg, 2.33 mmol) and azidotrimethylsilane (0.54 g, 4.66 mmol) were added to DMF (8 mL), copper sulfate pentahydrate (II) (0.12 g, 0.47 mmol), L-sodium ascorbate (0.18 g, 0.93 mmol) and water (2 mL) were added, and the mixture was warmed to 100° C. and reacted for 2 h. After the reaction was completed, the reaction system was diluted with ethyl acetate (20 ml). The organic phase was washed with water (5 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29F (0.75 g, 88%).

LC-MS (ESI): m/z=365.2[M+1]⁺.

Step 6:

Under hydrogen protection, compound 29F (0.75 g, 2.06 mmol) was dissolved in methanol (20 mL), palladium on carbon (0.033 g, 0.31 mmol) and palladium hydroxide (0.043 g, 0.31 mmol) were added, and the mixture was reacted at room temperature for 5 h. After the reaction was completed, the reaction liquid was filtered, the organic phase was collected and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 29G (0.35 g, 74%).

LC-MS (ESI): m/z=231.2[M+1]⁺.

Step 7:

Under nitrogen protection, compound 29G (0.12 g, 0.54 mmol) was added to a flask, dimethyl sulfoxide (2 mL) was added, followed by 1H (100 mg, 0.45 mmol), ethyldiisopropylamine (0.35 g, 2.7 mmol) and potassium iodide (0.015 g, 0.090 mmol), and the mixture was warmed to 100° C. and reacted at this temperature for 1 h. After the reaction was completed as monitored by LCMS, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; d. elution time: 20 min, retention time: 7.0 min, to afford compound 29 (40 mg, 21%).

LC-MS (ESI): m/z=417.3[M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 14.98 (s, 1H), 11.82 (s, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 8.15 (s, 1H), 7.84-7.76 (m, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.42 (dd, 1H), 3.66 (s, 2H), 3.27 (d, 4H), 2.62-2.56 (m, 4H), 2.54 (dd, 2H), 1.18 (t, 3H).

Example 30

7-((4-(6-(1H-pyrazol-5-yl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2 (1H)-one (Compound 30)

Step 1:

Compound 30A (1.5 g, 7.50 mmol) and ethylene glycol (1.40 g, 22.5 mmol) were dissolved in toluene (25 mL), p-toluenesulfonic acid (2.58 g, 15 mmol) was added, and the mixture was heated to reflux for 10 h. After the reaction was completed, the reaction system was diluted with ethyl acetate (30 ml). The organic phase was washed with saturated sodium bicarbonate (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 30B (1.5 g, 82%).

LC-MS (ESI): m/z=244.0[M+1]⁺.

Step 2:

Under nitrogen protection, compound 30B (1.5 g, 6.15 mmol) and benzyl piperazine-1-carboxylate (1.63 g, 7.38 mmol) were dissolved in 1,4-dioxane (20 mL), methanesulfonic acid(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (II) (0.26 g, 0.31 mmol) was added, and the mixture was warmed to 100° C. and reacted overnight. After the reaction was completed, the reaction system was diluted with ethyl acetate (30 ml). The organic phase was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 30C (1.8 g, 76%).

LC-MS (ESI): m/z=384.2[M+1]⁺.

Step 3:

Compound 30C (1.8 g, 4.69 mmol) was dissolved in tetrahydrofuran (20 mL), 4M hydrochloric acid (0.17 g, 4.69 mmol) was added, and the mixture was warmed to 100° C. and reacted for 2 h. After the reaction was completed, the reaction system was adjusted to pH 6 with sodium bicarbonate and diluted with ethyl acetate (50 ml). The organic phase was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 30D (1.3 g, 82%).

LC-MS (ESI): m/z=340.1[M+1]⁺.

Step 4:

Compound 30D (500 mg, 1.47 mmol) was added to (dimethoxymethyl)dimethylamine (9.00 g, 75.53 mmol), and the mixture was warmed to 110° C. and reacted for 15 h. After the reaction was completed, the reaction liquid was directly concentrated, to afford crude compound 30E (0.5 g).

LC-MS (ESI): m/z=395.2[M+1]⁺.

Step 5:

Compound 30E (500 mg, 1.27 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (0.64 g, 12.79 mmol) was added, and the mixture was warmed to 85° C. and reacted for 2 h. After the reaction was completed, the reaction liquid was directly concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 30F (0.42 g, 91%).

LC-MS (ESI): m/z=364.1[M+1]⁺.

Step 6:

Under hydrogen protection, compound 30F (300 mg, 0.83 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.013 g, 0.12 mmol) and palladium hydroxide (0.017 g, 0.12 mmol) were added, and the mixture was reacted overnight at room temperature. After the reaction was completed, the reaction liquid was filtered, the organic phase was collected and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 30G (0.15 g, 79%).

LC-MS (ESI): m/z=230.1[M+1]⁺.

Step 7:

Under nitrogen protection, compound 30G (0.07 g, 0.31 mmol) was added to a flask, dimethyl sulfoxide (2 mL) was added, followed by 1H (0.07 g, 0.31 mmol), ethyldiisopropylamine (0.24 g, 1.86 mmol) and potassium iodide (0.01 g, 0.062 mmol), and the mixture was warmed to 100° C. and reacted at this temperature for 1 h. After the reaction was completed as monitored by LCMS, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; d. elution time: 20 min, retention time: 7.0 min, to afford compound 30 (30 mg, 23%).

LC-MS (ESI): m/z=416.2[M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (s, 1H), 11.83 (s, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.88-7.53 (m, 4H), 7.38 (dd, 1H), 6.68 (d, 1H), 3.67 (s, 2H), 3.28-3.12 (m, 4H), 2.68-2.56 (m, 4H), 2.55 (dd, 2H), 1.19 (t, 3H).

Example 31

3-ethyl-7-((4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 31)

Step 1:

Under nitrogen protection, compound 31A (100 mg, 0.47 mmol) and piperazine (49 mg, 0.57 mmol) were dissolved in 1,4-dioxane (5 mL), cesium carbonate (460 mg, 1.41 mmol) and methanesulfonic acid(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (II) (20 mg, 0.024 mmol) were added, and the mixture was warmed to 100° C. and reacted overnight. After the reaction was completed, the reaction system was diluted with ethyl acetate (10 ml). The organic phase was washed with water (2 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: MeOH:DCM=0%-10%), to afford compound 31B (0.05 g, 49%).

LC-MS (ESI): m/z=218.1[M+1]⁺.

Step 2:

Under nitrogen protection, compound 31B (50 mg, 0.22 mmol) was added to a flask, dimethyl sulfoxide (2 mL) was added, followed by 1H (47.8 mg, 0.22 mmol), ethyldiisopropylamine (170 mg, 1.32 mmol) and potassium iodide (7.3 mg, 0.043 mmol), and the mixture was warmed to 100° C. and reacted at this temperature for 1 h. After the reaction was completed as monitored by LCMS, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; d. elution time: 20 min, retention time: 7.0 min, to afford compound 31 (23 mg, 26%).

LC-MS (ESI): m/z=404.2[M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.40 (d, 1H), 8.19 (dd, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.59-7.52 (m, 2H), 3.66 (s, 2H), 3.12 (t, 4H), 2.61-2.51 (m, 6H), 2.40 (s, 3H), 1.18 (t, 3H).

Example 32

3-ethyl-7-((4-(6-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 32)

Step 1:

Compound 32A (321 mg, 1 mmol), 1-methyl-1H-pyrazole-3-amine (145 mg, 1.5 mmol), Brettphos Pd G3 (45.3 mg, 0.05 mmol) and sodium tert-butoxide (192 mg, 2 mmol) were dissolved in 1,4-dioxane, and the mixture was reacted overnight at 95° C. under nitrogen protection. After the reaction was completed, the reaction liquid was cooled to room temperature and filtered, and the filtrate was collected and separated by silica gel chromatographic column (DCM:MeOH=20:1), to afford title compound 32B (289 mg, 82.1%).

LC-MS (ESI): m/z=359.2 [M+H]⁺.

Step 2:

32B (289 mg, 0.82 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 32C (225 mg, crude).

LC-MS (ESI): m/z=259.2 [M+H]⁺.

Step 3:

1H (100 mg, 0.45 mmol) and 32C (225 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 32 (88 mg, 44.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.77 (s, 1H), 8.40 (d, 1H), 7.79 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.44 (d, 1H), 7.30 (dd, 1H), 7.21 (d, 1H), 6.17 (d, 1H), 3.70 (s, 3H), 3.64 (s, 2H), 3.02 (t, 4H), 2.58-2.54 (m, 4H), 2.54-2.50 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=445.2 [M+H]⁺.

Example 33

N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 33)

Step 1:

Compound 1-methyl-1H-pyrazole-4-carboxylic acid (378 mg, 3 mmol) was dissolved in thionyl chloride (20 mL), the mixture was reacted at 70° C. for 1 h at reflux, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (20 mL), 14A (556 mg, 2 mmol) and triethylamine were added, and the mixture was stirred overnight at room temperature. 0.1M (20 mL) hydrochloric acid solution was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3), washed with saturated NaHCO₃ solution, dried, and separated by silica gel chromatographic column (PE:EA=2:1), to afford title compound 33A (277 mg, 42.5%).

LC-MS (ESI): m/z=387.2 [M+H]⁺.

Step 2:

33A (277 mg, 0.71 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 33B (233 mg, crude).

LC-MS (ESI): m/z=287.2 [M+H]⁺.

Step 3:

1H (120 mg, 0.54 mmol) and 33B (233 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (DCM:MeOH=1:0-10:1), to afford compound 33 (86 mg, 33.8%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.22 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.42 (dd, 1H), 3.87 (s, 3H), 3.65 (s, 2H), 3.17 (s, 4H), 2.59-2.55 (m, 4H), 2.55-2.52 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=473.2 [M+H]⁺.

Example 34

(1R,2R)—N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide (Compound 34)

Step 1:

Compound (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (312 mg, 3 mmol) was dissolved in thionyl chloride (10 mL), the mixture was reacted at 70° C. for 1 h at reflux, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (20 mL), 14A (556 mg, 2 mmol) and triethylamine were added, and the mixture was stirred overnight at room temperature. 0.1M (20 mL) hydrochloric acid solution was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3), washed with saturated sodium bicarbonate solution, dried, and separated by silica gel chromatographic column (PE:EA=2:1), to afford title compound 34A (389 mg, 53.3%).

LC-MS (ESI): m/z=365.1 [M+H]⁺.

Step 2:

34A (389 mg, 1.1 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 34B (294 mg, crude).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 3:

1H (180 mg, 0.8 mmol) and 34B (294 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 34 (121 mg, 33.6%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 10.65 (s, 1H), 8.40 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 7.37 (dd, 1H), 4.96-4.73 (m, 1H), 3.64 (s, 2H), 3.15 (t, 4H), 2.55 (t, 4H), 2.55-2.54 (m, 2H), 2.49-2.41 (m, 1H), 1.52-1.38 (m, 1H), 1.18 (t, 3H), 1.25-1.15 (m, 1H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 35

(1S,2R)—N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide (Compound 35)

Step 1:

Compound (1S,2R)-2-fluorocyclopropane-1-carboxylic acid (312 mg, 3 mmol) was dissolved in thionyl chloride (10 mL), the mixture was reacted at 70° C. for 1 h at reflux, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (20 mL), 14A (556 mg, 2 mmol) and triethylamine were added, and the mixture was stirred overnight at room temperature. 0.1M (20 mL) hydrochloric acid solution was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3), washed with saturated sodium bicarbonate solution, dried, and separated by silica gel chromatographic column (PE:EA=2:1), to afford title compound 35A (421 mg, 58.6%).

LC-MS (ESI): m/z=365.1 [M+H]⁺.

Step 2:

35A (421 mg, 1.1 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 35B (314 mg, crude).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 3:

1H (180 mg, 0.8 mmol) and 35B (300 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 35 (111 mg, 32.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 10.52 (s, 1H), 8.40 (d, 1H), 7.99 (d, 1H), 7.91 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.38 (dd, 1H), 2.74-5.01 (m, 1H), 3.65 (s, 2H), 3.15 (t, 4H), 2.58 (t, 4H), 2.54-2.53 (m, 2H), 2.27-2.03 (m, 1H), 1.68-1.54 (m, 1H), 1.18 (t, 3H), 1.15-1.08 (m, 1H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 36

(S)—N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1-methylpyrrolidine-3-carboxamide (Compound 36)

Step 1:

Compound (S)-1-methylpyrrolidine-3-carboxylic acid (387 mg, 3 mmol) was dissolved in thionyl chloride (10 mL), the mixture was reacted at 70° C. for 1 h at reflux, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane (20 mL), 14A (556 mg, 2 mmol) and triethylamine were added, and the mixture was stirred overnight at room temperature. 0.1M (20 mL) hydrochloric acid solution was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3), washed with saturated sodium bicarbonate solution, dried, and separated by silica gel chromatographic column (PE:EA=2:1), to afford title compound 36A (352 mg, 45.3%).

LC-MS (ESI): m/z=390.2 [M+H]⁺.

Step 2:

36A (352 mg, 0.9 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 36B (282 mg, crude).

LC-MS (ESI): m/z=290.2 [M+H]⁺.

Step 3:

1H (180 mg, 0.8 mmol) and 36B (282 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 36 (132 mg, 37.5%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.15 (s, 1H), 8.40 (d, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.38 (dd, 1H), 3.64 (s, 2H), 3.15 (t, 4H), 3.13-3.05 (m, 2H), 2.75 (t, 1H), 2.55 (t, 4H), 2.55-2.53 (m, 2H), 2.47 (dd, 1H), 2.40 (q, 1H), 2.24 (s, 3H), 2.04-1.89 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=476.2 [M+H]⁺.

Example 37

Cyclopropyl(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)pyridin-2-yl)carbamate (Compound 37)

Step 1:

Compound 14A (556 mg, 2 mmol) was dissolved in DMF (20 mL) under nitrogen protection and cooled in an ice-water bath, sodium hydride (320 mg, 60%) was then added, and the mixture was stirred and reacted for 1 h in the ice bath. Subsequently, carbonyldiimidazole (486 mg, 3 mmol) was added, and the mixture was stirred and reacted for another 30 min, at which time the color of the system was observed to become lighter. Excess cyclopropanol was finally added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, to the system was added ethyl acetate (100 mL), and the mixture was washed with water (100 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 37A (253 mg, 35.1%).

LC-MS (ESI): m/z=363.2 [M+H]⁺.

Step 2:

37A (253 mg, 0.7 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 37B (200 mg, crude).

LC-MS (ESI): m/z=290.2 [M+H]⁺.

Step 3:

1H (150 mg, 0.67 mmol) and 37B (200 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 37 (76 mg, 25.3%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.88 (d, 1H), 8.55 (d, 1H), 8.01 (d, 1H), 7.81 (s, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.48 (dd, 1H), 4.53 (s, 2H), 4.05 (tt, 1H), 3.15 (t, 4H), 2.65 (t, 4H), 2.62-2.53 (m, 2H), 1.20 (t, 3H), 0.83-0.57 (m, 4H).

LC-MS (ESI): m/z=449.2 [M+H]⁺.

Example 38

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-(spiro[3.3]heptan-2-yl)picolinamide (Compound 38)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, spiro[3.3]heptan-2-amine (222 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 38B (322 mg, 80.5%).

LC-MS (ESI): m/z=401.2 [M+H]⁺.

Step 2:

38B (332 mg, 0.8 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 38C (267 mg, crude).

LC-MS (ESI): m/z=301.2 [M+H]⁺.

Step 3:

1H (180 mg, 0.8 mmol) and 38C (267 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 38 (141 mg, 36.2%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.62-8.35 (m, 2H), 8.25 (d, 1H), 7.81 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.38 (dd, 1H), 4.26 (s, 1H), 3.65 (s, 2H), 3.34 (t, 4H), 2.61-2.52 (m, 6H), 2.32-2.24 (m, 2H), 2.13-1.98 (m, 4H), 1.90 (t, 2H), 1.79 (q, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=487.2 [M+H]⁺.

Example 39

N-(bicyclo[1.1.1]pentan-1-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 39)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, bicyclo[1.1.1]pentan-1-amine (166 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 39B (292 mg, 78.5%).

LC-MS (ESI): m/z=373.2 [M+H]⁺.

Step 2:

39B (292 mg, 0.78 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 39C (239 mg, crude).

LC-MS (ESI): m/z=273.2 [M+H]⁺.

Step 3:

1H (120 mg, 0.6 mmol) and 39C (239 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 39 (87 mg, 26.2%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.75 (s, 1H), 8.40 (d, 1H), 8.24 (d, 1H), 7.80 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 3.65 (s, 2H), 3.34 (t, 4H), 2.60-2.52 (m, 6H), 2.43 (s, 1H), 2.07 (s, 6H), 1.18 (t, 3H).

LC-MS (ESI): m/z=459.2 [M+H]⁺.

Example 40

N-(cyclopropylmethyl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 40)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, cyclopropylmethylamine (140 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 40B (332 mg, 92.2%).

LC-MS (ESI): m/z=361.2 [M+H]⁺.

Step 2:

40B (332 mg, 0.92 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 40C (281 mg, crude).

LC-MS (ESI): m/z=261.2 [M+H]⁺.

Step 3:

1H (180 mg, 0.8 mmol) and 40C (281 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 40 (143 mg, 39.7%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.47-8.35 (m, 2H), 8.28 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.66 (s, 2H), 3.34 (t, 4H), 3.14 (t, 2H), 2.66-2.52 (m, 6H), 1.19 (t, 3H), 1.12-0.95 (m, 1H), 0.49-0.33 (m, 2H), 0.30-0.16 (m, 2H).

LC-MS (ESI): m/z=447.2 [M+H]⁺.

Example 41

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-((1S,2R)-2-fluorocyclopropyl)picolinamide (Compound 41)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, cyclopropylmethylamine (150 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added water (50 mL) under stirring, at which time a large amount of white solid was observed to be precipitated out, and the mixture was stirred for another 10 min, filtered and dried under vacuum, to afford target compound 41B (327 mg, 89.8%).

LC-MS (ESI): m/z=365.2 [M+H]⁺.

Step 2:

41B (327 mg, 0.9 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 41C (271 mg, crude).

LC-MS (ESI): m/z=265.2 [M+H]⁺.

Step 3:

1H (160 mg, 0.7 mmol) and 41C (271 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 41 (118 mg, 37.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.40 (d, 1H), 8.31 (d, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.41 (dd, 1H), 4.89-4.65 (m, 1H), 3.65 (s, 2H), 3.35 (t, 4H), 2.90-2.82 (m, 1H), 2.62-2.52 (m, 6H), 1.24-1.19 (m, 1H), 1.18 (t, 3H), 1.15-1.03 (m, 1H).

LC-MS (ESI): m/z=451.2 [M+H]⁺.

Example 42

3-ethyl-7-((4-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 42)

Step 1:

42A (1.0 g, 5.45 mmol) and benzyl piperazine-1-carboxylate (1.4 g, 6.54 mmol) were dissolved in 1,4-dioxane (10 mL), cesium carbonate (5.3 g, 16.35 mmol) and RuPhos-Pd-G3 (182 mg, 0.22 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. Subsequently, the reaction liquid was quenched with water (15 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 42B (1.6 g, 91.1%).

LC-MS (ESI): m/z=323.1 [M+H]⁺.

Step 2:

42B (500 mg, 1.55 mmol) was dissolved in ethanol (5 mL), sodium methoxide (0.29 mL, 5.4 mol/L) was then added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by TLC, acetyl hydrazine (689 mg, 9.3 mmol) was added, and the mixture was refluxed overnight, concentrated and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 42C (220 mg, 37.5%).

LC-MS (ESI): m/z=379.1 [M+H]⁺.

Step 3:

42C (220 mg, 1.55 mmol) was dissolved in methanol (5 mL), Pd/C (44 mg) was added, and the mixture was reacted at room temperature in hydrogen environment for 2 hours, filtered and spun to dryness, to afford title compound 42D (120 mg, 84.7%).

LC-MS (ESI): m/z=223.1 [M+H]⁺.

Step 4:

1H (100 mg, 0.45 mmol) and 42D (110 mg, 0.45 mmol) were dissolved in anhydrous acetonitrile (5 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (291 mg, 2.25 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated and purified by preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonia water); b. gradient elution, mobile phase A: 5% to 50%; c. flow rate: 12 mL/min; d. elution time: 20 min, and the preparative liquid was concentrated and lyophilized, to afford compound 42 (30 mg, 15.5%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.41 (d, 1H), 8.34 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 3.66 (s, 2H), 3.36-3.32 (m, 4H, overlapped with H₂O peak), 2.61-2.52 (m, 6H), 2.31 (s, 3H), 1.19 (t, 3H).

LC-MS (ESI): m/z=431.2 [M+H]⁺.

Example 43

3-ethyl-7-((4-(2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 43)

Step 1:

43A (1.0 g, 5.71 mmol), 3-bromo-1,1,1-trifluoroacetone (2.7 g, 14.26 mmol), and N,N-dimethylacetamide (4 mL) were added to a sealed tube, and the mixture was stirred at 80° C. for 16 h. After the reaction was completed, the reaction liquid was purified by reverse-phase column, to afford 43B (460 mg, 30%).

LCMS m/z=266.0 [M+1]⁺.

Step 2:

Compound 43B (800 mg, 3.01 mmol), tert-butyl piperazine-1-carboxylate (840 mg, 4.52 mmol), Pd₂(dba)₃ (287 mg, 0.30 mmol), JohnPhos (90 mg, 0.30 mmol), sodium tert-butoxide (723 mg, 7.52 mmol) and toluene (10 mL) were added to a reaction flask, and the mixture was stirred at 110° C. under nitrogen protection for 4 h. After the reaction was completed, the reaction liquid was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (EA:PE=20%), to afford 43C (330 mg, 29%).

LCMS m/z=372.1 [M+1]⁺.

Step 3:

Compound 43C (330 mg, 0.89 mmol) and trifluoroacetic acid (3 mL) were added to a reaction flask, and the mixture was stirred at 25° C. for 1 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, to afford crude 43D (240 mg, 100%), which was used directly in the next step.

Step 4:

43D (240 mg, 0.88 mmol), 1H (235 mg, 1.06 mmol), DIPEA (341 mg, 2.64 mmol), potassium iodide (29 mg, 0.18 mmol) and acetonitrile (4 mL) were added to a reaction flask, and the mixture was stirred at 80° C. for 2 h. After the reaction was completed as monitored by LCMS, the reaction system was directly purified by preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; retention time: 7.0 min, to afford title compound 43 (27 mg, 7%).

LCMS m/z=458.3 [M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H), 8.99 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 7.93 (d, 1H), 7.76 (s, 1H), 7.64 (d, 1H), 3.67 (s, 2H), 3.33 (s, 4H), 2.62-2.54 (m, 6H), 1.19 (t, 3H).

Example 44

3-ethyl-7-((4-(2-ethylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 44)

Step 1:

43A (800 mg, 4.55 mmol), bromobutanone (687 mg, 4.55 mmol), and N,N-dimethylacetamide (4 mL) were added to a sealed tube, and the mixture was stirred at 80° C. for 16 h. After the reaction was completed, the reaction liquid was purified by reverse-phase column, to afford 44B (320 mg, 31%).

LCMS m/z=226.0 [M+1]⁺.

Step 2:

Compound 44B (220 mg, 0.97 mmol), tert-butyl piperazine-1-carboxylate (361 mg, 1.94 mmol), Pd₂(dba)₃ (89 mg, 0.10 mmol), JohnPhos (29 mg, 0.10 mmol), sodium tert-butoxide (233 mg, 2.42 mmol) and toluene (10 mL) were added to a reaction flask, and the mixture was stirred at 110° C. under nitrogen protection for 4 h. After the reaction was completed, the reaction liquid was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (EA:PE=80%), to afford 44C (71 mg, 22%).

LCMS m/z=332.2 [M+1]⁺.

Step 3:

Compound 44C (70 mg, 0.21 mmol) and trifluoroacetic acid (3 mL) were added to a reaction flask, and the mixture was stirred at 25° C. for 1 h. After the reaction was completed, the reaction liquid was directly concentrated under reduced pressure, to afford crude 44D (48 mg, 100%), which was used directly in the next step.

Step 4:

44D (48 mg, 0.21 mmol), 1H (71 mg, 0.32 mmol), DIPEA (81 mg, 0.63 mmol), potassium iodide (7 mg, 0.04 mmol) and acetonitrile (4 mL) were added to a reaction flask, and the mixture was stirred at 80° C. for 2 h. After the reaction was completed as monitored by LCMS, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; retention time: 7.0 min, to afford title compound 44 (4 mg, 5%).

LCMS m/z=418.3 [M+1]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.68 (s, 1H), 8.42 (d, 1H), 7.85 (s, 1H), 7.74 (d, 2H), 7.64 (s, 1H), 3.66 (s, 2H), 3.28 (s, 4H), 2.72 (q, 2H), 2.62-2.53 (m, 6H), 1.25 (t, 3H), 1.19 (t, 3H).

Example 45

2 (1H)-one (Compound 45)

Step 1:

45A (5 g, 40.27 mmol) was dissolved in anhydrous tetrahydrofuran, and the mixture was subjected to nitrogen replacement three times. Dibromomethane (14 g, 80.54 mmol) was added, the reaction system was cooled to −78° C., methyllithium (80.54 mmol) was added dropwise, and the mixture was reacted at −78° C. for 2 h. After the reaction was completed, saturated ammonium chloride solution was added at 0° C. to quench the reaction, and the mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by flash column chromatography (eluent: EA/PE=0%-20%), to afford compound 45B (5.01 g, 72%).

LC-MS (ESI): m/z=173.2[M+1]⁺.

Step 2:

45B (1 g, 5.78 mmol), 5-bromopyrazin-2-amine (0.33 g, 1.90 mmol), and N,N-dimethylacetamide (5 mL) were added to a sealed tube, and the mixture was stirred at 100° C. for 16 h. After the reaction was completed, the reaction system was purified by preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 40%-70%; c. flow rate: 12 mL/min; retention time: 10.0 min, to afford 45C (250 mg, 53%).

LC-MS (ESI): m/z=248.0[M+1]⁺.

Step 3:

Compound 45C (250 mg, 1.01 mmol), tert-butyl piperazine-1-carboxylate (280 mg, 1.5 mmol), Pd₂(dba)₃ (96 mg, 0.10 mmol), JohnPhos (30 mg, 0.10 mmol) and sodium tert-butoxide (290 mg, 3.03 mmol) were added to a reaction flask, and the mixture was stirred at 110° C. under nitrogen protection for 4 h. After the reaction was completed, the reaction liquid was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (EA:PE=20%), to afford target compound 45D (150 mg, 42%).

LC-MS (ESI): m/z=354.2[M+1]⁺.

Step 4:

Compound 45D (150 mg, 0.42 mmol) was added to 50 mL of reaction flask, dichloromethane (3 ml)/trifluoroacetic acid (2 ml) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction liquid was directly concentrated, to afford crude compound 45E (150 mg).

LC-MS (ESI): m/z=254.2[M+1]⁺.

Step 5:

45E (150 mg, 0.42 mmol), 1H (114 mg, 0.51 mmol), DIPEA (318 mg, 2.52 mmol), potassium iodide (16.6 mg, 0.1 mmol) and acetonitrile (4 mL) were added to a reaction flask, and the mixture was stirred at 80° C. for 2 h. After the reaction was completed as monitored by LCMS, the reaction system was directly subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; retention time: 7.0 min, to afford title compound 45 (50 mg, 27%).

LCMS m/z=440.2 [M+1]⁺.

¹H NMR (400 MHz, CDCl₃) 512.37 (s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H), 7.31 (s, 1H), 6.85 (t, 1H), 3.74 (s, 2H), 3.40 (s, 4H), 2.76 (d, 2H), 2.71 (s, 4H), 1.33 (d, 3H).

¹⁹F NMR (376 MHz, CDCl₃) 5=−111.39.

Example 46

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)-N-(1-phenylazetidin-3-yl)picolinamide (Compound 46)

Step 1:

Compound 46A (1 g, 5.79 mmol) was dissolved in 1,4-dioxane, iodobenzene (2.36 g, 11.58 mmol), Pd₂(dba)₃ (530 mg, 0.58 mmol), XantPhos (340 mg, 0.58 mmol) and cesium carbonate (5.66 g, 17.37 mmol) were added to a reaction flask under nitrogen, and the mixture was stirred overnight at 100° C. under nitrogen protection. After the reaction was completed, the reaction liquid was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (EA/PE=0-20%), to afford target compound 46B (350 mg, 18%).

LC-MS (ESI): m/z=249.2[M+1]⁺.

Step 2:

Compound 46B (0.25 g, 1.01 mmol) was added to 50 mL of reaction flask, dichloromethane (3 ml)/trifluoroacetic acid (3 ml) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction liquid was directly concentrated, to afford crude compound 46C (0.2 g).

LC-MS (ESI): m/z=149.1[M+1]⁺.

Step 3:

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinic acid (100 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 ml), compound 46C (60 mg, 0.38 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) and N,N-diisopropylethylamine (130 mg, 1 mmol) were added to the reaction system, and the mixture was reacted overnight at room temperature. After the reaction was completed as monitored by LCMS, the reaction system was purified by preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, mobile phase A: 10%-55%; c. flow rate: 12 mL/min; d. elution time: 20 min, retention time: 7.0 min, to afford compound 46 (10 mg, 5%).

LC-MS (ESI): m/z=524.2[M+1]⁺.

¹H NMR (400 MHz, CDCl₃) 510.93 (s, 1H), 8.51 (s, 1H), 8.24 (d, 1H), 8.14 (s, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.22 (d, 3H), 6.77 (t, 1H), 6.50 (d, 2H), 5.13-4.95 (m, 1H), 4.32 (t, 2H), 3.94-3.66 (m, 4H), 3.41 (s, 4H), 2.70 (d, 5H), 1.29 (t, 3H).

Example 47

3-ethyl-7-((4-(2-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2 (1H)-one (Compound 47)

Step 1:

47A (600 mg, 2.84 mmol) and piperazine (1.2 g, 14.2 mmol) were dissolved in toluene (10 mL), sodium tert-butoxide (546 mg, 5.69 mmol), JohnPhos (127 mg, 0.43 mmol) and palladium acetate (260 mg, 0.28 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection, directly filtered, spun to dryness, and separated by silica gel chromatographic column (MeOH:DCM=0:1-1:1), to afford title compound 47B (610 mg, 99.3%).

LC-MS (ESI): m/z=217.1 [M+H]⁺.

Step 2:

1H (50 mg, 0.22 mmol) and 47B (120 mg, 0.56 mmol) were dissolved in anhydrous acetonitrile (5 mL), potassium iodide (4 mg, 0.02 mmol) and DIPEA (144 mg, 1.12 mmol) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 2 hours. Upon complete depletion of raw materials monitored by LCMS, a product was generated, and the system was concentrated and subjected to preparative HPLC with preparative HPLC separation methods: 1. Instruments: waters 2767 (preparative liquid phase chromatographic instrument); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm). 2. The sample was filtered with a 0.45 μm filter to prepare a sample liquid. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonia water); b. gradient elution, mobile phase A: 5% to 50%; c. flow rate: 12 mL/min; d. elution time: 20 min, and the preparative liquid was concentrated and lyophilized, to afford compound 47 (12 mg, 13.3%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.40 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.64-7.61 (m, 1H), 7.51 (s, 1H), 7.28 (d, 1H), 7.12 (dd, 1H), 3.66 (s, 2H), 3.08-2.99 (m, 4H), 2.60-2.52 (m, 6H), 2.27 (s, 3H), 1.18 (t, 3H).

LC-MS (ESI): m/z=403.2 [M+H]⁺.

Example 48

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)picolinamide (Compound 48)

Step 1:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, 1-methyl-3-aminopyrazole (196 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 48B (351 mg, 90.6%).

LC-MS (ESI): m/z=387.2 [M+H]⁺.

Step 2:

48B (351 mg, 0.90 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 48C (276 mg, crude).

LC-MS (ESI): m/z=287.2 [M+H]⁺.

Step 3:

1H (150 mg, 0.67 mmol) and 48C (276 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 48 (144 mg, 50.1%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H), 10.03 (s, 1H), 8.41 (d, 1H), 8.35 (d, 1H), 7.93 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.61 (d, 1H), 7.45 (dd, 1H), 6.58 (d, 1H), 3.76 (s, 3H), 3.66 (s, 2H), 3.40 (t, 4H), 2.60-2.52 (m, 6H), 1.19 (t, 3H).

LC-MS (ESI): m/z=473.2 [M+H]⁺.

Example 49

5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(1-(methyl-d3)-1H-pyrazol-3-yl)picolinamide (Compound 49)

Step 1:

Compound 3-nitro-1H-pyrazole (1.13 g, 10 mmol) was dissolved in DMF (20 mL), DBU (1.67 g, 11 mmol) and deuterated iodomethane (1.45 g, 10 mmol) were added, and the mixture was stirred and reacted at room temperature for 16 h. After the reaction was completed, to the system was added ethyl acetate (100 mL), the mixture was washed with saturated brine (4×80 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE:EA=1:0-4:1), to afford target compound 49A (864 mg, 66.4%).

LC-MS (ESI): m/z=131.2 [M+H]⁺.

Step 2:

49A (520 mg, 4 mmol) was dissolved in methanol (80 mL), Pd/C (100 mg, 10%) was added, the mixture was subjected to hydrogen replacement, reacted at room temperature for 4 hours and filtered, and the filtrate was spun to dryness, to afford title compound 49B (387 mg, 96.7%).

LC-MS (ESI): m/z=101.2 [M+H]⁺.

Step 3:

Compound 4A (321 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, to the resulting solid was added DMF (10 mL), HATU (570 mg, 1.5 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (1 mL) was added, 49B (200 mg, 2 mmol) was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 49C (338 mg, 87.2%).

LC-MS (ESI): m/z=390.2 [M+H]⁺.

Step 4:

49C (338 mg, 0.87 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 49D (243 mg, crude).

LC-MS (ESI): m/z=290.2 [M+H]⁺.

Step 5:

1H (150 mg, 0.67 mmol) and 49D (243 mg, crude) were dispersed in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 49 (122 mg, 46.9%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 10.02 (s, 1H), 8.41 (d, 1H), 8.35 (d, 1H), 7.93 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.61 (d, 1H), 7.45 (dd, 1H), 6.58 (d, 1H), 3.66 (s, 2H), 3.40 (t, 4H), 2.60-2.52 (m, 6H), 1.19 (t, 3H).

LC-MS (ESI): m/z=476.2 [M+H]⁺.

Example 50

(S)—N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (Compound 50 or 51) (R)—N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazin-1-yl)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (Compound 51 or 50)

Step 1:

2,2-Difluorocyclopropane-1-carboxylic acid (488 mg, 4 mmol) and 14A (556 mg, 2 mmol) were dissolved in DMF (20 mL), HATU (2.28 g, 6 mmol) and DIEPA (3 mL) were added under stirring, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (100 mL), and the mixture was washed with water (80 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 50C (589 mg, 77.1%).

LC-MS (ESI): m/z=383.2 [M+H]⁺.

Step 2:

50C (589 mg, 1.54 mmol) was dissolved in methanol (10 mL), and a solution of hydrogen chloride in dioxane (8 mL, 4M) was added. The mixture was reacted at room temperature for 4 hours and spun to dryness, to afford title compound 50D (494 mg, crude).

LC-MS (ESI): m/z=283.2 [M+H]⁺.

Step 3:

1H (260 mg, 1.2 mmol) and 50D (494 mg, crude) were dispersed in anhydrous acetonitrile (20 mL), potassium iodide (16 mg, 0.05 mmol) and DIPEA (2 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 4 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford 50E (246 mg, 46.2%).

50E was subjected to chiral resolution, to afford compound 50 (65 mg) and compound 51 (74 mg). Analysis method: instrument: Shimadzu LC-30AD sf; chromatographic column: Chiralpak OJ-3 50×4.6 mm I.D., 3 μm; mobile phase: A: CO₂, B: MeOH (0.05% DEA); gradient: B 5%-40%; flow rate: 3 mL/min, back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm. Resolution method: instrument: Waters 150 SFC; chromatographic column: Chiralpak chromatographic column; mobile phase: A: CO₂, B: EtOH (0.1% NH₃·H₂O); gradient: 40% B, isocratic elution; flow rate: 100 mL/min; back pressure: 100 bar; column temperature: 25° C.; wavelength: 220 nm; cycle time: 4.5 min; sample preparation: 1 mg/ml compound, dissolved in acetonitrile. Injection: 5 ml/injection. Post treatment: the separated components were concentrated in a water bath at 30° C. using a rotary evaporator, and then lyophilized, to afford compound 50 and compound 51; retention time: compound 50: 2.201 min; and compound 51: 2.500 min.

Compound 50: ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 10.72 (s, 1H), 8.40 (d, 1H), 8.02 (d, 1H), 7.89 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.65 (s, 2H), 3.24-3.05 (m, 4H), 2.98-2.85 (m, 1H), 2.55 (t, 6H), 2.05-1.87 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=469.2 [M+H]⁺.

Compound 51: ¹H NMR (400 MHz, DMSO-d₆) δ 11.93-11.74 (m, 1H), 10.72 (s, 1H), 8.40 (d, 1H), 8.02 (d, 1H), 7.89 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.65 (s, 2H), 3.16 (t, 4H), 2.95-2.87 (m, 1H), 2.60-2.52 (m, 6H), 2.05-1.87 (m, 2H), 1.18 (t, 3H).

LC-MS (ESI): m/z=469.2 [M+H]⁺.

Example 52

N-(2-(2,2-difluorocyclopropoxy)ethyl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 52)

Step 1:

Ethylene glycol vinyl ether 52A (22.0 g, 249.70 mmol) was dissolved in dichloromethane (330 mL), and then to the reaction liquid was added triethylamine (75.80 g, 749.10 mmol). After the addition was completed, the reaction liquid was cooled to about 0° C., benzoyl chloride (42.12 g, 299.64 mmol) was weighed and slowly added dropwise to the reaction liquid under stirring, and the mixture was stirred overnight at room temperature after the dropwise addition was completed. After the reaction was completed, to the reaction liquid were added water (300 mL) and dichloromethane (400 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (eluent: PE:EA=40:1 to 20:1 to 15:1), to afford target compound 52B (47.0 g, yield: 97.73%).

¹H NMR (400 MHz, CDCl₃) δ 8.21-7.93 (m, 2H), 7.66-7.50 (m, 1H), 7.50-7.32 (m, 2H), 6.54-6.49 (m, 1H), 4.57-4.55 (m, 2H), 4.27-4.22 (m, 1H), 4.08-4.01 (m, 1H), 4.04-3.98 (m, 2H).

Step 2:

Compound 52B (19.2 g, 98.99 mmol) was dissolved in toluene (150 mL), and then a catalytic amount of potassium fluoride (460 mg) was added. After the addition was completed, the mixture was heated to 105° C. under nitrogen protection, trimethylsilyl-2-(fluorosulfonyl)difluoroacetate (50.00 g, 199.78 mmol) was weighed and slowly added to the reaction liquid, and the mixture was reacted at this temperature for another 1 h after the addition was completed. The reaction process was monitored by TLC (ethyl acetate:petroleum ether=10:1). After the reaction was completed, the reaction liquid was cooled to room temperature, and to the reaction liquid were added ethyl acetate (500 mL) and water (300 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (ethyl acetate:petroleum ether=1:10), to afford target compound 52C (6.90 g, 28.52%).

¹H NMR (400 MHz, CDCl₃) δ 8.07-8.04 (m, 2H), 7.59-7.55 (m, 1H), 7.46-7.43 (m, 2H), 4.51-4.49 (m, 2H), 3.95-3.93 (m, 2H), 3.78-3.59 (m, 1H), 1.69-1.35 (m, 2H).

¹⁹F NMR (400 MHz, CDCl₃): δ=−128.47 (d), −146.94 (d).

Step 3:

Compound 52C (6.90 g, 28.49 mmol) was dissolved in methanol (50 mL), sodium hydroxide aqueous solution (4.56 g, 113.96 mmol) [preparation of sodium hydroxide aqueous solution: weighing 4.56 g of solid sodium hydroxide and dissolving same in 10 ml of purified water, and then cooling the mixture to room temperature] was then slowly added, and the mixture was stirred at room temperature for 2 h after the dropwise addition was completed. After the reaction was completed as monitored by TLC (PE:EA=10:1), to the reaction liquid were added water (50 mL) and ethyl acetate (400 mL). The aqueous phase was separated, and the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated, to afford target compound 52D (2.42 g, 61.50%).

¹H NMR (400 MHz, CDCl₃) δ 3.81-3.76 (m, 2H), 3.73-3.69 (m, 2H), 3.68-3.64 (m, 1H), 1.58-1.49 (m, 2H).

¹⁹F NMR (400 MHz, CDCl₃): δ=−128.62 (d), −146.91 (d).

Step 4:

Compound 52D (2.42 g, 17.52 mmol, crude) was dissolved in dichloromethane (80 mL), and then triethylamine (3.55 g, 35.04 mmol) was added. After the addition was completed, the mixture was cooled to 0° C. under nitrogen protection, and then methanesulfonyl chloride (2.41 g, 21.02 mmol) was slowly added to the reaction liquid. After the addition was completed, the resulting mixture was stirred at room temperature for 20 h. After the reaction was completed, to the reaction liquid were added dichloromethane (100 ml) and purified water (100 mL). The aqueous phase was separated, and the organic phase was washed with dichloromethane (100 mL). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated, to afford crude target compound 52E (3.48 g, 91.87%), which was directly used in the subsequent reaction.

¹H NMR (400 MHz, CDCl₃) δ 4.40-4.38 (m, 2H), 3.89-3.86 (m, 2H), 3.63-3.76 (m, 1H), 3.05 (s, 3H), 1.63-1.50 (m, 1H), 1.50-1.35 (m, 1H).

Step 5:

Compound 52E (3.48 g, 16.10 mmol) was dissolved in DMF (20 mL), sodium azide (3.14 g, 48.30 mmol) was weighed and added to the reaction liquid, and the mixture was heated to 60° C. and reacted overnight after the addition was completed. After the reaction was completed, to the reaction liquid was added water (100 mL), and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (300 mL×2), and dried over anhydrous sodium sulfate, to afford crude target compound 52F (2.05 g, 78.05%), which was directly used in the next reaction.

¹H NMR (400 MHz, CDCl₃) δ 3.82-3.74 (m, 2H), 3.72-3.64 (m, 1H), 3.44-3.41 (m, 2H), 1.68-1.39 (m, 2H).

Step 6:

Compound 52F (0.24 g, 1.47 mmol) was dissolved in ethyl acetate (6 mL), triphenylphosphine (0.579 g, 2.20 mmol) was then added, and the mixture was stirred at room temperature for 16 h after the addition was completed. After the reaction was completed, to the reaction liquid was added a solution of hydrogen chloride in dioxane (2 mL), and the mixture was stirred for another 1 h. The reaction liquid was concentrated in vacuum under reduced pressure to afford an oil, ethyl acetate (5 mL) was then added for dissolution, and an anti-solvent petroleum ether (5 mL) was added following dissolution. After the addition was completed, the mixture was stirred at room temperature for 10 min and filtered, and the filter cake was washed with a mixed solvent (ethyl acetate:petroleum ether=1:1) (5 mL), filtered and dried, to afford crude target compound 52G hydrochloride (0.17 g), which was directly used in the next reaction.

Step 7:

Compound 52G (0.39 g, 1.24 mmol) was dissolved in DMF (10 mL), HATU (0.67 g, 1.75 mmol) and diisopropylethylamine (0.45 g, 3.51 mmol) were then successively added, and the mixture was stirred at room temperature for 30 min after the addition was completed. Subsequently, to the reaction liquid was added lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinate (0.16 g, 1.17 mmol) (synthesized with reference to patent US 2018141923), and then the mixture was stirred at room temperature for 18 h. After the reaction was completed, the reaction liquid was slowly added to water (50 mL), and then the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (eluent: ethyl acetate:petroleum ether=3:1), to afford target compound 52H (0.19 g, 38%).

LCMS m/z=427.2 [M+1]⁺.

Step 8:

Compound 52H (0.19 g, 0.45 mmol) was dissolved in dichloromethane (10 mL), and then a solution of hydrogen chloride in dioxane (5 mL) was added under stirring at room temperature. After the addition was completed, the mixture was reacted and stirred overnight at room temperature. After the reaction was completed, the reaction liquid was directly concentrated to dryness, to afford target compound 521 hydrochloride (0.19 g). The hydrochloride was directly used in the next reaction.

LCMS m/z=327.1 [M+1]⁺.

Step 9:

Compound 521 (0.17 g, 0.52 mmol) and compound 1H (0.12 g, 0.52 mmol) were dissolved in DMF (5 mL), DIPEA (0.6 mL) and potassium iodide (0.17 g, 1.04 mmol) were then successively added, and the mixture was heated to 65° C. and reacted for 1 h after the addition was completed. After the reaction was completed, to the reaction liquid was added water (40 mL), and then the mixture was extracted with ethyl acetate (150 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (eluent: dichloromethane:methanol=10:1), to afford target compound (0.095 g, 35.64%).

LCMS m/z=513.2 [M+1]⁺.

¹H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.57-8.38 (m, 2H), 8.29-8.28 (m, 1H), 7.85-7.83 (m, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41-7.38 (m, 1H), 4.11-3.82 (m, 1H), 3.77-3.62 (m, 4H), 3.50-3.46 (m, 2H), 3.41-3.33 (m, 4H), 2.57-2.54 (m, 6H), 1.73-1.62 (m, 1H), 1.57-1.48 (m, 1H), 1.20-1.17 (m, 3H).

Example 53

N-(2-cyclopropoxyethyl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (Compound 53)

Step 1:

Ultra-dry dichloromethane (50 mL) was placed in 500 mL three-necked flask and subjected to nitrogen replacement for protection, and then a solution of diethylzinc in n-hexane (1.0 M/L) (150 mL, 150 mmol) was added. After the addition was completed, the mixture was cooled with acetonitrile dry ice bath until the internal temperature dropped to −40° C., and then to the reaction liquid was slowly added a solution of diiodomethane in dichloromethane (26.78 g, 100 mmol) (26.78 g of diiodomethane was dissolved in 20 mL of dichloromethane). After the addition was completed, the mixture was stirred at −40° C. for 30 min, and then compound 52B (9.61 g, 50 mmol) (9.61 g of compound 52B was dissolved in dichloromethane (20 mL)) was slowly added to the reaction liquid. After the addition was completed, the mixture was slowly warmed to room temperature, and then stirred overnight at room temperature. After the reaction was completed, to the reaction liquid were added saturated ammonium chloride aqueous solution (200 mL) and ethyl acetate (600 mL), and the mixture was filtered to afford a filtrate. The aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:15), to afford target compound 53A (5.90 g, 57.21%).

¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (m, 2H), 7.57-7.53 (m, 1H), 7.45-7.42 (m, 2H), 4.47-4.45 (m, 2H), 3.85-3.83 (m, 2H), 3.40-3.37 (m, 1H), 0.65-0.54 (m, 2H), 0.52-0.48 (m, 2H).

Step 2:

Compound 53A (5.90 g, 28.61 mmol) was dissolved in methanol (50 mL), the prepared sodium hydroxide aqueous solution (4.58 g, 114.44 mmol) [preparation of sodium hydroxide aqueous solution: weighing 4.58 g of solid sodium hydroxide and dissolving same in 10 ml of purified water, and then cooling the mixture to room temperature for later use] was then slowly added, and the mixture was stirred overnight at room temperature after the addition was completed. After the reaction was completed as monitored by TLC (PE:EA=10:1), to the reaction liquid were added water (50 mL) and ethyl acetate (150 mL×3). The aqueous phase was separated, and the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated, to afford crude target compound 53B (1.29 g, 44.15%), which was directly used in the subsequent reaction.

¹H NMR (400 MHz, CDCl₃) δ 3.72-3.69 (m, 2H), 3.66-3.50 (m, 2H), 3.34-3.31 (m, 1H), 2.43 (s, 1H), 0.69-0.55 (m, 2H), 0.54-0.36 (m, 2H).

Step 3:

Compound 53B (1.29 g, 12.63 mmol) was dissolved in dichloromethane (120 mL), and then triethylamine (3.83 g, 37.89 mmol) was added. After the addition was completed, the mixture was cooled to 0° C. under nitrogen protection, and then methanesulfonyl chloride (1.74 g, 15.12 mmol) was slowly added to the mixture. After the addition was completed, the resulting mixture was naturally warmed to room temperature and stirred overnight. After the reaction was completed, to the reaction liquid were added dichloromethane (200 mL) and water (200 mL). The organic phase was separated, and the aqueous phase was extracted once with dichloromethane (200 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, to afford crude target compound 53C (1.77 g, 77.76%).

¹H NMR (400 MHz, CDCl₃) δ 4.36-4.34 (m, 2H), 378-3.76 (m, 2H), 337-3.35 (m, 1H), 3.04 (2, 3H), 0.61-0.58 (m, 2H), 0.52-0.51 (m, 2H).

Step 4:

Compound 53C (1.77 g, 9.82 mmol) was dissolved in DMF (10 mL), sodium azide (1.92 g, 29.46 mmol) was then weighed and added to the reaction liquid, and the mixture was heated to 60° C. and reacted overnight after the addition was completed. After the reaction was completed, to the reaction liquid was added water (50 mL), and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, to afford crude target compound 53D (0.48 g, 38.45%).

¹H NMR (400 MHz, CDCl₃) δ 3.77-3.60 (m, 2H), 3.40-3.26 (m, 3H), 0.63-0.59 (m, 2H), 0.52-0.50 (m, 2H).

Step 5:

Compound 53D (0.31 g, 2.44 mmol) was dissolved in ethyl acetate (6 mL), triphenylphosphine (0.770 g, 2.94 mmol) was then added, and the mixture was stirred at room temperature for 16 h after the addition was completed. After the reaction was completed, to the reaction liquid was added a solution of hydrogen chloride in dioxane (2 mL), and the mixture was stirred for another 1 h. The reaction liquid was concentrated in vacuum under reduced pressure to afford an oil, ethyl acetate (5 mL) was then added for dissolution, and an anti-solvent petroleum ether (5 mL) was added following dissolution. After the addition was completed, the mixture was stirred at room temperature for 10 min and filtered, and the filter cake was washed with a mixed solvent (ethyl acetate:petroleum ether=1:1) (5 mL), filtered and dried, to afford crude target compound 53E hydrochloride (0.24 g), which was directly used in the next reaction.

LCMS m/z=102.2 [M+1]⁺.

Step 6:

Compound 53E (0.24 g, 2.08 mmol) was dissolved in DMF (10 mL), HATU (0.99 g, 2.49 mmol) and diisopropylethylamine (0.54 g, 4.16 mmol) were then successively added, and the mixture was stirred at room temperature for 30 min after the addition was completed. Subsequently, to the reaction liquid was added lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinate (0.65 g, 2.08 mmol) (synthesized with reference to patent US 2018141923), and then the mixture was stirred at room temperature for 18 h. After the reaction was completed, the reaction liquid was slowly added to water (50 mL), and then the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, to afford a crude. The crude was purified by column chromatography (eluent: ethyl acetate:petroleum ether=3:1), to afford target compound 53F (0.19 g, 24%).

LCMS m/z=391.2 [M+1]⁺.

Step 7:

Compound 53F (0.19 g, 0.49 mmol) was dissolved in dichloromethane (10 mL), and then a solution of hydrogen chloride in dioxane (5 mL) was added under stirring at room temperature. After the addition was completed, the mixture was reacted and stirred overnight at room temperature. After the reaction was completed, the reaction liquid was directly concentrated to dryness, to afford target compound 53G hydrochloride (0.15 g). The hydrochloride was directly used in the next reaction.

LCMS m/z=291.2 [M+1]⁺.

Step 8:

Compound 53G (0.15 g, 0.52 mmol) and compound 1H (0.10 g, 0.45 mmol) were dissolved in DMF (5 mL), DIPEA (0.5 mL) and potassium iodide (0.03 g, 0.21 mmol) were then successively added, and the mixture was heated to 80° C. and reacted for 3 h after the addition was completed. After the reaction was completed, to the reaction liquid was added water (40 mL), and then the mixture was extracted with ethyl acetate (150 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (150 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: dichloromethane:methanol=10:1), to afford a crude, which was further purified by preparative HPLC to afford target compound 53 (25.1 mg, 10.20%).

LCMS m/z=477.3 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H), 8.31 (s, 1H), 7.92 (d, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.38 (d, 1H), 4.55 (s, 1H), 3.76 (s, 2H), 3.70-3.68 (m, 2H), 3.58-3.57 (m, 2H), 3.43-3.33 (m, 4H), 2.70 (s, 6H), 1.32-1.28 (m, 3H), 0.56 (s, 2H), 0.49-0.48 (m, 2H).

Example 54

N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)picolinamide (Compound 54)

Step 1:

3A (2.16 g, 10 mmol) and N-Boc-piperazine-d8 (2.03 g, 11 mmol) were dissolved in 1,4-dioxane (100 mL), cesium carbonate (6.5 g, 20 mmol) and RuPhos-Pd-G3 (253 mg, 0.3 mmol) were added, and the mixture was reacted overnight at 100° C. under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction was terminated, cooled to room temperature, and filtered. The filtrate was collected, and the filter residue was washed with ethyl acetate (20 mL×3). The filtrate was concentrated, a small amount of anhydrous ethanol was added, and the mixture was heated and dissolved. A large amount of petroleum ether was then added, and the mixture was cooled to collect the precipitated crystals, to afford title compound 54A (2.47 g, 73.4%).

LC-MS (ESI): m/z=330.2 [M+H]⁺.

Step 2:

Compound 54A (400 mg, 1.24 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide (30 mg, 1.24 mmol) was added, and the mixture was stirred and reacted at room temperature for 2 h. The solvent was removed by distillation under reduced pressure, water was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to dryness. To the resulting solid was added DMF (10 mL), HATU (565 mg, 1.49 mmol) was added under stirring, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (2 mL) was added, excess cyclopropylamine was finally added, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, to the system was added ethyl acetate (50 mL), and the mixture was washed with water (50 mL×4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by silica gel chromatographic column (PE:EA=1:0-1:1), to afford title compound 54B (319 mg, 72.2%).

LC-MS (ESI): m/z=355.2 [M+H]⁺.

Step 3:

54B (309 mg, 0.89 mmol) was dissolved in methanol (5 mL), and a solution of hydrogen chloride in dioxane (5 mL, 4M) was added. The mixture was reacted at room temperature for 2 hours and spun to dryness, to afford title compound 54C (200 mg, crude).

LC-MS (ESI): m/z=255.2 [M+H]⁺.

Step 4:

1H (120 mg, 0.48 mmol) and 54C (200 mg, 0.81 mmol) were dissolved in anhydrous acetonitrile (10 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL) were added, and the mixture was subjected to nitrogen replacement and reacted at 80° C. for 8 hours. Upon complete depletion of raw materials monitored by LCMS, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH=10:1 (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through column (DCM:MeOH=1:0-10:1), to afford compound 54 (81 mg, 39.4%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.40 (s, 1H), 8.35-8.13 (m, 2H), 7.91-7.69 (m, 2H), 7.63 (s, 1H), 7.38 (s, 1H), 3.65 (s, 2H), 2.97-2.74 (m, 1H), 2.67-2.52 (m, 2H), 1.33-1.06 (m, 3H), 0.81-0.46 (d, 4H).

LC-MS (ESI): m/z=441.2 [M+H]⁺.

Biological Test

1. PARP1 Enzyme Activity Test Experiment

PARP1 chemical fluorescence detection kit was purchased from BPS Bioscience. The histone solution in the kit was diluted 5× with 1×PBS, and 25 μL of the diluted histone solution was added to a microwell plate and incubated overnight at 4° C. After the incubation, the plate was washed three times with PBST (0.05% Tween-20). 100 μL of the blocking solution was added to the microwell plate and incubated at 25° C. for 90 minutes. After the incubation, the plate was washed three times with PBST. 2.5 μL of compounds at different concentrations diluted in test buffer and 12.5 μL of substrate mixed solution (1.25 μL 10×PARP test buffer; 1.25 μL 10×PARP test mixed solution; 2.5 μL Activated DNA, 7.5 μL double-distilled water) were added to the microwell plate. The PARP1 enzyme was diluted to 2 ng/μL, 10 μL of the diluent was added to the microwell plate, and the reaction system was incubated at 25° C. for 60 minutes.

After the incubation, the plate was washed three times with PBST. Streptavidin-HRP was diluted 50× with a blocking solution, and 25 μL of the diluent was added to the microwell plate and incubated at 25° C. for 30 minutes. After the incubation, the plate was washed three times with PBST. ELISA ECL substrate A and substrate B were mixed at a ratio of 1:1 (v/v), 50 μL of the mixture was added to the microwell plate, and the chemiluminescence value was read.

The inhibition rate was calculated according to formula 1, where RLUsample was the readout of the compound well, RLUmax was the readout of the solvent control well, and RLUmin was the readout of the control well without the PARP1 enzyme. Curve fitting was performed by four parameters (log(inhibitor) vs. response—Variable slope) using GraphPad Prism software, and the IC₅₀ value was calculated.

Inhibition %=(1−(RLUsample−RLUmin)/(RLUmax−RLUmin))×100%  (formula 1)

Test results: the compound of the present invention had a significant inhibitory effect on PARP-1 enzyme activity in vitro, and the IC₅₀ value of the example compounds on PARP-1 enzyme activity was less than 100 μM. The test results of some examples were as shown in Table 1.

TABLE 1
PARP-1 enzyme activity
Compound IC50 (nM)
1        3.66
2        2.01
3        1.33
4        0.67
6        0.56
7        0.32
8        0.58
9        0.73
10       0.56
11       0.54
12       1.6
13       0.76
14       0.71
15       0.65
16       0.51
17       0.35
18       0.33
19       0.29
20       0.32
21       0.31
22       0.51
23       0.67
24       0.73
25       0.88
26       0.48
27       0.75
29       0.45
30       0.45
31       1.7
32       2.0
33       0.74
34       0.66
35       0.97
36       0.58
37       0.96
38       0.70
39       0.77
40       0.61
41       0.84
42       0.67
43       0.93
44       0.92
45       0.73
46       0.56
48       0.35
50       0.69
51       0.66
Conclusion: the compound of the present invention has a significant inhibitory effect on PARP-1 enzyme activity in vitro.

2. PARP2, PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 Enzyme Activity Test Experiments

PARP2, PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 chemical fluorescence detection kits were purchased from BPS Bioscience. The histone solution in the kit was diluted 5× with 1×PBS, and 25 μL of the diluted histone solution was added to a microwell plate and incubated overnight at 4° C. After the incubation, the plate was washed three times with PBST (0.05% Tween-20). 100 μL of the blocking solution was added to the microwell plate and incubated at 25° C. for 90 minutes. After the incubation, the plate was washed three times with PBST. 2.5 μL of compound 4 diluted in test buffer and 5 μL of substrate mixed solution were added to the microwell plate. 5 μL of the diluted PARP enzyme was added to the microwell plate, and the reaction system was incubated at 25° C. for 60 minutes.

After the incubation, the plate was washed three times with PBST. Streptavidin-HRP was diluted 50× with a blocking solution, and 25 μL of the diluent was added to the microwell plate and incubated at 25° C. for 30 minutes. After the incubation, the plate was washed three times with PBST. ELISA ECL substrate A and substrate B were mixed at a ratio of 1:1 (v/v), 25 μL of the mixture was added to the microwell plate, and the chemiluminescence value was read.

The inhibition rate was calculated according to formula [(1−(RLU_sample-RLU_min)/(RLU_max−RLU_min))×100%], where RLU_sample was the readout of the compound well, RLU_max was the readout of the solvent control well, and RLU_min was the readout of the control well without the PARP1 enzyme. Curve fitting was performed by four parameters (log(inhibitor) vs. response—Variable slope) using GraphPad Prism software, and the IC₅₀ value was calculated.

Test results: compound 4 of the present invention had a weak inhibitory effect on PARP2 enzyme activity in vitro, and its corresponding IC₅₀ value was 27.47 nM; compound 4 had a very weak inhibitory effect on PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 enzyme activities in vitro, and their corresponding IC₅₀ values were all greater than 500 nM. The specific test results were as shown in Table 2.

TABLE 2
PARP2, PARP5A, PARP5B, PARP6, PARP7,
PARP14 and PARP15 enzyme activities
Compound	PARP enzyme	IC50 (nM)
4	PARP2	27.47
4	PARP5A	6076
4	PARP5B	576
4	PARP6	6860
4	PARP7	5356
4	PARP14	7064
4	PARP15	4304
Conclusion: the inhibitory effect of compound 4 of the present invention on PARP2, PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 enzyme activities in vitro is much weaker than the inhibitory effect on PARP1, indicating that it has good PARP1 inhibitory selectivity.

3. PARP1 DNA-Trap Test

PARP Trap™ detection kit (Cat #78317) was purchased from BPS bioscience. GST-tagged PARP1 (Cat #80501) and fluorescently labeled DNA (Cat #78273) were diluted with 1×PARP trap test buffer to 3.2 and 0.555 nM, respectively. The compound was prepared in DMSO as 10 mM stock solution and serially diluted. 100 nL of the compound was transferred to a 384-well reaction plate using Echo, 4 μL of fluorescently labeled DNA solution and 4 μL of PARP1 solution were added to the reaction well, and the mixture was centrifuged and incubated at room temperature for 60 minutes. 2 μL 1×NAD+ solution was added to each reaction well and incubated at 25° C. for 60 minutes. Fluorescence polarization (FP) signals were read using a BMG microplate reader. The obtained data were processed according to the formula [(FP_{negative control}−FP_compound)/(FP_{negative control}−FP_{positive control})×100%] to obtain the activation rate of the compound. The EC₅₀ value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.

PARP2 DNA-Trap Test

PARP Trap™ detection kit (Cat #78317) was purchased from BPS bioscience. GST-tagged PARP2 (Cat #80502) and fluorescently labeled DNA (Cat #78297) were diluted with 1×PARP trap test buffer to 34 and 0.555 nM, respectively. The compound was prepared in DMSO as 10 mM stock solution and serially diluted. 100 nL of the compound was transferred to a 384-well reaction plate using Echo, 4 μL of fluorescently labeled DNA solution and 4 μL of PARP2 solution were added to the reaction well, and the mixture was centrifuged and incubated at room temperature for 60 minutes. 2 μL 1×NAD+ solution was added to each reaction well and incubated at 25° C. for 60 minutes. Fluorescence polarization (FP) signals were read using a BMG microplate reader. The obtained data were processed according to the formula [(FP_{negative control}−FP_compound)/(FP_{negative control}−FP_{positive control})×100%] to obtain the activation rate of the compound. The EC₅₀ value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.

TABLE 3
PARP DNA-Trap
Compound	PARP DNA-Trap	EC50 (nM)	Emax
4	PARP1 DNA-Trap	1.71	84.01%
4	PARP2 DNA-Trap	9720	50.95%
Conclusion: compound 4 of the present invention has good PARP1 DNA-Trap activity in vitro, and its PARP2 DNA-Trap activity is much weaker than PARP1 DNA-Trap activity, indicating that it has good PARP1 DNA-Trap selectivity.

4. MDA-MB-436 Cell Activity Test Experiment

Breast tumor cells MDA-MB-436 were purchased from ATCC, the culture medium was Leibovitz's L-15+10% FBS, and the cells were cultured in a CO₂-free incubator at 37° C. On day 1, the cells in the exponential growth phase were collected, and the cell suspension was adjusted to 4000 cells/135 μL with the culture medium. 135 μL of the cell suspension was added to each well of a 96-well cell culture plate and incubated overnight. On day 2, compounds at different concentrations were added, and the plate was placed in the incubator and incubated for 7 days. After the incubation was completed, according to operation instructions for a CellTiter-Glo kit (Promega, G7573), 75 μL of CTG solution, which was already pre-melted and equilibrated to room temperature, was added to each well, and the mixture was uniformly mixed for 2 min using a microplate shaker. The plate was placed at room temperature for 10 min, and then fluorescence signal values were measured using an Envision2104 plate reader (PerkinElmer). The inhibition rate was calculated using formula (1), where RLU_compound was the readout of the drug treated group, RLU_control was the average value of the vehicle control group, and RLU_blank was the average value of the cell-free well. The IC₅₀ value was calculated using GraphPad Prism software.

$\begin{array}{cc}\mathrm{Inh}.\%=\left(1-\left({\mathrm{RLU}}_{\mathrm{compound}}-{\mathrm{RLU}}_{\mathrm{blank}}\right)/\left({\mathrm{RLU}}_{\mathrm{control}}-{\mathrm{RLU}}_{\mathrm{blank}}\right)\right)\times 100\%& \left(\mathrm{formula}1\right)\end{array}$

Test results: the compound of the present invention had a significant inhibitory effect on breast tumor cells MDA-MB-436, with IC₅₀ value of less than 100 nM, further IC₅₀ value of less than 50 nM, furthermore IC₅₀ value of less than 20 nM, and the most excellent IC₅₀ value of less than 10 nM. At 10 μM, the maximum inhibition rate of the compound of the present invention on breast tumor cells MDA-MB-436 was up to 70% or more, further up to 80% or more, further up to 90%, with the optimal inhibition rate of 95% or more. The results of some examples were as shown in Table 4.

TABLE 4
MDA-MB-436 cell inhibitory activity
Compound	IC50 (nM)	Max inh. % 10 μM
4	2	89.4
6	10	85.7
9	6	86.2
10	17	94.2
11	6	85.2
22	12	89.4
23	1.4	84.2
24	9	82.3
25	16	99.0
26	18	86.3
33	3.1	90.0
34	16.5	81.9
35	9.8	90.4
37	18.9	93.7
38	17.6	98.8
39	1.2	99.1
40	5.6	99.3
41	2.3	92.1
42	24.1	84.1
50	3.0	92.9
51	8.5	95.6
52	3.1	92.4
53	2.2	90.6
Conclusion: the compound of the present invention has good inhibitory activity on breast tumor cells MDA-MB-436.

5. MDA-MB-231 Cell Proliferation Inhibition Test

Human breast cancer MDA-MB-231 cells purchased from ATCC were placed in complete DMEM medium (supplemented with 10% fetal bovine serum and 1% double antibody) and cultured at 37° C. and 5% CO₂. The cells in the exponential growth phase were collected, and the cell suspension was adjusted to 1500 cells/135 μL with the culture medium. 135 μL of the cell suspension was added to each well of a 96-well cell culture plate and incubated overnight. On day 2, compounds at different concentrations were added, and the plate was placed in the incubator and incubated for 7 days. After the incubation was completed, according to operation instructions for a CellTiter-Glo kit (Promega, Cat #G7573), 75 μL of CTG solution, which was already pre-melted and equilibrated to room temperature, was added to each well, and the mixture was uniformly mixed for 2 min using a microplate shaker. The plate was placed at room temperature for 10 min, and then fluorescence signal values were measured using an Envision 2104 plate reader (PerkinElmer). The cell proliferation inhibition rate was calculated according to the formula [(1−(RLU_compound−RLU_blank)/(RLU_control−RLU_blank))×100%]. The IC₅₀ value was obtained by four-parameter nonlinear fitting using GraphPad Prism software.

TABLE 5
MDA-MB-231 cell inhibitory activity
Compound	IC50 (μM)	Max inh. % 10 μM
4	15.89	66.80
Conclusion: the compound of the present invention has weak inhibitory activity on BRCA WT cells MDA-MB-231, indicating that it has good cell selectivity.

6. Pharmacokinetic Test in Rats

• • 1.1 Experimental animals: male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound, purchased from Chengdu Ddossy Experimental Animals Co., Ltd.
  • 1.2 Experimental design: on the day of the test, 6 SD rats were randomly grouped according to their body weight; the animals were fasted with water available for 12 to 14 h one day before the administration, and were fed 4 h after the administration.

TABLE 6
Administration information
	Administration information
			Administration	Administration	Administration
	Quantity	Test	dosage	concentration	volume	Collected	Mode of
Group	Male	compound	(mg/kg)	(mg/mL)	(mL/kg)	samples	administration
G1	3	Compound	2.5	0.5	5	Plasma	Intravenously
G2	3	4	10	1	10	Plasma	Intragastrically
Notes:
Solvent for intravenous administration: 10% DMA + 10% Solutol + 80% Saline; Solvent for intragastric administration: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD)
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; DMSO: dimethyl sulfoxide; SBE-CD: β cyclodextrin)

Before and after the administration, 0.15 mL of blood was taken from the orbit of the animals under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4° C. for 10 min to collect plasma. The blood collection time points for the intravenous administration group and intragastric administration group were: 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. Before analysis and detection, all samples were stored at −80° C. The samples were analyzed quantitatively by LC-MS/MS. The test results of some examples were as shown in Table 7.

TABLE 7
Pharmacokinetic parameters of test compounds in plasma of rats
Test	Mode of	CL	Vdss	AUC0-t	F
compound	administration	(mL/min/kg)	(L/kg)	(hr*ng/mL)	(%)
Compound 4	i.v. (2.5 mg/kg)	0.896 ± 0.097	0.236 ± 0.022	46601 ± 4753	—
	i.g. (10 mg/kg)	—	—	184171 ± 72260	98.8 ± 39
—: not applicable.

Conclusion: compound 4 has good pharmacokinetic characteristics in rats.

7. Mouse MDA-MB-436 Subcutaneous In Vivo Transplanted Tumor Model

Human breast cancer MDA-MB-436 cells were placed in Leibovitz's L-15 medium (supplemented with 10 μg/mL insulin, 16 μg/mL glutathione, 10% fetal bovine serum and 1% double antibody) and cultured at 37° C. Conventional digestion treatment with trypsin was carried out twice a week for passage. When the cell saturation was 80%-90%, and the number reached the requirement, the cells were collected, counted, and inoculated. BALB/c nude mice (from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were subcutaneously inoculated with 0.2 mL (10×10⁶) of MDA-MB-436 cells (plus matrigel, with the volume ratio of 1:1) on the right back. When the average tumor volume reached about 180 mm³, grouping and administration were performed (marked as Day 0). The solvent group was given 5% DMSO, 30% PEG400 and 65% of 20% sulfobutyl-β-cyclodextrin solution, and the administration group was given compound 4 (Day 0-Day 10: 1 mg/kg; Day 11-Day 28: 0.1 mg/kg). The administration frequency was once a day, the administration cycle was 29 days, and the drug withdrawal observation period was set to 14 days. After grouping, the tumor diameter was measured twice a week with a vernier caliper. The formula for calculating the tumor volume was: V=0.5×a×b², where a and b represented the long and short diameters of the tumor, respectively. The tumor inhibitory effect of compound 4 was evaluated by TGI (%)=[(1−(average tumor volume at the end of administration in the treatment group−average tumor volume at the beginning of administration in the treatment group))/(average tumor volume at the end of treatment in the solvent control group−average tumor volume at the beginning of treatment in the solvent control group)]×100%. The tumor growth curve and the animal body weight change curve were as shown in FIG. 1 and FIG. 2, respectively.

Test results: after 28 days of administration, the TGI of the group given compound 4 was 119%; after the drug withdrawal, the tumor of the animals in the group given compound 4 did not grow again; there was no significant decrease in the body weight of the animals in the group given compound 4.

Conclusion: in the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model, compound 4 of the present invention has good efficacy in inhibiting tumor growth and inducing tumor regression, and is well tolerated.

Claims

1. A compound represented by formula (I), or a stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof,

2. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, having a structure of formula (II), (III), (IV), (V), or (VI):

3. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein each Rx is independently selected from H, D, halogen, cyano, amino, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkyl-O—C1-4 alkyl, —(CH2)r—C3-6 monocyclic cycloalkyl or —(CH2)r-(4- to 6-membered monocyclic heterocycloalkyl);R1 is selected from halogen, nitro, cyano, amino, hydroxyl, —SF5, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkyl-O—C1-4 alkyl, —(CH2)r—C3-6 monocyclic cycloalkyl, —(CH2)r—C5-9 spiro cycloalkyl, —(CH2)r-(4- to 6-membered monocyclic heterocycloalkyl) or —(CH2)r-(5- to 9-membered spiro heterocycloalkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino, hydroxyl, C1-3 alkyl or C1-3 alkoxy;R2 and R3 are each independently selected from H, D, halogen, cyano, amino, hydroxyl, C1-2 alkyl-O—C1-2 alkyl, hydroxy C1-3 alkyl, C1-3 alkoxy, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy or C1-4 alkyl; or R2 and R3 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl;R5 is selected from D, halogen, cyano, amino, hydroxyl, C1-4 alkyl, C1-4 alkoxy, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy;R5a is selected from cyano, amino, hydroxyl, —SF5, C1-4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy;ring A is selected from 5-membered monocyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, 6-membered monocyclic heteroaromatic ring containing 2-5 nitrogen, oxygen or sulfur atoms, or 2-pyridyl, wherein the heteroaromatic ring or 2-pyridyl is further substituted with 1 substituent selected from Ra; orring A is selected from 7- to 10-membered bicyclic heteroaromatic ring containing 1-5 nitrogen, oxygen or sulfur atoms, or 7- to 10-membered bicyclic aromatic ring, wherein the heteroaromatic ring or aromatic ring is optionally further substituted with 1 substituent selected from Rb;Ra is selected from —C(O)N(Ra1)2, —NRa1C(O)ORa1, —NRa1C(O)Ra1, —NRa1C(O)N(Ra1)2, —C(═S)N(Ra1)2, —S(O)2N(Ra1)2, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC1-2 alkyl, —N(C1-2 alkyl)2, C1-4 alkyl, halo C1-4 alkyl, C1-4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy;Rb is selected from —C(O)N(Ra1)2, —NRa1C(O)ORa1, —NRa1C(O)Ra1, —NRa1C(O)N(Ra1)2, —C(═S)N(Ra1)2, —S(O)2N(Ra1)2, ═O, D, halogen, cyano, hydroxyl, amino, —NHC1-4 alkyl, —N(C1-4 alkyl)2, C1-4 alkyl, C3-6 monocyclic cycloalkyl, C5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, C1-4 alkoxy, C1-2 alkyl-O—C1-2 alkyl, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy;Rc is selected from —C(O)Ra2, —NHRa2, —C(O)N(Ra2)2, —C(O)NHRa2, —NRa1C(O)ORa1, —NRa1C(O)Ra1, —NRa1C(O)Ra2, —NRa1Ra2, —NRa1C(O)N(Ra1)2, —C(═S)N(Ra1)2, —S(O)2N(Ra1)2, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 7-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 7-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC1-4 alkyl, —N(C1-4 alkyl)2, C1-4 alkyl, halo C1-4 alkyl, C1-4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy;each Ra1 is independently selected from H, C1-4 alkyl, C3-5 monocyclic cycloalkyl, C5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C1-4 alkoxy, C1-2 alkyl-O—C1-2 alkyl, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C1-2 alkyl;each Ra2 is independently selected from C3-5 monocyclic cycloalkyl, C1-2 alkyl-C3-5 monocyclic cycloalkyl, C5-9 spiro cycloalkyl, C5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C1-4 alkoxy, C1-2 alkyl-O—C1-2 alkyl, C1-4 alkyl-O—C3-4 cycloalkyl, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C1-2 alkyl, deuterated C1-2 alkyl, or phenyl;alternatively, two Ra2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C1-2 alkyl;each r is independently selected from 0, 1 or 2;p is selected from 0, 1 or 2.

4. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 3, wherein Rx is independently selected from H or D;R1 is selected from cyano, C1-2 alkyl, C2-3 alkenyl, C1-2 alkyl-O—C1-2 alkyl or C3-4 monocyclic cycloalkyl, wherein the alkyl is optionally further substituted with 1-3 groups selected from D, F, Cl, cyano, amino or hydroxyl;R2 and R3 are each independently selected from H or D;R5 is selected from D, F, Cl, cyano, amino, hydroxyl, C1-2 alkyl, C1-2 alkoxy, halo C1-2 alkyl, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;R5a is selected from cyano, amino, hydroxyl, —SF5, C1-2 alkoxy, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;Ra is selected from —C(O)N(Ra1)2, —NRa1C(O)ORa1, —NRa1C(O)Ra1, —NRa1C(O)N(Ra1)2, —C(═S)N(Ra1)2, —S(O)2N(Ra1)2, 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC1-2 alkyl, —N(C1-2 alkyl)2, C1-2 alkyl, halo C1-2 alkyl, C1-2 alkoxy, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;Rb is selected from —C(O)N(Ra1)2, —NRa1C(O)Ra1, ═O, D, halogen, cyano, hydroxyl, amino, —NHC1-2 alkyl, —N(C1-2 alkyl)2, C1-2 alkyl, C3-4 monocyclic cycloalkyl, 4- to 5-membered monocyclic heterocycloalkyl, C1-2 alkoxy, C1-2 alkyl-O—C1-2 alkyl, halo C1-2 alkyl, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;Rc is selected from —C(O)Ra2, —NHRa2, —C(O)N(Ra2)2, —C(O)NHRa2, —NRa1C(O)ORa1, —NRa1C(O)Ra1, —NRa1C(O)Ra2, —NRa1Ra2, —NRa1C(O)N(Ra1)2, —C(═S)N(Ra1)2, —S(O)2N(Ra1)2, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 5-membered monocyclic heterocycloalkyl containing 1-4 nitrogen, oxygen or sulfur atoms, or 3- to 5-membered monocyclic cycloalkyl, wherein the heteroaryl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 1-3 substituents selected from D, halogen, cyano, hydroxyl, amino, —NHC1-2 alkyl, —N(C1-4 alkyl)2, C1-4 alkyl, halo C1-4 alkyl, C1-2 alkoxy, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;each Ra1 is independently selected from H, C1-4 alkyl, C3-5 monocyclic cycloalkyl, C5-9 spiro cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C1-4 alkoxy, C1-2 alkyl-O—C1-2 alkyl, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C1-2 alkyl;each Ra2 is independently selected from C3-5 monocyclic cycloalkyl, C1-2 alkyl-C3-5 monocyclic cycloalkyl, C5-9 spiro cycloalkyl, C5-9 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 5- to 9-membered spiro heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, C1-4 alkoxy, C1-2 alkyl-O—C1-2 alkyl, C1-3 alkyl-O—C3-4 cycloalkyl, halo C1-4 alkyl, halo C1-4 alkoxy, deuterated C1-4 alkyl, or deuterated C1-4 alkoxy, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C1-2 alkyl, deuterated C1-2 alkyl, or phenyl;alternatively, two Ra2 together with the nitrogen atom to which they are attached form 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, or C1-2 alkyl;each r is independently selected from 0 or 1.

5. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 2, wherein

6. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 2, wherein

7. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 2, wherein

8. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, having a structure of formula (VI-1):

9. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, having a structure of formula (II-1), (II-2), (II-3), or (II-4):

10. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 9, wherein Rc is selected from —C(O)NHRa2, —NRa1C(O)Ra1, —NRa1C(O)Ra2, —NRa1C(O)ORa1, —NRa1C(O)N(Ra1)2 or 5- to 6-membered monocyclic heteroaryl containing 1-4 nitrogen, oxygen or sulfur atoms, wherein the heteroaryl is optionally further substituted with 1-2 groups selected from D, F, Cl, cyano, hydroxyl, amino, C1-2 alkyl, halo C1-2 alkyl, C1-2 alkoxy, halo C1-2 alkoxy, deuterated C1-2 alkyl, or deuterated C1-2 alkoxy;each R5 is independently selected from D, F, Cl, cyano, C1-2 alkyl, halo C1-2 alkyl or deuterated C1-2 alkyl;p is selected from 0 or 1;each Ra1 is independently selected from H, C1-2 alkyl, C3-5 monocyclic cycloalkyl or 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, wherein the cycloalkyl or heteroaryl is optionally substituted with 1-3 substituents selected from halogen, deuterium or C1-2 alkyl;each Ra2 is independently selected from C3-5 monocyclic cycloalkyl, 5- to 6-membered monocyclic heteroaryl containing 1-5 nitrogen, oxygen or sulfur atoms, 4- to 6-membered monocyclic heterocycloalkyl, C1-2 alkyl-O—C1-2 alkyl, C1-3 alkyl-O—C3-4 cycloalkyl, C1-2 alkyl-C3-5 cycloalkyl, C5-9 spiro cycloalkyl or C5-9 bridged cycloalkyl, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, deuterium, C1-2 alkyl, deuterated C1-2 alkyl or phenyl.

11. The compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from one of the following structures:

12. A pharmaceutical composition, comprising the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient and/or carrier.

13. Use of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating/preventing a PARP-1-mediated disease.

14. (canceled)

15. (canceled)

16. A method for treating a disease in a mammal, comprising administering to an individual a therapeutically effective amount of the compound, or the stereoisomer, deuterated material, solvate, or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient and/or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg; the disease is preferably cancer; and further, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, or pancreatic cancer.