Bicyclic derivative PARP inhibitor and application thereof

Abstract

The invention discloses a compound as shown in a formula (II), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuterated substance of the compound, or a pharmaceutical composition containing the stereoisomer, the pharmaceutically acceptable salt, the solvate, the co-crystal or the deuterated substance of the compound, and application of the compound as a PARP-1 inhibitor in preparation of drugs for treating related diseases, and all groups in the formula (II) are defined in the specification. # imgabs0 #

Description

Bicyclic derivative PARP inhibitors and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with PARP-1 inhibitory activity, its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated compounds, and uses thereof in treating related diseases. Background Art

[0002] Approximately 5% of breast cancer patients are associated with germline mutations in the BRCA1 / 2 genes (3% for BRCA1 and 2% for BRCA2). Breast cancers caused by BRCA1 mutations are mostly triple-negative (70%), while BRCA2 mutations are more likely to cause estrogen receptor-positive (ER-positive) breast cancer (70%). BRCA1 / 2 genes are tumor suppressor genes that play an important role in DNA damage repair and normal cell growth. Mutations in these genes can inhibit the normal repair ability after DNA damage, causing homologous recombination deficiency (HRD). This is characterized by loss of BRCA function or mutations or loss of function in other homologous recombination-related genes, preventing double-strand breaks from being repaired by homologous recombination (HRR), ultimately leading to cancer.

[0003] Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated when DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of recognizing and binding to the site of DNA breakage, thereby activating and catalyzing the poly(ADP-ribosylation) of the receptor protein and participating in the DNA repair process. PARP plays a key role in the excision and repair of single-stranded DNA bases. In HRD tumor cells, double-stranded DNA cannot be repaired, and PARP inhibitors block single-strand repair, resulting in a "synthetic lethality" effect, leading to tumor cell death.

[0004] PARP inhibitors have a "trapping" effect on PARP proteins, causing PARP proteins bound to damaged DNA to be trapped on the DNA and unable to get off. This directly prevents other DNA repair proteins from binding, ultimately leading to cell death. Currently, a number of PARP inhibitors have been successfully developed, such as Olaparib, Rucaparib, 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 for the PARP family. These side effects include intestinal toxicity caused by end-ankyropolymerase inhibition and hematotoxicity caused by PARP-2 inhibition. Therefore, it is of great clinical significance to develop highly selective PARP-1 inhibitors to reduce the related toxic side effects of non-selective PARP inhibitors.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a PARP-1 inhibitory compound, its stereoisomers, solvates, deuterated compounds, or pharmaceutically acceptable salts, and medical applications thereof. The compounds of the present invention have the advantages of good activity, low toxicity and side effects, good safety, high selectivity, good pharmacokinetics, and high bioavailability.

[0007] The present invention provides compounds of the following formulas (I), (III), (IV), (V), and stereoisomers, solvates, deuterated compounds, or pharmaceutically acceptable salts thereof:

[0008] Wherein, X1 is O, S or NR, and R is selected from CN, C 1-4 Alkyl; in some embodiments, X1 is O or S;

[0009] X2 is N, C or CR 5’ In some embodiments, X2 is N or CR 5’ ;

[0010] X3 is N, C or CR 5” ;

[0011] Ring A is a 4-12 membered heterocycloalkyl containing 1-3 N atoms and 0-2 heteroatoms selected from O and S; in some embodiments, Ring A is an unsubstituted piperazinyl; in some embodiments, Ring A is an optionally substituted 4-12 membered heterocycloalkyl containing 1-3 N atoms and 0-2 heteroatoms selected from O and S, excluding unsubstituted piperazinyl; in some embodiments, Ring A is a 4-9 membered monoheterocycloalkyl, a 6-12 membered spir ... In some embodiments, ring A is a substituted or unsubstituted 6-10 membered cycloheterocycloalkyl, a substituted or unsubstituted 6-11 membered spirocycloheterocycloalkyl, a substituted or unsubstituted 6-10 membered bridged heterocycloalkyl, a substituted or unsubstituted 4-5 membered monoheterocycloalkyl, a substituted or unsubstituted 7 membered monoheterocycloalkyl, a substituted or unsubstituted or substituted or unsubstituted In some embodiments, Ring A is selected from

[0012] R1, R2 and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0013] In some embodiments, R1 is H, D, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 1-4 In some embodiments, R1 is halogen, CN, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl being further substituted by D, halogen, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 1-4 In some embodiments, R1 is C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl, and optionally 1-5 selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R1 is C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl;

[0014] In some embodiments, R2 is H, D, halogen, or C 1-4 Alkyl, the alkyl group is optionally substituted with 1-5 groups selected from D, halogen, OH, CN and NH2; in some embodiments, R2 is H, D, F, Cl, Br, I or C 1-4 Alkyl, the alkyl group is optionally substituted with 1-5 groups selected from D, halogen, OH, CN and NH2; in some embodiments, R2 is H, D, Cl, Br, I, or C 1-4 Alkyl, the alkyl group is optionally substituted by 1-5 groups selected from D, halogen, OH, CN and NH2; in some embodiments, R2 is F, Cl, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-3 groups selected from D, F, and Cl;

[0015] R3 is independently H, D, halogen or C 1-4Alkyl, the alkyl group is optionally substituted with 1-5 groups selected from D, halogen, OH, CN and NH2; in some embodiments, R3 is H, D, F, Cl, Br or I; in some embodiments, at least one R3 is D, halogen or C 1-4 Alkyl, optionally substituted with 1-5 groups selected from D, halogen, OH, CN and NH2; in some embodiments, R3 is H;

[0016] Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN, NH2, C 1-4 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, said alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, at least one R4 is selected from D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN, NH2, C 1-4 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, said alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN or NH2, wherein the alkyl and cycloalkyl groups are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, at least one R4 is selected from D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN or NH2, wherein the alkyl and cycloalkyl groups are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, two R4 and the carbon atom to which they are attached together form C 3-6Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, the two R4 are not H at the same time, or the two R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, the substituents are as described above;

[0017] Each L is independently -NH-, -CH2-, -O-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; in some embodiments, each L is independently -NH-, -CH2-, -O-, or -C(=O)-; in some embodiments, at least one L is present, i.e., n and m are not both 0;

[0018] n and m are independently 0, 1, 2 or 3; in some embodiments, n and m are independently 0, 1, 2; in some embodiments, n and m are independently 0 or 1; in some embodiments, n and m are not both 0; in some embodiments, n and m are both 0;

[0019] Each R5, R 5’ 、R 5” are independently H, D, halogen, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, CN or C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, each R5, R 5’ 、R 5” are independently H, D, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from D, halogen, OH, CN and NH2;

[0020] In some embodiments, R5 is H, halogen, C 1-4 Alkyl or =O, the alkyl group is optionally substituted by 1-3 groups selected from D, halogen, OH, CN and NH2;

[0021] In some embodiments, R 5’ 、R 5”are independently H, halogen, C 1-4 Alkyl, optionally substituted by 1-3 groups selected from D, halogen, OH, CN and NH2;

[0022] In some embodiments, R5, R 5’ 、R 5” Not at the same time H;

[0023] In some embodiments, one R4 and R 5’ Form a bond, so that when n is 0, a double bond is formed between the C connected to R4 and ring A, and when n is not 0, a spiro ring is formed;

[0024] q is 0, 1, 2, 3, or 4. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0.

[0025] Ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl; in some embodiments, Ring B is not

[0026] R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4In some embodiments, R6 is D, F, Cl, C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl;

[0027] R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-OCONHR 11 、-COOR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC1-4 Alkylene OC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-COOR 11 、-OCONHR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-COOR 11 、-OCONHR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 In some embodiments, R8 is -CONHR 11 、-NHCOR 11 ;

[0028] Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, R 11is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiazolyl, thienyl, thiadiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, furanyl, oxadiazole, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl; in some embodiments, R 11 C 3-6 Cycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from D, F, Cl, C 1-2 Alkyl and C 1-2 In some embodiments, R 11 is cyclopropyl, pyrazolyl, and the cyclopropyl, pyrazolyl is optionally substituted by 1-3 groups selected from D, F, Cl, C 1-2 Alkyl and C 1-2 In some embodiments, R 11 is cyclopropyl, pyrazolyl, and the cyclopropyl, pyrazolyl is optionally substituted by 1-3 groups selected from C 1-2 alkyl groups; each r is independently 1, 2, or 3; in some embodiments, r is 1 or 2; in some embodiments, r is 1;

[0029] In some embodiments, for That is, the aforementioned compound has the structure of formula (II):

[0030] Ring B is a six-membered heteroaryl group, and the remaining groups are as described above.

[0031] In some embodiments, the compound of the present invention, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein the compound further satisfies at least one of the following conditions:

[0032] (1) R1 is D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the alkyl is surrounded by 1-5 heteroatoms selected from D, Cl, Br, I, C 1-4Alkoxy, OH, CN and NH2 groups are substituted, and the alkoxy or cycloalkyl group is substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted, and the alkenyl, alkynyl and heterocycloalkyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0033] (2) R2 is H, D, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the alkyl is surrounded by 1-5 heteroatoms selected from D, halogen, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted, and the alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0034] (3) At least one R3 is D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C1-4 haloalkyl radical substitution;

[0035] (4) The two R4 are not H at the same time, or the two R4 and the carbon atom to which they are connected together form a substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O;

[0036] (5) m and n are not 0 at the same time;

[0037] (6) no

[0038] (7) Ring B is not R6 is halogen or C 1-4 alkyl;

[0039] (8) R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-COOR 11 、-OCONHR 11 , or -CO(CH2)r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

[0040] In some embodiments, the aforementioned compound of the present invention, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein the compound satisfies at least one of the above conditions (1) to (5).

[0041] In some embodiments, the aforementioned compound of the present invention, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein the compound satisfies at least one of the aforementioned conditions (6) to (8).

[0042] In some embodiments, the aforementioned compound of the present invention, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein the compound satisfies at least one of the above conditions (4) to (8).

[0043] In some embodiments, the aforementioned compound of the present invention, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein the compound has the structure of the following formula (III):

[0044] Wherein, each group is as described in the previous embodiments and satisfies at least one of the conditions (1) to (3) and (6) to (8) above.

[0045] In some embodiments, the compound of the aforementioned formula (III), each group is as described in the aforementioned embodiments, and at least one of the aforementioned conditions (6) to (8) is satisfied.

[0046] The present invention provides a specific embodiment 1, a compound represented by formula (I), (II), or (III), a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof,

[0047] Wherein, X1 is O or S;

[0048] X2 is N, C or CR 5’ ;

[0049] X3 is N, C or CR 5” ;

[0050] Ring A is a 4-12 membered heterocycloalkyl group containing 1-3 N atoms and 0-2 heteroatoms selected from O and S;

[0051] R1, R2 and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0052] Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN, NH2, C 1-4 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, said alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0053] Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0054] Each L is independently -NH-, -CH2-, -O-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0055] n and m are independently 0, 1, 2 or 3;

[0056] Each R5, R 5’ 、R 5” are independently H, D, ═O, halogen, C 1-4 Alkyl, C 1-4Alkoxy, CN or C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0057] Optionally, an R4 with R 5’ forming bonds;

[0058] q is 0, 1, 2, 3, or 4;

[0059] X4 is N, NR7 or CR7 (Formula II or III);

[0060] X5 is N, NR 10 or CR 10 (Formula II or III);

[0061] Ring B is a six-membered heteroaryl group (in Formula I, Ring B may also be a phenyl group);

[0062] R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0063] R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-OCONHR 11 、-COOR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0064] Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0065] Each r is independently 1, 2 or 3.

[0066] The present invention provides scheme 2, the compounds of formula (I), (II) and (III) also meet the following conditions: for n and m are 0, for R6 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 When it is an alkyl group, R8 is not -CONHC1-4 The rest are as described in Scheme 1.

[0067] In scheme 3 provided by the present invention, the compound of formula (I) or formula (II) satisfies at least one of the conditions (1) to (8) above, and the compound of formula (III) satisfies at least one of the conditions (1) to (3) and (6) to (8) above, and the rest is as described in scheme 1.

[0068] The present invention provides Scheme 4, wherein the compound of formula (III) satisfies at least one of the conditions (6) to (8) above, and the remaining groups are as described in Scheme 1.

[0069] The present invention provides Scheme 5, a compound represented by Formula (II), a stereoisomer, a solvate, a deuterated substance, or a pharmaceutically acceptable salt thereof, wherein X1 is O or S;

[0070] X2 is N, C or CR 5’ ;

[0071] X3 is N, C or CR 5” ;

[0072] Ring A is a 4-12 membered heterocycloalkyl group containing 1-3 N atoms and 0-2 heteroatoms selected from O and S;

[0073] R1, R2 and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0074] Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN, NH2, C 1-4 Alkoxy, C 2-6 Alkenyl or C 2-6Alkynyl, said alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0075] Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0076] Each L is independently -NH-, -CH2-, -O-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0077] n and m are independently 0, 1, 2 or 3;

[0078] Each R5, R 5’ 、R 5” are independently H, D, ═O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, CN or C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0079] Optionally, an R4 with R 5’ forming bonds;

[0080] q is 0, 1, 2, 3, or 4;

[0081] X4 is N, NR7 or CR7;

[0082] X5 is N, NR 10 or CR 10 ;

[0083] Ring B is a six-membered heteroaryl group;

[0084] R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0085] R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-OCONHR 11 、-COOR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0086] Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0087] Each r is independently 1, 2 or 3;

[0088] The condition is that when for n and m are 0, for R6 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 When it is an alkyl group, R8 is not -CONHC 1-4 alkyl.

[0089] Scheme 6 of the present invention is the compound as described in Scheme 5, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein X1 is O;

[0090] X2 is N or CR 5’ ;

[0091] X3 is N, C or CR 5” ;

[0092] Ring A is a 4-9 membered monoheterocycloalkyl group, a 6-12 membered spirocyclic heterocycloalkyl group, a 6-12 membered cyclic heterocycloalkyl group or a 6-12 membered bridged heterocycloalkyl group containing 1-3 N atoms and 0-2 heteroatoms selected from O and S;

[0093] R1 is H, D, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r-heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl radical substitution;

[0094] R2 and R3 are independently H, D, halogen or C 1-4 Alkyl, optionally substituted by 1-5 groups selected from D, halogen, OH, CN and NH2;

[0095] Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN or NH2, wherein the alkyl and cycloalkyl groups are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0096] Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0097] Each L is independently -NH-, -CH2-, -O- or -C(=O)-;

[0098] n and m are independently 0, 1, 2 or 3;

[0099] Each R5, R 5’ 、R 5” are independently H, D, ═O, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from D, halogen, OH, CN and NH2;

[0100] Optionally, an R4 with R 5’ forming bonds;

[0101] q is 0, 1, or 2;

[0102] R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

[0103] Scheme 7 of the present invention is the compound as described in Scheme 6, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein:

[0104] Ring A is a substituted or unsubstituted 6-10 membered heterocyclic alkyl, a substituted or unsubstituted 6-11 membered spirocyclic heterocyclic alkyl, a substituted or unsubstituted 6-10 membered bridged heterocyclic alkyl, a substituted or unsubstituted 4-5 membered monoheterocyclic alkyl, a substituted or unsubstituted 7-8 membered monoheterocyclic alkyl, a substituted or unsubstituted or substituted or unsubstituted or

[0105] Selected from substituted or unsubstituted

[0106] or

[0107] R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R11 、-CONH(CH2) r OR 11 、-COOR 11 、-(CH2) r CONHR 11 、-OCONHR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

[0108] Scheme 8 of the present invention, the compound as described in Scheme 6, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt,

[0109] in,

[0110] Ring A is selected from

[0111] Scheme 9 of the present invention, the compound as described in Scheme 7 or 8, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt,

[0112] Wherein, R1 is H, D, F, Cl, Br, I, C 1-4 Alkyl or C 3-6 Cycloalkyl, the alkyl and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl radical substitution;

[0113] R2 is H, D, F, Cl, Br, I or C 1-4 Alkyl, optionally substituted by 1-5 groups selected from D, halogen, OH, CN and NH2;

[0114] R3 is H, D, F, Cl, Br or I;

[0115] Each R4 is independently selected from H, D, F, Cl, Br or I;

[0116] Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0117] n and m are 0;

[0118] Each R5, R 5’ 、R 5” are independently H, D, F, Cl, Br, I, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from D, halogen, OH, CN and NH2;

[0119] Optionally, an R4 with R 5’ forming bonds;

[0120] q is 0, 1, or 2;

[0121] Ring B is a six-membered heteroaryl group containing 1-2 N atoms;

[0122] R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

[0123] In scheme 10 of the present invention, the compound represented by formula (IV) or (V) or its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt,

[0124] in,

[0125] Ring A is selected from

[0126] R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2; in some embodiments, R1 is C 1-2 Alkyl, C 3-4Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, OH, CN or NH2; in some embodiments, R1 is -CH3, -CH2CH3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CF3, -CCl3, -CHFCH3, -CF2CH3, -CH2CH2F, -CH2CHF2, cyclopropyl, cyclobutyl,

[0127] R3 is H, D;

[0128] R2 is independently F, Cl, CN, NH2, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl group is optionally further substituted with 1-3 groups selected from D, F, Cl, OH, CN, and NH2; in some embodiments, R2 is F, Cl, CN, NH2, -CH3, -CD3, -CH2F, -CHF2, -CH2Cl, -CH2CN, -CH2NH2, -CH2CH3, -CH2CD3, -CH2CH2F, -CH2CH2Cl, -CH2CH2OH, -CH2CH2CN, -CH2CH2NH2, ethenyl, propenyl, ethynyl, or propynyl;

[0129] R6 is D, CN, OH, F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 groups selected from D, F, Cl, OH, CN, NH2; in some embodiments, R6 is D, CN, OH, F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, C 3-4Cycloalkyl, the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 groups selected from D, F, Cl, OH, CN, NH2; in some embodiments, R6 is D, CN, OH, F, Cl, -CH3, -CH2D, -CD3, -CH2F, -CHF2, -CH2Cl, -CH2CN, -CH2NH2, -CH2CH3, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN, -CH2CH2NH2, -OCH3, -OCD3, -OCH2F, -OCHF2, -OCH2Cl, -OCH2OH, -OCH2CH3, -OCH2CH2F, -OCH2CH2Cl, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2CN, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl,

[0130] R8 is -CONHR 11 、-NHCOR 11 ;

[0131] Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, R 11 C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heteroaryl are optionally substituted by 1, 2, or 3 heteroatoms selected from D, =O, F, Cl, C 1-2 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, R 11is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiazolyl, thienyl, thiadiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, furanyl, oxadiazole, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, said group being optionally substituted by 1, 2 or 3 groups selected from D, =O, F, Cl, methyl, ethyl, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, OH, CN, NH2 and C 1-4 In some embodiments, R 11 Cyclopropyl, Cyclobutyl, Pyrazolyl,

[0132] Scheme 11 of the present invention is a compound represented by formula (IV) or (V) as described in Scheme 10, or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, wherein:

[0133] R1 is C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl;

[0134] R3 is H;

[0135] R2 is F, Cl, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-3 groups selected from D, F, and Cl;

[0136] R6 is D, F, Cl, or C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl;

[0137] R8 is -CONHR 11 、-NHCOR 11 ;

[0138] R 11 C 3-6 Cycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from D, F, Cl, C 1-2 Alkyl and C 1-2 The haloalkyl group is substituted.

[0139] Scheme 12 of the present invention is a compound selected from one of the following structures, its stereoisomers, solvates, deuterated compounds, or pharmaceutically acceptable salts:

[0140] The present invention also provides a pharmaceutical composition comprising a compound according to any of the aforementioned technical solutions, a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The present invention also provides a use of a compound according to any of the aforementioned technical solutions, a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for treating / preventing PARP1-mediated diseases.

[0141] The PARP1-mediated disease of the present invention is selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer and prostate cancer.

[0142] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any one of the aforementioned Schemes 1 to 11, a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0143] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a stereoisomer, solvate, deuterated substance, pharmaceutically acceptable salt, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention includes a human.

[0144] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts 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 -500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5 -20mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-12 5mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-60 0mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20- 50mg, 20-40mg, 20-30mg; 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg , 50-125mg, 50-100mg; 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg.

[0145] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention or a stereoisomer, solvate, deuterated form, or pharmaceutically acceptable salt thereof, and an excipient and / or carrier. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is 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, 0mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1440mg of a compound of the present invention or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof.

[0146] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer, solvate, deuterated form, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0147] A method for treating a disease in a mammal, comprising administering a compound of the present invention, a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier to a subject at a daily dose of 1-1440 mg / day. The daily dose may 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, 200-400 mg / day, and in some embodiments, daily doses include but are 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, and 1440 mg / day.

[0148] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0149] The amount of the compound of the present invention or its stereoisomer, solvate, deuterated substance or pharmaceutically acceptable salt in the present invention is calculated based on the free base form in each case.

[0150] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0151] Synthesis route

[0152] Patent documents such as WO2021013735A1 describe methods for preparing PARP-1 inhibitors. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, starting with commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0153] Reference books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide reference to articles describing such preparations. Specific and similar reactants can be selectively identified through indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, with many standard chemical supply houses (e.g., those listed above) offering custom synthesis services.

[0154] the term

[0155] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0156] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0157] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0158] "Halo" or "halogen-substituted" refers to substitution with one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens. Typical examples include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0159] "Deuterium" refers to the isotope of hydrogen (H) and is synonymous with "D".

[0160] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one deuterium atom. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups 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.

[0161] “C x-y " group refers to a group containing x to y carbon atoms, such as "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and "C0" generally refers to a bond.

[0162] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Typically, it is an alkyl group having 1 to 20 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. The alkyl group may be further substituted with a substituent.

[0163] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.

[0164] "Haloalkyl" refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0165] "Alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like; the alkoxy groups may be optionally substituted with substituents.

[0166] "Haloalkoxy" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, they may be the same or different halogen substitutions; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0167] "Alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms, examples of which 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-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -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 and 1,4-hexadiene, etc.; the alkenyl group may be optionally further substituted with a substituent.

[0168] "Alkenylene" refers to a straight or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms. Non-limiting examples include ethynylene, and the alkenylene group may be optionally substituted with a substituent.

[0169] "Alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples 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, and 4-decynyl. The alkynyl group may be optionally substituted with a substituent.

[0170] "Alkynylene" refers to a straight or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, further containing 2-4 carbon atoms, non-limiting examples include ethynylene, propynylene, butynylene, and the alkynylene group may be optionally substituted with a substituent.

[0171] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole does not have aromaticity, and the connection point is on the non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl group, it contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl group, it contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, The cycloalkyl group may be optionally substituted with a substituent.

[0172] "Cycloalkylene" refers to a divalent radical of a cycloalkyl group.

[0173] "Aryl" refers to a carbocyclic ring having aromaticity and not containing heteroatoms, including monocyclic aryl and condensed ring aryl. It generally contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Aryl can optionally be substituted with a substituent.

[0174] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl. Carbocycles can be monocyclic, bicyclic, or polycyclic, including bridged, fused, and spirocyclic rings and combinations thereof. Carbocycles typically have 3 to 12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, and bicyclic bridged rings include etc., double ring and ring include etc., bicyclic spiro ring includes The carbocyclic ring may be optionally substituted with a substituent.

[0175] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. Heterocycloalkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be bridged, fused, spirocyclic, or a combination thereof. Bicyclic or polycyclic groups can include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic, and the attachment point is on the non-aromatic ring. Heterocycloalkyl groups are generally 3 to 20-membered rings. When they are monocyclic heterocycloalkyl groups, they are generally 3 to 15-membered rings, or 3-10-membered rings, or 3-8-membered rings, or 3-6-membered rings; when they are bicyclic or polycyclic heterocycloalkyl groups, they are generally 5 to 12-membered rings, or 5-11-membered rings, or 6-9-membered rings. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azolidinyl, azolinyl, oxolanyl, oxekinyl, and the like. Heterocycloalkyl groups may be optionally substituted with substituents.

[0176] "Heteroaromatic ring" or "heteroaryl" unless otherwise specified refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromatic properties, which may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings may be bridged, parallel, spirocyclic or combinations thereof; when bicyclic or polycyclic, it may be a fusion of a heteroaryl and an aryl, or a fusion of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site. Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, The heteroaryl group may be optionally substituted by a substituent.

[0177] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, and includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles, or combinations thereof. Heterocycles are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl , dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocyclic ring may be optionally substituted with a substituent.

[0178] "Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.

[0179] "Spiro" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the rings, which may contain 0 or more double bonds or triple bonds and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Typically, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Typically, the spiro ring is a trispirotri (representing a three-membered ring spirotricycle), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa. Non-limiting examples of spiro rings include The spiro ring may be optionally substituted with a substituent.

[0180] "Parallel ring" or "condensed ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, and may contain one or more double bonds or triple bonds, and the rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the cyclic 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. Usually, the cyclic ring is a three- to four-membered ring (representing a cyclic ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it is possible to have a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), a three- to five-ring ring, a three- to six-ring ring, a four- to four-ring ring, a four- to five-ring ring, a four- to six-ring ring, a five- to five-ring ring, a five- to six-ring ring, and a six- to six-ring ring. Non-limiting examples of cyclic rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, ; The ring may be aromatic or non-aromatic and optionally substituted by a substituent.

[0181] "Bridged ring" means two rings that share two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Typically, the number of ring atoms in a bridged ring is 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane,

[0182] "Substitution" or "substituent" unless otherwise specified refers to any substitution at a position permitted by chemical theory, and the number of substituents complies with the chemical bond rules. 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, 5-12 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 1-6 Alkyl, halogenated 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 1-6alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=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.

[0183] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0184] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0185] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0186] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0187] An "excipient" is a substance that is not itself a therapeutic agent but serves as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltodextrin. oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, 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 buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0188] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0189] The compounds of the present invention also include their tautomers. For example, when the present invention describes a compound on the left side in which the pyrimidine ring is substituted with OH, it also includes the tautomer compound on the right side.

[0190] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0191] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0192] The technical solutions of the present invention are described in detail below in conjunction with the embodiments, but the protection scope of the present invention includes but is not limited to them.

[0193] Detection method

[0194] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0195] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0196] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0197] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0198] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0199] Example 1:

[0200] N-cyclopropyl-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide (Compound 1)

[0201] N-cyclopropyl-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0202] Step 1: Dissolve compound 1A (synthesized according to patent US2022 / 0009901A1) (3.39 g, 10 mmol) in tetrahydrofuran (100 mL) and water (10 mL), add lithium hydroxide (400 mg, 16.7 mmol), stir and react at room temperature for 2 h, and remove the solvent by distillation under reduced pressure to obtain a white powdery solid 1B (3.38 g, 100%), which can be used directly in the next step without purification.

[0203] LC-MS (ESI): m / z = 324.2 [MH] + .

[0204] Step 2: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL), add HATU (565 mg, 1.49 mmol) with stirring, stir at room temperature, add DIEPA (2 mL) until the solid is completely dissolved, and finally add excess cyclopropylamine. Stir and react at room temperature for 4 h. After the reaction is completed as monitored by LCMS, add ethyl acetate (50 mL) to the system, wash with water (50 mL×4), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and separate by silica gel chromatography (PE:EA=1:0~1:1) to obtain the title compound 1C (327 mg, 89.8%).

[0205] LC-MS (ESI): m / z = 365.2 [M+H] + .

[0206] Step 3: Dissolve 1C (327 mg, 0.90 mmol) in methanol (10 mL), add dioxane hydrochloride solution (3 mL, 4 M), react at room temperature for 2 hours, and spin dry to obtain the title compound 1D (276 mg, crude product).

[0207] LC-MS (ESI): m / z = 265.1 [M+H] + .

[0208] Step 4: 1E (synthesized according to patent US2022 / 0009901A1) (200 mg, 0.74 mmol) and 1D (276 mg) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After nitrogen replacement, the reaction was carried out at 60 ° C. for 4 hours. LCMS detected that the reaction of the raw materials was complete. The system was concentrated, and a saturated solution of sodium bicarbonate (20 mL) was added. 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, and concentrated. Purification by column chromatography (DCM:MeOH = 1:0~0:1) gave compound 1 (189 mg, 63.5%).

[0209] 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.20–8.02(m,1H),7.96–7.72(m,1H),7.75–7.44(m,2H),7.36–7.19(m ,1H),3.69(s,2H),3.23–3.06(m,4H),2.90–2.79(m,1H),2.66–2.53(m,4H),2.42(s,3H),0.80–0.48(m,4H).

[0210] LC-MS (ESI): m / z = 455.2 [M+H] + .

[0211] Example 2

[0212] 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide (Compound 2)

[0213] 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0214] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL), add HATU (565 mg, 1.49 mmol) with stirring, and stir at room temperature. After the solid is completely dissolved, add DIEPA (2 mL), and finally add 1-methyl-1H-pyrazol-4-amine hydrochloride (246 mg, 1.84 mmol). Stir and react at room temperature for 4 h. After the reaction is completed as monitored by LCMS, add ethyl acetate (50 mL) to the system, wash with water (50 mL×4), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and separate by silica gel chromatography (PE:EA=1:0~1:1) to give the title compound 2C (352 mg, 87.03%).

[0215] LC-MS (ESI): m / z = 405.2 [M+H] + .

[0216] Step 2: Dissolve 2C (352 mg, 0.88 mmol) in methanol (10 mL), add dioxane hydrochloride solution (4 mL, 4 M), react at room temperature for 4 hours, and spin dry to obtain the title compound 2D (313 mg, crude product).

[0217] LC-MS (ESI): m / z = 305.2 [M+H] + .

[0218] Step 3: 1E (200 mg, 0.74 mmol) and 2D (313 mg) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 5.74 mmol) were added. After nitrogen replacement, the reaction was carried out at 60°C overnight. LCMS detection showed that the reaction of the raw materials was complete. The system was concentrated, and a saturated solution of sodium bicarbonate (20 mL) was added. 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 a column (DCM:MeOH = 1:0 to 0:1) to obtain compound 2 (236 mg, 64.48%).

[0219] 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.48(s,1H),8.03(s,1H),7.95–7.91(m,1H),7.70(s,1H),7.63–7.56(m,1H) ,7.54–7.49(m,1H),7.37–7.26(m,1H),3.81(s,3H),3.71(s,2H),3.24–3.16(m,4H),2.64–2.57(m,4H),2.42(s,3H).

[0220] LC-MS (ESI): m / z = 495.2 [M+H] + .

[0221] Example 3

[0222] N-(3,3-difluorocyclobutyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide (Compound 3)

[0223] N-(3,3-difluorocyclobutyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0224] Step 1: Compound 1B (331 mg, 1 mmol) was dissolved in DMF (10 mL), and HATU (565 mg, 1.5 mmol) was added with stirring. The mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (2 mL) was added, and finally 3,3-difluorocyclobutylamine (214 mg, 2 mmol) was added. The reaction was stirred at room temperature for 4 h. After the reaction was completed as monitored by LCMS, ethyl acetate (50 mL) was added to the system, and the mixture was washed with water (50 mL × 4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel chromatography (PE:EA = 1:0 to 1:1) to give the title compound 3C (349 mg, 84.30%).

[0225] LC-MS (ESI): m / z = 415.2 [M+H] + .

[0226] Step 2: Dissolve 3C (349 mg, 0.85 mmol) in methanol (10 mL), add dioxane hydrochloride solution (4 mL, 4 M), react at room temperature for 4 hours, and spin dry to obtain the title compound 3D (301 mg, crude product).

[0227] LC-MS (ESI): m / z = 315.2 [M+H] + .

[0228] Step 3: 1E (200 mg, 0.74 mmol) and 3D (301 mg) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol) were added. After nitrogen replacement, the reaction was carried out at 60°C overnight. LCMS detection showed that the reaction of the raw materials was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 to 0:1) to give compound 3 (196 mg, 52.5%).

[0229] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),8.99–8.92(m,1H),7.90–7.85(m,1H),7.72–7.56(m,2H),7.44–7.36(m ,1H),4.41(s,2H),4.32–4.24(m,1H),3.84–3.78(m,4H),3.54–3.48(m,4H),2.93–2.81(m,4H),2.45(s,3H).

[0230] LC-MS (ESI): m / z = 505.2 [M+H] + .

[0231] Example 4

[0232] 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1R,2S)-2-fluorocyclopropyl)picolinamide (Compound 4)

[0233] 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1R,2S)-2-fluorocyclopropyl)picolinamide

[0234] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL), add HATU (565 mg, 1.5 mmol) with stirring, stir at room temperature, wait until the solid is completely dissolved, add DIEPA (2 mL), and finally add (1R, 2S)-2-fluorocyclopropylamine p-toluenesulfonate (494 mg, 2 mmol). Stir and react at room temperature for 4 h. After the reaction is complete as monitored by LCMS, add ethyl acetate (50 mL) to the system, wash with water (50 mL × 4), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel chromatography (PE:EA = 1:0 to 1:1) to give the title compound 4C (294 mg, 76.8%).

[0235] LC-MS (ESI): m / z = 383.2 [M+H] + .

[0236] Step 2: Dissolve 4C (294 mg, 0.76 mmol) in methanol (10 mL), add dioxane hydrochloride (4 mL, 4 M) solution, react at room temperature for 4 hours, and spin dry to obtain the title compound 4D (241 mg, crude product).

[0237] LC-MS (ESI): m / z = 283.2 [M+H] + .

[0238] Step 3: 1E (200 mg, 0.74 mmol) and 4D (241 mg) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol) were added. After nitrogen replacement, the reaction was carried out at 60°C overnight. LCMS detection showed that the reaction of the raw materials was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by column chromatography (DCM:MeOH = 1:0 to 0:1) to give compound 4 (197 mg, 56.3%).

[0239] 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.36–8.31(m,1H),7.88–7.83(m,1H),7.63–7.45(m,2H),7.32–7.25(m,1H),4.87–4.61(m ,1H),3.70(s,2H),3.23–3.13(m,4H),2.94–2.72(m,1H),2.64–2.54(m,4H),2.42(s,3H),1.37–1.23(m,1H),1.14–1.00(m,1H).

[0240] LC-MS (ESI): m / z = 473.2 [M+H] + .

[0241] Example 5

[0242] 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1S,2R)-2-fluorocyclopropyl)picolinamide (Compound 5)

[0243] 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1S,2R)-2-fluorocyclopropyl)picolinamide

[0244] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL), add HATU (565 mg, 1.5 mmol) with stirring, stir at room temperature, wait until the solid is completely dissolved, add DIEPA (2 mL), and finally add (1S, 2R)-2-fluorocyclopropylamine (150 mg, 2 mmol). Stir and react at room temperature for 4 h. After the reaction is complete as monitored by LCMS, add ethyl acetate (50 mL) to the system, wash with water (50 mL × 4), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel chromatography (PE:EA = 1:0 to 1:1) to give the title compound 5C (324 mg, 84.6%).

[0245] LC-MS (ESI): m / z = 383.2 [M+H] + .

[0246] Step 2: Dissolve 5C (324 mg, 0.84 mmol) in methanol (10 mL), add dioxane hydrochloride (4 mL, 4 M) solution, react at room temperature for 4 hours, and spin dry to obtain the title compound 5D (292 mg, crude product).

[0247] LC-MS (ESI): m / z = 283.2 [M+H] + .

[0248] Step 3: 1E (200 mg, 0.74 mmol) and 5D (292 mg) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol) were added. After nitrogen replacement, the reaction was carried out at 60°C overnight. LCMS detection showed that the reaction of the raw materials was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by column chromatography (DCM:MeOH = 1:0 to 0:1) to give compound 5 (197 mg, 56.3%).

[0249] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.36–8.31(m,1H),7.88–7.83(m,1H),7.59–7.49(m,2H),7.32–7.26(m,1H),4.86–4.63(m ,1H),3.70(s,2H),3.22–3.13(m,4H),2.88–2.76(m,1H),2.63–2.56(m,4H),2.42(s,3H),1.38–1.24(m,1H),1.14–1.00(m,1H).

[0250] LC-MS (ESI): m / z = 473.2 [M+H] + .

[0251] Example 6

[0252] N-(Cyclopropylmethyl(-6-fluoro-5-(4-((2-methyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)piperazin-1-yl)picolinamide (Compound 6)

[0253] N-(cyclopropylmethyl)-6-fluoro-5-(4-((2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0254] Step 1: Dissolve 1B (626 mg, 1.89 mmol), cyclopropylmethylamine (0.16 g, 2.25 mmol), DIPEA (3.13 mL, 18.9 mmol), and HATU (1.44 g, 3.78 mmol) in DMF (20 mL) and react overnight at room temperature. After the starting material disappeared, the system was poured into water (100 mL), resulting in the precipitation of a large amount of solid. The solid was filtered and dried to yield compound 6A (630 mg, 88%).

[0255] LCMS m / z=379.1[M+1] + .

[0256] Step 2: 6A was dissolved in dioxane hydrochloride solution (10 mL, 4 N), and the reaction was carried out at room temperature overnight. The system was concentrated to obtain the crude hydrochloride of 6B, which was directly used in the next step.

[0257] LCMS m / z=279.1[M+1] + .

[0258] Step 3: The crude product 6B, 1E (0.36 g, 1.33 mmol), DIPEA (2.2 mL, 12.63 mmol), and potassium iodide (22 mg, 0.13 mmol) were dissolved in a mixture of DMF (2 mL) and acetonitrile (20 mL). The mixture was heated to 60°C and allowed to react overnight. The acetonitrile was removed by concentration, and the residue was poured into water (20 mL). A large amount of solid precipitated, which was filtered and dried. The filter cake was then purified by preparative HPLC (HPLC preparation conditions: C18 reverse phase preparative column, mobile phase: deionized water containing 0.1% ammonia (A), acetonitrile (B), gradient elution, B content = 5% to 55%, elution time 16 min, flow rate 12 mL / min, column temperature: 30°C) to obtain compound 6 (121 mg, 19%).

[0259] LCMS m / z=469.7[M+1] + .

[0260] 1 H NMR(400MHz, CDCl3)δ9.43(s,1H),8.02–7.96(m,1H),7.60–7.56(m,2H),7.37–7.27(m,2H),3.76(s,2H) ,3.38–3.16(m,6H),2.70(s,4H),2.61(s,3H),1.14–0.98(m,1H),0.58–0.49(m,2H),0.30–0.26(m,2H).

[0261] Example 7:

[0262] N-cyclopropyl-2-fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (Compound 7)

[0263] N-cyclopropyl-2-fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0264] Step 1: 7A (5.20 g, 22.22 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (8.24 g, 26.66 mmol), and potassium carbonate (6.14 g, 44.44 mmol) were added sequentially to a 100 mL N,N-dimethylformamide solution. After nitrogen replacement three times, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.86 g, 1.11 mmol) and water (1.00 g, 55.55 mmol) were added. After nitrogen replacement three more times, the temperature was raised to 110°C and the reaction was allowed to proceed for 4 hours. After completion of the reaction, the temperature was lowered to room temperature, ethyl acetate (200 mL) was added, stirred for 15 minutes, and filtered. The filtrate was washed with water (200 mL x 3), the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain compound 7B (7.20 g, yield 96.33%).

[0265] LC-MS (ESI): m / z = 337.2 [M+H] + .

[0266] Step 2: Intermediate 7B (4.00 g, 11.89 mmol) was added to a toluene (20 mL) solution, followed by addition of a 20% aqueous lithium hydroxide solution (10 mL) and methanol (2 mL). The mixture was stirred at 25°C overnight. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added. The mixture was separated, and the aqueous phase was collected and adjusted to pH 3-4 with 1 mol / L aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness. Intermediate 7C (3.70 g, 96.54% yield) was obtained.

[0267] LC-MS (ESI): m / z = 323.1 [M+H] + .

[0268] Step 3: Intermediate 7C (1.50 g, 4.65 mmol) and N,N,N',N'-tetramethyluronium chloride hexafluorophosphate (2.61 g, 9.30 mmol) were added to a dichloromethane (50 mL) solution. N-methylimidazole (0.8 g, 9.77 mmol) was slowly added and stirred for 15 minutes. Cyclopropylamine (0.32 g, 5.58 mmol) was then added and the mixture was allowed to react at 25°C for another 3 hours. After the reaction was complete, the mixture was washed with water (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified on a silica gel column (dichloromethane:methanol = 100% to 85%) to obtain Intermediate 7D (1.60 g, 95.21% yield).

[0269] LC-MS (ESI): m / z = 362.2 [M+H] + .

[0270] Step 4: Intermediate 7D (1.60 g, 4.43 mmol) was added to a 4.0 mol / L dioxane hydrochloride solution (20 mL), and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, and isopropanol (5 mL) and ethyl acetate (20 mL) were added. After stirring for 1 hour, the mixture was filtered to obtain intermediate 7E (1.35 g, yield 91.19%).

[0271] LC-MS (ESI): m / z = 262.1 [M+H] + .

[0272] Step 5: Compounds 7E (180 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixture of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were then added, and the mixture was heated to 80°C for 2 hours. After completion of the reaction, the mixture was concentrated to dryness, spin-dried, and purified using a preparative liquid phase column (liquid phase preparative conditions: C18 reversed-phase preparative column, mobile phase: deionized water containing 0.1% ammonia (A), acetonitrile (B), gradient elution, B content = 5% to 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30°C); the title compound 7 (50 mg, yield 22.60%, retention time approximately 2.821 min) was obtained.

[0273] LC-MS (ESI): m / z = 452.20 [M+H] + .

[0274] 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.57(d,1H),8.06(d,1H),7.90(d,1H),7.51(d,1H), 7.29(t,1H),6.23(s,1H),3.75(s,2H),3.17(d,2H),2.93–2.41(m,8H),0.74–0.61(m,4H).

[0275] Example 8:

[0276] 2-Fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (Compound 8)

[0277] 2-fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0278] Step 1: Add intermediate 7B (1.20 g, 3.57 mmol) to acetonitrile (10 mL) and then add 40% aqueous methylamine (10 mL). Stir at room temperature for 2 hours. After completion of the reaction, concentrate to dryness, and purify the residue on a silica gel column (ethyl acetate:petroleum ether = 0-100%) to afford the title compound 8A (1.00 g, 83.52%).

[0279] LC-MS (ESI): m / z = 336.20 [M+H] + .

[0280] Step 2: Intermediate 8A (1.00 g, 2.98 mmol) was added to a 4.0 mol / L dioxane hydrochloride solution (20 mL), and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, and isopropanol solution (5 mL) and ethyl acetate (20 mL) were added. After stirring for 1 hour, the mixture was filtered to obtain intermediate 8B (700 mg, yield 76.23%).

[0281] LC-MS (ESI): m / z = 236.20 [M+H] + .

[0282] Step 3: Compound 8B (170 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixture of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were then added, and the mixture was heated to 80°C for 2 hours. After completion of the reaction, the mixture was concentrated to dryness, spin-dried, and purified using a preparative liquid phase column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase: deionized water containing 0.1% ammonia (A), acetonitrile (B), gradient elution, B content = 5% to 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30°C); the title compound 8 (165 mg, yield 79.15%, retention time approximately 2.592 min) was obtained.

[0283] LC-MS (ESI): m / z = 426.20 [M+H] + .

[0284] 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.60(d,1H),8.09–8.04(m,1H),7.91(s,1H),7.53–7.50(m,1H), 7.33–7.29(m,1H),6.25–6.23(m,1H),3.81–3.70(m,2H),3.17(q,2H),2.79(d,3H),2.70–2.42(m,7H).

[0285] Example 9:

[0286] 2-Fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (Compound 9)

[0287] 2-fluoro-1'-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0288] Step 1: Intermediate 7C (1.00 g, 3.10 mmol) and N,N,N',N'-tetramethyluronium chloride hexafluorophosphate (1.04 g, 3.72 mmol) were added to a dichloromethane (50 mL) solution. N-methylimidazole (0.51 g, 6.15 mmol) was slowly added and stirred for 15 minutes. 1-Methyl-1H-pyrazol-4-amine (0.36 g, 3.71 mmol) was then added and the mixture was allowed to react at 25°C for another 3 hours. After the reaction was complete, the mixture was washed with water (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100% to 85%) to obtain Intermediate 9A (1.20 g, 96.43% yield).

[0289] LC-MS (ESI): m / z = 402.30 [M+H] + .

[0290] Step 2: Intermediate 9A (1.20 g, 2.99 mmol) was added to a 4.0 mol / L dioxane hydrochloride solution (20 mL), and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, and isopropanol (5 mL) and ethyl acetate (20 mL) were added. After stirring for 1 hour, the mixture was filtered to obtain intermediate 9B (0.90 g, yield 80.43%).

[0291] LC-MS (ESI): m / z = 302.40 [M+H] + .

[0292] Step 3: Compound 9B (200 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixture of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were then added, and the mixture was heated to 80°C for 2 hours. After completion of the reaction, the mixture was concentrated to dryness, spin-dried, and purified using a preparative liquid phase column (liquid phase preparative conditions: C18 reverse-phase preparative column, mobile phase: deionized water containing 0.1% ammonia (A), acetonitrile (B), gradient elution, B content = 5% to 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30°C); the title compound 9 (194 mg, yield 80.55%, retention time approximately 2.752 min) was obtained.

[0293] LC-MS (ESI): m / z = 492.20 [M+H] + .

[0294] 1 H NMR(400MHz,DMSO-d6)δ12.45(s,1H),10.73(s,1H),8.15–8.04(m,2H),8.00(s,1H),7.72(s,1H) ,7.52(d,1H),7.33–7.29(m,1H),6.28–6.26(m,1H),3.79(d,5H),3.19(d,2H),2.71–2.42(m,7H).

[0295] Example 12

[0296] N-cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide (Compound 12)

[0297] N-cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)pipera zin-1-yl)-6-fluoropicolinamide

[0298] Step 1: Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (23.8 g, 0.1 mol) in 1,4-dioxane (240 mL). Add serine methyl ester hydrochloride (16.5 g, 0.11 mol) and DIPEA (40 mL) with stirring. React at 40°C overnight. After the reaction is complete as monitored by LCMS, the solvent is dried and the target product 12A (19.4 g, 57.55%) is obtained after separation by silica gel column chromatography (PE:EA = 5:1 to 1:1).

[0299] LC-MS(ESI):m / z=337.2,339.1[M+H] + .

[0300] Step 2: Dissolve 12A (19.4 g, 57.55 mmol) in anhydrous methanol (250 mL) and water (25 mL). Add ammonium chloride (32.1 g, 600 mmol) and zinc powder (39 g, 600 mmol) and react at room temperature for 2 hours. LCMS confirmed the reaction was complete. The zinc powder was removed by filtration, and the filtrate was concentrated, diluted with ethyl acetate (200 mL), washed with water (200 mL), and extracted again with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the target compound 12B (14.5 g, 82.06%).

[0301] LC-MS(ESI):m / z=307.2,309.1[M+H] + .

[0302] Step 3: Dissolve 12B (14.5 g, 47.2 mmol) in anhydrous methanol (100 mL) and add 4 M hydrochloric acid in dioxane (4 mL). Allow to react at room temperature for 2 hours. LCMS confirmed the reaction was complete. The solvent was removed by concentration and filtration to yield the target compound 12C (10.7 g, 82.3%).

[0303] LC-MS(ESI):m / z=275.2,277.2[M+H] + .

[0304] Step 4: Disperse 12C (10.7 g, 38.9 mmol) in dichloromethane (200 mL). Add DDQ (9.72 g, 42.8 mmol) at room temperature and allow to react overnight. LCMS confirmed the reaction was complete. The solvent was removed by vortexing, and saturated aqueous sodium bicarbonate was added with stirring. When bubbling ceased, the mixture was filtered, the filter cake washed with water, and dried to yield the target compound 12D (8.4 g, 79.09%).

[0305] LC-MS(ESI):m / z=273.2,275.2[M+H] + .

[0306] Step 5: Disperse 12D (8.4 g, 30.76 mmol) in dichloromethane (150 mL) and add Dess-Martin periodinane (25.8 g, 61 mmol) at room temperature. The reaction was allowed to proceed for 6 h. LCMS confirmed the reaction was complete. The solvent was removed by vortexing, and saturated aqueous sodium bicarbonate was added with stirring. The mixture was filtered, and the filter cake was washed with water and dried to yield the target compound 12E (7.1 g, 86.6%).

[0307] LC-MS(ESI):m / z=271.2,273.2[M+H] + .

[0308] Step 6: Disperse 12E (7.1 g, 26.19 mmol) in 1,4-dioxane (100 mL). Slowly add DAST (21.7 g, 135 mmol) at room temperature and allow to react overnight. LCMS monitoring confirmed the complete reaction. Add water (200 mL) with stirring under an ice bath, extract with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After drying, the product was separated by silica gel column chromatography (PE:EA = 10:1 to 3:1) to yield the target compound 12F (2.1 g, 27.3%).

[0309] LC-MS(ESI):m / z=291.2,293.2[MH] + .

[0310] Step 7: 12F (2.1 g, 7.2 mmol) was dissolved in 1,4-dioxane (40 mL). (Tributylstannyl)methanol (2.54 g, 7.92 mmol) and X-phos Pd G2 (556 mg, 0.72 mmol) were added with stirring. The mixture was allowed to react at 80°C overnight. LCMS confirmed the completion of the reaction. The target compound 12G (1.65 g, 94.6%) was obtained after separation by silica gel column chromatography (PE:EA = 1:1 to 0:1).

[0311] LC-MS (ESI): m / z = 245.2 [M+H] + .

[0312] Step 8: Compound 12G (488 mg, 2.00 mmol) was dissolved in dichloromethane, and triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol) were added with stirring at 0°C. The reaction was stirred at room temperature for 2 h. After the reaction was completed as monitored by LCMS, the target product 12H (512 mg, 83.4%) was obtained after separation by silica gel column chromatography (PE:EA=5:1 to 1:1).

[0313] LC-MS(ESI):m / z=307.2,309.2[M+H] + .

[0314] Step 9: 1D (264 mg, 1 mmol) and 12H (300 mg, 0.97 mmol) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After nitrogen replacement, the reaction was carried out at 60°C for 4 hours. LCMS detection showed that the reaction of the raw material was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 a column (DCM:MeOH = 1:0 to 0:1) to obtain compound 12 (334 mg, 70.21%).

[0315] 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.39–8.32(m,1H),7.89–7.84(m,1H),7.85–7.78(m,1H),7.69–7.60(m,1H),7.54– 7.47(m,1H),7.27–6.94(m,1H),3.91(s,2H),3.41–3.32(m,4H),2.70–2.62(m,4H),2.90–2.81(m,1H),0.73–0.53(m,4H).

[0316] LC-MS (ESI): m / z = 491.2 [M+H] + .

[0317] Example 13

[0318] N-cyclopropyl-6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide (Compound 13)

[0319] N-cyclopropyl-6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0320] Step 1: Compound 13A (synthesized according to patent US2022 / 0009901A1) (524 mg, 2.00 mmol) was dissolved in dichloromethane, and triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol) were added with stirring at 0°C. The reaction was stirred at room temperature for 2 h. After the reaction was completed as monitored by LCMS, the target product 13B (552 mg, 84.9%) was obtained after separation by silica gel column chromatography (PE:EA=5:1~1:1).

[0321] LC-MS(ESI):m / z=325.2,327.2[M+H] + .

[0322] Step 2: 1D (264 mg, 1 mmol) and 13B (300 mg, 0.92 mmol) were dissolved in anhydrous acetonitrile (20 mL), and potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After nitrogen replacement, the reaction was carried out at 60°C for 4 hours. LCMS detection showed that the reaction of the raw materials was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by column chromatography (DCM:MeOH = 1:0 to 0:1) to give compound 13 (319 mg, 68.3%).

[0323] 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.34–8.28(m,1H),7.86–7.81(m,1H),7.74–7.69(m,1H),7.59–7.52(m,1 H),7.44–7.37(m,1H),3.75(s,2H),3.21–3.13(m,4H),2.89–2.81(m,1H),2.65–2.61(m,4H),0.69–0.59(m,4H).

[0324] LC-MS (ESI): m / z = 509.2 [M+H] + .

[0325] Example 14

[0326] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinolin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 14)

[0327] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 14)

[0328] The first step: Compound 13A (synthesized according to patent US2022 / 0009901A1) (1.3 g, 4.96 mmol) was dissolved in a mixed solution of anhydrous ethanol (26 mL) and water (2 mL), and solid ammonium chloride (3.18 g, 59.47 mmol) and zinc powder (3.24 g, 49.6 mmol) were added sequentially under stirring at room temperature. After the addition was completed, the reaction was reacted at room temperature for 90 minutes, and the reaction was monitored by LCMS. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (100 mL). Ethyl acetate (100 mL) was added to the filtrate, the aqueous phase was separated, the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the target compound 14A (1.30 g, yield: 99.21%) was filtered.

[0329] LCMS m / z=265.2[M+1] + .

[0330] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.16(s,1H),6.88–6.84(m,1H),6.63–6.61(m,1H),5.01–4.98(m,1H),4.87–4.80(m,1H),4.39–4.40(m,2H).

[0331] Step 2: Compound 14A (1.0 g, 3.79 mmol) was dissolved in tetrahydrofuran (20 mL), and then 25% (w / w) aqueous sodium hydroxide solution (5 mL) was added to the reaction solution with stirring at room temperature. After the addition was complete, the mixture was heated at 50°C for 2 h. The reaction was monitored by TLC (ethyl acetate: petroleum ether = 3:2). After the reaction was complete, ethyl acetate (40 mL) and water (20 mL) were added to the reaction solution, and the organic phase was separated. The aqueous phase was adjusted to pH = 6 with hydrochloric acid (6N hydrochloric acid) to precipitate a large amount of solid, which was filtered and the filter cake was dried to obtain the target compound 12G (0.7 g, yield: 75.64%).

[0332] LCMS m / z=245.2[M+1] + .

[0333] 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),7.73–7.70(m,1H),7.46–7.42(m,1H),7.19–6.93(m,1H),5.52–5.49(m,1H),4.69–4.67(m,2H).

[0334] 19 FNMR(400MHz,DMSO-d6)δ-122.41(s),-123.46(s).

[0335] Step 3: Compound 12G (488 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0°C. Triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol) were then added sequentially. After the addition was complete, the ice bath was removed, and the mixture was naturally warmed to room temperature and stirred at this temperature for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the mixture was directly concentrated and purified by column chromatography (eluent, PE:EA=5:1 to 1:1) to obtain the target compound 12H (530 mg, yield: 86.32%).

[0336] LC-MS(ESI):m / z=307.2,309.2[M+H] + .

[0337] Step 4: Compound 14B (2.52 g, 19.98 mmol) was dissolved in dichloromethane (50 mL), and then thionyl chloride (2.5 mL) was added. After the addition was complete, the mixture was heated under reflux for 3 h. After 3 h of reaction, the mixture was concentrated to obtain the crude target compound 14C (2.89 g), which was used directly in the next step.

[0338] Step 5: 5-iodo-6-fluoro-pyridin-2-amine (4.76 g, 19.99 mmol) was weighed and dissolved in dichloromethane (80 mL), followed by the addition of pyridine (4.74 g, 59.97 mmol) and the cooling of the reaction solution to 0°C. The crude compound 14C (2.89 g, 19.99 mmol) was weighed and dissolved in (20 mL) dichloromethane. The dichloromethane solution of compound 14C was slowly added to the above reaction solution. After the addition was complete, the temperature was raised to room temperature and stirring was continued for 1 h. After the reaction was complete, dichloromethane (50 mL) and water (100 mL) were added to the reaction solution. After stirring for 2 min, the aqueous phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to precipitate a solid. Then, n-hexane was added and stirred to crystallize. After filtration and drying, the target compound 14D (3.1 g, yield: 44.81%) was obtained.

[0339] LC-MS (ESI): m / z = 347.2 [M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.44(s,1H),8.34–8.30(m,1H),8.12(s,1H),7.96–7.94(m,1H),3.88(s,3H).

[0341] Step 6: Under nitrogen protection, compound 14D (1.35 g, 3.90 mmol) and N-Boc piperazine (1.45 g, 7.80 mmol) were weighed in 1,4-dioxane (30 mL), and then cesium carbonate (3.81 g, 11.7 mmol), Pd2(dba)3 (0.71 g, 0.78 mmol), and RuPhos (0.73 g, 1.56 mmol) were added. After the addition was complete, the mixture was heated to 100°C and reacted for 3 h. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 2:1) to obtain the crude target compound 14E (0.55 g, yield: 34.87%), which was used directly in the next reaction.

[0342] LC-MS (ESI): m / z = 405.2 [M+H] + .

[0343] Step 7: Dissolve 14E (0.55 g, crude) in methanol (10 mL), add dioxane hydrochloride (4 mL, 4 M) solution, react at room temperature for 4 hours, and spin dry to obtain the title compound 14F (460 mg, crude), which was used directly in the next reaction.

[0344] LC-MS (ESI): m / z = 305.2 [M+H] +.

[0345] Step 8: 14F (200 mg, crude product) and 12H (100 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (20 mL) and DIPEA (1 mL, 5.74 mmol). After nitrogen replacement, the reaction was carried out at 60°C for 2 h. LCMS monitoring showed that the starting material had disappeared. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give compound 14 (26 mg, yield: 14.86%).

[0346] LC-MS (ESI): m / z = 531.2 [M+H] + .

[0347] 1 H NMR(400MHz,DMSO-d6)δ12.96(s,1H),10.41(s,1H),8.38(s,1H),8.08(s,1H),8.01–7.96(m,1H),7.72–7.66(m,1H) ,7.60–7.52(m,1H),7.42–7.34(m,1H),7.07(t,1H),3.87(s,3H),3.74(s,2H),3.09–2.98(m,4H),2.65–2.56(m,4H).

[0348] Example 15

[0349] 5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(1-methyl)-1H-pyrazol-4-yl)picolinamide (Compound 15)

[0350] 5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(1-methyl-1H-pyrazol-4-yl)picolinamide (Compound 15)

[0351] Step 1: 2D (200 mg, crude product) and 12H (100 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (20 mL) and DIPEA (1 mL, 5.74 mmol). After nitrogen replacement, the reaction was carried out at 60°C for 2 h. LCMS monitoring showed that the starting material had disappeared. The system was concentrated and a saturated sodium bicarbonate solution (20 mL) was added. 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give compound 15 (37 mg, yield: 21.14%).

[0352] 1 H NMR(400MHz,DMSO-d6)δ12.93(s,1H),10.48(s,1H),8.03(s,1H),7.98–7.86(m,1H),7.77–7.67(m,2H),7.65– 7.55(m,1H),7.48–7.36(m,1H),7.07(t,1H),3.81(s,3H),3.76(s,2H),3.25–3.15(m,4H),2.68–2.58(m,4H).

[0353] LC-MS (ESI): m / z = 531.2 [M+H] + .

[0354] Example 16

[0355] N-(6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 16)

[0356] N-(6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (Compound 16)

[0357] Step 1: 14F (200 mg, crude product) and 1E (100 mg, 0.37 mmol) were dissolved in anhydrous acetonitrile (20 mL) and DIPEA (1 mL, 2.45 mmol). After nitrogen replacement, the reaction was carried out at 60°C for 2 h. LCMS monitoring showed that the starting material had disappeared. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. The product 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give compound 16 (37 mg, 21.14%).

[0358] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),10.41(s,1H),8.38(s,1H),8.08(s,1H),8.01–7.93(m,1H),7.59–7. 47(m,2H),7.34–7.27(m,1H),3.87(s,3H),3.69(s,2H),3.06–2.97(m,4H),2.62–2.53(m,4H),2.42(s,3H).

[0359] LC-MS (ESI): m / z = 495.2 [M+H] + .

[0360] Example 17

[0361] 1-(Difluoromethyl)-N-(5-(4-((2-(difluoroethyl(-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide (Compound 17)

[0362] 1-(difluoromethyl)-N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide (Compound 17)

[0363] Step 1: Dissolve compound 17A (synthesized according to patent WO2016051193A1) (9.62 g, 59 mmol) in DCM (60 mL). Add thionyl chloride (10 mL) and reflux for 2 h. Stop the reaction once the system is completely clear. Concentrate the solvent to obtain the title compound 17B (10.6 g, crude product). Use it directly in the next step without further purification.

[0364] Step 2: In a 500 mL eggplant-shaped flask, add 5-bromo-6-fluoropyridin-2-amine (10.6 g, 55.49 mmol) and pyridine (14.2 g, 180 mmol) in 200 mL of dichloromethane and dissolve in the solution. Cool to 0°C. Slowly add 100 mL of a dichloromethane solution of compound 17B (10.6 g, crude product) dropwise. After complete addition, continue the reaction at room temperature for 1 h. Add 200 mL of semi-saturated brine, shake thoroughly, let stand, separate the layers, separate the aqueous phase, concentrate the organic phase until a large amount of solid precipitates, filter, and wash the filter cake with petroleum ether. After vacuum drying, the title compound 17C (7.8 g, 41.95%) is obtained.

[0365] LC-MS(ESI): m / z=335.2, 337.2[M+H] + .

[0366] Step 3: Under nitrogen, compound 17C (7.8 g, 23 mmol) and N-Boc piperazine (6.34 g, 34 mmol) were weighed in 1,4-dioxane (100 mL), followed by the addition of cesium carbonate (15 g, 46 mmol), Pd2(dba)3 (4.2 g, 4.6 mmol), and Xphos (2.2 g, 4.6 mmol). After the addition was complete, the mixture was heated to 100°C and reacted overnight. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain the target compound 17D (0.464 g, yield: 4.8%).

[0367] LC-MS (ESI): m / z = 441.2 [M+H] + .

[0368] Step 4: 17D (0.464 g, 1.05 mmol) was dissolved in methanol (10 mL), and dioxane hydrochloride (5 mL, 4 M) solution was added. The mixture was reacted at room temperature for 2 h and concentrated to give the title compound 17E (388 mg, crude product).

[0369] LC-MS (ESI): m / z = 341.2 [M+H] + .

[0370] Step 5: 12H (305 mg, 1 mmol) and 17E (388 mg, crude product) were dissolved in anhydrous acetonitrile (20 mL), and DIPEA (0.5 mL) was added. After nitrogen replacement, the mixture was reacted at 60°C for 3 hours. LCMS detection showed that the reaction of the raw material was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to give compound 17 (181 mg, 31.95%).

[0371] 1 H NMR(400MHz,DMSO-d6)δ13.00(s,1H),10.76(s,1H),8.95(s,1H),8.37(s,1H),8.02–7.96(m,1H),8.04–7.73(m,1H) 7.71(d,1H),8.62–7.55(m,1H),7.43–7.37(m,1H),7.07(t,1H),3.74(s,2H),3.09–2.99(m,4H),2.65–2.55(m,4H).

[0372] LC-MS (ESI): m / z = 567.2 [M+H] + .

[0373] Example 18

[0374] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-3-fluoro-1-methyl-1H-pyrazole-4-carboxamide (Compound 18)

[0375] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-3-fluoro-1-methyl-1H-pyrazole-4-carboxamide (Compound 18)

[0376] Step 1: Compound 18A (1 g, 6.1 mmol) was dissolved in THF (20 mL). 500 mg (60%) of sodium hydride was added at 0°C and stirred for 30 min. Iodomethane (0.6 mL, 9.6 mmol) was added, and the mixture was slowly warmed to room temperature for 2 h. The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and separated by column chromatography (PE:EA = 20:1 to 5:1) to afford compound 18B (601 mg, 56%).

[0377] 1 H NMR (400MHz, CDCl3) δ7.23–7.21(m,1H),3.77–3.75(m,3H).

[0378] Step 2: Compound 18B (342 mg, 1.9 mmol) was dissolved in THF (5 mL) and cooled to -78°C. n-Butyl lithium (1.15 mL, 2.5 M in hexane) was added, and the mixture was stirred at -78°C for 15 min. DMF (0.3 mL, 3.9 mmol) was added and the reaction was maintained at -78°C for 1 h. Ethyl acetate and water were added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected, concentrated, and separated by column chromatography (PE:EA = 15:1 to 2:1) to afford compound 18C (84 mg, 35%).

[0379] LC-MS (ESI): m / z = 129.1 [M+H] + .

[0380] Step 3: Dissolve compound 18C (40 mg, 0.28 mmol) in 0.375 M KMnO₄ solution, heat to 75°C, and react for 1 h. Cool to room temperature and add 10% aqueous KOH to alkaline the system, resulting in the appearance of solids. The filtrate was filtered and adjusted to pH 2 with hydrochloric acid. Extract the mixture three times with ethyl acetate / methanol (10 / 1) (50 mL). The resulting organic phase was concentrated to yield 30 mg of crude compound 18D.

[0381] LC-MS (ESI): m / z = 145.1 [M+H] + .

[0382] Step 4: Add 5 mL of dichloromethane and 1 mL of thionyl chloride to the crude compound 18D. Heat the system to 50°C under a nitrogen atmosphere for 1 h. Cool to room temperature, concentrate until no solvent remains, and use directly in the next reaction.

[0383] Step 5: Compound 18F (4 g, 21 mmol) was dissolved in dichloromethane (50 mL). Pyridine (2.5 mL, 32 mmol) and acetyl chloride (1.7 mL, 23 mmol) were added at room temperature. After the disappearance of the starting material by TLC detection, the system was concentrated and slurried with ethyl acetate / petroleum ether = 1 / 15 (160 mL) to obtain compound 18G (4 g, 81.74%).

[0384] LC-MS (ESI): m / z = 233.1 [M+H] + .

[0385] Step 6: 18G (4 g, 17 mmol), N-Boc-piperazine (3.8 g, 21 mmol), Pd2dba3 (1.6 g, 1.7 mmol), RuPhos (1.4 g, 3.2 mmol), and potassium tert-butoxide (4.8 g, 43 mmol) were placed in a round-bottom flask. 1,4-dioxane (100 mL) was added. After replacing the nitrogen atmosphere, the temperature was raised to reflux and stirred overnight. After cooling to room temperature, silica gel was added. The solvent was concentrated to dryness and the product was separated by column chromatography (PE:EA = 5:1 to 1:3) to obtain compound 18H (1.1 g, 19%).

[0386] LC-MS (ESI): m / z = 339.1 [M+H] + .

[0387] Step 7: Compound 18H (400 mg, 1.2 mmol) was dissolved in TFA / DCM = 1:4 (10 mL), and the mixture was reacted at room temperature until the starting material disappeared. The system was then concentrated to obtain a crude trifluoroacetate salt of compound 18I, which was directly used for the next step.

[0388] LC-MS (ESI): m / z = 239.2 [M+H] + .

[0389] Step 8: The crude compound 18I and 12H (337 mg, 1.1 mmol) were dissolved in acetonitrile (15 mL), and DIPEA (3 mL) was added. The temperature was raised to 60°C for 2 h. After cooling to room temperature, the mixture was concentrated to dryness and separated by reverse phase column chromatography (water / acetonitrile = 1:1) to give compound 18J (160 mg, 27%).

[0390] LC-MS (ESI): m / z = 465.1 [M+H] + .

[0391] Step 9: Dissolve compound 18J (60 mg, 0.13 mmol) in a 2:1 mixture of concentrated hydrochloric acid and ethanol (6 mL) and heat to 70°C for 1 h. After cooling to room temperature, the mixture was concentrated to dryness to obtain the crude hydrochloride of compound 18K, which was directly used in the next step.

[0392] LC-MS (ESI): m / z = 423.2 [M+H] + .

[0393] Step 10: Dissolve the crude hydrochloride of compound 18K and compound 18E in 10 mL of dichloromethane, add 1.5 mL of pyridine, and react at room temperature for 30 min. After completion of the reaction by LCMS, the system was concentrated and the crude product was purified by preparative TLC (developing solvent: EA) to obtain the title compound 18 (8 mg, 11%).

[0394] 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.37(s,1H),7.95–7.88(m,1H),7.70–7.63(m,1H),7.6 1–7.51(m,1H),7.35(s,1H),7.06(t,1H),3.76(s,3H),3.73(s,2H),3.02(s,4H),2.60(s,4H).

[0395] 19 F NMR(400MHz, DMSO-d6)δ-73.75,-122.05,-125.45,-132.16.

[0396] LC-MS (ESI): m / z = 549.1 [M+H] + .

[0397] Example 19

[0398] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-N,1-dimethyl-1H-pyrazole-4-carboxamide (Compound 19)

[0399] N-(5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)-N,1-dimethyl-1H-pyrazole-4-carboxamide

[0400] Step 1: Compound 14E (0.505 g, 1.25 mmol) was accurately weighed and dissolved in DMF (10 mL). The mixture was then cooled to approximately 0°C under nitrogen. NaH (100 mg, 2.5 mmol, 60%) was then weighed and added to the reaction solution. The temperature was maintained and stirred for 30 min. Iodomethane (0.27 g, 1.9 mmol) was then added. The mixture was warmed to room temperature and reacted for 1 h. TLC indicated that the reaction was complete (developing solvent: EA). After the reaction was complete, saturated ammonium chloride was added to the reaction solution to disrupt the reaction. Water (100 mL) was then added and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the target compound 19A (0.44 g, yield: 84.12%). The crude product was used directly in the next step.

[0401] LC-MS (ESI): m / z = 419.5 [M+H] + .

[0402] Step 2: Compound 19A (0.44 g, 1.05 mmol) was weighed into dichloromethane (10 mL), and then a dioxane hydrochloride solution (4 M, 10 mL) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated to obtain the hydrochloride salt of the crude compound 19B (0.38 g), which was used directly in the next reaction.

[0403] LC-MS (ESI): m / z = 319.1 [M+H] + .

[0404] Step 3: Compound 19B (0.38 g, crude) and compound 12H (0.29 g, 0.94 mmol) were dissolved in anhydrous acetonitrile (20 mL). Diisopropylethylamine (1 mL) was then added and the mixture was heated to 75°C with stirring for 3 h. The reaction was monitored by LCMS. After completion, the mixture was cooled to room temperature and concentrated to remove acetonitrile and DIPEA to obtain a crude product. This crude product was purified by Pre-TLC (developing solvent: dichloromethane:methanol = 15:1) to obtain compound 19 (0.27 g, yield: 53.90%).

[0405] LC-MS (ESI): m / z = 545.6 [M+H] + .

[0406] 1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),7.73–7.71(m,1H),7.66(s,1H),7.52–7.48(m,1H),7.44–7 .40(m,1H),7.21–6.93(m,2H),6.86(s,1H),3.74(s,5H),3.26(s,3H),3.10(s,4H),2.61(s,4H).

[0407] Example 20

[0408] N-cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Compound 20)

[0409] N-cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Compound 20)

[0410] Step 1: Compound 1C (0.455 g, 1.25 mmol) was weighed into DMF (10 mL) and cooled to about 0°C under nitrogen. NaH (100 mg, 2.5 mmol, 60%) was then weighed and added to the reaction solution. After the addition was complete, stirring was maintained at this temperature for 30 min. Methyl iodide (0.27 g, 1.9 mmol) was then added. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to react for 1 h. The completion of the reaction was monitored by TLC (developing solvent: EA). After the reaction was complete, saturated ammonium chloride was added to the reaction solution to destroy the reaction. Water (100 mL) was then added and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 20A (0.39 g, 82.6%) without further purification.

[0411] LC-MS (ESI): m / z = 379.2 [M+H] + .

[0412] Step 2: 20A (0.39 g, crude) was dissolved in methanol (10 mL), and HCl / Dioxane (2 mL, 4 M) solution was added. The mixture was reacted at room temperature for 2 h and concentrated to give the title compound 20B (283 mg, crude).

[0413] LC-MS (ESI): m / z = 279.2 [M+H] + .

[0414] Step 3: 12H (200 mg, 0.65 mmol) and 20B (283 mg, crude product) were dissolved in anhydrous acetonitrile (20 mL), and DIPEA (0.5 mL) was added. The mixture was reacted at 60°C for 2 hours. LCMS detected that the reaction of the raw material was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 20 (172 mg, 52.5%).

[0415] 1 H NMR(400MHz,DMSO-d6)δ12.97(s,1H),7.56–7.48(m,1H),7.47–7.39(m,2H),7.19–6.88(m,2 H),3.67(s,2H),3.18–3.08(m,4H),3.00–2.90(m,4H),2.64–2.55(m,4H),0.63–0.19(m,4H).

[0416] LC-MS (ESI): m / z = 505.2 [M+H] + .

[0417] Example 21

[0418] 5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methyl-N-(1-methyl-1H-pyrazol-4-yl)picolinamide (Compound 21)

[0419] 5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methyl-N-(1-methyl-1H-pyrazol-4-yl)picolinamide (Compound 21)

[0420] Step 1: Compound 2D (0.404 g, 1 mmol) was weighed and dissolved in DMF (10 mL). The mixture was cooled to approximately 0°C under nitrogen. NaH (100 mg, 2.5 mmol, 60%) was then weighed and added to the reaction solution. The mixture was stirred at this temperature for 30 min. Methyl iodide (0.27 g, 1.9 mmol) was then added. The mixture was warmed to room temperature and reacted for 1 h. The completion of the reaction was monitored by TLC (developing solvent: EA). After the reaction was complete, saturated ammonium chloride solution was added to the reaction solution, followed by water (100 mL). The mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 21A (0.37 g, 88.3%) without further purification.

[0421] LC-MS (ESI): m / z = 419.2 [M+H] + .

[0422] Step 2: 21A (0.37 g, crude) was dissolved in methanol (10 mL), and HCl / Dioxane (2 mL, 4 M) solution was added. The mixture was reacted at room temperature for 2 h and concentrated to give the title compound 21B (253 mg, crude).

[0423] LC-MS (ESI): m / z = 319.2 [M+H] + .

[0424] Step 3: 12H (100 mg, 0.33 mmol) and 21B (150 mg, crude product) were dissolved in anhydrous acetonitrile (20 mL), and DIPEA (0.5 mL) was added. The mixture was reacted at 60°C for 2 hours. LCMS detected that the reaction of the raw material was complete. The system was concentrated, and a saturated sodium bicarbonate solution (20 mL) was added. 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 by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 21 (59 mg, 32.85%).

[0425] 1 H NMR(400MHz,DMSO-d6)δ13.03(s,1H),7.80–7.51(m,3H),7.47–7.25(m,2H),7.23–6.9 2(m,2H),3.81(s,2H),3.75(s,3H),3.28(s,3H),3.21–3.02(m,4H),2.66–2.53(m,4H).

[0426] LC-MS (ESI): m / z = 545.2 [M+H]+ .

[0427] Biological testing

[0428] 1. PARP-1 enzyme activity test

[0429] The PARP-1 chemiluminescence detection kit was purchased from BPS Bioscience. The histone solution in the kit was diluted 5 times with 1X PBS, 25 μL of the histone dilution was taken to the microplate, and incubated at 4°C overnight. After the incubation, the plate was washed 3 times with PBST (0.05% Tween-20), 100 μL of blocking solution was taken to the microplate, and incubated at 25°C for 90 minutes; after the incubation, the plate was washed 3 times with PBST. 2.5 μL of compounds of different concentrations diluted in the test buffer and 12.5 μL of substrate mixed solution (1.25 μL 10X PARP test buffer; 1.25 μL 10X PARP test mixture; 2.5 μL Activated DNA, 7.5 μL double distilled water) were taken to the microplate. The PARP-1 enzyme was diluted to 2 ng / μL, 10 μL was taken to the microplate, and the reaction system was incubated at 25°C for 60 minutes;

[0430] After incubation, wash the plate three times with PBST. Dilute Streptavidin-HRP 50-fold with blocking buffer, then transfer 25 μL to the microplate and incubate at 25°C for 30 minutes. After incubation, wash the plate three times with PBST. Mix ELISA ECL substrate A and substrate B at a 1:1 (v / v) ratio, transfer 50 μL to the microplate, and read the chemiluminescence value.

[0431] The inhibition rate was calculated according to formula 1, where RLUsample is the compound well reading, RLUmax is the solvent control well reading, and RLUmin is the PARP-1 enzyme-free control well reading. GraphPad Prism software was used to perform curve fitting using four parameters (log (inhibitor) vs. response--Variable slope) and calculate the IC 50 Inhibition% = (1-(RLUsample-RLUmin) / (RLUmax-RLUmin)) × 100% (Formula 1)

[0432] Experimental results: The compounds of the present invention have a significant inhibitory effect on PARP-1 enzyme activity in vitro. The IC values ​​of the compounds of the examples on PARP-1 enzyme activity are 50 The value is less than 100 μM. IC 50 The value is expressed as A, B, C, D, with A representing 0 <IC 50 ≤5nM, B means 5nM <IC 50≤10nM, C represents 10nM <IC 50 ≤50nM, D means 50nM <IC 50 ≤100nM. The test results of some embodiments are shown in Table 1.

[0433] Table 1 PARP-1 enzyme activity

[0434] Conclusion: The compounds of the present invention, such as the example compounds, have a significant inhibitory effect on PARP-1 enzyme activity in vitro, especially compound 2 has an IC of 50 The value is 0.79nM.

[0435] 2. MDA-MB-436 cell activity test experiment

[0436] Breast tumor cells MDA-MB-436 were purchased from ATCC. The culture medium was Leibovitz's L-15 + 10% FBS and cultured at 37°C in a CO2-free incubator. On the first day, cells in the exponential growth phase were collected and the cell suspension was adjusted to 4000 cells / 135 μL with culture medium. 135 μL of cell suspension was added to each well of a 96-well cell culture plate and incubated overnight. On the second day, different concentrations of compounds were added and placed in an incubator for 7 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 75 μL of CTG solution that had been pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and then placed at room temperature for 10 minutes before measuring the fluorescence signal value using an Envision2104 plate reader (PerkinElmer). The inhibition rate was calculated using formula (1), where RLU compound The readings for the drug-treated groups, RLU control is the average value of the solvent control group, RLU blank The IC values ​​were calculated using GraphPad Prism software. 50 Value. Inh.%=(1–(RLU compound –RLU blank ) / (RLU control –RLU blank ))×100%(Formula 1)

[0437] Test results: The compounds of this invention exhibited significant inhibitory effects on MDA-MB-436 cells, with IC50 values ​​of less than 100 nM, and some excellent compounds exhibiting IC50 values ​​less than 10 nM. The compounds exhibited inhibition rates greater than 70% against breast tumor MDA-MB-436 cells, with some excellent compounds exhibiting inhibition rates exceeding 85%. The results for some specific compounds are shown in Table 2.

[0438] Table 2 MDA-MB-436 cell activity

[0439] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against breast tumor cells MDA-MB-436.

[0440] 3. Pharmacokinetic test in rats

[0441] 3.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0442] 3.2 Experimental Design: On the day of the experiment, 30 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0443] Table 3. Dosing Information

[0444] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD)

[0445] (Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0446] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours for both the intravenous and oral gavage groups. Brain tissue was obtained 24 hours after drug administration, rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at −80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0447] Table 4. Pharmacokinetic parameters of test compounds in rat plasma

[0448] -:not applicable.

[0449] Conclusion: The compounds of the present invention, especially the exemplified compounds, such as compounds 4, 12, 14, 15, and 18, have good pharmacokinetic characteristics in rats.

[0450] 4. Pharmacokinetic test in mice

[0451] 4.1 Experimental Animals: Male Balb / c mice, 20-25 g, 12 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0452] 4.2 Experimental Design: On the day of the experiment, 60 Balb / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0453] Table 5. Dosing Information

[0454] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD)

[0455] (Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0456] Before and after administration, 0.06 mL of blood was collected from the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. Brain tissue was collected at 30 minutes, 2, and 24 hours after administration of compounds 12, 15, and 18, respectively. Brain tissue was collected at 24 hours after administration of compounds 2 and 5. The brain tissue was rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0457] Table 6. Pharmacokinetic parameters of test compounds in mouse plasma

[0458] -:not applicable.

[0459] Conclusion: The compounds of the present invention, especially the exemplified compounds, such as compounds 2, 5, 12, 15, and 18, have good pharmacokinetic characteristics in mice.

[0460] 5. Beagle dog pharmacokinetic test

[0461] 5.1 Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0462] 5.2 Experimental Methods: On the day of the experiment, six beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12–14 hours prior to dosing and fed 4 hours after dosing. Dosing was performed according to Table 1.

[0463] Table 7. Dosing Information

[0464] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE-CD)

[0465] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline;)

[0466] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0467] Table 8. Pharmacokinetic parameters of test compounds in beagle dog plasma

[0468] -:not applicable.

[0469] Conclusion: The compounds of the present invention, especially the compounds in the examples, such as compound 12, have good pharmacokinetic characteristics in dogs.

[0470] 6. Monkey pharmacokinetic test

[0471] 6.1 Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0472] 6.2 Experimental Methods: On the day of the experiment, 8 monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0473] Table 9. Dosing Information

[0474] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE-CD)

[0475] *Dosage is based on the free base.

[0476] Before and after dosing, 1.0 mL of blood was collected from a venous vein in each limb and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For the venous blood collection group, the following time points were used: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0477] Table 10. Pharmacokinetic parameters of test compounds in monkey plasma

[0478] Conclusion: The compounds of the present invention, especially the example compounds, such as compounds 12 and 14, have good pharmacokinetic characteristics in monkeys.

Claims

1. A compound of formula II, a stereoisomer, a solvate, a deuterated substance, or a pharmaceutically acceptable salt thereof, in, X1 is O or S; X2 is N, C or CR 5’ ; X3 is N, C or CR 5” ; Ring A is a 4-12 membered heterocycloalkyl group containing 1-3 N atoms and 0-2 heteroatoms selected from O and S; R1, R2 and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN, NH2, C 1-4 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, said alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Each L is independently -NH-, -CH2-, -O-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; n and m are independently 0, 1, 2 or 3; Each R5, R 5’ 、R 5” are independently H, D, ═O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, CN or C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Optionally, an R4 with R 5’ forming bonds; q is 0, 1, 2, 3, or 4; X4 is N, NR7 or CR7; X5 is N, NR 10 or CR 10 ; Ring B is a six-membered heteroaryl group; R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 alkyl -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-(CH2) r CONHR 11 、-OCONHR 11 、-COOR 11 , or -CO(CH2) r NHR 11 The alkyl, alkylene, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Each r is independently 1, 2 or 3; The condition is when for n and m are 0, for R6 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 When it is an alkyl group, R8 is not -CONHC 1-4 alkyl.

2. The compound according to claim 1, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, in, X1 is 0; X2 is N or CR 5’ ; X3 is N, C or CR 5” ; Ring A is a 4-9 membered monoheterocycloalkyl group, a 6-12 membered spirocyclic heterocycloalkyl group, a 6-12 membered cyclic heterocycloalkyl group or a 6-12 membered bridged heterocycloalkyl group containing 1-3 N atoms and 0-2 heteroatoms selected from O and S; R1 is H, D, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl or -(CH2) r -heterocycloalkyl, wherein the heterocycloalkyl is a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1-5 atoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl radical substitution; R2 and R3 are independently H, D, halogen or C 1-4 Alkyl, optionally substituted by 1-5 groups selected from D, halogen, OH, CN and NH2; Each R4 is independently selected from H, D, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, OH, CN or NH2, wherein the alkyl and cycloalkyl groups are optionally substituted by 1-5 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; Each L is independently -NH-, -CH2-, -O- or -C(=O)-; n and m are independently 0, 1, 2 or 3; Each R5, R 5’ 、R 5” are independently H, D, ═O, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from D, halogen, OH, CN and NH2; Optionally, an R4 with R 5’ forming bonds; q is 0, 1, or 2; R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

3. The compound according to claim 2, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, in, Ring A is a substituted or unsubstituted 6-10 membered heterocyclic alkyl, a substituted or unsubstituted 6-11 membered spirocyclic heterocyclic alkyl, a substituted or unsubstituted 6-10 membered bridged heterocyclic alkyl, a substituted or unsubstituted 4-5 membered monoheterocyclic alkyl, a substituted or unsubstituted 7-8 membered monoheterocyclic alkyl, a substituted or unsubstituted or substituted or unsubstituted or Selected from substituted or unsubstituted or R8 is C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, -NHCOOC 1-4 Alkyl, -OCONHC 1-4 Alkyl, -CONHC 1-4 Alkylene OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R 11 、-NHR 11 、-(CH2) r R 11 、-OR 11 、-COR 11 、-(CH2) r NHR 11 、-NH(CH2) r R 11 、-(CH2) r OR 11 、-O(CH2) r R 11 、-CONHR 11 、-NHCOR 11 、-NHCONHR 11 、-CONH(CH2) r R 11 、-CONH(CH2) r OR 11 、-COOR 11 、-(CH2) r CONHR 11 、-OCONHR 11 , or -CO(CH2) r NHR 11 The alkyl, alkoxy, alkenyl and alkynyl groups are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

4. The compound according to claim 2, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, in, Ring A is selected from 5. The compound according to claim 3 or 4, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein: R1 is H, D, F, Cl, Br, I, C 1-4 Alkyl or C 3-6 Cycloalkyl, the alkyl and cycloalkyl are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl radical substitution; R2 is H, D, F, Cl, Br, I or C 1-4 Alkyl, optionally substituted by 1-5 groups selected from D, halogen, OH, CN and NH2; R3 is H, D, F, Cl, Br or I; Each R4 is independently selected from H, D, F, Cl, Br or I; Alternatively, two R4 and the carbon atom to which they are attached together form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 heteroatoms selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 haloalkyl radical substitution; n and m are 0; Each R5, R 5’ 、R 5” are independently H, D, F, Cl, Br, I, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from D, halogen, OH, CN and NH2; Optionally, an R4 with R 5’ forming bonds; q is 0, 1, or 2; Ring B is a six-membered heteroaryl group containing 1-2 N atoms; R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl and alkoxy are optionally substituted by 1-3 groups selected from D, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

6. The compound according to claim 1, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein: The compound has the structure of formula (IV), (V): in, Ring A is selected from R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2; R3 is H, D; R2 is independently F, Cl, CN, NH2, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl group is optionally further substituted with 1-3 groups selected from D, F, Cl, OH, CN, and NH2; R6 is D, CN, OH, F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 groups selected from D, F, Cl, OH, CN, and NH2; R8 is -CONHR 11 、-NHCOR 11 ; Each R 11 Independently C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by 1-3 groups selected from D, =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The haloalkyl group is substituted.

7. The compound according to claim 6, its stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt, wherein: R1 is C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl; R3 is H; R2 is F, Cl, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-3 groups selected from D, F, and Cl; R6 is D, F, Cl, or C 1-2 Alkyl, which is optionally substituted by 1-3 groups selected from D, F, and Cl; R8 is -CONHR 11 、-NHCOR 11 ; R 11 C 3-6 Cycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, wherein the cycloalkyl and heteroaryl are optionally substituted by 1-3 heteroatoms selected from D, F, Cl, C 1-2 Alkyl and C 1-2 The haloalkyl group is substituted.

8. A compound represented by formula (II), formula (IV), or formula (V), or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, wherein: The compound is selected from one of the following structures:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, its stereoisomers, solvates, deuterated substances, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomer, solvate, deuterated form, or pharmaceutically acceptable salt, or the composition according to claim 9 in the preparation of a medicament for treating / preventing PARP1-mediated diseases.

11. The use according to claim 10, wherein the PARP1-mediated disease is selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

12. A pharmaceutical composition or pharmaceutical preparation comprising 1-1440 mg of the compound of any one of claims 1-8, a stereoisomer, solvate, deuterated form, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

13. A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is preferably 1-1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, or prostate cancer.

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