Bicyclic derivative PARP inhibitor and its use

Abstract

The present invention relates to a compound represented by formula (II), its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterides, or a pharmaceutical composition containing them, and their use in the manufacture of a drug for treating related diseases as a PARP-1 inhibitor, and each group represented by formula (II) is as defined in the specification. [Chemical formula 1] TIFF2025518592000087.tif43156

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a low-molecular compound having PARP-1 inhibitory activity, its stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterides, and their uses in the treatment of related diseases.

Background Art

[0002] Approximately 5% of breast cancer patients are associated with germline gene mutations in the BRCA1 / 2 genes (3% in the BRCA1 gene and 2% in the BRCA2 gene). Most breast cancers due to BRCA1 mutations are triple-negative breast cancers (70%), while BRCA2 mutations are more likely to cause estrogen receptor-positive breast cancers (70%). The BRCA1 / 2 genes are tumor suppressor genes and play important roles in DNA damage repair, normal cell growth, etc. Mutations in these genes suppress the normal repair ability after DNA damage, causing homologous recombination deficiency (HRD), that is, loss of function of BRCA or mutations or loss of function occurring in other homologous recombination-related genes, thereby preventing the repair of double-stranded DNA breaks by homologous recombinant repair (HRR), and ultimately leading to canceration.

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

[0004] PARP inhibitors have a "trapping" effect on PARP proteins. As a result, PARP proteins that bind to damaged DNA are trapped in the DNA, preventing other DNA repair proteins from binding and ultimately causing cell death. Currently, a number of PARP inhibitors such as olaparib, rucaparib, and niraparib have been successfully developed, but their ability to be used in combination with chemotherapeutic agents is limited due to adverse reactions. This may be related to the lack of selectivity of commercially available PARP inhibitors for the PARP family, and these side effects include gastrointestinal toxicity due to tankyrase inhibition and hematotoxicity due to PARP-2 inhibition. Therefore, developing highly selective PARP-1 inhibitors to reduce the side effects of the associated toxicity of non-selective PARP inhibitors has important clinical significance.

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a PARP-1 inhibitory compound, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and their pharmaceutical uses. The compounds of the present invention have advantages such as high activity, low toxic side effects, high safety, high selectivity, good pharmacokinetics, and high bioavailability.

Means for Solving the Problems

[0006] The present invention provides compounds of the following formulas (I), (III), (IV), (V), their stereoisomers, solvates, deuterides, or pharmaceutically acceptable salts,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0007] In some embodiments, a compound of the present invention, a stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt thereof, wherein the compound further satisfies one of the following conditions: (1) R1 is D, halogen, CN, NH2, -SF5, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6 cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group or -(CH2) r -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group is substituted with 1 to 5 groups selected from D, Cl, Br, I, C 1-4 alkoxy group, OH, CN, and NH2, and the alkoxy group or cycloalkyl group is substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4 haloalkyl group, and the alkenyl group, alkynyl group, and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4 haloalkyl group, (2) R2 is H, D, CN, NH2, -SF5, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6 cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group or -(CH2) r -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl group is substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, and the alkenyl group, alkynyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, (3) At least one of R3 is D, halogen, CN, NH2, -SF5, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6 cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group or -(CH2) r -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4Substituted with 1 to 5 groups selected from an alkoxy group, OH, CN, NH2, and C 1-4 an alkyl halide group, and (4) Two R4s cannot simultaneously be H, or two R4s and the atoms to which they are attached together form a substituted or unsubstituted C 3-6 cycloalkyl group or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, (5) m and n cannot simultaneously be 0, (6)

Chemical formula

Chemical formula

Chemical formula

[0008] In some embodiments, it is the aforementioned compound of the present invention, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and the compound satisfies at least one of the aforementioned conditions (1) to (5).

[0009] In some embodiments, it is the aforementioned compound of the present invention, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and the compound satisfies at least one of the aforementioned conditions (6) to (8).

[0010] In some embodiments, it is the aforementioned compound of the present invention, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and the compound satisfies at least one of the aforementioned conditions (4) to (8).

[0011] In some embodiments, it is the aforementioned compound of the present invention, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and the compound has the structure of the following formula (III),

Chemical formula

[0012] In some embodiments, for the compound of the foregoing formula (III), each group is as described in each of the above embodiments and satisfies at least one of the foregoing conditions (6) to (8).

[0013] In a specific embodiment 1 according to the present invention, a compound represented by formula (I), (II), or (III), a stereoisomer, a solvate, a deuteride, or a pharmaceutically acceptable salt thereof, X1 is O or S, X2 is N, C, or CR 5’ and X3 is N, C, or CR 5’’ and ring A is a 4- to 12-membered heterocycloalkyl group containing 1 to 3 N atoms and 0 to 2 heteroatoms selected from O and S, R1, R2, and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6 cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group, or -(CH2) r -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4Substituted with 1 to 5 groups selected from halogenated alkyl groups, each R4 is independently H, D, halogen, C 1-4 alkyl group, C 3-6 cycloalkyl group, OH, CN, NH2, C 1-4 alkoxy group, C 2-6 alkenyl group or C 2-6 alkynyl group, and the alkyl group, alkoxy group, cycloalkyl group, alkenyl group and alkynyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group, optionally, two R4s and the atoms to which they are attached together form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 3-6 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group, 1-4 each L is independently -NH-, -CH2-, -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-, n, m are independently 0, 1, 2 or 3, each R5, R are independently H, D, =O, halogen, C 5’ , R 5’’ is independently H, D, =O, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, CN or C 3-6 cycloalkyl group, and the alkyl group, alkoxy group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group, optionally, one R4 is R 5’to form a bond, q is 0, 1, 2, 3 or 4, X4 is N, NR7 or CR7 (Formula II or III), X5 is N, NR 10 or CR 10 (Formula II or III), Ring B is a 6-membered heteroaryl group (in Formula I, Ring B may further be a phenyl group), R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group, R8 is C 1-4 alkyl group, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -CONHC 1-4 alkyl group, -CONHC 1-4 alkylene OC 1-4 alkyl group, -NHCOC 1-4 alkyl group, -NHCOOC 1-4 alkyl group, -OCONHC 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, 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 wherein the alkyl group, alkylene group, alkoxy group, alkenyl group and alkynyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group, each R 11 is independently a C 3-6 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally substituted with 1 to 3 groups selected from D, =O, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -CONHC 1-4 alkyl group, -NHCOC 1-4 alkyl group, OH, CN, NH2 and C 1-4 halogenated alkyl group, each r is independently 1, 2 or 3.

[0014] In Embodiment 2 according to the present invention, the compounds of formulas (I), (II) and (III) further satisfy the following, [Chemical formula] where n and m are 0, [Chemical Formula] where R6 is H, halogen, C 1-4 alkyl group or halogenated C 1-4 alkyl group, when R8 is not -CONHC 1-4 alkyl group, and the others are as described in Embodiment 1.

[0015] In Embodiment 3 according to the present invention, the compound of formula (I) or formula (II) satisfies at least one of the aforementioned conditions (1) to (8), the compound of formula (III) satisfies at least one of the aforementioned conditions (1) to (3) and (6) to (8), and the others are as described in Embodiment 1.

[0016] In Embodiment 4 according to the present invention, the compound of formula (III) satisfies at least one of the aforementioned conditions (6) to (8), and the others are as described in Embodiment 1.

[0017] In Embodiment 5 according to the present invention, it is a compound represented by formula (II), its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, where X1 is O or S, X2 is N, C or CR 5’ and X3 is N, C or CR 5’’ and ring A is a 4- to 12-membered heterocycloalkyl group containing 1 to 3 N atoms and 0 to 2 heteroatoms selected from O and S, R1, R2 and R3 are independently H, D, halogen, CN, NH2, -SF5, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6A cycloalkyl group, a heterocycloalkyl group, an -O-heterocycloalkyl group or -(CH2) r -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, Each R4 is independently H, D, halogen, C 1-4 alkyl group, C 3-6 cycloalkyl group, OH, CN, NH2, C 1-4 alkoxy group, C 2-6 alkenyl group or C 2-6 alkynyl group, and the alkyl group, alkoxy group, cycloalkyl group, alkenyl group and alkynyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, Optionally, two R4s and the atoms connected thereto together form a C 3-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, 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’’is independently H, D, =O, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, CN or C 3-6 cycloalkyl group, and the alkyl group, alkoxy group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, optionally, one R4 is R 5’ to form a bond, q is 0, 1, 2, 3 or 4, X4 is N, NR7 or CR7, X5 is N, NR 10 or CR 10 and ring B is a 6-membered heteroaryl group, R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, R8 is C 1-4 alkyl group, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -CONHC 1-4 alkyl group, -CONHC 1-4 alkylene OC 1-4 alkyl group, -NHCOC 1-4 alkyl group, -NHCOOC 1-4 alkyl group, -OCONHC 1-4 alkyl group, C 2-6 alkenyl group, C 2-6An alkynyl group, 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 wherein the alkyl group, alkylene group, alkoxy group, alkenyl group and alkynyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 haloalkyl group, each R 11 is independently a C 3-6 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally D, =O, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -CONHC 1-4 alkyl group, -NHCOC 1-4Substituted with 1 to 3 groups selected from an alkyl group, OH, CN, NH2, and C 1-4 an alkyl halide group, each r is independently 1, 2, or 3, As a condition, [Chemical formula] and n, m are 0, [Chemical formula] and when R6 is H, a halogen, a C 1-4 alkyl group or a halogenated C 1-4 alkyl group, R8 is -CONHC 1-4 is not an alkyl group.

[0018] In aspect 6 of the present invention, it is the compound according to aspect 5, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, wherein X1 is O, X2 is N or CR 5’ and X3 is N, C, or CR 5’’ and ring A is a 4- to 9-membered monocycloheteroalkyl group, 6- to 12-membered spirocycloheteroalkyl group, 6- to 12-membered fused-ring cycloheteroalkyl group, or 6- to 12-membered bridged-ring cycloheteroalkyl group containing 1 to 3 N atoms and 0 to 2 heteroatoms selected from O and S, R1 is H, D, halogen, CN, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, -O-C 3-6 cycloalkyl group, -(CH2) r -C 3-6 cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group, or -(CH2) r-A heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, and C 1-4 haloalkyl group, R2 and R3 are independently H, D, halogen, or C 1-4 alkyl group, and the alkyl group is optionally substituted with 1 to 5 groups selected from D, halogen, OH, CN, and NH2, Each R4 is independently H, D, halogen, C 1-4 alkyl group, C 3-6 cycloalkyl group, OH, CN, or NH2, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4 haloalkyl group, Optionally, two R4s and the atoms to which they are attached together form a C 3-6 cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4 haloalkyl group, 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’’ is independently H, D, =O, halogen, C 1-4 alkyl group, or C 1-4an alkoxy group, and the alkyl group and the alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH2, optionally, one of R4 is R 5’ to form a bond, q is 0, 1, or 2, R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 alkyl group or C 1-4 alkoxy group, and the alkyl group and the alkoxy group are optionally D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2, and C 1-4 haloalkyl group, and are substituted with 1 to 3 groups selected therefrom.

[0019] In aspect 7 of the present invention, a compound according to aspect 6, a stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt thereof, Ring A is a substituted or unsubstituted 6- to 10-membered fused-ring heterocycloalkyl group, a substituted or unsubstituted 6- to 11-membered spiro-ring heterocycloalkyl group, a substituted or unsubstituted 6- to 10-membered bridged-ring heterocycloalkyl group, a substituted or unsubstituted 4- to 5-membered monocyclic heterocycloalkyl group, a substituted or unsubstituted 7- to 8-membered monocyclic heterocycloalkyl group, a substituted or unsubstituted

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0020] In aspect 8 of the present invention, it is the compound according to aspect 6, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, wherein ring A is [Chemical formula] selected from

[0021] In aspect 9 of the present invention, a compound according to aspect 7 or 8, a stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt thereof, wherein R1 is H, D, F, Cl, Br, I, C 1-4 an alkyl group or C 3-6 a cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 an alkyl group, C 1-4 an alkoxy group, and C 1-4 a haloalkyl group; R2 is H, D, F, Cl, Br, I, or C 1-4 an alkyl group, and the alkyl group is optionally substituted with 1 to 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; optionally, two R4s and the atoms to which they are attached together form a C 3-6 a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 an alkyl group, C 1-4 an alkoxy group, OH, CN, NH2, and C 1-4 a haloalkyl group; n and m are 0; each R5, R 5’ 、R 5’’ is independently H, D, F, Cl, Br, I, C 1-4 an alkyl group or C 1-4 an alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH2; optionally, one R4 is R5’ forms a bond with q is 0, 1 or 2, ring B is a 6-membered heteroaryl group containing 1 to 2 N atoms, R6, R7, R9, R 10 are independently H, D, CN, OH, halogen, C 1-4 alkyl group or C 1-4 alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, CN, NH2 and C 1-4 halogenated alkyl group.

[0022] In embodiment 10 of the present invention, a compound represented by formula (IV) or (V), its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0023] In aspect 11 of the present invention, a compound represented by formula (IV) or (V) described in aspect 10, its stereoisomers, solvates, deuterides, or pharmaceutically acceptable salts, R1 is C 1-2 an alkyl group, and the alkyl group is optionally substituted with 1 to 3 groups selected from D, F, and Cl; R3 is H; R2 is F, Cl, C 1-2 an alkyl group, and the alkyl group is optionally further substituted with 1 to 3 groups selected from D, F, and Cl; R6 is D, F, Cl, C 1-2 an alkyl group, and the alkyl group is optionally substituted with 1 to 3 groups selected from D, F, and Cl; R8 is -CONHR 11 -NHCOR 11 ; R 11 is a cycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group and the heteroaryl group are optionally selected from D, F, Cl, C 3-6 alkyl groups and C 1-2 alkyl halides and is substituted with 1 to 3 groups selected therefrom. 1-2 In aspect 12 of the present invention,

[0024] A compound selected from one of the structures of

Chemical formula

Chemical formula

Chemical formula

[0025] The present invention further provides a pharmaceutical composition, which contains the compound described in any one of the foregoing technical solutions, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The present invention further provides a use, that is, the use of the compound described in any one of the foregoing technical solutions, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt or the foregoing pharmaceutical composition in the manufacture of a drug for treating / preventing PARP1-mediated diseases.

[0026] The PARP1-mediated diseases of the present invention are selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0027] The present invention further provides a method for treating diseases in mammals, the method including administering to a subject a therapeutically effective amount of the compound described in any one of the foregoing first to eleventh aspects, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or carrier, the therapeutically effective amount being preferably 1 to 1440 mg, and the disease being preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0028] The present invention further provides a method for treating diseases in mammals, which includes administering to the mammal a therapeutically effective amount of the compound described in the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the mammals described in the present invention include humans.

[0029] As used herein, an "effective amount" or "therapeutically effective amount" includes administering a sufficient amount of a compound disclosed herein, which alleviates to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in a biological system. For example, an "effective amount" for therapeutic use is an amount that includes a compound disclosed herein necessary 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 - 500 mg, 5 - 400 mg, 5 - 300 mg, 5 - 250 mg, 5 - 200 mg, 5 - 150 mg, 5 - 125 mg, 5 - 100 mg, 5 - 90 mg, 5 - 80 mg, 5 - 70 mg, 5 - 60 mg, 5 - 50 mg, 5 - 40 mg, 5 - 30 mg, 5 - 25 mg, 5 - 20 mg, 10 - 1000 mg, 10 - 900 mg, 10 - 800 mg, 10 - 700 mg, 10 - 600 mg, 10 - 500 mg, 10 - 450 mg, 10 - 400 mg, 10 - 300 mg, 10 - 250 mg, 10 - 200 mg, 10 - 150 mg, 10 - 125 mg, 10 - 100 mg, 10 - 90 mg, 10 - 80 mg, 10 - 70 mg, 10 - 60 mg, 10 - 50 mg, 10 - 40 mg, 10 - 30 mg, 10 - 20 mg, 20 - 1000 mg, 20 - 900 mg, 20 - 800 mg, 20 - 700 mg, 20 - 600 mg, 20 - 500 mg, 20 - 400 mg, 20 - 350 mg, 20 - 300 mg, 20 - 250 mg, 20 - 200 mg, 20 - 150 mg, 20 - 125 mg, 20 - 100 mg, 20 - 90 mg, 20 - 80 mg, 20 - 70 mg, 20 - 60 mg, 20 - 50 mg, 20 - 40 mg, 20 - 30 mg, 50 - 1000 mg, 50 - 900 mg, 50 - 800 mg, 50 - 700 mg, 50 - 600 mg, 50 - 500 mg, 50 - 400 mg, 50 - 300 mg, 50 - 250 mg, 50 - 200 mg, 50 - 150 mg, 50 - 125 mg, 50 - 100 mg, 100 - 1000 mg, 100 - 900 mg, 100 - 800 mg, 100 - 700 mg, 100 - 600 mg, 100 - 500 mg, 100 - 400 mg, 100 - 300 mg, 100 - 250 mg, 100 - 200 mg.

[0030] The present invention relates to a pharmaceutical composition or a pharmaceutical preparation, and the pharmaceutical composition or the pharmaceutical preparation contains a therapeutically effective amount of the compound described in the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt, as well as excipients and / or carriers. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification"). In some embodiments, the pharmaceutical composition contains 1 to 1440 mg, 5 to 1000 mg, 10 to 800 mg, 20 to 600 mg, 25 to 500 mg, 40 to 200 mg, 50 to 100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1440 mg of the compound of the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt, but not limited thereto.

[0031] A method for treating a mammalian disease, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or carrier, the therapeutically effective amount being preferably 1 to 1440 mg, and the disease being preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer and prostate cancer.

[0032] A method for treating a mammalian disease, said method comprising administering to a subject a compound of the present invention which is a drug, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or carrier in a daily dose of 1 to 1440 mg / day, said daily dose may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10 to 1440 mg / day, 20 to 1440 mg / day, 25 to 1440 mg / day, 50 to 1440 mg / day, 75 to 1440 mg / day, 100 to 1440 mg / day, 200 to 1440 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, 100 to 1000 mg / day, 200 to 1000 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, 200 to 400 mg / day, and in some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1440 mg / day.

[0033] The present invention relates to a kit, which may include a composition in the form of a single dose or multiple doses, and the kit contains a compound of the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt, and the amount of the compound of the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt is the same as its amount in the above pharmaceutical composition.

[0034] In the present invention, the amount of the compound of the present invention or its stereoisomer, solvate, deuteride, pharmaceutically acceptable salt is, in each case, converted in the form of the free base.

[0035] "Formulation specification" refers to the weight of the active ingredient contained in one unit formulation, one tablet unit formulation, or each other unit formulation.

[0036] Synthetic route In patent documents such as WO2021013735A1, the manufacturing method of PARP-1 inhibitors is described. Those skilled in the art can combine this document with known organic synthesis techniques to manufacture the compounds of the present invention, and the starting materials thereof are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are those obtained from regular commercial suppliers, and the suppliers include companies such as Titan Technology, Energy Chemical, Shanghai Dermochem, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmatech, WuXi AppTec, and Alfa Chemistry.

[0037] Reference books and specialized books in the art have introduced in detail the synthesis of reactants that can be used in the manufacture of the compounds described in this specification, or for reference, articles explaining the manufacturing methods are provided. By the index of known chemical substances created by the Chemical Information Service of the American Chemical Society, specific and similar reactants can be selectively identified, and these indexes are available in many public libraries, university libraries, and online. For chemicals that are known but not available in catalogs, optionally, a custom chemical synthesis contractor can be commissioned to manufacture them, and many of the standard chemical suppliers (for example, the companies listed above) provide custom synthesis services.

[0038] Term Unless otherwise specified in the present invention, the terms of the present invention have the following meanings.

[0039] Carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen related to the groups and compounds described in the present invention all include their isotopes. That is, carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen related to the groups and compounds described in the present invention are optionally further substituted by one or more corresponding isotopes thereof. Here, the isotopes of carbon are 12 C and 13 C and 14It contains C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called triple hydrogen), and the isotopes of oxygen are 16 O, and 17 O, and 18 O. The isotopes of sulfur include 32 S, and 33 S, and 34 S, and 36 S. The isotopes of nitrogen include 14 N and 15 N. The isotope of fluorine is 19 F, and the isotopes of chlorine include 35 Cl and 37 Cl. The isotopes of bromine include 79 Br and 81 Br.

[0040] In this specification, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0041] "Halogenation" or "halogen substitution" refers to substitution by one or more selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, it may be substituted with the same or different halogens. Usually, cases of 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution are included.

[0042] "Deuterium" refers to deuterium, which is an isotope of hydrogen (H), and has the same meaning as "D".

[0043] "Deuteration" or "deuteride" refers to the case where at least one hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, alkynyl group, etc. is substituted by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of replaceable hydrogens in the group to be substituted. Unless otherwise particularly limited, the number of deuterations is any integer between 1 and the upper limit. For example, it can be 1 to 20 deuterium atom substitutions, 1 to 10 deuterium atom substitutions, 1 to 6 deuterium atom substitutions, 1 to 3 deuterium atom substitutions, 1 to 2 deuterium atom substitutions, or 1 deuterium atom substitution.

[0044] "C x-y " group refers to a group containing x to y carbon atoms. For example, "C 1-6 alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms, and "C0" usually refers to a bond.

[0045] "Alkyl group" refers to a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Usually, 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 group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc. The alkyl group may be further substituted by substituents.

[0046] "Alkylene group" refers to a divalent straight-chain and branched-chain saturated alkyl group. Examples of the alkylene group include, but are not limited to, methylene group, ethylene group, etc.

[0047] "Haloalkyl group" refers to the case where one or more hydrogens in an alkyl group are replaced by one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine or their isotopes), and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens in the alkyl group. Unless otherwise specifically limited, the number of halogen substituents is any integer between 1 and the upper limit. Usually, the alkyl group is substituted with 1 to 5 halogens, or substituted with 1 to 3 halogens, or substituted with 1 to 2 halogens, or substituted with 1 halogen. When the number of halogen substituents is greater than 1, it may be substituted with the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0048] "Alkoxy group" or "alkyloxy group" refers to -O-alkyl group. For example, -O-C 1-8 alkyl group, -O-C 1-6 alkyl group, -O-C 1-4 alkyl group or -O-C 1-2 alkyl group. Specific non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group and cyclobutoxy group, etc. The alkoxy group may optionally be substituted with a substituent.

[0049] "Haloalkoxy group" refers to -O-haloalkyl group. For example, -O-halogenated C 1-8 alkyl group, -O-halogenated C 1-6 alkyl group, -O-halogenated C 1-4 alkyl group or -O-halogenated C 1-2It is an alkyl group. The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of halogen substituents is any integer between 1 and the upper limit. Preferably, it is 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, or 1 halogen substitution. When the number of halogen substituents is greater than 1, it may be substituted by the same or different halogens. Non-limiting examples include monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethyloxy group, etc.

[0050] "Alkenyl group" refers to a straight-chain hydrocarbon group or a branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C). Usually, it contains 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, or for example, 2 to 6 carbon atoms, or further for example, 2 to 4 carbon atoms. Examples thereof include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 1-octenyl group, 3-octenyl group, 1-nonenyl group, 3-nonenyl group, 1-decenyl group, 4-decenyl group, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc., but are not limited thereto. The alkenyl group may optionally be further substituted with a substituent.

[0051] "Alkenylene group" refers to a linear or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), usually containing 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, further for example, 2 to 6 carbon atoms, still further for example, 2 to 4 carbon atoms, and non-limiting embodiments include an ethynylene group, and the alkenylene group may optionally be substituted with a substituent.

[0052] "Alkynyl group" refers to a linear hydrocarbon group or a branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms, and examples thereof include an ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 4-pentynyl group, 3-pentynyl group, 1-methyl-2-butynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynyl group, and 4-decynyl group, etc., but are not limited thereto, and the alkynyl group may optionally be substituted with a substituent.

[0053] "Alkynylene group" refers to a linear or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms, and non-limiting examples include an ethynylene group, propynylene group, and butynylene group, and the alkynylene group may optionally be substituted with a substituent.

[0054] "Cycloalkyl group" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cycloheteroatoms. The cycloalkyl group may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic may be in the form of fused rings, spiro rings, bridged rings or combinations thereof, and the bicyclic or polycyclic may contain one or more aromatic rings, but the entire ring system is not aromatic and the linking site is on a non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3 to 8 carbon atoms, even further contains 3 to 6 carbon atoms. When it is a monocyclic cycloalkyl group, it contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl group, it contains 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, butenyl group, cyclopentenyl group, cyclohexenyl group,

Chemical formula

[0055] "Cycloalkylene group" is a divalent group of a cycloalkyl group.

[0056] "Aryl group" refers to an aromatic carbocyclic ring that does not contain heteroatoms, including monocyclic aryl groups and fused-ring aryl groups. Usually, it contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl group, naphthyl group, anthryl group, phenanthryl group, and the aryl group may optionally be substituted with substituents.

[0057] "Carbon ring" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbocyclic ring, and its meaning includes aryl groups and cycloalkyl groups. The carbocyclic ring may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings include bridged rings, fused rings and spiro rings and combinations thereof. The carbocyclic ring usually has 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting examples, monocyclic carbocyclic rings include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or phenyl group, etc., and bicyclic bridged rings include [Chemical formula] etc., and bicyclic fused rings include [Chemical formula] etc., and bicyclic spiro rings include [Chemical formula] etc., and the carbocyclic ring may optionally be substituted with substituents.

[0058] "Heterocycloalkyl group" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. The heterocycloalkyl group may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic may be in the form of a bridged ring, a fused ring, a spiro ring, or a combination thereof. The bicyclic or polycyclic may contain one or more aromatic rings or heteroaromatic rings, but the entire ring system is not aromatic, and the connecting site is on the non-aromatic ring. Usually, the heterocycloalkyl group is a 3- to 20-membered ring. When it is a monocyclic heterocycloalkyl group, it is usually a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3- to 8-membered ring, or a 3- to 6-membered ring. When it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. Here, the heteroatoms N and S include their oxidation states. Non-limiting examples of the heterocycloalkyl group include an azetidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a tetrahydropyranyl group, an oxetanyl group, a pyranyl group, an azacyclopentenyl group, an azacyclohexenyl group, an oxolyl group, an oxynyl group, etc. The heterocycloalkyl group may optionally be substituted with substituents.

[0059] "Heteroaromatic ring" or "heteroaryl group" refers to a ring having aromaticity and containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, unless otherwise specified. It may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic may be in the form of a bridged ring, a fused ring, a spiro ring, or a combination thereof. When it is bicyclic or polycyclic, it may be a condensation of a heteroaryl group and an aryl group, or a condensation of a heteroaryl group and a heteroaryl group. Here, both the heteroaryl group and the aryl group can be the connecting sites. Non-limiting examples include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, an indolyl group, a purinyl group,

Chemical formula

[0060] "Heterocycle" or "heterocyclic group" 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, which includes heteroaryl groups and heterocycloalkyl groups. Heterocycles include monocyclic heterocycles, bridged bicyclic heterocycles, fused bicyclic heterocycles and spiro bicyclic heterocycles or combinations thereof. Usually, it is a 3- to 12-membered heterocycle or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle. The heterocyclic group may be linked on a heteroatom or a carbon atom, and non-limiting examples are oxiranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, piperazinyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, pyridazinyl group, imidazolyl group, piperidinyl group, piperidyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group and oxaspiro[3.3]heptyl group,

Chemical formula

[0061] "Heterocyclylene group" refers to a divalent heterocyclic group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include

Chem.

[0062] "Spiro ring" refers to a polycyclic group in which the rings share one carbon atom (referred to as a spiro atom), which may contain 0 or one 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. Usually, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Usually, the spiro ring is 3 spiro 3 (representing a 3-membered ring spiro 3-membered ring), 3 spiro 4, 3 spiro 5, 3 spiro 6, 4 spiro 4, 4 spiro 5, 4 spiro 6, 5 spiro 5, or 5 spiro 6. Non-limiting examples of spiro rings include

Chem.

[0063] "Fused ring" or "condensed ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and one chemical bond, which may contain one or more double bonds or triple bonds, and the fused ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Usually, the fused ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Usually, the fused ring is 3 fused 4 ring (representing a fused ring formed by a 3-membered ring and a 4-membered ring, based on the IUPC nomenclature rules, a fused ring with a 3-membered ring as the basic ring is possible, and a fused ring with a 4-membered ring as the basic ring is also possible, and the same applies hereinafter), 3 fused 5 ring, 3 fused 6 ring, 4 fused 4 ring, 4 fused 5 ring, 4 fused 6 ring, 5 fused 5 ring, 5 fused 6 ring, 6 fused 6 ring. Non-limiting examples of fused rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene,

Chem.

[0064] "Bridged ring" refers to a structure where two rings share two non-adjacent ring atoms and may contain one or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Usually, the ring atoms of the bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings are adamantane,

Chemical formula

[0065] "Substituted" or "substituent" means that any substitution occurs at a chemically acceptable position and the number of substituents satisfies the laws of chemical bonding, unless otherwise specified. Exemplary substituents are C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 heteroalkyl group, C 5-12 aryl group, 5- to 12-membered heteroaryl group, hydroxy group, C 1-6 alkoxy group, C 5-12 aryloxy group, thiol group, C 1-6 alkylthio group, cyano group, halogen, C 1-6 alkylthiocarbonyl group, C 1-6 alkylcarbamoyl group, N-carbamoyl group, nitro group, silyl group, sulfinyl group, sulfonyl group, sulfoxide, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, amino group, phosphonic acid, -CO2(C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO2(C 1-6 alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 alkyl group)2, -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C1-6 (alkyl group)C(=O)(C 1-6 (alkyl group), -NHCO2(C 1-6 (alkyl group), -NHC(=O)N(C 1-6 (alkyl group)2, -HC(=O)NH(C 1-6 (alkyl group), -NHC(=O)NH2, -NHSO2(C 1-6 (alkyl group), -SO2N(C 1-6 (alkyl group)2, -SO2NH(C 1-6 (alkyl group), -SO2NH2, -SO2C 1-6 (alkyl group) and the like, but not limited thereto.

[0066] "Optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted by F" means that the alkyl group may be substituted by F, but does not necessarily have to be substituted by F, indicating that it includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0067] "Pharmaceutically acceptable salt" refers to a salt obtained by maintaining the biological effectiveness and properties of the compound of the present invention as a free acid or free base and reacting the free acid with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.

[0068] "Pharmaceutical composition" represents one or more of the compounds of the present specification or their stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals, mixtures with other components, where the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0069] The "carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of the given compound, changes the administration form and in-vivo distribution of the drug in the human body, controls the drug release rate, and can deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0070] "Excipient" refers to a substance that is not a therapeutic agent itself but is added to a pharmaceutical composition as a diluent, excipient, adhesive, and / or vehicle to improve its handling and storage properties or to permit or facilitate the compound or pharmaceutical composition to form a dosage form for administration. As is known to those skilled in the art, pharmaceutical excipients can provide various functions and may be described as wetting agents, buffers, suspending aids, lubricants, emulsifying agents, disintegrants, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to, the following: (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 carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethyl cellulose (e.g., cross-linked sodium carboxymethyl cellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter, suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, castor oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water for endotoxin test; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic and compatible substances used in pharmaceutical formulations.

[0071] "Stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule and includes cis-trans isomers, enantiomers, and conformational isomers.

[0072] The compounds of the present invention further include their tautomers. For example, when the left compound in which the pyrimidine ring is substituted with OH is described in the present invention, the right tautomeric compound is also included.

Chemical formula

[0073] "Solvate" refers to a substance formed by the intermolecular non-covalent binding of a compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0074] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds. Here, the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are multi-component crystals, including not only two-component co-crystals formed between two neutral solids, but also multi-component co-crystals formed between a neutral solid and a salt or a solvate.

Modes for Carrying Out the Invention

[0075] Hereinafter, the technical solutions of the present invention will be described in detail in conjunction with examples. However, the protection scope of the present invention includes but is not limited to them.

[0076] Detection Method The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR measurement is carried out using a nuclear magnetic meter (Bruker Avance III 400 and Bruker Avance 300), and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The MS measurement is carried out using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC measurement was performed using an Agilent 1260 DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM). For thin-layer chromatography, silica gel plates from Yantai Huanghai HSGF254 or Qingdao GF254 were used. The standard of the silica gel plates employed in thin-layer chromatography (TLC) was 0.15 mm - 0.20 mm, and the standard adopted for the separation and purification of the finished product by thin-layer chromatography was 0.4 mm - 0.5 mm. Column chromatography generally used silica gel with a mesh size of 200 - 300 from Yantai Huanghai as the carrier.

[0077] Example 1: N-Cyclopropyl-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide (Compound 1)

Chemical Structure

[0078] Step 1: Compound 1A (synthesized according to Patent US2022 / 0009901 A1) (3.39 g, 10 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), lithium hydroxide (400 mg, 16.7 mmol) was added, and the mixture was stirred at room temperature for 2 h to react. The solvent was removed by distillation under reduced pressure to obtain a white powdery solid 1B (3.38 g, 100%), which was used directly in the next step without purification.

[0079] LC-MS (ESI): m / z = 324.2 [M-H] + 。

[0080] Step 2: Compound 1B (331 mg, 1 mmol) was dissolved in DMF (10 mL). While stirring, HATU (565 mg, 1.49 mmol) was added, and the mixture was stirred at room temperature. After the solid was completely dissolved, DIEPA (2 mL) was added, and finally, excess cyclopropylamine was added. The reaction was stirred at room temperature for 4 h. After monitoring by LCMS and determining that the reaction was complete, ethyl acetate (50 mL) was added to the system, and it was washed with water (50 mL × 4). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by a silica gel chromatography column (PE:EA = 1:0 to 1:1) to obtain the title compound 1C (327 mg, 89.8%).

[0081] LC-MS (ESI): m / z = 365.2 [M+H] + 。

[0082] Step 3: 1C (327 mg, 0.90 mmol) was dissolved in methanol (10 mL), and a hydrochloric acid dioxane solution (3 mL, 4 M) was added. The reaction was carried out at room temperature for 2 h and then spin-dried to obtain the title compound 1D (276 mg, crude product).

[0083] LC-MS (ESI): m / z = 265.1 [M+H] + 。

[0084] Step 4: 1E (synthesized according to Patent US2022 / 0009901 A1) (200 mg, 0.74 mmol), 1D (276 mg) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After purging with nitrogen gas, the reaction was carried out at 60 °C for 4 h. After detecting by LCMS that the raw materials had completely reacted, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and it 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 then purified by column chromatography (DCM:MeOH = 1:0 to 0:1) to obtain Compound 1 (189 mg, 63.5%).

[0085] 11H NMR (400 MHz, DMSO-d6) δ 12.18 (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).

[0086] LC-MS (ESI): m / z = 455.2 [M+H] + 。

[0087] Example 2 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)pyridineamide (Compound 2)

Chemical Structure

[0088] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL). While stirring, add HATU (565 mg, 1.49 mmol), 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 at room temperature for 4 h to react. After monitoring by LCMS and confirming complete reaction, 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 column chromatography on silica gel (PE:EA = 1:0~1:1) to obtain the title compound 2C (352 mg, 87.03%).

[0089] LC-MS (ESI): m / z = 405.2 [M+H] + 。

[0090] Step 2: 2C (352 mg, 0.88 mmol) was dissolved in methanol (10 mL), and a hydrochloric acid dioxane solution (4 mL, 4 M) was added. The reaction was carried out at room temperature for 4 hours and then spin-dried to obtain the title compound 2D (313 mg, crude product).

[0091] LC-MS (ESI): m / z = 305.2 [M+H] + 。

[0092] Step 3: 1E (200 mg, 0.74 mmol) and 2D (313 mg) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 5.74 mmol) were added. After purging with nitrogen gas, the reaction was carried out at 60 °C overnight. It was detected by LCMS that the raw materials had completely reacted. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and extraction was carried out 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 = 1:0~0:1) to obtain compound 2 (236 mg, 64.48%).

[0093] 1 1H NMR (400 MHz, DMSO-d6) δ 12.40 (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).

[0094] LC-MS (ESI): m / z = 495.2 [M+H] + 。

[0095] Example 3 N-(3,3-Difluorocyclobutyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide (Compound 3) [Chemical Structure]

[0096] Step 1: Dissolve Compound 1B (331 mg, 1 mmol) in DMF (10 mL). While stirring, add HATU (565 mg, 1.5 mmol), stir at room temperature. After the solid is completely dissolved, add DIEPA (2 mL), and finally add 3,3-difluorocyclobutanamine (214 mg, 2 mmol). Stir at room temperature for 4 h to allow the reaction to proceed. After monitoring by LCMS to confirm complete reaction, 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 then separate by column chromatography on silica gel (PE:EA = 1:0~1:1) to obtain the title compound 3C (349 mg, 84.30%).

[0097] LC-MS (ESI): m / z = 415.2 [M+H] + .

[0098] Step 2: Dissolve 3C (349 mg, 0.85 mmol) in methanol (10 mL), add hydrochloric acid dioxane solution (4 mL, 4 M), react at room temperature for 4 h, and spin-dry to obtain the title compound 3D (301 mg, crude product).

[0099] LC-MS (ESI): m / z = 315.2 [M+H] + .

[0100] Step 3: 1E (200 mg, 0.74 mmol) and 3D (301 mg) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol) were added, and after purging with nitrogen gas, the reaction was carried out at 60 °C overnight. It was detected by LCMS that the raw materials had completely reacted. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and extraction was carried out 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 obtain Compound 3 (196 mg, 52.5%).

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (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).

[0102] LC-MS (ESI): m / z = 505.2 [M+H] + 。

[0103] Example 4 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1R,2S)-2-fluorocyclopropyl)pyridineamide (Compound 4)

Chemical Structure

[0104] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL). While stirring, add HATU (565 mg, 1.5 mmol), stir at room temperature. After the solid is completely dissolved, add DIEPA (2 mL), and finally add (1R,2S)-2-fluorocyclopropylamine p-toluenesulfonate (494 mg, 2 mmol). Stir at room temperature for 4 h to react. After monitoring by LCMS and determining that the reaction is complete, 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 then separate by column for silica gel chromatography (PE:EA = 1:0~1:1) to obtain the title compound 4C (294 mg, 76.8%).

[0105] LC-MS (ESI): m / z = 383.2 [M+H] + 。

[0106] Step 2: Dissolve 4C (294 mg, 0.76 mmol) in methanol (10 mL), add hydrochloric acid dioxane (4 mL, 4M) solution, react at room temperature for 4 h, and spin dry to obtain the title compound 4D (241 mg, crude product).

[0107] LC-MS (ESI): m / z = 283.2 [M+H] + 。

[0108] Step 3: Dissolve 1E (200 mg, 0.74 mmol) and 4D (241 mg) in anhydrous acetonitrile (20 mL), add potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol), replace with nitrogen gas, then react at 60 °C overnight. After detecting by LCMS that the raw materials have completely reacted, concentrate the system, add saturated sodium bicarbonate solution (20 mL), extract with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and then separate by column chromatography (DCM:MeOH = 1:0~0:1) to obtain compound 4 (197 mg, 56.3%).

[0109] 1 1H NMR (400 MHz, DMSO-d6) δ 12.19 (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).

[0110] LC-MS (ESI): m / z = 473.2 [M+H] + .

[0111] Example 5 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1S,2R)-2-fluorocyclopropyl)pyridineamide (Compound 5) [Chemical Structure Diagram]

[0112] Step 1: Dissolve compound 1B (331 mg, 1 mmol) in DMF (10 mL). While stirring, add HATU (565 mg, 1.5 mmol). Stir at room temperature until the solid is completely dissolved, then add DIEPA (2 mL). Finally, add (1S,2R)-2-fluorocyclopropylamine (150 mg, 2 mmol) and stir at room temperature for 4 h to allow the reaction to proceed. After monitoring by LCMS to confirm complete reaction, add ethyl acetate (50 mL) to the system, wash with water (50 mL × 4), collect the organic phase, dry it over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate by column chromatography on silica gel (PE:EA = 1:0 to 1:1) to obtain the title compound 5C (324 mg, 84.6%).

[0113] LC-MS (ESI): m / z = 383.2 [M+H] + 。

[0114] Step 2: 5C (324 mg, 0.84 mmol) was dissolved in methanol (10 mL), a hydrochloric acid dioxane (4 mL, 4 M) solution was added, and the mixture was reacted at room temperature for 4 hours and spin-dried to obtain the title compound 5D (292 mg, crude product).

[0115] LC-MS (ESI): m / z = 283.2 [M+H] + 。

[0116] Step 3: 1E (200 mg, 0.74 mmol), 5D (292 mg) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL, 25.74 mmol) were added, and after substitution with nitrogen gas, the mixture was reacted at 60 °C overnight. It was detected by LCMS that the raw materials had completely reacted. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM:MeOH = 1:0~0:1) to obtain compound 5 (197 mg, 56.3%).

[0117] 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (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).

[0118] LC-MS (ESI): m / z = 473.2 [M+H] + 。

[0119] Example 6 N-(Cyclopropylmethyl)-6-fluoro-5-(4-((2-methyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)piperazin-1-yl)pyridineamide (Compound 6)

Chemical Structure

[0120] Step 1: 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) were dissolved in DMF (20 mL) and reacted overnight at room temperature. After the raw materials were consumed, the system was poured into water (100 mL), a large amount of solid precipitated, and the solid was collected by suction filtration and dried to obtain Compound 6A (630 mg, 88%).

[0121] LCMS m / z = 379.1 [M +1] + .

[0122] Step 2: 6A was dissolved in hydrochloric acid dioxane solution (10 mL, 4N) and reacted overnight at room temperature. After the system was concentrated, the crude hydrochloride of 6B was obtained and directly proceeded to the next step.

[0123] LCMS m / z = 279.1 [M +1] + .

[0124] Step 3: 6B crude product, 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 mixed solution of DMF (2 mL) and acetonitrile (20 mL), heated to 60 °C and reacted overnight. It was concentrated to remove acetonitrile in the system, the residue was poured into water (20 mL), a large amount of solid precipitated, suction filtration was carried out, and after drying the filter cake, it was purified by preparative HPLC (conditions for liquid phase fractionation: C18 reverse phase preparative column, the mobile phase was deionized water (A) containing 0.1% aqueous ammonia and acetonitrile (B), gradient elution, B content = 5% - 55%, elution time 16 min, flow rate 12 mL / min, column temperature: 30 °C), and compound 6 (121 mg, 19%) was obtained.

[0125] LCMS m / z = 469.7 [M +1] + 。

[0126] 1 1H NMR (400 MHz, CDCl3) δ 9.43 (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).

[0127] Example 7: 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)

Chemical Structure

[0128] 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 sequentially added to a solution of N,N-dimethylformamide (100 mL). After replacing the gas with nitrogen 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 replacing the gas with nitrogen again three times, the temperature was raised to 110 °C and the reaction was carried out for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (200 mL) was added, and after stirring for 15 minutes, filtration was performed. The filtrate was washed with water (200 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by silica gel column (dichloromethane:methanol = 50:1) to obtain compound 7B (7.20 g, yield 96.33%).

[0129] LC-MS (ESI): m / z = 337.2 [M+H] + 。

[0130] Step 2: Intermediate 7B (4.00 g, 11.89 mmol) was added to a solution of toluene (20 mL), 20% aqueous lithium hydroxide solution (10 mL) and methanol (2 mL) were added, the temperature was controlled at 25 °C, and stirring was carried out overnight. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added, liquid separation was performed, the aqueous phase was collected, and then adjusted to pH = 3 - 4 with 1 mol / L hydrochloric acid aqueous solution, extracted with ethyl acetate (200 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated to dryness. Intermediate 7C (3.70 g, yield 96.54%) was obtained.

[0131] LC-MS (ESI): m / z = 323.1 [M+H] + 。

[0132] Step 3: Intermediate 7C (1.50 g, 4.65 mmol) and chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (2.61 g, 9.30 mmol) were added to a dichloromethane (50 mL) solution. After slowly adding N-methylimidazole (0.8 g, 9.77 mmol), the mixture was stirred for 15 min. Next, cyclopropylamine (0.32 g, 5.58 mmol) was added, and the temperature was maintained at 25 °C for 3 h of reaction. After complete reaction, it was washed with water (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness. The residue was separated and purified by silica gel column (dichloromethane:methanol = 100% - 85%) to obtain Intermediate 7D (1.60 g, yield 95.21%).

[0133] LC-MS (ESI): m / z = 362.2 [M+H] + 。

[0134] Step 4: Intermediate 7D (1.60 g, 4.43 mmol) was added to a 4.0 mol / L hydrochloric acid dioxane (20 mL) solution, and the reaction was carried out at room temperature for 5 h. The reaction solution was concentrated to dryness, isopropanol (5 mL) solution and ethyl acetate (20 mL) solution were added, and after stirring for 1 h, it was filtered to obtain Intermediate 7E (1.35 g, yield 91.19%).

[0135] LC-MS (ESI): m / z = 262.1 [M+H] + 。

[0136] Step 5: Compound 7E (180 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixed solution of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Next, potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were added, and the temperature was raised to 80 °C and reacted for 2 hours. After the reaction was completed, it was concentrated to dryness and spin-dried, and then separated and purified by preparative liquid chromatography (conditions for preparative liquid chromatography: C18 reversed-phase preparative column, mobile phase was deionized water containing 0.1% aqueous ammonia (A) and acetonitrile (B), gradient elution, B content = 5% - 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C), and the title compound 7 (50 mg, yield 22.60%, retention time about 2.821 min) was obtained.

[0137] LC-MS (ESI): m / z = 452.20 [M+H] + 。

[0138] 1 1H NMR (400 MHz, DMSO-d6) δ 12.43 (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).

[0139] Example 8: 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)

Chemical Structure

[0140] Step 1: Intermediate 7B (1.20 g, 3.57 mmol) was added to an acetonitrile (10 mL) solution, and then 40% aqueous methylamine (10 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated to dryness, and the residue was separated and purified by silica gel column (ethyl acetate: petroleum ether = 0 - 100%) to obtain the title compound 8A (1.00 g, 83.52%).

[0141] LC-MS (ESI): m / z = 336.20 [M+H] + 。

[0142] Step 2: Intermediate 8A (1.00 g, 2.98 mmol) was added to a 4.0 mol / L hydrochloric acid dioxane (20 mL) solution and reacted at room temperature for 5 hours. The reaction solution was concentrated to dryness, isopropanol (5 mL) solution and ethyl acetate (20 mL) solution were added, and after stirring for 1 hour, it was filtered to obtain Intermediate 8B (700 mg, yield 76.23%).

[0143] LC-MS (ESI): m / z = 236.20 [M+H] + 。

[0144] Step 3: Compound 8B (170 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixed solution of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Then potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were added, and the temperature was raised to 80 °C and reacted for 2 hours. After the reaction was completed, it was concentrated to dryness and spin-dried, and then separated and purified by preparative liquid chromatography column (preparative liquid chromatography conditions: C18 reverse phase preparative column, mobile phase was deionized water containing 0.1% aqueous ammonia (A) and acetonitrile (B), gradient elution, B content = 5% - 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C) to obtain the title compound 8 (165 mg, yield 79.15%, retention time about 2.592 min).

[0145] LC-MS (ESI): m / z = 426.20 [M+H] +。

[0146] 1 1H NMR (400 MHz, DMSO-d6) δ 12.43 (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).

[0147] Example 9: 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)

Chemical Structure

[0148] Step 1: Intermediate 7C (1.00 g, 3.10 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.04 g, 3.72 mmol) were added to a solution of dichloromethane (50 mL). After slowly adding N-methylimidazole (0.51 g, 6.15 mmol), the mixture was stirred for 15 min, then 1-methyl-1H-pyrazol-4-amine (0.36 g, 3.71 mmol) was added, and the temperature was maintained at 25 °C for 3 h. After complete reaction, it was washed with water (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was separated and purified by silica gel column (dichloromethane:methanol = 100% - 85%) to obtain Intermediate 9A (1.20 g, yield 96.43%).

[0149] LC-MS (ESI): m / z = 402.30 [M+H] + 。

[0150] Step 2: Intermediate 9A (1.20 g, 2.99 mmol) was added to a 4.0 mol / L hydrochloric acid dioxane (20 mL) solution, and the reaction was carried out at room temperature for 5 hours. The reaction solution was concentrated to dryness, and an isopropanol (5 mL) solution and an ethyl acetate (20 mL) solution were added. After stirring for 1 hour, filtration was carried out to obtain Intermediate 9B (0.90 g, yield 80.43%).

[0151] LC-MS (ESI): m / z = 302.40 [M+H] + 。

[0152] Step 3: Compound 9B (200 mg, 0.54 mmol) and 1E (150 mg, 0.49 mmol) were added to a mixed solution of acetonitrile (20 mL) and N,N-dimethylformamide (5 mL). Next, potassium iodide (81 mg, 0.49 mmol) and N,N-diisopropylethylamine (1.00 mL) were added, and the temperature was raised to 80 °C and the reaction was carried out for 2 hours. After the reaction was completed, it was concentrated to dryness and spin-dried, and then separated and purified by preparative liquid chromatography (conditions for preparative liquid chromatography: C18 reverse-phase preparative column, the mobile phase was deionized water (A) containing 0.1% aqueous ammonia and acetonitrile (B), gradient elution, B content = 5% - 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C) to obtain the title compound 9 (194 mg, yield 80.55%, retention time about 2.752 min).

[0153] LC-MS (ESI): m / z = 492.20 [M+H] + 。

[0154] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (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).

[0155] Example 12 N-Cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoropyridine amide (Compound 12) [Chemical formula]

[0156] Step 1: Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (23.8 g, 0.1 mol) in 1,4-dioxane (240 mL). While stirring, add serine methyl ester hydrochloride (16.5 g, 0.11 mol) and DIPEA (40 mL), and react at 40 °C overnight. After monitoring by LCMS and determining that the reaction was complete, spin-dry the solvent and separate by silica gel column chromatography (PE:EA = 5:1 to 1:1) to obtain the target product 12A (19.4 g, 57.55%).

[0157] LC-MS (ESI): m / z = 337.2, 339.1 [M+H] + .

[0158] 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. Monitor by LCMS to determine that the raw material has completely reacted, filter to remove the zinc powder, concentrate the filtrate, dilute with ethyl acetate (200 mL), wash with water (200 mL), extract again with ethyl acetate (100 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the target compound 12B (14.5 g, 82.06%).

[0159] LC-MS (ESI): m / z = 307.2, 309.1 [M+H] + .

[0160] Step 3: 12B (14.5 g, 47.2 mmol) was dissolved in anhydrous methanol (100 mL), 4M hydrochloric acid dioxane solution (4 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction was monitored by LCMS to ensure complete reaction of the starting material, concentrated to remove some of the solvent, and filtered to obtain the target compound 12C (10.7 g, 82.3%).

[0161] LC-MS (ESI): m / z = 275.2, 277.2 [M+H] + 。

[0162] Step 4: 12C (10.7 g, 38.9 mmol) was dispersed in dichloromethane (200 mL), DDQ (9.72 g, 42.8 mmol) was added at room temperature, and the mixture was reacted at room temperature overnight. The reaction was monitored by LCMS to ensure complete reaction of the starting material, the solvent was removed by spin evaporation, saturated aqueous sodium bicarbonate solution was added with stirring, and when the foaming stopped, the mixture was filtered, the filter cake was washed with water, and after drying, the target compound 12D (8.4 g, 79.09%) was obtained.

[0163] LC-MS (ESI): m / z = 273.2, 275.2 [M+H] + 。

[0164] Step 5: 12D (8.4 g, 30.76 mmol) was dispersed in dichloromethane (150 mL), Dess-Martin periodinane (25.8 g, 61 mmol) was added at room temperature, and the mixture was reacted at room temperature for 6 h. The reaction was monitored by LCMS to ensure complete reaction of the starting material, the solvent was removed by spin evaporation, saturated aqueous sodium bicarbonate solution was added with stirring, filtered, the filter cake was washed with water, and after drying, the target compound 12E (7.1 g, 86.6%) was obtained.

[0165] LC-MS (ESI): m / z = 271.2, 273.2 [M+H] + 。

[0166] Step 6: 12E (7.1 g, 26.19 mmol) was dispersed in 1,4-dioxane (100 mL), and DAST (21.7 g, 135 mmol) was slowly added at room temperature. The reaction was carried out overnight at room temperature. Monitoring by LCMS showed that the raw material had completely reacted. While stirring under an ice bath, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After drying, separation was carried out by silica gel column chromatography (PE:EA = 10:1~3:1) to obtain the target compound 12F (2.1 g, 27.3%).

[0167] LC-MS (ESI): m / z = 291.2, 293.2 [M-H] + 。

[0168] Step 7: 12F (2.1 g, 7.2 mmol) was dissolved in 1,4-dioxane (40 mL), and (tributylstannyl)methanol (2.54 g, 7.92 mmol) and X-phos Pd G2 (556 mg, 0.72 mmol) were added while stirring. The reaction was carried out overnight at 80 °C. Monitoring by LCMS showed that the raw material had completely reacted. Separation was carried out by silica gel column chromatography (PE:EA = 1:1~0:1) to obtain the target compound 12G (1.65 g, 94.6%).

[0169] LC-MS (ESI): m / z = 245.2 [M+H] + 。

[0170] 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 while stirring at 0 °C. The reaction was stirred at room temperature for 2 h. After monitoring by LCMS and showing complete reaction, separation was carried out by silica gel column chromatography (PE:EA = 5:1~1:1) to obtain the target product 12H (512 mg, 83.4%).

[0171] LC-MS (ESI): m / z = 307.2, 309.2 [M+H] + 。

[0172] Step 9: 1D (264 mg, 1 mmol) and 12H (300 mg, 0.97 mmol) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After purging with nitrogen gas, the mixture was reacted at 60 °C for 4 hours. It was detected by LCMS that the raw materials had completely reacted. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and passed through a column (DCM:MeOH = 1:0 to 0:1) to obtain Compound 12 (334 mg, 70.21%).

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (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).

[0174] LC-MS (ESI): m / z = 491.2 [M+H] + 。

[0175] Example 13 N-Cyclopropyl-6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide (Compound 13)

Chemical Structure

[0176] Step 1: Compound 13A (synthesized according to Patent US2022 / 0009901 A1) (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 while stirring at 0 °C. The mixture was stirred at room temperature for 2 h to react. After monitoring by LCMS and determining that the reaction was complete, it was separated by silica gel column chromatography (PE:EA = 5:1~1:1) to obtain the target product 13B (552 mg, 84.9%).

[0177] LC-MS (ESI): m / z = 325.2, 327.2 [M+H] + 。

[0178] Step 2: 1D (264 mg, 1 mmol), 13B (300 mg, 0.92 mmol) were dissolved in anhydrous acetonitrile (20 mL), potassium iodide (8 mg, 0.05 mmol) and DIPEA (1 mL) were added. After replacing with nitrogen gas, the mixture was reacted at 60 °C for 4 h. After detecting by LCMS that the raw materials had completely reacted, the system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and it 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 = 1:0~0:1) to obtain Compound 13 (319 mg, 68.3%).

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (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, 1H), 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).

[0180] LC-MS (ESI): m / z = 509.2 [M+H]+ .

[0181] Example 14 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)

Chem.

[0182] Step 1: Compound 13A (synthesized according to Patent US2022 / 0009901 A1) (1.3 g, 4.96 mmol) was dissolved in a mixed solution of anhydrous ethanol (26 mL) and water (2 mL). While stirring at room temperature, ammonium chloride solid (3.18 g, 59.47 mmol) and zinc powder (3.24 g, 49.6 mmol) were added sequentially. After the addition was complete, the reaction was carried out at room temperature for 90 min, and the reaction was monitored by LCMS. After the reaction was completed, saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, diatomaceous earth was spread and filtered, and the filter cake was washed with ethyl acetate (100 mL). Further, 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 filtered to obtain the target compound 14A (1.30 g, yield: 99.21%).

[0183] LCMS m / z = 265.2 [M+1] + .

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (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).

[0185] Step 2: Dissolve compound 14A (1.0 g, 3.79 mmol) in tetrahydrofuran (20 mL), and while stirring at room temperature, add 25% (w / w) aqueous sodium hydroxide solution (5 mL) to the reaction solution. After the addition is complete, heat the solution and react it at 50 °C for 2 h. Monitor the reaction by TLC (ethyl acetate: petroleum ether = 3:2). After the reaction is complete, add ethyl acetate (40 mL) and water (20 mL) to the reaction solution, separate the organic phase, adjust the pH of the aqueous phase to 6 with hydrochloric acid (6N hydrochloric acid), and a large amount of solid will precipitate. Filter the solid, dry the filter cake, and obtain the target compound 12G (0.7 g, yield: 75.64%).

[0186] LCMS m / z=245.2 [M+1] + 。

[0187] 1 H NMR (400MHz,DMSO-d6) δ 12.97 (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)。

[0188] 19 FNMR (400MHz,DMSO-d6) δ -122.41(s),-123.46(s)。

[0189] Step 3: Dissolve compound 12G (488 mg, 2.0 mmol) in dichloromethane (20 mL), cool the solution to 0 °C, and sequentially add triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol). After the addition is complete, remove the ice bath and allow the solution to warm up to room temperature naturally. Stir the solution at this temperature for 2 h. Monitor the reaction by LCMS. After the reaction is complete, concentrate the solution immediately and purify it by column chromatography (eluent, PE:EA = 5:1~1:1) to obtain the target compound 12H (530 mg, yield: 86.32%).

[0190] LC-MS (ESI):m / z=307.2,309.2 [M+H]+ 。

[0191] Step 4: Dissolve compound 14B (2.52 g, 19.98 mmol) in dichloromethane (50 mL), add thionyl chloride (2.5 mL), heat the mixture under reflux for 3 h after addition, concentrate the reaction mixture after 3 h of reaction to obtain the crude target compound 14C (2.89 g), and directly use the obtained crude product in the reaction of the next step.

[0192] Step 5: Weigh 5-iodo-6-fluoro-pyridin-2-amine (4.76 g, 19.99 mmol), dissolve it in dichloromethane (80 mL), add pyridine (4.74 g, 59.97 mmol), cool the reaction solution to 0 °C, weigh the crude compound 14C (2.89 g, 19.99 mmol), dissolve it in dichloromethane (20 mL), and slowly add the dichloromethane solution of compound 14C to the above reaction solution. After addition, warm the reaction solution to room temperature and continue stirring for 1 h. After the reaction is completed, add dichloromethane (50 mL) and water (100 mL) to the reaction solution, stir for 2 min, separate the aqueous phase, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the solution until a solid precipitates, add n-hexane, stir for crystallization, filter and dry to obtain the target compound 14D (3.1 g, yield: 44.81%).

[0193] LC-MS (ESI): m / z = 347.2 [M+H] + 。

[0194] 1 1H NMR (400 MHz, DMSO-d6) δ 10.76 (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).

[0195] Step 6: Under nitrogen gas protection, compound 14D (1.35 g, 3.90 mmol) and N-Boc piperazine (1.45 g, 7.80 mmol) were sequentially weighed and placed in 1,4-dioxane (30 mL). 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 the reaction was completed, 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%). The crude product was directly used in the reaction of the next step.

[0196] LC-MS (ESI): m / z = 405.2 [M+H] + 。

[0197] Step 7: 14E (0.55 g, crude product) was dissolved in methanol (10 mL), and a hydrochloric acid dioxane (4 mL, 4 M) solution was added. The mixture was reacted at room temperature for 4 h and then spin-dried to obtain the title compound 14F (460 mg, crude product). The crude product was directly used in the reaction of the next step.

[0198] LC-MS (ESI): m / z = 305.2 [M+H] + 。

[0199] Step 8: 14F (200 mg, crude product) and 12H (100 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (20 mL). After replacing with DIPEA (1 mL, 5.74 mmol) and nitrogen gas, the mixture was reacted at 60 °C for 2 h. The disappearance of the raw materials was monitored by LCMS. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 14 (26 mg, yield: 14.86%).

[0200] LC-MS (ESI): m / z = 531.2 [M+H] + 。

[0201] 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (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).

[0202] Example 15 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)pyridineamide (Compound 15)

Chemical Structure

[0203] Step 1: 2D (200 mg, crude product), 12H (100 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (20 mL), purged with DIPEA (1 mL, 5.74 mmol) and nitrogen gas, then reacted at 60 °C for 2 h. The disappearance of the starting material was monitored by LCMS. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (DCM:MeOH = 1:0 - 10:1) to obtain Compound 15 (37 mg, yield: 21.14%).

[0204] 11H NMR (400 MHz, DMSO-d6) δ 12.93 (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).

[0205] LC-MS (ESI): m / z = 531.2 [M+H] + .

[0206] Example 16 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) [Chemical Structure]

[0207] Step 1: Dissolve 14F (200 mg, crude product) and 1E (100 mg, 0.37 mmol) in anhydrous acetonitrile (20 mL), replace with DIPEA (1 mL, 2.45 mmol) and nitrogen gas, then react at 60 °C for 2 h. Monitor the disappearance of the raw materials by LCMS, concentrate the system, add saturated sodium bicarbonate solution (20 mL), extract with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (DCM:MeOH = 1:0 - 10:1) to obtain Compound 16 (37 mg, 21.14%).

[0208] 11H NMR (400 MHz, DMSO-d6) δ 12.38 (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).

[0209] LC-MS (ESI): m / z = 495.2 [M+H] + .

[0210] Example 17 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) [Chemical formula]

[0211] Step 1: Compound 17A (synthesized according to Patent WO 2016051193A1) (9.62 g, 59 mmol) was dissolved in DCM (60 mL), thionyl chloride (10 mL) was added, and the mixture was refluxed for 2 h. After the system became completely transparent, the reaction was stopped. After concentrating the system solvent, the title compound 17B (10.6 g, crude product) was obtained. It was directly used in the next step without further purification.

[0212] Step 2: Take a 500 mL eggplant-shaped flask, sequentially add 5-bromo-6-fluoropyridin-2-amine (10.6 g, 55.49 mmol) and pyridine (14.2 g, 180 mmol), dissolve them in 200 mL of dichloromethane, and cool to 0 °C. Slowly add dropwise 100 mL of a dichloromethane solution of compound 17B (10.6 g, crude product). After the addition was complete, the reaction was continued at room temperature for 1 h. Add 200 ml of semi-saturated brine, shake well, let stand, separate the layers, separate the aqueous phase, concentrate a portion of the organic phase until a large amount of solid precipitates, filter, wash the filter cake with petroleum ether, and dry under vacuum to obtain the title compound 17C (7.8 g, 41.95%).

[0213] LC-MS (ESI): m / z = 335.2, 337.2 [M+H] + 。

[0214] Step 3: Under nitrogen gas protection, sequentially weigh compound 17C (7.8 g, 23 mmol) and N-Boc piperazine (6.34, 34 mmol), put them into 1,4-dioxane (100 mL), and add 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 is complete, heat to 100 °C and react overnight. After the reaction is complete, concentrate the reaction solution and purify it by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the target compound 17D (0.464 g, yield: 4.8%).

[0215] LC-MS (ESI): m / z = 441.2 [M+H] + 。

[0216] Step 4: Dissolve 17D (0.464 g, 1.05 mmol) in methanol (10 mL), add a hydrochloric acid dioxane (5 mL, 4M) solution, react at room temperature for 2 h, concentrate, and obtain the title compound 17E (388 mg, crude product).

[0217] LC-MS (ESI): m / z = 341.2 [M+H] + 。

[0218] Step 5: Dissolve 12H (305 mg, 1 mmol) and 17E (388 mg, crude product) in anhydrous acetonitrile (20 mL), add DIPEA (0.5 mL), replace with nitrogen gas, then react at 60 °C for 3 hours. Detect by LCMS that the raw materials have completely reacted, concentrate the system, add saturated sodium bicarbonate solution (20 mL), extract with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 17 (181 mg, 31.95%).

[0219] 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (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).

[0220] LC-MS (ESI): m / z = 567.2 [M+H] + 。

[0221] Example 18 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)

Chemical Structure

[0222] Step 1: Dissolve compound 18A (1 g, 6.1 mmol) in THF (20 mL), add 500 mg (60%) of sodium hydride at 0 °C, and stir for 30 min. Add iodomethane (0.6 mL, 9.6 mmol), slowly warm to room temperature, react for 2 h, then add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, collect the organic phase, concentrate, and separate by column chromatography (PE:EA = 20:1~5:1) to obtain compound 18B (601 mg, 56%).

[0223] 1 H NMR (400 MHz, CDCl3) δ 7.23 ‐ 7.21 (m, 1H), 3.77 ‐ 3.75 (m, 3H).

[0224] Step 2: Dissolve compound 18B (342 mg, 1.9 mmol) in THF (5 mL), cool to -78 °C. Add n-butyllithium (1.15 mL, 2.5 M hexane solution), stir at -78 °C for 15 min. Add DMF (0.3 mL, 3.9 mmol), maintain at -78 °C and react for 1 h. Add ethyl acetate and water to the system to quench, then extract with ethyl acetate, collect the organic phase and concentrate, and then separate by column chromatography (PE:EA = 15:1~2:1) to obtain compound 18C (84 mg, 35%).

[0225] LC-MS (ESI): m / z = 129.1 [M+H] + 。

[0226] Step 3: Dissolve compound 18C (40 mg, 0.28 mmol) in 0.375 M KMnO4 solution, warm to 75 °C, and react for 1 h. Cool to room temperature, add 10% KOH aqueous solution to adjust the system to be basic, and a solid appears in the system. Filter by suction, take the filtrate, add hydrochloric acid to adjust the pH value = 2, extract 3 times with ethyl acetate / methanol = 10 / 1 system (50 mL), concentrate the obtained organic phase, and obtain 30 mg of the crude product of compound 18D.

[0227] LC-MS (ESI): m / z = 145.1 [M+H] + 。

[0228] Step 4: 5 mL of dichloromethane and 1 mL of thionyl chloride were added to the crude product of Compound 18D. The system was heated to 50 °C under a nitrogen gas atmosphere and reacted for 1 h. After cooling to room temperature, it was concentrated until no solvent remained, and the crude product was directly used in the reaction of the next step.

[0229] Step 5: Compound 18F (4 g, 21 mmol) was dissolved in (50 mL) dichloromethane. Pyridine (2.5 mL, 32 mmol) and acetyl chloride (1.7 mL, 23 mmol) were added at room temperature. After monitoring by TLC until the raw material disappeared, the system was concentrated and triturated with ethyl acetate / petroleum ether = 1 / 15 (160 mL) to obtain Compound 18G (4 g, 81.74%).

[0230] LC-MS (ESI): m / z = 233.1 [M+H] + 。

[0231] 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 tert-butoxide (4.8 g, 43 mmol) were added to a round-bottom flask. (100 mL) of 1,4-dioxane was added, and after replacing with nitrogen gas, it was heated to reflux and stirred overnight. After cooling to room temperature, silica gel was added, the solvent was concentrated to dryness, and separated by column chromatography (PE:EA = 5:1~1:3) to obtain Compound 18H (1.1 g, 19%).

[0232] LC-MS (ESI): m / z = 339.1 [M+H] + 。

[0233] Step 7: Compound 18H (400 mg, 1.2 mmol) was dissolved in TFA / DCM = 1:4 (10 mL), and the reaction was carried out at room temperature until the raw materials disappeared. Then, the system was directly concentrated to obtain the trifluoroacetate salt, which is the crude product of compound 18I, and directly proceeded to the next step.

[0234] LC-MS (ESI): m / z = 239.2 [M+H] + 。

[0235] Step 8: The crude product of compound 18I and 12H (337 mg, 1.1 mmol) were dissolved in (15 mL) acetonitrile, (3 mL) DIPEA was added, the temperature was raised to 60 °C, and the reaction was carried out for 2 h. After cooling to room temperature, it was concentrated to dryness and separated by reverse-phase column chromatography (water / acetonitrile = 1:1) to obtain compound 18J (160 mg, 27%).

[0236] LC-MS (ESI): m / z = 465.1 [M+H] + 。

[0237] Step 9: Compound 18J (60 mg, 0.13 mmol) was dissolved in a mixed solvent (6 mL) of concentrated hydrochloric acid / ethanol = 2:1, heated to 70 °C, and reacted for 1 h. After cooling to room temperature, the system was immediately concentrated to dryness to obtain the crude hydrochloride salt of compound 18K, and directly proceeded to the next step.

[0238] LC-MS (ESI): m / z = 423.2 [M+H] + 。

[0239] Step 10: The crude hydrochloride salt of compound 18K and compound 18E were dissolved in (10 mL) dichloromethane, (1.5 mL) pyridine was added, and the reaction was carried out at room temperature for 30 min. After detecting by LCMS that the reaction was complete, the system was concentrated to obtain a crude product, and the crude product was purified by preparative TLC (developing solvent: EA) to obtain the target compound 18 (8 mg, 11%).

[0240] 11H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.95 ‐ 7.88 (m, 1H), 7.70 ‐ 7.63 (m, 1H), 7.61 ‐ 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).

[0241] 19 19F NMR (400 MHz, DMSO-d6) δ -73.75, -122.05, -125.45, -132.16.

[0242] LC-MS (ESI): m / z = 549.1 [M+H] + .

[0243] Example 19 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) [Chemical Structure]

[0244] Step 1: Weigh exactly 0.505 g (1.25 mmol) of Compound 14E, put it into 10 mL of DMF, and cool it to about 0 °C under nitrogen gas protection. Then weigh 100 mg (2.5 mmol, 60%) of NaH and add it to the reaction solution. After addition, maintain the temperature and stir for 30 min, then add iodomethane (0.27 g, 1.9 mmol). After addition, warm the reaction mixture to room temperature and react for 1 h. When the reaction is complete as detected by TLC spot plate (developing solvent: EA), after the reaction is complete, add saturated ammonium chloride to the reaction solution to quench the reaction, then add 100 mL of water, extract with ethyl acetate (150 mL × 2), combine the organic phases, wash the organic phase with saturated brine (150 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the target compound 19A (0.44 g, yield: 84.12%). The crude product was directly used in the reaction of the next step.

[0245] LC-MS (ESI): m / z = 419.5 [M + H] + 。

[0246] Step 2: Weigh 0.44 g (1.05 mmol) of Compound 19A, put it into 10 mL of dichloromethane, and add dioxane hydrochloride solution (4 M, 10 mL). Stir and react overnight at room temperature. After the reaction is complete, concentrate to obtain the crude hydrochloride salt of Compound 19B (0.38 g). The crude product was directly used in the reaction of the next step.

[0247] LC-MS (ESI): m / z = 319.1 [M + H] + 。

[0248] Step 3: Weigh 19B (0.38 g, crude product), dissolve 12H (0.29 g, 0.94 mmol) in anhydrous acetonitrile (20 mL), add diisopropylethylamine (1 mL), heat to 75 °C, stir and react for 3 h. Monitor the reaction by LCMS. After the reaction is completed, cool to room temperature, concentrate, and then acetonitrile and DIPEA precipitate to obtain a crude product. Purify the crude product by Pre-TLC (developing solvent: dichloromethane:methanol = 15:1) to obtain 19 (0.276, yield: 53.90%).

[0249] LC-MS (ESI): m / z = 545.6 [M+H] + 。

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (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).

[0251] Example 20 N-Cyclopropyl-5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Compound 20)

Chemical Structure

[0252] Step 1: Weigh 1C (0.455 g, 1.25 mmol), put it into DMF (10 mL), cool it to about 0 °C under nitrogen gas protection, then weigh NaH (100 mg, 2.5 mmol, 60%), add it to the reaction solution, and maintain the temperature for 30 min with stirring after addition. Then add iodomethane (0.27 g, 1.9 mmol), warm up to room temperature after addition, react for 1 h, monitor the completion of the reaction by TLC (developing solvent: EA). After the reaction is completed, add saturated ammonium chloride to the reaction solution to destroy the reaction, then add water (100 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash the organic phase with saturated brine (150 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the target compound 20A (0.39 g, 82.6%), which does not require further purification.

[0253] LC-MS (ESI): m / z = 379.2 [M+H] + 。

[0254] Step 2: Dissolve 20A (0.39 g, crude product) in methanol (10 mL), add HCl / dioxane (2 mL, 4M) solution, react at room temperature for 2 h, concentrate, and obtain the title compound 20B (283 mg, crude product).

[0255] LC-MS (ESI): m / z = 279.2 [M+H] + 。

[0256] Step 3: Dissolve 12H (200 mg, 0.65 mmol) and 20B (283 mg, crude product) in anhydrous acetonitrile (20 mL), add DIPEA (0.5 mL), react at 60 °C for 2 h, detect by LCMS that the raw materials have completely reacted, concentrate the system, add saturated sodium bicarbonate solution (20 mL), extract with a mixed solution of DCM:MeOH = 10:1 (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (DCM:MeOH = 1:0~10:1) to obtain compound 20 (172 mg, 52.5%).

[0257] 1 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.56 - 7.48 (m, 1H), 7.47 - 7.39 (m, 2H), 7.19 - 6.88 (m, 2H), 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).

[0258] LC-MS (ESI): m / z = 505.2 [M+H] + .

[0259] Example 21 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)pyridineamide (Compound 21) [Chemical Structure]

[0260] Step 1: Weigh 0.404 g (1 mmol) of Compound 2D, put it into DMF (10 mL), cool it to about 0 °C under nitrogen gas protection, then weigh 100 mg (2.5 mmol, 60%) of NaH and add it to the reaction solution. After adding, maintain the temperature at this temperature and react for 30 min, then add iodomethane (0.27 g, 1.9 mmol). After adding, warm the temperature to room temperature and react for 1 h. Monitor the completion of the reaction by TLC (developing solvent: EA). After the reaction is completed, add saturated ammonium chloride solution to the reaction solution, then add water (100 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine (150 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the target compound 21A (0.37 g, 88.3%), and further purification is not required.

[0261] LC-MS (ESI): m / z = 419.2 [M+H] +。

[0262] Step 2: 21A (0.37 g, crude product) was dissolved in methanol (10 mL), and an HCl / dioxane (2 mL, 4 M) solution was added. The reaction was carried out at room temperature for 2 h. After concentration, the title compound 21B (253 mg, crude product) was obtained.

[0263] LC-MS (ESI): m / z = 319.2 [M+H] + 。

[0264] Step 3: 12H (100 mg, 0.33 mmol) and 21B (150 mg, crude product) were dissolved in anhydrous acetonitrile (20 mL), DIPEA (0.5 mL) was added, and the reaction was carried out at 60 °C for 2 h. It was detected by LCMS that the raw materials had completely reacted. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and extraction was carried out with a mixed solution (10 mL×3) of DCM:MeOH = 10:1. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then separated by silica gel column chromatography (DCM:MeOH = 1:0~10:1) to obtain compound 21 (59 mg, 32.85%).

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.80 ‐ 7.51 (m, 3H), 7.47 ‐ 7.25 (m, 2H), 7.23 ‐ 6.92 (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).

[0266] LC-MS (ESI): m / z = 545.2 [M+H] + 。

[0267] Biological tests Enzyme activity test experiment of PARP-1 The PARP-1 chemiluminescence detection kit was purchased from BPS Bioscience. The histone solution in the kit was diluted 5-fold with 1X PBS. 25 μL of the diluted histone solution was placed in a microplate well and incubated overnight at 4 °C. After incubation, the plate was washed 3 times with PBST (0.05% Tween-20). 100 μL of the blocking solution was placed in the microplate well and incubated at 25 °C for 90 minutes. After incubation, the plate was washed 3 times with PBST. 2.5 μL of compounds diluted with the test buffer and 12.5 μL of the substrate mixed solution (1.25 μL of 10X PARP test buffer, 1.25 μL of 10X PARP test mixture, 2.5 μL of Activated DNA, 7.5 μL of double-distilled water) were placed in the microplate well. The PARP-1 enzyme was diluted to 2 ng / μL and 10 μL was placed in the microplate well. The reaction system was incubated in an incubator at 25 °C for 60 minutes, After incubation, the plate was washed 3 times with PBST. Streptavidin-HRP was diluted 50-fold with the blocking solution and 25 μL was placed in the microplate well and incubated at 25 °C for 30 minutes. After incubation, the plate was washed 3 times with PBST. ELISA ECL substrate A and substrate B were uniformly mixed at 1:1 (v / v) and 50 μL was placed in the microplate well, and the chemiluminescence value was read.

[0268] The inhibition rate was calculated according to Equation 1, where RLUsample is the reading value of the compound well, RLUmax is the reading value of the solvent control well, and RLUmin is the reading value of the control well without PARP-1 enzyme. Curve fitting was performed using GraphPad Prism software with four parameters (log(inhibitor) vs. response -- Variable slope), and the IC 50 value was calculated.

[0269] Inhibition%=(1-(RLUsample-RLUmin) / (RLUmax-RLUmin))×100% (Equation 1) Experimental results: The compounds of the present invention have a significant inhibitory effect on the enzyme activity of PARP-1 in vitro. The compounds of the examples have an IC 50 value less than 100 μM for the enzyme activity of PARP-1. The IC 50 value is represented by grades A, B, C, and D. A represents 0 < IC 50 ≤ 5 nM, B represents 5 nM < IC 50 ≤ 10 nM, C represents 10 nM < IC 50 ≤ 50 nM, and D represents 50 nM < IC 50 ≤ 100 nM. Here, the test results of some examples are as shown in Table 1.

[0270]

Table 1

[0271] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a significant inhibitory effect on the enzyme activity of PARP-1 in vitro. In particular, Compound 2 has an IC 50 value of 0.79 nM for PARP-1.

[0272] 2. MDA-MB-436 Cell Activity Test Experiment The breast cancer cells MDA-MB-436 were purchased from ATCC, cultured in Leibovitz’s L-15 + 10% FBS medium in an incubator at 37°C without CO2. On the first day, cells in the exponential growth phase were collected and adjusted to 4000 cells / 135 μL with the medium to prepare a cell suspension. The cell suspension was added to a 96-well cell culture plate at 135 μL per well and incubated overnight. The next day, compounds at different concentrations were added, and the plate was placed in the incubator for 7 days of culture and incubation. After the culture was completed, according to the instructions of the CellTiter-Glo kit (Promega, G7573), 75 μL of CTG solution pre-dissolved and equilibrated to room temperature was added per well, mixed uniformly for 2 minutes with a microplate shaker, left at room temperature for 10 minutes, and then the fluorescence signal value was measured with an Envision 2104 plate reader (PerkinElmer). The inhibition rate was calculated using Equation (1), where RLU compound is the reading value of the drug-treated group, and RLU control is the average value of the solvent control group, and RLU blank is the average value of the wells without cells. The IC 50 value was calculated using GraphPad Prism software.

[0273] Inh.%=(1‐ (RLU compound ‐ RLU blank ) / (RLU control ‐ RLU blank ))×100% (Equation 1) Test results: The compounds of the present invention have a significant inhibitory effect on MDA-MB-436 cells. The IC50 value of the compounds against MDA-MB-436 cells is less than 100 nM, and the IC50 value of some excellent compounds against MDA-MB-436 cells is less than 10 nM. The inhibition rate of the compounds against breast cancer cells MDA-MB-436 is greater than 70%, and the inhibition rate of some excellent compounds is greater than 85%. The results of some specific compounds are as shown in Table 2.

[0274]

Table 2

[0275] Conclusion: The compounds of the present invention, for example, the compounds of the examples, have good inhibitory activity against breast cancer cell MDA-MB-436.

[0276] 3. Pharmacokinetic study in rats 3.1 Test animals: Male SD rats, about 220 g, 6 - 8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0277] 3.2 Test design: On the test day, 30 SD rats were randomly grouped by body weight. One day before dosing, they were fasted for 12 - 14 h without water restriction and fed 4 h after dosing.

[0278]

Table 3

[0279] Before and after dosing, 0.15 ml of blood was collected from the orbital socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4 °C for 10 min, and plasma was collected. The blood sampling time points for both the intravenous group and the intragastric administration group were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. After 24 h of dosing, the brain tissue was removed, the blood remaining on the surface of the brain tissue was washed with cold saline, wiped and dried, and then homogenized. Before analysis and detection, all samples were stored at -80 °C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0280]

Table 4

[0281] Conclusion: The compounds of the present invention, especially the compounds of the examples, for example, compounds 4, 12, 14, 15, 18, have good in vivo pharmacokinetic characteristics in rats.

[0282] 4. Pharmacokinetic study in mice 4.1 Test animals: male Balb / c mice, 20-25g, 12 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0283] 4.2 Study design: On the day of the study, 60 Balb / c mice were randomly divided into groups according to weight. They were fasted for 12-14 h without water restriction one day before administration, and fed 4 h after administration.

[0284] [Table 5]

[0285] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection times for the intravenous and intragastric administration groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. After administration of compounds 12, 15, and 18, brain tissue was removed at 30 min, 2, and 24 h, respectively. After administration of compounds 2 and 5, brain tissue was removed at 24 h, and the blood remaining on the surface of the brain tissue was washed with cold saline, wiped off, dried, and then homogenized. Before analytical detection, all samples were stored at -80°C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0286] [Table 6]

[0287] Conclusion: The compounds of the present invention, especially the compounds of the examples, such as compounds 2, 5, 12, 15, 18, have good in vivo pharmacokinetic characteristics in mice.

[0288] 5. Pharmacokinetic study in beagle dogs 5.1 Test animals: male beagle dogs, weighing approximately 8-11 kg, 6 dogs / compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0289] 5.2 Test method: On the test day, six beagle dogs were randomly grouped by body weight. One day before dosing, they were fasted for 12 - 14 h without water deprivation and fed 4 h after dosing. They were dosed according to Table 1.

[0290]

Table 7

[0291] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. It was centrifuged at 5000 rpm at 4 °C for 10 min to collect plasma. The blood sampling time points for both the intravenous group and the intragastric administration group were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and detection, all samples were stored at -80 °C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0292]

Table 8

[0293] Conclusion: The compounds of the present invention, especially the compounds of the examples, such as compound 12, have good in vivo pharmacokinetic characteristics in dogs.

[0294] 6. Pharmacokinetic study in monkeys 6.1 Test animals: Male cynomolgus monkeys, 3 - 5 kg, 3 - 6 years old, 4 monkeys / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0295] 6.2 Test method: On the test day, eight monkeys were randomly grouped by body weight. One day before dosing, they were fasted for 14 - 18 h without water deprivation and fed 4 h after dosing.

[0296]

Table 9

[0297] *The dosage is based on the free base.

[0298] Before and after administration, 1.0 mL of blood was collected from the peripheral vein and placed in an EDTAK2 centrifuge tube. Centrifugation was performed at 5000 rpm at 4 °C for 10 min, and the plasma was collected. The blood sampling time points for the venous group were all 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis and detection, all samples were stored at -80 °C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0299]

Table 10

[0300] Conclusion: The compounds of the present invention, particularly the compounds of the examples, such as compound 12 and 14, have good in vivo pharmacokinetic characteristics in monkeys.

Claims

1. A compound represented by Formula II, a stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt thereof, 【Chemical Formula 1】 where X １ is O or S, X ２ is N, C or CR ５’ and X ３ is N, C or CR ５’’ and Ring A is a 4- to 12-membered heterocycloalkyl group containing 1 to 3 N atoms and 0 to 2 heteroatoms selected from O and S, R １ , R ２ and R ３ are independently H, D, halogen, CN, NH ２ , -SF ５ , C １－４ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group, -O-C ３－６ cycloalkyl group, -(CH ２ ) ｒ -C ３－６ cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group or -(CH ２ ) ｒ -heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ haloalkyl group, Each R ４ is independently H, D, halogen, C １－４ alkyl group, C ３－６A cycloalkyl group, OH, CN, NH ２ , C １－４ An alkoxy group, C ２－６ An alkenyl group or C ２－６ An alkynyl group, and the alkyl group, alkoxy group, cycloalkyl group, alkenyl group and alkynyl group are optionally substituted with 1 to 5 groups selected from D, halogen, C １－４ An alkyl group, C １－４ An alkoxy group, OH, CN, NH ２ And C １－４ And a haloalkyl group, Optionally, two Rs ４ And the atoms linked thereto together form a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－６ A cycloalkyl group or N, S, O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ An alkyl group, C １－４ An alkoxy group, OH, CN, NH ２ And C １－４ And a haloalkyl group, Each L is independently —NH—, —CH ２ —, —O—, —S—, —S(═O)—, —S(═O) ２ — or —C(═O)—, n and m are independently 0, 1, 2 or 3, Each R ５ , R ５’ , R ５’’ Is independently H, D, ═O, halogen, C １－４ An alkyl group, C １－４ An alkoxy group, CN or C ３－６ A cycloalkyl group, and the alkyl group, alkoxy group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ An alkyl group, C １－４ An alkoxy group, OH, CN, NH ２ And C １－４ And a haloalkyl group, Optionally, one R ４is R ５’ forms a bond with q is 0, 1, 2, 3 or 4, X ４ is N, NR ７ or CR ７ wherein X ５ is N, NR １０ or CR １０ wherein ring B is a 6-membered heteroaryl group, R ６ , R ７ , R ９ , R １０ are independently H, D, CN, OH, halogen, C １－４ alkyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, wherein the alkyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ haloalkyl group, R ８ is C １－４ alkyl group, C １－４ alkoxy group, -NH C １－４ alkyl group, -CONH C １－４ alkyl group, -CONH C １－４ alkylene OC １－４ alkyl group, -NHCO C １－４ alkyl group, -NHCOOC １－４ alkyl group, -OCONH C １－４ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, R １１ , -NHR １１ , -(CH ２ ) ｒ R １１ , -OR １１ , -COR １１ , -(CH ２) ｒ NHR １１ 、 -NH(CH ２ ) ｒ R １１ 、 -(CH ２ ) ｒ OR １１ 、 -O(CH ２ ) ｒ R １１ 、 -CONHR １１ 、 -NHCOR １１ 、 -NHCONHR １１ 、 -CONH(CH ２ ) ｒ R １１ 、 -CONH(CH ２ ) ｒ OR １１ 、 -(CH ２ ) ｒ CONHR １１ 、 -OCONHR １１ 、 -COOR １１ 、 or -CO(CH ２ ) ｒ NHR １１ and the alkyl group, alkylene group, alkoxy group, alkenyl group and alkynyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ haloalkyl group, Each R １１ is independently a C ３－６ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally D, =O, halogen, C １－４ alkyl group, C １－４ alkoxy group, -NH C １－４ alkyl group, -CONH C １－４ alkyl group, -NHCO C １－４ alkyl group, OH, CN, NH ２ and C １－４ substituted with 1 to 3 groups selected from alkyl halide groups, each r is independently 1, 2 or 3, provided that, 【Chemical formula 2】 where n and m are 0, 【Chemical formula 3】 where R ６ is H, halogen, C １－４ alkyl group or halogenated C １－４ alkyl group, R ８ is -CONHC １－４ not an alkyl group, a compound, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt.

2. X １ is O, X ２ is N or CR ５’ and, X ３ is N, C or CR ５’’ and, ring A is a 4- to 9-membered monocyclic heteroalkyl group, 6- to 12-membered spirocyclic heteroalkyl group, 6- to 12-membered fused-ring heteroalkyl group or 6- to 12-membered bridged-ring heteroalkyl group containing 1 to 3 N atoms and 0 to 2 heteroatoms selected from O and S, R １ is H, D, halogen, CN, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group, -O-C ３－６ cycloalkyl group, -(CH ２ ) ｒ -C ３－６ cycloalkyl group, heterocycloalkyl group, -O-heterocycloalkyl group or -(CH ２ ) ｒ- a heterocycloalkyl group, wherein the heterocycloalkyl group is a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally, D, halogen, C １－４ alkyl group, C １－４ alkoxy group, and C １－４ substituted with 1 to 5 groups selected from halogenated alkyl groups, R ２ 、R ３ are independently H, D, halogen, or C １－４ alkyl group, and the alkyl group is optionally substituted with 1 to 5 groups selected from D, halogen, OH, CN, and NH ２ Each R ４ is independently H, D, halogen, C １－４ alkyl group, C ３－６ cycloalkyl group, OH, CN, or NH ２ selected from, and the alkyl group and cycloalkyl group are optionally D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ substituted with 1 to 5 groups selected from halogenated alkyl groups, Optionally, two R ４ and the atoms to which they are attached together form a C ３－６ cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group and heterocycloalkyl group are optionally D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ substituted with 1 to 3 groups selected from halogenated alkyl groups, Each L is independently -NH-, -CH ２ -, -O-, or -C(=O)-; n and m are independently 0, 1, 2, or 3.​ Each R ５ , R ５’ , R ５’’ is independently H, D, =O, halogen, C １－４ alkyl group or C １－４ alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH ２ . Optionally, one R ４ forms a bond with R ５’ . q is 0, 1, or 2. R ６ , R ７ , R ９ , R １０ is independently H, D, CN, OH, halogen, C １－４ alkyl group or C １－４ alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ haloalkyl group, the compound according to claim 1, its stereoisomers, solvates, deuterides, or pharmaceutically acceptable salts.

3. Ring A is a substituted or unsubstituted 6- to 10-membered fused-ring heterocycloalkyl group, a substituted or unsubstituted 6- to 11-membered spiro-ring heterocycloalkyl group, a substituted or unsubstituted 6- to 10-membered bridged-ring heterocycloalkyl group, a substituted or unsubstituted 4- to 5-membered monocycloheterocycloalkyl group, a substituted or unsubstituted 7- to 8-membered monocycloheterocycloalkyl group, a substituted or unsubstituted 【Chemical Formula 4】 or a substituted or unsubstituted 【Chemical Formula 5】 and is, or 【Chemical Formula 6】 is a substituted or unsubstituted 【Chemical Formula 7】 selected from, or R ８ is a C １－４ alkyl group, C １－４ alkoxy group, -NH C １－４ alkyl group, -NHCO C １－４ alkyl group, -NHCOOC １－４ alkyl group, -OCONH C １－４ alkyl group, -CONH C １－４ alkylene OC １－４ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, R １１ , -NHR １１ , -(CH ２ ) ｒ R １１ , -OR １１ , -COR １１ , -(CH ２ ) ｒ NHR １１ , -NH(CH ２ ) ｒ R １１ , -(CH ２ ) ｒ OR １１ , -O(CH ２ ) ｒ R １１ , -CONHR １１ , -NHCOR １１ , -NHCONHR １１ , -CONH(CH ２ ) ｒ R １１ , -CONH(CH ２ ) ｒ OR １１ , -COOR １１ , -(CH ２ ) ｒ CONHR １１ , -OCONHR １１ , or -CO(CH ２ ) ｒ NHR １１ and the alkyl group, alkoxy group, alkenyl group and alkynyl group are optionally D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ The compound according to claim 2, a stereoisomer thereof, a solvate, a deuteride, or a pharmaceutically acceptable salt, which is substituted with 1 to 3 groups selected from haloalkyl groups.

4. Ring A is 【Chemical Formula 8】 The compound according to claim 2, a stereoisomer thereof, a solvate, a deuteride, or a pharmaceutically acceptable salt, which is selected from

5. R １ is H, D, F, Cl, Br, I, C １－４ alkyl group or C ３－６ cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group and C １－４ haloalkyl group, R ２ is H, D, F, Cl, Br, I or C １－４ alkyl group, and the alkyl group is optionally substituted with 1 to 5 groups selected from D, halogen, OH, CN and NH ２ R ３ is H, D, F, Cl, Br or I, Each R ４ is independently selected from H, D, F, Cl, Br or I, Optionally, two Rs ４ and the atoms connected thereto together form a C ３－６ cycloalkyl group or a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, CN, NH ２ and C １－４ haloalkyl group, n, m are 0, Each R ５ 、R ５’ 、R ５’’ is, independently, H, D, F, Cl, Br, I, C １－４ alkyl group or C １－４ alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH ２ ; optionally, one R is combined with R ４ to form a bond, ５’ q is 0, 1, or 2; ring B is a 6-membered heteroaryl group containing 1 to 2 N atoms; R ６ 、R ７ 、R ９ 、R １０ 、R １－４ is, independently, H, D, CN, OH, halogen, C １－４ alkyl group or C １－４ alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 3 groups selected from D, halogen, C １－４ alkyl group, C ２ alkoxy group, OH, CN, NH １－４ and C １ haloalkyl group; a compound, a stereoisomer, a solvate, a deuteride, or a pharmaceutically acceptable salt thereof according to claim 3 or 4.

6. The compound has the structures of formula (IV) and (V), 【Chemical Formula 9】 wherein, ring A is 【Chemical Formula 10】 selected from, R １－４ is a C ３－６ alkyl group or a C ２ cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, NH ３ ; R ２is H, D, R ２ each independently is F, Cl, CN, NH ２ , C １－２ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, and the alkyl group is optionally further substituted with 1 to 3 groups selected from D, F, Cl, OH, CN, NH ２ ; R ６ is D, CN, OH, F, Cl, C １－２ alkyl group, C １－２ alkoxy group, C ３－４ cycloalkyl group or a 4- to 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from D, F, Cl, OH, CN, NH ２ ; R ８ is -CONHR １１ , -NHCOR １１ ; each R １１ is independently a C ３－６ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally substituted with 1 to 3 groups selected from D, =O, halogen, C １－４ alkyl group, C １－４ alkoxy group, -NH C １－４ alkyl group, -CONH C １－４ alkyl group, -NHCO C １－４ alkyl group, OH, CN, NH ２ and C １－４ halogenated alkyl group, the compound according to claim 1, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt.

7. R １ is C １－２ is an alkyl group, and the alkyl group is optionally substituted with 1 to 3 groups selected from D, F, and Cl. R ３ is H. R ２ is F, Cl, C １－２ is an alkyl group, and the alkyl group is optionally further substituted with 1 to 3 groups selected from D, F, and Cl. R ６ is D, F, Cl, C １－２ is an alkyl group, and the alkyl group is optionally substituted with 1 to 3 groups selected from D, F, and Cl. R ８ is -CONHR １１ -NHCOR １１ and R １１ is C ３－６ is a cycloalkyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O. The cycloalkyl group and the heteroaryl group are optionally substituted with 1 to 3 groups selected from D, F, Cl, C １－２ alkyl group and C １－２ halogenated alkyl group. The compound according to claim 6, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt.

8. The compound represented by formula (II), formula (IV), or formula (V), its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, wherein the compound is 【Chemical formula 11】 【Chemical formula 12】 【Chemical formula 13】 【Chemical formula 14】 selected from one of the structures, the compound, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, or the composition according to claim 9, in the manufacture of a drug for treating / preventing a PARP1-mediated disease.

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 to 1440 mg of the compound according to any one of claims 1 to 8, its stereoisomer, solvate, deuteride, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

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

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