Polycyclic poly(ADP-ribose) polymerase selective inhibitors

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a polycyclic poly(ADP-ribose) polymerase (PARP) selective inhibitor compound represented by general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a pharmaceutical composition containing the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and uses of the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. JPEG2025535834000114.jpg38170

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a polycyclic poly(ADP-ribose) polymerase selective inhibitor compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; a pharmaceutical composition and formulation containing said compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; a method for preparing said compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and uses of said compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [Background technology]

[0002] Targeted therapy by inhibiting poly(ADP-ribose) polymerase 1 (PARP1) is currently a focus of domestic and international research. PARP1 is the most representative PARP family member, accounting for over 90% of the PARP family's functions. PARP1 is a ribozyme that, through PARylation (i.e., poly(ADP-ribosyl)ation), regulates multiple cellular processes, including DNA damage signaling, chromatin remodeling, transcription, replication fork stabilization, induction of unbound Okazaki fragments during replication, inflammation, and metabolism. PARP1 consists of 1,014 amino acid residues and contains three domains: an N-terminal DNA-binding domain (DBD), an intermediate autoregulatory domain (AD), and a C-terminal catalytic domain (CAT). The N-terminal DNA-binding domain contains three zinc finger motifs (ZnI, ZnII, and ZnIII) ​​and a DNA strand break-sensitive element (NLS). ZnI and ZnII identify damaged DNA, while ZnIII is involved in the association between the domains and activates the protein. The middle autoregulatory region contains the carboxyl terminus of the BRCA1 (Breast Cancer 1) gene (DNA repair and cell signaling) and has the Capase-3 enzyme cleavage function. The C-terminal catalytic domain contains a tryptophan-glycine-arginine-rich domain (WGR), an α-helical domain (HD), and an ADP-ribose transferase domain (ART). PARP1 is crucial for the timely and accurate repair of DNA single-strand damage. Upon DNA damage, PARP1 is rapidly recruited to single-strand breaks (SSBs), where it binds to single-stranded DNA (ssDNA) and polymerizes itself and other proteins, thereby completing the recruitment of downstream DNA repair factors.

[0003] DNA homologous recombination repair (HRR) is an important repair mechanism for DNA double-strand breaks. BRCA1 and BRCA2 (Breast Cancer 2 genes) are recruited and coordinate homologous recombination repair. BRCA1 initiates HR by promoting the resection of double-strand breaks (DSBs). BRCA2 then acts downstream with PALB2 (Partner and Localizer of BRCA2; a BRCA2 chaperone and positioning protein gene) to stimulate RAD51 to target the resected single-stranded DNA, subsequently using the damper chromatin monomer as a template to precisely repair the DNA damage. In addition to their role in HR, BRCA1 and BRCA2 are also important during S phase, protecting stalled copy yolks from nuclease degradation. Given the above-mentioned effects of BRCA1 and BRCA2, mutations in both genes increase the incidence of breast, ovarian, prostate, and pancreatic cancers, resulting from high levels of genomic instability due to the loss of the remaining wild-type allele and defective HR. BRCA1 / 2-mutated tumors with defective HR rely on compensatory DNA repair pathways, and drugs can cause DNA damage by inhibiting key components of these pathways (e.g., PARP1), leading to significant genomic instability, mitotic catastrophe, and cell death in the absence of BRCA1 / 2, ultimately resulting in synthetic lethality of BRCA1 / 2 and PARP.

[0004] The mechanism of action of PARP inhibitor molecules involves two aspects. On the one hand, PARP1 inhibitors inhibit the catalytic activity of PARP-1 by competitively binding to its catalytic domain (CAT, the C-terminal catalytic domain), preventing timely repair of SSBs and generating DSBs. On the other hand, PARP-1 inhibitors inhibit PARP1 auto-PARylation and induce allostery of PARP1 by binding to CAT, enhancing the binding strength of PARP1 to damaged DNA. This "traps" PARP1 on damaged DNA, making it difficult for other PARP1 molecules in the cell nucleus to bind to damaged DNA. This further blocks potential DSB repair pathways and promotes apoptosis.

[0005] Since the approval of olaparix for BRCA-mutated ovarian cancer in 2014, many PARP inhibitors have been developed and have been widely successful. However, adverse drug reactions limit their ability to be used in combination with chemotherapy. Most first-generation PARP inhibitors were developed and optimized before the discovery of the concept of PARP1-DNA trapping, the mechanism by which PARP inhibitors exert synthetic lethal effects on BRCAm cells. Furthermore, because first-generation PARP inhibitors are not optimized for selectivity across the PARP family, they may cause adverse side effects, including intestinal toxicity due to tankyrase inhibition and hematologic toxicity due to PARP2 inhibition. Therefore, developing inhibitors with trapping ability and high selectivity for PARP1, which can ensure efficacy while reducing the toxicity of conventional PARP inhibitors, has become a new direction in PARP inhibitor research. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide polycyclic compounds that have novel structures and exhibit good selective inhibitory activity against PARP 1. Furthermore, such compounds can be applied to the prevention and / or treatment of PARP-related diseases.

[0007] The technical means of the present invention are as follows: In one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000002.jpg33170, wherein X, Y, and Z are each independently selected from N, C, or CH; Ring A and ring B are each independently selected from 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 7-membered heteroaryl; Ring C is selected from 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, 6- to 11-membered aryl, or 5- to 11-membered heteroaryl; Ar is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, 6-11 membered aryl or 5-11 membered heteroaryl, optionally substituted with 1-3 substituents Q, each Q independently being H, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocycloalkyl, -(CH2) p -N(R a )(R b ), -(CH2) p -OR a , -(CH2) p -P(O)(R a )(R b ), -(CH2) p -S(O)(R a ), -(CH2) p -S(O)2(R a ), -(CH2) p -C(O)(R a ), -(CH2) p -C(O)O(R a), -(CH2) p -OC(O)(R a ), -(CH2) p -C(O)N(R a )(R b ), -(CH2) p -N(R b )-C(O)(R a ) and Each R1 and each R2 independently represent hydrogen, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl, or R1 and R2 together with the carbon atoms to which they are attached form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocyclyl; R1' and R2' are each independently hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C1-6 alkyl, Each R3, each R4, and each R5 independently represents H, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl, R a , R b are each independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 selected from alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; m is selected from 0, 1, or 2, and when m is 2, two adjacent ring carbon atoms are connected by a single or double bond; n and t are each independently selected from 0, 1, 2, or 3; p and k are each independently selected from 0, 1, or 2; q is selected from 0, 1, 2, 3 or 4; JPEG2025535834000003.jpg6170Indicates a single or double bond.

[0008] In some embodiments, X, Y, and Z are each independently selected from N or C.

[0009] In some embodiments, X, Y, and Z are each independently selected from N or C, and at most one of X, Y, and Z is N.

[0010] In some embodiments, X is N and Y, Z are C.

[0011] In some embodiments, Y is N and X, Z are C.

[0012] In some embodiments, Z is N and X, Y are C.

[0013] In some embodiments, X, Y, and Z are all C.

[0014] In some embodiments, ring A and ring B are independently selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0015] In some embodiments, ring A and ring B are independently selected from a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms, phenyl, or a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms, wherein the heteroatoms are selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0016] In some embodiments, ring A is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl, and ring B is selected from a phenyl or a 5-6 membered heteroaryl.

[0017] In some embodiments, ring A is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl containing 1-2 heteroatoms, a phenyl, or a 5-6 membered heteroaryl containing 1-2 heteroatoms, and ring B is selected from a phenyl, or a 5-6 membered heteroaryl containing 1-2 heteroatoms, wherein the heteroatoms are selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0018] In some embodiments, Ring B is selected from phenyl or a 6-membered heteroaryl containing 1-2 nitrogen atoms.

[0019] In some embodiments, Ring A and Ring B are each independently selected from cyclopentane, cyclohexane, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl, and tetrahydrooxazolyl.

[0020] In some embodiments, Ring A is selected from cyclopentane, cyclohexane, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl, or tetrahydrooxazolyl.

[0021] Ring B is selected from phenyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, dihydropyrazolyl, imidazolyl, dihydroimidazolyl, pyridyl, dihydropyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, piperidinyl, dihydropiperidinyl, piperazinyl, dihydropiperazinyl, furanyl, pyranyl, dihydropyranyl, thiazolyl, oxazolyl, or triazole.

[0022] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000004.jpg42170

[0023] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000005.jpg43170

[0024] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000006.jpg40170

[0025] In some embodiments, Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a phenyl, a 5-6 membered heteroaryl, an 8-11 membered fused ring group, an 8-11 membered spiro ring group, a 7-9 membered bridged ring group, an 8-11 membered fused heterocyclic group, an 8-11 membered spiro heterocyclic group, or a 7-9 membered bridged heterocyclic group.

[0026] In some embodiments, Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a phenyl, a 5-6 membered heteroaryl, an 8-11 membered fused alkyl, an 8-11 membered spirocyclic group, a 7-9 membered bridged cyclic group, an 8-11 membered fused heterocyclic group, an 8-11 membered spiroheterocyclic group, or a 7-9 membered bridged heterocyclic group.

[0027] In some embodiments, Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 7-9 membered bridged cyclic group, or a 7-9 membered bridged heterocyclic group.

[0028] In some embodiments, Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 7-8 membered bridged cyclic group, or a 7-8 membered bridged heterocyclic group.

[0029] In some embodiments, Ring C is selected from the following groups: JPEG2025535834000007.jpg39170Here, the a end is connected to Ar. In some embodiments, Ring C is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl.

[0030] In some embodiments, Ring C is selected from the following groups: JPEG2025535834000008.jpg22170Here, the a end is connected to Ar.

[0031] In some embodiments, Ar is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl optionally substituted with 1-2 Q, each Q being independently H, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, -(CH2) p -N(R a )(R b ), -(CH2) p -OR a , -(CH2) p -P(O)(R a)(R b ), -(CH2) p -S(O)(R a ), -(CH2) p -S(O)2(R a ), -(CH2) p -C(O)(R a ), -(CH2) p -C(O)O(R a ), -(CH2) p -OC(O)(R a ), -(CH2) p -C(O)N(R a )(R b ), -(CH2) p -N(R b )-C(O)(R a ) is selected.

[0032] R a , R b are each independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 It is selected from alkyl, cyclopropyl or cyclobutyl.

[0033] In some embodiments, Ar is selected from phenyl or 5-6 membered heteroaryl optionally substituted with 1-2 Q.

[0034] In some embodiments, Ar is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-2 Q.

[0035] In some embodiments, Ar is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, optionally substituted with 1-2 Q.

[0036] In some embodiments, Ar is selected from phenyl or 6-membered heteroaryl optionally substituted with 1-2 Q.

[0037] In some embodiments, Ar is selected from phenyl or 6-membered nitrogen-containing heteroaryl optionally substituted with 1-2 Q.

[0038] In some embodiments, Ar is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, optionally substituted with 1-2 Q.

[0039] In some embodiments, X, Y, and Z are each independently selected from N or C, and ring A and ring B together with X, Y, and Z are selected from the following groups: JPEG2025535834000009.jpg41170 Ring C is selected from 5- to 6-membered cycloalkyl and 5- to 6-membered heterocyclyl. Ar is selected from pyridyl optionally substituted with 1-2 Q, each Q independently being H, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, -(CH2) p -C(O)N(R a )(R b ), -(CH2) p -N(R b )-C(O)(R a ) and Each R1 and each R2 independently represent hydrogen, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl, or R1, R2 together with the carbon atoms to which they are attached form a 3- or 4-membered cycloalkyl or a 3- or 4-membered heterocyclyl. R1' and R2' are each independently hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl. Each R3, each R4, and each R5 independently represents H, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl. R a , R b are each independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 It is selected from alkyl or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0, 1, 2, or 3; p and k are each independently selected from 0, 1, or 2; q is selected from 0, 1, 2, 3 or 4. JPEG2025535834000010.jpg7170 is selected from a single bond or a double bond.

[0040] In some embodiments, X, Y, and Z are each independently selected from N or C. Ring A and ring B together with X, Y, and Z constitute the following group. JPEG2025535834000011.jpg42170 Ring C is selected from the following group. JPEG2025535834000012.jpg22170Here, the a end is connected to Ar. Ar is selected from pyridyl optionally substituted with 1-2 Q. Each Q is independently H, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, -(CH2) p -C(O)N(R a )(R b ), -(CH2) p -N(R b )-C(O)(R a ) is selected. Each R1 and each R2 independently represent hydrogen, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl, or R1, R2 together with the carbon atoms to which they are attached form a 3- or 4-membered cycloalkyl or a 3- or 4-membered heterocyclyl. R1' and R2' are each independently hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C1-6 Alkoxy-C 1-6 alkyl. Each R3, each R4, and each R5 independently represents H, halogen, hydroxyl, amino, cyano, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, Hydroxy C 1-6 Alkoxy, Amino C 1-6 Alkoxy, Hydroxy C 1-6 Alkylthio, Amino C 1-6 Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl. R a , R b are each independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 It is selected from alkyl or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0, 1, 2, or 3; p and k are each independently selected from 0, 1, or 2; q is selected from 0, 1, 2, 3 or 4. JPEG2025535834000013.jpg6170Indicates a single or double bond.

[0041] In some embodiments, ring C is JPEG2025535834000014.jpg21170, and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via methylene. In some embodiments, X, Y, and Z are each independently selected from N or C. Ring A and ring B together with X, Y, and Z constitute the following group. JPEG2025535834000015.jpg42170 Ring C is JPEG2025535834000016.jpg21170, and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via methylene. Ar is selected from pyridyl optionally substituted with 1-2 Q, each Q independently being H, fluorine, chlorine, hydroxyl, amino, C 1-4 Alkyl, Fluorinated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, Fluorinated C 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, -C(O)N(R a )(R b ) and Each R1 and each R2 independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4alkyl, or R1, R2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. R1' and R2' are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 alkyl. Each R3, each R4, and each R5 independently represent H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 alkyl. R a , R b are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0, 1, or 2. k is 1. q is selected from 0 or 1. JPEG2025535834000017.jpg6170 indicates a single or double bond.

[0042] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000018.jpg44170 Ring C is JPEG2025535834000019.jpg19170, and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via a methylene. Ar is selected from pyridyl optionally substituted with 1-2 Q. Each Q is independently H, fluorine, chlorine, hydroxyl, amino, C 1-4 Alkyl, Fluorinated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, Fluorinated C 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, -C(O)N(R a )(R b ) is selected. Each R1 and each R2 independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl, or R1, R2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. R1' and R2' are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl. R3 and R4 each independently represent H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 alkyl. R a , R b are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0 or 1. k is 1. q is 0. JPEG2025535834000020.jpg6170 indicates a single or double bond.

[0043] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000021.jpg24170 Ring C is JPEG2025535834000022.jpg18170, and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via a methylene. Ar is selected from pyridyl optionally substituted with 1-2 Q. Each Q is independently H, fluorine, chlorine, hydroxyl, amino, C 1-4 Alkyl, Fluorinated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, Fluorinated C 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, -C(O)N(R a )(R b ) is selected. Each R1 and each R2 independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl, or R1, R2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl. R1' and R2' are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl. R3 and R4 each independently represent H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 alkyl. R a , R b are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0 or 1. k is 1. q is 0. JPEG2025535834000023.jpg6170 indicates a single or double bond.

[0044] In some embodiments, ring A and ring B together with X, Y, and Z form the following group: JPEG2025535834000024.jpg22170 Ring C is JPEG2025535834000025.jpg20170, and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via a methylene. Ar is selected from pyridyl optionally substituted with 1-2 Q. Each Q is independently H, fluorine, chlorine, hydroxyl, amino, C 1-4 Alkyl, Fluorinated C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Alkoxy, Fluorinated C 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, -C(O)N(R a )(R b ) is selected. Each R1 and each R2 independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl, or together with R1, R2 and the carbon atoms attached thereto, constitute cyclopropyl or cyclobutyl. R1' and R2' are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl or C 1-4 Alkoxy-C 1-4 alkyl. R3 and R4 each independently represent H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, or C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, Amino C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, Hydroxy C 1-4 Alkoxy, Amino C 1-4 Alkoxy, Hydroxy C 1-4 Alkylthio, Amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 alkyl. R a , R b are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. m is selected from 0 or 1. n and t are each independently selected from 0 or 1. k is 1. q is 0. JPEG2025535834000026.jpg6170 indicates a single or double bond.

[0045] In another aspect, the present invention provides a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000027.jpg32170In formula, R1, R2, R1', R2', R3, R4, R5, R a , R b , Q, X, Y, Z, ring A, ring B, m, n, t, k, q, The definition of JPEG2025535834000028.jpg6170 is as described in any of the technical means mentioned above.

[0046] In another aspect, the present invention provides a compound represented by the following general formula (II-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000029.jpg33170In formula, R1, R2, R1', R2', R3, R4, R5, R a , R b , Q, Y, ring A, m, n, t, k, q, The definition of JPEG2025535834000030.jpg6170 is as described in any of the technical means mentioned above.

[0047] In another aspect, the present invention provides a compound represented by the following general formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000031.jpg28170In formula, R1, R2, R1', R2', R3, R4, R5, R a , R b , Q, Y, ring A, m, n, t, k, q, The definition of JPEG2025535834000032.jpg6170 is as described in any of the technical means mentioned above.

[0048] In another aspect, the present invention provides a compound represented by the following general formula (II-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000033.jpg29170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, Y, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0049] In another aspect, the present invention provides a compound represented by the following general formula (II-4), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000034.jpg28170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, Y, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0050] In another aspect, the present invention provides a compound represented by the following general formula (II-5), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000035.jpg30170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. JPEG2025535834000036.jpg6170 indicates a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0051] In another aspect, the present invention provides a compound represented by the following general formula (II-6), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000037.jpg29170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. JPEG2025535834000038.jpg6170 indicates a single or double bond. R1, R2, R3, R4, R5, R a , R b , Q, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0052] In another aspect, the present invention provides a compound represented by the following general formula (II-7), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000039.jpg30170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0053] In another aspect, the present invention provides a compound represented by the following general formula (II-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000040.jpg27170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, ring A, ring B, n, t, k, and q are defined as described in any of the above-mentioned technical means.

[0054] In another aspect, the present invention provides a compound represented by the following general formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000041.jpg30170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, n, t, k, and q are defined as described in any of the technical means mentioned above.

[0055] In another aspect, the present invention provides a compound represented by the following general formula (III-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000042.jpg29170In the formula, m' is selected from 1 or 2, and when m' is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond. R1, R2, R3, R4, R5, R a , R b , Q, n, t, k, and q are defined as described in any of the technical means mentioned above.

[0056] In another aspect, the present invention provides a compound represented by the following general formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000043.jpg27170In formula, R1, R2, R3, R4, R5, R a , R b The definitions of Q, n, t, and q are as described in any of the technical means mentioned above.

[0057] In another aspect, the present invention provides a compound represented by the following general formula (IV-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000044.jpg26170In formula, R1, R2, R3, R4, R a , R bThe definitions of Q, n, and t are as described in any of the above-mentioned technical means. In another aspect, the present invention provides a compound represented by the following general formula (IV-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000045.jpg28170In formula, R1, R2, R3, R4, R a , R b The definitions of n and t are as described in any of the technical means mentioned above.

[0058] In another aspect, the present invention provides a compound represented by the following general formula (IV-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000046.jpg28170In the formula, R1, R2, R3, R4, n, and t are defined as described in any of the technical means mentioned above. In another aspect, the present invention provides a compound represented by the following general formula (V), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000047.jpg29170, where n is selected from 0 or 1, and R1, R2, R3, R4, R5, R a , R b The definitions of Q, t, and q are as described in any of the technical means mentioned above.

[0059] In another aspect, the present invention provides a compound represented by the following general formula (V-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000048.jpg28170, where n is selected from 0 or 1, and R1, R2, R3, R4, R a , R b The definitions of Q and t are as described in any of the technical means mentioned above.

[0060] In another aspect, the present invention provides a compound represented by the following general formula (V-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000049.jpg29170, where n is selected from 0 or 1, and R1, R2, R3, R4, R a , R b The definitions of t are as described in any of the above technical means.

[0061] In another aspect, the present invention provides a compound represented by the following general formula (V-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000050.jpg26170In the formula, n is selected from 0 or 1, and the definitions of R1, R2, R3, R4, and t are as described in any of the above-mentioned technical means.

[0062] In another aspect, the present invention provides a compound represented by the following general formula (VI) or (VII), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000051.jpg28170, where n is selected from 0 or 1, and R1, R2, R3, R4, R5, R a , R b The definitions of Q, t, and q are as described in any of the technical means mentioned above.

[0063] In another aspect, the present invention provides a compound represented by the following general formula (VI-1) or (VII-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000052.jpg29170, where n is selected from 0 or 1, and R1, R2, R3, R4, R a , R b The definitions of Q and t are as described in any of the technical means mentioned above.

[0064] In another aspect, the present invention provides a compound represented by the following general formula (VI-2) or (VII-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000053.jpg30170In the formula, n is selected from 0 or 1, and R1, R2, R3, R4, Ra , R b The definitions of t are as described in any of the above technical means.

[0065] In another aspect, the present invention provides a compound represented by the following general formula (VI-3) or (VII-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000054.jpg30170In the formula, n is selected from 0 or 1, and the definitions of R1, R2, R3, R4, and t are as described in any of the above-mentioned technical means.

[0066] In another aspect, the present invention provides the following compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: JPEG2025535834000055.jpg185170JPEG2025535834000056.jpg234170JPEG2025535834000057.jpg224170

[0067] In another aspect, the present invention further provides a pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be in any pharmaceutically acceptable dosage form. A pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient, and biologically suitable for use in an organism. The choice of a particular excipient depends on the method of administration or the type and condition of the disease intended to be treated in a particular patient.

[0068] In some embodiments, the pharmaceutical composition may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition may be formulated into a conventional oral solid formulation, such as a tablet, capsule, pill, or granule, or into an oral liquid formulation, such as an oral solution, oral suspension, or syrup. For parenteral administration, the pharmaceutical composition may be formulated into an injection, such as an injection solution, a sterile powder for injection, or a concentrated solution for injection. For rectal administration, the pharmaceutical composition may be formulated into a suppository, etc. For pulmonary administration, the pharmaceutical composition may be an inhalation formulation, an aerosol, a powder mist, or a spray, etc.

[0069] In another embodiment, a pharmaceutical composition according to the present invention comprises the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and may further comprise one or more second therapeutically active agents.

[0070] In another aspect, the present invention also relates to the use of the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating a disease associated with PARP overexpression, wherein the disease is selected from neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, schizophrenia, chronic and acute pain, ischemia, post-hypoxic nerve damage, neurodegenerative diseases, arteriosclerosis, hyperlipidemia, cardiac tissue damage, coronary artery disease, myocardial infarction, cardiogenic shock, diabetic neuropathy, osteoarthritis, and osteoporosis.

[0071] In another aspect, the present invention also relates to the use of said compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating cancer.

[0072] Furthermore, the present invention also relates to the use of a pharmaceutical composition comprising said compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating cancer associated with PARP overexpression.

[0073] In some embodiments, the cancer is deficient in an HR-dependent DNA DSB repair pathway.

[0074] In some embodiments, the cancer cells comprise one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

[0075] In some embodiments, the cancer comprises one or more cancer cells, wherein the cancer cells are deficient in BRCA1 and / or BRCA2.

[0076] In some embodiments, the cancer comprises one or more cancer cells, wherein the cancer cells have a BRCA1 and / or BRCA2 defective phenotype.

[0077] In another aspect, the present invention further provides a method for treating a disease associated with PARP, the method comprising administering to a patient in need thereof an effective amount of the compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition.

[0078] Furthermore, the present invention further provides a method for treating cancer, which method comprises administering to a patient in need thereof an effective amount of the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition described above.

[0079] In some embodiments, the cancer is deficient in an HR-dependent DNA DSB repair pathway.

[0080] In some embodiments, the cancer cells comprise one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

[0081] In some embodiments, the cancer comprises one or more cancer cells, wherein the cancer cells are deficient in BRCA1 and / or BRCA2.

[0082] In some embodiments, the cancer comprises one or more cancer cells, wherein the cancer cells have a BRCA1 and / or BRCA2 defective phenotype.

[0083] In another aspect, the present invention further provides a kit comprising an effective amount of one or more of the above compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0084] In another aspect, the present invention further provides a kit comprising: (a) an effective amount of one or more of the compounds described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; (b) an effective amount of one or more anticancer agents; Includes.

[0085] The term "effective amount" as used herein refers to a drug dose that can prevent, alleviate, delay, suppress, or cure a disease in a subject. The size of the dose depends on the drug's dosage form, the pharmacokinetics of the drug, the severity of the disease, and the individual characteristics of the subject (gender, weight, height, age, etc.). In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. In order to better understand the present invention, the definitions of some terms are provided below. If the definitions and interpretations of terms provided in the present invention are not consistent with the meanings that are commonly understood by those skilled in the art, the definitions and interpretations of terms provided in the present invention shall prevail.

[0086] "Halogen" according to the present invention means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0087] "C" described in the present invention 1-6 "Alkyl" means an alkyl containing 1-6 carbon atoms in a straight or branched chain, e.g., "C 1-4 Alkyl," "C 1-3 Alkyl," "C 1-2 Alkyl," "C 2-6 Alkyl," "C 2-5 Alkyl," "C 2-4 Alkyl," "C2-3 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. 1-4 "Alkyl" means C 1-6 It refers to specific examples of alkyl containing 1-4 carbon atoms.

[0088] "C" described in the present invention 1-6 "Alkoxy" means "C 1-6 alkyl-O-" and the above "C 1-6 The term "alkyl" has the same meaning as above. 1-4 "Alkoxy" means "C 1-4 alkyl-O-" and the above "C 1-4 The term "alkyl" has the same meaning as above.

[0089] "C" according to the present invention 1-6 Alkylthio is a compound of C 1-6 alkyl-S-" and the above "C 1-6 The term "alkyl" has the same meaning as above. 1-4 Alkylthio is a compound of C 1-4 alkyl-S-" and the above "C 1-4 The term "alkyl" has the same meaning as above.

[0090] The "hydroxy C" according to the present invention 1-6 Alkyl, Amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, Cyano C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 "Alkyl" means C 1-6One or more hydrogens in the alkyl are each replaced by one or more hydroxyl, amino, halogen, cyano or C 1-6 It refers to those substituted by alkoxy. C 1-6 Alkyl, C 1-6 The alkoxy has the same meaning as above.

[0091] The "hydroxy C" according to the present invention 1-6 Alkoxy, Amino C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, Cyano C 1-6 "Alkoxy" means "C 1-6 "Alkoxy" refers to an alkoxy in which one or more hydrogen atoms are replaced by one or more hydroxyl, amino, halogen, or cyano.

[0092] The "hydroxy C" according to the present invention 1-6 Alkylthio, Amino C 1-6 Alkylthio, halogenated C 1-6 Alkylthio is a compound of C 1-6 "Alkylthio" refers to a group in which one or more hydrogen atoms are replaced by one or more hydroxyl, amino or halogen atoms.

[0093] The "fluorinated C" described in the present invention 1-6 Alkyl, Fluorinated C 1-6 "Alkoxy" means "C 1-6 Alkyl," "C 1-6 "Alkoxy" refers to an alkoxy in which one or more hydrogen atoms have been replaced by one or more fluorine atoms.

[0094] According to the present invention, "3- to 11-membered heterocyclyl" refers to a saturated or partially saturated, non-aromatic monocyclic or polycyclic ring group containing at least one heteroatom or group (e.g., 1, 2, 3, 4, or 5) and having 3 to 11 ring atoms. The heteroatom or group is selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure may be replaced with oxygen. "3- to 11-membered heterocyclyl" includes, but is not limited to, "3- to 10-membered heterocyclyl," "3- to 8-membered monoheterocyclyl," "8- to 11-membered fused heterocyclic group," "8- to 11-membered spiro heterocyclic group," and "7- to 9-membered bridged heterocyclic group."

[0095] According to the present invention, a "3-8-membered monoheterocyclyl" refers to a saturated or partially saturated, non-aromatic monocyclic ring group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5 atoms) and having 3-8 ring atoms. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure may be replaced with oxygen. According to the present invention, a "3-8-membered monoheterocyclyl" includes a "3-8-membered saturated monoheterocyclyl" and a "3-8-membered partially saturated monoheterocyclyl." Preferably, a "3-8-membered monoheterocyclyl" according to the present invention contains 1-3 heteroatoms. Preferably, a "3-8-membered monoheterocyclyl" according to the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from a nitrogen atom and / or an oxygen atom. Preferably, the "3-8 membered monoheterocyclyl" according to the present invention contains one heteroatom, said heteroatom being a nitrogen atom, an oxygen atom and / or a sulfur atom. The "3-8 membered monoheterocyclyl" is preferably "3-7 membered monoheterocyclyl", "3-6 membered monoheterocyclyl", "4-7 membered monoheterocyclyl", "4-6 membered monoheterocyclyl", "6-8 membered monoheterocyclyl", "5-7 membered monoheterocyclyl", "5-7 membered saturated monoheterocyclyl", "5-7 membered partially saturated monoheterocyclyl", "5-6 membered monoheterocyclyl", "5-6 membered saturated monoheterocyclyl", "5-6 membered partially saturated monoheterocyclyl", "3-6 membered saturated monoheterocyclyl", "5-6 membered saturated monoheterocyclyl", "3-6 membered nitrogen-containing monoheterocyclyl", "3-6 membered saturated nitrogen-containing monoheterocyclyl", "5-6 membered nitrogen-containing monoheterocyclyl", "5-6 membered saturated nitrogen-containing monoheterocyclyl", "5-6 membered saturated nitrogen-containing monoheterocyclyl", "5-6 membered partially saturated nitrogen-containing monoheterocyclyl", "6-membered saturated monoheterocyclyl", "6-membered saturated nitrogen-containing monoheterocyclyl" and the like.Specific examples of "3- to 8-membered monoheterocyclyl" include aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, oxetanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxacyclopentanyl, 1,4-dioxycyclohexadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydropyrazolyl, and 2,5-dihydropyrazolyl. Including, but not limited to, hydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridonyl, dihydropiperidonyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, and the like.

[0096] The term "8- to 11-membered fused heterocyclic group" as used herein refers to a saturated or partially saturated non-aromatic cyclic group having 8 to 11 ring atoms formed by two or more ring structures sharing two adjacent atoms, and at least one ring atom being a heteroatom. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Here, ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be optionally substituted with oxygen. Specific examples include dihydrofuranopyridine, 3,4-dihydro-2H-pyranopyridine, 3,4-dihydro-2H-oxazinopyridine, dihydrooxazinopyrimidine, benzodihydrofuranyl, This includes, but is not limited to, JPEG2025535834000058.jpg26170.

[0097] The term "8-11-membered spiro heterocyclic group" as used herein refers to a saturated or partially saturated ring structure having 8-11 ring atoms formed by two or more ring structures sharing one ring atom with each other. At least one ring atom is a heteroatom or group, such as N, NH, O, S, CO, SO, SO2, etc., and the number of heteroatoms or groups is preferably 1, 2, 3, 4, or 5, more preferably 1 or 2. Examples include "9-11-membered spiro heterocyclic group," "9-11-membered saturated spiro heterocyclic group," and "9-11-membered partially saturated spiro heterocyclic group." Specific examples include: Including but not limited to JPEG2025535834000059.jpg28170.

[0098] The term "7-9-membered bridged heterocyclic group" as used herein refers to a saturated or partially saturated ring structure containing 7-9 ring atoms formed by two or more ring structures sharing two ring atoms that are not adjacent to each other. Here, at least one ring atom is a heteroatom or group, such as N, NH, O, S, CO, SO, or SO2. Preferably, the number of heteroatoms or groups is 1, 2, 3, 4, or 5, more preferably 1 or 2. Examples include "7-8-membered bridged heterocyclic group," "7-8-membered saturated bridged heterocyclic group," "8-membered bridged heterocyclic group," and "8-membered saturated bridged heterocyclic group." Specific examples include: Including but not limited to JPEG2025535834000060.jpg21170.

[0099] The "3-11 membered cycloalkyl" according to the present invention refers to a saturated or partially saturated, aromatic monocyclic or polycyclic ring group containing 3-11 ring atoms. The "3-11 membered cycloalkyl" according to the present invention includes, but is not limited to, "3-10 membered cycloalkyl", "3-8 membered monocyclic cycloalkyl", "5-7 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl", "8-11 membered fused alkyl", "8-11 membered spirocyclic group", and "7-9 membered bridged cyclic group". The "3-8 membered monocyclic cycloalkyl" includes cyclopentyl, cyclohexyl, Including but not limited to JPEG2025535834000061.jpg18170.

[0100] The term "8-11-membered spirocyclic group" as used herein refers to a saturated or partially saturated ring structure having 8-11 ring carbon atoms formed by one or more ring structures sharing one ring atom with each other. Examples include "9-11-membered spirocyclic group", "9-11-membered saturated spiroheterocyclic group", and "9-11-membered partially saturated spiroheterocyclic group". Specific examples include: Including, but not limited to, JPEG2025535834000062.jpg27170.

[0101] The term "7- to 9-membered bridged cyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 7 to 9 ring carbon atoms formed by two or more cyclic structures sharing two ring atoms that are not adjacent to each other, and includes, for example, "7- to 8-membered bridged cyclic group", "7- to 8-membered saturated bridged cyclic group", "8-membered bridged heterocyclic group", "8-membered saturated bridged cyclic group", "8-membered partially saturated bridged cyclic group", etc. Specific examples include: Including, but not limited to, JPEG2025535834000063.jpg21170. The term "8-11-membered fused alkyl" as used herein refers to a saturated or partially saturated non-aromatic cyclic group containing 8-11 ring carbon atoms formed by two or more ring structures sharing two adjacent atoms. One ring in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity. Examples thereof include: JPEG2025535834000064.jpg20170 and the like. The term "8- to 11-membered fused cyclic group" is synonymous with the term "8- to 11-membered fused alkyl."

[0102] The "6- to 11-membered aryl" according to the present invention includes "6- to 8-membered monocyclic aryl" and "8- to 11-membered fused ring aryl".

[0103] The "6-8 membered monocyclic aryl" according to the present invention refers to a monocyclic aryl containing 6-8 ring carbon atoms, examples of which include, but are not limited to, phenyl, cyclooctatetraenyl, etc., preferably phenyl.

[0104] The "5-11 membered heteroaryl" according to the present invention includes "5-8 membered monocyclic heteroaryl" and "8-11 membered fused heteroaryl".

[0105] The term "5-8-membered monocyclic heteroaryl" as used herein refers to a monocyclic ring group containing 5-8 ring atoms (at least one ring atom is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom) and having aromaticity. Optionally, a ring atom (e.g., a carbon atom, nitrogen atom, or sulfur atom) in the ring structure may be replaced with oxygen. The term "5-8-membered monocyclic heteroaryl" includes, for example, "5-7-membered monocyclic heteroaryl," "5-6-membered monocyclic heteroaryl," "5-6-membered nitrogen-containing monocyclic heteroaryl," "6-membered nitrogen-containing monocyclic heteroaryl," etc. The heteroatom in the "nitrogen-containing heteroaryl" includes at least one nitrogen atom, for example, only one or two nitrogen atoms, or one nitrogen atom and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom), or two nitrogen atoms and one or two other heteroatoms (e.g., oxygen atom and / or sulfur atom). Illustrative examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The term "5-6 membered monocyclic heteroaryl" refers to a specific example of a 5-8 membered heteroaryl containing 5-6 ring atoms.

[0106] The term "8-10-membered fused heteroaryl" as used herein refers to an unsaturated, aromatic ring structure containing 8-10 ring atoms (at least one ring atom is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom) formed by two or more ring structures sharing two adjacent atoms. Optionally, a ring atom (e.g., a carbon atom, nitrogen atom, or sulfur atom) in the ring structure may be substituted with oxygen. It includes "9-10-membered fused heteroaryl," "8-9-membered fused heteroaryl," and the like. The fusion method may be a benzo 5-6-membered heteroaryl, or a fusion of a 5-6-membered heteroaryl with a 5-6-membered heteroaryl, etc. Specific examples include, but are not limited to, pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanthiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.

[0107] The term "oxygen substitution" as used herein means that when the substituted position is a carbon atom, a nitrogen atom, or a sulfur atom, the carbon atom, the nitrogen atom, or the sulfur atom may be substituted with oxygen to form a C=O, N=O, S=O, or SO2 structure.

[0108] "Optionally substituted" as used herein refers to two cases: one or more hydrogen atoms on the substituted group are "substituted" with one or more substituents, or "not substituted."

[0109] The full English name of "DSB" used in the present invention is double-strand breaks, which refers to DNA double-strand breaks.

[0110] "HR" as used herein refers to Homologous Recombination.

[0111] "CH" as used herein refers to the following structure: JPEG2025535834000065.jpg16170

[0112] "N" as used herein refers to the following structure: JPEG2025535834000066.jpg16170

[0113] "C" according to the present invention refers to the following structure: JPEG2025535834000067.jpg16170

[0114] The "-(CH)" described in the present invention p -P(O)(R a )(R b )" means, JPEG2025535834000068.jpg19170. Other similar groups in the present invention include "-(CH2) p -P(O)(R a )(R b )" is synonymous with "

[0115] "Each R" described in the present invention 1 ", when m is 2, 3 or 4, multiple R 1 Each R in 1 are independently selected from the groups described in any of the technical means mentioned above.

[0116] "Each R" described in the present invention 2 ", when n is 2, 3 or 4, multiple R 2 Each R in 2 are independently selected from the groups described in any of the technical means mentioned above.

[0117] "Optionally substituted" as used herein refers to two cases: one or more hydrogen atoms on the substituted group are "substituted" with one or more substituents, or "not substituted."

[0118] Ring A contains NH, for example: JPEG2025535834000069.jpg19170, then H in NH on that ring is R 1 may be substituted with

[0119] When ring B is selected from a nitrogen-containing heterocycle or heteroaryl and contains NH, the H at NH on the ring is R 2 may be substituted with

[0120] The "pharmaceutically acceptable salt" according to the present invention is a salt formed from an acidic functional group present in the compound (e.g., -COOH, -OH, -SOH, etc.) and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases, and a salt formed from a basic functional group present in the compound (e.g., -NH, etc.) and a suitable inorganic or organic anion (acid), including salts formed with inorganic acids or organic acids (e.g., carboxylic acids, etc.).

[0121] The "stereoisomers" described in this invention can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers because the compounds of this invention contain one or more asymmetric centers. The compounds of this invention may have asymmetric centers, and each of these asymmetric centers independently generates two optical isomers. The scope of this invention includes all possible optical isomers and their mixtures.

[0122] When a compound described in this invention contains an olefinic double bond, it includes both cis and trans isomers unless otherwise specified. The compound described in this invention may exist in the form of a tautomer (a type of functional isomer) that has one or more double bond shifts, resulting in different hydrogen attachment points; for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are within the scope of this invention.

[0123] All stereoisomers, cis-trans isomers, tautomers, geometric isomers, diastereomers and mixtures thereof of these compounds are within the scope of the present invention.

[0124] The compounds of the present invention can be obtained as individual enantiomers by enantiomer-specific synthesis or by resolution from an enantiomeric mixture. Typical resolution techniques involve separating a mixture of enantiomers of either the starting material or the final product using a variety of known chromatographic methods.

[0125] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to other stereoisomers. When a single isomer is named or drawn by structure, the drawn or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity by weight is the ratio of the weight of the enantiomer to the weight of the enantiomer plus its optical isomer. [Effects of the Invention]

[0126] 1. The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has excellent PARP1 inhibitory activity, can effectively suppress the growth of tumor cells, and has good pharmacokinetic properties in living organisms (e.g., mice, rats, dogs, etc.), long-lasting effect, and high bioavailability. 2. The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has good therapeutic effect on cancer and high stability in liver microsomes. 3. The compound of the present invention has a simple preparation process, high chemical purity, stable quality, and is easy to be produced in large scale industrial production. DETAILED DESCRIPTION OF THE INVENTION

[0127] The technical solutions of the present invention will be described below with reference to specific embodiments, and the above content of the present invention will be explained in more detail, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention. Abbreviation NBS: N-bromosuccinimide; TBSCl: tert-butyldimethylchlorosilicon; TBAF: tetrabutylammonium fluoride; Prep-TLC: preparative thin-layer chromatography; Xphos Pdg2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); DIPEA: N,N-diisopropylethylamine; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DBU: 1,8-diazabicyclo[5.4.0]undecane-7-ene; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; TfO: trifluoromethanesulfonic anhydride; select F: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate); LDA: lithium diisopropylamide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; RuPhosPdG3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; DAST: diethylaminosulfur trifluoride; T3P: 1-propylphosphonic anhydride; DIAD: diisopropyl azodicarboxylate.

[0128] Example 1 Preparation of 6-fluoro-5-(4-((9-fluoro-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 1) JPEG2025535834000070.jpg56170JPEG2025535834000071.jpg54170

[0129] Preparation of methyl 1,4-amino-5-bromo-2-fluorobenzoate Methyl 4-amino-2-fluorobenzoate (20.0 g, 118.3 mmol) was dissolved in acetonitrile (300 mL), NBS (19.0 g, 106.5 mmol) was added at 0 °C, and the mixture was allowed to react at 0 °C for 1 hour. The mixture was then transferred to 25 °C and allowed to react for 8 hours until the reaction was complete. The mixture was then dried over a rotary evaporator and purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain the product (21.0 g, yield: 71.9%).

[0130] Preparation of methyl 2,4-amino-5-bromo-2-fluoro-3-nitrobenzoate Methyl 4-amino-5-bromo-2-fluorobenzoate (21.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (300 mL), and potassium nitrate (9.5 g, 93.5 mmol) was slowly added at 0°C. The reaction was continued for 0.5 hours. After the reaction was completed, the reaction solution was poured into ice water to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain the target compound (24.0 g, yield: 96.4%).

[0131] 3. Preparation of methyl (E)-4-amino-5-(2-ethoxyvinyl)-2-fluoro-3-nitrobenzoate Methyl 4-amino-5-bromo-2-fluoro-3-nitrobenzoate (12.0 g, 41.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9.7 g, 49.2 mmol) were dissolved in dioxane (200 mL) and water (40 mL). Sodium carbonate (13.0 g, 123.0 mmol) and Pd(dppf)Cl (3.0 g, 4.1 mmol) were added and the mixture was reacted at 100 °C for 6 h under nitrogen protection. After completion of the reaction, the mixture was extracted with water (200 mL) and ethyl acetate (200 mL x 2). The organic phase was collected and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to give the product (6.0 g, 51.3% yield).

[0132] Preparation of methyl 4,6-fluoro-7-nitro-1H-indole-5-carboxylate Methyl (E)-4-amino-5-(2-ethoxyvinyl)-2-fluoro-3-nitrobenzoate (6.0 g, 21.0 mmol) was dissolved in glacial acetic acid (70 mL) and reacted at 125°C for 0.5 hours. After the reaction was completed, the mixture was concentrated, and the crude ethyl acetate was triturated to obtain the product (3.6 g, yield 71.3%).

[0133] Preparation of methyl 5,7-amino-6-fluoro-1H-indole-5-carboxylate Methyl 6-fluoro-7-nitro-1H-indole-5-carboxylate (3.6 g, 15.1 mmol) was dissolved in methanol (20 mL), Pd / C (550 mg, N / A) was added, and the mixture was purged with hydrogen gas three times. The mixture was reacted under hydrogen gas at 25°C for 3 hours. After the reaction was completed, the product was filtered to obtain the product (3.0 g, yield 95.1%).

[0134] 6. Preparation of (7-amino-6-fluoro-1H-indol-5-yl)methanol Methyl 7-amino-6-fluoro-1H-indole-5-carboxylate (700 mg, 3.3 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium aluminum hydride (380 mg, 10.0 mmol) was added at 0 ° C. The reaction was allowed to proceed for 1 h at 70 ° C. After completion of the reaction, the reaction was quenched with water, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give the product (400 mg, yield 67.3%).

[0135] Preparation of 7,5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-amine (7-Amino-6-fluoro-1H-indol-5-yl)methanol (350 mg, 1.9 mmol) was dissolved in dichloromethane (20 mL), and imidazole (258 mg, 3.8 mmol) and TBSCl (437 mg, 2.9 mmol) were added. The reaction was carried out at 25 °C for 1 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain the target compound (400 mg, yield: 71.5%).

[0136] 8. Preparation of N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-2-chloroacetamide 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-amine (350 mg, 1.2 mmol) was dissolved in dichloromethane (8 mL), pyridine (142 mg, 1.8 mmol) and chloroacetyl chloride (203 mg, 1.8 mmol) were added at 0 ° C., and the reaction was carried out at 25 ° C. for 1 hour to complete the reaction. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain the product (300 mg, yield 67.4%).

[0137] Preparation of 9,8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-2-chloroacetamide (250 mg, 0.67 mmol) was dissolved in DMF (5 mL) and NaH (60%) (80 mg, 2.0 mmol) was added. The reaction was allowed to proceed at 25°C for 0.5 h. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give the product (100 mg, yield 44.5%).

[0138] Preparation of 10,9-fluoro-8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-(((tert-Butyldimethylsilyl)oxy)methyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (80 mg, 0.24 mmol) was dissolved in tetrahydrofuran (3 mL) and TBAF (0.50 mL) was added. The reaction was allowed to proceed at 25°C for 1 h. After completion of the reaction, the mixture was concentrated, washed with water, and filtered to give the product (40 mg, yield 75.4%).

[0139] Preparation of 11,8-(bromomethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 9-Fluoro-8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (20 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and triphenylphosphine (37 mg, 0.14 mmol) and carbon tetrabromide (46 mg, 0.14 mmol) were added at 0° C. The reaction was carried out at 0° C. for 6 hours. After completion of the reaction, the mixture was concentrated and used directly in the next step.

[0140] Preparation of 12,6-fluoro-5-(4-((9-fluoro-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (39 mg, 0.14 mmol) and 8-(bromomethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) were dissolved in acetonitrile (4 mL) and N,N-diisopropylethylamine (36 mg, 0.28 mmol) was added. The reaction was allowed to proceed at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated and purified by TLC (methanol / dichloromethane = 1 / 10) to give the product (5.8 mg, two-step yield: 14.6%).

[0141] Molecular formula:C 22 H 22F2N6O2 molecular weight: 440.2 LC-MS (M / e): 441.2 (M+H + ) 1 H-NMR(400MHz,DMSO-d6)δ:11.08(s,1H),8.41-8.39(m,1H),7.83(d,1H,J=7.64),7.31-7.30(m,1H),7.29(s,1H),7.1 0-7.09(m,1H),6.46-6.45(m,1H),4.99(s,2H),3.61(s,2H),3.17-3.14(m,4H),2.77-2.75(m,3H),2.50-2.47(s,4H).

[0142] Example 2 Preparation of 6-fluoro-5-(4-(9-fluoro-3-methyl-2-oxy-2,3-dihydro-1h-pyrrole[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-n-methylpyridineamide (Compound 3) JPEG2025535834000072.jpg55170

[0143] Preparation of 1,2-bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)propionamide 5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-amine (500 mg, 1.7 mmol) was dissolved in ethyl acetate (50 mL), pyridine (500 mg, 6.3 mmol) and 2-bromopropionic acid (550 mg, 3.6 mmol) were added, and 1-propylphosphoric anhydride (wt 50%, 3.3 g, 5.2 mmol) was added at -50 °C. The reaction was allowed to proceed for 2 hours, and water was added to quench the reaction. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to give the product (300 mg, yield 41.2%).

[0144] Preparation of 2,8-((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-3-methyl-1h-pyrrole[1,2,3-de]quinoxalin-2(3H)-1one 2-Bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)propionamide (250 mg, 0.58 mmol) was dissolved in DMF (5 mL), and NaH (60%) (50 mg, 1.3 mmol) was added. The reaction was allowed to proceed at 25°C for 0.5 h. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic phase was collected and concentrated, and the crude product was used directly in the next reaction.

[0145] Preparation of 3,9-fluoro-8-(hydroxymethyl)-3-methyl-1h-pyrrole[1,2,3-de]quinoxalin-2(3H)-one The crude product from the previous step was dissolved in tetrahydrofuran (10 mL) and TBAF (5 mL) was added. The reaction was allowed to proceed at 25°C for 1 h. After the reaction was complete, the mixture was concentrated, washed with water, and purified by column chromatography (EA:PE = 100%) to give the product (100 mg, 73.3% yield for the two steps).

[0146] Preparation of 4,8-(chloromethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 9-Fluoro-8-(hydroxymethyl)-3-methyl-1h-pyrrole[1,2,3-de]quinoxalin-2(3H)-one (80 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), and sulfonyl chloride (450 mg, 3.8 mmol) and DMF (0.1 mL) were added at 0 ° C. The reaction was allowed to proceed at 30 ° C. for 1 h. After completion of the reaction, the mixture was concentrated and used directly in the next step.

[0147] Preparation of 5,6-fluoro-5-(4-(9-fluoro-3-methyl-2-oxy-2,3-dihydro-1h-pyrrole[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-n-methylpyridineamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (200 mg, 0.73 mmol) and 8-(chloromethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) were dissolved in acetonitrile (10 mL) and N,N-diisopropylethylamine (250 mg, 1.9 mmol) was added. The reaction mixture was allowed to react at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated and purified by TLC (methanol:dichloromethane = 10%) and reverse-phase column chromatography (MeOH:HO = 70%) to give the product (7 mg, 4.7% yield for two steps).

[0148] Molecular formula:C 23 H 24 F2N6O2 molecular weight: 454.5 LC-MS(M / e): 455.3(M+H + ) 1 H-NMR(400MHz,DMSO-d6)δ:8.09(s,1H),7.99(d,J=7.88Hz,1H),7.50(d,J=4.68Hz,1H),7.28-7.32(m,1H),7.14-7.19(m,2H),6.54( d,J=2.88Hz,1H),5.13-5.18(m,1H),3.71-3.77(m,2H),3.22-3.26(m,4H),3.00-3.05(m,3H),2.65-2.72(s,4H),1.85-1.87(m,3H).

[0149] Example 3 Preparation of 6-fluoro-N-methyl-5-(4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridineamide (Compound 8) JPEG2025535834000073.jpg76170

[0150] Preparation of methyl 1,2-(5-bromo-7-nitro-1H-indazol-1-yl)acetate 5-Bromo-7-nitro-1H-indazole (3.0 g, 12.4 mmol) and methyl bromoacetate (2.3 g, 15.0 mmol) were dissolved in acetonitrile (100 mL), potassium carbonate (5.1 g, 36.9 mmol) was added, and the mixture was heated at 50° C. for 3 hours. The solid was removed by filtration, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1) to give the product (800 mg, yield 20.5%).

[0151] Preparation of methyl 2,2-(7-amino-5-bromo-1H-indazol-1-yl)acetate Methyl 2-(5-bromo-7-nitro-1H-indazol-1-yl)acetate (800 mg, 2.5 mmol) was dissolved in methanol / water (20 mL / 2 mL), and zinc powder (1.3 g, 19.9 mmol) and ammonium chloride (1.1 g, 20.6 mmol) were added, followed by a reaction at 50° C. for 3 h. The solid was removed by filtration, concentrated, extracted with water (50 mL) and ethyl acetate (50 mL), dried, and concentrated to give the crude product (500 mg).

[0152] Preparation of 3,8-bromo-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one Methyl 2-(7-amino-5-bromo-1H-indazol-1-yl)acetate (500 mg, crude product) was dissolved in methanol (10 mL) and a 4 M solution of hydrogen chloride in ethyl acetate (2 mL) was added. The reaction was allowed to proceed at 25 °C for 1 h. The mixture was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with water (20 mL) and ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to give the product (300 mg, 46.7% yield over two steps).

[0153] Preparation of tert-butyl 4,4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazine-1-formate 8-Bromo-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (350 mg, 1.4 mmol) and potassium (4-tert-butyloxycarbonylpiperazin-1-yl)methyltrifluoroborate (560 mg, 1.8 mmol) were dissolved in 1,4-dioxane / water (15 mL / 2.5 mL), XPhos Pdg2 (112 mg, 0.14 mmol) and cesium carbonate (910 mg, 2.8 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was carried out at 80 °C for 2 hours under nitrogen gas. The crude product was concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to give the product (270 mg, yield: 52.4%).

[0154] Preparation of 5,8-(piperazin-1-ylmethyl)-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one tert-Butyl 4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazine-1-formate (270 mg, 0.73 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in ethyl acetate (1 mL) was added. The reaction was allowed to proceed at 25 °C for 1 h. The mixture was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with water (20 mL) and ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 12:1) to give the product (50 mg, 25.4% yield).

[0155] Preparation of methyl 6,6-fluoro-5-(4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)picolinate 8-(Piperazin-1-ylmethyl)-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (50 mg, 0.18 mmol) and methyl 5-bromo-6-fluoropicolinate (65 mg, 0.28 mmol) were dissolved in 1,4-dioxane (5 mL), and RuPhos Pdg3 (10 mg, 0.026 mmol) and cesium carbonate (179 mg, 0.55 mmol) were added. The mixture was purged with nitrogen gas and microwave-stimulated at 140 °C for 1 hour under nitrogen. The crude product was concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (15 mg, 19.2% yield).

[0156] Preparation of 7,6-fluoro-N-methyl-5-(4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridineamide Methyl 6-fluoro-5-(4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)picolinate (15 mg, 0.035 mmol) was dissolved in acetonitrile (3 mL) and methylamine solution (0.5 mL) was added. The reaction was carried out at 25 °C for 3 h. After the reaction was completed, the mixture was concentrated and purified by prep-TLC (dichloromethane:methanol = 12:1) to obtain the crude product (5 mg). This was then purified by prep-HPLC (water:methanol = 1:8) to obtain the product (3.5 mg, yield 23.4%).

[0157] Molecular formula:C 21 H 22 FN7O2 molecular weight: 423.5 LC-MS (M / e): 424.2 (M+H + ) 1H-NMR(400MHz,DMSO-d6)δ:11.07(s,1H),8.40(s,1H),8.01(s,1H),7.83(d,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7. 20(s,1H),6.74(s,1H),5.19(s,2H),3.60-3.40(m,2H),3.20-3.15(m,4H),2.76(d,J=4.8Hz,3H),2.60-2.40(m,4H)

[0158] Example 4 Preparation of 6-fluoro-N-methyl-5-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridineamide (Compound 11) JPEG2025535834000074.jpg102170

[0159] Preparation of 1,1-(5-bromoindol-1-yl)ethan-1-one 5-Bromoindoline (3.9 g, 19.8 mmol) was dissolved in acetic acid (20 mL), cooled to 0 °C, and acetic anhydride (20 mL) was slowly added. The reaction was continued at 25 °C for 1 hour until completion. The product was concentrated to give the product (4.0 g), which was used directly in the next step.

[0160] Preparation of 2,1-(5-bromo-7-nitroindol-1-yl)ethan-1-one 1-(5-Bromoindol-1-yl)ethan-1-one (3.7 g, crude product) was dissolved in concentrated sulfuric acid (50 mL), potassium nitrate (1.9 g, 18.5 mmol) was added at 0 °C, and the mixture was reacted at 0 °C for 1 hour. Cold water was added to precipitate a solid, which was filtered and dried to give the crude product (3.6 g), which was used directly in the next step.

[0161] Preparation of 3,5-bromo-7-nitroindoline 1-(5-Bromo-7-nitroindol-1-yl)ethan-1-one (3.4 g, 11.9 mmol) and sodium hydroxide (4.8 g, 119 mmol) were dissolved in THF (40 mL), MeOH (8 mL) was added, and the reaction was carried out at 25 °C for 4 h. After the reaction was completed, the mixture was concentrated, and the residue was washed with water, filtered, and dried to obtain the product (2.9 g). It was used directly in the next step.

[0162] Preparation of 4,5-bromo-7-nitro-1H-indole 5-Bromo-7-nitroindoline (2.9 g, crude product) was dissolved in DCM (50 mL), manganese dioxide (9.5 g, 106.6 mmol) was added, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=5:1) to obtain the product (2.4 g).

[0163] Preparation of 5,2-(5-bromo-7-nitro-1H-indol-1-yl)ethyl acetate 5-Bromo-7-nitro-1H-indole (2.1 g, 8.7 mmol) was dissolved in acetonitrile (40 mL), potassium carbonate (1.8 g, 13.0 mmol), and ethyl bromoacetate (2.2 g, 13.2 mmol) were added, and the mixture was reacted at 50 °C for 2 h. After the reaction was completed, the mixture was extracted with water (30 mL) and ethyl acetate (40 mL x 2). The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-70%) to obtain the product (2.4 g, yield 84.1%).

[0164] Preparation of 6,8-bromo-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one Ethyl 2-(5-bromo-7-nitro-1H-indol-1-yl)acetate (2.2 g, 6.7 mmol) and zinc powder (4.3 g, 66.1 mmol) were added to methanol (30 mL), and water (3 mL) and ammonium chloride (3.7 g, 66.0 mmol) were added. The mixture was reacted at 50 °C for 1 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give the product (260 mg, 15.4% yield).

[0165] Preparation of 7,8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-Bromo-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (230 mg, 0.92 mmol) was dissolved in dioxane (10 mL), and Ruphos Pdg 2 (79 mg, 0.085 mmol) and hydroxymethyltri-n-butyltin (518 mg, 1.6 mmol) were added. The mixture was reacted at 75 °C for 3 h under nitrogen gas protection. After the reaction was completed, the mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to give the product (90 mg, yield 48.4%).

[0166] Preparation of 8,8-(bromomethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-(Hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (70 mg, 0.35 mmol), triphenylphosphine (136 mg, 0.52 mmol), and carbon tetrabromide (172 mg, 0.52 mmol) were dissolved in DCM (10 mL) and reacted at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated at 25°C, and the crude product was used directly in the next step.

[0167] Preparation of 9,6-fluoro-N-methyl-5-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridineamide 8-(Bromomethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) was dissolved in acetonitrile (5 mL) and DIPEA (4M) (90 mg, 0.70 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide (83 mg, 0.35 mmol) were added. The reaction was allowed to proceed at 25 °C for 2 h. After completion of the reaction was confirmed by LCMS, the mixture was concentrated. The organic phase was concentrated and purified on a silica gel plate (SiO, dichloromethane:methanol = 20:1) to give the desired compound (12 mg, 14.6% yield).

[0168] Molecular formula:C 22 H 23 FN6O2 molecular weight: 422.25 LC-MS(M / e): 423.2(M+H + ) 1 H-NMR(400MHz,DMSO-d6)δ:10.79(s,1H),8.41(s,1H),7.85(m,1H),7.58-7.56(m,1H),7.29(s,1H), 7.05(s,1H),6.57(s,1H),6.44-6.43(m,1H),5.33(s,2H),3.46(s,2H),3.29-3.15(m,4H),2.77(s,3 H),2.57-2.47(m,4H)

[0169] Example 5 Preparation of 6-fluoro-5-(4-((10-fluoro-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepine[3,2,1-hi]indol-9-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 15) JPEG2025535834000075.jpg61170

[0170] 1. Preparation of N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-3-chloropropanamide 5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-amine (350 mg, 1.2 mmol) was dissolved in dichloromethane (20 mL), the temperature was lowered to 0°C, 3-chloropropanyl chloride (226 mg, 1.8 mmol) was added, and the reaction was carried out at 0°C for 30 minutes. Completion of the reaction was confirmed by LCMS. Saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (30 mL), dried, and concentrated to obtain the product (crude product, 400 mg).

[0171] Preparation of 2,9-(((tert-butyldimethylsilyl)oxy)methyl)-10-fluoro-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-3-chloropropanamide (400 mg, crude product from the previous step) was dissolved in DMF (10 mL), cooled to 0 °C, and sodium hydride (60%) (125 mg, 5.2 mmol) was added. The mixture was allowed to react at 25 °C for 20 minutes. Water was added to quench the reaction, and water (30 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the organic phase was washed with water (30 mL) and concentrated to give the crude product (400 mg). Purification by silica gel column chromatography (n-heptane:ethyl acetate = 6:1) gave the product (200 mg, two-step yield 48.3%).

[0172] Preparation of 3,10-fluoro-9-(hydroxymethyl)-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one 9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-fluoro-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one (200 mg, 0.57 mmol) was dissolved in tetrahydrofuran (20 mL) and TBAF (1.4 mL, 1.4 mmol) was added. The reaction was allowed to proceed at 25°C for 2 h. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:2) to obtain the product (120 mg, yield 89.3%).

[0173] Preparation of 4,9-(chloromethyl)-10-fluoro-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one 10-Fluoro-9-(hydroxymethyl)-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one (60 mg, 0.26 mmol) and N,N-dimethylformamide (6 mg, 0.082 mmol) were dissolved in dichloromethane (7 mL), cooled to -5 °C, and sulfonyl chloride (60 mg, 0.50 mmol) was added. The mixture was allowed to react at -5 °C for 20 minutes. LCMS confirmed the completion of the reaction. The mixture was concentrated, and the crude product was used directly in the next step.

[0174] Preparation of 5,6-fluoro-5-(4-((10-fluoro-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepine[3,2,1-hi]indol-9-yl)methyl)piperazin-1-yl)-N-methylpyridineamide 9-(Chloromethyl)-10-fluoro-3,4-dihydro-[1,4]diazepine[3,2,1-hi]indol-2(1H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (72 mg, 0.26 mmol) were dissolved in acetonitrile (10 mL), DIEA (170 mg, 1.3 mmol) was added, and the mixture was then reacted at 80 °C for 2 hours. LCMS confirmed the completion of the reaction. After concentration, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give the crude product (48 mg). Purification by prep-TLC (dichloromethane:methanol = 25:1) gave the product (37 mg, 31.8% yield over two steps).

[0175] Molecular formula:C 23 H 24 F2N6O2 molecular weight: 454.5 LC-MS (m / z): 455.2 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:10.71(s,1H),7.99(d,J=8.0Hz,1H),7.52(s,1H),7.39-7.20(m,3H),6.49( s,1H),4.11-4.08(m,2H),3.73(s,2H),3.25-3.20(m,6H),3.01(d,J=5.2Hz,3H),2.77-2.69(m,4H).

[0176] Example 6 Preparation of 5-(4-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Compound 24) With reference to the preparation in Example 2, the raw material 2-bromopropionic acid was changed to 2-bromobutyric acid.

[0177] Molecular formula:C 24 H 26 F2N6O2 molecular weight: 468.5 LC-MS (M / e): 469.2 (M+H + ) 1H-NMR(400MHz,DMSO-d6)δ:8.14(s,1H),7.99-77(m,1H),7.51-7.49(m,1H),7.31-7.28(m,1H),7.18(s,1H),7.11(s,1H),6.55(s,1H),5.22- 5.20(m,1H),3.75-3.71(m,2H),3.25-3.22(m,4H),3.00(s,3H),2.73- 2.71(s,4H),2.44-2.39(m,1H),2.16-2.13(m,1H),0.85(t,J=6.8,3H).

[0178] Example 7 Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,4,5,6-tetrahydro-1H-benzo[de]quinolin-8-yl)methyl)piperazin-1-yl)pyridinamide (Compound 25) JPEG2025535834000076.jpg99170

[0179] Preparation of 1,2-(diethoxyphosphoryl)propionic acid Ethyl 2-(diethoxyphosphoryl)propionate (5.0 g, 21.0 mmol) was dissolved in ethanol / water (100 mL / 20 mL), sodium hydroxide (1.7 g, 42.5 mmol) was added, and the reaction was carried out for 2 hours at 25° C. After the reaction was completed, the mixture was concentrated to remove ethanol, and the pH was adjusted to 1-2 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL), dried, and concentrated to obtain the product (4.7 g).

[0180] Preparation of 2,7-hydroxy-8-nitro-3,4-dihydronaphthalen-1(2H)-one 7-Hydroxy-3,4-dihydronaphthalen-1(2H)-one (50 g, 308.3 mmol) was dissolved in concentrated sulfuric acid (400 mL), the mixture was cooled to -5 °C, and potassium nitrate (32 g, 316.5 mmol) was added in batches. The mixture was allowed to react for 2 hours while maintaining the temperature. The reaction mixture was then poured into ice water, extracted with ethyl acetate, and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (using n-heptane and ethyl acetate as the mobile phase, with the ethyl acetate ratio ranging from 0% to 55%) to obtain the product (24.5 g, yield 38.4%).

[0181] Preparation of 3,7-hydroxy-6-iodo-8-nitro-3,4-dihydronaphthalen-1(2H)-one 7-Hydroxy-8-nitro-3,4-dihydronaphthalen-1(2H)-one (20 g, 96.5 mmol) was dissolved in acetonitrile (300 mL), and N-iodosuccinimide (21.8 g, 96.9 mmol) was added thereto. The mixture was reacted at 80°C for 24 hours. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane and ethyl acetate were used as the mobile phase, with the ethyl acetate ratio ranging from 0% to 45%) to obtain the product (12.4 g, yield 38.6%).

[0182] Preparation of ethyl 4,3-hydroxy-4-nitro-5-oxo-5,6,7,8-tetralin-2-formate 7-Hydroxy-6-iodo-8-nitro-3,4-dihydronaphthalen-1(2H)-one (6.0 g, 18.0 mmol) was dissolved in ethanol (50 mL) / N,N-dimethylformamide (100 mL), palladium acetate (410 mg, 1.8 mmol), XantPhos (1.0 g, 1.7 mmol), and triethylamine (5.5 g, 54.3 mmol) were added, and the mixture was purged with CO and reacted at 90°C for 4 hours. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (1.5 g, 29.8% yield).

[0183] Preparation of ethyl 5,4-nitro-5-oxo-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetralin-2-carboxylate 3-Hydroxy-4-nitro-5-oxo-5,6,7,8-tetralin-2-ethyl formate (500 mg, 1.8 mmol) and N,N-diisopropylethylamine (910 mg, 7.0 mmol) were dissolved in dichloromethane (20 mL), cooled to -10°C, trifluoromethanesulfonic anhydride (760 mg, 2.7 mmol) was added, and the reaction was carried out at -10°C for 1 hour. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:2) to obtain the product (500 mg, yield 67.9%).

[0184] Preparation of ethyl 6,4-amino-5-oxo-5,6,7,8-tetralin-2-formate Ethyl 4-nitro-5-oxo-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetralin-2-carboxylate (500 mg, 1.2 mmol) was dissolved in ethanol (20 mL), palladium on carbon (500 mg) was added, the mixture was purged with hydrogen gas, and the reaction was carried out under a hydrogen atmosphere at 25°C for 3 hours. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1) to obtain the product (60 mg, yield 21.2%).

[0185] Preparation of ethyl 7,4-(2-(diethoxyphosphoryl)propionamido)-5-oxo-5,6,7,8-tetralin-2-carboxylate Ethyl 4-amino-5-oxo-5,6,7,8-tetralin-2-formate (60 mg, 0.26 mmol) and 2-(diethoxyphosphoryl)propionic acid (216 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (4 mL), EDCI (210 mg, 1.1 mmol) was added, and the mixture was reacted at 25 °C for 2 hours. After the reaction was completed, water (10 mL) and ethyl acetate (15 mL × 2) were added, and the organic phase was washed with water (20 mL × 2), dried, and concentrated to give the crude product (100 mg). The crude product was used directly in the next step.

[0186] Preparation of ethyl 8,3-methyl-2-oxo-2,4,5,6-tetrahydro-1H-benzo[de]quinoline-8-carboxylate Ethyl 4-(2-(diethoxyphosphoryl)propionamido)-5-oxo-5,6,7,8-tetralin-2-carboxylate (100 mg, crude product) was dissolved in tetrahydrofuran (8 mL), DBU (140 mg, 0.92 mmol) was added, and the mixture was stirred at 25°C for 5 minutes. Lithium chloride (20 mg, 0.47 mmol) was added, and the mixture was reacted at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (33 mg, two-step yield 47.3%).

[0187] Preparation of 9,8-(hydroxymethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one Ethyl 3-methyl-2-oxo-2,4,5,6-tetrahydro-1H-benzo[de]quinoline-8-carboxylate (33 mg, 0.12 mmol) was dissolved in tetrahydrofuran (7 mL), cooled to 0° C., and lithium aluminum tetrahydride (33 mg, 0.87 mmol) was added and reacted at 0° C. for 1 hour. After completion of the reaction, water was added to quench the reaction, anhydrous sodium sulfate was added, and the mixture was stirred for 10 minutes. The mixture was filtered and concentrated, and the crude product was purified by preparative TLC (n-heptane:ethyl acetate=1:2) to obtain the product (15 mg, yield 54.1%).

[0188] Preparation of 10,8-(chloromethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one 8-(Hydroxymethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one (15 mg, 0.065 mmol) and N,N-dimethylformamide (9 mg, 0.12 mmol) were dissolved in dichloromethane (7 mL), and sulfonyl chloride (78 mg, 0.66 mmol) was added, followed by reaction at 25° C. for 16 hours. The mixture was concentrated, and the crude product was used directly in the next step.

[0189] Preparation of 11,6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,4,5,6-tetrahydro-1H-benzo[de]quinolin-8-yl)methyl)piperazin-1-yl)pyridineamide 8-(Chloromethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (27 mg, 0.098 mmol) were dissolved in acetonitrile (7 mL), DIEA (63 mg, 0.49 mmol), and potassium carbonate (33 mg, 0.24 mmol) were added, and the mixture was reacted at 85 °C for 10 h. LCMS confirmed the completion of the reaction. After concentration, the crude product was purified by preparative TLC (dichloromethane:methanol = 16:1) to give the crude product (20 mg). The product was purified by preparative TLC (two times with dichloromethane:methanol = 16:1 and ethyl acetate) to give the product (17 mg, 54.4% yield for two steps).

[0190] Molecular formula:C 25 H 28 FN5O2 molecular weight: 449.5 LC-MS (m / z): 450.2 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:10.05(s,1H),7.99(d,J=8.0Hz,1H),7.52(s,1H),7.34-7.31(m,1H),7.05(s,1H),6.99(s,1H),3.62(s,2H),3.26(t ,J=6.0Hz,4H),3.01(d,J=5.2Hz,3H),2.95(t,J=6.0Hz,2H),2.89(t,J=6.0Hz,2H),2.68(t,J=6.0Hz,4H),2.23(s,3H),2.04(t,J=5.8Hz,2H).

[0191] Example 8 Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 26) JPEG2025535834000077.jpg49170

[0192] Preparation of 1,2-bromo-N-(5-bromo-1H-indol-7-yl)propionamide 5-Bromo-1H-indol-7-amine (279 mg, 1.3 mmol) was dissolved in ethyl acetate (10 mL), pyridine (411 mg, 5.2 mmol) and 2-bromopropionic acid (367 mg, 2.4 mmol) were added, and 1-propylphosphoric anhydride (2.5 g, 50% ethyl acetate solution, 3.9 mmol) was added at -10 °C. The reaction was allowed to proceed for 0.5 h, and the reaction was quenched by the addition of water. The crude product was concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to give the product (300 mg, yield 65.6%).

[0193] Preparation of 2,8-bromo-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 2-Bromo-N-(5-bromo-1H-indol-7-yl)propionamide (300 mg, 0.9 mmol) was dissolved in DMF (5 mL) and NaH (60%) (72 mg, 1.8 mmol) was added. The mixture was allowed to react at 25 °C for 0.5 h. After the reaction was completed, the mixture was extracted with water and ethyl acetate. The organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to give the product (212 mg, 92.2%).

[0194] Preparation of 3,8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-Bromo-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (186 mg, 0.7 mmol), tri-n-butyltinmethanol (257 mg, 0.8 mmol), and Xphos Pdg2 (55 mg, 0.07 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 80 °C for 2 h. The organic phase was dried, concentrated, and purified by column chromatography (SiO, dichloromethane:methanol = 15:1) to obtain the target compound (150 mg, 91.7% yield).

[0195] Preparation of 4,8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-(Hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (150 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), and sulfonyl chloride (333 mg, 2.8 mmol) and DMF (0.1 mL) were added at 0° C. The reaction was allowed to proceed at 30° C. for 1 h. After completion of the reaction, the mixture was concentrated and used directly in the next step.

[0196] Preparation of 5,6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (383 mg, 1.6 mmol) and 8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) were dissolved in acetonitrile (10 mL) and N,N-diisopropylethylamine (724 mg, 5.6 mmol) was added. The reaction mixture was heated at 80 °C for 8 h. After completion of the reaction, the mixture was concentrated and purified by TLC (methanol:dichloromethane = 10%) and reverse-phase column chromatography (MeOH:HO = 70%) to give the product (10 mg, 3.3% yield for two steps).

[0197] Molecular formula:C 23 H 25FN6O2 molecular weight: 436.5 LC-MS (M / e): 437.3 (M+H + ) 1 H-NMR(400MHz,DMSO-d6)δ:8.18(s,1H),8.00-7.96(d,1H),7.55-7.45(s,1H),7.32-7.26(m,1H),7.23-7.19(s,1H),7.15-7.11(s,1 H),6.65(s,1H),6.55(s,1H),5.19-5.10(m,1H),3.66-3.63(m,2H),3.30-3.23(m,4H),3.00-2.99(s,3H),2.67(s,4H),1.88(d,3H).

[0198] Example 9 Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[1,2,3-de]quinoxalin-9-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 32) JPEG2025535834000078.jpg49170

[0199] Preparation of ethyl 1,2-(3,4-dihydroquinolin-1(2H)-yl)propionate 1,2,3,4-Tetrahydroquinoline (2.6 g, 19.5 mmol), ethyl 2-bromopropionate (4.2 g, 23.4 mmol), and DIEA (7.5 g, 58.5 mmol) were dissolved in DMF (50 mL). After the addition was complete, the mixture was reacted at 100°C for 16 h. The mixture was added to water and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1) to obtain the target compound (2.0 g, yield 44.0%).

[0200] Preparation of ethyl 2,2-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)propionate Ethyl 2-(3,4-dihydroquinolin-1(2H)-yl)propionate (2.0 g, 8.6 mmol) was dissolved in dichloromethane (50 mL), and DMF (6.3 g, 86.0 mmol) and phosphorus oxychloride (4.0 g, 25.8 mmol) were added at 0 °C. The reaction was then allowed to proceed at 15 °C for 2 h. Water was added to quench the reaction, and the mixture was adjusted to pH 7 with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified using a silica gel column (SiO, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.5 g, yield 67.0%).

[0201] Preparation of ethyl 3,2-(6-carbamoyl-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate Ethyl 2-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)propionate (1.5 g, 5.7 mmol) was dissolved in concentrated sulfuric acid (10 mL), and potassium nitrate (688 mg, 6.8 mmol) was added at 0° C. The mixture was then reacted for 1 h at 0° C. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated and used directly in the next step.

[0202] Preparation of ethyl 4,2-(6-(hydroxymethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate Ethyl 2-(6-carbamoyl-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (crude product from the previous step) was dissolved in methanol (30 mL), and sodium borohydride (650 mg, 17.1 mmol) was added. The mixture was then reacted at 10° C. for 2 hours. The mixture was concentrated and purified by column chromatography (SiO, petroleum ether:ethyl acetate=1:1) to give the target compound (150 mg, 8.6% yield).

[0203] Preparation of ethyl 5,2-(6-(chloromethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate Ethyl 2-(6-(hydroxymethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (150 mg, 0.49 mmol) was dissolved in dichloromethane (12 mL), and sulfonyl chloride (583 mg, 4.9 mmol) was added at 0°C. The mixture was then reacted at 0°C for 1 hour. LCMS confirmed the completion of the reaction. The mixture was concentrated and used directly in the next step.

[0204] Preparation of ethyl 6,2-(6-((4-(2-fluoro-6-(methylaminocarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate Ethyl 2-(6-(chloromethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (134 mg, 0.49 mmol) were dissolved in acetonitrile (25 mL), DIEA (194 mg, 1.5 mmol) was added, and the mixture was then reacted at 80 °C for 2 h. LCMS confirmed the completion of the reaction. The organic phase was concentrated and purified on a silica gel plate (SiO, 100% ethyl acetate) to give the desired compound (200 mg, 77.8% yield).

[0205] Preparation of 7,6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[1,2,3-de]quinoxalin-9-yl)methyl)piperazin-1-yl)pyridinecarboxamide Ethyl 2-(6-((4-(2-fluoro-6-(methylaminocarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (200 mg, 0.38 mmol) was dissolved in methanol (30 mL), palladium carbon (40 mg) was added, and the mixture was allowed to react at 25°C for 1 hour. Completion of the reaction was confirmed by LCMS. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified using a C18 column (MeCN-0-40%). The product was then purified by high-pressure liquid-phase preparative separation (MeCN-0-40%) to obtain the target compound (3.8 mg, yield 2.2%).

[0206] Molecular formula:C 24 H 29 FN6O2 molecular weight: 452.5 LC-MS (m / z): 453.1 (M+H + ) 1 H-NMR(400 MHz,MeOD)δ:7.89(d,J=7.8Hz,1H),7.49-7.53(m,1H),6.72(s,1H),6.66(s,1H),3.81-3.83(m,1H),3.46(s,2H),332-3.43(m,1H) ),3.23-3.43(m,4H),3.08-3.16(m,1H),2.92(s,3H),2.68-2.82(m,2H),2.59-2.65(m,4H),1.95-2.10(m,2H),1.19-1.26(m,3H).

[0207] Example 10 Preparation of 6-fluoro-5-(4-((9-fluoro-3,5-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 34) JPEG2025535834000079.jpg58170

[0208] Preparation of methyl 1,6-fluoro-2-methyl-7-nitro-1H-indole-5-carboxylate A solution of methyl 4-amino-5-bromo-2-fluoro-3-nitrobenzoate (3.2 g, 10.9 mmol) in toluene (20 mL) was added with tri-n-butyl(methoxy)tin (10.5 g, 32.7 mmol), isopropenyl acetate (5.5 g, 54.9 mmol), palladium acetate (245 mg, 1.1 mmol), and tri(o-tolyl)phosphine (332 mg, 1.1 mmol) and microwave-induced cleavage under nitrogen protection at 90 °C for 1 hour. Saturated potassium fluoride solution was added to the mixture, which was stirred for 30 minutes, filtered, and the solid was washed with ethyl acetate. The filtrate was extracted with ethyl acetate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:petroleum ether = 1:1) to give the product (650 mg, 23.6% yield).

[0209] Preparation of methyl 2,7-amino-6-fluoro-2-methyl-1H-indole-5-carboxylate Methyl 6-fluoro-2-methyl-7-nitro-1H-indole-5-carboxylate (800 mg, 3.2 mmol) was dissolved in methanol (50 mL), Pd / C (350 mg, N / A) was added, and the mixture was purged with hydrogen gas three times. The mixture was reacted under hydrogen gas at 25°C for 3 h. After the reaction was completed, the mixture was filtered and the solid was collected to give the crude product (600 mg).

[0210] 3. Preparation of (7-amino-6-fluoro-2-methyl-1H-indol-5-yl)methanol Methyl 7-amino-6-fluoro-2-methyl-1H-indole-5-carboxylate (600 mg, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium aluminum hydride (308 mg, 8.1 mmol) was added at 0 ° C. The reaction was allowed to proceed for 1 h at 50 ° C. After completion of the reaction, the reaction was quenched with water, anhydrous sodium sulfate was added, and the mixture was stirred and extracted with suction. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the product (280 mg, two-step yield 45.5%).

[0211] Preparation of 4,5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-amine (7-Amino-6-fluoro-2-methyl-1H-indol-5-yl)methanol (260 mg, 1.3 mmol) was dissolved in dichloromethane (20 mL), and imidazole (266 mg, 3.9 mmol) and tert-butyldimethylchlorosilane (294 mg, 2.0 mmol) were added. The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, water and dichloromethane were added to the system, and the organic phase was extracted, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain the product (370 mg, yield: 89.6%).

[0212] Preparation of 5,2-bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-yl)propionamide 5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-amine (330 mg, 1.1 mmol) was dissolved in ethyl acetate (10 mL), pyridine (331 mg, 4.2 mmol) and 2-bromopropionic acid (252 mg, 1.6 mmol) were added, and 1-propylphosphoric anhydride (wt 50%, 2.0 g, 3.1 mmol) was added at -50 °C and reacted for 2 hours. Water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:6) to obtain the product (465 mg, yield 98.3%).

[0213] Preparation of 6,8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 2-Bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-yl)propionamide (440 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), and NaH (60%) (80 mg, 2.0 mmol) was added. The reaction was allowed to proceed at 25°C for 0.5 h. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated, and the crude product was used directly in the next reaction.

[0214] Preparation of 7,9-fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) was dissolved in tetrahydrofuran (6 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5.5 mL) was added. The reaction was allowed to proceed at 25 °C for 3 h. After completion of the reaction, water was added to the system, the organic phase was extracted with ethyl acetate, concentrated, and the crude product was purified by column chromatography (EA:PE = 100%) to give the product (240 mg, 97.1% yield for two steps).

[0215] Preparation of 8,8-(chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one hydrochloride 9-Fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (50 mg, 0.20 mmol) was dissolved in acetonitrile (3 mL), and a solution of hydrogen chloride in ethyl acetate (3.0 mL) was added. The mixture was reacted at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated and used directly in the next step.

[0216] Preparation of 9,6-fluoro-5-(4-((9-fluoro-3,5-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (55 mg, 0.20 mmol) and 8-(chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one hydrochloride (crude product from the previous step) were dissolved in acetonitrile (10 mL) and N,N-diisopropylethylamine (155 mg, 1.2 mmol) was added. The reaction was allowed to proceed at 80 °C for 2 h. After the reaction was completed, water was added to the system, the organic phase was extracted with ethyl acetate, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give the product (30 mg, 31.8% yield for two steps).

[0217] Molecular formula:C 24 H 26 F2N6O2 molecular weight: 468.5 LC-MS (M / e): 469.2 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:7.99-7.96(m,1H),7.82(s,1H),7.50-7.48(m,1H),7.31-7.28(m,1H),7.10-7.05(m,1H),6.23(s,1H), 5.14-5.09(m,1H),3.76-3.70(m,2H),3.24-3.20(m,4H),3.02-2.99(m,3H),2.71-2.69(m,4H),2.43(s,3H),1.69-1.67(m,3H).

[0218] Example 11 Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 36) JPEG2025535834000080.jpg56170

[0219] 1. Preparation of (4-bromo-3-fluoro-2-nitrophenyl)-D-alanine methyl ester 1-Bromo-2,4-difluoro-3-nitrobenzene (2.5 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and (D)-alanine methyl ester hydrochloride (1.6 g, 11.5 mmol) and N,N-diisopropylethylamine (3.6 g, 27.9 mmol) were added thereto and reacted for 5 hours at 50° C. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the product (2.0 g, yield 59.3%).

[0220] 2. Preparation of (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (4-Bromo-3-fluoro-2-nitrophenyl)-D-alanine methyl ester (1.6 g, 5.0 mmol), tri-n-butyltinmethanol (1.8 g, 5.6 mmol), and Xphos Pdg2 (390 mg, 0.50 mmol) were dissolved in 1,4-dioxane (70 mL). The mixture was purged with nitrogen gas and reacted at 80°C under nitrogen for 5 hours. The crude product was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to give the product (1.1 g, 81.1% yield).

[0221] 3. Preparation of (6-bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (3-Fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (1.1 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (30 mL), N-bromosuccinimide (1.1 g, 6.2 mmol) was added, and the mixture was reacted at 25 ° C for 5 hours. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL × 2). The organic phase was washed with water (100 mL × 2), dried, and concentrated. The crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1) to obtain the product (790 mg, yield 55.7%).

[0222] 4. Preparation of (R)-5-bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (6-Bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (400 mg, 1.1 mmol) was dissolved in methanol (10 mL) / tetrahydrofuran (20 mL) / water (4 mL), and iron powder (370 mg, 6.6 mmol) and ammonium chloride (590 mg, 11.0 mmol) were added. The mixture was reacted at 70° C. for 2 hours. The solid was removed by filtration, concentrated, and extracted with water (30 mL) and ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to give the product (300 mg, yield 91.1%).

[0223] 5. Preparation of (R,E)-5-(2-ethoxyvinyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (R)-5-Bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (300 mg, 1.0 mmol) was dissolved in 1,4-dioxane (10 mL) / water (2 mL), and 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.5 mmol), Pd(dppf)Cl 2( The mixture was purged with nitrogen gas and reacted under nitrogen at 90°C for 5 hours. The mixture was concentrated and extracted with water (30 mL) and ethyl acetate (30 mL). The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to give the product (260 mg, yield 89.4%).

[0224] 6. Preparation of (R)-8-(chloromethyl)-9-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (R,E)-5-(2-ethoxyvinyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (20 mg, 0.071 mmol) was dissolved in acetonitrile (3 mL) and a 4 M solution of hydrogen chloride in ethyl acetate (0.3 mL) was added. The reaction was allowed to proceed at 25 °C for 1 h. The mixture was concentrated and the crude product was used directly in the next step.

[0225] 7. Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (R)-8-(chloromethyl)-9-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (20 mg, 0.073 mmol) was dissolved in acetonitrile (7 mL), DIEA (46 mg, 0.36 mmol) was added, and the mixture was reacted at 70 ° C for 5 hours. After concentration, the mixture was extracted with water (20 mL) and ethyl acetate (20 mL), and the crude product was purified by preparative TLC (dichloromethane:methanol = 16:1) to give the product (20 mg, 61.7% yield for two steps).

[0226] Molecular formula:C 23 H 24 F2N6O2 molecular weight: 454.5 LC-MS (m / z): 455.0 (M+H + ) 1 H-NMR(400 MHz, CDCl3)δ:7.99(d,J=7.0Hz,1H),7.78(s,1H),7.54-7.41(m,1H),7.32-7.25(m,1H),7.18(d,J=5.6Hz,1H),7.14(d,J=2.8Hz,1H),6. 54(d,J=2.8Hz,1H),5.15(t,J=7.0Hz,1H),3.73(s,2H),3.26-3.22(m,4H),3.05-3.00(m,3H),2.76-2.65(m,4H),1.85(d,J=7.0Hz,3H).

[0227] Example 12 Preparation of (S)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 35) This was prepared in accordance with the method of Example 11, except that the raw material (D)-alanine methyl ester hydrochloride was changed to (L)-alanine methyl ester hydrochloride.

[0228] Molecular formula:C 23 H 24 F2N6O2 molecular weight: 454.5 LC-MS (m / z): 454.9 (M+H + ) 1 H-NMR(400 MHz, CDCl3)δ:7.99(d,J=7.8Hz,1H),7.78(s,1H),7.55-7.42(m,1H),7.32-7.25(m,1H),7.18(d,J=5.6Hz,1H),7.14(d,J=3.0Hz,1H),6. 54(d,J=3.0Hz,1H),5.15(q,J=6.9Hz,1H),3.73(s,2H),3.28-3.22(m,4H),3.05-3.00(m,3H),2.76-2.65(m,4H),1.85(d,J=7.0Hz,3H).

[0229] Example 13 Preparation of 6-fluoro-5-(4-((6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 41) JPEG2025535834000081.jpg50170

[0230] 1. Preparation of N-(5-bromo-1H-indol-7-yl)acetamide 5-Bromo-1H-indole-7-amine (1.4 g, 6.6 mmol) was dissolved in DCM (50 mL), triethylamine (2.0 g, 19.8 mmol) was added to the reaction mixture, and acetyl chloride (0.67 g, 8.5 mmol) was added dropwise thereto. The reaction mixture was allowed to react at 15°C for 1 hour. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate and petroleum ether were used as the mobile phase, with the ethyl acetate ratio ranging from 0% to 50%) to obtain the product (1.1 g, yield 65.5%).

[0231] 2. Preparation of N-(5-bromo-3-fluoro-1H-indol-7-yl)acetamide N-(5-Bromo-1H-indol-7-yl)acetamide (900 mg, 3.6 mmol) was dissolved in acetonitrile (15 mL) and water (3 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (1.9 g, 5.4 mmol) was added. The mixture was reacted at 10° C. for 2 hours, and then water was added to quench the reaction. The mixture was concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain the crude product (1.0 g).

[0232] Preparation of 3,5-bromo-3-fluoro-1H-indol-7-amine N-(5-bromo-3-fluoro-1H-indol-7-yl)acetamide (1.0 g, 3.7 mmol) was dissolved in methanol (50 mL), sulfonyl chloride (2.5 g, 21.0 mmol) was added, and the mixture was reacted at 60°C for 1 hour. The mixture was then concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the product (700 mg, yield 82.8%).

[0233] Preparation of 4,2-bromo-N-(5-bromo-3-fluoro-1H-indol-7-yl)propionamide 5-Bromo-3-fluoro-1H-indol-7-amine (650 mg, 2.8 mmol) was dissolved in ethyl acetate (20 mL), pyridine (460 mg, 5.8 mmol) and 2-bromopropionic acid (800 mg, 5.2 mmol) were added, and 1-cyclopropylphosphoric acid anhydride (50%, 3.6 g, 5.7 mmol) was added dropwise at -50 °C. After 2 hours of reaction, water was added to quench the reaction. The crude product was concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to give the product (700 mg, 67.8% yield).

[0234] Preparation of 5,8-bromo-6-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 2-Bromo-N-(5-bromo-3-fluoro-1H-indol-7-yl)propionamide (700 mg, 1.9 mmol) was dissolved in DMF (10 mL) and NaH (60%) (160 mg, 4.0 mmol) was added. The reaction was allowed to proceed at 25°C for 1.5 h. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic phase was collected, concentrated, and purified using a thin-layer preparative plate (ethyl acetate:petroleum ether = 2:3) to give the product (500 mg, yield 91.8%).

[0235] Preparation of 6,6-fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-Bromo-6-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (300 mg, 1.1 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributyltin)methanol (710 mg, 2.2 mmol) and chloro(2-dicyclohexylphosphino-2-hexylphosphino,2-triisopropyl-1,1-phosphinobiphenyl)[2-(2,amino-1,1(2-biphenyl)]palladium(II) (100 mg, 0.13 mmol) were added. The reaction was stirred at 80°C for 1 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 3:2) to give the product (200 mg, 80.6% yield).

[0236] Preparation of 7,8-(chloromethyl)-6-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 6-Fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (50 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL) and acetonitrile (10 mL), and sulfonyl chloride (150 mg, 1.3 mmol) and DMF (0.1 mL) were added at 0° C. The reaction was carried out at 30° C. for 5 h. After completion of the reaction, the mixture was concentrated and used directly in the next step.

[0237] Preparation of 8,6-fluoro-5-(4-((6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (60 mg, 0.22 mmol) and the crude product from the previous step were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (55 mg, 0.43 mmol) was added. The reaction was allowed to proceed at 70 °C for 2 h. After completion of the reaction, the mixture was concentrated and purified by TLC (methanol:dichloromethane = 1:10) to give the product (13 mg, 13.4% yield for two steps).

[0238] Molecular formula:C 23 H 24 F2N6O2 molecular weight: 454.5 LC-MS (M / e): 455.1 (M+H + ) 1 H-NMR(400 MHz, CDCl3)8.11(s,1H),8.00(d,J=7.84Hz,1H),7.51(d,J=4.68Hz,1H),7.33-7.30(m,1H),7.28-7.18(m,1H),6.95(s, 1H),6.67(s,1H),5.05-5.03(m,1H),3.63-3.50(m,2H),3.23(m,4H),3.01-2.98(m,3H),2.66(m,4H),1.81-1.79(m,3H).

[0239] 9, separated by chiral column to give isomers Compound 41-1 and Compound 41-2, characterized as follows: 1) Compound 41-1 HPLC, residence time: 14.2min 1 H-NMR(400 MHz, CDCl3)8.11(s,1H),8.00(d,J=7.84Hz,1H),7.51(d,J=4.68Hz,1H),7.33-7.30(m,1H),7.28-7.18(m,1H),6.95(s, 1H),6.67(s,1H),5.05-5.03(m,1H),3.63-3.50(m,2H),3.23(m,4H),3.01-2.98(m,3H),2.66(m,4H),1.81-1.79(m,3H).

[0240] 2) Compound 41-2 HPLC, residence time: 16.2min 1 H-NMR(400 MHz, CDCl3)8.11(s,1H),8.00(d,J=7.84Hz,1H),7.51(d,J=4.68Hz,1H),7.33-7.30(m,1H),7.28-7.18(m,1H),6.95(s, 1H),6.67(s,1H),5.05-5.03(m,1H),3.63-3.50(m,2H),3.23(m,4H),3.01-2.98(m,3H),2.66(m,4H),1.81-1.79(m,3H).

[0241] Example 14 Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3,5-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 44) JPEG2025535834000082.jpg56170

[0242] 1. Preparation of (4-bromo-3-fluoro-2-nitrophenyl)-D-alanine methyl ester 1-Bromo-2,4-difluoro-3-nitrobenzene (10 g, 42.0 mmol) was dissolved in N,N-dimethylformamide (100 mL), and D-alanine methyl ester hydrochloride (5.9 g, 42.0 mmol) and N,N-diisopropylethylamine (16.8 g, 0.13 mol) were added thereto and reacted for 5 hours at 50° C. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the product (7.5 g, yield 56.0%).

[0243] 2. Preparation of (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (4-Bromo-3-fluoro-2-nitrophenyl)-D-alanine methyl ester (7.5 g, 23.4 mmol), (tri-n-butyltin)methanol (8.2 g, 25.7 mmol), and Xphos Pdg2 (1.8 g, 2.3 mmol) were dissolved in 1,4-dioxane (150 mL), purged with nitrogen gas, and reacted at 80 °C under nitrogen for 3 hours. The crude product was concentrated, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to give the product (4.6 g, 72.4% yield).

[0244] 3. Preparation of (6-bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (3-Fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (4.6 g, 16.9 mmol) was dissolved in N,N-dimethylformamide (100 mL), N-bromosuccinimide (3.3 g, 18.6 mmol) was added, and the mixture was reacted at 25 ° C for 16 hours. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL × 2). The organic phase was washed with water (100 mL × 2), dried, and concentrated. The crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 3:1) to obtain the product (3.5 g, yield 59.3%).

[0245] 4. Preparation of (R)-5-bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (6-Bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (390 mg, 1.1 mmol) was dissolved in methanol (15 mL) / tetrahydrofuran (15 mL) / water (5 mL), and iron powder (622 mg, 11.1 mmol) and ammonium chloride (1.2 g, 22.2 mmol) were added and the mixture was reacted at 70° C. for 1 hour. The solid was removed by filtration, concentrated, and extracted with water (30 mL) and ethyl acetate (30 mL). The organic phase was dried and concentrated to give the product (300 mg, 93.2% yield).

[0246] 5. Preparation of (R)-9-fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (R)-5-Bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (300 mg, 1.0 mmol) was dissolved in toluene (11 mL), tributyl(methoxy)tin (995 mg, 3.1 mmol), isopropenyl acetate (520 mg, 5.2 mmol), Pd(OAc) (23 mg, 0.1 mmol), and tri-o-tolylphosphine (32 mg, 0.1 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was microwaved under nitrogen at 100 °C for 1 hour. The mixture was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to give the product (100 mg, 38.9% yield).

[0247] 6. Preparation of (R)-8-(chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (R)-9-Fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.4 mmol) was dissolved in dichloromethane (12 mL) and a solution of hydrogen chloride in ethyl acetate (1.2 mL) was added. The reaction was allowed to proceed at 5° C. for 1 h. The mixture was concentrated and the crude product was used directly in the next step.

[0248] 7. Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3,5-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (R)-8-(chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (110 mg, 0.4 mmol) were dissolved in acetonitrile (15 mL), DIEA (157 mg, 1.2 mmol) was added, and the mixture was reacted at 80 °C for 1 hour. The mixture was concentrated and purified on a silica gel column (dichloromethane:methanol = 15:1) to give the crude product. The crude product was purified by prep-TLC (dichloromethane:methanol = 15:1) to give the target compound (25 mg, 13.1% yield for two steps).

[0249] Molecular formula:C 24 H 26 F2N6O2 molecular weight: 468.5 LC-MS (m / z): 469.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)7.86-8.3(m,1H),7.90(s,1H),7.45-7.53(m,1H),7.25-7.32(m,1H),7.03-7.12(m,1H),6.23(s,1H),5.12-5.2 6(m,1H),3.65-3.75(m,2H),3.20-3.30(m,4H),3.00-3.05(m,3H),2.65-2.75(m,4H),2.45(s,3H),1.62-1.74(m,3H).

[0250] Example 15 Preparation of (R)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 27) JPEG2025535834000083.jpg43170

[0251] 1. Preparation of (4-(hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (4-Fluoro-3-nitrophenyl)methanol (25.0 g, 146.1 mmol) was dissolved in tetrahydrofuran (500 mL), and (D)-alanine methyl ester hydrochloride (30.6 g, 219.2 mmol) and N,N-diisopropylethylamine (46.6 g, 438.3 mmol) were added thereto, followed by reaction at 80 °C for 16 hours. Completion of the reaction was confirmed by LCMS. The crude product was concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (20.0 g, yield 53.9%).

[0252] 2. Preparation of (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)-D-alanine methyl ester (4-(Hydroxymethyl)-2-nitrophenyl)-D-alanine methyl ester (12.0 g, 47.2 mmol) and TBSCl (10.7 g, 70.8 mmol) were dissolved in DCM (200 mL), and imidazole (6.4 g, 94.4 mmol) was added. The mixture was allowed to react at 10°C for 0.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (13.6 g, 78.2% yield).

[0253] 3. Preparation of (2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitrophenyl)-D-alanine methyl ester (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)-D-alanine methyl ester (13.0 g, 35.3 mmol) and N-bromosuccinimide (7.5 g, 42.4 mmol) were dissolved in N,N-dimethylformamide (200 mL), and the mixture was reacted at 40° C. for 1 hour. The resulting mixture was used directly in the next step.

[0254] 4. Preparation of (2-bromo-4-(hydroxymethyl)-6-nitrophenyl)-D-alanine methyl ester (2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitrophenyl)-D-alanine methyl ester (crude product from the previous step) was added to TBAF (1 M, 35.3 mL) and then reacted at 16° C. for 1 hour. The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to give the product (9.0 g, two-step yield 76.6%).

[0255] 5. Preparation of (R)-5-bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (2-Bromo-4-(hydroxymethyl)-6-nitrophenyl)-D-alanine methyl ester (10.8 g, 32.4 mmol) was dissolved in methanol (90 mL) / tetrahydrofuran (90 mL) / water (30 mL), and iron powder (9.0 g, 161.2 mmol) and ammonium chloride (17.3 g, 323.3 mmol) were added and the mixture was reacted at 70° C. for 2 hours. The solid was removed by filtration, concentrated, and extracted with water (100 mL) and ethyl acetate (100 mL). The organic phase was dried and concentrated to give the target compound (7.2 g, 81.9% yield).

[0256] 6. Preparation of (R,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (R)-5-Bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (7.1 g, 26.2 mmol) was dissolved in 1,4-dioxane (150 mL) and water (20.0 mL). 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (7.8 g, 39.3 mmol), Pd(dppf)Cl2 (1.9 g, 2.6 mmol), and sodium carbonate (5.6 g, 52.4 mmol) were added. The mixture was purged with nitrogen gas and reacted at 100 °C for 2 hours under nitrogen. The reaction mixture was monitored by LCMS. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:3) to give the product (4.6 g, 67.0% yield).

[0257] 7. Preparation of (R)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (R,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (1.9 g) was dissolved in dichloromethane (100 mL) and a solution of hydrogen chloride in ethyl acetate (16 mL) was added. The reaction was allowed to proceed at 5° C. for 10 minutes. The mixture was concentrated and the crude product was used directly in the next step.

[0258] 8. Preparation of (R)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (R)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (1.97 g, 7.2 mmol) was dissolved in acetonitrile (200 mL), DIEA (9.3 g, 71.8 mmol) was added, and the mixture was reacted at 80 ° C for 2 hours. The mixture was concentrated, diluted with water, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give the product (600 mg, yield 19.0%).

[0259] Molecular formula:C 23 H 25 FN6O2 molecular weight: 436.5 LC-MS (m / z): 437.2 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:7.95-8.05(m,1H),7.70-7.82(m,1H),7.41-7.58(m,1H),7.12-7.28(m,2H),6.49-6.58(m ,2H),5.09-5.20(m,1H),3.64(s,2H),3.15-3.30(m,4H),2.90-3.05(m,3H),2.55-2.70(m,4H),1.85-1.92(m,3H).

[0260] Example 16 Preparation of (S)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 28) JPEG2025535834000084.jpg53170

[0261] 1. Preparation of (4-(hydroxymethyl)-2-nitrophenyl)-L-alanine methyl ester (4-Fluoro-3-nitrophenyl)methanol (10.3 g, 60.2 mmol) was dissolved in tetrahydrofuran (200 mL), and (L)-alanine methyl ester hydrochloride (12.6 g, 90.3 mmol) and N,N-diisopropylethylamine (23.3 g, 0.18 mol) were added thereto, followed by a reaction at 80 °C for 16 hours. LCMS confirmed the completion of the reaction. The crude product was concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (10.0 g, yield 65.4%).

[0262] 2. Preparation of (2-bromo-4-(hydroxymethyl)-6-nitrophenyl)-L-alanine methyl ester (4-(hydroxymethyl)-2-nitrophenyl)-L-alanine methyl ester (10.0 g, 39.4 mmol) and N-bromosuccinimide (7.7 g, 43.3 mmol) were dissolved in N,N-dimethylformamide (100 mL) and then reacted at 10°C for 16 hours. The mixture was added to water and extracted with ethyl acetate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (7.0 g, yield 53.6%).

[0263] 3. Preparation of (S)-5-bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (2-Bromo-4-(hydroxymethyl)-6-nitrophenyl)-L-alanine methyl ester (7.0 g, 21.1 mmol) was dissolved in methanol (40 mL) / tetrahydrofuran (40 mL) / water (10 mL), and iron powder (7.3 g, 0.13 mol) and ammonium chloride (13 g, 0.25 mol) were added and the mixture was reacted at 70° C. for 2 hours. The solid was removed by filtration, concentrated, and extracted with water (30 mL) and ethyl acetate (30 mL). The organic phase was dried and concentrated to give the target compound (4.0 g, 70.2% yield).

[0264] 4. Preparation of (S,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (S)-5-Bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (70 mg, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (61 mg, 0.31 mmol), Pd(dppf)Cl2 (19 mg, 26.0 μmol), and sodium carbonate (55 mg, 0.52 mmol) were added. The mixture was purged with nitrogen gas and reacted at 90 °C under nitrogen for 2 hours. After confirming completion of the reaction by LCMS, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:3) to give the product (40 mg, 58.8% yield).

[0265] 5. Preparation of (S)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (S,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (40 mg, 0.15 mmol) was dissolved in dichloromethane (10 mL) and a solution of hydrogen chloride in ethyl acetate (0.8 mL) was added. The reaction was allowed to proceed at 5° C. for 10 minutes. The mixture was concentrated and the crude product was used directly in the next step.

[0266] 6. Preparation of (S)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (S)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (41 mg, 0.15 mmol) were dissolved in acetonitrile (10 mL), DIEA (58 mg, 0.45 mmol) was added, and the mixture was reacted at 80 °C for 2 h. The mixture was concentrated, diluted with water, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified on a silica gel plate (dichloromethane:methanol = 15:1) to give the product (11 mg, 16.7% yield for two steps).

[0267] Molecular formula:C 23 H 25 FN6O2 molecular weight: 436.5 LC-MS (m / z): 437.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:7.95-8.05(m,1H),7.70-7.82(m,1H),7.41-7.58(m,1H),7.12-7.28(m,2H),6.49-6.58(m,2H),5 .09-5.20(m,1H),3.64(s,2H),3.15-3.30(m,4H),2.90-3.05(m,3H),2.55-2.70(m,4H),1.85-1.92(m,3H).

[0268] Example 17 Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopentane[de]quinolin-7-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 31) JPEG2025535834000085.jpg80170

[0269] Preparation of 1,5-(3-bromo-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 0 oIn C, formic acid (130 mL) was added dropwise to triethylamine (100 mL), stirred for 30 minutes, and then 3-bromo-5-nitrobenzeneformaldehyde (9.0 g, 39.1 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (5.6 g, 39.1 mmol), and N,N-dimethylformamide (50 mL) were added. o The reaction was carried out at C for 12 hours. After the reaction was completed, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was collected and rotary dried to obtain the crude product (20.0 g), which was used directly in the next reaction.

[0270] Preparation of 2,3-(3-bromo-5-nitrophenyl)propionic acid To a solution of 5-(3-bromo-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (20.0 g, crude product) in acetonitrile (100 mL) was added water (10 mL). o C for 6 hours. After the reaction was completed, the reaction solution was spun down, water (100 mL) was added, and the pH was adjusted to 1 with 2 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (100 mL * 3), and the organic phase was collected, spun down, and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1) to obtain the product (10.0 g, two-step yield 93.2%).

[0271] Preparation of 3,3-(3-amino-5-bromophenyl)propionic acid To a solution of 3-(3-bromo-5-nitrophenyl)propionic acid (10.0 g, 36.5 mmol) in ethanol / water (100 mL / 20 mL) was added iron powder (6.1 g, 109.5 mmol) and ammonium chloride (5.9 g, 109.5 mmol). o C for 12 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (SiO2, 100% ethyl acetate) to obtain the product (6.4 g, yield 71.9%).

[0272] Preparation of 4,3-(3-acetamido-5-bromophenyl)propionic acid 3-(3-amino-5-bromophenyl)propionic acid (6.4 g, 26.2 mmol) was added to acetic anhydride (50 mL) and reacted for 1 hour at 25° C. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the product (2.4 g, yield 32.0%).

[0273] 5. Preparation of N-(6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)acetamide 3-(3-acetamido-5-bromophenyl)propionic acid (2.4 g, 8.4 mmol) was added to chlorosulfonic acid (20 mL). The reaction was allowed to proceed at 0°C for 3 hours. After completion of the reaction, the reaction mixture was slowly poured into ice water and extracted with ethyl acetate (50 mL * 2). The organic phase was collected and concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 4:1) to obtain the product (898 mg, yield 39.9%).

[0274] Preparation of 6,7-amino-5-bromo-2,3-dihydro-1H-inden-1-one Lithium hydroxide monohydrate (286 mg, 6.8 mmol) was added to a solution of N-(6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)acetamide (898 mg, 3.4 mmol) in methanol (20 mL). The reaction was allowed to proceed at 25°C for 1 hour. After completion of the reaction, the reaction solution was rotary evaporated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (600 mg, yield 79.2%).

[0275] 7. Preparation of diethyl (1-((6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphonate 7-Amino-5-bromo-2,3-dihydro-1H-inden-1-one (300 mg, 1.3 mmol) and 2-(diethoxyphosphoryl)propionic acid (307 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (4 mL), EDCI (633 mg, 3.3 mmol) was added, and the mixture was reacted at 25 °C for 2 hours. After the reaction was completed, water (10 mL) and ethyl acetate (15 mL × 2) were added, and the organic phase was washed with water (20 mL × 2), dried, and concentrated to give the crude product (500 mg). The crude product was used directly in the next step.

[0276] Preparation of 8,7-bromo-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one Diethyl (1-((6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphonate (500 mg, crude product) was dissolved in ultra-dry N,N-dimethylformamide (10 mL), NaH (60%) (156 mg, 3.9 mmol) was added, and the mixture was subjected to a microwave reaction at 100°C for 30 minutes. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the product (200 mg, two-step yield 57.1%).

[0277] Preparation of 9,7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one 7-Bromo-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one (200 mg, 0.76 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributyltin)methanol (365 mg, 1.1 mmol) and XPhos Pdg2 (60 mg, 0.076 mmol) were added. The mixture was reacted at 90°C for 2 hours. After the reaction was completed, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the product (80 mg, yield 49.1%).

[0278] Preparation of 10,7-(chloromethyl)-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one 7-(Hydroxymethyl)-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one (80 mg, 0.37 mmol) and N,N-dimethylformamide (9 mg, 0.12 mmol) were dissolved in dichloromethane (7 mL), and sulfonyl chloride (78 mg, 0.66 mmol) was added and the mixture was allowed to react for 1 hour at 25° C. The mixture was concentrated and the crude product was used directly in the next step.

[0279] Preparation of 11,6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopentane[de]quinolin-7-yl)methyl)piperazin-1-yl)pyridinecarboxamide 7-(Chloromethyl)-3-methyl-4,5-dihydrocyclopentane[de]quinolin-2(1H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (90 mg, 0.37 mmol) were dissolved in acetonitrile (7 mL), DIEA (143 mg, 1.1 mmol) and potassium carbonate (152 mg, 1.1 mmol) were added, and the mixture was reacted at 85 °C for 10 hours. After the reaction was completed, the mixture was concentrated, and the crude product was purified by prep-TLC (dichloromethane:methanol = 10:1) to give the product (25 mg, 15.5% yield for two steps).

[0280] Molecular formula:C 24 H 26 FN5O2 molecular weight: 435.2 LC-MS (m / z): 436.2 (M+H + ) 1 H-NMR(400MHz,DMSO-d6)δ:11.33(s,1H),8.38(s,1H),7.83(d,J=8.0Hz,1H),7.55(t,J=9.4Hz,1H),6 .99(s,1H),6.94(s,1H),3.57(s,2H),3.32-3.07(m,8H),2.76(s,3H),2.65-2.50(m,4H),2.00(s,3H).

[0281] Example 18 Preparation of 6-fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopentyl[de]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 6) JPEG2025535834000086.jpg76170

[0282] Preparation of 1,6-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one A solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (24 g, 159.5 mmol) in 1,2-dichloroethane (100 mL) was added to a solution of aluminum trichloride (53.3 g, 399.8 mmol) in 1,2-dichloroethane (400 mL), and the mixture was allowed to react at 25 ° C. for 10 minutes. Bromine (38 g, 237.8 mmol) was then added dropwise to the reaction mixture, and the mixture was heated to 70 ° C. and allowed to react for 2 hours. The reaction mixture was poured into ice water and 1 M hydrochloric acid solution (300 mL), ethyl acetate (300 mL) was added, filtered through diatomaceous earth, the filtrate was separated, the organic phase was concentrated, and the product was purified by column chromatography (n-heptane: ethyl acetate = 2:1) to obtain the product (11.1 g, yield 30.3%).

[0283] Preparation of 2,5-bromo-6-fluoro-2,3-dihydro-1H-indene 6-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (7.0 g, 30.6 mmol) was added to trifluoroacetic acid (80 mL), and triethylsilane (80 mL) was added, followed by a reaction for 18 hours at 25° C. The reaction mixture was concentrated and purified by column chromatography (eluted with n-heptane) to obtain the product (5.5 g, yield 83.7%).

[0284] Preparation of 3,6-bromo-5-fluoro-4-iodo-2,3-dihydro-1H-indene 5-Bromo-6-fluoro-2,3-dihydro-1H-indene (5.75 g, 26.75 mmol) was dissolved in tetrahydrofuran (125 mL), cooled to -75°C, and stirred for 10 minutes. LDA (20.4 mL, 40.8 mmol) was slowly added dropwise and the mixture was allowed to react at -65 to -75°C for 30 minutes. The reaction mixture was then quenched by adding saturated sodium sulfite (70 mL). The mixture was extracted with ethyl acetate (150 mL), the organic phase was concentrated, and purified by reverse-phase column chromatography (acetonitrile / water = 10% to 90%) to obtain the product (3.7 g, yield 40.4%).

[0285] 4. Preparation of tert-butyl (6-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl)aminoformate 6-Bromo-5-fluoro-4-iodo-2,3-dihydro-1H-indene (2.7 g, 7.92 mmol), NHBoc (0.93 g, 7.94 mmol), XantPhos (0.46 g, 0.80 mmol), Pd(dba) (0.36 g, 0.39 mmol), and cesium carbonate (5.2 g, 16.0 mmol) were added to toluene (100 mL) in this order and reacted at 105 °C for 18 hours under N2 protection. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 30%) to obtain the product (1.1 g, yield 42.1%).

[0286] 5. Preparation of tert-butyl (6-bromo-5-fluoro-3-oxy-2,3-dihydro-1H-inden-4-yl)aminoformate Tert-butyl (6-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl)aminoformate (1.0 g, 3 mmol) was dissolved in acetone (60 mL), and aqueous magnesium sulfate (6.4 g, 15%) and potassium permanganate (1.5 g, 9.5 mmol) were added. The mixture was allowed to react for 18 hours at 25°C. After the reaction was complete, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 33%) to obtain the product (0.9 g, yield 86.3%).

[0287] Preparation of 6,7-amino-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one Tert-butyl (6-bromo-5-fluoro-3-oxy-2,3-dihydro-1H-inden-4-yl)aminoformate (900 mg, 2.6 mmol) was dissolved in ethyl acetate (5 mL), and HCl / EA (9 mL, 36 mmol) was added and reacted for 16 hours at 25° C. After completion of the reaction, the mixture was concentrated to obtain the product (700 mg, yield 95.4%).

[0288] 7. Preparation of diethyl (1-((6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphate 2-(Diethoxyphosphoryl)propionic acid (810 mg, 3.8 mmol) was dissolved in DCM (20 mL), and oxalyl chloride (800 mg, 6.3 mmol) and N,N-dimethylformamide (0.5 mL) were added, followed by reaction at 25° C. for 0.5 hours to obtain a solution. 7-Amino-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (600 mg, 2.1 mmol) and DIEA (1.1 g, 8.5 mmol) were dissolved in THF (20 mL), and then the above solution was added to the reaction solution and reacted for 2 hours at 25 ° C. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the product (1.0 g, yield 93.2%).

[0289] Preparation of 8,7-bromo-8-fluoro-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one Diethyl (1-((6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphate (500 mg, 1.15 mmol) and NaH (124 mg, 3.1 mmol) were dissolved in DMF (15 mL) and stirred at 100°C for 20 minutes under microwave irradiation. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10% to 50%) to obtain the product (100 mg, yield 30.9%).

[0290] Preparation of 9,8-fluoro-7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one 7-Bromo-8-fluoro-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one (150 mg, 0.53 mmol), potassium (acetoxymethyl)trifluoroborate (150 mg, 1.06 mmol), sodium carbonate (170 mg, 1.6 mmol), and RuPhosPdG3 (46 mg, 0.05 mmol) were added sequentially to dioxane (25 mL) and water (1 mL) and reacted at 95 °C for 16 hours under N2 protection. After completion of the reaction, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20% to 100%) to give the product (50 mg, yield 40.3%).

[0291] Preparation of 10,7-(chloromethyl)-8-fluoro-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one 8-Fluoro-7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one (50 mg, 0.21 mmol) and N,N-dimethylformamide (200 mg) were dissolved in dichloromethane (7 mL), and sulfonyl chloride (250 mg, 2.1 mmol) was added and the reaction was carried out for 2 hours at 20° C. The mixture was concentrated and the crude product was used directly in the next step.

[0292] Preparation of 11,6-fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopentyl[de]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridineamide 7-(Chloromethyl)-8-fluoro-3-methyl-4,5-dihydrocyclopentadiene[de]quinolin-2(1H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (82 mg, 0.3 mmol) were dissolved in acetonitrile (40 mL), DIEA (257 mg, 1.99 mmol) was added, and the mixture was reacted at 85 °C for 2 hours. After the reaction was completed, the solid was precipitated and filtered. The filter cake was washed with acetonitrile (5 mL), and the filter cake was collected to give the product (35 mg, two-step yield 36.0%).

[0293] Molecular formula:C 24 H 25 F2N5O2 molecular weight: 453.5 LC-MS (m / z): 454.3 (M+H + ) 1 H-NMR(400MHz,DMSO)δ:11.59(s,1H),8.37(d,J=4.6Hz,1H),7.81(d,J=7.8Hz,1H),7.53(t,J=8.7Hz,1H),7.01 (d,J=4.2Hz,1H),3.63(s,2H),3.30(s,2H),3.12-3.17(m,6H),2.74(d,J=4.5Hz,3H),2.56(s,4H),1.96(s,3H).

[0294] Example 19: Preparation of (R)-6-fluoro-N-methyl-5-(4-((4-methyl-5-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 29-1) JPEG2025535834000087.jpg54170

[0295] Preparation of 1,5-bromo-7-nitro-1H-benzo[d]imidazole 5-Bromo-3-nitrobenzene-1,2-diamine (4.0 g, 17.2 mmol) was dissolved in HCl (4 M, 50 mL), and formic acid (950 mg, 20.7 mmol) was added. The system was reacted at 120°C for 1 hour, and then the pH was adjusted to 7 with aqueous ammonia to precipitate a solid. The solid was filtered, and the filter cake was rotary dried to obtain the product (3.8 g, yield 91.1%).

[0296] 2. Preparation of methyl (R)-2-(5-bromo-7-nitro-1H-benzo[d]imidazol-1-yl)propionate 5-Bromo-7-nitro-1H-benzo[d]imidazole (1.2 g, 5.0 mmol) was dissolved in tetrahydrofuran (50 mL), and triphenylphosphine (2.0 g, 7.5 mmol), (S)-methyl 2-hydroxypropionate (885 mg, 7.5 mmol), and diisopropyl azodicarboxylate (1.5 g, 7.5 mmol) were added. The system was reacted at 20°C for 1 hour, then concentrated, washed with water, extracted with ethyl acetate, and concentrated. The crude product was purified by column chromatography (EA:PE=1:1) to obtain the product (600 mg, yield 35.3%).

[0297] 3. Preparation of (R)-8-bromo-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one Methyl (R)-2-(5-bromo-7-nitro-1H-benzo[d]imidazol-1-yl)propionate (300 mg, 0.91 mmol), zinc powder (572 mg, 8.8 mmol), and ammonium chloride (466 mg, 8.8 mmol) were dissolved in methanol (20 mL), water (5 mL), and tetrahydrofuran (20 mL), and the mixture was reacted at 70°C for 2 h. After extraction with ethyl acetate, the organic phase was concentrated and used directly in the next step.

[0298] 4. Preparation of (R)-8-(hydroxymethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (R)-8-Bromo-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (crude product from the previous step), tributyltinmethanol (282 mg, 0.88 mmol), and XPhos Pdg2 (69 mg, 88.0 μmol) were dissolved in dioxane (10 mL) and reacted at 80 °C for 2 h. After the reaction was completed, the mixture was extracted with water and ethyl acetate. The organic phase was collected, concentrated, and purified by column chromatography (MeOH:DCM = 1:10) to give the product (60 mg, yield 31.6%).

[0299] 5. Preparation of (R)-8-(chloromethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (R)-8-(hydroxymethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (60 mg, 0.28 mmol) was dissolved in DCM (10 mL), and sulfonyl chloride (322 mg, 2.8 mmol) and DMF (21 mg, 0.28 mmol) were added. The mixture was then reacted at 20°C for 6 h. After completion of the reaction, the mixture was concentrated, and the crude product was used directly in the next reaction.

[0300] 6. Preparation of (R)-6-fluoro-N-methyl-5-(4-((4-methyl-5-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (R)-8-(Chloromethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (crude product from the previous step) was dissolved in acetonitrile (10 mL), and DIEA (98 mg, 0.76 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (77 mg, 0.28 mmol) were added. The mixture was reacted at 70 °C for 2 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography (MeOH:DCM=1:10) to give the product (30 mg, two-step yield: 24.8%).

[0301] Molecular formula:C 22 H 24FN7O2 molecular weight: 437.5 LC-MS (M / e): 438.1 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:7.98(m,2H),7.81(s,1H),7.49(s,1H),7.37(s,1H),7.30(s,1H),6.75(s,1H),5. 27-5.25(m,1H),3.65(s,2H),3.21-3.09(m,4H),2.99-2.98(m,3H),2.65-2.61(m,4H),1.93-1.92(m,3H).

[0302] Example 20: Preparation of (S)-6-fluoro-N-methyl-5-(4-((4-methyl-5-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 29-2) Prepared with reference to the method of Example 19, except that the chiral intermediate was changed from (S)-methyl 2-hydroxypropionate to (R)-methyl 2-hydroxypropionate.

[0303] Molecular formula:C 22 H 24 FN7O2 molecular weight: 437.5 LC-MS (M / e): 438.1 (M+H + ) 1 H-NMR(400MHz,CDCl3)δ:7.98(m,2H),7.81(s,1H),7.49(s,1H),7.37(s,1H),7.30(s,1H),6.75(s,1H),5. 27-5.25(m,1H),3.65(s,2H),3.21-3.09(m,4H),2.99-2.98(m,3H),2.65-2.61(m,4H),1.93-1.92(m,3H).

[0304] Example 21: Preparation of (Compound 38) JPEG2025535834000088.jpg86170

[0305] Preparation of 1,5-bromo-6-fluoroindole-2,3-dione 6-Fluoroindole-2,3-dione (10.0 g, 60.6 mmol) was dissolved in DMF (150 mL), NBS (12.0 g, 67.4 mmol) was added, and the reaction was allowed to proceed at 10 °C for 16 h. The reaction mixture was slowly poured into ice water to precipitate a solid, which was then filtered to remove the filtrate and dried to give the crude product (8.0 g). The product was purified by silica gel column chromatography (ethyl acetate:tetrahydrofuran = 9:1) to give the product (4 g, yield 27.1%).

[0306] Preparation of 2,5-bromo-3,3,6-trifluoroindol-2-one 5-Bromo-6-fluoroindole-2,3-dione (4.0 g, 16.4 mmol) was dissolved in dichloromethane (110 mL), and DAST (7.9 g, 49.0 mmol) was added and reacted for 3 hours at 15° C. The reaction was quenched by adding water, extracted, and purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1) ​​to obtain the product (2.2 g, yield 50.5%).

[0307] Preparation of 3,5-bromo-3,3,6-trifluoro-7-nitroindol-2-one 5-Bromo-3,3,6-trifluoroindol-2-one (2.2 g, 8.3 mmol) was dissolved in concentrated sulfuric acid (30 mL) and potassium nitrate (1.3 g, 12.9 mmol), and the mixture was allowed to react for 1 hour at 0° C. The reaction mixture was slowly poured into ice water to precipitate a solid, which was then filtered to remove the filtrate and dried to obtain the product (2.0 g, 77.8% yield).

[0308] Preparation of 4,5-bromo-3,6-difluoro-1H-indol-7-amine 5-Bromo-3,3,6-trifluoro-7-nitroindol-2-one (2.0 g, 6.4 mmol) was dissolved in tetrahydrofuran (10 mL), and a 1 M borane-tetrahydrofuran solution (30 mL) was added. The mixture was reacted at 70 °C for 2 hours. The reaction was quenched by the addition of methanol, concentrated, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to give the crude product (1.2 g). Purification using a C18 column (methanol:water = 0-46%) gave the product (700 mg, 44.1% yield).

[0309] Preparation of 5,2-bromo-N-(5-bromo-3,6-difluoro-1H-indol-7-yl)propionamide 5-Bromo-3,6-difluoro-1H-indol-7-amine (700 mg, 2.8 mmol), 2-bromopropionic acid (875 mg, 5.7 mmol), and pyridine (890 mg, 11.3 mmol) were dissolved in ethyl acetate (40 mL), cooled to -10 ° C., and a solution of 1-cyclopropylphosphoric acid anhydride in ethyl acetate (50%, 5.4 g, 8.5 mmol) was added and reacted at -10 ° C. for 1 hour. Extraction with water and ethyl acetate was performed, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1) to obtain the product (1.0 g, yield 92.4%).

[0310] Preparation of 6,8-bromo-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 2-Bromo-N-(5-bromo-3,6-difluoro-1H-indol-7-yl)propionamide (1.0 g, 2.6 mmol) was dissolved in DMF (30 mL) and 60% sodium hydride (266 mg, 6.7 mmol) was added. The reaction was allowed to proceed at 20 °C for 0.5 h. Water was added to quench the reaction, and the crude product was extracted with water and ethyl acetate. The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to give the product (68 mg, yield 86.3%).

[0311] Preparation of 7,6,9-difluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 8-Bromo-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (680 mg, 2.3 mmol), tri-n-butyltinmethanol (872 mg, 2.7 mmol), and Xphos Pdg2 (182 mg, 0.23 mmol) were dissolved in 1,4-dioxane (70 mL) and reacted at 85 ° C for 2 hours. After concentration, the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:2) to give the product (440 mg, 77.3% yield).

[0312] Preparation of 8,8-(chloromethyl)-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one 6,9-Difluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.40 mmol) was dissolved in dichloromethane (20 mL), and N,N-dimethylformamide (74 mg, 1.0 mmol) and sulfonyl chloride (240 mg, 2.0 mmol) were added dropwise in this order, followed by reaction at 20° C. for 2 hours. The mixture was concentrated, and the crude product was used directly in the next step.

[0313] Preparation of 9,5-(4-((6,9-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide 8-(Chloromethyl)-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinamide hydrochloride (110 mg, 0.40 mmol) were dissolved in acetonitrile (20 mL), DIEA (260 mg, 2.0 mmol) was added, and the mixture was reacted at 80 °C for 16 hours. The mixture was concentrated, extracted with water and (dichloromethane:methanol = 10:1), and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give the product (130 mg, 69.4% yield for two steps).

[0314] Molecular formula:C 23 H 23 F3N6O2 molecular weight: 472.5 LC-MS (m / z): 473.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)7.99(d,J=8.0Hz,1H),7.84(s,1H),7.49(d,J=4.8Hz,1H),7.32-7.29(m,1H),7.18(d,J=5.6Hz,1H),6.94(d,J=3.2Hz,1H) ),5.03(t,J=6.8Hz,1H),3.73(s,2H),3.24(t,J=4.8Hz,4H),3.00(d,J=5.0Hz,3H),2.71(t,J=4.8Hz,4H),1.79(d,J=7.0Hz,3H)

[0315] Example 22 Preparation of 5-(4-((3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Compound 46) JPEG2025535834000089.jpg55170

[0316] Preparation of methyl 1,2-((2-bromo-4-carbamoyl-6-nitrophenyl)amino)-2-methylpropionate 3-Bromo-4-fluoro-5-nitrobenzeneformaldehyde (3.0 g, 12.1 mmol) was dissolved in DMF (50 mL), and methyl 2-amino-2-methylpropionate hydrochloride (1.9 g, 12.1 mmol) and DIEA (4.7 g, 36.3 mmol) were added. The mixture was then reacted at 15°C for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified using a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.4 g, yield: 33.7%).

[0317] Preparation of methyl 2,2-((2-bromo-4-(hydroxymethyl)-6-nitrophenyl)amino)-2-methylpropionate Methyl 2-((2-bromo-4-carbamoyl-6-nitrophenyl)amino)-2-methylpropionate (1.4 g, 4.1 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (234 mg, 6.1 mmol) was added. The mixture was then reacted at 20°C for 1 hour, concentrated, washed with water, extracted with ethyl acetate, and concentrated. The crude product was then purified by column chromatography (EA:PE = 3:1) to obtain the product (810 mg, yield 57.4%).

[0318] Preparation of 3,5-bromo-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one Methyl 2-((2-bromo-4-(hydroxymethyl)-6-nitrophenyl)amino)-2-methylpropionate (200 mg, 0.57 mmol), iron powder (319 mg, 5.7 mmol), and ammonium chloride (302 mg, 5.7 mmol) were dissolved in methanol (15 mL), water (3 mL), and tetrahydrofuran (15 mL), and the mixture was reacted at 70°C for 3 h. After filtration through diatomaceous earth, the filtrate was concentrated and diluted with water and ethyl acetate. The organic phase was concentrated to give the target compound (130 mg, yield: 79.2%).

[0319] 4. Preparation of (E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one 5-Bromo-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (130 mg, 0.46 mmol), 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (137 mg, 0.69 mmol), Pd(dppf)Cl2 (34 mg, 46.0 μmol), sodium carbonate (98 mg, 0.92 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and then reacted at 90 °C for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate hydrate. The organic phase was collected, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the product (80 mg, yield 63.5%).

[0320] Preparation of 5,8-(chloromethyl)-3,3-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (80 mg, 0.29 mmol) was dissolved in DCM (10 mL), and hydrochloric acid / ethyl acetate (0.5 mL) was added. The mixture was then reacted at 20°C for 0.5 h. After completion of the reaction, the mixture was concentrated, and the crude product was used directly in the next reaction.

[0321] Preparation of 6,5-(4-((3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide 8-(Chloromethyl)-3,3-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) was dissolved in acetonitrile (10 mL), and DIEA (112 mg, 0.87 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (80 mg, 0.29 mmol) were added. The mixture was reacted at 70 °C for 2 h, then concentrated and purified by silica gel plate (MeOH:DCM=1:15) to give the product (2.5 mg, two-step yield: 1.9%).

[0322] Molecular formula:C 24 H 27 FN6O2 molecular weight: 450.5 LC-MS (M / e): 451.2 (M+H + ) 1 H-NMR(400MHz,CDCL3)δ:7.98-8.08(m,2H),7.45-7.52(m,1H),7.28-7.31(m,1H),7.15-7.20(m,2H),6.6 3(s,1H),6.53(s,1H),3.65(s,2H),3.21-3.27(m,4H),2.98-2.99(m,3H),2.61-2.67(m,4H),1.81(s,6H).

[0323] Example 23 Preparation of (R)-6-fluoro-5-(4-(((6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 49-2) JPEG2025535834000090.jpg60170

[0324] Preparation of 1,5-bromo-3-fluoro-7-nitro-1H-indazole 5-Bromo-7-nitro-1H-indazole (350 mg, 1.4 mmol) was dissolved in acetonitrile (7 mL), Select F (1.0 g, 2.8 mmol) was added, and the mixture was subjected to a microwave reaction at 125° C. for 1 hour. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1) to obtain the product (120 mg, yield 31.9%). For other synthetic steps see Example 39.

[0325] Characterization data of compound 49-2 Molecular formula:C 22 H 23 F2N7O2 molecular weight: 455.5 LC-MS (m / z): 456.2 (M+H + ) 1H-NMR(400MHz, CDCl3)δ:8.21(s,1H),7.99(d,J=7.2Hz,1H),7.50(d,J=4.8Hz,1H),7.32-7.29(m,1H),7.17(s,1H),6.83(s,1H),5. 18(t,J=7.0Hz,1H),3.60(s,2H),3.25-3.15(m,4H),3.00(d,J=5.0Hz,3H),2.76-2.65(m,4H),1.86(d,J=7.0Hz,3H).

[0326] Example 24: Preparation of (S)-6-fluoro-5-(4-(((6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 49-1) JPEG2025535834000091.jpg59170

[0327] See Example 23. Characterization Data: Molecular formula:C 22 H 23 F2N7O2 molecular weight: 455.5 LC-MS (m / z): 456.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.01(s,1H),7.99(d,J=7.2Hz,1H),7.50(d,J=4.8Hz,1H),7.32-7.29(m,1H),7.17(s,1H),6.83(s,1H),5. 18(t,J=7.0Hz,1H),3.60(s,2H),3.25-3.15(m,4H),3.00(d,J=5.0Hz,3H),2.76-2.65(m,4H),1.86(d,J=7.0Hz,3H).

[0328] Example 25: Preparation of (R)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 63-1) Referring to Example 23, 5-bromo-7-nitro-1H-indazole was reacted directly with ethyl (S)-2-hydroxypropionate.

[0329] Characterization data for compound 63-1: Molecular formula:C 22 H 24 FN7O2 molecular weight: 437.5 LC-MS (m / z): 438.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.22(s,1H),8.00-7.94(m,2H),7.50(d,J=4.8Hz,1H),7.32-7.24(m,2H),6.79(s,1H),5.37(t,J= 7.0Hz,1H),3.62(s,2H),3.27-3.15(m,4H),2.99(d,J=5.0Hz,3H),2.70-2.60(m,4H),1.94(d,J=7.0Hz,3H).

[0330] Example 26: Preparation of (S)-6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 63-2) See Examples 23 and 25, 5-bromo-7-nitro-1H-indazole was reacted directly with ethyl (R)-2-hydroxypropionate. Molecular formula:C 22 H 24 FN7O2 molecular weight: 437.5 LC-MS (m / z): 438.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.08(s,1H),8.00-7.94(m,2H),7.50(d,J=4.8Hz,1H),7.32-7.24(m,2H),6.79(s,1H),5.37(t,J= 7.0Hz,1H),3.62(s,2H),3.27-3.15(m,4H),2.99(d,J=5.0Hz,3H),2.70-2.60(m,4H),1.94(d,J=7.0Hz,3H).

[0331] Example 27: Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 64-1) JPEG2025535834000092.jpg55170

[0332] Preparation of 1,5-bromo-6-fluoro-7-nitro-1H-indazole 5-Bromo-6-fluoro-1H-indazole (2.0 g, 9.3 mmol) was dissolved in concentrated sulfuric acid (50 mL), cooled to 0°C, potassium nitrate (1.1 g, 10.9 mmol) was added, and the mixture was reacted at 15°C for 16 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and purified by silica gel column chromatography (n-heptane:ethyl acetate = 2:1). The crude product was purified by C18 column (methanol:water = 3:2) to obtain the product (1.2 g, yield 49.6%).

[0333] 2. Preparation of ethyl (R)-2-(5-bromo-6-fluoro-7-nitro-1H-indazol-1-yl)propionate 5-Bromo-6-fluoro-7-nitro-1H-indazole (500 mg, 1.9 mmol), (S)-ethyl 2-hydroxypropionate (340 mg, 2.9 mmol), and triphenylphosphine (760 mg, 2.9 mmol) were dissolved in tetrahydrofuran (20 mL), and DIAD (580 mg, 2.9 mmol) was added and reacted for 1 hour at 15 ° C. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 10:1) to obtain the product (100 mg, yield 14.4%).

[0334] 3. Preparation of ethyl (R)-2-(7-amino-5-bromo-6-fluoro-1H-indazol-1-yl)propionate Ethyl (R)-2-(5-bromo-6-fluoro-7-nitro-1H-indazol-1-yl)propionate (100 mg, 0.28 mmol) was dissolved in tetrahydrofuran / methanol / water (8 / 8 / 2 mL), and zinc powder (272 mg, 4.2 mmol) and ammonium chloride (297 mg, 5.6 mmol) were added. The reaction was carried out at 70 °C for 3 hours. The solid was removed by filtration, and the filtrate was used directly in the next step.

[0335] 4. Preparation of (R)-8-bromo-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one To the previous filtrate, a solution of hydrogen chloride in ethyl acetate (4 M, 1 mL) was added. The mixture was allowed to react at 15°C for 1 hour. The mixture was concentrated, adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with water and ethyl acetate, and the organic phase was dried and concentrated to give the product (90 mg).

[0336] 5. Preparation of (R)-9-fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (R)-8-Bromo-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (90 mg, 0.32 mmol) and (tributyltin)methanol (122 mg, 0.38 mmol) were dissolved in 1,4-dioxane (10 mL), and Xphos Pdg2 (49 mg, 0.062 mmol) was added and reacted for 2 hours at 80 ° C. The crude product was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (45 mg, 60.4% yield).

[0337] 6. Preparation of (R)-8-(chloromethyl)-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (R)-9-Fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (45 mg, 0.19 mmol) and N,N-dimethylformamide (45 mg, 0.62 mmol) were dissolved in dichloromethane (13 mL), and sulfonyl chloride (182 mg, 1.5 mmol) was added and reacted for 1 hour at 20° C. The mixture was concentrated and the crude product was used directly in the next step.

[0338] 7. Preparation of (R)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (R)-8-(chloromethyl)-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (68 mg, 0.25 mmol) was dissolved in acetonitrile (15 mL), DIEA (160 mg, 1.2 mmol) was added, and the mixture was reacted at 80 ° C for 3 hours. After concentration, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (35 mg, 40.2% yield for two steps).

[0339] Molecular formula:C 22 H 23 F2N7O2 molecular weight: 455.5 LC-MS (m / z): 456.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.00-7.95(m,2H),7.91(s,1H),7.48(d,J=4.8Hz,1H),7.30-7.25(m,2H),5.34(t,J=7.0Hz ,1H),3.70(s,2H),3.23-3.21(m,4H),2.99(d,J=5.0Hz,3H),2.72-2.68(m,4H),1.93(d,J=7.0Hz,3H)

[0340] Example 28: Preparation of (S)-6-fluoro-5-(4-((9-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Compound 64-2) Referring to Example 27, the chiral intermediate ethyl (S)-2-hydroxypropionate was changed to ethyl (R)-2-hydroxypropionate.

[0341] Feature data: Molecular formula:C 22 H 23 F2N7O2 molecular weight: 455.5 LC-MS (m / z): 456.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.00-7.95(m,2H),7.93(s,1H),7.49(d,J=4.8Hz,1H),7.31-7.25(m,2H),5.34(t,J=7.0Hz, 1H),3.70(s,2H),3.23-3.21(m,4H),2.99(d,J=5.0Hz,3H),2.72-2.68(m,4H),1.93(d,J=7.0Hz,3H).

[0342] Example 29: Preparation of (R)-6-fluoro-N-methyl-5-(4-((4-methyl-5-oxo-5,6-dihydro-4H-[1,2,3]triazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 68-1) JPEG2025535834000093.jpg55170

[0343] Preparation of 1,5-bromo-7-nitro-1H-benzo[d][1,2,3]triazole 5-Bromo-3-nitrobenzene-1,2-diamine (3.6 g, 15.5 mmol) was dissolved in acetic acid (80 mL), sodium nitrite (1.18 g, 17.1 mmol) was added, and the mixture was heated to 60 °C and reacted for 2 hours. The mixture was poured into water (200 mL), filtered, and the filter cake was washed with water (200 mL) and dried under vacuum at 50 °C for 5 hours to obtain the product (3.6 g, yield 95.5%).

[0344] Other steps were as per Example 27. Characterization data of compound 68-1: Molecular formula:C 21 H 23 FN8O2 molecular weight: 438.5 LC-MS (m / z): 439.2 (M+H + ) 1 H-NMR(400MHz, CDCl3)δ:8.85(s,1H),7.99(d,J=7.8Hz,1H),7.55(s,1H),7.52(d,J=8.6Hz,1H),7.27-7.33(m,1H),6.95(s,1H) ),5.59-5.64(m,1H),3.67(s,2H),3.21(s,4H),3.00(d,J=4.5Hz,3H),2.60-2.65(m,4H),2.08(d,J=6.9Hz,3H).

[0345] Example 30: Preparation of (S)-6-fluoro-N-methyl-5-(4-((4-methyl-5-oxo-5,6-dihydro-4H-[1,2,3]triazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 68-2) See Examples 29 and 27, except that the chiral intermediate was changed to (R)-ethyl 2-hydroxypropionate.

[0346] Feature data: Molecular formula:C 21 H 23 FN8O2 molecular weight: 438.5 LC-MS (m / z): 439.2 (M+H + ) 1H-NMR(400MHz, CDCl3)δ:8.53(s,1H),7.99(d,J=8.2Hz,1H),7.55(s,1H),7.51(d,J=3.7Hz,1H),7.28-7.31(m,1H),6.94(s, 1H),5.59-5.64(m,1H),3.67(s,2H),3.21(s,4H),3.00(d,J=5.0Hz,3H),2.66(s,4H),2.08(d,J=7.0Hz,3H).

[0347] The following compounds were prepared by the same or similar methods as in the above preparations. JPEG2025535834000094.jpg76170

[0348] Experimental design The following provides exemplary experimental plans for some compounds of the present invention to demonstrate the advantageous activity and beneficial technical effects of the compounds of the present invention, which are merely illustrative of the content of the present invention and do not limit the scope of the present invention.

[0349] Experimental Example 1: In vitro cytological inhibitory activity of the compounds of the present invention Test sample: the compound of the present invention; its structural formula and preparation method are shown in the examples. Reagents and cell lines used in the experiments DMEM: Dulbecco's modified eagle medium (improved basal medium) ITS-G: Insulin, transferrin, and selenium supplement CTG:CellTiter-Glo Cell Viability Assay Kit Glutathione FBS: fetal bovine serum MDA-MB-436: BRCA1-mutated human breast adenocarcinoma cells.

[0350] Experimental method (CelltiterGlo assay) 1. Cell Preparation 1.1 Cell culture MDA-MB-436 cells are adherent cells, and the culture medium is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione. 1.2 Preparation of cell suspension Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion and ensured to be above 90%. After adjusting the appropriate concentration, 90 μL of cell suspension was added to a 96-well plate.

[0351] Table 1: Number of cell inoculations JPEG2025535834000095.jpg14170

[0352] 2. Preparation of Test Compounds 2.1 A DMSO stock solution of the test compound was prepared, and the concentration of the stock solution of the test compound was 10 mM. 2.2 Preparation of test compound working solution A 10 mM test compound stock solution was diluted to 1 mM with 10x DMSO, then serially diluted with 3x DMSO for a total of nine concentrations. 2 μL of the compound serially diluted with DMSO was then added to 198 μL of culture medium (DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione) to prepare a test compound working solution (the concentration of the compound working solution was 10 times the final concentration, with the maximum working solution concentration being 10 μM). 2.3 Compound treatment 10 μL of compound working solution (10-fold dilution, final DMSO concentration 0.1%) was added to each well of the 96-well plate inoculated with cells. The final concentrations of the test compounds were 1000.00 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.11 nM, 1.37 nM, 0.46 nM, 0.15 nM. 2.4 Installation of control wells Solvent control: 0.1% DMSO (2 μL of DMSO was diluted into 198 μL of culture medium, and then 10 μL was added to the well plate). Blank control: The 96-well plate was detected and read at 0 h after administration. 2.5 The 96-well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 7 days.

[0353] 3. Detection The CTG reagent was dissolved, equilibrated, and left at room temperature for 30 minutes. 60 μL of the reagent (Celltiterglo assay kit) was added to each well, and the plate was shaken for 2 minutes on a shaker to mix evenly (in the dark), followed by incubation at room temperature for 20 minutes (in the dark). The optical signal was read using a multi-function microplate reader. 4. Data Processing 1) Inhibition rate (%) = (reading value of DMSO solvent control well - reading value of test substance well) / (reading value of DMSO solvent control well - reading value of blank control well) x 100% 2) Plot the graph and compare the curve and IC 50 obtained. Experimental results and conclusions

[0354] Table 2: In vitro cellular activity of compounds of the invention JPEG2025535834000096.jpg126170

[0355] As can be seen from Table 2, the compounds of the present invention can effectively inhibit the proliferation of MDA-MB-436 cells, indicating that the compounds of the present invention can significantly inhibit the growth of cells with DNA repair deficiency, and have potential clinical application in treating cancer diseases caused by DNA repair deficiency.

[0356] Experimental Example 2: In vitro enzyme activity of compounds of the present invention Test sample: Compound of the present invention. For its structural formula and preparation method, see the Examples.

[0357] Experimental Reagents JPEG2025535834000097.jpg56170JPEG2025535834000098.jpg48170

[0358] Experimental Consumables JPEG2025535834000099.jpg20170

[0359] Experimental Method 1. Preparation of Histone-Coated 384-Well Plates 5 μL of histone solution was added to each well of a 384-well plate, and the plate was incubated at 4° C. overnight.

[0360] 2. The histone-coated 384-well plate was washed three times with PBST buffer. 50 μL of blocking buffer was added and incubated at room temperature for 1 hour. The well plate was washed three times with PBST buffer.

[0361] 3. Compound dilution 1) The compound of the present invention was prepared in DMSO to a concentration of 20 mM to prepare a test preliminary solution. 2) The preliminary solution of the compound of the present invention was serially diluted 4-fold to 10 concentrations, the maximum concentration being 20 mM. 3) 50 nL of the diluted compound solution was added to each well of a 96-well plate, and 19.95 μL of working solution was added to each well. The plate was then centrifuged at 1000 rpm for 1 minute. 5 μL of the compound was then transferred to a compound-treated 384-well plate.

[0362] 4. Enzyme reaction experiments 1. 10 μL of DNA solution was added to the negative control wells, and 10 μL of PARP1 & DNA (or PARP2 & DNA) mixture was added to wells other than the control wells. Then, 10 μL of NAD+ reagent was added to each well and incubated at 25°C for 60 minutes. 2. The 384-well plate was washed three times with PBST buffer. 3. Final concentrations of test compounds were 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM, 0.0038 nM.

[0363] 5. Detection 1. 20 μL of anti-Poly / Mono-ADP Ribose Rabbit mAb was added to each well and incubated at room temperature for 1.5 hours. The 384-well plate was then washed three times with PBST buffer. 2. Anti-rabbit IgG, HRP-linked antibody was diluted 2000-fold with blocking buffer, and 200 μL of the diluted antibody was added to each well. The plate was incubated at room temperature for 1 hour, and the 384-well plate was washed three times with PBST buffer. 3. 25 μL of SuperSignal ELISA Femto Substrate was added to each well and chemiluminescent detection was performed.

[0364] 6. Data analysis The inhibition rate (% inh) was calculated using the following formula. JPEG2025535834000100.jpg16170In the formula, Max indicates the luminescence signal intensity of the positive control well to which no compound was added. Min indicates the luminescence signal intensity of the negative control well to which no enzyme was added. Signal indicates the luminescence signal intensity of the test compound. IC calculated using the following formula 50 was calculated. JPEG2025535834000101.jpg17170In the formula, Y indicates % inhibition. X indicates the concentration of the compound. Top: Maximum inhibition rate Bottom: Minimum inhibition rate HillSlope: The absolute value of the maximum slope of the curve (i.e., the midpoint of the curve)

[0365] Experimental results

[0366] Table 3: Enzyme inhibitory activity of compounds of the invention JPEG2025535834000102.jpg70170Note:+:100-1000nM;++:10-100nM;+++:3-10nM;++++:1-3nM;+++++:less than 1nM.

[0367] Experimental Conclusion As can be seen from Table 3, the compounds of the present invention have good inhibitory activity and selectivity against PARP1, and are highly selective and effective PARP1 inhibitors.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof: wherein X, Y, and Z are each independently selected from N, C, or CH; Ring A and Ring B are each independently selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-7 membered heteroaryl; Ring C is selected from 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, 6- to 11-membered aryl, or 5- to 11-membered heteroaryl; Ar is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, 6-11 membered aryl, or 5-11 membered heteroaryl, optionally substituted with 1-3 substituents Q, each Q independently being H, halogen, hydroxyl, amino, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkoxy, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, -(CH ２ ) ｐ -3-10-membered cycloalkyl, -(CH ２ ) ｐ -3-10 membered heterocycloalkyl, -(CH ２ ) ｐ -N(R ａ ) (R ｂ ), -(CH ２ ) ｐ -O-R ａ , -(CH ２ ) ｐ -P(O)(R ａ ) (R ｂ ), -(CH ２ ) ｐ -S(O)(R ａ ), -(CH ２ ) ｐ -S(O) ２ (R ａ ), -(CH ２ ) ｐ -C(O)(R ａ ), -(CH ２ ) ｐ -C(O)O(R ａ ), -(CH ２ ) ｐ —O—C(O)(R ａ ), -(CH ２ ) ｐ -C(O)N(R ａ ) (R ｂ ), -(CH ２ ) ｐ -N(R ｂ )-C(O)(R ａ ) are selected from Each R １ , each R ２ are each independently hydrogen, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, or R １ , R ２ together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocyclyl; R １ ', R ２ ' are each independently hydrogen, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, Each R ３ , each R ４ , each R ５ are each independently H, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, R ａ , R ｂ are each independently hydrogen, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy-C １－６ selected from alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; m is selected from 0, 1, or 2, and when m is 2, two adjacent ring carbon atoms are connected by a single bond or a double bond; n and t are each independently selected from 0, 1, 2, or 3; p and k are each independently selected from 0, 1, or 2; q is selected from 0, 1, 2, 3 or 4; represents a single or double bond.)

2. Ring A and Ring B are independently selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; Preferably, ring A and ring B are each independently cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyrimidinyl, or tetrahydropyrimidinyl. thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl or tetrahydrooxazolyl; More preferably, ring A and ring B together with X, Y and Z The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, which comprises:

3. Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a phenyl, a 5-6 membered heteroaryl, an 8-11 membered fused ring group, an 8-11 membered spirocyclic group, a 7-9 membered bridged ring group, an 8-11 membered fused heterocyclic group, an 8-11 membered spiroheterocyclic group, or a 7-9 membered bridged heterocyclic group; Preferably, Ring C is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 7-9 membered bridged cyclic group, or a 7-9 membered bridged heterocyclic group; More preferably, ring C is and the a-terminus is bonded to Ar, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. Ar is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl optionally substituted with 1-2 Q, preferably Ar is selected from phenyl or 5-6 membered heteroaryl optionally substituted with 1-2 Q; More preferably, Ar is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, optionally substituted by 1-2 Q; Each Q is independently H, halogen, hydroxyl, amino, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkoxy, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, -(CH ２ ) ｐ -N(R ａ ) (R ｂ ), -(CH ２ ) ｐ -O-R ａ , -(CH ２ ) ｐ -P(O)(R ａ ) (R ｂ ), -(CH ２ ) ｐ -S(O)(R ａ ), -(CH ２ ) ｐ -S(O) ２ (R ａ ), -(CH ２ ) ｐ -C(O)(R ａ ), -(CH ２ ) ｐ -C(O)O(R ａ ), -(CH ２ ) ｐ —O—C(O)(R ａ ), -(CH ２ ) ｐ -C(O)N(R ａ ) (R ｂ ), -(CH ２ ) ｐ -N(R ｂ )-C(O)(R ａ ) are selected from R ａ , R ｂ are each independently hydrogen, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy-C １－６ 4. The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the aryl group is selected from alkyl, cyclopropyl or cyclobutyl.

5. X, Y, and Z are each independently selected from N or C; Ring A and ring B, together with X, Y, and Z, Configure Ring C is and the a-end is bonded to Ar; Ar is selected from pyridyl optionally substituted with 1-2 Q, each Q independently being H, halogen, hydroxyl, amino, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkoxy, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, -(CH ２ ) ｐ -C(O)N(R ａ ) (R ｂ ), -(CH ２ ) ｐ -N(R ｂ )-C(O)(R ａ ) are selected from R １ , R ２ are each independently hydrogen, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, or R １ , R ２ together with the carbon atoms attached thereto form a 3- or 4-membered cycloalkyl or a 3- or 4-membered heterocyclyl; R １ ', R ２ ' are each independently hydrogen, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, Each R ３ , each R ４ , each R ５ are each independently H, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, cyano C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, halogenated C １－６ Alkoxy, halogenated C １－６ Alkylthio, hydroxy C １－６ Alkoxy, Amino C １－６ Alkoxy, hydroxy C １－６ Alkylthio, amino C １－６ Alkylthio, C １－６ Alkoxy-C １－６ alkyl, R ａ , R ｂ are each independently hydrogen, C １－６ Alkyl, halogenated C １－６ Alkyl, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy-C １－６ alkyl or cyclopropyl; m is selected from 0 or 1; n and t are each independently selected from 0, 1, 2, or 3; p and k are each independently selected from 0, 1, or 2; q is selected from 0, 1, 2, 3 or 4; The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein represents a single bond or a double bond.

6. Ring C is and the a-end is bonded to Ar, and the other end is bonded to the para-position of X in ring B via a methylene group; Ar is selected from pyridyl optionally substituted with 1-2 Q, each Q independently being H, fluorine, chlorine, hydroxyl, amino, C １－４ Alkyl, Fluorinated C １－４ Alkyl, hydroxy C １－４ Alkyl, Amino C １－４ Alkyl, C １－４ Alkoxy-C １－４ Alkyl, C １－４ Alkoxy, Fluorinated C １－４ Alkoxy, hydroxy C １－４ Alkoxy, Amino C １－４ Alkoxy, —C(O)N(R ａ ) (R ｂ ) are selected from R １ , R ２ are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C １－４ Alkyl, halogenated C １－４ Alkyl, hydroxy C １－４ Alkyl, Amino C １－４ Alkyl, cyano C １－４ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, halogenated C １－４ Alkoxy, halogenated C １－４ Alkylthio, hydroxy C １－４ Alkoxy, Amino C １－４ Alkoxy, hydroxy C １－４ Alkylthio, amino C １－４ Alkylthio, C １－４ Alkoxy-C １－４ alkyl, or R １ , R ２ together with the carbon atom attached thereto constitute a cyclopropyl or cyclobutyl; R １ ', R ２ ' are each independently hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C １－４ Alkyl, halogenated C １－４ Alkyl, hydroxy C １－４ Alkyl, Amino C １－４ Alkyl, cyano C １－４ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, halogenated C １－４ Alkoxy, halogenated C １－４ Alkylthio, hydroxy C １－４ Alkoxy, Amino C １－４ Alkoxy, hydroxy C １－４ Alkylthio, amino C １－４ Alkylthio, C １－４ Alkoxy-C １－４ alkyl, Each R ３ , each R ４ , each R ５ are each independently H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C １－４ Alkyl, halogenated C １－４ Alkyl, hydroxy C １－４ Alkyl, Amino C １－４ Alkyl, cyano C １－４ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, halogenated C １－４ Alkoxy, halogenated C １－４ Alkylthio, hydroxy C １－４ Alkoxy, Amino C １－４ Alkoxy, hydroxy C １－４ Alkylthio, amino C １－４ Alkylthio, C １－４ Alkoxy-C １－４ alkyl, R ａ , R ｂ are each independently selected from hydrogen, methyl, ethyl, isopropyl, or cyclopropyl; n and t are each independently selected from 0, 1, or 2; k is 1, The compound according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is selected from 0 or 1.

7. The compound of claim 1, its pharmaceutically acceptable salt or its stereoisomer, selected from:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

9. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a disease associated with PARP overexpression, The disease is selected from neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, schizophrenia, chronic and acute pain, ischemia, nerve damage after hypoxia, neurodegenerative diseases, arteriosclerosis, hyperlipidemia, cardiac tissue damage, coronary artery disease, myocardial infarction, cardiogenic shock, diabetic neuropathy, osteoarthritis and osteoporosis.

10. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating cancer associated with PARP overexpression, Preferably, said cancer has a defect in the HR-dependent DNA DSB repair pathway; More preferably, the cancer comprises one or more types of cancer cells, wherein the cancer cells lack BRCA1 and / or BRCA2 or the cancer cells have a BRCA1 and / or BRCA2 deficient phenotype.

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