Polycyclic poly (ADP ribose) polymerase selective inhibitors

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a polycyclic poly (ADP ribose) polymerase (PARP) selective inhibitor compound shown in a general formula (I), pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof. The present invention relates to compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, processes for preparing the compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof. # imgabs0 #

Description

Selective inhibitors of poly(ADP-ribose) polymerase with multiple rings

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a class of compounds of selective inhibitors of poly(ADP-ribose) polymerase, pharmaceutically acceptable salts thereof or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts thereof or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts thereof or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof or stereoisomers thereof.

[0002] Targeted therapy for inhibiting PARP1 (poly(ADP-ribose) polymerase 1) is one of the research hotspots at home and abroad at present. PARP1 is the most typical member of the PARP family and plays more than 90% of the functions in the PARP family. PARP1 is a nuclear enzyme that regulates various cellular processes through PARylation (i.e., Poly(ADP-ribosyl)ation, poly ADP-ribosylation modification), including DNA damage signaling, chromatin remodeling, transcription, stabilizing replication forks, sensing unligated Okazaki fragments during replication, inflammation, and metabolism. PARP1 consists of 1014 amino acid residues and includes three domains: an N-terminal DNA binding domain (DBD), a middle autoregulatory domain (AD), and a C-terminal catalytic domain (CAT). The N-terminal DNA binding domain includes three zinc finger motifs (ZnⅠ, ZnⅡ, ZnⅢ) and a DNA strand break-sensitive element (NLS). ZnⅠ and ZnⅡ recognize damaged DNA, and ZnⅢ participates in the connection between domains and activates proteins. The middle autoregulatory domain includes a carboxyl terminus of BRCA1 (Breast Cancer 1) (DNA repair and cell signal transduction) and has Caspase-3 cleavage function. The C-terminal catalytic domain includes a tryptophan-glycine-arginine-rich domain (WGR), an α-helix domain (HD), and an ADP ribosyltransferase domain (ART). PARP1 is crucial for timely and accurate repair of DNA single-strand damage. When DNA is damaged, PARP1 is rapidly recruited to single-strand breaks (SSBs), and through binding to single-stranded DNA (ssDNA), it polymerizes itself and other proteins to complete the recruitment of downstream DNA repair factors.

[0003] DNA homologous recombination repair (HRR) is one of the core repair mechanisms for DNA double-strand damage. After BRCA1 and BRCA2 (Breast Cancer 2) are recruited, they regulate homologous recombination repair. BRCA1 initiates HR by promoting the resection of the ends of double-strand breaks (DSBs), and then acts together with BRCA2 and PALB2 (Partner and Localizer of BRCA2) downstream to stimulate the aggregation of RAD51 to the resected single-stranded DNA, and then uses the sister chromatid as a template to precisely repair the DNA damage. In addition to their roles in HR, BRCA1 and BRCA2 are also important in the S phase, protecting stalled replication forks from degradation by nucleases. Given the above roles of BRCA1 and BRCA2, mutations in both will increase the incidence of breast, ovarian, prostate, and pancreatic cancers, due to the loss of the remaining wild alleles and the high level of genomic instability caused by HR defects. BRCA1 / 2 mutant tumors with HR defects rely on compensatory DNA repair pathways, and pharmacological inhibition of key components of these pathways (such as PARP1) can cause DNA damage, leading to key genomic instability, mitotic catastrophe, and cell death in the absence of BRCA1 / 2, ultimately resulting in synthetic lethality between BRCA1 / 2 and PARP.

[0004] The molecular mechanism of action of PARP inhibitors includes two aspects. On the one hand, PARP1 inhibitors competitively bind to the CAT (catalytic domain) of PARP-1, inhibiting its catalytic activity, so that single-strand breaks (SSBs) cannot be repaired in time, resulting in double-strand breaks (DSBs). On the other hand, PARP-1 inhibitors inhibit the auto-PARylation of PARP1, and the binding to CAT causes allosteric changes in PARP1, enhancing the binding strength of PARP1 to damaged DNA, "trapping" PARP1 on the damaged DNA, making it difficult for other PARP1 in the nucleus to bind to the damaged DNA, further blocking the possible repair pathways of DSBs, and promoting apoptosis.

[0005] Since olaparib was approved for BRCA-mutated ovarian cancer in 2014, multiple PARP inhibitors have been developed and marketed, achieving widespread success. However, the adverse reactions of the drugs limit their ability to be combined with chemotherapy drugs. Most first-generation PARP inhibitors were developed and optimized before the concept of PARP1-DNA trapping was discovered, which is the mechanism by which PARP inhibitors exert a synthetic lethal effect on BRCAm cells. In addition, since the first-generation PARP inhibitors were not selectively optimized within the PARP family, this may lead to adverse side effects, including intestinal toxicity caused by tankyrase inhibition or hematotoxicity caused by PARP2 inhibition. Therefore, the development of inhibitors with trapping ability and high selectivity for PARP1, in order to reduce the toxicity of existing PARP inhibitors while ensuring drug efficacy, has become a new direction in PARP inhibitor research.

[0006]

[0007] The technical problem to be solved by the present invention is to provide a polycyclic compound with a novel structure and good selective inhibitory effect on PARP1. Further, this type of compound can be used for preventing and / or treating PARP-related diseases.

[0008] The technical solution of the present invention is as follows:

[0009] On the one hand, the present invention provides a compound represented by the following general formula (I), its pharmaceutically acceptable salt or its stereoisomer,

[0010] Wherein,

[0011] X, Y, and Z are each independently selected from N, C, or CH;

[0012] Ring A and ring B are each independently selected from 5-7-membered cycloalkyl, 5-7-membered heterocyclic group, phenyl, or 5-7-membered heteroaryl;

[0013] Ring C is selected from 3-11-membered cycloalkyl, 3-11-membered heterocyclic group, 6-11-membered aryl, or 5-11-membered heteroaryl;

[0014] Ar is selected from 3-11-membered cycloalkyl, 3-11-membered heterocyclic group, 6-11-membered aryl, or 5-11-membered heteroaryl optionally substituted by 1-3 substituents Q; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 alkyl, halo 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, halo C1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, -(CH 2 ) p -3- to 10-membered cycloalkyl, -(CH 2 ) p -3- to 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 );

[0015] Each R 1 、each R 2 is independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo C 1-6Alkylthio, 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 commonly attached form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocyclic group;

[0016] R 1 ’, R 2 ’ are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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;

[0017] Each R 3 、each R 4 、each R 5 is independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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;

[0018] R a 、R bIndependently selected from hydrogen, C 1-6 alkyl, halo-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 alkyl, a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group;

[0019] m is selected from 0, 1 or 2, and when m is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0020] n and t are independently selected from 0, 1, 2 or 3;

[0021] p and k are independently selected from 0, 1 or 2;

[0022] q is selected from 0, 1, 2, 3 or 4;

[0023] represents a single bond or a double bond.

[0024] In certain embodiments, X, Y, and Z are independently selected from N or C.

[0025] In certain embodiments, X, Y, and Z are independently selected from N or C; and at most one of X, Y, and Z is N.

[0026] In certain embodiments, X is N, and Y and Z are C.

[0027] In certain embodiments, Y is N, and X and Z are C.

[0028] In certain embodiments, Z is N, and X and Y are C.

[0029] In certain embodiments, X, Y, and Z are all C.

[0030] In certain embodiments, ring A and ring B are independently selected from a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclic group, a phenyl, or a 5- to 6-membered heteroaryl.

[0031] In certain embodiments, ring A and ring B are independently selected from a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms, a phenyl, or a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms; the heteroatoms are selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0032] In certain embodiments, ring A is selected from a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclic group, a phenyl, or a 5- to 6-membered heteroaryl; ring B is selected from a phenyl or a 5- to 6-membered heteroaryl.

[0033] In certain embodiments, ring A is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms; ring B is selected from phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms; the heteroatoms are selected from nitrogen atom, oxygen atom, or sulfur atom.

[0034] In certain embodiments, ring B is selected from phenyl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms.

[0035] In certain 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, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, furyl, dihydrofuryl, tetrahydrofuryl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl, or tetrahydrooxazolyl.

[0036] In certain embodiments, ring A is selected from cyclopentane, cyclohexane, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, furyl, dihydrofuryl, tetrahydrofuryl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl, or tetrahydrooxazolyl;

[0037] ring B is selected from phenyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, dihydropyrazolyl, imidazolyl, dihydroimidazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, piperidinyl, dihydropiperidinyl, piperazinyl, dihydropiperazinyl, furyl, pyranyl, dihydropyranyl, thiazolyl, oxazolyl, or triazole.

[0038] In certain embodiments, ring A, ring B, and X, Y, Z together form the following groups:

[0039] In certain embodiments, ring A, ring B, and X, Y, Z together form the following groups:

[0040] In certain embodiments, ring A, ring B, and X, Y, Z together form the following group:

[0041] In certain embodiments, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, phenyl, 5- to 6-membered heteroaryl, 8- to 11-membered fused ring, 8- to 11-membered spiro ring, 7- to 9-membered bridged ring, 8- to 11-membered fused heterocyclic, 8- to 11-membered spiro heterocyclic, or 7- to 9-membered bridged heterocyclic.

[0042] In certain embodiments, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, phenyl, 5- to 6-membered heteroaryl, 8- to 11-membered fused cycloalkyl, 8- to 11-membered spiro ring, 7- to 9-membered bridged ring, 8- to 11-membered fused heterocyclic, 8- to 11-membered spiro heterocyclic, or 7- to 9-membered bridged heterocyclic.

[0043] In certain embodiments, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, 7- to 9-membered bridged ring, or 7- to 9-membered bridged heterocyclic.

[0044] In certain embodiments, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, 7- to 8-membered bridged ring, or 7- to 8-membered bridged heterocyclic.

[0045] In certain embodiments, ring C is selected from the following groups:

[0046] and the a end is connected to Ar.

[0047] In certain embodiments, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic.

[0048] In certain embodiments, ring C is selected from the following groups:

[0049] and the a end is connected to Ar.

[0050] In certain embodiments, Ar is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl optionally substituted with 1-2 Qs; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 alkyl, halo 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, halo C 1-6Alkoxy, 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 );

[0051] R a 、R b are each independently selected from hydrogen, C 1-6 alkyl, halo 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 alkyl, cyclopropyl or cyclobutyl.

[0052] In certain embodiments, Ar is selected from phenyl or 5-6 membered heteroaryl optionally substituted with 1-2 Q.

[0053] In certain embodiments, Ar is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-2 Q.

[0054] In certain embodiments, Ar is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, optionally substituted with 1-2 Q groups.

[0055] In certain embodiments, Ar is selected from phenyl or a 6-membered heteroaryl, optionally substituted with 1-2 Q groups.

[0056] In certain embodiments, Ar is selected from phenyl or a 6-membered nitrogen-containing heteroaryl, optionally substituted with 1-2 Q groups.

[0057] In certain embodiments, Ar is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, optionally substituted with 1-2 Q groups.

[0058] In certain embodiments, X, Y, and Z are each independently selected from N or C;

[0059] Ring A, ring B, and X, Y, and Z together form the following groups:

[0060] Ring C is selected from a 5-6 membered cycloalkyl or a 5-6 membered heterocyclic group;

[0061] Ar is selected from pyridyl, optionally substituted with 1-2 Q groups; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, halo-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, halo-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 );

[0062] Each R 1 、each R 2 is independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo-C 1- 6 alkyl, hydroxy-C 1-6 alkyl, amino-C1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halo C 1-6 alkoxy, halo 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 commonly attached form a 3- to 4-membered cycloalkyl or 3- to 4-membered heterocyclic group;

[0063] R 1 ’, R 2 ’ are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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;

[0064] each R 3 , each R 4 , each R 5 are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo C 1-6 alkylthio, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy, hydroxy C 1- 6 alkylthio, amino C 1-6Alkylthio, C 1-6 Alkoxy-C 1-6 alkyl;

[0065] R a 、R b are each independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl or cyclopropyl;

[0066] m is selected from 0 or 1;

[0067] n and t are each independently selected from 0, 1, 2 or 3;

[0068] p and k are each independently selected from 0, 1 or 2;

[0069] q is selected from 0, 1, 2, 3 or 4;

[0070] represents a single bond or a double bond.

[0071] In certain embodiments, X, Y, and Z are each independently selected from N or C;

[0072] Ring A, ring B, and X, Y, and Z together form the following group:

[0073] Ring C is selected from the following groups:

[0074] and the a end is connected to Ar;

[0075] Ar is selected from a pyridyl group optionally substituted with 1-2 Qs; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, halo 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, halo 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 );

[0076] Each R 1 、each R 2 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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 and the carbon atom to which it is attached together form a 3- to 4-membered cycloalkyl or 3- to 4-membered heterocyclic group;

[0077] R 1 ’, R 2 ’ are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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;

[0078] Each R 3 , each R 4 , each R 5 is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo 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;

[0079] R a 、R b are each independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl or cyclopropyl;

[0080] m is selected from 0 or 1;

[0081] n and t are each independently selected from 0, 1, 2 or 3;

[0082] p and k are each independently selected from 0, 1 or 2;

[0083] q is selected from 0, 1, 2, 3 or 4;

[0084] represents a single bond or a double bond.

[0085] In certain embodiments, ring C is and the a end is connected to Ar, and the other end is connected to the para position of X in ring B through an alkylene group.

[0086] In certain embodiments, X, Y, and Z are each independently selected from N or C;

[0087] Ring A, ring B and X, Y, Z together form the following group:

[0088] Ring C is and the a end is connected to Ar, and the other end is connected to the para position of X in ring B through an alkylene group;

[0089] Ar is selected from pyridyl optionally substituted by 1-2 Qs; each Q is independently selected from H, fluorine, chlorine, hydroxy, amino, C1-4 alkyl, fluoro-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, fluoro-C 1-4 alkoxy, hydroxy-C 1-4 alkoxy, amino-C 1-4 alkoxy, -C(O)N(R a )(R b )

[0090] Each R 1 and each R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, amino, cyano, C 1-4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-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 and R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl;

[0091] R 1 ’ and R 2 ’ are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, amino, cyano, C 1-4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-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 1-4Alkoxy-C 1-4 alkyl;

[0092] Each R 3 、each R 4 、each R 5 is independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-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;

[0093] R a 、R b is independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0094] m is selected from 0 or 1;

[0095] n and t are independently selected from 0, 1 or 2;

[0096] k is 1;

[0097] q is selected from 0 or 1;

[0098] represents a single bond or a double bond.

[0099] In certain embodiments, ring A, ring B and X, Y, Z together form the following group:

[0100] Ring C is and the a end is connected to Ar, and the other end is connected to the para position of X in ring B through an alkylene group;

[0101] Ar is selected from pyridyl optionally substituted by 1-2 Qs; each Q is independently selected from H, fluorine, chlorine, hydroxyl, amino, C 1-4 alkyl, fluoro-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-4Alkoxy-C 1-4 alkyl, C 1-4 alkoxy, fluoro-C 1-4 alkoxy, hydroxy-C 1-4 alkoxy, amino-C 1-4 alkoxy, -C(O)N(R a )(R b );

[0102] Each R 1 、each R 2 is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, amino, cyano, C 1-4 alkyl, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl;

[0103] Or R 1 、R 2 and the carbon atom to which they are commonly attached together form cyclopropyl or cyclobutyl;

[0104] R 1 ’, R 2 ’ are independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, amino, cyano, C 1-4 alkyl, halo-C 1- 4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl;

[0105] R 3 、R 4 are independently selected from H, fluorine, chlorine, bromine, hydroxy, amino, cyano, C 1-4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-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;

[0106] R a and R b are each independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0107] m is selected from 0 or 1;

[0108] n and t are each independently selected from 0 or 1;

[0109] k is 1;

[0110] q is 0;

[0111] represents a single bond or a double bond.

[0112] In certain embodiments, ring A, ring B and X, Y, Z together form the following group:

[0113] Ring C is and the a end is connected to Ar, and the other end is connected to the para position of X in ring B through an alkylene group;

[0114] Ar is selected from pyridyl optionally substituted by 1-2 Qs; each Q is independently selected from H, fluorine, chlorine, hydroxyl, amino, C 1-4 alkyl, fluoro-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, fluoro-C 1-4 alkoxy, hydroxy-C 1-4 alkoxy, amino-C 1-4 alkoxy, -C(O)N(R a )(R b );

[0115] Each R 1 and each R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkyl, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl;

[0116] or R 1 and R 2 and the carbon atom to which they are commonly attached together form cyclopropyl or cyclobutyl;

[0117] R1 ’, R 2 ’ are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 -alkyl, halo-C 1- 4 -alkyl, hydroxy-C 1-4 -alkyl, amino-C 1-4 -alkyl or C 1-4 -alkoxy-C 1-4 -alkyl;

[0118] R 3 , R 4 are each independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 -alkyl, halo-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, halo-C 1-4 -alkoxy, halo-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;

[0119] R a , R b are each independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0120] m is selected from 0 or 1;

[0121] n and t are each independently selected from 0 or 1;

[0122] k is 1;

[0123] q is 0;

[0124] represents a single bond or a double bond.

[0125] In certain embodiments, ring A, ring B and X, Y, Z together form the following group:

[0126] Ring C is and the a end is connected to Ar, and the other end is connected to the para position of X in ring B through an alkylene group;

[0127] Ar is selected from a pyridyl group optionally substituted by one or two Qs; each Q is independently selected from H, fluorine, chlorine, hydroxyl, amino, C 1-4 alkyl, fluoro-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, fluoro-C 1-4 alkoxy, hydroxy-C 1-4 alkoxy, amino-C 1-4 alkoxy, -C(O)N(R a )(R b );

[0128] Each R 1 and each R 2 are independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkyl, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl;

[0129] Or R 1 , R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl;

[0130] R 1 ’, R 2 ’ are independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkyl, halo-C 1- 4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl;

[0131] R 3 , R 4 are independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, hydroxy-C1-4 Alkoxy, amino C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 Alkylthio, C 1-4 Alkoxy-C 1-4 Alkyl;

[0132] R a and R b are each independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0133] m is selected from 0 or 1;

[0134] n and t are each independently selected from 0 or 1;

[0135] k is 1;

[0136] q is 0;

[0137] represents a single bond or a double bond.

[0138] In one aspect, the present invention provides a compound represented by the following general formula (II), its pharmaceutically acceptable salt or its stereoisomer,

[0139] wherein R 1 and R 2 and R 1 ', R 2 ', R 3 and R 4 and R 5 and R a and R b and Q, X, Y, Z, ring A, ring B, m, n, t, k, q, are defined as described in any of the previous aspects.

[0140] In one aspect, the present invention provides a compound represented by the following general formula (II-1), its pharmaceutically acceptable salt or its stereoisomer,

[0141] wherein R 1 and R 2 and R 1 ', R 2 ', R 3 and R 4 and R 5 and R a and R b and Q, Y, ring A, m, n, t, k, q, is defined as described in any of the previous embodiments.

[0142] In one aspect, the present invention provides a compound represented by the following general formula (II-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0143] wherein R 1 , R 2 , R 1 ’, R 2 ’, R 3 , R 4 , R 5 , R a , R b , Q, Y, ring A, m, n, t, k, q, are defined as described in any of the previous embodiments.

[0144] In one aspect, the present invention provides a compound represented by the following general formula (II-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0145] wherein m’ is selected from 1 or 2, and when m’ is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0146] R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , Q, Y, ring A, ring B, n, t, k, q are defined as described in any of the previous embodiments.

[0147] In one aspect, the present invention provides a compound represented by the following general formula (II-4), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0148] wherein m’ is selected from 1 or 2, and when m’ is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0149] R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , Q, Y, ring A, ring B, n, t, k, q are defined as described in any of the previous embodiments.

[0150] In one aspect, the present invention provides a compound represented by the following general formula (II-5), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0151] wherein m' is selected from 1 or 2, and when m' is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond; represents a single bond or a double bond; R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b 、Q, ring A, ring B, n, t, k, q are defined as described in any of the previous aspects.

[0152] In one aspect, the present invention provides a compound represented by the following general formula (II-6), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0153] wherein m' is selected from 1 or 2, and when m' is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond; represents a single bond or a double bond;

[0154] R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b 、Q, ring A, ring B, n, t, k, q are defined as described in any of the previous aspects.

[0155] In one aspect, the present invention provides a compound represented by the following general formula (II-7), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0156] wherein m' is selected from 1 or 2, and when m' is selected from 2, the adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0157] R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R bThe definitions of, Q, ring A, ring B, n, t, k, and q are as described in any of the previous embodiments.

[0158] In one aspect, the present invention provides a compound represented by the following general formula (II-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0159] wherein m' is selected from 1 or 2, and when m' is selected from 2, adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0160] R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b The definitions of, Q, ring A, ring B, n, t, k, and q are as described in any of the previous embodiments.

[0161] In one aspect, the present invention provides a compound represented by the following general formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0162] wherein m' is selected from 1 or 2, and when m' is selected from 2, adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0163] R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b The definitions of, Q, n, t, k, and q are as described in any of the previous embodiments.

[0164] In one aspect, the present invention provides a compound represented by the following general formula (III-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0165] wherein m' is selected from 1 or 2, and when m' is selected from 2, adjacent two ring carbon atoms are connected by a single bond or a double bond;

[0166] R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b The definitions of, Q, n, t, k, and q are as described in any of the previous embodiments.

[0167] In one aspect, the present invention provides a compound represented by the following general formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0168] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b 、Q, n, t, and q are defined as described in any of the previous aspects.

[0169] In one aspect, the present invention provides a compound represented by the following general formula (IV-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0170] wherein R 1 、R 2 、R 3 、R 4 、R a 、R b 、Q, n, and t are defined as described in any of the previous aspects.

[0171] In one aspect, the present invention provides a compound represented by the following general formula (IV-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0172] wherein R 1 、R 2 、R 3 、R 4 、R a 、R b 、n and t are defined as described in any of the previous aspects.

[0173] In one aspect, the present invention provides a compound represented by the following general formula (IV-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0174] wherein R 1 、R 2 、R 3 、R 4 、n and t are defined as described in any of the previous aspects.

[0175] In one aspect, the present invention provides a compound represented by the following general formula (V), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0176] Among them, n is selected from 0 or 1; R 1 and R 2 and R 3 and R 4 and R 5 and R a and R b and Q, t, q are defined as described in any of the previous embodiments.

[0177] In one aspect, the present invention provides a compound represented by the following general formula (V-1), its pharmaceutically acceptable salt or its stereoisomer,

[0178] Among them, n is selected from 0 or 1; R 1 and R 2 and R 3 and R 4 and R a and R b and Q, t are defined as described in any of the previous embodiments.

[0179] In one aspect, the present invention provides a compound represented by the following general formula (V-2), its pharmaceutically acceptable salt or its stereoisomer,

[0180] Among them, n is selected from 0 or 1; R 1 and R 2 and R 3 and R 4 and R a and R b and t are defined as described in any of the previous embodiments.

[0181] In one aspect, the present invention provides a compound represented by the following general formula (V-3), its pharmaceutically acceptable salt or its stereoisomer,

[0182] Among them, n is selected from 0 or 1; R 1 and R 2 and R 3 and R 4 and t are defined as described in any of the previous embodiments.

[0183] In one aspect, the present invention provides a compound represented by the following general formula (VI) or (VII), its pharmaceutically acceptable salt or its stereoisomer,

[0184] Among them, n is selected from 0 or 1; R 1, R 2 , R 3 , R 4 , R 5 , R a , R b , Q, t, q are defined as described in any of the previous aspects.

[0185] In one 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,

[0186] wherein n is selected from 0 or 1; R 1 , R 2 , R 3 , R 4 , R a , R b , Q, t are defined as described in any of the previous aspects.

[0187] In one 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,

[0188] wherein n is selected from 0 or 1; R 1 , R 2 , R 3 , R 4 , R a , R b , t is defined as described in any of the previous aspects.

[0189] In one 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,

[0190] wherein n is selected from 0 or 1; R 1 , R 2 , R 3 , R 4 , t is defined as described in any of the previous aspects.

[0191] In one aspect, the present invention provides a compound represented by the following, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0192] In another aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients, and the pharmaceutical composition can be any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances that are non-toxic, compatible with the active ingredient and otherwise biologically suitable for organisms. The choice of specific excipients will depend on the mode of administration or the type and condition of the disease for treating a particular patient.

[0193] In certain embodiments, the above-mentioned pharmaceutical composition can be administered to a patient or subject in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. When used for parenteral administration, the above-mentioned pharmaceutical composition can also be made into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition can be made into inhalation preparations, aerosols, powder aerosols or sprays, etc.

[0194] In another aspect, the pharmaceutical composition of the present invention, which contains the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, may further contain one or more second therapeutic active agents.

[0195] In another aspect, the present invention also relates to the use of the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for preventing and / or treating diseases associated with overexpression of PARP, and the diseases are 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 neuronal injury, neurodegenerative diseases, atherosclerosis, hyperlipidemia, heart tissue injury, coronary artery disease, myocardial infarction, cardiogenic shock, diabetic neuropathy, osteoarthritis and osteoporosis.

[0196] In another aspect, the present invention also relates to the use of the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for preventing and / or treating cancer.

[0197] Furthermore, the present invention also relates to the use of a pharmaceutical composition containing the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for preventing and / or treating cancer associated with overexpression of PARP.

[0198] In certain embodiments, the cancer lacks the HR-dependent DNA DSB repair pathway.

[0199] In certain embodiments, it comprises one or more cancer cells that have a reduced or eliminated ability to repair DNA DSBs by HR relative to normal cells.

[0200] In certain embodiments, the cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2.

[0201] In certain embodiments, the cancer comprises one or more cancer cells that have a BRCA1 and / or BRCA2-deficient phenotype.

[0202] In another aspect, the present invention also provides a method for treating a PARP-related disease, the method comprising administering to a patient in need an effective amount of the foregoing compound, its pharmaceutically acceptable salt or its stereoisomer, or the foregoing pharmaceutical composition.

[0203] Furthermore, the present invention also provides a method for treating cancer, the method comprising administering to a patient in need an effective amount of the foregoing compound, its pharmaceutically acceptable salt or its stereoisomer, or the foregoing pharmaceutical composition.

[0204] In certain embodiments, the cancer lacks the HR-dependent DNA DSB repair pathway.

[0205] In certain embodiments, it comprises one or more cancer cells that have a reduced or eliminated ability to repair DNA DSBs by HR relative to normal cells.

[0206] In certain embodiments, the cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2.

[0207] In certain embodiments, the cancer comprises one or more cancer cells that have a BRCA1 and / or BRCA2-deficient phenotype.

[0208] In another aspect, the present invention also provides a kit comprising an effective amount of one or more of the foregoing compounds, its pharmaceutically acceptable salt or its stereoisomer.

[0209] In another aspect, the present invention also provides a kit comprising:

[0210] (a) an effective amount of one or more of the foregoing compounds, its pharmaceutically acceptable salt or its stereoisomer,

[0211] and (b) an effective amount of one or more anti-cancer agents.

[0212] As used herein, an "effective amount" of the present invention refers to the dosage of a drug that can prevent, alleviate, delay, inhibit, or cure the disease of a subject. The size of the dosage administered is related to the mode of drug administration, the pharmacokinetics of the pharmaceutical agent, the severity of the disease, the individual characteristics of the subject (gender, weight, height, age), etc.

[0213] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations provided in the present invention shall prevail.

[0214] As used herein, "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0215] As used herein, "C 1-6 alkyl" represents a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms, including, for example, "C 1-4 alkyl", "C 1-3 alkyl", "C 1-2 alkyl", "C 2-6 alkyl", "C 2-5 alkyl", "C 2-4 alkyl", "C 2-3 alkyl", etc. 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. As used herein, "C 1-4 alkyl" refers to specific examples of C 1-6 alkyl containing 1-4 carbon atoms.

[0216] As used herein, "C 1-6 alkoxy" means "C 1-6 alkyl-O-", and the "C 1-6 alkyl" is as defined above. As used herein, "C 1-4 alkoxy" means "C 1-4 alkyl-O-", and the "C 1-4 alkyl" is as defined above.

[0217] As used herein, "C 1-6"Alkylthio" means "C 1-6 alkyl - S -", where the " 1-6 alkyl" is as defined above. The " 1-4 alkylthio" in the present invention means "C 1-4 alkyl - S -", where the " 1-4 alkyl" is as defined above.

[0218] The "hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy - C 1-6 alkyl" in the present invention means that one or more hydrogens in C 1-6 alkyl are respectively replaced by one or more hydroxy groups, amino groups, halogens, cyano groups or C 1-6 alkoxy groups. C 1-6 alkyl and C 1-6 alkoxy are as defined above.

[0219] The "hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy, halo C 1-6 alkoxy, cyano C 1-6 alkoxy" in the present invention means that one or more hydrogens in " 1-6 alkoxy" are replaced by one or more hydroxy groups, amino groups, halogens or cyano groups.

[0220] The "hydroxy C 1-6 alkylthio, amino C 1-6 alkylthio, halo C 1-6 alkylthio" in the present invention means that one or more hydrogens in " 1-6 alkylthio" are replaced by one or more hydroxy groups, amino groups or halogens.

[0221] The "fluoro C 1-6 alkyl" and "fluoro C 1-6 alkoxy" in the present invention respectively mean that one or more hydrogens in " 1-6 alkyl" and " 1-6 alkoxy" are replaced by one or more fluorine atoms.

[0222] The "3- to 11-membered heterocyclic group" as used in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic or polycyclic group having at least one heteroatom or group (for example, having 1, 2, 3, 4 or 5) and having 3 to 11 ring atoms, and the heteroatom or group is selected from a nitrogen atom, an oxygen atom and a sulfur atom. Optionally, the ring atoms (such as a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo-substituted. The "3- to 11-membered heterocyclic group" includes, but is not limited to, a "3- to 10-membered heterocyclic group", a "3- to 8-membered monocyclic heterocyclic group", an "8- to 11-membered fused heterocyclic group", an "8- to 11-membered spiro heterocyclic group", and a "7- to 9-membered bridged heterocyclic group".

[0223] The "3- to 8-membered monocyclic heterocyclic group" as used in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic ring group having at least one heteroatom (e.g., having 1, 2, 3, 4 or 5), and having 3 to 8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. The "3- to 8-membered monocyclic heterocyclic group" as used in the present invention includes "3- to 8-membered saturated monocyclic heterocyclic group" and "3- to 8-membered partially saturated monocyclic heterocyclic group". Preferably, the "3- to 8-membered monocyclic heterocyclic group" of the present invention contains 1 to 3 heteroatoms; preferably, the "3- to 8-membered monocyclic heterocyclic group" of the present invention contains 1 to 2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3- to 8-membered monocyclic heterocyclic group" of the present invention contains 1 heteroatom, and the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. The "3- to 8-membered monocyclic heterocyclic group" is preferably "3- to 7-membered monocyclic heterocyclic group", "3- to 6-membered monocyclic heterocyclic group", "4- to 7-membered monocyclic heterocyclic group", "4- to 6-membered monocyclic heterocyclic group", "6- to 8-membered monocyclic heterocyclic group", "5- to 7-membered monocyclic heterocyclic group", "5- to 7-membered saturated monocyclic heterocyclic group", "5- to 7-membered partially saturated monocyclic heterocyclic group", "5- to 6-membered monocyclic heterocyclic group", "5- to 6-membered saturated monocyclic heterocyclic group", "5- to 6-membered partially saturated monocyclic heterocyclic group", "3- to 6-membered saturated monocyclic heterocyclic group", "5- to 6-membered saturated monocyclic heterocyclic group", "3- to 6-membered nitrogen-containing monocyclic heterocyclic group", "3- to 6-membered saturated nitrogen-containing monocyclic heterocyclic group", "5- to 6-membered nitrogen-containing monocyclic heterocyclic group", "5- to 6-membered saturated nitrogen-containing monocyclic heterocyclic group", "5- to 6-membered partially saturated nitrogen-containing monocyclic heterocyclic group", "6-membered saturated monocyclic heterocyclic group", "6-membered saturated nitrogen-containing monocyclic heterocyclic group", etc. Specific examples of the "3- to 8-membered monocyclic heterocyclic group" include but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, oxetanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridyl, piperidone, tetrahydropyridone, dihydropiperidone, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, etc.

[0224] The "8-11 membered fused heterocyclic group" as used in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-11 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, with at least one ring atom being a heteroatom, and one of the fused rings in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Among them, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can optionally be oxo-substituted. Specific examples include but are not limited to: dihydrofuropyridine, 3,4-dihydro-2H-pyranopyridine, 3,4-dihydro-2H-oxazinopyridine, dihydrooxazinopyrimidine, benzodihydrofuranyl, etc.

[0225] The "8-11 membered spiro heterocyclic group" as used in the present invention refers to a saturated or partially saturated cyclic structure containing 8-11 ring atoms formed by two or more cyclic structures sharing 1 ring atom with each other, where at least one ring atom is a heteroatom or a group, such as N, NH, O, S, CO, SO, SO 2 etc., preferably the number of heteroatoms or groups is 1, 2, 3, 4 or 5, and more preferably 1 or 2. For example, it includes "9-11 membered spiro heterocyclic group", "9-11 membered saturated spiro heterocyclic group", "9-11 membered partially saturated spiro heterocyclic group", etc. Specific examples include but are not limited to:

[0226] The "7-9 membered bridged heterocyclic group" as used in the present invention refers to a saturated or partially saturated cyclic structure containing 7-9 ring atoms formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, where at least one ring atom is a heteroatom or a group, such as N, NH, O, S, CO, SO, SO 2 etc., preferably the number of heteroatoms or groups is 1, 2, 3, 4 or 5, and more preferably 1 or 2. For example, it includes "7-8 membered bridged heterocyclic group", "7-8 membered saturated bridged heterocyclic group", "8 membered bridged heterocyclic group", "8 membered saturated bridged heterocyclic group", etc. Specific examples include but are not limited to:

[0227] The "3-11 membered cycloalkyl" as described in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic or polycyclic group containing 3-11 ring atoms. The "3-11 membered cycloalkyl" as described in 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 cycloalkyl", "8-11 membered spiro group", "7-9 membered bridged cycloalkyl". Among them, the "3-8 membered monocyclic cycloalkyl" includes but is not limited to cyclopentyl, cyclohexyl,

[0228] The "8-11 membered spiro group" as described in the present invention refers to a saturated or partially saturated cyclic structure containing 8-11 ring carbon atoms formed by two or more cyclic structures sharing 1 ring atom with each other, such as "9-11 membered spiro group", "9-11 membered saturated spiroheterocyclic group", "9-11 membered partially saturated spiroheterocyclic group", etc. Specific examples include but are not limited to:

[0229] The "7-9 membered bridged cycloalkyl" as described in the present invention refers to a saturated or partially saturated cyclic structure containing 7-9 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, such as including "7-8 membered bridged cycloalkyl", "7-8 membered saturated bridged cycloalkyl", "8 membered bridged heterocyclic group", "8 membered saturated bridged cycloalkyl", "8 membered partially saturated bridged cycloalkyl", etc. Specific examples include but are not limited to:

[0230] The "8-11 membered fused cycloalkyl" as described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-11 ring carbon atoms formed by two or more cyclic structures sharing two adjacent atoms with each other. One of the rings in the fused rings can be an aromatic ring, but the fused rings as a whole do not have aromaticity. Its examples include but are not limited to: etc. The definition of the "8-11 membered fused ring group" is the same as that of the "8-11 membered fused cycloalkyl".

[0231] The "6-11 membered aryl" as described in the present invention includes "6-8 membered monocyclic aryl" and "8-11 membered fused aryl".

[0232] The "6-8 membered monocyclic aryl" as described in the present invention refers to a monocyclic aryl containing 6-8 ring carbon atoms. Its examples include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0233] The "5-11 membered heteroaryl" as described in the present invention includes "5-8 membered monocyclic heteroaryl" and "8-11 membered fused heteroaryl".

[0234] The "5-8 membered monocyclic heteroaryl" as described in the present invention refers to a monocyclic aromatic cyclic group containing 5-8 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. The "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" contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (such as an oxygen atom and / or a sulfur atom), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (such as an oxygen atom and / or a sulfur atom). Specific examples of the "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, 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-pyridone, 4-pyridone, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepine, 1,3-diazepine, azocine, etc. The "5-6 membered monocyclic heteroaryl" refers to specific examples of the 5-8 membered heteroaryl containing 5-6 ring atoms.

[0235] The "8-10 membered fused heteroaryl" as used in the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (where at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. It includes "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl fused with 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0236] The "oxo group" as used in the present invention 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 can be oxo-substituted to form a C=O, N=O, S=O or SO 2 structure.

[0237] The term "optionally substituted" as used in the present invention refers to two situations where one or more hydrogen atoms on the substituent can be "substituted" or "not substituted" by one or more substituents.

[0238] The "DSB" as used in the present invention has the full English name of Double-strand breaks, which refers to DNA double-strand breaks.

[0239] The "HR" as used in the present invention refers to Homologous Recombination, that is, homologous recombination.

[0240] The "CH" as used in the present invention refers to the following structure:

[0241] The "N" as used in the present invention refers to the following structure:

[0242] The "C" as used in the present invention refers to the following structure:

[0243] The "-(CH 2 ) p -P(O)(R a )(R b)” means In the present invention, the definitions of other similar groups are the same as “-(CH 2 ) p -P(O)(R a )(R b )”.

[0244] “Each R 1 ” in the present invention means that when m is 2, 3 or 4, each R 1 in a plurality of R 1 is independently selected from the groups described in the above technical solutions.

[0245] “Each R 2 ” in the present invention means that when n is 2, 3 or 4, each R 2 in a plurality of R 2 is independently selected from the groups described in the above technical solutions.

[0246] “Optionally substituted” in the present invention means two situations where one or more hydrogen atoms on the substituted group are “substituted” or “not substituted” by one or more substituents.

[0247] When ring A contains NH, for example the H in NH on the ring can be substituted by R 1 .

[0248] When ring B is selected from a nitrogen-containing heterocycle or heteroaryl and contains NH, the H in NH on the ring can be substituted by R 2 .

[0249] “Pharmaceutically acceptable salts” in the present invention means salts formed by acidic functional groups (such as -COOH, -OH, -SO 3 H, etc.) present in the compound with appropriate inorganic or organic cations (bases), including salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH 2 , etc.) present in the compound with appropriate inorganic or organic anions (acids), including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).

[0250] “Stereoisomers” in the present invention means that the compounds of the present invention contain one or more asymmetric centers, and thus can exist as racemates and racemic mixtures, single enantiomers, diastereoisomer mixtures and single diastereoisomers. The compounds of the present invention can have asymmetric centers, and each such asymmetric center independently gives rise to two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures.

[0251] Unless otherwise specified, the compounds described in the present invention containing olefin double bonds include cis isomers and trans isomers. The compounds described in the present invention may exist in the form of tautomers (a type of functional group isomers), which have different hydrogen attachment points through the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included within the scope of the present invention.

[0252] All stereoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and their mixtures of the compounds are included within the scope of the present invention.

[0253] The compounds of the present invention can be prepared in the form of individual enantiomers by enantioselective synthesis or resolution from a mixture of enantiomers. Conventional resolution techniques include the use of various well-known chromatographic methods to resolve mixtures of enantiomers of the starting material or the final product.

[0254] When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomers are at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight or 99.9% by weight pure relative to other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight or 99.9% by weight pure. The weight % of optical purity is the ratio of the weight of the enantiomer to the sum of the weight of the enantiomer and the weight of its optical isomer.

[0255] Advantages of the Invention

[0256] 1. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have excellent PARP1 inhibitory effects, can effectively inhibit the growth of tumor cells, and have good pharmacokinetic properties in vivo (such as mice, rats, dogs, etc.), with a long-lasting effect and high bioavailability.

[0257] 2. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good therapeutic effects on cancer and high stability in liver microsomes.

[0258] 3. The preparation process of the compounds of the present invention is simple, the drug purity is high, the quality is stable, and it is easy to carry out large-scale industrial production. Specific Embodiments

[0259] The technical solutions of the present invention will be described below in conjunction with specific embodiments. The above content of the present invention will be further described in detail, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following embodiments. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0260] Abbreviation:

[0261] NBS: N-bromosuccinimide; TBSCl: tert-butyldimethylchlorosilane; TBAF: tetrabutylammonium fluoride; Prep-TLC: preparative thin-layer chromatography; Xphos Pd G2: 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]undec-7-ene; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Tf 2 O: trifluoromethanesulfonic anhydride; select F: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate); LDA: lithium diisopropylamide; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; RuPhosPdG3: methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); DAST: diethylaminosulfur trifluoride; T3P: 1-propylphosphonic anhydride; DIAD: diisopropyl azodicarboxylate.

[0262] 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-methylpicolinamide (Compound 1)

[0263] 1. Preparation of methyl 4-amino-5-bromo-2-fluorobenzoate

[0264] Dissolve methyl 4-amino-2-fluorobenzoate (20.0 g, 118.3 mmol) in acetonitrile (300 mL), add NBS (19.0 g, 106.5 mmol) at 0 °C, and react at 0 °C for 1 hour. Then transfer to 25 °C and react for 8 hours until the reaction is complete. Concentrate in vacuo and purify by column chromatography (ethyl acetate / petroleum ether = 0 - 20%) to obtain the product (21.0 g, yield: 71.9%).

[0265] 2. Preparation of methyl 4-amino-5-bromo-2-fluoro-3-nitrobenzoate

[0266] Methyl 4-amino-5-bromo-2-fluorobenzoate (21.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (300 mL). Potassium nitrate (9.5 g, 93.5 mmol) was slowly added at 0 °C, and the reaction was continued for 0.5 h. After the reaction was completed, the reaction solution was added to ice water to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was collected, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0 - 20%) to obtain the target compound (24.0 g, yield: 96.4%).

[0267] 3. Preparation of methyl (E)-4-amino-5-(2-ethoxyvinyl)-2-fluoro-3-nitrobenzoate

[0268] 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-dioxaborolane (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 2 (3.0 g, 4.1 mmol) were added. Under nitrogen protection, the reaction was carried out at 100 °C for 6 h. After the reaction was completed, the mixture was extracted with water (200 mL) and ethyl acetate (200 mL × 2), and the organic phase was collected. The crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to obtain the product (6.0 g, yield 51.3%).

[0269] 4. Preparation of methyl 6-fluoro-7-nitro-1H-indole-5-carboxylate

[0270] 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). The reaction was carried out at 125 °C for 0.5 h. After the reaction was completed, the mixture was concentrated, and the crude product was slurried with ethyl acetate to obtain the product (3.6 g, yield 71.3%).

[0271] 5. Preparation of methyl 7-amino-6-fluoro-1H-indole-5-carboxylate

[0272] 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 three times. The reaction was carried out at 25 °C under hydrogen for 3 h. After the reaction was completed, the mixture was filtered to obtain the product (3.0 g, yield 95.1%).

[0273] 6. Preparation of (7-amino-6-fluoro-1H-indol-5-yl)methanol

[0274] 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 carried out at 70 °C for 1 h. After the reaction was completed, 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 obtain the product (400 mg, yield 67.3%).

[0275] 7. Preparation of 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-amine

[0276] (7-Amino-6-fluoro-1H-indol-5-yl)methanol (350 mg, 1.9 mmol) was dissolved in dichloromethane (20 mL), 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 the reaction was completed, it was concentrated, and column chromatography (ethyl acetate / petroleum ether = 0 - 20%) was carried out to obtain the target compound (400 mg, yield: 71.5%).

[0277] 8. Preparation of N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-2-chloroacetamide

[0278] 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. After the reaction was completed, it 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%).

[0279] 9. Preparation of 8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0280] 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 carried out at 25 °C for 0.5 h. After the reaction was completed, water and ethyl acetate were added for extraction, the organic phase was collected, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain the product (100 mg, yield 44.5%).

[0281] 10. Preparation of 9-Fluoro-8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0282] Dissolve 8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (80 mg, 0.24 mmol) in tetrahydrofuran (3 mL), and add TBAF (0.50 mL). React at 25 °C for 1 h. After the reaction is completed, concentrate, wash with water, and filter to obtain the product (40 mg, yield 75.4%).

[0283] 11. Preparation of 8-(Bromomethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0284] Dissolve 9-fluoro-8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (20 mg, 0.09 mmol) in dichloromethane (3 mL), add triphenylphosphine (37 mg, 0.14 mmol) and carbon tetrabromide (46 mg, 0.14 mmol) at 0 °C. React at 0 °C for 6 h. After the reaction is completed, concentrate and use directly for the next step.

[0285] 12. 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-methylpyridinecarboxamide

[0286] Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide 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) in acetonitrile (4 mL), and add N,N-diisopropylethylamine (36 mg, 0.28 mmol). React at 25 °C for 2 h. After the reaction is completed, concentrate and purify by TLC (methanol / dichloromethane = 1 / 10) to obtain the product (5.8 mg, overall yield in two steps: 14.6%).

[0287] Molecular formula: C 22 H 22 F2N 6 O 2 Molecular weight: 440.2 LC-MS (M / e): 441.2 (M + H + )

[0288] 1 H-NMR (400 MHz, DMSO-d 6)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), 7.10 - 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).

[0289] Example 2: Preparation of 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 - methylpicolinamide (Compound 3)

[0290] 1. Preparation of 2 - bromo - N - (5 - (((tert - butyldimethylsilyl)oxy)methyl) - 6 - fluoro - 1H - indol - 7 - yl)propanamide

[0291] Dissolve 5 - (((tert - butyldimethylsilyl)oxy)methyl) - 6 - fluoro - 1H - indol - 7 - amine (500 mg, 1.7 mmol) in ethyl acetate (50 mL), add pyridine (500 mg, 6.3 mmol) and 2 - bromopropanoic acid (550 mg, 3.6 mmol). Add 1 - propylphosphonic anhydride (w50% 3.3 g, 5.2 mmol) at - 50 °C and react for 2 hours. Quench with water. After concentration, the crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 40%) to obtain the product (300 mg, yield 41.2%).

[0292] 2. Preparation of 8 - ((tert - butyldimethylsilyl)oxy)methyl) - 9 - fluoro - 3 - methyl - 1H - pyrrolo[1,2,3 - de]quinoxalin - 2(3H) - one

[0293] Dissolve 2 - bromo - N - (5 - (((tert - butyldimethylsilyl)oxy)methyl) - 6 - fluoro - 1H - indol - 7 - yl)propanamide (250 mg, 0.58 mmol) in DMF (5 mL), add NaH (60%) (50 mg, 1.3 mmol). React at 25 °C for 0.5 h. After the reaction is completed, add water and ethyl acetate for extraction, collect the organic phase, concentrate, and the crude product is directly used for the next step of the reaction.

[0294] 3. Preparation of 9 - fluoro - 8 - (hydroxymethyl) - 3 - methyl - 1H - pyrrolo[1,2,3 - de]quinoxalin - 2(3H) - one

[0295] The crude product from the previous step was dissolved in tetrahydrofuran (10 mL), and TBAF (5 mL) was added. The reaction was carried out at 25 °C for 1 h. After completion of the reaction, it was concentrated, washed with water, and purified by column chromatography (EA:PE = 100%) to obtain the product (100 mg, two-step yield 73.3%).

[0296] 4. Preparation of 8-(Chloromethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0297] 9-Fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (80 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (450 mg, 3.8 mmol) and DMF (0.1 mL) were added at 0 °C. The reaction was carried out at 30 °C for 1 h. After completion of the reaction, it was concentrated and directly used for the next step.

[0298] 5. Preparation of 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

[0299] 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (200 mg, 0.73 mmol) and 8-(chloromethyl)-9-fluoro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (the 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 was carried out at 25 °C for 2 h. After completion of the reaction, it was concentrated, purified by TLC (methanol:dichloromethane = 10%), and then purified by reverse-phase column chromatography (MeOH:H 2 O = 70%) to obtain the product (7 mg, two-step yield 4.7%). Molecular formula: C 23 H 24 F 2 N 6 O 2 Molecular weight: 454.5 LC-MS (M / e): 455.3 (M + H + )

[0300] 1 H-NMR (400 MHz, DMSO-d 6)δ: 8.09 (s, 1H), 7.99 (d, J = 7.88 Hz, 1H), 7.50 (d, J = 4.68 Hz, 1H), 7.28 - 7.32 (m, 1H), 7.14 - 7.19 (m, 2H), 6.54 (d, J = 2.88 Hz, 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).

[0301] 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)picolinamide (Compound 8)

[0302] 1. Preparation of Methyl 2-(5-bromo-7-nitro-1H-indazol-1-yl)acetate

[0303] Dissolve 5-bromo-7-nitro-1H-indazole (3.0 g, 12.4 mmol) and methyl bromoacetate (2.3 g, 15.0 mmol) in acetonitrile (100 mL), add potassium carbonate (5.1 g, 36.9 mmol), and react at 50 °C for 3 hours. Filter to remove the solid, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to obtain the product (800 mg, yield 20.5%).

[0304] 2. Preparation of Methyl 2-(7-amino-5-bromo-1H-indazol-1-yl)acetate

[0305] Dissolve methyl 2-(5-bromo-7-nitro-1H-indazol-1-yl)acetate (800 mg, 2.5 mmol) in methanol / water (20 mL / 2 mL), add zinc powder (1.3 g, 19.9 mmol) and ammonium chloride (1.1 g, 20.6 mmol), and react at 50 °C for 3 h. Filter to remove the solid, concentrate, extract with water (50 mL) and ethyl acetate (50 mL), dry, and concentrate to obtain the crude product (500 mg).

[0306] 3. Preparation of 8-Bromo-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one

[0307] Methyl 2-(7-amino-5-bromo-1H-indazol-1-yl)acetate (500 mg, crude) was dissolved in methanol (10 mL), and ethyl acetate solution of hydrogen chloride (4 M) (2 mL) was added. The reaction was carried out at 25 °C for 1 h. The mixture was concentrated, and the pH was adjusted to 8 - 9 with saturated sodium bicarbonate solution. It was extracted with water (20 mL) and ethyl acetate (30 mL), and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to obtain the product (300 mg, two-step yield 46.7%).

[0308] 4. Preparation of tert-butyl 4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazine-1-carboxylate

[0309] 8-Bromo-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (350 mg, 1.4 mmol) and potassium ((4-tert-butoxycarbonylpiperazin-1-yl)methyl)trifluoroborate (560 mg, 1.8 mmol) were dissolved in 1,4-dioxane / water (15 mL / 2.5 mL), XPhos Pd G2 (112 mg, 0.14 mmol) and cesium carbonate (910 mg, 2.8 mmol) were added, and the air was replaced with nitrogen. The reaction was carried out at 80 °C for 2 h under nitrogen. 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 (270 mg, yield: 52.4%).

[0310] 5. Preparation of 8-(piperazin-1-ylmethyl)-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one

[0311] tert-Butyl 4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazine-1-carboxylate (270 mg, 0.73 mmol) was dissolved in dichloromethane (5 mL), and ethyl acetate solution of hydrogen chloride (4 M) (1 mL) was added. The reaction was carried out at 25 °C for 1 h. The mixture was concentrated, and the pH was adjusted to 8 - 9 with saturated sodium bicarbonate solution. It was extracted with water (20 mL) and ethyl acetate (30 mL), and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain the product (50 mg, yield 25.4%).

[0312] 6. Preparation of methyl 6-fluoro-5-(4-((2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)methyl)piperazin-1-yl)picolinate

[0313] 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), RuPhos Pd G3 (10 mg, 0.026 mmol) and cesium carbonate (179 mg, 0.55 mmol) were added, the mixture was purged with nitrogen, and then reacted under nitrogen at 140 °C by microwave for 1 hour. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (15 mg, yield 19.2%).

[0314] 7. 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)picolinamide

[0315] 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 aqueous methylamine solution (0.5 mL) was added. The reaction was carried out at 25 °C for 3 h. After completion of the reaction, the mixture was concentrated and purified by Prep-TLC (dichloromethane:methanol = 12:1) to obtain the crude product (5 mg), which was further purified by Prep-HPLC (water:methanol = 1:8) to obtain the product (3.5 mg, yield 23.4%). Molecular formula: C 21 H 22 FN 7 O 2 Molecular weight: 423.5 LC-MS (M / e): 424.2 (M + H + )

[0316] 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.07 (s, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 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 = 4.8 Hz, 3H), 2.60 - 2.40 (m, 4H)

[0317] 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)picolinamide (Compound 11)

[0318] 1. Preparation of 1-(5-bromo-1H-indol-1-yl)ethan-1-one

[0319] Dissolve 5-bromoindoline (3.9 g, 19.8 mmol) in acetic acid (20 mL), cool to 0 °C, slowly add acetic anhydride (20 mL), react at 25 °C for 1 hour, and the reaction is completed. Concentrate to obtain the product (4.0 g), which is directly used for the next step.

[0320] 2. Preparation of 1-(5-bromo-7-nitro-1H-indol-1-yl)ethan-1-one

[0321] Dissolve 1-(5-bromo-1H-indol-1-yl)ethan-1-one (3.7 g, crude product) in concentrated sulfuric acid (50 mL), add potassium nitrate (1.9 g, 18.5 mmol) at 0 °C, react at 0 °C for 1 hour, pour into cold water, precipitate solid, filter, and dry to obtain the crude product (3.6 g), which is directly used for the next step.

[0322] 3. Preparation of 5-bromo-7-nitroindoline

[0323] Dissolve 1-(5-bromo-7-nitro-1H-indol-1-yl)ethan-1-one (3.4 g, 11.9 mmol) and sodium hydroxide (4.8 g, 119 mmol) in THF (40 mL), add MeOH (8 mL), and react at 25 °C for 4 h. After the reaction is completed, concentrate, wash the residue with water, filter, and dry to obtain the product (2.9 g), which is directly used for the next step.

[0324] 4. Preparation of 5-bromo-7-nitro-1H-indole

[0325] Dissolve 5-bromo-7-nitroindoline (2.9 g, crude product) in DCM (50 mL), add manganese dioxide (9.5 g, 106.6 mmol), react at 25 °C for 1 hour, after the reaction is completed, filter through diatomaceous earth, concentrate the filtrate, and purify the residue by silica gel column chromatography (n-heptane:ethyl acetate = 5:1) to obtain the product (2.4 g).

[0326] 5. Preparation of ethyl 2-(5-bromo-7-nitro-1H-indol-1-yl)acetate

[0327] Dissolve 5-bromo-7-nitro-1H-indole (2.1 g, 8.7 mmol) in acetonitrile (40 mL), add potassium carbonate (1.8 g, 13.0 mmol), ethyl bromoacetate (2.2 g, 13.2 mmol), and react at 50 °C for 2 h. After the reaction is completed, extract with water (30 mL) and ethyl acetate (40 mL × 2). Combine the organic phases, concentrate, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 70%) to obtain the product (2.4 g, yield 84.1%).

[0328] 6. Preparation of 8-bromo-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0329] Add 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) to methanol (30 mL), add water (3 mL) and ammonium chloride (3.7 g, 66.0 mmol). React at 50 °C for 1 h. After the reaction is completed, filter through diatomaceous earth, concentrate the filtrate, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain the product (260 mg, yield 15.4%).

[0330] 7. Preparation of 8-(hydroxymethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0331] Dissolve 8-bromo-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (230 mg, 0.92 mmol) in dioxane (10 mL), add Ruphos Pd G 2 (79 mg, 0.085 mmol) and hydroxymethyltributyltin (518 mg, 1.6 mmol), protect with nitrogen, and react at 75 °C for 3 h. After the reaction is completed, cool, concentrate, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain the product (90 mg, yield 48.4%).

[0332] 8. Preparation of 8-(bromomethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0333] Dissolve 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) in DCM (10 mL), react at 25 °C for 1 h. After the reaction is completed, concentrate at 25 °C, and use the crude product directly for the next step.

[0334] 9. 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)picolinamide

[0335] Dissolve 8-(bromomethyl)-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step) in acetonitrile (5 mL), add DIPEA (4M) (90 mg, 0.70 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (83 mg, 0.35 mmol). React at 25 °C for 2 h. After the reaction is completed as detected by LCMS, concentrate. The concentrated organic phase is purified by silica gel plate (SiO 2 , dichloromethane:methanol = 20:1) to obtain the target compound (12 mg, yield 14.6%).

[0336] Molecular formula: C 22 H 23 FN 6 O 2 Molecular weight: 422.25 LC-MS (M / e): 423.2 (M + H + )

[0337] 1 H-NMR (400 MHz, DMSO-d 6 ) 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, 3H), 2.57 - 2.47 (m, 4H)

[0338] Example 5: Preparation of 6-Fluoro-5-(4-((10-fluoro-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indol-9-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Compound 15)

[0339] 1. Preparation of N-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-3-chloropropanamide

[0340] 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 cooled to 0 °C, and 3-chloropropanoyl chloride (226 mg, 1.8 mmol) was added. The reaction was carried out at 0 °C for 30 minutes. The reaction was monitored by LCMS until completion. 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, 400 mg).

[0341] 2. Preparation of 9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-fluoro-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one

[0342] N-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-fluoro-1H-indol-7-yl)-3-chloropropanamide (400 mg, crude from the previous step) was dissolved in DMF (10 mL). The temperature was cooled to 0 °C, and sodium hydride (60%) (125 mg, 5.2 mmol) was added. The reaction was carried out at 25 °C for 20 minutes. The reaction was quenched by adding water. Water (30 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The organic layer was washed with water (30 mL) and concentrated to obtain the crude product (400 mg), which was purified by silica gel column chromatography (n-heptane:ethyl acetate = 6:1) to obtain the product (200 mg, overall yield for two steps 48.3%).

[0343] 3. Preparation of 10-Fluoro-9-(hydroxymethyl)-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one

[0344] 9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-fluoro-3,4-dihydro-[1,4]diazepino[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 carried out at 25 °C for 2 h. After the reaction was completed, 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%).

[0345] 4. Preparation of 9-(Chloromethyl)-10-fluoro-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one

[0346] Dissolve 10-fluoro-9-(hydroxymethyl)-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one (60 mg, 0.26 mmol) and N,N-dimethylformamide (6 mg, 0.082 mmol) in dichloromethane (7 mL). Cool the solution to -5 °C, add thionyl chloride (60 mg, 0.50 mmol), and react at -5 °C for 20 minutes. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture, and use the crude product directly in the next step.

[0347] 5. Preparation of 6-fluoro-5-(4-((10-fluoro-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indol-9-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0348] Dissolve 9-(chloromethyl)-10-fluoro-3,4-dihydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one (the crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (72 mg, 0.26 mmol) in acetonitrile (10 mL). Add DIEA (170 mg, 1.3 mmol), and react at 80 °C for 2 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture, purify the crude product by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain a crude product (48 mg), and further purify it by Prep-TLC (dichloromethane:methanol = 25:1) to obtain the product (37 mg, overall yield of two steps: 31.8%).

[0349] Molecular formula: C 23 H 24 F 2 N 6 O 2 Molecular weight: 454.5 LC-MS (m / z): 455.2 (M + H + )

[0350] 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.71 (s, 1H), 7.99 (d, J = 8.0 Hz, 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 = 5.2 Hz, 3H), 2.77 - 2.69 (m, 4H).

[0351] 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-methylpicolinamide (Compound 24)

[0352] Referring to the preparation in Example 2, replace the raw material 2-bromopropionic acid with 2-bromobutyric acid.

[0353] Molecular formula: C 24 H 26 F 2 N 6 O 2 Molecular weight: 468.5 LC-MS (M / e): 469.2 (M+H + )

[0354] 1 H-NMR (400 MHz, DMSO-d 6 ) 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).

[0355] 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)picolinamide (Compound 25)

[0356] 1. Preparation of 2-(Diethoxyphosphoryl)propanoic acid

[0357] Dissolve ethyl 2-(diethoxyphosphoryl)propionate (5.0 g, 21.0 mmol) in ethanol / water (100 mL / 20 mL), add sodium hydroxide (1.7 g, 42.5 mmol), and react at 25 °C for 2 hours. The reaction is completed. Concentrate to remove ethanol, adjust the pH to 1 - 2 with 2 M hydrochloric acid, add ethyl acetate (100 mL) for extraction, dry, and concentrate to obtain the product (4.7 g).

[0358] 2. Preparation of 7-Hydroxy-8-nitro-3,4-dihydronaphthalen-1(2H)-one

[0359] Dissolve 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one (50 g, 308.3 mmol) in concentrated sulfuric acid (400 mL). Cool the mixture to -5 °C, and add potassium nitrate (32 g, 316.5 mmol) thereto in portions. After maintaining the reaction at this temperature for 2 hours, pour the reaction solution into ice water, extract with ethyl acetate, separate the layers to obtain the organic phase. After drying the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (n-heptane and ethyl acetate as the mobile phase, with the proportion of ethyl acetate ranging from 0% to 55%) to obtain the product (24.5 g, yield 38.4%).

[0360] 3. Preparation of 7-hydroxy-6-iodo-8-nitro-3,4-dihydronaphthalen-1(2H)-one

[0361] Dissolve 7-hydroxy-8-nitro-3,4-dihydronaphthalen-1(2H)-one (20 g, 96.5 mmol) in acetonitrile (300 mL), add N-iodosuccinimide (21.8 g, 96.9 mmol) thereto, and react at 80 °C for 24 hours. Then concentrate the reaction solution, and purify the crude product by silica gel column chromatography (n-heptane and ethyl acetate as the mobile phase, with the proportion of ethyl acetate ranging from 0% to 45%) to obtain the product (12.4 g, yield 38.6%).

[0362] 4. Preparation of ethyl 3-hydroxy-4-nitro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0363] Dissolve 7-hydroxy-6-iodo-8-nitro-3,4-dihydronaphthalen-1(2H)-one (6.0 g, 18.0 mmol) in ethanol (50 mL) / N,N-dimethylformamide (100 mL), add palladium acetate (410 mg, 1.8 mmol), XantPhos (1.0 g, 1.7 mmol) and triethylamine (5.5 g, 54.3 mmol), purge with CO, and react at 90 °C under CO for 4 hours. The reaction is completed. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (1.5 g, yield 29.8%).

[0364] 5. Preparation of ethyl 4-nitro-5-oxo-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0365] Ethyl 3-hydroxy-4-nitro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (500 mg, 1.8 mmol) and N,N-diisopropylethylamine (910 mg, 7.0 mmol) were dissolved in dichloromethane (20 mL). The temperature was lowered to -10 °C, and trifluoromethanesulfonic anhydride (760 mg, 2.7 mmol) was added. The reaction was carried out at -10 °C for 1 hour. The reaction was completed. 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%).

[0366] 6. Preparation of ethyl 4-amino-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0367] Ethyl 4-nitro-5-oxo-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (500 mg, 1.2 mmol) was added to ethanol (20 mL), and palladium / carbon (500 mg) was added. The mixture was purged with hydrogen, and the reaction was carried out under hydrogen at 25 °C for 3 hours. The reaction was completed. 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%).

[0368] 7. Preparation of ethyl 4-(2-(diethoxyphosphoryl)propanamido)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0369] Ethyl 4-amino-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (60 mg, 0.26 mmol) and 2-(diethoxyphosphoryl)propanoic acid (216 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (4 mL). EDCI (210 mg, 1.1 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. The reaction was completed. Water (10 mL) and ethyl acetate (15 mL × 2) were added. The organic phase was washed with water (20 mL × 2), dried, and concentrated to obtain the crude product (100 mg). The crude product was directly used for the next step.

[0370] 8. Preparation of ethyl 3-methyl-2-oxo-2,4,5,6-tetrahydro-1H-benzo[de]quinoline-8-carboxylate

[0371] Ethyl 4-(2-(diethoxyphosphoryl)propanamido)-5-oxo-5,6,7,8-tetrahydronaphthalene-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 reaction was carried out at 25 °C for 1 hour. The reaction was completed. 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%).

[0372] 9. Preparation of 8-(Hydroxymethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one

[0373] 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). The temperature was lowered to 0 °C, and lithium aluminum hydride (33 mg, 0.87 mmol) was added. The reaction was carried out at 0 °C for 1 hour. The reaction was completed. The reaction was quenched with water, anhydrous sodium sulfate was added and stirred for 10 minutes, filtered, 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%).

[0374] 10. Preparation of 8-(Chloromethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one

[0375] 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). Thionyl chloride (78 mg, 0.66 mmol) was added, and the reaction was carried out at 25 °C for 16 hours. Concentrated, the crude product was directly used for the next step.

[0376] 11. 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)picolinamide

[0377] 8-(Chloromethyl)-3-methyl-5,6-dihydro-1H-benzo[de]quinolin-2(4H)-one (crude product from the previous step), 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 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 reaction was carried out at 85 °C for 10 hours. The reaction was monitored by LCMS until completion. Concentrated, the crude product was purified by preparative-TLC (dichloromethane:methanol = 16:1) to obtain the crude product (20 mg), and then purified by preparative-TLC (dichloromethane:methanol = 16:1 and separated with ethyl acetate twice) to obtain the product (17 mg, overall yield of two steps 54.4%).

[0378] Molecular formula: C 25 H 28 FN 5 O 2 Molecular weight: 449.5 LC-MS (m / z): 450.2 (M + H + )

[0379] 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.05 (s, 1H), 7.99 (d, J = 8.0 Hz, 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 = 6.0 Hz, 4H), 3.01 (d, J = 5.2 Hz, 3H), 2.95 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 4H), 2.23 (s, 3H), 2.04 (t, J = 5.8 Hz, 2H).

[0380] 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)picolylamide (Compound 26)

[0381] 1. Preparation of 2-Bromo-N-(5-bromo-1H-indol-7-yl)propanamide

[0382] Dissolve 5-bromo-1H-indol-7-amine (279 mg, 1.3 mmol) in ethyl acetate (10 mL), add pyridine (411 mg, 5.2 mmol) and 2-bromopropanoic acid (367 mg, 2.4 mmol). Add 1-propylphosphonic anhydride (2.5 g, 50% ethyl acetate solution, 3.9 mmol) at -10 °C and react for 0.5 h. Quench with water. After concentration, the crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 40%) to obtain the product (300 mg, yield 65.6%).

[0383] 2. Preparation of 8-Bromo-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0384] Dissolve 2-bromo-N-(5-bromo-1H-indol-7-yl)propanamide (300 mg, 0.9 mmol) in DMF (5 mL), add NaH (60%) (72 mg, 1.8 mmol). React at 25 °C for 0.5 h. After the reaction is completed, add water and ethyl acetate for extraction. Collect the organic phase, concentrate, and purify the crude product by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 40%) to obtain the product (212 mg, 92.2%).

[0385] 3. Preparation of 8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0386] Dissolve 8-bromo-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (186 mg, 0.7 mmol), tri-n-butylstannylmethanol (257 mg, 0.8 mmol), and Xphos Pd G2 (55 mg, 0.07 mmol) in 1,4-dioxane (10 mL), and react at 80 °C for 2 hours. Dry and concentrate the organic phase, and obtain the target compound (150 mg, yield 91.7%) by column chromatography (SiO 2 , dichloromethane:methanol = 15:1).

[0387] 4. Preparation of 8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0388] Dissolve 8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (150 mg, 0.7 mmol) in dichloromethane (5 mL), add thionyl chloride (333 mg, 2.8 mmol) and DMF (0.1 mL) at 0 °C. React at 30 °C for 1 h, after the reaction is completed, concentrate and directly use it for the next step.

[0389] 5. 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)picolinamide

[0390] Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 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) in acetonitrile (10 mL), and add N,N-diisopropylethylamine (724 mg, 5.6 mmol). React at 80 °C for 8 h, after the reaction is completed, concentrate, purify by TLC (methanol:dichloromethane = 10%), and then obtain the product (10 mg, the overall yield in two steps is 3.3%) by reverse-phase column chromatography (MeOH:H 2 O = 70%).

[0391] Molecular formula: C 23 H 25 FN 6 O 2 Molecular weight: 436.5 LC-MS (M / e): 437.3 (M + H + )

[0392] 1 H-NMR (400 MHz, DMSO-d 6 ) 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, 1H), 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).

[0393] 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)picolylamide (Compound 32)

[0394] 1. Preparation of Ethyl 2-(3,4-dihydroquinolin-1(2H)-yl)propionate

[0395] Dissolve 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) in DMF (50 mL). After addition, react at 100 °C for 16 h. Pour into water and extract with ethyl acetate. Concentrate the organic phase and purify by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 5:1) to obtain the target compound (2.0 g, yield 44.0%).

[0396] 2. Preparation of Ethyl 2-(6-formyl-3,4-dihydroquinolin-1(2H)-yl)propionate

[0397] Dissolve ethyl 2-(3,4-dihydroquinolin-1(2H)-yl)propionate (2.0 g, 8.6 mmol) in dichloromethane (50 mL). Add DMF (6.3 g, 86.0 mmol) and phosphorus oxychloride (4.0 g, 25.8 mmol) at 0 °C. After addition, react at 15 °C for 2 h. Quench with water, adjust the pH to 7 with aqueous sodium hydroxide solution, and extract with ethyl acetate. Concentrate the organic phase and purify by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.5 g, yield 67.0%).

[0398] 3. Preparation of Ethyl 2-(6-formyl-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate

[0399] Dissolve ethyl 2-(6-formyl-3,4-dihydroquinolin-1(2H)-yl)propionate (1.5 g, 5.7 mmol) in concentrated sulfuric acid (10 mL). Add potassium nitrate (688 mg, 6.8 mmol) at 0 °C. After addition, react at 0 °C for 1 h. Pour into water for dilution, extract with ethyl acetate, and concentrate the organic phase directly for the next step.

[0400] Preparation of ethyl 2-(6-(hydroxymethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate

[0401] Dissolve ethyl 2-(6-formyl-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (crude product from the previous step) in methanol (30 mL). Add sodium borohydride (650 mg, 17.1 mmol). After addition, react at 10 °C for 2 h. Concentrate and purify by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:1) to obtain the target compound (150 mg, yield 8.6%).

[0402] Preparation of ethyl 2-(6-(chloromethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate

[0403] Dissolve ethyl 2-(6-(hydroxymethyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate (150 mg, 0.49 mmol) in dichloromethane (12 mL). Add thionyl chloride (583 mg, 4.9 mmol) at 0 °C. After addition, react at 0 °C for 1 h. Monitor the reaction by LCMS until completion. Concentrate directly for the next step.

[0404] Preparation of ethyl 2-(6-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-nitro-3,4-dihydroquinolin-1(2H)-yl)propionate

[0405] Dissolve 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)nicotinamide hydrochloride (134 mg, 0.49 mmol) in acetonitrile (25 mL). Add DIEA (194 mg, 1.5 mmol). After addition, react at 80 °C for 2 h. Monitor the reaction by LCMS until completion. Concentrate the organic phase and purify by silica gel plate (SiO 2 , 100% ethyl acetate) to obtain the target compound (200 mg, yield 77.8%).

[0406] 7. 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)picolylamide

[0407] Ethyl 2-(6-((4-(2-fluoro-6-(methylcarbamoyl)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), and palladium on carbon (40 mg) was added. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by C18 column (MeCN-0-40%) and then by preparative HPLC (MeCN-0-40%) to obtain the target compound (3.8 mg, yield 2.2%).

[0408] Molecular formula: C 24 H 29 FN 6 O 2 Molecular weight: 452.5 LC-MS (m / z): 453.1 (M + H + )

[0409] 1 1H-NMR (400 MHz, MeOD) δ: 7.89 (d, J = 7.8 Hz, 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), 3.32 - 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).

[0410] 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-methylpicolylamide (Compound 34)

[0411] 1. Preparation of methyl 6-fluoro-2-methyl-7-nitro-1H-indole-5-carboxylate

[0412] To a toluene (20 mL) solution of methyl 4-amino-5-bromo-2-fluoro-3-nitrobenzoate (3.2 g, 10.9 mmol), add 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 tris(o-tolyl)phosphine (332 mg, 1.1 mmol). Under nitrogen protection, react at 90 °C for 1 hour by microwave. Add saturated potassium fluoride solution to the system, stir for 30 minutes, filter, and wash the solid with ethyl acetate. Extract the filtrate with ethyl acetate, concentrate, and purify the crude product by silica gel column chromatography (dichloromethane:petroleum ether = 1:1) to obtain the product (650 mg, yield 23.6%).

[0413] 2. Preparation of methyl 7-amino-6-fluoro-2-methyl-1H-indole-5-carboxylate

[0414] Dissolve methyl 6-fluoro-2-methyl-7-nitro-1H-indole-5-carboxylate (800 mg, 3.2 mmol) in methanol (50 mL), add Pd / C (350 mg, N / A), purge with hydrogen 3 times, and react at 25 °C for 3 h under hydrogen. After the reaction is complete, filter to collect the solid to obtain the crude product (600 mg).

[0415] 3. Preparation of (7-amino-6-fluoro-2-methyl-1H-indol-5-yl)methanol

[0416] Dissolve methyl 7-amino-6-fluoro-2-methyl-1H-indole-5-carboxylate (600 mg, 2.7 mmol) in tetrahydrofuran (10 mL), and add lithium aluminum hydride (308 mg, 8.1 mmol) at 0 °C. React at 50 °C for 1 h. After the reaction is complete, quench the reaction with water, add anhydrous sodium sulfate and stir, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain the product (280 mg, two-step yield 45.5%).

[0417] 4. Preparation of 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-amine

[0418] Dissolve (7-amino-6-fluoro-2-methyl-1H-indol-5-yl)methanol (260 mg, 1.3 mmol) in dichloromethane (20 mL), add imidazole (266 mg, 3.9 mmol) and tert-butyldimethylchlorosilane (294 mg, 2.0 mmol). React at 25 °C for 1 h. After the reaction is complete, add water to the system, extract the organic phase with dichloromethane, concentrate, and perform column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain the product (370 mg, yield: 89.6%).

[0419] 5. Preparation of 2-Bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-yl)propanamide

[0420] Dissolve 5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-amine (330 mg, 1.1 mmol) in ethyl acetate (10 mL), add pyridine (331 mg, 4.2 mmol) and 2-bromopropanoic acid (252 mg, 1.6 mmol), and add 1-propylphosphonic anhydride (w50%, 2.0 g, 3.1 mmol) at -50 °C. React for 2 hours. Quench the reaction system with water, extract the organic phase with ethyl acetate, concentrate, and purify the crude product by silica gel column chromatography (ethyl acetate:petroleum ether = 1:6) to obtain the product (465 mg, yield 98.3%).

[0421] 6. Preparation of 8-(((tert-butyldimethylsilyl)oxy)methyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0422] Dissolve 2-Bromo-N-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-2-methyl-1H-indol-7-yl)propanamide (440 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL), and add NaH (60%) (80 mg, 2.0 mmol). React at 25 °C for 0.5 h. After the reaction is completed, add water and extract with ethyl acetate. Collect the organic phase, concentrate, and use the crude product directly for the next reaction.

[0423] 7. Preparation of 9-Fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0424] Dissolve 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) in tetrahydrofuran (6 mL), and add a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 5.5 mL). React at 25 °C for 3 h. After the reaction is completed, add water to the system, extract the organic phase with ethyl acetate, concentrate, and purify the crude product by column chromatography (EA:PE = 100%) to obtain the product (240 mg, two-step yield 97.1%).

[0425] 8. Preparation of 8-(Chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one Hydrochloride

[0426] Dissolve 9-fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (50 mg, 0.20 mmol) in acetonitrile (3 mL), add ethyl acetate solution of hydrogen chloride (3.0 mL), react at 25 °C for 1 h. After the reaction is completed, concentrate it and directly use it for the next step.

[0427] 9. 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-methylnicotinamide

[0428] Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)nicotinamide 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) in acetonitrile (10 mL), add N,N-diisopropylethylamine (155 mg, 1.2 mmol). React at 80 °C for 2 h. After the reaction is completed, add water to the system, extract the organic phase with ethyl acetate, concentrate it, and purify the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain the product (30 mg, overall yield in two steps is 31.8%).

[0429] Molecular formula: C 24 H 26 F 2 N 6 O 2 Molecular weight: 468.5 LC-MS (M / e): 469.2 (M + H + )

[0430] 1 H-NMR (400 MHz, CDCl 3 ) 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).

[0431] Example XI: 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-methylnicotinamide (Compound 36)

[0432] 1. Preparation of Methyl (4-bromo-3-fluoro-2-nitrophenyl)-D-alaninate

[0433] Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (2.5 g, 10.5 mmol) in N,N-dimethylformamide (50 mL), add (D)-alanine methyl ester hydrochloride (1.6 g, 11.5 mmol) and N,N-diisopropylethylamine (3.6 g, 27.9 mmol) thereto, and react at 50 °C for 5 hours. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (2.0 g, yield 59.3%).

[0434] 2. Preparation of Methyl (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate

[0435] Dissolve methyl (4-bromo-3-fluoro-2-nitrophenyl)-D-alaninate (1.6 g, 5.0 mmol), tri-n-butylstannylmethanol (1.8 g, 5.6 mmol), and Xphos Pd G2 (390 mg, 0.50 mmol) in 1,4-dioxane (70 mL), purge with nitrogen, and react at 80 °C under nitrogen for 5 hours. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (1.1 g, yield 81.1%).

[0436] 3. Preparation of Methyl (6-bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate

[0437] Dissolve methyl (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate (1.1 g, 4.0 mmol) in N,N-dimethylformamide (30 mL), add N-bromosuccinimide (1.1 g, 6.2 mmol), and react at 25 °C for 5 hours. Add water (100 mL) and ethyl acetate (100 mL × 2) for extraction, wash the organic phase with water (100 mL × 2), dry, concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (790 mg, yield 55.7%).

[0438] 4. Preparation of (R)-5-bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0439] (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), iron powder (370 mg, 6.6 mmol) and ammonium chloride (590 mg, 11.0 mmol) were added, and the reaction was carried out at 70 °C for 2 hours. The solid was removed by filtration, concentrated, water (30 mL) and ethyl acetate (30 mL) were added for extraction, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (300 mg, yield 91.1%).

[0440] 5. Preparation of (R,E)-5-(2-Ethoxyvinyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0441] (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), 2-(2-Ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.5 mmol), Pd(dppf)Cl 2 (75 mg, 0.10 mmol) and sodium carbonate (320 mg, 3.0 mmol) were added, the air was replaced with nitrogen, and the reaction was carried out at 90 °C for 5 hours under nitrogen. It was concentrated, water (30 mL) and ethyl acetate (30 mL) were added for extraction, and the crude product was purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (260 mg, yield 89.4%).

[0442] 6. Preparation of (R)-8-(Chloromethyl)-9-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0443] (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 ethyl acetate solution of hydrogen chloride (4 M) (0.3 mL) was added. The reaction was carried out at 25 °C for 1 h. It was concentrated, and the crude product was directly used for the next step.

[0444] 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-methylnicotinamide

[0445] Dissolve (R)-8-(chloromethyl)-9-fluoro-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)picolinamide hydrochloride (20 mg, 0.073 mmol) in acetonitrile (7 mL), add DIEA (46 mg, 0.36 mmol), and react at 70 °C for 5 hours. Concentrate, add water (20 mL) and ethyl acetate (20 mL) for extraction, and purify the crude product by preparative-TLC (dichloromethane:methanol = 16:1) to obtain the product (20 mg, overall yield of two steps 61.7%).

[0446] Molecular formula: C 23 H 24 F 2 N 6 O 2 Molecular weight: 454.5 LC-MS (m / z): 455.0 (M + H + )

[0447] 1 1H-NMR (400 MHz, CDCl 3 ) δ: 7.99 (d, J = 7.0 Hz, 1H), 7.78 (s, 1H), 7.54 - 7.41 (m, 1H), 7.32 - 7.25 (m, 1H), 7.18 (d, J = 5.6 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 5.15 (t, J = 7.0 Hz, 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 = 7.0 Hz, 3H).

[0448] Example XII: 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-methylpicolinamide (Compound 35)

[0449] Prepared according to the method of Example XI, replacing the raw material (D)-alanine methyl ester hydrochloride with (L)-alanine methyl ester hydrochloride.

[0450] Molecular formula: C 23 H 24 F 2 N 6 O 2 Molecular weight: 454.5 LC-MS (m / z): 454.9 (M + H + )

[0451] 1 H-NMR(400 MHz, CDCl 3 ) δ: 7.99 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.55 - 7.42 (m, 1H), 7.32 - 7.25 (m, 1H), 7.18 (d, J = 5.6 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 5.15 (q, J = 6.9 Hz, 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 = 7.0 Hz, 3H).

[0452] Example XIII: 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-methylpicolinamide (Compound 41)

[0453] 1. Preparation of N-(5-bromo-1H-indol-7-yl)acetamide

[0454] Dissolve 5-bromo-1H-indol-7-amine (1.4 g, 6.6 mmol) in DCM (50 mL). Add triethylamine (2.0 g, 19.8 mmol) to the reaction mixture, and then add acetyl chloride (0.67 g, 8.5 mmol) dropwise. After reacting at 15 °C for 1 hour, concentrate the reaction solution. Purify the crude product by silica gel column chromatography (using ethyl acetate and petroleum ether as the mobile phase, with the proportion of ethyl acetate ranging from 0% to 50%) to obtain the product (1.1 g, yield 65.5%).

[0455] 2. Preparation of N-(5-bromo-3-fluoro-1H-indol-7-yl)acetamide

[0456] Dissolve N-(5-bromo-1H-indol-7-yl)acetamide (900 mg, 3.6 mmol) in acetonitrile (15 mL) and water (3 mL). Add 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.9 g, 5.4 mmol), and react at 10 °C for 2 hours. Quench with water. After concentration, purify by silica gel column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain the crude product (1.0 g).

[0457] 3. Preparation of 5-bromo-3-fluoro-1H-indol-7-amine

[0458] N-(5-Bromo-3-fluoro-1H-indol-7-yl)acetamide (1.0 g, 3.7 mmol) was dissolved in methanol (50 mL), and thionyl chloride (2.5 g, 21.0 mmol) was added. After reacting at 60 °C for 1 hour, 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 (700 mg, yield 82.8%).

[0459] 4. Preparation of 2-bromo-N-(5-bromo-3-fluoro-1H-indol-7-yl)propanamide

[0460] 5-Bromo-3-fluoro-1H-indol-7-amine (650 mg, 2.8 mmol) was dissolved in ethyl acetate (20 mL), and pyridine (460 mg, 5.8 mmol) and 2-bromopropanoic acid (800 mg, 5.2 mmol) were added. 1-Cyclopropylphosphonic anhydride (50%, 3.6 g, 5.7 mmol) was added dropwise at -50 °C, and the reaction was quenched with water after 2 hours. After concentration, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the product (700 mg, yield 67.8%).

[0461] 5. Preparation of 8-bromo-6-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0462] 2-Bromo-N-(5-bromo-3-fluoro-1H-indol-7-yl)propanamide (700 mg, 1.9 mmol) was dissolved in DMF (10 mL), and NaH (60%) (160 mg, 4.0 mmol) was added. The reaction was carried out at 25 °C for 1.5 h. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was collected and concentrated. The product was purified by preparative thin layer plate (ethyl acetate: petroleum ether = 2:3) to obtain the product (500 mg, yield 91.8%).

[0463] 6. Preparation of 6-fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0464] 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 (tributylstannyl)methanol (710 mg, 2.2 mmol) and chloro(2-dicyclohexylphosphino-2-hexylphosphino,2-triisopropyl-1,1-phosphinobiphenyl)[2-(2,amino-1,1(2biphenyl)]palladium(II) (100 mg, 0.13 mmol) were added. The reaction was carried out at 80 °C for 1 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 3:2) to obtain the product (200 mg, yield 80.6%).

[0465] 7,8-(Chloromethyl)-6-fluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one Preparation

[0466] Dissolve 6-fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (50 mg, 0.21 mmol) in dichloromethane (10 mL) and acetonitrile (10 mL). Add thionyl chloride (150 mg, 1.3 mmol) and DMF (0.1 mL) at 0 °C. React at 30 °C for 5 h. After the reaction is completed, concentrate it and directly use it for the next step.

[0467] 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-methylpicolinamide Preparation

[0468] Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (60 mg, 0.22 mmol) and the crude product from the previous step in acetonitrile (10 mL). Add N,N-diisopropylethylamine (55 mg, 0.43 mmol). React at 70 °C for 2 h. After the reaction is completed, concentrate it and purify it by TLC (methanol:dichloromethane = 1:10) to obtain the product (13 mg, the two-step yield is 13.4%).

[0469] Molecular formula: C 23 H 24 F 2 N 6 O 2 Molecular weight: 454.5 LC-MS (M / e): 455.1 (M + H + )

[0470] 1 H-NMR (400 MHz, CDCl 3 ) 8.11 (s, 1H), 8.00 (d, J = 7.84 Hz, 1H), 7.51 (d, J = 4.68 Hz, 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).

[0471] 9. Chiral column separation to obtain isomeric compounds 41-1 and compound 41-2, characterized as follows:

[0472] 1) Compound 41-1:

[0473] HPLC, retention time: 14.2 min;

[0474] 1 H-NMR (400 MHz, CDCl 3 ) 8.11 (s, 1H), 8.00 (d, J = 7.84 Hz, 1H), 7.51 (d, J = 4.68 Hz, 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).

[0475] 2) Compound 41-2:

[0476] HPLC, retention time: 16.2 min;

[0477] 1 H-NMR (400 MHz, CDCl 3 ) 8.11 (s, 1H), 8.00 (d, J = 7.84 Hz, 1H), 7.51 (d, J = 4.68 Hz, 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). 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-methylpicolinamide (Compound 44)

[0478] 1. Preparation of methyl (4-bromo-3-fluoro-2-nitrophenyl)-D-alaninate

[0479] Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (10 g, 42.0 mmol) in N,N-dimethylformamide (100 mL), add D-alanine methyl ester hydrochloride (5.9 g, 42.0 mmol) and N,N-diisopropylethylamine (16.8 g, 0.13 mol) thereto, and react at 50 °C for 5 hours. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (7.5 g, yield 56.0%).

[0480] 2. Preparation of methyl (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate

[0481] Dissolve methyl (4-bromo-3-fluoro-2-nitrophenyl)-D-alaninate (7.5 g, 23.4 mmol), (tri-n-butylstannyl)methanol (8.2 g, 25.7 mmol), and Xphos Pd G2 (1.8 g, 2.3 mmol) in 1,4-dioxane (150 mL), purge with nitrogen, and react at 80 °C for 3 hours under nitrogen. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (4.6 g, yield 72.4%).

[0482] 3. Preparation of methyl (6-bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate

[0483] Dissolve methyl (3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate (4.6 g, 16.9 mmol) in N,N-dimethylformamide (100 mL), add N-bromosuccinimide (3.3 g, 18.6 mmol), and react at 25 °C for 16 hours. Add water (100 mL) and ethyl acetate (100 mL × 2) for extraction, wash the organic phase with water (100 mL × 2), dry, concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 3:1) to obtain the product (3.5 g, yield 59.3%).

[0484] 4. Preparation of (R)-5-bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0485] Dissolve methyl (6-bromo-3-fluoro-4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate (390 mg, 1.1 mmol) in methanol (15 mL) / tetrahydrofuran (15 mL) / water (5 mL), add iron powder (622 mg, 11.1 mmol) and ammonium chloride (1.2 g, 22.2 mmol), and react at 70 °C for 1 hour. Filter to remove the solid, concentrate, add water (30 mL) and ethyl acetate (30 mL) for extraction, dry and concentrate the organic phase to obtain the product (300 mg, yield 93.2%).

[0486] 5. Preparation of (R)-9-Fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0487] Dissolve (R)-5-Bromo-8-fluoro-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (300 mg, 1.0 mmol) in toluene (11 mL), add tributyl(methoxy)tin (995 mg, 3.1 mmol), isopropenyl acetate (520 mg, 5.2 mmol), Pd(OAc) 2 (23 mg, 0.1 mmol) and tri-o-tolylphosphine (32 mg, 0.1 mmol), purge with nitrogen, and react under nitrogen at 100 °C by microwave for 1 hour. Concentrate and purify by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (100 mg, yield 38.9%).

[0488] 6. Preparation of (R)-8-(Chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0489] Dissolve (R)-9-Fluoro-8-(hydroxymethyl)-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.4 mmol) in dichloromethane (12 mL), and add an ethyl acetate solution of hydrogen chloride (1.2 mL). React at 5 °C for 1 h. Concentrate, and use the crude product directly for the next step.

[0490] 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-methylnicotinamide

[0491] Dissolve (R)-8-(Chloromethyl)-9-fluoro-3,5-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (crude product from the previous step), 6-Fluoro-N-methyl-5-(piperazin-1-yl)nicotinamide hydrochloride (110 mg, 0.4 mmol) in acetonitrile (15 mL), add DIEA (157 mg, 1.2 mmol), and react at 80 °C for 1 hour. Concentrate, purify by silica gel column (dichloromethane:methanol = 15:1) to obtain the crude product, and purify the crude product by Prep-TLC (dichloromethane:methanol = 15:1) to obtain the target compound (25 mg, overall yield of two steps 13.1%).

[0492] Molecular formula: C 24 H 26 F 2 N6 O 2 Molecular weight: 468.5 LC-MS (m / z): 469.2 (M+H + )

[0493] 1 H-NMR (400 MHz, CDCl 3 ) 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 - 5.26 (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).

[0494] 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)picolylamide (Compound 27)

[0495] 1. Preparation of Methyl (4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate

[0496] Dissolve (4-fluoro-3-nitrophenyl)methanol (25.0 g, 146.1 mmol) in tetrahydrofuran (500 mL), add (D)-alanine methyl ester hydrochloride (30.6 g, 219.2 mmol) and N,N-diisopropylethylamine (46.6 g, 438.3 mmol) thereto, and react at 80 °C for 16 hours. LCMS was used to detect the end of the reaction. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (20.0 g, yield 53.9%).

[0497] 2. Preparation of Methyl (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)-D-alaninate

[0498] Dissolve methyl (4-(hydroxymethyl)-2-nitrophenyl)-D-alaninate (12.0 g, 47.2 mmol) and TBSCl (10.7 g, 70.8 mmol) in DCM (200 mL), add imidazole (6.4 g, 94.4 mmol), and react at 10 °C for 0.5 hour. Pour into water and extract with ethyl acetate. Concentrate the organic phase, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (13.6 g, yield 78.2%).

[0499] 3. Preparation of Methyl (2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitrophenyl)-D-alaninate

[0500] Dissolve methyl (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)-D-alaninate (13.0 g, 35.3 mmol) and N-bromosuccinimide (7.5 g, 42.4 mmol) in N,N-dimethylformamide (200 mL). After addition, react at 40 °C for 1 hour. Directly use for the next step.

[0501] 4. Preparation of Methyl (2-Bromo-4-(hydroxymethyl)-6-nitrophenyl)-D-alaninate

[0502] Add methyl (2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitrophenyl)-D-alaninate (crude product from the previous step) to TBAF (1 M, 35.3 mL). After addition, react at 16 °C for 1 hour. Purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (9.0 g, overall yield of two steps 76.6%).

[0503] 5. Preparation of (R)-5-Bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0504] Dissolve methyl (2-bromo-4-(hydroxymethyl)-6-nitrophenyl)-D-alaninate (10.8 g, 32.4 mmol) in methanol (90 mL) / tetrahydrofuran (90 mL) / water (30 mL), add iron powder (9.0 g, 161.2 mmol) and ammonium chloride (17.3 g, 323.3 mmol), and react at 70 °C for 2 hours. Filter to remove the solid, concentrate, add water (100 mL) and ethyl acetate (100 mL) for extraction, and dry and concentrate the organic phase to obtain the target compound (7.2 g, yield 81.9%).

[0505] 6. Preparation of (R,E)-5-(2-Ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0506] Dissolve (R)-5-bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (7.1 g, 26.2 mmol) in 1,4-dioxane (150 mL) and water (20.0 mL), add 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.8 g, 39.3 mmol), Pd(dppf)Cl 2(1.9 g, 2.6 mmol), sodium carbonate (5.6 g, 52.4 mmol), purged with nitrogen, reacted at 100 °C under nitrogen for 2 hours. Detected by LCMS, the reaction was completed. Diluted with water, extracted with ethyl acetate, the organic phase was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate = 1:3) to obtain the product (4.6 g, yield 67.0%).

[0507] 7. Preparation of (R)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0508] Dissolve (R,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (1.9 g) in dichloromethane (100 mL), add an ethyl acetate solution of hydrogen chloride (16 mL). React at 5 °C for 10 minutes. Concentrate, and the crude product is directly used for the next step.

[0509] 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)picolinamide

[0510] Dissolve (R)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (the crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (1.97 g, 7.2 mmol) in acetonitrile (200 mL), add DIEA (9.3 g, 71.8 mmol), react at 80 °C for 2 hours. Concentrate, dilute with water, extract with ethyl acetate, dry and concentrate the organic phase, and purify by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the product (600 mg, yield 19.0%).

[0511] Molecular formula: C 23 H 25 F N 6 O 2 Molecular weight: 436.5 LC-MS (m / z): 437.2 (M + H + )

[0512] 1 H-NMR (400 MHz, CDCl 3)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).

[0513] Example XVI: 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)picolylamide (Compound 28)

[0514] 1. Preparation of methyl (4-(hydroxymethyl)-2-nitrophenyl)-L-alaninate

[0515] Dissolve (4-fluoro-3-nitrophenyl)methanol (10.3 g, 60.2 mmol) in tetrahydrofuran (200 mL), add (L)-alanine methyl ester hydrochloride (12.6 g, 90.3 mmol) and N,N-diisopropylethylamine (23.3 g, 0.18 mol) thereto, and react at 80 °C for 16 hours. LCMS was used to detect the end of the reaction. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (10.0 g, yield 65.4%).

[0516] 2. Preparation of methyl (2-bromo-4-(hydroxymethyl)-6-nitrophenyl)-L-alaninate

[0517] Dissolve methyl (4-(hydroxymethyl)-2-nitrophenyl)-L-alaninate (10.0 g, 39.4 mmol) and N-bromosuccinimide (7.7 g, 43.3 mmol) in N,N-dimethylformamide (100 mL). After adding, react at 10 °C for 16 hours. Pour into water and extract with ethyl acetate. Concentrate the organic phase, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:1) to obtain the product (7.0 g, yield 53.6%).

[0518] 3. Preparation of (S)-5-bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0519] Dissolve methyl (2-bromo-4-(hydroxymethyl)-6-nitrophenyl)-L-alaninate (7.0 g, 21.1 mmol) in methanol (40 mL) / tetrahydrofuran (40 mL) / water (10 mL), add iron powder (7.3 g, 0.13 mol) and ammonium chloride (13 g, 0.25 mol), and react at 70 °C for 2 hours. Filter to remove the solid, concentrate, add water (30 mL) and ethyl acetate (30 mL) for extraction, and dry and concentrate the organic phase to obtain the target compound (4.0 g, yield 70.2%).

[0520] 4. Preparation of (S,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0521] Dissolve (S)-5-bromo-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (70 mg, 0.26 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), add 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 mg, 0.31 mmol), Pd(dppf)Cl 2 (19 mg, 26.0 μmol), sodium carbonate (55 mg, 0.52 mmol), purge with nitrogen, and react at 90 °C under nitrogen for 2 hours. Monitor by LCMS until the reaction is complete. Dilute with water, extract with ethyl acetate, concentrate the organic phase, and purify by silica gel column chromatography (n-heptane:ethyl acetate = 1:3) to obtain the product (40 mg, yield 58.8%).

[0522] 5. Preparation of (S)-8-(chloromethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0523] Dissolve (S,E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (40 mg, 0.15 mmol) in dichloromethane (10 mL), and add ethyl acetate solution of hydrogen chloride (0.8 mL). React at 5 °C for 10 minutes. Concentrate, and use the crude product directly for the next step.

[0524] 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)picolinamide

[0525] Dissolve (S)-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)picolylamine hydrochloride (41 mg, 0.15 mmol) in acetonitrile (10 mL), add DIEA (58 mg, 0.45 mmol), and react at 80 °C for 2 hours. Concentrate, dilute with water, extract with ethyl acetate, dry and concentrate the organic phase, and purify by silica gel plate (dichloromethane:methanol = 15:1) to obtain the product (11 mg, overall yield in two steps 16.7%).

[0526] Molecular formula: C 23 H 25 FN 6 O 2 Molecular weight: 436.5 LC-MS (m / z): 437.2 (M + H + )

[0527] 1 H-NMR (400 MHz, CDCl 3 ) 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).

[0528] Example XVII: Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinolin-7-yl)methyl)piperazin-1-yl)picolylamine (Compound 31)

[0529] 1. Preparation of 5-(3-bromo-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0530] At 0 °C, add formic acid (130 mL) dropwise to triethylamine (100 mL), stir for 30 minutes, add 3-bromo-5-nitrobenzaldehyde (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). React at 25 °C for 12 h. After the reaction is completed, quench the reaction with water (200 mL), and extract with ethyl acetate (100 mL * 3). Collect the organic phase and rotary evaporate to obtain the crude product (20.0 g). Directly use it for the next step of the reaction.

[0531] 2. Preparation of 3-(3-bromo-5-nitrophenyl)propanoic acid

[0532] To a solution of 5-(3-bromo-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (20.0 g, crude) in acetonitrile (100 mL) was added water (10 mL). The reaction was carried out at 120 °C for 6 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 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), the organic phase was collected, concentrated under reduced pressure, and purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:1) to obtain the product (10.0 g, two-step yield 93.2%).

[0533] 3. Preparation of 3-(3-amino-5-bromophenyl)propanoic acid

[0534] To a solution of 3-(3-bromo-5-nitrophenyl)propanoic acid (10.0 g, 36.5 mmol) in ethanol / water (100 mL / 20 mL) were added iron powder (6.1 g, 109.5 mmol) and ammonium chloride (5.9 g, 109.5 mmol). The reaction was carried out at 80 °C for 12 h. After completion of the reaction, the reaction solution was concentrated, and purified by column chromatography (SiO 2 , 100% ethyl acetate) to obtain the product (6.4 g, yield 71.9%).

[0535] 4. Preparation of 3-(3-acetamido-5-bromophenyl)propanoic acid

[0536] To acetic anhydride (50 mL) was added 3-(3-amino-5-bromophenyl)propanoic acid (6.4 g, 26.2 mmol), and the reaction was carried out at 25 °C for 1 h. The reaction was completed. The reaction 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%).

[0537] 5. Preparation of N-(6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)acetamide

[0538] To chlorosulfonic acid (20 mL) was added 3-(3-acetamido-5-bromophenyl)propanoic acid (2.4 g, 8.4 mmol). The reaction was carried out at 0 °C for 3 h. The reaction was completed. The reaction solution was slowly poured into ice water, extracted with ethyl acetate (50 mL × 2), the organic phase was collected, 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%).

[0539] 6. Preparation of 7-amino-5-bromo-2,3-dihydro-1H-inden-1-one

[0540] 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) was added lithium hydroxide monohydrate (286 mg, 6.8 mmol). The reaction was carried out at 25 °C for 1 hour. The reaction was completed. The reaction solution was concentrated by rotary evaporation, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (600 mg, yield 79.2%).

[0541] 7. Preparation of Diethyl (1-((6-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphonate

[0542] 7-Amino-5-bromo-2,3-dihydro-1H-inden-1-one (300 mg, 1.3 mmol) and 2-(diethoxyphosphoryl)propanoic acid (307 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (4 mL), and EDCI (633 mg, 3.3 mmol) was added. The reaction was carried out at 25 °C for 2 hours. The reaction was completed. Water (10 mL) and ethyl acetate (15 mL × 2) were added. The organic phase was washed with water (20 mL × 2), dried, and concentrated to obtain the crude product (500 mg). The crude product was directly used in the next step.

[0543] 8. Preparation of 7-Bromo-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0544] 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), and NaH (60%) (156 mg, 3.9 mmol) was added. The reaction was carried out by microwave at 100 °C for 30 minutes. The reaction was completed. The reaction solution 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%).

[0545] 9. Preparation of 7-(Hydroxymethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0546] 7-Bromo-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one (200 mg, 0.76 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributylstannyl)methanol (365 mg, 1.1 mmol), XPhos Pd G2 (60 mg, 0.076 mmol) were added. The reaction was carried out at 90 °C for 2 hours. The reaction was completed. The reaction solution 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%).

[0547] 10. Preparation of 7-(chloromethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0548] Dissolve 7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one (80 mg, 0.37 mmol) and N,N-dimethylformamide (9 mg, 0.12 mmol) in dichloromethane (7 mL), add thionyl chloride (78 mg, 0.66 mmol), and react at 25 °C for 1 hour. Concentrate, and use the crude product directly for the next step.

[0549] 11. Preparation of 6-fluoro-N-methyl-5-(4-((3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinolin-7-yl)methyl)piperazin-1-yl)picolylamine

[0550] Dissolve 7-(chloromethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one (crude product from the previous step), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamine hydrochloride (90 mg, 0.37 mmol) in acetonitrile (7 mL), add DIEA (143 mg, 1.1 mmol) and potassium carbonate (152 mg, 1.1 mmol), and react at 85 °C for 10 hours. The reaction is completed. Concentrate, and purify the crude product by Prep-TLC (dichloromethane:methanol = 10:1) to obtain the product (25 mg, overall yield in two steps 15.5%).

[0551] Molecular formula: C 24 H 26 FN 5 O 2 Molecular weight: 435.2 LC-MS (m / z): 436.2 (M + H + )

[0552] 1 1H-NMR (400 MHz, DMSO-d6) δ: 11.33 (s, 1H), 8.38 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 9.4 Hz, 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).

[0553] Example XVIII: Preparation of 6-fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolylamine (Compound 6)

[0554] 1. Preparation of 6-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one

[0555] 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). The reaction was carried out at 25 °C for 10 minutes, and then bromine (38 g, 237.8 mmol) was added dropwise to the reaction solution. The mixture was heated to 70 °C and reacted for 2 hours. The reaction solution was poured into ice water and 1 M hydrochloric acid solution (300 mL), and then ethyl acetate (300 mL) was added. The mixture was filtered through diatomaceous earth, and the filtrate was separated. The organic phase was concentrated and purified by column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (11.1 g, yield 30.3%).

[0556] 2. Preparation of 5-Bromo-6-fluoro-2,3-dihydro-1H-indene

[0557] 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 then triethylsilane (80 mL) was added. The reaction was carried out at 25 °C for 18 hours. The reaction solution was concentrated and purified by column chromatography (eluted with n-heptane) to obtain the product (5.5 g, yield 83.7%).

[0558] 3. Preparation of 6-Bromo-5-fluoro-4-iodo-2,3-dihydro-1H-indene

[0559] 5-Bromo-6-fluoro-2,3-dihydro-1H-indene (5.75 g, 26.75 mmol) was dissolved in tetrahydrofuran (125 mL), and the temperature was lowered to -75 °C and stirred for 10 minutes. LDA (20.4 mL, 40.8 mmol) was slowly added dropwise, and the reaction was carried out at -65 to -75 °C for 30 minutes. Then, saturated sodium sulfite (70 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (150 mL) was added for extraction. The organic phase was concentrated and purified by reverse-phase column chromatography (acetonitrile / water = 10% - 90%) to obtain the product (3.7 g, yield 40.4%).

[0560] 4. Preparation of tert-Butyl (6-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl)carbamate

[0561] 6-Bromo-5-fluoro-4-iodo-2,3-dihydro-1H-indene (2.7 g, 7.92 mmol), NH 2 Boc (0.93 g, 7.94 mmol), XantPhos (0.46 g, 0.80 mmol), Pd2 (dba) 3 (0.36 g, 0.39 mmol) and cesium carbonate (5.2 g, 16.0 mmol) were successively added to toluene (100 mL), and the reaction was carried out at 105 °C for 18 hours under N 2 protection. After the reaction was completed, it was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% - 30%) to obtain the product (1.1 g, yield 42.1%).

[0562] 5. Preparation of tert-butyl (6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)carbamate

[0563] tert-Butyl (6-bromo-5-fluoro-2,3-dihydro-1H-inden-4-yl)carbamate (1.0 g, 3 mmol) was dissolved in acetone (60 mL), magnesium sulfate aqueous solution (6.4 g, 15%) and potassium permanganate (1.5 g, 9.5 mmol) were added, and the reaction was carried out at 25 °C for 18 hours. After the reaction was completed, it was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% - 33%) to obtain the product (0.9 g, yield 86.3%).

[0564] 6. Preparation of 7-amino-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one

[0565] tert-Butyl (6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)carbamate (900 mg, 2.6 mmol) was dissolved in ethyl acetate (5 mL), HCl / EA (9 mL, 36 mmol) was added, and the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, it was concentrated to obtain the product (700 mg, yield 95.4%).

[0566] 7. Preparation of diethyl (1-((6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphate

[0567] 2-(Diethoxyphosphoryl)propanoic acid (810 mg, 3.8 mmol) was dissolved in DCM (20 mL), oxalyl chloride (800 mg, 6.3 mmol) and N,N-dimethylformamide (0.5 mL) were added, and the reaction was carried out at 25 °C for 0.5 hours to obtain a solution for later use.

[0568] 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. The reaction was carried out at 25 °C for 2 hours. The reaction was completed. 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%).

[0569] 8. Preparation of 7-bromo-8-fluoro-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0570] Diethyl (1-((6-bromo-5-fluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)amino)-1-oxopropan-2-yl)phosphonate (500 mg, 1.15 mmol) and NaH (124 mg, 3.1 mmol) were dissolved in DMF (15 mL), and the mixture was stirred at 100 °C for 20 minutes under microwave irradiation. After the reaction was completed, the reaction solution was poured into water (50 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10% - 50%) to obtain the product (100 mg, yield 30.9%).

[0571] 9. Preparation of 8-fluoro-7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0572] 7-Bromo-8-fluoro-3-methyl-4,5-dihydrocyclopenta[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 successively added to dioxane (25 mL) and water (1 mL). The reaction was carried out at 95 °C for 16 hours under N2 protection. After the reaction was completed, the mixture was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20% - 100%) to obtain the product (50 mg, yield 40.3%).

[0573] 10. Preparation of 7-(chloromethyl)-8-fluoro-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one

[0574] 8-Fluoro-7-(hydroxymethyl)-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one (50 mg, 0.21 mmol) and N,N-dimethylformamide (200 mg) were dissolved in dichloromethane (7 mL), and thionyl chloride (250 mg, 2.1 mmol) was added. The reaction was carried out at 20 °C for 2 hours. It was concentrated, and the crude product was directly used for the next step.

[0575] 11. Preparation of 6-Fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0576] 7-(Chloromethyl)-8-fluoro-3-methyl-4,5-dihydrocyclopenta[de]quinolin-2(1H)-one (crude product from the previous step) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (82 mg, 0.3 mmol) were dissolved in acetonitrile (40 mL), and DIEA (257 mg, 1.99 mmol) was added. The reaction was carried out at 85 °C for 2 hours. After the reaction, a solid was precipitated, filtered, and the filter cake was washed with acetonitrile (5 mL). The filter cake was collected to obtain the product (35 mg, the yield in two steps was 36.0%).

[0577] Molecular formula: C 24 H 25 F 2 N 5 O 2 Molecular weight: 453.5 LC-MS (m / z): 454.3 (M + H + )

[0578] 1 1H-NMR (400 MHz, DMSO) δ: 11.59 (s, 1H), 8.37 (d, J = 4.6 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 8.7 Hz, 1H), 7.01 (d, J = 4.2 Hz, 1H), 3.63 (s, 2H), 3.30 (s, 2H), 3.12 - 3.17 (m, 6H), 2.74 (d, J = 4.5 Hz, 3H), 2.56 (s, 4H), 1.96 (s, 3H).

[0579] Example XIX: 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)picolinamide (Compound 29-1)

[0580] 1. Preparation of 5-Bromo-7-nitro-1H-benzo[d]imidazole

[0581] Dissolve 5-bromo-3-nitrobenzene-1,2-diamine (4.0 g, 17.2 mmol) in HCl (4 M, 50 mL), add formic acid (950 mg, 20.7 mmol). After the reaction system reacts at 120 °C for 1 hour, adjust the pH to 7 with ammonia water, precipitate the solid, filter and rotary evaporate the filter cake to obtain the product (3.8 g, yield 91.1%).

[0582] 2. Preparation of Methyl (R)-2-(5-bromo-7-nitro-1H-benzo[d]imidazol-1-yl)propionate

[0583] Dissolve 5-bromo-7-nitro-1H-benzo[d]imidazole (1.2 g, 5.0 mmol) in tetrahydrofuran (50 mL), add 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). After the reaction system reacts at 20 °C for 1 hour, concentrate it, wash with water, extract with ethyl acetate and concentrate. The crude product is purified by column chromatography (EA:PE = 1:1) to obtain the product (600 mg, yield 35.3%).

[0584] 3. Preparation of (R)-8-Bromo-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one

[0585] Dissolve 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) in methanol (20 mL), water (5 mL) and tetrahydrofuran (20 mL), react at 70 °C for 2 h, extract with ethyl acetate and then concentrate the organic phase, which is directly used for the next step.

[0586] 4. Preparation of (R)-8-(Hydroxymethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one

[0587] Dissolve (R)-8-bromo-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (crude product from the previous step), tributylstannylmethanol (282 mg, 0.88 mmol) and XPhos Pd G2 (69 mg, 88.0 μmol) in dioxane (10 mL). After adding, react at 80 °C for 2 h. After the reaction is completed, add water and extract with ethyl acetate, collect the organic phase, concentrate, and purify by column chromatography (MeOH:DCM = 1:10) to obtain the product (60 mg, yield 31.6%).

[0588] 5. Preparation of (R)-8-(chloromethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one

[0589] Dissolve (R)-8-(hydroxymethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (60 mg, 0.28 mmol) in DCM (10 mL), add thionyl chloride (322 mg, 2.8 mmol) and DMF (21 mg, 0.28 mmol). After addition, react at 20 °C for 6 h. After the reaction is completed, concentrate the crude product and directly use it for the next reaction.

[0590] 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)picolylamine

[0591] Dissolve (R)-8-(chloromethyl)-4-methyl-4H-imidazo[1,5,4-de]quinoxalin-5(6H)-one (crude product from the previous step) in acetonitrile (10 mL), add DIEA (98 mg, 0.76 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolylamine hydrochloride (77 mg, 0.28 mmol), and react at 70 °C for 2 h. After the reaction is completed, concentrate and purify by column chromatography (MeOH:DCM = 1:10) to obtain the product (30 mg, the two-step yield is: 24.8%).

[0592] Molecular formula: C 22 H 24 FN 7 O 2 Molecular weight: 437.5 LC-MS (M / e): 438.1 (M + H + )

[0593] 1 H-NMR (400 MHz, CDCl 3 ) 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).

[0594] 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)picolylamide (Compound 29-2)

[0595] Prepared according to the method of Reference Example 19, wherein the chiral intermediate was replaced by methyl (R)-2-hydroxypropionate instead of methyl (S)-2-hydroxypropionate.

[0596] Molecular formula: C 22 H 24 FN 7 O 2 Molecular weight: 437.5 LC-MS (M / e): 438.1 (M + H + )

[0597] 1 H-NMR (400 MHz, CDCl 3 ) 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).

[0598] Example 21: Preparation of (Compound 38)

[0599] 1. Preparation of 5-bromo-6-fluoroindole-2,3-dione

[0600] Dissolve 6-fluoroindole-2,3-dione (10.0 g, 60.6 mmol) in DMF (150 mL), add NBS (12.0 g, 67.4 mmol), and react at 10 °C for 16 h. Slowly pour the reaction solution into ice water, filter to remove the filtrate, and dry to obtain the crude product (8.0 g). Purify by silica gel column chromatography (ethyl acetate:tetrahydrofuran = 9:1) to obtain the product (4 g. Yield 27.1%).

[0601] 2. Preparation of 5-bromo-3,3,6-trifluoroindole-2-one

[0602] Dissolve 5-bromo-6-fluoroindole-2,3-dione (4.0 g, 16.4 mmol) in dichloromethane (110 mL), add DAST (7.9 g, 49.0 mmol), and react at 15 °C for 3 h. Quench with water, extract, and purify by silica gel column chromatography

[0603] (n - heptane: ethyl acetate = 2:1), to obtain the product (2.2 g, yield 50.5%).

[0604] 3. Preparation of 5 - bromo - 3,3,6 - trifluoro - 7 - nitroindol - 2 - one

[0605] Dissolve 5 - bromo - 3,3,6 - trifluoroindol - 2 - one (2.2 g, 8.3 mmol) in concentrated sulfuric acid (30 mL), add potassium nitrate (1.3 g, 12.9 mmol), and react at 0 °C for 1 hour. Slowly pour the reaction solution into ice water, filter to remove the filtrate, and dry to obtain the product (2.0 g, yield 77.8%).

[0606] 4. Preparation of 5 - bromo - 3,6 - difluoro - 1H - indol - 7 - amine

[0607] Dissolve 5 - bromo - 3,3,6 - trifluoro - 7 - nitroindol - 2 - one (2.0 g, 6.4 mmol) in tetrahydrofuran (10 mL), add borane - tetrahydrofuran solution (1 M, 30 mL), and react at 70 °C for 2 hours. Quench with methanol, concentrate, and purify by silica gel column chromatography (n - heptane: ethyl acetate = 1:1) to obtain the crude product (1.2 g), and then purify by C18 column (methanol: water = 0 - 46%) to obtain the product (700 mg, yield 44.1%).

[0608] 5. Preparation of 2 - bromo - N - (5 - bromo - 3,6 - difluoro - 1H - indol - 7 - yl) propanamide

[0609] Dissolve 5 - bromo - 3,6 - difluoro - 1H - indol - 7 - amine (700 mg, 2.8 mmol), 2 - bromopropanoic acid (875 mg, 5.7 mmol) and pyridine (890 mg, 11.3 mmol) in ethyl acetate (40 mL), cool to - 10 °C, add ethyl acetate solution of 1 - cyclopropylphosphonic anhydride (50%, 5.4 g, 8.5 mmol), and react at - 10 °C for 1 hour. Extract with water and ethyl acetate, and purify the crude product by silica gel column chromatography (n - heptane: ethyl acetate = 2:1) to obtain the product (1.0 g, yield 92.4%).

[0610] 6. Preparation of 8 - bromo - 6,9 - difluoro - 3 - methyl - 1H - pyrrolo[1,2,3 - de] quinoxalin - 2(3H) - one

[0611] Dissolve 2-bromo-N-(5-bromo-3,6-difluoro-1H-indol-7-yl)propanamide (1.0 g, 2.6 mmol) in DMF (30 mL), and add 60% sodium hydride (266 mg, 6.7 mmol). React at 20 °C for 0.5 h. Quench with water, extract with water and ethyl acetate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 2:1) to obtain the product (68 mg, yield 86.3%).

[0612] 7. Preparation of 6,9-difluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0613] Dissolve 8-bromo-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (680 mg, 2.3 mmol), tri-n-butylstannylmethanol (872 mg, 2.7 mmol), and Xphos Pd G2 (182 mg, 0.23 mmol) in 1,4-dioxane (70 mL), and react at 85 °C for 2 h. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 1:2) to obtain the product (440 mg, yield 77.3%).

[0614] 8. Preparation of 8-(chloromethyl)-6,9-difluoro-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0615] Dissolve 6,9-difluoro-8-(hydroxymethyl)-3-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.40 mmol) in dichloromethane (20 mL), and successively add dropwise N,N-dimethylformamide (74 mg, 1.0 mmol) and thionyl chloride (240 mg, 2.0 mmol). React at 20 °C for 2 h. Concentrate, and directly use the crude product in the next step.

[0616] 9. Preparation of 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-methylnicotinamide

[0617] 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)picolinamide hydrochloride (110 mg, 0.40 mmol) were dissolved in acetonitrile (20 mL), DIEA (260 mg, 2.0 mmol) was added, and the reaction was carried out at 80 °C for 16 hours. The mixture was concentrated, water and (dichloromethane:methanol = 10:1) were added for extraction, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain the product (130 mg, overall yield of two steps 69.4%).

[0618] Molecular formula: C 23 H 23 F 3 N 6 O 2 Molecular weight: 472.5 LC-MS (m / z): 473.2 (M + H + )

[0619] 1 1H-NMR (400 MHz, CDCl 3 ) 7.99 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.18 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 3.2 Hz, 1H), 5.03 (t, J = 6.8 Hz, 1H), 3.73 (s, 2H), 3.24 (t, J = 4.8 Hz, 4H), 3.00 (d, J = 5.0 Hz, 3H), 2.71 (t, J = 4.8 Hz, 4H), 1.79 (d, J = 7.0 Hz, 3H)

[0620] 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-methylpicolinamide (Compound 46)

[0621] 1. Preparation of methyl 2-((2-bromo-4-formyl-6-nitrophenyl)amino)-2-methylpropionate

[0622] 3-Bromo-4-fluoro-5-nitrobenzaldehyde (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. After the addition was complete, the reaction system was reacted at 15 °C for 16 h. It was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (1.4 g, yield: 33.7%).

[0623] 2. Preparation of methyl 2-((2-bromo-4-(hydroxymethyl)-6-nitrophenyl)amino)-2-methylpropionate

[0624] Methyl 2-((2-bromo-4-formyl-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. After the addition was complete, it was reacted at 20 °C for 1 h and then directly concentrated. After washing with water and extracting and concentrating with ethyl acetate, the crude product was purified by column chromatography (EA:PE = 3:1) to obtain the product (810 mg, yield: 57.4%).

[0625] 3. Preparation of 5-bromo-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one

[0626] 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 reacted at 70 °C for 3 h. It was filtered through diatomaceous earth, the filtrate was concentrated, diluted with water and ethyl acetate, and the organic phase was concentrated to obtain the title compound (130 mg, yield: 79.2%).

[0627] 4. Preparation of (E)-5-(2-ethoxyvinyl)-7-(hydroxymethyl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one

[0628] 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-dioxaborolane (137 mg, 0.69 mmol) and Pd(dppf)Cl 2(34 mg, 46.0 μmol), sodium carbonate (98 mg, 0.92 mmol) was dissolved in dioxane (10 mL) and water (1 mL). After addition, the reaction was carried out at 90 °C for 1 h. After the reaction was completed, water and ethyl acetate were added for extraction. 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%).

[0629] 5. Preparation of 8-(chloromethyl)-3,3-dimethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0630] (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. After addition, the reaction was carried out at 20 °C for 0.5 h. After the reaction was completed, the crude product was concentrated and directly used for the next step of the reaction.

[0631] 6. 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-methylpyridinecarboxamide

[0632] 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)picolinamide hydrochloride (80 mg, 0.29 mmol) were added. The reaction was carried out at 70 °C for 2 h. After the reaction was completed, it was concentrated and purified by silica gel plate (MeOH:DCM = 1:15) to obtain the product (2.5 mg, two-step yield: 1.9%).

[0633] Molecular formula: C 24 H 27 FN 6 O 2 Molecular weight: 450.5 LC-MS (M / e): 451.2 (M + H + )

[0634] 1 H-NMR (400 MHz, CDCL 3)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), 6.63 (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).

[0635] 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-methylpicolinamide (Compound 49-2)

[0636] 1. Preparation of 5-bromo-3-fluoro-7-nitro-1H-indazole

[0637] Dissolve 5-bromo-7-nitro-1H-indazole (350 mg, 1.4 mmol) in acetonitrile (7 mL), add Select F (1.0 g, 2.8 mmol), and react under microwave at 125 °C for 1 hour. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 9:1) to obtain the product (120 mg, yield 31.9%).

[0638] For the remaining synthesis steps, refer to Example 19.

[0639] Characterization data of Compound 49-2:

[0640] Molecular formula: C 22 H 23 F 2 N 7 O 2 Molecular weight: 455.5 LC-MS (m / z): 456.2 (M + H + )

[0641] 1 1H-NMR (400 MHz, CDCl 3 ) δ: 8.21 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 5.18 (t, J = 7.0 Hz, 1H), 3.60 (s, 2H), 3.25 - 3.15 (m, 4H), 3.00 (d, J = 5.0 Hz, 3H), 2.76 - 2.65 (m, 4H), 1.86 (d, J = 7.0 Hz, 3H).

[0642] 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-methylpicolinamide (Compound 49-1)

[0643] Referring to Example 23, characterization data:

[0644] Molecular formula: C 22 H 23 F 2 N 7 O 2 Molecular weight: 455.5 LC-MS (m / z): 456.2 (M+H + )

[0645] 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 5.18 (t, J = 7.0 Hz, 1H), 3.60 (s, 2H), 3.25 - 3.15 (m, 4H), 3.00 (d, J = 5.0 Hz, 3H), 2.76 - 2.65 (m, 4H), 1.86 (d, J = 7.0 Hz, 3H).

[0646] 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)picolylamine (Compound 63-1)

[0647] Referring to Example 23, 5-bromo-7-nitro-1H-indazole was directly reacted with ethyl (S)-2-hydroxypropionate.

[0648] Characterization data of Compound 63-1:

[0649] Molecular formula: C 22 H 24 FN 7 O 2 Molecular weight: 437.5 LC-MS (m / z): 438.2 (M+H + )

[0650] 1 H-NMR (400 MHz, CDCl3 ) δ: 8.22 (s, 1H), 8.00 - 7.94 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.79 (s, 1H), 5.37 (t, J = 7.0 Hz, 1H), 3.62 (s, 2H), 3.27 - 3.15 (m, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.70 - 2.60 (m, 4H), 1.94 (d, J = 7.0 Hz, 3H).

[0651] 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)picolylamide (Compound 63-2)

[0652] Referring to Reference Examples 23 and 25, 5-Bromo-7-nitro-1H-indazole is directly reacted with ethyl (R)-2-hydroxypropionate.

[0653] Molecular formula: C 22 H 24 FN 7 O 2 Molecular weight: 437.5 LC-MS (m / z): 438.2 (M + H + )

[0654] 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.08 (s, 1H), 8.00 - 7.94 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.79 (s, 1H), 5.37 (t, J = 7.0 Hz, 1H), 3.62 (s, 2H), 3.27 - 3.15 (m, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.70 - 2.60 (m, 4H), 1.94 (d, J = 7.0 Hz, 3H).

[0655] 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-methylpicolinamide (Compound 64-1)

[0656] 1. Preparation of 5-Bromo-6-fluoro-7-nitro-1H-indazole

[0657] Dissolve 5-bromo-6-fluoro-1H-indazole (2.0 g, 9.3 mmol) in concentrated sulfuric acid (50 mL), cool down to 0 °C, add potassium nitrate (1.1 g, 10.9 mmol), and react at 15 °C for 16 hours. Pour the reaction solution into ice water, extract with ethyl acetate, purify by silica gel column chromatography (n-heptane:ethyl acetate = 2:1), and purify the crude product by C18 column (methanol:water = 3:2) to obtain the product (1.2 g, yield 49.6%).

[0658] 2. Preparation of ethyl (R)-2-(5-bromo-6-fluoro-7-nitro-1H-indazol-1-yl)propionate

[0659] Dissolve 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) in tetrahydrofuran (20 mL), add DIAD (580 mg, 2.9 mmol), and react at 15 °C for 1 hour. Concentrate, and purify the crude product by silica gel column chromatography (n-heptane:ethyl acetate = 10:1) to obtain the product (100 mg, yield 14.4%).

[0660] 3. Preparation of ethyl (R)-2-(7-amino-5-bromo-6-fluoro-1H-indazol-1-yl)propionate

[0661] Dissolve ethyl (R)-2-(5-bromo-6-fluoro-7-nitro-1H-indazol-1-yl)propionate (100 mg, 0.28 mmol) in tetrahydrofuran / methanol / water (8 / 8 / 2 mL), add zinc powder (272 mg, 4.2 mmol) and ammonium chloride (297 mg, 5.6 mmol). React at 70 °C for 3 hours. Filter to remove the solid, and use the filtrate directly for the next step.

[0662] 4. Preparation of (R)-8-bromo-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one

[0663] Add an ethyl acetate solution of hydrogen chloride (4 M, 1 mL) to the filtrate of the previous step. React at 15 °C for 1 hour. Concentrate, adjust the pH to 8 - 9 with saturated sodium bicarbonate solution, extract with water and ethyl acetate, dry the organic phase, and concentrate to obtain the product (90 mg).

[0664] 5. Preparation of (R)-9-fluoro-8-(hydroxymethyl)-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one

[0665] (R)-8-Bromo-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one (90 mg, 0.32 mmol) and (tributylstannyl)methanol (122 mg, 0.38 mmol) were dissolved in 1,4-dioxane (10 mL). Xphos Pd G2 (49 mg, 0.062 mmol) was added, and the reaction was carried out at 80 °C for 2 h. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (45 mg, yield 60.4%).

[0666] 6. Preparation of (R)-8-(chloromethyl)-9-fluoro-3-methyl-1H-pyrazolo[1,5,4-de]quinoxalin-2(3H)-one

[0667] (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). Thionyl chloride (182 mg, 1.5 mmol) was added, and the reaction was carried out at 20 °C for 1 h. The mixture was concentrated, and the crude product was directly used for the next step.

[0668] 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-methylpyridinecarboxamide

[0669] (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)pyridinecarboxamide hydrochloride (68 mg, 0.25 mmol) were dissolved in acetonitrile (15 mL). DIEA (160 mg, 1.2 mmol) was added, and the reaction was carried out at 80 °C for 3 h. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (35 mg, overall yield of two steps 40.2%).

[0670] Molecular formula: C 22 H 23 F 2 N 7 O 2 Molecular weight: 455.5 LC-MS (m / z): 456.2 (M + H + )

[0671] 1 1H-NMR (400 MHz, CDCl 3)δ: 8.00 - 7.95 (m, 2H), 7.91 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.30 - 7.25 (m, 2H), 5.34 (t, J = 7.0 Hz, 1H), 3.70 (s, 2H), 3.23 - 3.21 (m, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.72 - 2.68 (m, 4H), 1.93 (d, J = 7.0 Hz, 3H)

[0672] 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-methylpicolinamide (Compound 64-2)

[0673] Referring to Example 27, replace ethyl (S)-2-hydroxypropionate with ethyl (R)-2-hydroxypropionate.

[0674] Characterization data:

[0675] Molecular formula: C 22 H 23 F 2 N 7 O 2 Molecular weight: 455.5 LC-MS (m / z): 456.2 (M + H + )

[0676] 1 1H-NMR (400 MHz, CDCl 3 ) δ: 8.00 - 7.95 (m, 2H), 7.93 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.31 - 7.25 (m, 2H), 5.34 (t, J = 7.0 Hz, 1H), 3.70 (s, 2H), 3.23 - 3.21 (m, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.72 - 2.68 (m, 4H), 1.93 (d, J = 7.0 Hz, 3H).

[0677] 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)picolinamide (Compound 68-1)

[0678] 1. Preparation of 5-Bromo-7-nitro-1H-benzo[d][1,2,3]triazole

[0679] Dissolve 5-bromo-3-nitrobenzene-1,2-diamine (3.6 g, 15.5 mmol) in acetic acid (80 mL), add sodium nitrite (1.18 g, 17.1 mmol), and react at 60 °C for 2 hours. Pour it into water (200 mL), filter, wash the filter cake with water (200 mL), and dry it under vacuum at 50 °C for 5 hours to obtain the product (3.6 g, yield 95.5%).

[0680] For the remaining steps, refer to Example 27. Characterization data of compound 68-1:

[0681] Molecular formula: C 21 H 23 FN 8 O 2 Molecular weight: 438.5 LC-MS (m / z): 439.2 (M + H + )

[0682] 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.85 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 8.6 Hz, 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 = 4.5 Hz, 3H), 2.60 - 2.65 (m, 4H), 2.08 (d, J = 6.9 Hz, 3H).

[0683] 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)picolylamide (Compound 68-2)

[0684] Refer to Example 29 and 27, and replace the chiral intermediate with ethyl (R)-2-hydroxypropionate.

[0685] Characterization data:

[0686] Molecular formula: C 21 H 23 FN 8 O 2 Molecular weight: 438.5 LC-MS (m / z): 439.2 (M + H + )

[0687] 1 H-NMR (400 MHz, CDCl 3)δ: 8.53 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J = 3.7 Hz, 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 = 5.0 Hz, 3H), 2.66 (s, 4H), 2.08 (d, J = 7.0 Hz, 3H).

[0688] The following compounds were prepared by the same or similar method as the above Preparation Example:

[0689] Experimental protocol

[0690] The following provides exemplary experimental protocols for some compounds of the present invention to demonstrate the advantageous activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental protocols are merely examples of the content of the present invention and not limitations on the scope of the present invention.

[0691] Experimental Example 1 In vitro cytological inhibitory activity of the compounds of the present invention

[0692] Test article: The compound of the present invention, the structural formula and preparation method of which are shown in the Examples.

[0693] Reagents and cell lines used in the experiment:

[0694] DMEM: dulbecco's modified eagle medium, a modified basal medium;

[0695] ITS-G: Insulin-Transferrin-Selenium additive;

[0696] CTG: CellTiter-Glo Cell Viability Assay Kit;

[0697] Glutathione

[0698] FBS: Fetal bovine serum;

[0699] MDA-MB-436: BRCA1 mutant human breast cancer cells.

[0700] Experimental method (CelltiterGlo assay)

[0701] 1. Prepare cells

[0702] 1.1 Cell culture:

[0703] MDA-MB-436 cells are adherent cells, and the culture medium is DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione.

[0704] 1.2 Preparation of cell suspension:

[0705] Harvest the cells in the logarithmic growth phase and perform cell counting using a platelet counter. Detect cell viability by trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to the appropriate concentration and add 90 μL of cell suspension to each well of a 96-well plate respectively.

[0706] Table 1. Number of cells seeded

[0707] 2. Preparation of test compounds

[0708] 2.1 Prepare a DMSO stock solution of the test compound, and the concentration of the stock solution of the test compound is 10 mM

[0709] 2.2 Prepare a working stock solution of the test compound

[0710] Dilute the 10 mM stock solution of the test compound 10-fold with DMSO to 1 mM, and then perform 3-fold serial dilution with DMSO for a total of 9 concentrations. Then, take 2 μL of the compound diluted with DMSO gradient and add it to 198 μL of the culture medium (DMEM + 10% FBS + 1% ITS-G + 16 μg / ml glutathione) to obtain a working stock solution of the test compound (the concentration of the working stock solution of the compound is 10 times the final concentration, and the highest concentration of the working stock solution is 10 μM)

[0711] 2.3 Compound treatment

[0712] Add 10 μL of the working stock solution of the compound (10-fold dilution, final DMSO concentration is 0.1%) to each well of the 96-well plate seeded with cells.

[0713] The final concentrations of the test compounds are: 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.

[0714] 2.4 Setting of control wells

[0715] Solvent control: 0.1% DMSO (after diluting 2 μL of DMSO in 198 μL of the culture medium and then taking 10 μL and adding it to the well plate).

[0716] Blank control: Detect and read the 96-well plate at 0 h when adding the drug

[0717] 2.5 Place the 96-well plate in a cell culture incubator at 37 °C with 5% CO 2 for 7 days.

[0718] 3. Detection

[0719] Thaw the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of the reagent (Celltiter Glo assay kit) to each well, shake on an oscillator for 2 min to mix (protected from light), and incubate at room temperature for 20 minutes (protected from light). Read the optical signal value with a multifunctional microplate reader.

[0720] 4. Data processing

[0721] 1) Inhibition rate (%) = (reading of DMSO solvent control well - reading of test substance well) / (reading of DMSO solvent control well - reading of blank control well) × 100%;

[0722] 2) Plot a graph to obtain a curve and IC 50 .

[0723] Experimental results and conclusions

[0724] Table 2. In vitro cytological activities of the compounds of the present invention

[0725] 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 defective DNA repair ability and have the potential for clinical application in treating cancerous diseases with DNA repair defects.

[0726] Experimental Example 2 In vitro enzymatic activity of the compounds of the present invention

[0727] Test article: The compound of the present invention, the structural formula and preparation method are shown in the examples.

[0728] Experimental reagents:

[0729] Experimental consumables:

[0730] Experimental method:

[0731] 1. Prepare a histone-coated 384-well plate

[0732] Add 5 μL of histone solution to each well of the 384-well plate and incubate overnight at 4 °C.

[0733] 2. Wash the histone-coated 384-well plate three times with PBST buffer. Incubate with 50 μL of blocking buffer at room temperature for 1 hour. Wash the well plate three times with PBST buffer.

[0734] 3. Compound dilution

[0735] 1) Prepare the compound of the present invention to 20 mM using DMSO as the test stock solution.

[0736] 2) Serial dilute the stock solution of the compound of the present invention by a factor of 4 to 10 concentrations, with the highest concentration being 20 mM.

[0737] 3) Add 50 nL of the diluted compound solution to each well of a 96-well plate, then add 19.95 μL of the working solution to each well, and centrifuge and shake at 1000 rpm for 1 min. Transfer 5 μL of the compound to the treated 384-well plate.

[0738] 4. Enzyme reaction experiment

[0739] 1. Add 10 μL of DNA solution to the negative control wells, add 10 μL of PARP1&DNA (or PARP2&DNA) mixture to the wells except the control wells, and then add 10 μL of NAD+ reagent to each well, and incubate at 25 °C for 60 min.

[0740] 2. Wash the 384-well plate three times with PBST buffer;

[0741] 3. The final concentrations of the test compounds are 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.

[0742] 5. Detection

[0743] 1. Add 20 μL of anti-Poly / Mono-ADP Ribose Rabbit mAb to each well, wash the 384-well plate three times with PBST buffer after incubating at room temperature for 1.5 h;

[0744] 2. Dilute anti-rabbit IgG, HRP-linked Antibody 2000-fold with blocking buffer, add 200 μL of the diluted antibody to each well, incubate at room temperature for 1 h, and wash the 384-well plate three times with PBST buffer.

[0745] 3. Add 25 μL of SuperSignal ELISA Femto Substrate to each well for chemiluminescence detection.

[0746] 6. Data analysis

[0747] The inhibition rate inhibition (%) is calculated using the following formula:

[0748] Where Max represents the luminescence signal intensity of the positive control well without the compound;

[0749] Min represents the luminescence signal intensity of the negative control well without the enzyme;

[0750] Signal represents the luminescence signal intensity of the test compound;

[0751] The IC 50 is calculated using the following formula:

[0752] Where Y represents % inhibition;

[0753] X represents the concentration of the compound;

[0754] Top: maximum inhibition rate; Bottom: minimum inhibition rate;

[0755] HillSlope: absolute value of the maximum slope of the curve (i.e., the midpoint of the curve).

[0756] Experimental results:

[0757] Table 3 Enzymatic inhibition activity of the compounds of the present invention Note: +: 100 - 1000 nM; ++: 10 - 100 nM; +++: 3 - 10 nM; ++++: 1 - 3 nM; +++++: less than 1 nM.

[0758] Experimental conclusion:

[0759] As can be seen from Table 3, the compounds of the present invention have good inhibitory activity and selectivity against PARP1 and are effective PARP1 inhibitors with high selectivity.

Claims

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- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic, phenyl, or 5- to 7-membered heteroaryl; ring C is selected from 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclic, 6- to 11-membered aryl, or 5- to 11-membered heteroaryl; Ar is selected from 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclic, 6- to 11-membered aryl, or 5- to 11-membered heteroaryl optionally substituted with 1 to 3 substituents Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, halo-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, halo-C 1-6 alkoxy, hydroxy-C 1-6 alkoxy, amino-C 1-6 alkoxy, -(CH 2 ) p -3- to 10-membered cycloalkyl, -(CH 2 ) p -3- to 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 ); each R 1 and each R 2 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 -alkyl, halo-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, halo-C 1-6 -alkoxy, halo-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 and the carbon atom to which they are commonly attached together form a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclic group; R 1 ', R 2 ' are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 -alkyl, halo-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, halo-C 1-6 -alkoxy, halo-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 independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 -alkyl, halo-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, halo-C 1-6 Alkoxy, halo-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 selected from hydrogen, C 1-6 alkyl, halo-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 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclic group; m is selected from 0, 1 or 2, and when m is selected from 2, the adjacent two 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 bond or a double bond. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Ring A and ring B are independently selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; preferably, ring A and ring B are each independently selected from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, furyl, dihydrofuryl, tetrahydrofuryl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, triazole, dihydrothiazolyl, tetrahydrothiazolyl, dihydrooxazolyl or tetrahydrooxazolyl; more preferably, ring A, ring B and X, Y, Z together form the following group: The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, 8- to 11-membered fused ring group, 8- to 11-membered spiro ring group, 7- to 9-membered bridged ring group, 8- to 11-membered fused heterocyclic group, 8- to 11-membered spiro heterocyclic group or 7- to 9-membered bridged heterocyclic group; preferably, ring C is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group, 7- to 9-membered bridged ring group or 7- to 9-membered bridged heterocyclic group; more preferably, ring C is selected from the following groups: and the a end is connected to Ar. The compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Ar is selected from a 5- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, which is optionally substituted by 1 or 2 Q; preferably, Ar is selected from a phenyl group or a 5- to 6-membered heteroaryl group, which is optionally substituted by 1 or 2 Q; more preferably, Ar is selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, or a pyridazinyl group, which is optionally substituted by 1 or 2 Q; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 alkyl, halo-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, halo-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 );R a 、R b are each independently selected from hydrogen, C 1-6 alkyl, halo-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 Alkyl, cyclopropyl or cyclobutyl. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, X, Y, Z are each independently selected from N or C; ring A, ring B and X, Y, Z together form the following group: Ring C is selected from the following groups: and the a end is connected to Ar; Ar is selected from a pyridyl group optionally substituted with 1-2 Qs; each Q is independently selected from H, halogen, hydroxyl, amino, C 1-6 alkyl, halo 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, halo 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 );R 1 、R 2 are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo C 1-6 alkoxy, 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 and the carbon atom to which they are commonly attached together form a 3-4 membered cycloalkyl or 3-4 membered heterocyclic group; R 1 ’, R 2 ’ are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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 selected from H, halogen, hydroxy, amino, cyano, C 1-6 alkyl, halo 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, halo C 1-6 alkoxy, halo 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 selected from hydrogen, C 1-6 alkyl, halo 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; represents a single bond or a double bond. The compound according to claim 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Ring C is and the a end is connected to Ar, and the other end is connected to the para-position of X in ring B through an alkylene group; Ar is selected from pyridyl optionally substituted by 1-2 Qs; each Q is independently selected from 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 ); R 1 , R 2 are independently selected from 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 and the carbon atom to which they are commonly attached together form cyclopropyl or cyclobutyl; R 1 ’, R 2 ’ are independently selected from 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 is independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1- 4 alkyl, halo-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, halo-C 1-4 alkoxy, halo-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 is independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl; n and t are independently selected from 0, 1 or 2; k is 1; q is selected from 0 or 1. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the following compounds: A pharmaceutical composition, which comprises the compound according to any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients. Use of the compound according to any one of claims 1-7, its pharmaceutically acceptable salt or its stereoisomer, and the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a disease associated with overexpression of PARP, said disease being 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 neuronal injury, neurodegenerative diseases, atherosclerosis, hyperlipidemia, cardiac tissue injury, coronary artery disease, myocardial infarction, cardiogenic shock, diabetic neuropathy, osteoarthritis and osteoporosis. Use of the compound according to any one of claims 1-7, its pharmaceutically acceptable salt or its stereoisomer, and the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating cancer associated with overexpression of PARP; preferably, said cancer lacks the HR-dependent DNA DSB repair pathway; more preferably, said cancer comprises one or more cancer cells that lack BRCA1 and / or BRCA2, or said cancer cells have a BRCA1 and / or BRCA2-deficient phenotype.

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