Compound with multi-element heterocyclic structure as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a compound with a multi-element heterocyclic structure as well as a pharmaceutical composition and application of the compound. The invention provides a compound with a multi-heterocyclic structure as shown in a formula I, pharmaceutically acceptable salts thereof, solvates thereof, solvates of the pharmaceutically acceptable salts thereof, crystal forms thereof, stereoisomers thereof, tautomers thereof or isotope compounds thereof. As an inhibitor, the compound with the multi-element heterocyclic structure can meet the requirements of tumor treatment and is beneficial to reducing adverse reactions caused by PARP-2 inhibition.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of multi-element heterocyclic structure compound, its pharmaceutical composition and application. BACKGROUND

[0002] Poly (ADP ribose) polymerase (PARP) family consists of 17 members, which mainly mediate the phosphorylation of target proteins, and the increased negative charge by phosphorylation changes the structure of target proteins and the interaction between PARP and target proteins. Therefore, PARP has an impact on many biological processes, including the regulation of chromatin structure, transcription, cell cycle progression, apoptosis, and DNA replication and repair, of which the most in-depth study is the repair of single-strand DNA damage by PARP-1 and PARP-2.

[0003] Studies have shown that PARP is overexpressed in diseases such as tumors, inflammation-related diseases, autoimmune diseases, neurodegenerative diseases and metabolic stress. Among them, the role of PARP in tumors has been most thoroughly studied, and inhibiting the activity of PARP in tumor cells can reduce DNA repair in tumor cells, thereby promoting tumor cell death, so PARP has become an important target for the development of tumor drugs. PARP inhibitors can produce synergistic lethal effects on breast cancer susceptibility gene (BRCA) mutant tumors, and can target tumor cells with defects in homologous recombination repair (HRR), thereby killing tumor cells more effectively. BRCA mutations were first discovered in ovarian cancer and breast cancer, and there is also a certain relationship between BRCA gene mutations and prostate cancer and pancreatic cancer.

[0004] PARP inhibitors are expected to become ideal drugs for cancer treatment, and have broad research significance. In recent years, several PARP inhibitors have been approved by the FDA for the treatment of tumors. These marketed PARP inhibitors have low selectivity, as they inhibit PARP-1 while also affecting PARP-2, and all have significant adverse reactions. Studies have found that the absence of PARP-2 can shorten the lifespan of mouse red blood cells, damage the differentiation of erythroid progenitor cells, and thus lead to chronic anemia, and can cause neuronal damage after ischemic injury, and chemical damage makes pancreatitis more likely to occur. In addition, the sperm production, adipogenesis and thymus production of PARP-2 knockout mice are also impaired.

[0005] Since the first PARP inhibitor was launched in 2014, six PARP inhibitors have been successively launched worldwide, all of which are non-selective PARP inhibitors. Low-toxicity and high-selectivity inhibitors can not only meet the requirements of tumor treatment, but also help reduce adverse reactions caused by PARP-2 inhibition. The successful development of PARP inhibitors has brought revolutionary changes to the drug treatment plan for some tumors, especially in the field of ovarian cancer, and has brought the drug treatment of recurrent ovarian cancer into the era of precision treatment. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a high-selectivity inhibitor which can not only meet the requirements of tumor treatment, but also help reduce adverse reactions caused by PARP-2 inhibition, in view of the lack of selective PARP inhibitors in the prior art.

[0007] The present application provides a polybasic heterocyclic compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof or an isotopic compound thereof:

[0008]

[0009] wherein ring D is

[0010] is a single bond or a double bond;

[0011] M is -C(R 1 ) =, -C(R 1 R 2 )- or -N(R a )-;

[0012] D1 is C-L D1 -R 6 , N, NR or S;

[0013] D2 is nothing, C-L D2 -R 7 or N, wherein when D1 is S or NR, D2 is nothing;

[0014] D3 is C-L D3 -R 8 or N;

[0015] D4 is nothing, O, S, N, NR 4 or -C(R 4 R 5 );

[0016] D5 is C-L D5 -R 9or N;

[0017] L 0 C 1-6 alkylene or C 1-6 alkyl substituted C 1-6 alkylene;

[0018] when is a double bond, M is -C(R 1 )=, the following (1), (2) and (3) apply:

[0019] (1) D4 is N; R 1 is hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl substituted by one or more halogens;

[0020] (2) D4 is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 together with the carbon atom to which they are attached form ring A is a benzene ring, a "3-8 membered cycloalkene", a "5-7 membered heterocycloalkene containing 1-3 heteroatoms independently selected from O, N and S" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S";

[0021] (3) D4 is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 are independently hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl substituted by one or more halogens; or, R 4 and L D1 -R 6 form a benzene ring or a "5-6 membered heteroaromatic ring containing 1-4 heteroatoms independently selected from O, N and S";

[0022] when is a single bond, D4 is NR 4 , M is -C(R 1 )=, R 1 is absent, M and R 4It forms "5-7 membered partial unsaturated monoheterocyclic olefins containing 1-3 heteroatoms, one of which is N and the other heteroatoms are independently selected from O, N and S" or "5-10 membered heteroaromatic rings containing 1-4 heteroatoms, one of which is N and the other heteroatoms are independently selected from O, N and S".

[0023] The benzene ring, "a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms, the heteroatoms being independently selected from O, N, and S", "a 5-7 membered partially unsaturated monoheterocyclic olefin containing 1-3 heteroatoms, one of which is N, and the other heteroatoms being independently selected from O, N, and S", and "a 5-10 membered heteroaromatic ring containing 1-4 heteroatoms, one of which is N, and the other heteroatoms being independently selected from O, N, and S" may be substituted by any of the following groups: C 1-6 Alkyl, Halogen, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O) 2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2 or -SON(R)2;

[0024] when It is a single bond, and M is -C(R) 1 R 2 - or -N(R) a When -), D4 is non-existent, O, S, or -C(R). 4 R 5 ); R 1 and R 2 Independently hydrogen, halogen, C 1-6 Alkyl, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2 or -SON(R)2, or optionally substituted with any of the following groups: C 1-6alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N, and S", "6-8 membered saturated or partially unsaturated bicyclic heterocyclyl containing from 1-4 heteroatoms independently selected from O, N, and S"; or, R 1 and R 2 and the carbon atom to which they are attached form a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monocyclic heterocycle containing from 1-3 heteroatoms independently selected from O, N, and S", "6-10 membered saturated or partially unsaturated bicyclic heterocycle containing from 1-4 heteroatoms independently selected from O, N, and S"; or,

[0025] R 2 and R 4 and the carbon atom to which they are attached form a Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or "3-7 membered saturated or partially unsaturated monocyclic heterocycle containing from 1-3 heteroatoms independently selected from O, N, and S";

[0026] R a is hydrogen or

[0027] L R3 is a bond or C 1-6 alkylene or C 1-6 alkylene substituted with one or more C 1-6 alkyl groups;

[0028] R 3 is hydrogen or optionally substituted C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, "8-10 membered bicyclic aryl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N, and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing from 1-4 heteroatoms independently selected from O, N, and S", "5-6 membered heteroaryl containing from 1-4 heteroatoms independently selected from O, N, and S" or "8-10 membered bicyclic heteroaryl containing from 1-4 heteroatoms independently selected from O, N, and S";

[0029] R 4 and R 5independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2, or optionally substituted by any of the following: C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, N, and S," "6-8 membered saturated or partially unsaturated bicyclic heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N, and S;" or,

[0030] R 4 and R 5 form -C=O-, -C=S-, -C=NR L -3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, N, and S," "6-10 membered saturated or partially unsaturated bicyclic heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N, and S;" or,

[0031] R L is hydrogen, -CN, -OR L1 or optionally substituted C 1-6 alkyl;

[0032] R L1 is hydrogen, C 1-6 alkyl or halogen substituted C 1-6 alkyl;

[0033] each L is independently a bond or optionally substituted C 1-6 alkylene;

[0034] each R A1 is independently halogen, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R'、-S(O)(=R m R' or -P(O)(R)2, or arbitrarily substituted with any of the following groups: C 1-6 Alkyl groups, 3-7 saturated or partially unsaturated monocyclic carbocyclic groups, 6-8 saturated or partially unsaturated bicyclic carbocyclic groups, "3-7 saturated or partially unsaturated monoheterocyclic groups containing 1-3 heteroatoms independently selected from O, N and S", and "6-8 saturated or partially unsaturated heterobicyclic groups containing 1-4 heteroatoms independently selected from O, N and S".

[0035] L D1 L D2 L D3 and L D5 Independently for the linking key or any arbitrarily replaced C 1-6 Alkylene;

[0036] R 6 R 7 R 8 and R 9 Independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m-NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted with any of the following: C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated bicyclic heterocyclyl containing from 1-4 heteroatoms independently selected from O, N and S" or "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing from 1-4 heteroatoms independently selected from O, N and S";

[0037] Ring C is e and f are independently 0, 1 or 2; B is O, S or NR b , X and Y are independently CR d , O, S or NR e ; R d and R e are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR', -C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted with any of the following: C 1-6alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N, and S", "6-8 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms independently selected from O, N, and S", or "6-10 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms independently selected from O, N, and S";

[0038] R b is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted with one or more halogen; m alkyl, -C(O)R', -COOR, -C(O)N(R)2, -SO3R', -NHR, -C(O)NR(OR), -C(=NR m )N(R)2, or optionally substituted with any of C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N, and S", "6-8 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms independently selected from O, N, and S", or "6-10 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms independently selected from O, N, and S";

[0039] R C is -L C -R C1 ;

[0040] each L C is independently a bond or optionally substituted C 1-6 alkylene;

[0041] each R C1 is independently hydrogen, oxo, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NRm )NR', -C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R', -P(O)(R)2, "5-12 membered heteroaryl containing from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S," or any of the above groups optionally substituted with any of the following: C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S," "6-8 membered saturated or partially unsaturated heterobicyclyl containing from 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S," or "6-10 membered saturated or partially unsaturated heterobicyclyl containing from 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S;"

[0042] each R is independently hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or "4-10 membered saturated or partially unsaturated heterocyclyl containing from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S;" said C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or "4-10 membered saturated or partially unsaturated heterocyclyl containing from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S;" said C 1-6 alkyl, -OC 1-6 alkyl, C 1-6 cycloalkyl, C 3-8 cycloalkenyl, or "4-10 membered saturated or partially unsaturated heterocyclyl containing from 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S;" said C 1-6 alkyl, -OC

[0043] two R's and the N atom to which they are attached form "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from the group consisting of O, N, and S;"

[0044] each R' is independently optionally substituted or unsubstituted C 1-6alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms, independently selected from O, N and S", "6-10 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms, independently selected from O, N and S", "5-6 membered heteroaryl containing from 1-4 heteroatoms, independently selected from O, N and S" or "8-10 membered bicyclic heteroaryl containing from 1-4 heteroatoms, independently selected from O, N and S", or,

[0045] two R' with the N atom to which they are attached form "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms, one of which is N and the others are independently selected from O, N and S";

[0046] each R m is independently -OH, -CN or R;

[0047] m and n are independently 0, 1, 2, 3 or 4;

[0048] q is 0, 1, 2, 3, 4 or 5.

[0049] In one aspect, in a structure according to Formula I,

[0050] Ring D is

[0051] is a single or double bond;

[0052] M is -C(R 1 ) = or -C(R 1 R 2 );

[0053] D1 is C-L D1 -R 6 or N, L D1 is a bond, R 6 is hydrogen;

[0054] D2 is C-L D2 -R 7 , L D2 is a bond, R 7 is hydrogen;

[0055] D3 is C-L D3 -R 8 , L D3 is a bond, R 8 is hydrogen or halogen;

[0056] D4 is O, N, NR 4 or -C(R4 R 5 );

[0057] L 0 is C 1-6 alkylene or C 1-6 alkylene substituted by one or more C 1-6 alkyl groups;

[0058] when is a double bond, M is -C(R 1 )=, the following (1), (2) and (3) apply:

[0059] (1) D4 is N; R 1 is hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogen;

[0060] (2) D4 is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 together with the carbon atom to which they are attached form a ring A is a phenyl ring or a "3-8 membered cycloalkene" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms, independently selected from O, N and S"; m is 0 or 1, L is C 1-6 alkylene, R A1 is hydrogen;

[0061] (3) D4 is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl substituted by one or more halogen;

[0062] when is a single bond, D4 is NR 4 , M is -C(R 1 )=, R 1 is absent, the double bond in M and R 4 are connected to form a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms, one of which is N, the other of which are independently selected from O, N and S"; said "5-7 membered heteroaromatic ring containing 1-3 heteroatoms, one of which is N, the other of which are independently selected from O, N and S" is optionally substituted by C 1-6 alkyl groups;

[0063] When is a single bond, M is -C(R 1 R 2 is -O-, D4 is O, R 1 and R 2 are independently hydrogen or C 1-6 alkyl;

[0064] Ring C is e and f are independently 1 or 2; B is O, S or NH;

[0065] q is 1;

[0066] R C is -L C -R C1 ;

[0067] L C is a bond;

[0068] R C1 is CN or -C(O)N(R)2; each R is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl substituted with one or more halo, or C 1-6 cycloalkyl substituted with one or more -OC 3-8 alkyl.

[0069] In one aspect, L 0 is methylene or methyl-substituted methylene.

[0070] In one aspect, when L D1 , L D2 , L D3 and L D5 are independently any substituted C 1-6 alkylene, the C 1-6 alkylene is substituted with any of C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 cycloalkenyl.

[0071] In one aspect, , in which is a double bond, M is -C(R 1 )=, D4 is N; R 1 is C 1-6 alkyl.

[0072] In one aspect, is

[0073]

[0074]

[0075] In an embodiment, For

[0076] In an embodiment, the compound of the polybasic heterocyclic structure as shown in Formula I is any one of the following structures:

[0077]

[0078]

[0079]

[0080] The present application also provides a compound with the following structure:

[0081]

[0082] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the polybasic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, as described above, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0083] The present application also provides a use of the compound of the polybasic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, as described above, in the manufacture of a PARP inhibitor drug.

[0084] The present application also provides a use of the compound of the polybasic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, as described above, in the manufacture of a drug for treating cancer, ischemic diseases, or neurodegenerative diseases.

[0085] In the present application, when referring to C 1-6 alkyl, the C 1-6 alkyl can be C 1-4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

[0086] In an embodiment, when referring to halogen, the halogen is fluorine, chlorine, bromine, or iodine.

[0087] In one particular solution, when C is mentioned 3-8 When cycloalkyl, the C 3-8 Cycloalkyl group is C 3-6 Cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0088] The positive and progressive effect of this invention is that the multi-component heterocyclic compound with the structure shown in Formula I provided by this invention can meet the requirements of tumor treatment as a highly selective inhibitor. Detailed Implementation

[0089] DIEAN-Ethyl-N-isopropylpropyl-2-amine

[0090] XPhos Pd G2 CAS No.:1310584-14-5

[0091] Dys-Martin Oxidizer CAS No.: 87413-09-0

[0092] Synthesis of key intermediates:

[0093] Synthetic route of intermediate 1 (YL230769-283)

[0094]

[0095] Synthesis of compound YL230769-262

[0096] 5-Nitro-6-methylnicotinic acid ethyl ester (7880 mg, 37.490 mmol), selenium dioxide (6240.38 mg, 56.235 mmol), and 1,4-dioxane (70 mL) were added sequentially to a 250 mL three-necked flask. The reaction was carried out at 110 °C for 18 hours under nitrogen protection. LC-MS showed the reaction was complete. After filtration, the filtrate was concentrated, and column chromatography yielded YL230769-262 (7000 mg, 31.226 mmol, 83.29%). LC-MS (ESI): m / z 225.0 (M+H) + .

[0097] Synthesis of compound YL230769-269

[0098] Into a 250 mL three-necked flask was added sodium hydride (2997.72 mg, 74.943 mmol), tetrahydrofuran (40 mL) successively. It was cooled to 0 °C under nitrogen protection, then 2-butylpropyl triethyl (18904.40 mg, 74.943 mmol) was added slowly. It was reacted for 10 minutes at 0 °C, then it was continuously reacted for 10 minutes after slowly warming to room temperature, and it was continuously reacted for 5 minutes after warming to 40 °C. Then the reaction solution was cooled to -78 °C, and YL230769-262 (7000 mg, 31.226 mmol) was added. It was continuously reacted for 1 hour at this temperature. LCMS showed that the reaction was completed, saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic phase was concentrated. Column chromatography (petroleum ether: ethyl acetate = 40:1-30:1) gave YL230769-269 (8300 mg, 25.751 mmol, 82.47%). LC-MS (ESI): m / z 323.2 (M+H) + .

[0099] Synthesis of compound YL230769-270

[0100] Into a 250 mL three-necked flask was added YL230769-269 (8300 mg, 25.751 mmol), 10% palladium-carbon (4100 mg, 38.527 mmol), and ethanol (60 mL) successively. It was reacted for 18 hours at room temperature under hydrogen protection. LCMS showed that the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to give YL230769-270 (4800 mg, 16.307 mmol, 63.33%). LC-MS (ESI): m / z 295.3 (M+H) + .

[0101] Synthesis of compound YL230769-272

[0102] Into a 100 mL three-necked flask was added YL230769-270 (4800 mg, 16.307 mmol) and 4 mol / L hydrochloric acid 1,4-dioxane solution (35 mL) successively. It was reacted for 1 hour at room temperature under nitrogen protection. LCMS showed that the reaction was completed, a large amount of ethyl ether was added to it, the reaction solution was filtered, and the filter cake was dried to give YL230769-272 (3914 mg, 15.764 mmol, 96.67%). LC-MS (ESI): m / z 249.2 (M+H) + .

[0103] Synthesis of compound YL230769-274

[0104] Into a 250 mL three-necked flask, was added YL230769-272 (3900 mg, 15.708 mmol), 2,3-dichloro-5,6-dicyano-l,4-benzoquinone) (4278.88 mg, 18.850 mmol), 1,4-dioxane (65 mL) successively. The reaction was carried out at 110 °C for 3 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated, then saturated aqueous sodium bicarbonate solution was added to it. The mixture was filtered and the filter cake was dried to give YL230769-274 (2440 mg, 9.908 mmol, 63.07 %). LC-MS (ESI): m / z 247.2 (M+H) + .

[0105] Synthesis of compound YL230769-275

[0106] Into a 250 mL three-necked flask, was added YL230769-274 (2440 mg, 9.908 mmol), tetrahydrofuran (50 mL) successively. The reaction was carried out at 0 °C for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated, then ethyl acetate was added to it. The mixture was directly concentrated and column chromatography (dichloromethane:methanol = 20: 1-10: 1) to give YL230769-275 (1550 mg, 7.589 mmol, 76.60 %). LC-MS (ESI): m / z 205.1 (M+H) + .

[0107] Synthesis of compound YL230769-283 (Intermediate 1)

[0108] Into a 50 mL three-necked flask, was added YL230769-275 (408 mg, 1.998 mmol), dichloromethane (10 mL), N,N-dimethylformamide (0.016 mL, 0.200 mmol) successively. The reaction was carried out at 0 °C for 1 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated, then saturated aqueous sodium bicarbonate solution and dichloromethane were added to it. The organic phase was concentrated and column chromatography (dichloromethane:methanol = 30: 1-20: 1) to give YL230769-283 (Intermediate 1, 254 mg, 1.141 mmol, 57.10 %). LC-MS (ESI): m / z 223.1 (M+H) + .

[0109] Synthetic route of intermediate 2 (YL230783-174-A)

[0110]

[0111] Synthesis of compound YL230783-167-A

[0112] Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (45 g, 189.084 mmol), L-alanine methyl ester hydrochloride (26.39 g, 189.084 mmol) in DMF (180 mL), then slowly add N,N-diisopropylethylamine (73.32 g, 567.251 mmol), then continue to react overnight at room temperature. After the reaction is completed, spin off most of the reaction solvent, then dilute with ethyl acetate and water. Separate the organic phase, extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, evaporate to dryness, and purify the resulting crude product automatically on a column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 4 to 100 / 8) to obtain compound YL230783-167-A (33.5 g, 103.807 mmol, 54.90%), ESI: (m / z) = 320.9 / 322.9 [M+H] + , 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (dd, J = 9.3, 6.9 Hz, 1H), 7.23 (s, 1H), 6.40 (dd, J = 9.4, 1.8 Hz, 1H), 4.20 (p, J = 7.0 Hz, 1H), 3.78 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H).

[0113] Synthesis of compound YL230783-170-A

[0114] Dissolve zinc powder (54.57 g, 834.631 mmol), YL230783-167-A (33.5 g, 104.329 mmol), ammonium chloride (44.64 g, 834.631 mmol) in a mixed solution of methanol (360 mL) and water (18 mL) under ice bath conditions, and react overnight at room temperature. After the reaction is completed, filter off the remaining reaction solid residue and rinse with a large amount of methanol:dichloromethane (1:5) solution, concentrate the filtrate, then dilute with ethyl acetate and water. Separate the organic phase, extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, evaporate to dryness, and obtain a mixture of compound YL230783-170-A (31.8 g, 86.294 mmol, 82.71%), ESI: (m / z) = 291.0 / 293.0 [M+H] + , some of which has been ring-closed to form the desired product for the next step.

[0115] Synthesis of compound YL230783-171-A

[0116] YL230783-170-A (31.8 g, 109.233 mmol) was dissolved in a mixture solution of ethyl acetate (170 mL) and methanol (170 mL), then hydrochloric acid-1,4 dioxane solution (4 M, 25 mL) was added, and the reaction was continued at room temperature for 1 hour. After the reaction was completed, the reaction solvent was removed by rotary evaporation to directly obtain the crude product of the target compound YL230783-171-A (29.5 g, 74.012 mmol, 67.76%), ESI: (m / z) = 259.1 [M+H] + .

[0117] Synthesis of compound YL230783-172-A

[0118] YL230783-171-A (29.5 g, 113.864 mmol) was dissolved in dichloromethane (1100 mL), then DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (31.02 g, 136.637 mmol) was added at once, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solvent was removed by rotary evaporation, a large amount of saturated sodium bicarbonate was added to quench, and the stirring was continued at room temperature overnight. After filtration, the filter cake was washed with a large amount of water, then washed with ether, and the filter cake was evaporated to directly obtain compound YL230783-172-A (16.7 g, 40.928 mmol, 35.94%), ESI: (m / z) = 257.0 / 259.0 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.53 - 7.45 (m, 2H), 2.40 (s, 3H).

[0119] Synthesis of compound YL230783-173-A

[0120] YL230783-172-A (10 g, 38.901 mmol), XPhos Pd G2 (1.53 g, 1.945 mmol) were dissolved in 1,2-dioxane (200 mL) and protected by nitrogen, then (tributylstannyl)methanol (14.99 g, 46.682 mmol) was added, and the reaction was protected by nitrogen again, and then the temperature was raised to 80 °C for 11 hours. After the reaction was completed, the reaction solvent was removed by rotary evaporation, and the obtained crude product was automatically purified by column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 8 to 100 / 12) to obtain compound YL230783-173-A (4.5 g, 19.453 mmol, 50.01%), ESI: (m / z) = 209.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.51 (dd, J = 8.3, 1.1 Hz, 1H), 7.37-7.28 (m, 1H), 5.41 (t, J = 5.8 Hz, 1H), 4.63 (dd, J = 5.6, 1.4 Hz, 2H), 2.40 (s, 3H).

[0121] Synthesis of compound YL230783-174-A (Intermediate 2)

[0122] YL230783-173-A (3.05 g, 14.650 mmol) was dissolved in HBr-H2O (48%, 600 mL) at room temperature, and then the temperature was raised to 80 °C for a total of 3 days. After the reaction was completed, the remaining reaction solvent was removed by rotary evaporation, and ethyl acetate and water were added for dilution. After filtration, a large amount of ethyl acetate was added to the filtrate for extraction, and the organic phase was washed with water and saturated NaCl. The organic layer was dried by rotary evaporation, and the residue was added to a large amount of ethyl acetate and acetonitrile for ultrasonic treatment and then filtered. The filtrate was concentrated to directly obtain compound YL230783-174-A (Intermediate 2, 2.65 g, 7.869 mmol, 53.71%), ESI: (m / z) = 271.0 / 273.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 4.86-4.72 (m, 2H), 2.41 (s, 3H).

[0123] Synthetic route of intermediate 3

[0124]

[0125] Synthesis of compound YL230774-420

[0126] To a mixture of 4-bromo-2,6-difluorobenzonitrile (5.00 g, 22.94 mmol) in ammonia water (28 mL) and isopropanol (10 mL) was heated to 80 °C for 5 h. The reaction was cooled to room temperature and poured into water, stirred for 10 min and filtered. The solid was collected and dried under vacuum at 40 °C to give YL230774-420 (3.50 g, 70.99% yield). 1 H NMR (400 MHz, CDC13) δ 6.72 (t, J = 1.4 Hz, 1H), 6.67 (dd, J = 8.4, 1.6 Hz, 1H), 4.62 (s, 2H).

[0127] Synthesis of compound YL230774-430

[0128] To a mixture of 98% concentrated sulfuric acid (6 mL) was slowly added formic acid (48 mL) and stirred at room temperature for 10 min. Then YL230774-420 (4.00 g, 18.60 mmol) was added portionwise and heated to 100 °C for 2 h. The reaction was cooled to 0 °C, diluted with water (10 mL) and stirred for 0.5 h. The solid was collected by filtration and dried under vacuum at low temperature to give YL230774-430 (3.00 g, 66.37% yield). (ESI): m / z 243.0, 245.0 [M+H] + .

[0129] Synthesis of compound YL230774-433

[0130] To a solution of YL230774-430 (3.00 g, 12.34 mmol) in DMSO (20 mL) was added p-methoxybenzylamine (8.47 g, 61.72 mmol) and heated to 80 °C for 6 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated and concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give YL230774-433 (3.00 g, 67.42% yield). (ESI): m / z 360.0, 362.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.05 (t, J = 5.0 Hz, 1H), 7.97 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.04 - 6.88 (m, 2H), 6.84 (d, J = 1.8 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 4.37 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H).

[0131] Synthesis of compound YL230774-453

[0132] DBU (CAS: 6674-22-2) (1.81 g, 11.91 mmol) and Curtius reagent (CAS; 56602-33-6) (4.79 g, 10.83 mmol) were added to a solution of YL230774-433 (1.3 g, 3.61 mmol) in DMF (13 mL), stirred at room temperature for 15 min, then methylamine (0.56 g, 18.05 mmol) was added, and reacted at room temperature for 16 h. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was separated. After the organic phase was concentrated, YL230774-453 (90 mg, yield 6.67%) was obtained by reverse phase (C18, NH4HCO3) purification. (ESI): m / z 373.1, 375.1 [M+H] + .

[0133] Synthesis of compound YL230774-461 (intermediate 3)

[0134] Under the condition of 0 ℃ ice water bath, triphosgene (72 mg, 0.24 mmol) in dichloromethane (1.5 mL) was added dropwise to a solution of YL230774-453 (90 mg, 0.24 mmol) and DIEA (312 mg, 2.41 mmol) in dichloromethane (3 mL), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction solution was concentrated, YL230774-461 (intermediate 3, 30 mg, yield 31.16%) was obtained by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) purification. (ESI): m / z 399.0, 401.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.02 (d, J = 1.4 Hz, 1H), 6.92 - 6.86 (m, 2H), 5.23 (s, 2H), 3.79 (s, 3H), 3.69 (s, 3H).

[0135] Synthetic route of intermediate 4 (YL230774-454)

[0136]

[0137] Synthesis of compound YL230804-108

[0138] Dissolve 3-bromo-2-fluoroaniline (1 g, 6.723 mmol) in dichloromethane (15 mL), add pyridine (0.766 mL, 9.473 mmol), stir at room temperature for 5 minutes, and then add (E)-3-ethoxyacryloyl chloride (1.06 g, 7.894 mmol). React at room temperature for 2 hours. Dilute with ethyl acetate and water, wash the organic phase with saturated sodium chloride twice. Separate the organic phase, extract the aqueous phase with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and slurry with petroleum ether / ethyl acetate = 10 / 1 to obtain compound YL230804-108-A1 (1.5 g, 98.93%), ESI: (m / z) = 288.0 / 290.0 [M+H] + .

[0139] Synthesis of compound YL230774-451

[0140] Add YL230804-108-A1 (1.40 g, 4.86 mmol) to a concentrated H2SO4 (15 mL) solution, and react at room temperature for 2 hours. Cool the reaction solution to 0°C, and then slowly add an aqueous solution. White solid precipitates, filter, and dry the filter cake under vacuum to obtain YL230774-451 (1.00 g, yield 85.02%). (ESI): m / z 242.0, 244.0 [M+H] + .

[0141] Synthesis of compound YL230774-454 (intermediate 4)

[0142] At room temperature, add sodium difluoromethylsulfinate (1.14 g, 8.26 mmol) and potassium persulfate (4.47 g, 16.53 mmol) to a mixture of YL230774-451 (1.00 g, 4.13 mmol) in acetonitrile (20 mL) and water (6 mL), and then heat to 100°C for 16 hours. Dilute the reaction solution with water and ethyl acetate, separate the organic phase, and concentrate the organic phase. Purify by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-2%) to obtain YL230774-454 (intermediate 4, 100 mg, yield 8.26%). (ESI): m / z 292.0, 294.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.36 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 8.5, 6.1 Hz, 1H), 6.96 (t, J = 54.5 Hz, 1H).

[0143] Synthetic route of intermediate 5 (YL230774-428)

[0144]

[0145] Synthesis of compound YL230774-407

[0146] Under nitrogen protection, triphenylphosphine (0.29 g, 1.09 mmol) and Pd(Ph3P)2Cl2(0.43 g, 0.55 mmol) were added to a mixture of YL230774-405 (5.00 g, 18.23 mmol), bis(pinacolato)diboron (5.09 g, 20.06 mmol) and potassium carbonate (3.78 g, 27.35 mmol) in 1,4-dioxane (100 mL), and heated to 80 °C for 5 hours. The reaction solution was filtered with a diatomite filter cake, and the filtrate was concentrated and dried in vacuum to obtain YL230774-407 (5.00 g, crude product).

[0147] Synthesis of compound YL230774-410

[0148] Under nitrogen protection, Pd(dtbpf)Cl2(26 mg, 0.04 mmol) was added to a mixture of YL230774-407 (100 mg, 0.397 mmol), 6-chloro-5-nitrosnicotinic acid methyl ester (86 mg, 0.40 mmol) and triethylamine (0.17 mL, 1.19 mmol) in N,N-dimethylformamide (3 mL) and water (0.6 mL), and heated to 100 °C for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-410 (30 mg, yield 25.00%). (ESI): m / z 307.1 [M+H] + .

[0149] Synthesis of compound YL230774-416

[0150] Iron powder (27 mg, 0.49 mmol) and ammonium chloride (16 mg, 0.29 mmol) were added to a mixture of YL230774-410 (30 mg, 0.098 mmol) in ethanol (2 mL) and water (0.2 mL) under nitrogen protection, and heated to 80 °C for 2 h. The reaction mixture was filtered through celite, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated and purified by reverse phase (C18, 1.0 mmol HC1) to give YL230774-416 (15 mg, 54.53% yield). (ESI): m / z 245.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 3.92 (s, 3H), 3.19 (t, J = 7.8 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.13 (p, J = 7.6 Hz, 2H).

[0151] Synthesis of compound YL230774-425

[0152] A solution of lithium aluminum hydride in tetrahydrofuran (1 M) (1.6 mL, 1.6 mmol) was added to a mixture of YL230774-416 (200 mg, 0.82 mmol) in tetrahydrofuran (8 mL) at 0 °C, and stirred at 0 °C for 1.5 h. The reaction mixture was quenched with water (1 drop) at 0 °C, followed by sodium hydroxide solution (3 drops), and stirred for 10 min. Anhydrous sodium sulfate (0.1 g, Na2SO4) was added, and stirred for 30 min. The mixture was filtered, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated to give a crude product, which was purified by trituration with dichloromethane and petroleum ether (v / v = 1:1) to give YL230774-425 (100 mg, 55.56% yield). (ESI): m / z 217.2 [M+H] + .

[0153] Synthesis of compound YL230774-428 (intermediate 5)

[0154] Dichlorosulfoxide (550 mg, 4.6 mmol) was added to a mixture of YL230774-425 (100 mg, 0.46 mmol) in dichloromethane (10 mL) at room temperature, and stirred for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution to neutral, and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give YL230774-428 (intermediate 5, 70 mg, crude). (ESI): m / z 235.1 [M+H] + .

[0155] Synthetic route of intermediate 6 (YL230774-414)

[0156]

[0157] Synthesis of compound YL230774-405

[0158] -78 °C, triflic anhydride (10.92 g, 38.69 mmol) was slowly added into a solution of methyl 2-oxocyclopentane-1-carboxylate (5.00 g, 35.17 mmol) and DIEA (6.82 g, 52.76 mmol) in dichloromethane (70 mL). After the addition, it was stirred for 0.5 h, then it was warmed to room temperature and reacted for 1.5 h. The reaction was quenched with water, and the organic phase was separated. The organic phase was concentrated, and then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:3) to give YL230774-405 (9.00 g, yield 93.26%). 1 H NMR (400 MHz, CDCl3) δ 3.87 (d, J = 51.6 Hz, 3H), 3.11-2.52 (m, 4H), 2.27-1.90 (m, 2H).

[0159] Synthesis of compound YL230774-406

[0160] Under nitrogen protection, XPhos Pd G2 (1.15 g, 1.46 mmol) was added into a mixture of YL230774-405 (4.00 g, 14.59 mmol), (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (3.94 g, 17.50 mmol) and cesium carbonate (9.51 g, 29.17 mmol) in 1,4-dioxane (80 mL), and heated to 80 °C for 4 h. The reaction was filtered with a filter cake of diatomite, and the filtrate was concentrated, and then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give YL230774-406 (3.30 g, yield 74.16%). (ESI): m / z 306.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 1.6 Hz, 1H), 8.24 (dd, J = 8.0, 1.7 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.50 (s, 3H), 2.89 (tt, J = 7.7, 2.4 Hz, 2H), 2.82 (tt, J = 7.7, 2.5 Hz, 2H), 2.13 (p, J = 7.6 Hz, 2H).

[0161] Synthesis of compound YL230774-411

[0162] Iron powder (1.19 g, 21.29 mmol) and ammonium chloride (0.68 g, 12.78 mmol) were added to a mixture of YL230774-406 (1.30 g, 4.26 mmol) in ethanol (40 mL) and water (8 mL) under nitrogen protection, and heated to 80 °C for 2 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to give a solid crude. The crude was slurried with acetonitrile and water (v / v = 1:5), filtered, and the filter cake was dried under vacuum at low temperature to give YL230774-411 (0.60 g, yield 57.69 %). (ESI): m / z 244.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H), 7.96 (d, J = 73.9 Hz, 2H), 7.59 (s, 1H), 4.00 (s, 3H), 3.54-2.92 (m, 4H), 2.29 (s, 2H).

[0163] Synthesis of compound YL230774-412

[0164] A solution of lithium aluminum hydride in tetrahydrofuran (1.6 mL, 1 M) was added dropwise to a solution of YL230774-411 (200 mg, 0.82 mmol) in tetrahydrofuran (10 mL) at 0 °C with ice water bath, and the temperature was maintained (0 °C) for 1.5 h. The reaction mixture was quenched with water (1 drop) at 0 °C, then sodium hydroxide solution (3 drops) was added, and stirred for 10 min. Anhydrous sodium sulfate (0.1 g, Na2SO4) was added, and stirred for 30 min. The mixture was filtered, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated to give a crude, which was purified by slurry with acetonitrile and water (v / v = 1:1) to give YL230774-412 (80 mg, yield 45.21 %). (ESI): m / z 216.2 [M+H] + .

[0165] Synthesis of compound YL230774-414 (intermediate 6)

[0166] Sulfoxyl chloride (442 mg, 3.72 mmol) was added to a mixture of YL230774-412 (80 mg, 0.37 mmol) in dichloromethane (2 mL) at room temperature, and the mixture was stirred for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution to neutral, and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give YL230774-414 (intermediate 6, 70 mg, crude). (ESI): m / z 234.1 [M+H] + .

[0167] Synthetic route of intermediate 7 (YL230804-056-A)

[0168]

[0169] Synthesis of compound YL230804-038-A

[0170] 3-Bromo-2-chloro-6-methyl-5-nitropyridine (25 g, 99.419 mmol) was dissolved in methanol (140 mL), substituted with N2, cooled to 0 °C, and sodium methoxide (19.7 g, 109.361 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness, and ethyl acetate and water were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, then washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give compound YL230804-038-A (24.1 g, 98.12%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.69(s,3H).

[0171] Synthesis of compound YL230804-039-A

[0172] YL230804-038-A (24.1 g, 97.551 mmol) was dissolved in DMF (100 mL), and N,N-dimethylformamide dimethyl acetal (100 mL) was added. The mixture was then replaced with N2 and reacted at 100 °C for 2 hours. Most of the DMF was removed by rotary evaporation, and ethyl acetate and water were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, then with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain compound YL230804-039-A (29.3 g, 99.42%). ESI: (m / z) = 302.0 [M+H] + ;

[0173] Synthesis of compound YL230804-045-A

[0174] YL230804-039-A (29.3 g, 96.978 mmol) was dissolved in tetrahydrofuran (120 mL) and water (120 mL), substituted with N2, cooled to 0 °C, and sodium periodate (45.63 mL, 213.352 mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was quenched with an aqueous sodium thiosulfate solution, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give compound YL230804-045-A (25.2 g, 99.57%).

[0175] Synthesis of compound YL230804-046-A

[0176] YL230804-045-A (25.2 g, 96.541 mmol) was dissolved in ethanol (250 mL), and ethyl 3,3- diethoxypropanoate (73.46 g, 386.163 mmol), stannous chloride (91.53 g, 482.703 mmol) were added. The reaction was stirred at 80 °C overnight. The reaction was poured into saturated aqueous NaHC03solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl, dried over anhydrous Na2S04, filtered, and evaporated to dryness. Purification by normal phase column (petroleum ether / ethyl acetate = 10 / 1) gave compound YL230804-046-A (19.3 g, 64.25 %). ESI: (m / z) = 311.1 [M+H] + .

[0177] Synthesis of compound YL230804-048-A

[0178] YL230804-046-A (1.9 g, 6.107 mmol) was dissolved in 1,4-dioxane (20 mL), and (tributylstannyl)methanol (2.16 g, 6.717 mmol), XPhos Pd G2 (38 mg, 0.048 mmol) were added. The reaction was replaced by N2and stirred at 80 °C overnight. The reaction was extracted with ethyl acetate and water. The organic phase was washed with saturated NaCl, dried over anhydrous Na2S04, filtered, and evaporated to dryness. Purification by normal phase column (dichloromethane / methanol = 20 / 1) gave compound YL230804-048-A (840 mg, 52.45 %). ESI: (m / z) = 263.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 2.0, 0.8 Hz, 1H), 8.25 (q, J = 1.4 Hz, 1H), 5.67 (d, J = 69.6 Hz, 1H), 4.62 (d, J = 1.5 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0179] Synthesis of compound YL230804-051-A

[0180] YL230804-048-A (0.84 g, 3.203 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin Oxidizing Agent (1.63 g, 3.884 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was quenched by adding sodium thiosulfate aqueous solution, and extracted with dichloromethane. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. Purification by normal phase column (petroleum ether / ethyl acetate = 4 / 1) gave compound YL230804-051-A (1 g). ESI: (m / z) = 261.1 [M-H] + ;1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.29 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.63 - 8.60 (m, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.17 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0181] Synthesis of compound YL230804-053-A

[0182] YL230804-051-A (0.8 g, 3.074 mmol) was dissolved in tetrahydrofuran (15 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (2.72 g, 12.296 mmol) was added at 0 °C. The reaction was stirred at 50 °C for 2 h. The reaction was diluted with saturated ammonium chloride aqueous solution and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. Purification by normal phase column (petroleum ether / ethyl acetate = 4 / 1) gave compound YL230804-053-A (310 mg, 35.73 %). ESI: (m / z) = 283.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.57 (s, 1H), 7.25 (t, J = 54.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0183] Synthesis of compound YL230804-054-A

[0184] YL230804-053-A (310 mg, 1.098 mmol) was dissolved in acetonitrile (8 mL), trimethylsilyl iodide (879 mg, 4.393 mmol) was added, and the reaction was stirred at 50 °C for 5 h. The reaction was diluted with ethyl acetate and water. The organic phase was washed with aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. Purification by column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave compound YL230804-054-A (250 mg, 86.21 %). ESI: (m / z) = 269.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.98 (d, J = 1.9 Hz, 1H), 8.22 (dq, J = 1.7, 0.8 Hz, 2H), 7.21 - 6.77 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0185] Synthesis of compound YL230804-055-A

[0186] YL230804-054-A (250 mg, 0.932 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (1.86 mL, 1.864 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was quenched with ethyl acetate, evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 10 / 1) to give compound YL230804-055-A (60 mg, 28.57 %). ESI: (m / z) = 227.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.70 (dd, J = 1.9, 0.9 Hz, 1H), 6.97 (t, J = 54.5 Hz, 1H), 5.57 (t, J = 5.5 Hz, 1H), 4.67 (d, J = 4.1 Hz, 2H).

[0187] Synthesis of compound YL230804-056-A

[0188] YL230804-055-A (52 mg, 0.230 mmol) was dissolved in dichloromethane (5 mL), and triphenylphosphine (90 mg, 0.345 mmol) was added. Carbon tetrabromide (114 mg, 0.345 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 2 h. The reaction was evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 10 / 1) to give compound YL230804-056-A (intermediate 7, 50 mg).

[0189] Synthesis route of intermediate 8 (YL230783-198-A)

[0190]

[0191] Synthesis of compound YL230783-189-A

[0192] Methyl 2-bromobenzoate (3 g, 13.950 mmol), 3-amino-4-(dihydroxyboranyl)benzoic acid methyl ester hydrochloride (3.23 g, 13.950 mmol), potassium carbonate (9.64 g, 69.751 mmol) were dissolved in 1,4 dioxane (180 mL), water (18 mL) and then palladium(l,l’-diphenylphosphino)ferrocene dichloride (1.41 g, 1.932 mmol) was added, protected with nitrogen and then reacted at 100 °C for 2 hours. Diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness and the resulting crude was purified automatically on a column (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 12) to obtain the compound YL230783-189-A as a solid (2.9 g, 11.107 mmol, 79.62%) LC-MS (ESI): m / z 254.1 (M+H) + 1H NMR (400 MHz, DMSO-d6) d 11.87 (s, 1H), 8.55 (dd, J = 16.9, 8.3 Hz, 2H), 8.35 (dd, J = 8.0, 1.4 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.78 (dd, J = 8.4, 1.7 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 3.90 (s, 3H).

[0193] Synthesis of compound YL230783-192-A

[0194] To a reaction flask was added YL230783-189-A (1.6 g, 6.318 mmol) and anhydrous tetrahydrofuran (340 mL) and the mixture was cooled to 0 °C. Lithium aluminum hydride tetrahydrofuran solution (1 M) (15.8 mL, 15.794 mmol) was then added slowly. The mixture was then stirred at 0 °C for an additional 1.5 h, quenched with 20 mL of ethyl acetate, followed by 5 mL of water. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 8) to give compound YL230783-192-A (1.25 g, 5.549 mmol, 87.84%) LC-MS (ESI): m / z 224.0 (M-H)-, 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.36 - 8.27 (m, 2H), 7.83 (ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 8.2, 1.6 Hz, 1H), 5.36 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.7 Hz, 2H).

[0195] Synthesis of compound YL230783-198-A

[0196] To a reaction flask was added YL230783-192-A (500 mg, 2.220 mmol), dichloromethane (110 mL), DMF (0.018 mL, 0.222 mmol), protected with nitrogen, cooled to 0 °C, and then chlorosulfoxide (1584.37 mg, 13.319 mmol) was added slowly dropwise. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 30 to 100 / 40) to give compound YL230783-198-A (intermediate 8, 170 mg, 0.565 mmol, 25.46%) as a off-white solid, LC-MS (ESI): m / z 244.0 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.54 - 8.30 (m, 3H), 7.92 - 7.81 (m, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.3, 1.8 Hz, 1H), 4.86 (s, 2H).

[0197] Synthetic route of intermediate 9 (YL230804-156-A)

[0198]

[0199] Synthesis of compound YL230804-145-A1

[0200] Dissolve 7-bromo-2(1H)-quinoxalinone (5 g, 22.218 mmol) in dimethyl sulfoxide (50 mL), add sodium difluoromethylsulfinate (6.22 g, 44.437 mmol), 2,3-butanedione (9.8 mL, 111.091 mmol), irradiate with blue light, react at room temperature for 7 days. Add ethyl acetate and water to the reaction solution, separate the phases, extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, evaporate to dryness, purify by normal phase column (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to obtain compound YL230804-145-A1 (3 g, 49.1%). ESI: (m / z) = 275.1 / 277.1 [M+H] + ;

[0201] Synthesis of compound YL230804-153-A

[0202] Dissolve YL230804-145-A1 (1 g, 3.636 mmol) in 1,4-dioxane (15 mL), add (tributylstannyl)methanol (1.28 g, 3.999 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) (0.14 g, 0.182 mmol), replace with N2, react at 80 °C overnight. Add ethyl acetate and water, separate the phases, extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, wash with saturated NaCl, dry over anhydrous Na2SO4, filter, evaporate to dryness, purify by normal phase column (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-153-A (300 mg, 36.59%). ESI: (m / z) = 227.0 [M+H] + ;

[0203] Synthesis of compound YL230804-156-A

[0204] YL230804-153-A (100 mg, 0.444 mmol) was dissolved in dichloromethane (8 mL), added 1 drop of DMF, replaced by N2, cooled to 0 °C, added dichlorosulfoxide (315 mg, 2.653 mmol), reacted overnight at room temperature. The reaction solution was cooled to 0 °C, neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane / methanol = 10 / 1. The combined organic phase was washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-156-A (intermediate 9, 60 mg, 54.55%). ESI: (m / z) = 245.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.05 (t, J = 53.2 Hz, 1H), 4.91 (s, 2H).

[0205] Synthetic route of intermediate 10 (YL230769-384)

[0206]

[0207] Synthesis of compound YL230769-371

[0208] A 50 mL three-necked flask was added 5-methyl-2H-pyrazole-3-carboxylic acid (4000 mg, 31.718 mmol), and dichlorosulfoxide (40 mL) in sequence. Under nitrogen protection, the reaction was carried out at 80 °C for 18 hours. LCMS showed that the reaction was successful. The reaction solution was cooled to room temperature, and then slowly poured into saturated sodium bicarbonate solution. Dichloromethane was added to the solution. The organic phase was concentrated to obtain YL230769-371 (2440 mg, 11.286 mmol, 35.58%). LC-MS (ESI): m / z 217.2 (M+H) + .

[0209] Synthesis of compound YL230769-377

[0210] Into a 250 mL three-necked flask was added YL230769-371 (2162 mg, 10.000 mmol), 3-bromo-2,6-difluoroaniline (4160.20 mg, 20.000 mmol), tetrahydrofuran (80 mL) successively. It was cooled to -10 °C under nitrogen protection, then sodium bis(trimethylsilyl)amide (25.000 mL) was added slowly. The reaction was continued at this temperature for 2 hours. LCMS showed that the reaction was successful, acetic acid was added to the reaction solution until the pH was 7, then ethyl acetate was added, the organic phase was concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) could obtain YL230769-377 (3130 mg, 9.902 mmol, 99.02 %). LC-MS (ESI): m / z 318.0 (M+H) + .

[0211] Synthesis of compound YL230769-378

[0212] Into a 50 mL three-necked flask was added YL230769-377 (3130 mg, 9.902 mmol), sodium hydride (594.10 mg, 14.852 mmol), N,N-dimethylacetamide (30 mL) successively. It was reacted at room temperature for 1 hour under nitrogen protection, then it was heated to 120 °C for 18 hours. LCMS showed that the reaction was complete, saturated ammonium chloride and ethyl acetate were added, the organic phase was concentrated and column chromatography (petroleum ether: ethyl acetate = 10:1-5:1) could obtain YL230769-378 (560 mg, 1.891 mmol, 19.10 %). LC-MS (ESI): m / z 296.0 (M+H) + .

[0213] Synthesis of compound YL230769-380

[0214] Into a 50 mL three-necked flask was added YL230769-378 (355 mg, 1.199 mmol), (tributylstannyl)methanol (461.95 mg, 1.439 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (94.21 mg, 0.120 mmol), 1,4-dioxane (25 mL) successively. It was reacted at 80 °C for 18 hours under nitrogen protection. LCMS showed that the reaction was complete, the reaction solution was directly concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) could obtain YL230769-380 (206 mg, 0.833 mmol, 69.50 %). LC-MS (ESI): m / z 248.1 (M+H) + .

[0215] Synthesis of compound YL230769-384

[0216] Into a 50 mL three-necked flask was added YL230769-380 (124 mg, 0.502 mmol), N,N-dimethylformamide (0.006 mL, 0.068 mmol), dichloromethane (10 mL) successively. Under nitrogen protection, oxysulfur chloride (357.99 mg, 3.009 mmol) was added slowly. The reaction was continued at room temperature for 18 hours. LCMS showed that the reaction was completed. Saturated sodium bicarbonate solution and dichloromethane were added. The organic phase was concentrated and column chromatography (dichloromethane:methanol = 30:1-20:1) gave compound YL230769-384 (intermediate 10, 120 mg, 0.452 mmol, 90.06 %). LC-MS (ESI): m / z 266.1 (M+H) + .

[0217] Synthetic route of intermediate 11 (YL230769-410)

[0218]

[0219] Synthesis of compound YL230769-405

[0220] Into a 250 mL three-necked flask was added 3-amino-5-bromopyridine-2-carboxylic acid (5000 mg, 23.039 mmol), dichloromethane (100 mL) successively. Under nitrogen protection, it was cooled to -78 °C, then diisobutylaluminum hydride (46.079 mL, 46.079 mmol) was added. The reaction was continued for 2 hours. LCMS showed that the reaction was completed. 5 mL water was slowly added to the reaction solution, then 5 mL of 15% sodium hydroxide was added, 15 mL of water was continued to be added, then a small amount of magnesium sulfate was dried, the reaction solution was filtered, the filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate = 10:1-5:1) gave YL230769-405 (220 mg, 1.094 mmol, 4.75 %). MS (ESI): m / z 201.1 (M+H) + .

[0221] Synthesis of compound YL230769-406

[0222] Into a 50 mL three-necked flask was added methyl cyclopropylacetate (210.41 mg, 1.642 mmol), tetrahydrofuran (10 mL) successively. It was cooled to -78 °C under nitrogen protection, then lithium bis(trimethylsilyl)amide (3.830 mL) was added. The reaction was continued at this temperature for 30 min, then YL230769-405 (220 mg, 1.094 mmol) was added. The reaction was continued at -78 °C for 30 min, then it was slowly warmed to room temperature and continued for 18 h. LCMS showed the reaction was completed, the reaction mixture was directly concentrated and column chromatography (dichloromethane:methanol = 50:1-20:1) gave YL230769-406 (160 mg, 0.604 mmol, 55.15 %). MS (ESI): m / z 265.0 (M+H) + .

[0223] Synthesis of compound YL230769-409

[0224] Into a 50 mL three-necked flask was added YL230769-406 (150 mg, 0.566 mmol), tributylstannylmethanol (218.01 mg, 0.679 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (44.46 mg, 0.057 mmol), 1,4-dioxane (10 mL) successively. The reaction was continued at 80 °C for 18 h under nitrogen protection. LCMS showed the reaction was completed, the reaction mixture was concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) gave YL230769-409 (96 mg, 0.444 mmol, 78.46 %). MS (ESI): m / z 217.2 (M+H) + .

[0225] Synthesis of compound YL230769-410 (Intermediate 11)

[0226] Into a 50 mL three-necked flask was added YL230769-409 (96 mg, 0.444 mmol), N,N-dimethylformamide (0.004 mL, 0.044 mmol), dichloromethane (10 mL) successively. Under nitrogen protection, it was cooled to 0 °C, then sulfurous dichloride (316.87 mg, 2.664 mmol) was added. The reaction was continued for 30 minutes, then it was warmed to room temperature and the reaction was continued for 6 hours. LCMS showed that the reaction was completed, saturated sodium bicarbonate aqueous solution and dichloromethane were added to the reaction solution, the organic phase was concentrated and column chromatography (dichloromethane:methanol = 40:1-20:1) could obtain compound YL230769-410 (intermediate 11, 86 mg, 0.366 mmol, 82.54 %). MS (ESI): m / z 235.1 (M+H) + .

[0227] Example 1: Synthetic route of compound 1

[0228]

[0229] Synthesis of compound YL230769-366

[0230] Into a 50 mL three-necked flask was added 2-methyl-2-propyl-4-oxohexahydropyridine-1-carboxylate (1990 mg, 9.987 mmol), cyanamide (839.75 mg, 19.975 mmol), elemental sulfur (680.74 mg, 19.975 mmol), pyridine (10 mL) successively. Under nitrogen protection, it was reacted at 130 °C for 1.5 hours. LCMS showed that the reaction was successful, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ether twice, and the filter cake was dried to obtain YL230769-366 (1300 mg, 5.091 mmol, 50.98 %). LC-MS (ESI): m / z 256.2 (M+H) + .

[0231] Synthesis of compound YL230769-369

[0232] Into a 50 mL three-necked flask was added YL230769-366 (510 mg, 1.997 mmol), 3-bromo-2-oxopropyl acetate (433.80 mg, 2.397 mmol), 1,4-dioxane (15 mL) successively. Under nitrogen protection, it was reacted at 100 °C for 18 hours. LCMS showed that the reaction was completed, the reaction solution was directly concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) could obtain YL230769-369 (70 mg, 0.207 mmol, 10.39 %). LC-MS (ESI): m / z 338.2 (M+H) + .

[0233] Synthesis of compound YL230769-370

[0234] Into a 50 mL three-necked flask was added YL230769-369 (70 mg, 0.207 mmol), methylamine (8 mL) in ethanol successively. The reaction was stirred at room temperature for 18 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated to give YL230769-370 (69 mg, 0.205 mmol, 98.86 %). LC-MS (ESI): m / z 337.2 (M+H) + .

[0235] Synthesis of compound YL230769-372

[0236] Into a 50 mL three-necked flask was added YL230769-370 (69 mg, 0.205 mmol), dichloromethane (10 mL), trifluoroacetic acid (1 mL, 13.059 mmol) successively. The reaction was stirred at room temperature for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was directly concentrated to give YL230769-372 (48 mg, 0.203 mmol, 99.04 %). LC-MS (ESI): m / z 237.2 (M+H) + .

[0237] Synthesis of compound 1

[0238] Into a 50 mL three-necked flask was added YL230769-372 (48 mg, 0.203 mmol), 7-(bromomethyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (66.08 mg, 0.244 mmol), N,N-diisopropylethylamine (131.28 mg, 1.016 mmol), potassium iodide (6.74 mg, 0.041 mmol), acetonitrile (8 mL) successively. The reaction was stirred at 80 °C for 1 h under nitrogen atmosphere. LCMS showed the reaction was successful. The reaction mixture was directly concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to give compound 1 (7.6 mg, 0.018 mmol, 8.77 %). LC-MS (ESI): m / z 427.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.25-8.05 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 3.88 (s, 2H), 3.63 (s, 2H), 2.95 (d, J = 5.7 Hz, 2H), 2.81 (s, 2H), 2.74 (d, J = 4.8 Hz, 3H), 2.41 (s, 3H).

[0239] Example 2: Synthesis of compound 2

[0240]

[0241] Into a 50 mL three-necked flask was added YL230769-372 (20 mg, 0.085 mmol), YL230769-283 (22.62 mg, 0.102 mmol), potassium iodide (2.81 mg, 0.017 mmol), N,N-diisopropylethylamine (54.70 mg, 0.423 mmol), acetonitrile (10 mL) successively. The reaction was carried out at 80 °C for 2 h under nitrogen protection. LCMS showed that the reaction was successful. The reaction solution was concentrated and prepared by basic method to obtain compound 2 (10 mg, 0.024 mmol, 27.96 %). LC-MS (ESI): m / z 423.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 8.12 (q, J = 4.7 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 1.8 Hz, 1H), 3.86 (s, 2H), 3.63 (d, J = 2.2 Hz, 2H), 2.96 (t, J = 5.5 Hz, 2H), 2.82 (s, 2H), 2.75 (d, J = 4.7 Hz, 3H), 2.59 - 2.53 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

[0242] Example 3: Synthesis route of compound 3

[0243]

[0244] Synthesis of compound YL230769-391

[0245] Into a 100 mL three-necked flask was added YL230783-192 (666 mg, 2.957 mmol), N,N-dimethylformamide (0.01 mL), dichloromethane (20 mL) in sequence. Under nitrogen protection, it was cooled to 0 °C, then sulfurous chloride (2110.38 mg, 17.740 mmol) was added slowly. The reaction was continued at room temperature for 6 hours. LCMS showed the reaction was completed. The reaction was cooled to 0 °C, then saturated aqueous sodium bicarbonate solution and dichloromethane were added slowly. The aqueous phase was extracted with dichloromethane / methanol = 5 / 1 for 3 times. The organic phase was combined and concentrated. Column chromatography (petroleum ether: tetrahydrofuran = 5:1-1:1) gave YL230769-391 (700 mg, 2.873 mmol, 97.15 %). LC-MS (ESI): m / z 244.2 (M+H) + .

[0246] Synthesis of compound 3

[0247] Into a 50 mL three-necked flask was added YL230769-391 (49 mg, 0.201 mmol), YL230769-372 (57.01 mg, 0.241 mmol), potassium iodide (6.68 mg, 0.040 mmol), N,N-diisopropylethylamine (129.94 mg, 1.005 mmol), acetonitrile (10 mL) in sequence. Under nitrogen protection, the reaction was continued at 80 °C for 2 hours. LCMS showed the reaction was successful. The reaction was concentrated. Reverse phase preparation (alkali method) gave compound 3 (14 mg, 0.032 mmol, 15.70 %). LC-MS (ESI): m / z 444.3 (M+H) + . 1 HNMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.33 (dd, J = 19.7, 8.1 Hz, 2H), 8.15 (d, J = 18.4 Hz, 2H), 7.85 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.39 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 3.83 (s, 2H), 3.63 (s, 2H), 2.97 (t, J = 5.7 Hz, 2H), 2.84 (d, J = 5.4 Hz, 2H), 2.75 (d, J = 4.7 Hz, 3H).

[0248] Example 4: Synthesis route of compound 4

[0249]

[0250] Into a 50 mL three-necked flask, was added YL230774-414 (37 mg, 0.158 mmol), YL230769-372 (44.89 mg, 0.190 mmol), potassium iodide (5.26 mg, 0.032 mmol), N,N-diisopropyl ethylamine (102.32 mg, 0.792 mmol), acetonitrile (10 mL) successively. The reaction was carried out at 80 °C for 2 h under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction solution was concentrated and purified by reverse phase column chromatography (alkali method) to give compound 4 (1.2 mg, 0.003 mmol, 1.75 %). LC-MS (ESI): m / z 434.3 (M+H) + .

[0251] Synthetic route of compound 5 of example 5

[0252]

[0253] Synthesis of compound YL230774-481

[0254] LAH (4 mL, 4 mmol) was added to a mixture of YL230774-419 (500 mg, 2.05 mmol) in tetrahydrofuran (20 mL) at 0 °C under ice-water bath condition dropwise. The reaction was carried out at 0 °C for 1.5 h. The reaction solution was quenched by adding water (1 drop) at 0 °C, then sodium hydroxide solution (3 drops) was added. After stirring for 10 min, anhydrous sodium sulfate (0.1 g) was added and stirred for 30 min. Filtration was performed and the filter cake was rinsed with tetrahydrofuran and methanol for several times. The filtrate was concentrated to give a crude product which was purified by slurry with dichloromethane and petroleum ether (v / v = 1:1) to give YL230774-481 (300 mg, yield 68.18 %). (ESI): m / z 217.2 [M+H] + .

[0255] Synthesis of compound YL230774-482

[0256] Sulfoxyl chloride (1.65 g, 13.87 mmol) was added to a mixture of YL230774-481 (0.3 g, 1.39 mmol) in dichloromethane (20 mL) and the reaction was carried out at room temperature for 16 h. The reaction solution was quenched by saturated sodium bicarbonate solution to neutral, and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated to give YL230774-482 (150 mg, 0.639 mmol, 46.07 %). (ESI): m / z 235.2 [M+H] + .

[0257] Synthesis of compound 5

[0258] Potassium iodide (4 mg, 0.026 mmol) was added to a mixture of YL230774-482 (30 mg, 0.128 mmol), YL230769-372 (33.23 mg, 0.141 mmol) and DIEA (50 mg, 0.38 mmol) in acetonitrile (2 mL) and heated to 70 °C for 2 hours. The reaction solution was dissolved in DMSO and filtered to obtain the filter cake and filtrate. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to obtain sample 1, and then the filter cake was purified by reverse phase (C18, NH4HCO3) to obtain sample 2, and the two samples were combined to obtain compound 5 (9 mg, yield 15.00%). (ESI): m / z 435.2 [M+H] + .

[0259] Synthetic route of compound 6 of Example 6

[0260]

[0261] Synthesis of compound YL230804-082-A

[0262] YL230804-055-A (55 mg, 0.243 mmol) was dissolved in dichloromethane (8 mL), triphenylphosphine (127.5 mg, 0.486 mmol) was added, and carbon tetrabromide (161 mg, 0.486 mmol) was added at 0 °C. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was rotary evaporated, and purified by normal phase column (dichloromethane / methanol = 10 / 1) to obtain compound YL230804-082-A (55 mg, 47.14%). ESI: (m / z) = 289.0 [M+H] + .

[0263] Synthesis of compound 6

[0264] YL230804-082-A (20 mg, 0.069 mmol), YL230769-372 (25 mg, 0.104 mmol), N,N- diisopropylethylamine (27 mg, 0.207 mmol) and potassium iodide (1.1 mg, 0.007 mmol) were added to a reaction bottle, acetonitrile (2 mL) was added, and the nitrogen was replaced. The reaction was allowed to react at 80 °C for 2 hours. The reaction solution was rotary evaporated, and purified by normal phase column (dichloromethane / methanol = 20 / 1) and preparation to obtain compound 6 (8.1 mg, 27%). LCMS (ESI): m / z 445.2 (M+H) + ;

[0265] Synthetic route of compound 7 of Example 7

[0266]

[0267] Synthesis of compound YL230804-144-A

[0268] YL230804-141-A (20 mg, 0.082 mmol), YL230769-372 (21 mg, 0.086 mmol), N,N- diisopropylethylamine (32 mg, 0.246 mmol) and potassium iodide (1.3 mg, 0.008 mmol) were added to a reaction vial, acetonitrile (2 mL) was added, the nitrogen was replaced, and the reaction was stirred at 80 °C for 2 hours. The reaction was spun down and purified by normal phase column (dichloromethane / methanol = 20 / 1) and prep to give compound 7 (19 mg, 47%). LCMS (ESI): m / z 444.2 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 8.12 (q, J = 4.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.25 (dd, J = 8.1, 1.5 Hz, 1H), 6.94 (t, J = 54.9 Hz, 1H), 3.84 (s, 2H), 3.63 (d, J = 2.2 Hz, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.83 (s, 2H), 2.75 (d, J = 4.8 Hz, 3H).

[0269] Example 8. Synthetic route of compound 8

[0270]

[0271] YL230804-156-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), YL230769-372 (21 mg, 0.090 mmol), N,N-diisopropylethylamine (32 mg, 0.147 mmol), potassium iodide (1.4 mg, 0.008 mmol) were added, and the reaction was stirred at 80 °C for 2 hours. The reaction was spun down and purified by prep to give compound 8 (13 mg). ESI: (m / z) = 445.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.17 (s, 1H), 8.12 (q, J = 4.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.21 - 6.87 (m, 1H), 3.88 (s, 2H), 3.64 (d, J = 2.2 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H), 2.83 (dd, J = 5.3, 2.8 Hz, 2H), 2.75 (d, J = 4.8 Hz, 3H).

[0272] Synthetic route of compound 9 of Example 9

[0273]

[0274] Into a 50 mL three-necked flask were added YL230769-410 (20 mg, 0.085 mmol), YL230769-372 (24.16 mg, 0.102 mmol), potassium iodide (2.83 mg, 0.017 mmol), N,N-diisopropylethylamine (55.07 mg, 0.426 mmol), acetonitrile (10 mL) successively. The reaction was carried out at 80 °C for 4 h under nitrogen protection. LCMS showed that the reaction was completed. The reaction solution was concentrated, and compound 9 (7.7 mg, 0.018 mmol, 20.79%) was obtained by basic preparation. LC-MS (ESI): m / z 435.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 1.8 Hz, 1H), 8.16 (s, 1H), 8.11 (q, J = 4.7 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.42 (s, 1H), 3.85 (s, 2H), 3.63 (d, J = 2.1 Hz, 2H), 2.95 (t, J = 5.7 Hz, 2H), 2.88 - 2.77 (m, 2H), 2.75 (d, J = 4.8 Hz, 3H), 2.14 (tt, J = 8.5, 5.3 Hz, 1H), 1.06 - 0.92 (m, 2H), 0.88 - 0.68 (m, 2H).

[0275] Synthetic route of compound 10 of Example 10

[0276]

[0277] Synthesis of compound YL230769-402

[0278] Into a 50 mL three-necked flask, was added YL230769-384 (27 mg, 0.102 mmol), YL230769-372 (24.01 mg, 0.102 mmol), potassium iodide (3.37 mg, 0.020 mmol), N,N-diisopropyl ethylamine (65.68 mg, 0.508 mmol), acetonitrile (10 mL) successively. The reaction was carried out at 80 °C for 6 h under nitrogen protection. LCMS showed that the reaction was successful. The reaction solution was concentrated and purified by reverse phase column chromatography (alkali method) to obtain compound 10 (1.7 mg, 0.004 mmol, 3.59 %). LC-MS (ESI): m / z 466.2 (M+H) + .

[0279] Synthetic route of compound 11 of Example 11

[0280]

[0281] YL230804-156-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), and YL230769-372 (21 mg, 0.090 mmol), N,N-diisopropyl ethylamine (32 mg, 0.147 mmol), potassium iodide (1.4 mg, 0.008 mmol) were added, and the reaction was carried out at 80 °C for 2 h. The reaction solution was rotary dried, and compound 11 (13 mg) was obtained by preparation. ESI: (m / z) = 445.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.17 (s, 1H), 8.12 (q, J = 4.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.21 - 6.87 (m, 1H), 3.88 (s, 2H), 3.64 (d, J = 2.2 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H), 2.83 (dd, J = 5.3, 2.8 Hz, 2H), 2.75 (d, J = 4.8 Hz, 3H).

[0282] Synthetic route of compound 12 of Example 12

[0283]

[0284] Synthesis of compound YL230783-140-A

[0285] To a reaction flask was added 2-methyl-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazine-6-carboxylic acid methyl ester (1 g, 4.521 mmol) and anhydrous tetrahydrofuran (75 mL), protected by nitrogen, the mixture was cooled to 0 °C. Then LiAlH4(10 mL, 1 M, 113.015 mmol) was added slowly. The mixture was then stirred at 0 °C for 1 h, then quenched with 15 mL of ethyl acetate, followed by 5 mL of water. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by automatic column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to give compound YL230783-140-A (360 mg, 1.694 mmol, 37.47%). LC-MS (ESI): m / z 192.1 (M+H) + .

[0286] Synthesis of compound YL230783-142

[0287] To a reaction flask was added 2-methyl-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazine-6-carboxylic acid methyl ester (1 g, 4.521 mmol) and anhydrous tetrahydrofuran (75 mL), protected by nitrogen, the mixture was cooled to 0 °C. Then LiAlH4(10 mL, 1 M, 113.015 mmol) was added slowly. The mixture was then stirred at 0 °C for 1 h, then quenched with 15 mL of ethyl acetate, followed by 5 mL of water. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by automatic column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to give compound YL230783-140-A (360 mg, 1.694 mmol, 37.47%). LC-MS (ESI): m / z 192.1 (M+H)

[0288] Synthesis of compound 12

[0289] Into a 50 mL three-necked flask was added YL230769-142 (20 mg, 0.085 mmol), YL230769-372 (24.16 mg, 0.102 mmol), potassium iodide (2.83 mg, 0.017 mmol), N, N-diisopropyl ethylamine (55.07 mg, 0.426 mmol), acetonitrile (10 mL) successively. The reaction was carried out at 80 °C for 4 h under nitrogen protection. LCMS showed that the reaction was completed. The reaction solution was concentrated, and compound 12 (7.7 mg, 0.018 mmol, 20.79%) was obtained by basic preparation. LC-MS (ESI): m / z 411.6 (M+H) + .

[0290] Synthetic route of compound 13

[0291]

[0292] Synthesis of compound YL230784-385-C1

[0293] Into a 100 mL three-necked flask was added YL230784-375-C1 (40 mg, 0.169 mmol), thionyl chloride (5 mL) and N, N-dimethylformamide (0.15 mL) successively. The reaction was carried out at 25 °C for 15 min under nitrogen protection. Saturated sodium bicarbonate was added dropwise under ice water bath until neutral. Ethyl acetate was added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude YL230784-385-C1 (45 mg, 0.106 mmol, 62.62%, P = 60%). LC-MS (ESI): m / z 255.1 (M+H) + .

[0294] Synthesis of compound 13

[0295] Into a 50 mL three-necked flask was added crude YL230784-385-C1 (45 mg, 0.106 mmol), acetonitrile (10 mL), YL230769-372 (37.57 mg, 0.159 mmol), potassium iodide (3.52 mg, 0.021 mmol) and N, N-diisopropyl ethylamine (68.51 mg, 0.530 mmol) successively. The reaction was carried out at 80 °C for 40 h under nitrogen protection. It was concentrated under reduced pressure, and compound 13 (10 mg, 0.022 mmol, 20.76%) was obtained by prep-HPLC purification. LC-MS (ESI): m / z 455.2 (M+H) + .

[0296] 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.65 (s, 1H), 8.09 (s, 2H), 7.86 (d, J = 1.6 Hz, 1H), 4.46 (q, J = 6.7 Hz, 1H), 3.71 (d, J = 5.8 Hz, 2H), 3.00 - 2.89 (m, 2H), 2.74 (d, J = 4.8 Hz, 5H), 2.54 (d, J = 7.5 Hz, 2H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 7.4 Hz, 3H).

[0297] Synthetic route of compound 14 of example 14

[0298]

[0299] Synthesis of compound YL230784-400-C1

[0300] Into a 50 mL three-necked flask, was added YL230783-239 (150 mg, 0.445 mmol), dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) successively, and the mixture was stirred at room temperature for 1 h under nitrogen. The mixture was concentrated under reduced pressure, dissolved in methanol, neutralized by dropwise addition of ammonia methanol solution under ice water bath, and concentrated under reduced pressure to give crude YL230784-400-C1 (102 mg, 0.432 mmol, 97.26 %). LC-MS (ESI): m / z 238.1 (M+H) + .

[0301] Synthesis of compound YL230784-401-C1

[0302] Into a 50 mL three-necked flask, was added YL230784-400-C1 (100 mg, 0.421 mmol), acetonitrile (10 mL), YL230769-391 (79 mg, 0.324 mmol), potassium iodide (10 mg, 0.065 mmol), N,N-diisopropylethylamine (209.51 mg, 1.621 mmol) successively, and the mixture was stirred at 60 °C for 3 h under nitrogen. The mixture was concentrated under reduced pressure, and purified by column chromatography (methanol / dichloromethane = 0~3 %) to give YL230784-401-C1 (140 mg, 0.252 mmol, 77.72 %). LC-MS (ESI): m / z 445.2 (M+H) + .

[0303] Synthesis of compound YL230784-408-C1

[0304] Into a 50 mL three-necked flask was added YL230784-408-C1 (45 mg, 0.105 mmol), N,N-dimethylformamide (5 mL), cyclopropylamine (6 mg, 0.105 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (59 mg, 0.157 mmol) under nitrogen protection, cooled to 0 °C, added triethylamine (32 mg, 0.314 mmol) dropwise, then warmed to room temperature and reacted for 2 hours. Concentrated under reduced pressure, prep-HPLC purification to obtain compound 14 (12 mg, 0.026 mmol, 24.44 %). LC-MS (ESI): m / z 470.2 (M+H) + .

[0305] Synthesis of compound 14

[0306] Into a 50 mL three-necked flask was added YL230784-408-C1 (45 mg, 0.105 mmol), N,N-dimethylformamide (5 mL), cyclopropylamine (6 mg, 0.105 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (59 mg, 0.157 mmol) under nitrogen protection, cooled to 0 °C, added triethylamine (32 mg, 0.314 mmol) dropwise, then warmed to room temperature and reacted for 2 hours. Concentrated under reduced pressure, prep-HPLC purification to obtain compound 14 (12 mg, 0.026 mmol, 24.44 %). LC-MS (ESI): m / z 470.2 (M+H) + .

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.31 (dd, J = 8.0, 1.5 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.85 (ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 7.63 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 8.2, 1.6 Hz, 1H), 3.83 (s, 2H), 3.64 (s, 2H), 2.97 (t, J = 5.7 Hz, 2H), 2.87 - 2.81 (m, 3H), 0.66 - 0.58 (m, 4H).

[0308] Synthesis route of compound 15 of example 15

[0309]

[0310] Synthesis of compound 15

[0311] Into a 50 mL three-necked flask, was charged with YL230784-408-C1 (45 mg, 0.105 mmol), N,N-dimethylformamide (5 mL), 2,2,2-trifluoroethylamine (10 mg, 0.105 mmol) and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (59 mg, 0.157 mmol), under nitrogen protection, the temperature was lowered to 0 °C, triethylamine (32 mg, 0.314 mmol) was added dropwise, then the temperature was raised to room temperature, and the reaction was carried out for 2 hours. Concentration under reduced pressure gave compound 15 (16 mg, 0.031 mmol, 29.92 %). LC-MS (ESI): m / z 512.2 (M+H) + .

[0312] 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.74 (t, J = 6.6 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.34 - 8.29 (m, 2H), 7.88 - 7.82 (m, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.3, 1.6 Hz, 1H), 4.02 (qd, J = 9.6, 6.4 Hz, 2H), 3.84 (s, 2H), 3.65 (s, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.86 (d, J = 5.5 Hz, 2H).

[0313] Synthesis of compound 16

[0314]

[0315] Synthesis of compound YL230783-249-A

[0316] Methyl 6-chloro-5-nitropyridine-3-carboxylate (3.4 g, 15.699 mmol) was dissolved in ethanol (330 mL) and saturated aqueous ammonium chloride (110 mL) at room temperature, then iron powder (5.26 g, 94.192 mmol) was added, and the temperature was raised to 80 °C, and the reaction was carried out for 3 hours. After the reaction was completed, the reaction solvent was distilled off, diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to directly give compound YL230783-249-A (3.2 g, 15.263 mmol, 97.23 %), ESI: (m / z) = 187.2 [M+H] + .

[0317] Synthesis of compound YL230783-254-A

[0318] YL230783-249-A (3.2 g, 17.150 mmol), 2-(methoxycarbonyl)benzeneboronic acid (6.17 g, 34.300 mmol), SPhos Pd G2 (1.24 g, 1.715 mmol), potassium phosphate (10.92 g, 51.450 mmol) were dissolved in 1,4-dioxane (370 mL) and the reaction mixture was heated to 100 °C overnight. After the reaction was completed, the reaction mixture was evaporated, diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting crude product was purified by automatic column instrument (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 20 to 100 / 34) to give compound YL230783-254-A (82 mg, 0.306 mmol, 1.79 %), ESI: (m / z) = 255.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) d 11.97 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 8.1 Hz, 1H), 8.39 - 8.30 (m, 1H), 8.23 (d, J = 1.9 Hz, 1H), 7.98 (td, J = 8.2, 7.7, 1.3 Hz, 1H), 7.88 - 7.79 (m, 1H), 3.94 (s, 3H).

[0319] Synthesis of compound YL230783-258-A1

[0320] YL230783-254-A (80 mg, 0.315 mmol) and tetrahydrofuran (25 mL) were added to a reaction flask, and the mixture was cooled to 0 °C. Then, lithium aluminum hydride tetrahydrofuran solution (1M) (15.8 mL, 15.794 mmol) was slowly added to the mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with 10 mL of ethyl acetate, and then 3 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The resulting residue was purified by automatic column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 12) to give compound YL230783-258-A1 (55 mg, 0.243 mmol, 77.26 %), LC-MS (ESI): m / z 227.2 (M+H) + .

[0321] Synthesis of compound YL230783-259-A

[0322] Into a reaction vial was placed YL230783-258-A1 (55 mg, 0.243 mmol), dichloromethane (40 mL), DMF (0.004 mL, 0.049 mmol), protected by nitrogen, placed in the zero Celsius, then slowly added dropwise sulfoxide chloride (433.80 mg, 3.647 mmol), after adding to room temperature, stirring the reaction for 2 hours, after the reaction, spin the solvent, directly to get solid compound YL230783-259-A (60 mg, 0.150 mmol, 61.53%), LC-MS (ESI): m / z 245.1 (M+H) + .

[0323] Synthesis of compound YL230783-281-A

[0324] YL230769-369 (2 g, 5.928 mmol), lithium hydroxide (0.25 g, 5.928 mmol) were dissolved in tetrahydrofuran (270 mL) and water (90 mL), then reacted at room temperature for 3 hours, after the reaction, spin the reaction organic solvent, then add dilute hydrochloric acid solution to neutralize, precipitate the solid, suction filtration, spin dry the filter cake, directly to get compound YL230783-281-A (1.6 g, 4.552 mmol, 76.79%), ESI: (m / z) = 324.3 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 4.52 (s, 2H), 3.73 (t, J = 5.7 Hz, 2H), 2.81 (tt, J = 5.5, 2.2 Hz, 2H), 1.43 (s, 9H).

[0325] Synthesis of compound YL230783-282-A

[0326] YL230783-281-A (1.6 g, 4.948 mmol), cyclopropylamine (0.51 g, 8.906 mmol), HATU (2.82 g, 7.422 mmol) were dissolved in DMF (80 mL), then triethylamine (3.439 mL, 24.739 mmol) was added, then continue to react at room temperature for 2 hours, dilute with ethyl acetate and water, separate the organic phase, the aqueous phase is extracted with ethyl acetate. Combine the organic phase, wash with water, saturated aqueous solution, dry over anhydrous sodium sulfate, filter, evaporate to dryness, directly to get compound YL230783-282-A (1.6 g, 4.061 mmol, 82.08%), ESI: (m / z) = 363.6 [M+H] + ,1 H NMR (400 MHz, DMSO-d6) d 8.18 (s, 1H), 8.14 (d, J = 4.9 Hz, 1H), 4.51 (s, 2H), 3.73 (t, J = 5.7 Hz, 2H), 2.89 (s, 1H), 2.83 - 2.81 (m, 2H), 1.43 (s, 9H), 0.66 - 0.60 (m, 4H).

[0327] Synthesis of compound YL230783-285-A

[0328] YL230783-282-A (250 mg, 0.690 mmol) was dissolved in hydrochloric acid-1,4-dioxane (4 M) (20 mL) at room temperature, then the reaction was continued at room temperature for 2 hours. After the reaction was completed, it was rotary evaporated under vacuum to obtain compound YL230783-285-A (210 mg, 0.967 mmol, 109%), which was directly used for the next step, ESI: (m / z) = 263.2 [M+H] + .

[0329] YL230783-259-A (150 mg, 0.368 mmol), YL230783-285-A (115.79 mg, 0.441 mmol), potassium iodide (305.30 mg, 1.839 mmol) were dissolved in acetonitrile (60 mL) at room temperature, then N,N-diisopropylethylamine (47.54 mg, 0.368 mmol) was added, then the reaction was continued at 80 °C for 6 hours. Diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The obtained crude product was purified by preparation (Welch Xtimate C18, 21.2*250 mm, 10 um, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25 °C, detection wavelength 254 nm) to obtain compound 16 (49 mg, 0.102 mmol, 27.74%), ESI: (m / z) = 471.4 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J = 4.8 Hz, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.78 - 7.71 (m, 2H), 3.90 (s, 2H), 3.67 (s, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.84 (s, 3H), 0.67 - 0.59 (m, 4H).

[0330] Synthetic route of compound 17 of example 17

[0331]

[0332] Synthesis of compound YL230784-420-C1

[0333] Into a 50 mL three-necked flask was added YL230769-369 (150 mg, 0.445 mmol) successively, ammonia methanol solution (10 mL), and the reaction was carried out at 60 °C overnight under nitrogen protection. Filtration, concentration under reduced pressure to obtain the crude product YL230784-420-C1 (159 mg, 0.0.493 mmol, 110.92 %). LC-MS (ESI): m / z 323.4 (M+H) + .

[0334] Synthesis of compound YL230784-428-C1

[0335] Into a 50 mL three-necked flask was added YL230784-420-C1 (140 mg, 0.434 mmol), trifluoroacetic acid (5 mL), triethylamine (176 mg, 1.736 mmol) successively, and the reaction was carried out at 60 °C for 2 hours under nitrogen protection after dropwise addition of trifluoroacetic anhydride (0.5 mL). Concentration under reduced pressure, column chromatography (methanol / dichloromethane = 0-4 %) purification to obtain YL230784-428-C1 (40 mg, 0.131 mmol, 30.26 %). LC-MS (ESI): m / z 305.3 (M+H) + .

[0336] Synthesis of compound YL230784-431-C1

[0337] Into a 50 mL three-necked flask was added YL230784-428-C1 (40 mg, 0.131 mmol), dichloromethane (5 mL), trifluoroacetic acid (1.5 mL) successively, and the reaction was carried out at room temperature for 1 hour under nitrogen protection. Concentration under reduced pressure, dissolution in methanol, neutralization by dropwise addition of ammonia methanol solution under ice water bath, concentration under reduced pressure, and the crude product YL230784-431-C1 (80 mg, 0.118 mmol, 89.42%) was obtained. LC-MS (ESI): m / z 205.2 (M+H) + .

[0338] Synthesis of compound 17

[0339] Into a 50 mL three-necked flask was added YL230784-431-C1 (80 mg, 0.118 mmol), acetonitrile (5 mL), YL230783-286 (34 mg, 0.098 mmol), potassium iodide (3 mg, 0.020 mmol), N,N-diisopropylethylamine (63 mg, 0.490 mmol) successively, and the reaction was carried out at 60°C for 3 hours under nitrogen protection. Concentration under reduced pressure, prep-HPLC purification, and compound 17 (13 mg, 0.032 mmol, 32.19%) was obtained. LC-MS (ESI): m / z 413.2 (M+H) + .

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.0 Hz, 1H), 8.71 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.34 - 8.27 (m, 1H), 7.99 - 7.87 (m, 1H), 7.78 - 7.72 (m, 2H), 3.91 (s, 2H), 3.70 (d, J = 2.3 Hz, 2H), 3.00 (t, J = 5.7 Hz, 2H), 2.83 (d, J = 6.0 Hz, 2H).

[0341] Synthesis route of compound 18 of example 18

[0342]

[0343] Synthesis of compound YL230783-242-A

[0344] To a solution of YL230783-242-A (2.4 g, 6.796 mmol) in dichloromethane (80 mL) was added di-tert-butyl dicarbonate (1.78 g, 8.155 mmol) and triethylamine (2.834 mL, 20.388 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate 100 / 15 to 100 / 25) to give compound YL230783-245-A (2.3 g, 4.922 mmol, 72.43%) as a yellow solid. ESI: (m / z) = 453.1 / 455.1 [M+H] + , 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 8.53 - 8.42 (m, 2H), 8.07 (dd, J = 7.6, 2.0 Hz, 1H), 7.71 (ddd, J = 8.3, 6.8, 1.7 Hz, 1H), 7.42 (dd, J = 7.7, 4.7 Hz, 1H), 7.25 (dd, J = 8.1, 1.2 Hz, 1H), 3.93 (s, 3H).

[0345] Synthesis of compound YL230783-245-A

[0346] To a solution of YL230783-242-A (2.4 g, 6.796 mmol) in dichloromethane (80 mL) was added di-tert-butyl dicarbonate (1.78 g, 8.155 mmol) and triethylamine (2.834 mL, 20.388 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate 100 / 15 to 100 / 25) to give compound YL230783-245-A (2.3 g, 4.922 mmol, 72.43%) as a yellow solid. ESI: (m / z) = 453.1 / 455.1 [M+H] + , 1H NMR (500 MHz, DMSO-d6) δ 8.52 (dd, J = 4.9, 1.9 Hz, 1H), 8.07 (dd, J = 7.6, 1.9 Hz, 1H), 8.00 (ddd, J = 8.2, 6.6, 1.8 Hz, 1H), 7.87 (s, 1H), 7.63 (dd, J = 7.6, 4.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 3.89 (s, 3H), 1.16 (s, 9H).

[0347] Synthesis of compound YL230783-267-A

[0348] YL230783-245-A (2.2 g, 4.854 mmol) was dissolved in dichloromethane (220 mL), then trifluoroacetic acid (22 mL, 287.300 mmol) was added under ice bath, then the reaction was continued at room temperature for 7 hours, diluted with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to directly obtain compound YL230783-267-A (1.75 g, 4.708 mmol, 96.99%), ESI: (m / z) = 353.0 / 355.0 [M+H] + .

[0349] Synthesis of compound YL230783-296-A

[0350] YL230783-267-A (1.6 g, 4.531 mmol), potassium carbonate (1.88 g, 13.592 mmol) was dissolved in DMF (60 mL), then p-methoxychlorobenzene (0.85 g, 5.437 mmol) was added, then the reaction was continued at 90°C for 2 hours. Diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to directly obtain compound YL230783-296-A (2.2 g, 4.648 mmol, 102.59%), ESI: (m / z) = 473.1 / 475.1 [M+H] + .

[0351] Synthesis of compound YL230783-298-A

[0352] YL230783-296-A (2.2 g, 4.648 mmol), 1,3-bisdiphenylphosphinopropane (0.59 g, 1.394 mmol), potassium carbonate (1.93 g, 13.945 mmol), palladium acetate (0.31 g, 1.394 mmol), tributylphosphine (57.26 mg, 0.283 mmol) were dissolved in DMF (110 mL), protected by nitrogen, and reacted under microwave conditions at 140 °C for 1 hour. The reaction was monitored by LCMS until the starting material was consumed. The solvent was removed by rotary evaporation, and the resulting crude product was purified automatically by column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 1 to 100 / 3 and dichloromethane / methanol 100 / 25 to 100 / 30) to obtain compound YL230783-298-A (2.15 g, 5.479 mmol, 106%), ESI: (m / z) = 393.6 [M+H] + .

[0353] Synthesis of compound YL230783-305-A

[0354] First, compound YL230783-298-A (2.15 g, 5.479 mmol) was weighed into a reaction flask, and the flask was placed in an ice bath. Then, trifluoroacetic acid (180 mL) was added, and the reaction mixture was warmed to 60 °C and reacted for 5 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The resulting crude product was purified automatically by column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to obtain compound YL230783-305-A (565 mg, 2.075 mmol, 37.88%), ESI: (m / z) = 273.2 [M+H] + , 1 HNMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 9.13 (d, J = 4.1 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.6 Hz, 1H), 7.84 - 7.67 (m, 2H), 3.92 (s, 3H).

[0355] Synthesis of compound YL230783-307-A

[0356] To a reaction flask was added YL230783-305-A (565 mg, 2.075 mmol) and anhydrous tetrahydrofuran (220 mL), the mixture was cooled to 0 °C, then lithium aluminum hydride tetrahydrofuran solution (1 M) (10.4 mL) was added slowly, then the mixture was stirred at room temperature for 2 hours, after the reaction was completed, 50 mL of ethyl acetate was added to quench the reaction, then 5 mL of water was added. The resulting mixture was dried with anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, the resulting residue was purified by automatic column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to obtain compound YL230783-307-A (275 mg, 1.088 mmol, 52.41%), LC-MS (ESI): m / z 245.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.06 (dd, J = 4.6, 1.8 Hz, 1H), 8.62 (dd, J = 8.0, 1.8 Hz, 1H), 8.41 (dd, J = 8.3, 1.1 Hz, 1H), 7.69 (dd, J = 8.0, 4.6 Hz, 1H), 7.39 (dd, J = 8.3, 6.6 Hz, 1H), 5.44 (t, J = 5.8 Hz, 1H), 4.68 (dd, J = 5.8, 1.4 Hz, 2H).

[0357] Synthesis of compound YL230783-311-A

[0358] To a reaction flask was added YL230783-307-A (240 mg, 0.983 mmol), dichloromethane (150 mL), DMF (0.040 mL, 0.491 mmol), nitrogen was replaced, cooled to 0 °C, then thionyl chloride (1753.49 mg, 14.740 mmol) was added slowly dropwise, then the temperature was raised to room temperature and stirred for 2 hours, after the reaction was completed, the solvent was rotary evaporated, to directly obtain compound YL230783-311-A (270 mg, 0.759 mmol, 77.20%), LC-MS (ESI): m / z 263.2 (M+H) + .

[0359] Synthesis of compound YL230783-308-A

[0360] YL230769-369 (620 mg, 1.838 mmol), lithium hydroxide (616.86 mg, 14.701 mmol) were dissolved in a mixture of tetrahydrofuran (60 mL) and water (20 mL), and then the reaction was carried out at room temperature for 6 hours. After the reaction was completed, the organic solvent of the reaction was evaporated, and then diluted hydrochloric acid solution was added for neutralization. A solid was precipitated, and was filtered and dried to obtain compound YL230783-308-A (440 mg, 1.287 mmol, 70.05%) directly. ESI: (m / z) = 324.4 [M+H] + .

[0361] Synthesis of compound YL230783-309-A

[0362] YL230783-308-A (435 mg, 1.345 mmol), cis-3-methoxycyclobutylamine hydrochloride (222.12 mg, 1.614 mmol), HATU (767.25 mg, 2.018 mmol) were dissolved in DMF (30 mL), and then triethylamine (0.935 mL, 6.726 mmol) was added. The reaction was continued at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain compound YL230783-309-A (550 mg, 1.245 mmol, 92.53%) directly. ESI: (m / z) = 407.7 [M+H] + .

[0363] Synthesis of compound YL230783-313-A

[0364] YL230783-309-A (600 mg, 1.476 mmol) was dissolved in 1,4-dioxane (20 mL) at room temperature, and then hydrochloric acid-1,4-dioxane solution (4M) (20 mL) was added. The reaction was continued at room temperature for 2 hours. The reaction solvent was evaporated to obtain compound YL230783-313-A (420 mg, 1.261 mmol, 85.44%) directly. ESI: (m / z) = 307.7 [M+H] + .

[0365] Synthesis of compound 18

[0366] YL230783-311-A (80 mg, 0.305 mmol), YL230783-313-A (93 mg, 0.305 mmol), potassium iodide (252.79 mg, 1.523 mmol) were dissolved in acetonitrile (50 mL) at room temperature, then N,N-diisopropylethylamine (39.36 mg, 0.305 mmol) was added, then the reaction was continued at 80 °C for 2 hours, after the reaction was completed, the reaction solvent was spun off, diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The obtained crude product was purified by preparation (Welch Xtimate C18, 21.2*250 mm, 10 um, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25 °C, detection wavelength 254 nm) to obtain compound 18 (35 mg, 0.063 mmol, 20.67%), ESI: (m / z) = 533.6 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.08 (dd, J = 4.5, 1.8 Hz, 1H), 8.64 (dd, J = 8.0, 1.8 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H), 7.71 (dd, J = 8.0, 4.6 Hz, 1H), 7.40 (dd, J = 8.3, 6.5 Hz, 1H), 3.99 (q, J = 8.3 Hz, 1H), 3.93 (s, 2H), 3.67 (s, 2H), 3.60 - 3.53 (m, 1H), 3.13 (s, 3H), 2.99 (t, J = 5.7 Hz, 2H), 2.84 (s, 2H), 2.02 - 1.96 (m, 2H).

[0367] Synthetic route of compound 19 of example 19

[0368]

[0369] Synthesis of compound YL230783-243-A

[0370] Synthesis of compound YL230783-306-A + .

[0371] Synthesis of compound YL230783-306-A

[0372] YL230783-243-A (3.4 g, 9.655 mmol), potassium carbonate (4.00 g, 28.964 mmol) were dissolved in DMF (100 mL), then p-methoxychlorobenzene (1.81 g, 11.586 mmol) was added, then the reaction was continued at 90 °C for 2 hours. Dilution with ethyl acetate and water, separation of the organic phase, extraction of the aqueous phase with ethyl acetate, combined organic phases, saturated aqueous sodium chloride solution wash, anhydrous sodium sulfate drying, filtration, rotary evaporation of the solvent, the resulting crude was automatically purified on a column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 2 to 100 / 3), compound YL230783-306-A (3.2 g, 6.165 mmol, 63.86%) was obtained, ESI: (m / z) = 472.1 / 474.1 [M+H] + .

[0373] Synthesis of compound YL230783-310-A

[0374] YL230783-306-A (3.2 g, 6.775 mmol), 1,3-bisdiphenylphosphinopropane (0.86 g, 2.033 mmol), palladium acetate (0.46 g, 2.033 mmol), tributylphosphine (5.88 g, 6.775 mmol), potassium carbonate (2.81 g, 20.326 mmol) were dissolved in DMF (160 mL), protected by nitrogen, and reacted under microwave conditions at 140 °C for 2 hours. The reaction was monitored by LCMS until the starting material was consumed. The reaction solvent was removed by rotary evaporation. The resulting crude product was automatically purified by column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 1 to 100 / 2 and dichloromethane / methanol 100 / 25 to 100 / 30) to obtain compound YL230783-310-A (2.8 g, 4.018 mmol, 89.8%), ESI: (m / z) = 392.2 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ 8.60 (d, J = 8.2 Hz, 1H), 8.47 - 8.37 (m, 2H), 7.99 - 7.89 (m, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.69 (dd, J = 8.5, 6.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.90 - 6.78 (m, 2H), 5.58 (s, 2H), 3.84 (s, 3H), 3.70 (s, 3H).

[0375] Synthesis of compound YL230783-318-A

[0376] Compound YL230783-310-A (2.75 g, 7.026 mmol) was weighed in a reaction bottle at room temperature, then trifluoroacetic acid (45 mL, 587.660 mmol) was added, and the temperature was immediately raised to 60 °C for reaction for 2 hours. After the reaction was completed, it was poured into ice water, and a large amount of solid was precipitated. The filter residue was obtained by suction filtration and dried to directly obtain compound YL230783-318-A (1.98 g, 6.935 mmol, 98.70%), ESI: (m / z) = 272.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ 11.81 (s, 1H), 8.55 (d, J = 8.2 Hz, 1H), 8.34 (dd, J = 24.6, 8.3 Hz, 2H), 7.92 (t, J = 7.7 Hz, 1H), 7.71 (dt, J = 37.7, 7.6 Hz, 2H), 3.90 (s, 3H).

[0377] Synthesis of compound YL230783-320-A

[0378] To a reaction flask was added YL230783-318-A (650 mg, 2.396 mmol) and anhydrous tetrahydrofuran (150 mL), the mixture was cooled to 0 °C, then lithium aluminum hydride tetrahydrofuran solution (1 M) (10.4 mL) was added slowly, then the mixture was stirred at 0 °C for 2 hours, after the reaction was completed, it was quenched with 30 mL of ethyl acetate, then 5 mL of water was added. The resulting mixture was dried with anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, the resulting residue was purified by automatic column instrument (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 7), to obtain compound YL230783-320-A (350 mg, 1.425 mmol, 59.45%), LC-MS (ESI): m / z 244.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.34 (dd, J = 7.9, 1.4 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.87 (ddd, J = 8.3, 7.1, 1.5 Hz, 1H), 7.67 (td, J = 7.6, 7.2, 1.1 Hz, 1H), 7.33 (dd, J = 8.3, 6.9 Hz, 1H), 5.39 (t, J = 5.8 Hz, 1H), 4.66 (dd, J = 5.9, 1.4 Hz, 2H).

[0379] Synthesis of compound YL230783-322-A

[0380] To a reaction flask was added YL230783-320-A (340 mg, 1.398 mmol), dichloromethane (110 mL), DMF (0.023 mL, 0.280 mmol), nitrogen was replaced, protected, cooled to 0 °C, then thionyl chloride (997.69 mg, 8.387 mmol) was added slowly dropwise, after the addition was completed, it was stirred at room temperature for 1 hour, after the reaction was completed, the solvent was rotary evaporated, to directly obtain compound YL230783-322-A (400 mg, 1.345 mmol, 96.23%), LC-MS (ESI): m / z 262.2 (M+H) + .

[0381] Synthesis of compound 19

[0382] YL230783-322-A (100 mg, 0.382 mmol), YL230783-313-A (117 mg, 0.382 mmol), potassium iodide (63.44 mg, 0.382 mmol) were dissolved in acetonitrile (50 mL) at room temperature, then N,N-diisopropylethylamine (246.96 mg, 1.911 mmol) was added, then the reaction was continued at 80 °C for 2 hours. Diluted with ethyl acetate and water. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The resulting crude was purified by preparative purification (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25 °C, detection wavelength 254 nm) to give compound 19 (96 mg, 0.185 mmol, 60.49%), ESI: (m / z) = 532.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) d 11.63 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.37 - 8.28 (m, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.88 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.32 (dd, J = 8.3, 6.7 Hz, 1H), 3.99 (q, J = 8.2 Hz, 1H), 3.90 (s, 2H), 3.65 (s, 2H), 3.60 - 3.52 (m, 1H), 3.12 (s, 3H), 2.97 (t, J = 5.7 Hz, 2H), 2.82 (s, 2H), 2.56 - 2.51 (m, 2H), 2.04 - 1.90 (m, 2H).

[0383] Synthetic route of compound 20 of example 20

[0384]

[0385] Synthesis of compound YL230769-476-A

[0386] Into a 50 mL three-necked flask, was added methyl 2-pyrrolecarboxylate (1.1 g, 8.8 mmol), 1-bromo-2,4-difluoro-3-nitrobenzene (3.1 g, 13.2 mmol), potassium carbonate (2.4 g, 17.6 mmol), N,N-dimethylformamide (10 mL) successively. The reaction was carried out at 100 °C for 2 hours under nitrogen protection. LCMS showed that the reaction was successful. Water and ethyl acetate were added to the reaction solution. The organic phase was concentrated and column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1) was performed to obtain YL230769-476-A (1.47 g, 48.7%). ESI: (m / z) = 343.0 [M+H] + ;

[0387] Synthesis of compound YL230804-244-A

[0388] YL230769-476-A (1.4 g, 4.080 mmol) was dissolved in acetic acid (15 mL), and iron powder (1.14 g, 20.402 mmol) was added. N2 was replaced, and the reaction was carried out at 75 °C for 3 hours. The reaction solution was filtered through diatomite, washed with methanol, and rotary evaporated. Normal phase column purification (mobile phase: dichloromethane / methanol = 20 / 1) was performed to obtain compound YL230804-244-A (1.1 g, 95.65%). ESI: (m / z) = 281.0 [M+H] + ;

[0389] Synthesis of compound YL230804-254-A

[0390] YL230804-244-A (500 mg, 1.779 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributylstannyl)methanol (685 mg, 2.135 mmol) was added. Xphos Pd G2 (140 mg, 0.178 mmol) was added, N2 was replaced, and the reaction was carried out at 80 °C overnight. The reaction solution was rotary evaporated, and normal phase column purification (mobile phase: dichloromethane / methanol = 20 / 1) was performed to obtain compound YL230804-254-A (370 mg, 85.37%). ESI: (m / z) = 231.3 [M+H] + ;

[0391] Synthesis of compound YL230804-264-A

[0392] YL230804-254-A (370 mg, 1.593 mmol) was dissolved in dichloromethane (10 mL), added 1 drop of DMF, replaced by N2, cooled to 0 °C, added dichloro sulfoxide (1.13 g, 9.560 mmol), reacted overnight at room temperature. The reaction solution was cooled to 0 °C, neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane / methanol = 10 / 1. The combined organic phase was washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain the crude compound YL230804-264-A (370 mg, 92.5%). ESI: (m / z) = 251.0 [M+H] + ;

[0393] Synthesis of compound 20

[0394] YL230804-264-A (40 mg, 0.160 mmol) was dissolved in acetonitrile (1.5 mL), added YL230783-313-A (60 mg, 0.191 mmol), N,N-diisopropyl ethylamine (62 mg, 0.479 mmol), potassium iodide (2.6 mg, 0.016 mmol), reacted at 80 °C for 4 hours. The reaction solution was evaporated to dryness, and compound 20 (27 mg, 33.75%) was obtained by preparation. ESI: (m / z) = 521.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.26 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.19 (dd, J = 2.9, 1.5 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (dd, J = 3.8, 1.4 Hz, 1H), 6.71 (dd, J = 3.9, 2.8 Hz, 1H), 3.99 (h, J = 8.4 Hz, 1H), 3.84 (s, 2H), 3.63 (s, 2H), 3.56 (h, J = 6.8 Hz, 1H), 3.12 (s, 3H), 2.96 (t, J = 5.7 Hz, 2H), 2.81 (s, 2H), 2.53 (d, J = 8.8 Hz, 2H), 1.98 (dt, J = 11.5, 8.8 Hz, 2H).

[0396] The application will be further described in the following by way of examples without limiting the application to the examples described. The experimental methods in the following examples, where no specific conditions are mentioned, are carried out according to the conventional methods and conditions, or according to the instructions of the commercial products. The solvents involved in the following examples are all of analytical purity or chromatographic purity. When the solvents involved in the following examples are mixed solvents, the volume ratio is all 1 :1 unless otherwise specified.

[0397] Materials used in the biological activity test of examples:

[0398] • PARP1 (BPS, Cat. No. 80501)

[0399] • PARP2 (BPS, Cat. No. 80502)

[0400] • Histone (Active Motif, Cat. No. 81167)

[0401] • Activited DNA (Genscript, Cat. No. L05182-01 & 02 & 03)

[0402] • anti-rabbit IgG, HRP-linked Antibody (CST, Cat. No. 7074P2)

[0403] • anti-Poly / Mono-ADP Ribose (E6F6A) Rabbit mAb (CST, Cat. No. 83732S)

[0404] • SuperSignal ELISA Femto Substrate (THERMO PIERCE, Cat. No. 37074)

[0405] • Biotin-NAD+ (R&D, Cat. No. 6573)

[0406] • NAD+ (TCI, Cat. No. D0919-5G)

[0407] • Strep-HRP (Thermo Pierce, Cat. No. 21127)

[0408] • QuantaRed Enhanced Chemifluorescent HRP Substrate Kit (Thermo Pierce, Cat. No. 15159)

[0409]

[0410] Experimental procedure:

[0411] PARP1:

[0412] 1. Preparation of buffer

[0413] PBST: 1X PBS, 0.05% Tween-20

[0414] Blocking buffer: 1X PBS, 0.05% Tween-20, 5% BSA

[0415] Reaction buffer: 50mM Tris-HCl (pH7.5), 0.005% Tween-20, 0.01% BSA

[0416] 2. Coating

[0417] Prepare 50ng / mL Histone coating solution with 1x PBS, transfer 25uL coating solution to 384-well reaction plate, coat at 4°C overnight.

[0418] 3. Washing

[0419] After coating, discard the coating solution, wash with PBST solution, transfer 50uL PBST to 384-well reaction plate, stand for 5 minutes, discard the washing solution, refill, repeat washing 3 times, finally pat dry the reaction plate and wait for the next step of blocking.

[0420] 4. Blocking

[0421] Transfer 50uL blocking buffer to 384-well reaction plate, stand for 1 hour.

[0422] 5. Washing

[0423] After blocking, discard the blocking buffer, wash 3 times according to the method of step 2 with PBST solution, finally pat dry the reaction plate.

[0424] 6. Prepare 2000-fold compound in 384-well Echo plate, transfer 50nL compound to 384-well intermediate plate, add 20uL reaction buffer and mix, transfer 5uL mixed compound to 384-well reaction plate.

[0425] 7. Prepare 25 / 10-fold PARP1-DNA solution with reaction buffer, transfer 10uL PARP1-DNA solution to 384-well reaction plate, for negative control wells, transfer 10uL DNA solution, the final concentration of PARP1 is 0.007nM and the final concentration of DNA is 0.8nM.

[0426] 8. Prepare 25 / 10-fold NAD+ solution with reaction buffer, transfer 10uL NAD+ solution to 384-well reaction plate, the final concentration of NAD+ is 3.5uM, incubate at room temperature for 60 minutes.

[0427] 9. Wash

[0428] After the reaction is complete, discard the reaction solution and wash 3 times with PBST solution according to Step 2, and finally pat dry the reaction plate.

[0429] 10. Dilute 2000-fold primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) with blocking solution, add 20 uL of primary antibody, and incubate at room temperature for 1.5 hours.

[0430] 11. Wash

[0431] Discard the primary antibody and wash 3 times with PBST solution according to Step 2, and finally pat dry the reaction plate.

[0432] 12. Dilute 2000-fold secondary antibody (anti-rabbit IgG, HRP-linked Antibody) with blocking solution, add 20 uL of secondary antibody, and incubate at room temperature for 1 hour.

[0433] 13. Wash

[0434] Discard the secondary antibody and wash 3 times with PBST solution according to Step 2, and finally pat dry the reaction plate.

[0435] 14. Color development

[0436] Mix Femto-ECL Substrate A and Femto-ECL Substrate B at a ratio of 1:1, and transfer 25 uL to the 384 reaction plate.

[0437] 15. Read

[0438] Read the chemiluminescence value RLU using Envision.

[0439] PARP2:

[0440] 1. Preparation of buffer

[0441] PBST: 1X PBS, 0.05% Tween-20

[0442] Blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA

[0443] Reaction buffer: 50 mM HEPES (pH 7.5), 0.002% Tween-20, 0.1% BSA, 100 mM NaCl, 2 mM DTT

[0444] 2. Coating

[0445] Prepare 100 ng / mL Histone coating solution with 1xPBS, transfer 25uL coating solution to 384-well reaction plate, coat at 4℃ overnight.

[0446] 3. Wash

[0447] After coating, discard the coating solution, wash with PBST solution, transfer 50uL PBST to 384-well reaction plate, stand for 5 minutes, discard the wash solution, refill, repeat the washing for 3 times, finally pat dry the reaction plate and wait for the next step.

[0448] 4. Block

[0449] Transfer 50uL blocking solution to 384-well reaction plate, stand for 1 hour.

[0450] 5. Wash

[0451] After blocking, discard the blocking solution, wash with PBST solution according to the method of step 2 for 3 times, finally pat dry the reaction plate.

[0452] 6. Prepare 25 / 10-fold PARP2 solution, transfer 10uL PARP2 solution to 384-well reaction plate, for negative control wells, transfer 10uL reaction buffer, the final concentration of PARP2 is 1.5nM.

[0453] 7. Prepare 2000-fold compound, transfer 50nL compound with echo, add 20uL reaction buffer to the compound, mix, transfer 5uL mixed compound to 384-well reaction plate.

[0454] 8. Prepare 25 / 10-fold Biotin-NAD+ solution, transfer 10uL Biotin-NAD+ solution to 384-well reaction plate, the final concentration of Biotin-NAD+ is 2uM, incubate at room temperature for 60 minutes.

[0455] 9. Wash

[0456] After reaction, discard the reaction solution, wash with PBST solution according to the method of step 2 for 3 times, finally pat dry the reaction plate.

[0457] 10. Dilute Stre-HRP solution with blocking solution, transfer 25uL Stre-HRP solution to the reaction plate, incubate at room temperature for 1 hour, the final concentration of Stre-HRP is 0.1ug / mL.

[0458] 11. Wash

[0459] Discard the Stre-HRP solution, wash with PBST solution according to the method of step 2 for 3 times, finally pat dry the reaction plate.

[0460] 12. Color development

[0461] 50:50:1 mix Femto-ECL Substrate A, Femto-ECL Substrate B, QuantaRed ADHP transfer 25 uL to 384 reaction plate, incubate at room temperature for 10 minutes, add 2.5 uL QuantaRed Stop Solution.

[0462] 13. Readout

[0463] Read fluorescence values (Ex 550 / Em 620) with Paradigm.

[0464] Results + represent IC 50 < = 10 nM ++ represent 10 nM < IC 50 < = 1000 nM

[0465] Table 1

[0466]

[0467] It is to be understood that the embodiments and implementations outlined herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

1. A compound of a polycyclic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopologue thereof: Formula I wherein, two R with the N atom to which they are attached form a "3-7 membered saturated or partially unsaturated mono-heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; two R' with the N atom to which they are attached form a "3-7 membered saturated or partially unsaturated mono-heterocyclic ring containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; m and n are independently 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, 4 or 5. wherein, Ring D is is a single or double bond; M is -C(R) 1 =, -C(R) 1 R 2 - or -N(R) a )-; D1is C-L D1 -R 6 N, NR or S; D2 is absent, C-L D2 -R 7 or N, wherein when D1 is S or NR, D2 is absent; D3 is C-L D3 -R 8 or N; D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 ); D5 is C-L D5 -R 9 or N; L 0 C 1-6 alkylene or C 1-6 alkyl-substituted C 1-6 alkylene; When is a double bond, M is -C(R 1 ) =, any of the following (1), (2) and (3) applies: (1) D4 is N; R 1 is hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl; (2) D4is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 form, together with the carbon atom to which they are attached, a "3-8 membered cycloalkene" or a "5-7 membered heterocycloalkene containing 1-3 heteroatoms independently selected from O, N and S" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S"; ring A is a phenyl ring, a "3-8 membered cycloalkene", a "5-7 membered heterocycloalkene containing 1-3 heteroatoms independently selected from O, N and S" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S"; (3) D4 is -C(R) 4 R 5 ), R 5 Does not exist; R 1 and R 4 Independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 cycloalkyl or C substituted with one or more halogens 1-6 Alkyl; or, R 4 and L D1 -R 6 It forms a benzene ring with the attached carbon atom or "a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms, the heteroatoms being independently selected from O, N and S"; When D4 is a single bond, D4 is NR 4 , M is -C(R 1 )=, R 1 is absent, M and R 4 form "a 5-7 membered partially unsaturated monocyclic heterocycle containing 1-3 heteroatoms, one of which is N, the others of which are independently selected from O, N, and S" or "a 5-10 membered heteroaromatic ring containing 1-4 heteroatoms, one of which is N, the others of which are independently selected from O, N, and S"; said phenyl ring, "5-6 membered heteroaromatic ring containing 1-4 heteroatoms independently selected from O, N and S", "5-7 membered partially unsaturated monocyclic heterocycloalkene containing 1-3 heteroatoms, one of which is N and the other heteroatoms are independently selected from O, N and S" and "5-10 membered heteroaromatic ring containing 1-4 heteroatoms, one of which is N and the other heteroatoms are independently selected from O, N and S" are optionally substituted with any of the following: C 1-6 alkyl, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2; When is a single bond, M is -C(R 1 R 2 )- or -N(R a )-, D4 is absent, O, S or -C(R 4 R 5 ); R 1 and R 2 are independently hydrogen, halogen, C 1-6 alkyl, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2, or optionally substituted by any of C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S"; or, R 1 and R 2 together with the carbon atom to which they are attached form a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from O, N and S"; or, R 2 and R 4 with the carbon atom to which they are attached forming ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a "3-7 membered saturated or partially unsaturated monoheterocyclic ring containing 1-3 heteroatoms independently selected from O, N and S"; R a is hydrogen or L R3 is a bond or C 1-6 alkylene or C 1-6 alkyl substituted C 1-6 alkylene; R 3 is hydrogen or optionally substituted C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, "8-10 membered bicyclic aryl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing from 1-4 heteroatoms independently selected from O, N and S", "5-6 membered heteroaryl containing from 1-4 heteroatoms independently selected from O, N and S" or "8-10 membered bicyclic heteroaryl containing from 1-4 heteroatoms independently selected from O, N and S"; R 4 and R 5 independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2, or optionally substituted by any of C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monoheterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S", "6-8 membered saturated or partially unsaturated biheterocyclic ring containing 1-4 heteroatoms independently selected from O, N, and S"; or, R 4 and R 5 form a -C=0-, -C=S-, -C=NR L -3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monoheterocyclyl containing from 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated biheterocyclyl containing from 1-4 heteroatoms independently selected from O, N and S"; or, R L is hydrogen, -CN, -OR L1 or optionally substituted C 1-6 alkyl; R L1 is hydrogen, C 1-6 alkyl or halogen substituted C 1-6 alkyl; each L is independently a bond or optionally substituted C 1-6 alkylene; Each R A1 Independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R'、-S(O)(=R m R' or -P(O)(R)2, or arbitrarily substituted with any of the following groups: C 1-6 Alkyl groups, 3-7 saturated or partially unsaturated monocyclic carbocyclic groups, 6-8 saturated or partially unsaturated bicyclic carbocyclic groups, "3-7 saturated or partially unsaturated monoheterocyclic groups containing 1-3 heteroatoms independently selected from O, N and S", and "6-8 saturated or partially unsaturated heterobicyclic groups containing 1-4 heteroatoms independently selected from O, N and S". L D1 , L D2 , L D3 and L D5 are independently a bond or optionally substituted C 1-6 alkylene; R 6 , R 7 , R 8 , and R 9 are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR', -C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R', or -P(O)(R)2, or optionally substituted with any of C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monoheterocyclyl containing from 1-3 heteroatoms, independently selected from O, N, and S", "6-8 membered saturated or partially unsaturated biheterocyclyl containing from 1-4 heteroatoms, independently selected from O, N, and S", or "6-10 membered saturated or partially unsaturated biheterocyclyl containing from 1-4 heteroatoms, independently selected from O, N, and S"; Ring C is e and f are independently 0, 1 or 2; B is O, S or NR b , X and Y are independently CR d , O, S or NR e ; R d and R e are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR', -C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted by any one of the following: C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monoheterocyclyl containing from 1 to 3 heteroatoms, independently selected from O, N and S", "6-8 membered saturated or partially unsaturated biheterocyclyl containing from 1 to 4 heteroatoms, independently selected from O, N and S" or "6-10 membered saturated or partially unsaturated biheterocyclyl containing from 1 to 4 heteroatoms, independently selected from O, N and S"; R b is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl substituted by one or more halogen, -C(O)R', -COOR, -C(O)N(R)2, -SO3R', -NHR, -C(O)NR(OR), -C(=NR m )NR', -C(=NR m )N(R)2, or optionally substituted by any of C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-8 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monoheterocyclyl containing from 1 to 3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated biheterocyclyl containing from 1 to 4 heteroatoms independently selected from O, N and S" or "6-10 membered saturated or partially unsaturated biheterocyclyl containing from 1 to 4 heteroatoms independently selected from O, N and S"; R C -L C -R C1 ; each L is independently a bond or optionally substituted C1-C6alkylene; C independently a bond or optionally substituted C1-C6alkylene; 1-6 alkylene; Each R C1 Independently hydrogen, oxo, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R'、-S(O)(=R m R', -P(O)(R)2, "containing 1-3 heteroatoms, the heteroatoms being independently selected from 5-12 membered heteroaryls of O, N, and S", or the above groups are arbitrarily substituted by any of the following groups: C 1-6 Alkyl groups, 3-7 saturated or partially unsaturated monocyclic carbocyclic groups, 6-8 saturated or partially unsaturated bicyclic carbocyclic groups, "3-7 saturated or partially unsaturated monoheterocyclic groups containing 1-3 heteroatoms, the heteroatoms being independently selected from O, N and S", "6-8 saturated or partially unsaturated heterobicyclic groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, N and S", or "6-10 saturated or partially unsaturated heterobicyclic groups containing 1-4 heteroatoms, the heteroatoms being independently selected from O, N and S". each R is independently hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or "4-10 membered saturated or partially unsaturated heterocyclyl containing from 1 to 3 heteroatoms independently selected from O, N, and S"; said C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or "4-10 membered saturated or partially unsaturated heterocyclyl containing from 1 to 3 heteroatoms independently selected from O, N, and S" can be substituted with deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, cyano substituted C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, and C 1-6 alkyl substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, C In the structure as shown in Formula I, each R' is independently an optionally substituted or unsubstituted C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing from 1-3 heteroatoms independently selected from O, N, and S", "6-10 membered saturated or partially unsaturated heterobicyclyl containing from 1-4 heteroatoms independently selected from O, N, and S", "5-6 membered heteroaryl containing from 1-4 heteroatoms independently selected from O, N, and S", or "8-10 membered bicyclic heteroaryl containing from 1-4 heteroatoms independently selected from O, N, and S", or, q is 1; Each R m Independently -OH, -CN, or R; the compound of a polycyclic heterocyclic structure as shown in Formula I is any one of the following structures:

4. A compound having the following structure:

2. The compound of claim 1, which is a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopologue thereof, wherein, 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of a polycyclic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopologue thereof according to any one of claims 1-3, and one or more pharmaceutically acceptable carriers, diluents or excipients. ​ Ring D is is a single or double bond; M is -C(R 1 ) = or -C(R 1 R 2 ); D1is C-L D1 -R 6 or N, L D1 is a bond, R 6 is hydrogen; D2is C-L D2 -R 7 , L D2 is a bond, R 7 is hydrogen; D3 is C-L D3 -R 8 , L D3 is a bond, R 8 is hydrogen or halogen; D4 is O, N, NR 4 or -C(R 4 R 5 ); L 0 C 1-6 alkylene or C 1-6 alkyl substituted C 1-6 alkylene; When is a double bond, M is -C(R 1 ) =, any of the following (1), (2) and (3) applies: (1) D4 is N; R 1 is hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl or C 1-6 alkyl; (2) D4is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 form, together with the carbon atom to which they are attached, a "3-8 membered cycloalkene" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S"; m is 0 or 1, L is C ring A is a phenyl ring or a "3-8 membered cycloalkene" or a "5-7 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S"; m is 0 or 1, L is C 1-6 alkylene, R A1 is hydrogen; (3) D4is -C(R 4 R 5 ), R 5 is absent; R 1 and R 4 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkyl substituted by one or more halogens; When D4 is NR 4 , M is -C(R 1 )=, R 1 is absent, the double bond on M and R 4 are joined to form "a 5-7 membered heteroaromatic ring containing 1-3 heteroatoms, one of which is N, the others of which are independently selected from the group consisting of O, N, and S"; said "a 5-7 membered heteroaromatic ring containing 1-3 heteroatoms, one of which is N, the others of which are independently selected from the group consisting of O, N, and S" is optionally substituted with C 1-6 alkyl; When is a single bond, M is -C(R 1 R 2 is O, R 1 and R 2 are independently hydrogen or C 1-6 alkyl; Ring C is e and f are independently 1 or 2; B is O, S or NH; 6. Use of a compound of a polycyclic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopologue thereof according to any one of claims 1-3 in the manufacture of a PARP inhibitor medicament. R C -L C -R C1 ; L C is a bond; R C1 CN or -C(O)N(R)2; each R is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl or C 1-6 alkyl substituted with one or more -OC 3-8 cycloalkyl.

3. The compound of a multivalent heterocyclic structure represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof according to claim 1 or 2, characterized in that, 7. Use of a compound of a polycyclic heterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopologue thereof according to any one of claims 1-3 in the manufacture of a medicament for treating cancer, ischemic disease or neurodegenerative disease. ​ ​ ​ ​

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