Pyrimidine-2, 4 (1H, 3H)-diketone compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a 1-(4-fluoro-3-(piperazine-1-formyl) benzyl) pyrimidine-2, 4 (1H, 3H)-diketone PARP-1 inhibitor as well as a preparation method, a pharmaceutical composition and an application of the 1-(4-fluoro-3-(piperazine-1-formyl) benzyl) pyrimidine-2, 4 (1H, 3H)-diketone PARP-1 inhibitor. Specifically, the invention relates to a 1-(4-fluoro-3-(piperazine-1-formyl) benzyl) pyrimidine-2, 4 (1H, 3H)-diketone compound with a new structure as shown in a formula I, a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition containing one or more of the compounds, and applications of the compounds in inhibition of PARP-1 and treatment of PARP-1-related diseases, especially in treatment of PARP-1-related diseases, such as PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases, PARP-1-related diseases and PARP-1-related diseases. The invention also relates to application in preparation of medicines for preventing and / or treating cancers.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a 1-(4-fluoro-3-(piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione compound of a novel structure shown in formula I, a physiologically acceptable salt thereof, a preparation method thereof, a composition containing one or more such compounds, and the use of the compound as a drug, especially as an antitumor drug or as a tumor drug sensitizer in combination with an antitumor drug. Background Art

[0002] Poly(ADP-ribose) polymerase (PARP) is an enzyme that catalyzes the conversion of ADP-ribose from nicotinamide adenine dinucleotide (NAD + ) is a type of cellular nuclear enzyme that transfers DNA to receptor proteins. The PARP family contains 17 subtypes [Journal of Medicinal Chemistry, 2016, 59, 21: 9575–9598], which are involved in various life activities of cells, including damaged DNA repair, chromatin stability maintenance and gene transcription regulation [Genes & development, 2017, 31 (2): 101-126]. In the PARP family, PARP-1 has the highest content and is the most intensively studied subtype. Damaged DNA activates PARP-1, which recognizes and binds to the damaged site of DNA and recruits DNA repair proteins to repair the damaged DNA [Journal of Medicinal Chemistry. 2010, 53: 4561–4584]. Since most chemotherapy drugs kill tumor cells by directly or indirectly damaging DNA chains, inhibiting the activity of PARP-1 can effectively block the repair of damaged DNA, thereby enhancing the anti-tumor effect of chemotherapy drugs. In addition, PARP-1 inhibitors are more sensitive to tumor cells with BRCA-1 / 2 mutations and abnormal copies and can be used alone to treat tumors with BRCA mutations.

[0003] In the PARP family, the catalytic domain homology of PARP-2 and PARP-1 is the highest, up to 69%. Both contain DNA binding domains, which can bind to damaged DNA and repair damaged DNA [Journal of Biological Chemistry.1999,274:17860-17868]. Early studies have shown that PARP-1 / 2 inhibitors can be used as anti-tumor drugs for the treatment of tumors. Since 2014, PARP1 / 2 non-selective inhibitors Olaparib, Rucaparib, Niraparib and Talaziparib have been approved by the FDA for marketing. Recently, Fluzoparib and Pamiparib have been approved for marketing in China [Expert Opinion on Therapeutic Patents.2021,31,7:609-623]. With the continuous deepening of the research on the pathophysiological functions of PARP-1 and PARP-2, it was found that PARP-2, in addition to participating in DNA damage repair, is also involved in many other physiological processes, including cell cycle regulation, metabolism, angiogenesis, adipogenesis, T cell development and sperm production [Proceedings of the National Academy of Sciences of the United States of America. 103, 40: 14854-14859]. Studies have also confirmed that the blood toxicity of PARP1 / 2 non-selective inhibitors is mainly related to the inhibition of PARP-2 [Cell Death and Differentiation. 2015, 22: 1144-1157]. Therefore, the research on PARP-1 selective inhibitors has received more and more attention. Compared with the research on non-selective PARP-1 / 2 inhibitors, the research on PARP-1 selective inhibitors is still in its early stages. Currently, AZD5305 [Journal of Medicinal Chemistry. 2021, 64, 19: 14498–14512] and AZD9574 have entered the clinical research stage. The research and development of new structural types, highly active, and highly selective PARP-1 inhibitors has important clinical application value.

[0004] This patent designs and synthesizes a new structure of 1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)pyrimidine-2,4(1H,3H)-dione compounds, which have significant inhibitory activity against PARP-1 and provide a new material basis for the treatment of diseases related to PARP-1. Summary of the invention

[0005] The technical problem solved by the present invention is to provide 1-(4-fluoro-3-(piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione compounds and physiologically acceptable salts thereof as shown in formula I, preparation methods and pharmaceutical compositions thereof, and uses thereof in preparing PARP-1 inhibitors and potential drugs thereof, and uses thereof in preparing drugs for treating cancer.

[0006] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0007] The first aspect of the technical solution of the present invention is to provide a 1-(4-fluoro-3-(piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione derivative or a physiologically acceptable salt thereof as shown in general formula I:

[0008]

[0009] In Formula I,

[0010] R1 is selected from the following atoms, groups or structural fragments, including

[0011] H, F, Cl, Br, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl, substituted or unsubstituted C2, C3, C4 straight or branched alkenyl, substituted or unsubstituted C2, C3, C4 straight or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

[0012] R2 is selected from the following atoms, groups or structural fragments, including

[0013] H, F, Cl, Br, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl, substituted or unsubstituted C2, C3, C4 straight or branched alkenyl, substituted or unsubstituted C2, C3, C4 straight or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

[0014] R3 is selected from the following atoms, groups or structural fragments, including

[0015] H, F, Cl, Br, CF3, CN, ORj1, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl; wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl;

[0016] R4 is selected from the following atoms, groups or structural fragments:

[0017] (1) hydrogen, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H , methyl, ethyl,; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom;

[0018] (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S;

[0019] (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0020] The second aspect of the technical solution of the present invention is to provide a (R)-1-(4-fluoro-3-(piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione derivative or a physiologically acceptable salt thereof as shown in the general formula IA:

[0021]

[0022] In Formula IA

[0023] R1 and R2 are the same as those described in the first aspect of the technical solution;

[0024] R3' is independently selected from the following atoms, groups or structural fragments, including

[0025] H, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl; wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl;

[0026] R4 is selected from the following atoms, groups or structural fragments:

[0027] (1) substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl;

[0028] (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom;

[0029] (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S;

[0030] (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0031] The third aspect of the technical solution of the present invention is to provide a (R)-1-(4-fluoro-3-(piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione derivative or a physiologically acceptable salt thereof as shown in the general formula IB:

[0032]

[0033] In Formula IB,

[0034] R1 and R2 are the same as those described in the first aspect of the technical solution;

[0035] R3' is independently selected from the following atoms, groups or structural fragments, including

[0036] F, Cl, Br, O Rj1, wherein said Rj1 is independently selected from H, methyl, ethyl;

[0037] R4 is selected from the following atoms, groups or structural fragments:

[0038] (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl;

[0039] (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom;

[0040] (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S;

[0041] (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0042] The fourth aspect of the technical solution of the present invention is to provide a (R)-1-(4-fluoro-3-(3-ethyl-piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione derivative or a physiologically acceptable salt thereof as shown in the general formula IA-1:

[0043]

[0044] In Formula IA-1,

[0045] R1 and R2 are the same as those described in the first aspect of the technical solution;

[0046] R4 is selected from the following atoms, groups or structural fragments:

[0047] (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl;

[0048] (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom;

[0049] (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S;

[0050] (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0051] The fifth aspect of the technical solution of the present invention is to provide a (R)-1-(4-fluoro-3-(3-hydroxyethyl-piperazine-1-formyl)benzyl)pyrimidine-2,4(1H,3H)-dione derivative or a physiologically acceptable salt thereof as shown in the general formula IA-2:

[0052]

[0053] In Formula IA-2,

[0054] R1 and R2 are the same as those described in the first aspect of the technical solution;

[0055] R4 is selected from the following atoms, groups or structural fragments:

[0056] (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl;

[0057] (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom;

[0058] (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S;

[0059] (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

[0060] In the sixth aspect of the technical solution of the present invention, in order to achieve the purpose of the present invention, preferred compounds include but are not limited to:

[0061]

[0062]

[0063]

[0064]

[0065] The seventh aspect of the technical solution of the present invention provides a method for preparing the compounds described in the first aspect to the sixth aspect, and the technical solution adopted comprises the following steps:

[0066] The present invention adopts the following method to prepare the compound shown in formula I: 6-R2-5-iodo-2,4-dimethoxypyrimidine is used as a raw material, and a substituent R is introduced by a coupling reaction. 1 , then undergoes a selective alkylation reaction with 5-bromomethyl-2-fluorobenzoic acid methyl ester under the action of HMDS, and after hydrolysis, obtains 5-((2,4-dioxo-uracil-1(2H)-yl)methyl)benzoic acid containing different substitutions of R1 and R2, and then undergoes a condensation reaction with substituted piperazine to obtain uracildione PARP-1 inhibitor (I). The specific description is as follows:

[0067] Using 2-fluoro-5-methylbenzoic acid methyl ester 1 as the starting material, intermediate 2 was obtained through bromination reaction;

[0068] Using 6-differently substituted 5-iodo-2,4-dimethoxypyrimidine 3 as the starting material, substituents were introduced by coupling reaction to obtain intermediate 4;

[0069] Intermediate 4 was treated with TMSCl to remove the methyl ether protecting group to obtain intermediate 5;

[0070] Intermediate 5 undergoes nucleophilic substitution with intermediate 2 to give intermediate 6;

[0071] Intermediate 6 undergoes hydrolysis reaction under lithium hydroxide conditions to obtain intermediate 7;

[0072] Using intermediate 8 as the starting material, different substituents were introduced through nucleophilic substitution reaction and coupling reaction to obtain intermediate 9;

[0073] Intermediate 9 was subjected to trifluoroacetic acid conditions to remove the Boc protecting group to obtain intermediate 10;

[0074] Intermediate 7 and intermediate 10 undergo acid-amine condensation reaction to obtain a compound of formula I;

[0075]

[0076] Scheme 1.Reagents and conditions: (i) NBS, AIBN, CCl4; (ii) R1B(OH)2, Pd(OAc)2,Tricyclohexyl phosphine,K2CO3,DCE,H2O;(iii)TMSCl,H2O,MeCN;(iv)HMDS,NH4Cl,DCE;(v)LiOH,THF,MeOH,H2O;(vi)R4-Br,DIEA,MeCN or Pd2(dba)3,Ruphos,tBuONa,Toluene,or Pd2(dba)3,Davephos,Cs2CO3,Toluene;

[0077] The definitions of R1, R2, R3, and R4 are the same as those in any one of the first to fifth aspects of the technical solution;

[0078] The starting materials and intermediates in the above reaction are easy to obtain, and each step of the reaction can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art. The compound described in general formula I can exist in the form of a solvate or an unsolvate, and different solvates may be obtained by crystallization using different solvents. The pharmaceutically acceptable salts described in general formula I include salts of different acids, such as the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts described in general formula I also include different alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and salts of organic bases that can provide physiologically acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine salts. All of these salts within the scope of the present invention can be prepared by conventional methods.

[0079] The eighth aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof as described in the first to fifth aspects of the technical solution of the present invention and a commonly used pharmaceutical carrier.

[0080] The composition includes at least one compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compound of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight. The compound of the present invention or a pharmaceutical composition containing it can be administered in a unit dose form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc. The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w type, w / o type and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and ointments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0081] The compounds of the present invention can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems. These preparations are prepared according to methods well known to those skilled in the art. The auxiliary materials used to make tablets, capsules and coatings are conventional auxiliary agents, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and the solvents used in liquid dosage forms are, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. The preparations containing the compounds of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, etc.

[0082] In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0083] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0084] In order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0085] To prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of a solubilizer, cosolvent, pH adjuster, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a support agent.

[0086] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0087] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0088] The dosage of the pharmaceutical composition of the compound of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Generally speaking, the suitable dosage range of the compound of the present invention is 0.1-1000 mg / Kg body weight per day, preferably 1-500 mg / Kg body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and the dosage regimen including the use of other treatment means.

[0089] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0090] The ninth aspect of the technical solution of the present invention provides the use of the compounds and pharmaceutically acceptable salts thereof described in the first to sixth aspects of the present invention in the preparation of PARP-1 inhibitors, in the preparation of drugs for preventing and / or treating diseases related to PARP-1, in the preparation of drugs for treating neuropsychiatric diseases, cardiovascular diseases, metabolic diseases, and cancer, especially in the preparation of drugs related to diseases such as stroke or tumors.

[0091] Beneficial technical effects:

[0092] The 1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)pyrimidine-2,4(1H,3H)-dione compounds in this patent application are PARP-1 inhibitors with a completely new structure and have significant inhibitory activity against PARP-1. DETAILED DESCRIPTION

[0093] The invention will be further described below with reference to the embodiments, but the scope of the invention is not limited thereto.

[0094] The structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). NMR is measured using Varian mercury 400 or Varian mercury 500, the solvent is CDCl3, DMSO-d6, MD3OD, the internal standard is TMS, and the chemical shift is given in ppm. mp is the melting point given in °C, and the temperature is not corrected. Silica gel column chromatography generally uses 200-300 mesh silica gel as the carrier.

[0095] List of abbreviations:

[0096] Na2CO3: Sodium carbonate; Cs2CO3: Cesium carbonate; NaHCO3: Sodium bicarbonate; K2CO3: Potassium carbonate TFA: Trifluoroacetic acid; NaCl: Sodium chloride; NH4Cl: Ammonium chloride; MgSO4: Magnesium sulfate

[0097] TEA: triethylamine; DIEA: N,N-diisopropylethylamine; NMI: N-methylimidazole

[0098] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; TBDMSCl: tert-butyldimethylsilyl chloride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; MeCN: acetonitrile

[0099] Ar: argon; min: minute; rt: room temperature; h: hour

[0100] Boc anhydride: di-tert-butyl dicarbonate;

[0101] Pd(OAc)2: palladium acetate; Pd2(dba)3: trisdibenzylideneacetone dipalladium

[0102] Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; Davephos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl

[0103] NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide;

[0104] CD3OD: deuterated methanol

[0105] TLC: thin-layer chromatography

[0106] Synthesis of intermediates

[0107] (1) Synthesis of methyl 5-(bromomethyl)-2-fluorobenzoate (Intermediate 2)

[0108]

[0109] Methyl 2-fluoro-5-methylbenzoate (840 mg, 5 mmol), NBS (889 mg, 5 mmol) and AIBN (164 mg, 0.2 mmol) were dissolved in a mixture of CCl4 (20 mL) and MeCN (4 mL). The mixture was heated to reflux at 70°C under Ar protection. After TLC showed that the reaction was no longer proceeding, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (20 mL×3), and the organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, PE / EA, EA=4%) to obtain 798 mg of a white solid with a yield of 64.59%.

[0110] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.99 (dd, J1=7.6Hz, J2=2.4Hz, 1H), 7.75 (ddd, J1= 7.6Hz, J2=4.8Hz, J3=2.4Hz, 1H), 7.36(t, J=8.8Hz, 1H), 4.78(s, 2H), 3.86(s, 3H).

[0111] (2) Synthesis of 5-cyclopropyl-2,4-dimethoxypyrimidine (Intermediate 4a)

[0112]

[0113] 5-Bromo-2,4-dimethoxypyrimidine (215 mg, 0.98 mmol), K2CO3 (832 mg, 6.02 mmol), tricyclohexylphosphine (63 mg, 0.22 mmol), Pd(OAc)2 (22 mg, 0.1 mmol) and cyclopropylboric acid (258 mg, 3 mmol) were added to 1,2-dimethoxyethane (6 mL), and refluxed under argon protection. The reaction was stopped after 28 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with H2O (5 mL) and saturated NaCl aqueous solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, EA / PE, EA=7%) to obtain 128 mg of a light yellow oil with a yield of 72.5%.

[0114] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 7.85 (s, 1H), 4.02 (s, 3H), 3.96 (s, 3H), 1.81–1.74 (m, 1H), 0.90–0.85 (m, 2H), 0.63–0.59 (m, 2H).

[0115] The preparation method of intermediate 4b is the same as that of 4a

[0116]

[0117]

[0118] (3) Synthesis of 5-cyclopropylpyrimidine-2,4(1H,3H)-dione (Intermediate 5a)

[0119]

[0120] Intermediate 4a (388 mg, 2.15 mmol) and potassium iodide (1.12 g, 6.8 mmol) were dissolved in acetonitrile (10 mL), and then trimethylsilyl chloride (706 mg, 6.50 mmol) was added. The reaction was stirred at room temperature for 6 h and then stopped. H2O (5 mL) was added to quench the reaction, filtered, and the filter cake was washed with water and acetone to obtain 167 mg of an off-white solid with a yield of 51.1%.

[0121] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.99 (s, 1H), 10.64 (s, 1H), 6.99 (d, J = 5.6Hz, 1H), 1.56–1.50 (m, 1H), 0.69–0.63 (m, 2H), 0.52–0.46 (m, 2H).

[0122] The preparation methods of intermediates 5b and 5c are the same as those of 5a

[0123]

[0124] (4) Synthesis of methyl 5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoate (Intermediate 6a)

[0125]

[0126] 5-Ethylpyrimidine-2,4(1H,3H)-dione (560 mg, 4 mmol) was placed in HMDS (5 mL), NH4Cl (20 mg, 0.4 mmol) and a catalytic amount of concentrated sulfuric acid were added, and the mixture was heated to 140°C for reaction. After the reaction solution became clear and transparent, the reaction was stopped and concentrated. 1,2-dichloroethane (10 mL) and intermediate 2 (1.23 g, 5 mmol) were added, and the mixture was heated under reflux at 100°C for reaction. The reaction was stopped after TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, isopropanol (6 mL) was added, and the mixture was stirred for 30 min. A white solid was precipitated, which was filtered and the filter cake was washed with a mixed solution of DCM:PE=1:1 to obtain 870 mg of an off-white solid with a yield of 71%.1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 7.85 (dd, J=6.8, 2.4Hz, 1H), 7.65 (s, 1H), 7.62 (ddd, J1=8.8Hz, J2=4.8Hz, J3= 2.4Hz,1H),7.35(dd,J1=10.8Hz,J2=8.4Hz,1H),4.88(s,2H),3.85(s,3H),2.19(q,J1=7.6Hz,2H),1.02(t,J=7.6Hz,3H).

[0127] The preparation method of intermediates 6b-6m is the same as 6a

[0128]

[0129]

[0130]

[0131]

[0132]

[0133] (5) Synthesis of 5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoic acid (Intermediate 7a)

[0134]

[0135] The intermediate 6a (612 mg, 2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and methanol (8 mL), and an aqueous solution (4 mL) of lithium hydroxide (252 mg, 6 mmol) was added dropwise. The reaction was stirred at 37°C for 8 hours, the reaction was stopped, concentrated, and water (mL) was added. The aqueous phase was extracted with DCM (7 mL), EA (7 mL×2), and anhydrous ether (7 mL×2). Under an ice bath, the pH was adjusted to about 3 with 2N dilute hydrochloric acid. Solid precipitated and was filtered. The filter cake was washed with water (4 mL) and anhydrous ether (7 mL×3) and dried to obtain 596 mg of a white solid with a yield of 100%.

[0136] 1H NMR (500MHz, DMSO-d6) δ (ppm): 11.31 (s, 1H), 7.82 (dd, J1=7.0Hz, J2=2.5Hz, 1H), 7.64 (s, 1H), 7.58–7.54 (m,1H),7.30(dd,J1=10.5Hz,J2=8.5Hz,1H),,4.87(s,2H),2.20(q,J=7.5Hz,2H),1.02(t,J=7.5Hz,3H).

[0137] The preparation method of intermediates 7b-7m is the same as 7a

[0138]

[0139]

[0140]

[0141]

[0142] (6) Synthesis of (R)-tert-butyl 3,4-diethylpiperazine-1-carboxylate (Intermediate 9a)

[0143]

[0144] (R)-1-Boc-2-ethylpiperazine (214 mg, 1 mmol) and bromoethane (164 mg, 1.5 mmol) were dissolved in acetonitrile (5 mL), DIEA (258 mg, 2 mmol) was added, the tube was sealed and heated to 54°C for reaction, the reaction was stopped after 6 h, the reaction was quenched with saturated NH4Cl solution (5 mL), extracted with DCM (5 mL×3), the organic phases were combined, washed with saturated NaCl solution (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) to obtain 123 mg of a yellow oil with a yield of 50.8%.

[0145] 1 H NMR(500MHz,Chloroform-d)δ(ppm):3.64(brs,2H),3.32(brs,2H),2.81(s,2H),2.58(s,1H),2. 43(s,2H),1.62(s,1H),1.44(s,9H),1.37–1.21(m,1H),1.19–1.03(m,3H),0.93(t,J=7.6Hz,3H).

[0146] The preparation method of intermediates 9b-9j is the same as 9a

[0147]

[0148]

[0149]

[0150]

[0151] (5) Synthesis of (R)-1,2-diethylpiperazine trifluoroacetate (Intermediate 10a)

[0152]

[0153] Intermediate 9a (120 mg, 0.5 mmol) was dissolved in DCM (5 mL), and TFA (370 μL, 5 mmol) was added. The reaction was stirred at room temperature and stopped after 4 h. The mixture was concentrated to dryness and concentrated several times with toluene to obtain 206 mg of a yellow oily liquid with a yield of >100%.

[0154] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.57(s,2H),3.78–3.22(m,8H),3.22–3.15(m,1 H),1.89(brs,1H),1.67(brs,1H),1.21(t,J=7.2Hz,3H),0.92(t,J=7.2Hz,3H).

[0155] The preparation method of intermediates 10b-10m is the same as 10a

[0156]

[0157]

[0158]

[0159]

[0160] (6) Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (Intermediate 12)

[0161]

[0162] (R)-tert-Butyl 2-(Hydroxymethyl)piperazine-1-carboxylate (666 mg, 3.08 mmol) was placed in a reaction flask, and EA (10 mL), water (10 mL), and Na2CO3 (671 mg, 6.33 mmol) were added. Benzyloxycarbonyl chloride (650 μL, 4.62 mmol) was added dropwise to the reaction flask under an ice bath. After the addition was completed, the temperature was gradually raised to room temperature and stirred for 5 h. The reaction was stopped, and EA (20 mL) was added. The organic phase was washed with water (10 mL) and saturated NaCl solution (10 mL), respectively, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, EA / DCM, EA=4%) to obtain 1.028 g of a yellow oil with a yield of 95.4%.

[0163] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.40–7.29(m,5H),5.16(s,2H),4.18(brs,2H), 4.02(brs,1H),3.85(brs,1H),3.59(s,2H),3.00(brs,3H),2.07(s,1H),1.46(s,9H).

[0164] (7) Synthesis of (R)-3-(Hydroxymethyl)piperazine-1-carboxylic acid benzyl ester (Intermediate 13)

[0165]

[0166] The intermediate 12 (970 mg, 2.77 mmol) was dissolved in DCM (15 mL), and TFA (2.2 mL, 28.5 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after 3 h, concentrated, dissolved in methanol, and trifluoroacetic acid was neutralized by adding 20 eq of ammonia methanol solution under ice bath. The solution was concentrated, and DCM (5 mL) was added. Solid precipitated and filtered. The filtrate was concentrated to obtain 1.43 g of yellow oily liquid with a yield of >100%.

[0167] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.43-7.30(m,5H),5.18(s,2H),4.69-4.51(m,1H),4.24(brs,2H),4.03–3.62(m,2H),3.46-3.13(m,5H).

[0168] (8) Synthesis of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-ethylpiperazine-1-carboxylic acid benzyl ester (Intermediate 14)

[0169]

[0170] Intermediate 13 (103 mg, 0.28 mmol) and bromoethane (70 mg, 0.64 mmol) were dissolved in acetonitrile (1 mL), DIEA (118 μL, 0.67 mmol) was added, and the mixture was sealed and reacted at 65°C. After TLC showed that the starting material disappeared, the reaction was stopped, and ethyl acetate (20 mL) was added. The organic phase was washed with water (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) to obtain 86 mg of a yellow oil with a yield of 78.2%.

[0171] 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.41–7.27(m,5H),5.13(d,J=3.0Hz,2H),3.98–3.78(m,3H),3.50 (brs,1H),3.26–3.07(m,2H),2.92–2.27(m,4H),1.61(s,1H),1.07(s,3H),0.87(s,9H),0.04(s,6H).

[0172] (9) Synthesis of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethylpiperazine (Intermediate 15)

[0173]

[0174] Intermediate 14 (78 mg, 0.20 mmol) was placed in a reaction bottle, ethanol (3 mL) and 10% Pd / C (17 mg) were added, and the reaction was stopped after hydrogenation at room temperature and pressure for 4 h. Filter and concentrate the filtrate to obtain 49 mg of colorless oil, with a yield of 96.1%.

[0175] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 3.85 (dd, J1 = 10.4Hz, J2 = 4.4Hz, 1H), 3.50 (dd, J 1=10.0Hz,J2=6.8Hz,1H),3.12(dd,J1=12.0Hz,J2=3.2Hz,1H),2.96(dt,J1=12.0Hz,J 2=3.2Hz,1H),2.88–2.78(m,2H),2.64–2.50(m,2H),2.49–2.41(m,1H),2.33(td,J1= 10.8Hz, J2=3.6Hz, 1H), 1.98 (s, 2H), 1.05 (t, J=7.2Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

[0176] (10) Synthesis of (R)-4-(benzyl(2-ethoxy-2-oxoethyl)amino)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid benzyl ester (Intermediate 17)

[0177]

[0178] N-tert-Butyloxycarbonyl-D-aspartic acid 1-benzyl ester (352 mg, 1.09 mmol), EDCI (416 mg, 2.17 mmol), HOBt (296 mg, 2.19 mmol), DIEA (560 μL, 3.22 mmol) were dissolved in anhydrous DCM (8 mL), stirred at room temperature for 5 min, and then N-benzylglycine ethyl ester (28 mg, 0.18 mmol) in DCM (2 mL) was added to the reaction solution, and the reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the raw material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), the organic phases were combined, washed with saturated NaCl (10 mL), dried, filtered and concentrated over anhydrous MgSO4 to obtain a crude product, which was purified by column chromatography (SiO2, EA / PE, EA=16%) to obtain 242 mg of a yellow oil with a yield of 44.6%.

[0179] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.37–7.27(m,8H),7.24–7.17(m,2H),5.52-5.39(m,1H),5.22–5.11(m,3H),4.94–4.70(m,1H),4.66–4.52(m,1 H),4.14-4.10(m,1H),4.10-3.99(m,1H),3.92–3.82(m,1H),2.95-2.84(m ,1H),2.79–2.70(m,1H),1.42(s,3H),1.34(s,6H),1.23(t,J=6.8Hz,3H).

[0180] (11) Synthesis of (R)-2-(4-benzyl-3,6-dioxopiperazin-2-yl)benzyl acetate (Intermediate 18)

[0181]

[0182] The intermediate 17 (890 mg, 1.79 mmol) was dissolved in DCM (10 mL), and a DCM solution (2 mL) of TFA (1.4 mL, 3.75 mmol) was added dropwise. The mixture was stirred at room temperature and concentrated. The residue was dissolved in isopropanol (10 mL), and the mixture was stirred under reflux at 90°C. The reaction was stopped after TLC showed that the raw material had reacted completely. DCM (20 mL) was added for dilution, and the mixture was washed with a saturated sodium bicarbonate solution (10 mL) and a saturated sodium chloride solution (10 mL), respectively. After drying over anhydrous magnesium sulfate, the mixture was concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=2-5%) to obtain 597 mg of a yellow oil with a yield of 94.9%.

[0183] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.39–7.32(m,8H),7.25–7.23(m,2H),6.53(s,1H),5.15(d,J=2.4Hz,2H),4.58(q,J=14.8Hz,2H ),4.47-4.41(m,1H),3.84(dd,J1=4.0Hz,J2=1.2Hz,,2H),3.16(dd,J1=18.0Hz,J2=3.2Hz,1H),2.87(dd,J1=17.6Hz,J2=8.8Hz,1H).

[0184] (12) Synthesis of (R)-tert-butyl 4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate (Intermediate 19)

[0185]

[0186] Intermediate 18 (550 mg, 1.56 mmol) was placed in a reaction bottle, anhydrous THF (5 mL) was added, and 2.4 M LiAlH4 THF solution (2.6 mL, 6.24 mmol) was added dropwise at room temperature under argon protection. After the addition was completed, the temperature was raised to 60°C and stirred for reaction. The reaction was stopped after 8 h, and the mixture was cooled to room temperature. Water was slowly added dropwise in an ice bath to terminate the reaction. The mixture was filtered, and the filter cake was washed with a mixture of THF:MeOH=8:1. The filtrate was concentrated to dryness and THF was added. (6mL), saturated sodium bicarbonate solution (3mL) and (Boc)2O (655mg, 3.00mmol), stir the reaction at room temperature. The next day, stop the reaction, add ethyl acetate (20mL), wash with water (10mL) and saturated NaCl solution (10mL), dry with anhydrous magnesium sulfate, filter and concentrate to obtain a crude product, which is purified by column chromatography (SiO2, EA / PE, EA=19-41%) to obtain 342mg of a yellow oil with a yield of 68.4%. 1H NMR (500MHz, Chloroform-d) δ (ppm): 7.33–7.25 (m, 5H), 4.30 (s, 1H), 3.83 (d, J = 14.8Hz, 1H), 364–3.61 (m, 1H), 3.49 (brs ,2H),3.37(t,J=8.8Hz,1H),3.02(s,1H),2.73(s,2H),2.34–2.17(m,2H),2.04–2.00(m,1H),1.67(brs,2H),1.46(s,9H).

[0187] (13) Synthesis of (R)-2-(4-benzylpiperazin-2-yl)ethan-1-ol (Intermediate 20)

[0188]

[0189] Intermediate 19 (195 mg, 0.61 mmol) was placed in a reaction bottle, and DCM (5 mL) and TFA (0.48 mL, 6.27 mmol) were added. The mixture was stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The mixture was concentrated and dissolved in methanol. 20 eq of ammonia methanol solution (2 M, 6 mL) was added under an ice bath to separate the mixture. The mixture was concentrated to dryness. After adding DCM, some solids did not dissolve. The solids were filtered and none of them was the product. The filtrate was concentrated to obtain 245 mg of an oily liquid with a yield of >100%.

[0190] 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.43–7.22(m,5H),4.84(s,1H),3.65–3.42(m,4H),3.42–3.19(m,3H),3 .06–2.91(m,2H),2.79(d,J=12.4Hz,1H),2.26(t,J=11.2Hz,1H),2.20–2.07(m,1H),1.82–1.57(m,2H).

[0191] (14) Synthesis of (R)-2-(4-benzylpiperazin-2-yl)ethan-1-ol (Intermediate 21)

[0192]

[0193] Take intermediate 20 (102 mg, 0.25 mmol), add DCM (1 mL), add imidazole (28 mg, 0.41 mmol) under ice bath and stir for 15 min, then add TBDMSCl (62 mg, 0.41 mmol), warm to room temperature and stir to react. After TCL shows that the starting material disappears, stop the reaction, filter, add DCM (10 mL) to the filtrate, wash with water (5 mL), dry over anhydrous magnesium sulfate, filter, and concentrate to obtain 79 mg of a yellow oil with a yield of 92.9%. 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.35–7.24(m,5H),3.80–3.62(m,2H),3.56(s,2H) ),3.43-3.26(m,2H),3.09(t,J=10.4Hz,1H),2.99(d,J=9.0Hz,1H),2.91–2.79(m,1H) ,,2.63-2.47(m,1H),2.38(dd,J1=12.4Hz,J2=10.0Hz,1H),2.13–2.02(m,1H),1.86–1 .74(m,1H),1.33–1.20(m,1H),0.91(s,2H),0.84(s,9H),-0.01(s,3H),-0.02(s,3H).

[0194] (15) Synthesis of (R)-4-benzyl-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-ethylpiperazine (Intermediate 22)

[0195]

[0196] The intermediate 21 (96 mg, 0.25 mmol) and bromoethane (35 mg, 0.32 mmol) were dissolved in acetonitrile (1 mL), and DIEA (87 μL, 0.50 mmol) was added. The tube was sealed and reacted at 52°C. The reaction was stopped after 8 h, and ethyl acetate (20 mL) was added. The organic phase was washed with water (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) to obtain 42 mg of a yellow oil with a yield of 77.8%.

[0197] 1H NMR(400MHz,Chloroform-d)δ(ppm):7.29–7.21(m,5H),3.67–3.58(m,1H),3.57–3.48(m,2H),3.48–3.40(m,1H),2.93–2.76(m,2H),2.75–2. 59(m,3H),2.58–2.31(m,3H),2.27–2.15(m,1H),1.87–1.76(m,1H),1. 74–1.59(m,1H),1.08(s,3H),0.84(s,9H),-0.03(s,3H),-0.02(s,3H).

[0198] (16) Synthesis of (R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-ethylpiperazine (Intermediate 23)

[0199]

[0200] Intermediate 22 (178 mg, 0.49 mmol), 10% Pd / C (19 mg, 0.18 mmol) and 10% Pd(OH)2 (19 mg, 0.14 mmol) were placed in a reaction bottle, methanol (5 mL) was added, and the reaction was hydrogenated at normal pressure under 50°C oil bath heating. The reaction was stopped after TLC showed that the raw material disappeared. Filter and concentrate to obtain 110 mg of colorless oil, with a yield of 82.1%.

[0201] 1 H NMR(400MHz,Chloroform-d)δ(ppm):3.70–3.57(m,2H),3.00–2.75(m,4H),2.70–2.60(m,1H),2.49–2.36(m,2 H),2.36-2.23(m,1H),1.97-1.72(m,3H),1.67-1.52(m,1H),1.03(t,J=7.2Hz,3H),0.87(s,9H),0.03(s,6H).

[0202] Embodiment 1:

[0203] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Compound 1)

[0204]

[0205] Intermediate 7a (136 mg, 0.46 mmol), intermediate 10a (206 mg, 0.56 mmol), EDCI (191 mg, 1 mmol), HOBt (135 mg, 1 mmol), DIEA (322 mg, 2.5 mmol) were dissolved in anhydrous DMF (10 mL). The reaction was stirred at room temperature under argon protection. The reaction was stopped after TLC showed the disappearance of the starting material. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=7%) to obtain 152 mg of a white solid with a yield of 79.3%.

[0206] 1 H NMR (500MHz, Chloroform-d) δ (ppm): 8.33 (s, 1H), 7.37 (s, 2H), 7.13–7.08 (m, 1H), 6.92 (d, J = 3.5Hz, 1H), 4.95 (s, 2H), 4.14–3.34 (m, 3H) ),2.86(brs,2H),2.51(s,2H),2.35–2.31(m,2H),1.69–1.47(m,2H),1.11–1.09(m,6H),1.03(s,2H),0.68(s,1H); HRMS(ESI)m / z:calcd For C 21 H 27 O3N4F2[M+H] + ,417.2296;Found 417.2287.

[0207] Embodiment 2:

[0208] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-methylpyrimidine-2,4(1H,3H)-dione (Compound 2)

[0209]

[0210] Intermediate 7b (139 mg, 0.46 mmol), intermediate 10a (222 mg, 0.56 mmol), EDCI (191 mg, 1 mmol), HOBt (135 mg, 1 mmol) and DIEA (322 mg, 2.5 mmol) were dissolved in anhydrous DMF (10 mL). The reaction was stirred at room temperature under argon protection. The reaction was stopped after TLC showed the disappearance of the starting material. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=8%) to obtain 43 mg of a white solid with a yield of 21.4%.

[0211] 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.35(s,1H),7.68(s,1H),7.47-7.40(m,1H) ,7.34–7.26(m,2H),4.83(s,2H),3.77(brs,1H),3.20(brs,2H),3.00(brs,1 H),2.76–2.62(m,2H),2.41–2.20(m,2H),1.75(s,3H),1.56–1.24(m,2H),0. 96(s,3H),0.90(t,J=7.2Hz,2H),0.52(t,J=6.8Hz,1H); HRMS(ESI)m / z:calcd For C 21 H 28 O3N4F[M+H] + ,403.2140;Found403.2141.

[0212] Embodiment 3:

[0213] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 3)

[0214]

[0215] Intermediate 7c (141 mg, 0.46 mmol), intermediate 10a (222 mg, 0.56 mmol), EDCI (191 mg, 1 mmol), HOBt (135 mg, 1 mmol) and DIEA (322 mg, 2.5 mmol) were dissolved in anhydrous DMF (10 mL). The reaction was stirred at room temperature under argon protection. The reaction was stopped after TLC showed that the raw material had reacted completely. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=8%) to obtain 78 mg of a white solid with a yield of 38.4%.

[0216] 1 H NMR (400MHz, Methanol-d4) δ (ppm): 7.95 (d, J = 6.4 Hz, 1H), 7.57–7.53 (m, 1H), 7.45 (dd, J1 = 6.4 Hz,J2=1.6Hz,1H),7.25(td,J1=8.8Hz,J2=2.0Hz,1H),4.90(s,2H),4.00(brs,1H),3.78(brs, 1H),3.58-3.48(m,1H),3.35–3.34(m,2H),3.17–3.08(m,2H),2.96–2.80(m,2H),1.90–1.30(m ,2H),1.22(t,J=7.2Hz,3H),1.08(t,J=7.2Hz,2H),0.68(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd For C 20 H 25 O3N4F2[M+H] + ,407.1889;Found407.1888.

[0217] Embodiment 4:

[0218] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-chloropyrimidine-2,4(1H,3H)-dione (Compound 4)

[0219]

[0220] Intermediate 7d (120 mg, 0.4 mmol), intermediate 10a (240 mg, 0.45 mmol), EDCI (153 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol) and DIEA (0.5 mL, 2 mmol) were dissolved in anhydrous DMF (10 mL). The reaction was stirred at room temperature under argon protection. The reaction was stopped after TLC showed the disappearance of the starting material. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to give a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) to give 150 mg of a white solid with a yield of 89.3%.

[0221] 1 H NMR(400MHz, Methanol-d4)δ(ppm):8.06(s,1H),7.61-7.48(m,1H),7.42–7.40(m,1H),7.25–7. 19(m,1H),4.93(s,2H),3.98(d,J=12.0Hz,1H),3.49(brs,1H),3.40–3.37(m,1H),3.12–3.06(m ,0.5H),2.91(brs,0.5H),2.83–2.73(m,2H),2.56–2.45(m,2H),2.40-2.30(m,1H),1.79-1.20( m,2H),1.06(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,2H),0.61(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd For C 20 H 25 O3N4ClF[M+H] + ,423.1594;Found 423.1602.

[0222] Embodiment 5:

[0223] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethyl-6-methylpyrimidine-2,4(1H,3H)-dione

[0224]

[0225] (1) Synthesis of 5-ethyl-6-methyluracil (Intermediate 25)

[0226]

[0227] Take urea (390 mg, 6.5 mmol), add ether solution of boron trifluoride (0.757 mL, 6 mmol), add ethyl 2-ethylacetoacetate (750 mg, 5 mmol), microwave at 145 ° C, react for 15 min, add a mixture of DCM and methanol, mix the sample and perform column chromatography (SiO2, MeOH / DCM, MeOH = 4%) to obtain 250 mg of light yellow solid with a yield of 32.46%.

[0228] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.89 (s, 1H), 10.58 (s, 1H), 2.21 (q, J = 7.6Hz, 2H), 2.04 (s, 3H), 0.91 (t, J = 7.6Hz, 3H).

[0229] (2) Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethyl-6-methylpyrimidine-2,4(1H,3H)-dione (Compound 5)

[0230]

[0231] Intermediate 7e (121 mg, 0.395 mmol) was dissolved in anhydrous DMF (4 mL) with EDCI (156 mg, 0.81 mmol), HOBt (135 mg, 0.82 mmol) and DIEA (440 μL, 2.4 mmol). After stirring at room temperature for 10 min, intermediate 10a (217 mg, 0.41 mmol) was added and the reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the raw material had reacted completely. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) to obtain 100 mg of a light yellow solid with a yield of 58.8%.

[0232] 1H NMR(400MHz,Chloroform-d)δ(ppm):7.25–7.20(m,2H),7.12–7.06(m,1H),5.10(s,2H),4.16(brs,1H),3.38(brs,2H),2.93–2.75(m,2H),2.50 (brs,2H),2.43(q,J=7.2Hz,2H),2.18(s,3H),1.67–1.53(m,2H),1.09-1.00(m,6H),0.90–0.86(m,2H),0.72–0.66(m,1H); HRMS(ESI)m / z:calcd For C 23 H 32 O3N4F[M+H] + ,431.2453;Found 431.2459.

[0233] Embodiment 6:

[0234] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (Compound 6)

[0235]

[0236] Intermediate 7f (105 mg, 0.43 mmol) was dissolved in anhydrous DMF (4 mL) with EDCI (157 mg, 0.82 mmol), HOBt (111 mg, 0.82 mmol) and DIEA (440 μL, 2.4 mmol). After stirring at room temperature for 10 min, intermediate 10a (227 mg, 0.5 mmol) was added and the reaction was continued under stirring at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 51 mg of a white solid with a yield of 26.0%.

[0237] 1H NMR (400MHz, Chloroform-d) δ (ppm): 7.70 (dd, J1=4.4Hz, J2=1.2Hz, 1H), 7.44–7.34 (m, 2H), 7.16–7.11 (m, 1H), 4.93 (s, 2H), 4.13 (brs, 1H), 3.50–3.09 (m ,3H),2.90–2.75(m,2H),2.61–2.31(m,3H),1.71–1.51(m,2H),1.06(t,J=7. 2Hz,3H),1.00(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 21 H 25 O3N4F4[M+H] + ,457.1857;Found 457.1861.

[0238] Embodiment 7:

[0239] Synthesis of (R)-5-bromo-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 7)

[0240]

[0241] Intermediate 7g (137 mg, 0.4 mmol), EDCI (155 mg, 0.81 mmol), HOBt (114 mg, 0.84 mmol) and DIEA (440 μL, 2.4 mmol) were dissolved in anhydrous DMF (4 mL). After stirring at room temperature for 10 min, intermediate 10a (226 mg, 0.5 mmol) was added and the reaction was stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 70 mg of a white solid with a yield of 37.5%.

[0242] 1H NMR(400MHz,Chloroform-d)δ(ppm):7.53(d,J=5.2Hz,1H),7.39–7.35(m,2H) ,7.16–7.09(m,1H),4.89(s,2H),4.13(brs,1H),3.45–3.30(m,2.5H),3.10(br s,0.5H),2.91–2.74(m,2H),2.58–2.33(m,3H),1.72–1.47(m,2H),1.06(t,J= 7.2Hz,3H),1.00(t,J=7.6Hz,2H),0.68(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 20 H 25 O3N4BrF[M+H] + ,467.1089;Found 467.1101.

[0243] Embodiment 8:

[0244] Synthesis of (R)-5-bromo-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 8)

[0245]

[0246] Intermediate 7h (124 mg, 0.4 mmol), EDCI (154 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol), and DIEA (0.6 mL, 3.2 mmol) were dissolved in anhydrous DMF (5 mL). After stirring at room temperature for 10 min, intermediate 10a (334 mg, 0.5 mmol) was added and stirring at room temperature was continued. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 82 mg of a light yellow solid with a yield of 47.7%.

[0247] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.58 (s, 1H), 7.35-7.32 (m, 2H), 7.11 (td, J1=9.2Hz, J2=4.0Hz, 1H), 6.93(d,J=3.6Hz,1H),4.87(s,2H),4.13(brs,1H),3.50–3.27(m,2.5H),3.09(s,0.5H),2.91-2.76(m,2H) ,2.58–2.32(s,3H),2.26(t,J=7.2Hz,2H),1.68(brs,1H),1.50(sex,J=7.2Hz,2H),1.34(brs,1H),1.07( d,J=7.2Hz,3H),1.00(t,J=7.6Hz,2H),0.91(t,J=7.2Hz,3H),0.68(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd ForC 23 H 32 O3N4F[M+H] + ,431.2453;Found431.2457.

[0248] Embodiment 9:

[0249] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione

[0250]

[0251] (1) Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine-2,4(1H,3H)-dione (Intermediate 26)

[0252]

[0253] Take 5-(Hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (734 mg, 5.17 mmol), add it to DMF (10 mL), add imidazole (523 mg, 7.7 mmol) under ice bath and stir for 10 min, then add TBDMSCl (1.195 g, 7.93 mmol), warm to room temperature and stir to react, solid precipitates, add water (10 mL) after the reaction, filter, wash the filter cake with DCM (3 mL) and water (5 mL), respectively, and dry to obtain 1.251 g of white solid, yield 94.8%.

[0254] 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.12 (s, 1H), 10.73 (d, J = 5.6Hz, 1H), 7.24 (d, J = 5.6Hz, 1H), 4.30 (s, 2H), 0.87 (s, 9H), 0.06 (s, 6H).

[0255] (2) Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (Compound 9)

[0256]

[0257] Intermediate 7i (112 mg, 0.38 mmol), EDCI (133 mg, 0.69 mmol), HOBt (133 mg, 0.69 mmol), and DIEA (0.35 mL, 2 mmol) were dissolved in anhydrous DMF (2.5 mL). After stirring at room temperature for 10 min, intermediate 10a (327 mg, 0.5 mmol) was added and the reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH (2% ammonia water) / DCM, MeOH=11%) and slurried with n-hexane to obtain 139 mg of a light yellow solid with a yield of 87.4%.

[0258] 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.18(s,1H),7.67(s,1H),7.51–7.43(m,1H) ),7.49–7.41(m,1H),7.31(t,J=9.2Hz,1H),5.02(s,1H),4.98(s,2H),4.13 (d,J=4.4Hz,2H),3.84(brs,1H),3.17–2.63(m,8H),1.72–1.63(m,2H),1.0 4(s,3H),0.93(t,J=7.2Hz,2H),0.54(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd For C 21 H 28 O4N4F[M+H] + ,419.2089;Found419.2084.

[0259] Embodiment 10:

[0260] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-(fluoromethyl)pyrimidine-2,4(1H,3H)-dione (Compound 10)

[0261]

[0262] Compound 9 (102 mg, 0.24 mmol) was added to DCM (5 mL). The compound was almost insoluble. Under argon protection, a DCM (1 mL) solution of DAST (63 μL, 0.48 mmol) was added dropwise in an ice bath.

[0263] After the addition was completed, the reaction was stirred in an ice bath. After 6 h, no obvious reaction was observed. A solution of DAST (63 μL, 0.48 mmol) in DCM (1 mL) was added and the reaction was continued to be stirred at room temperature. The reaction was stopped after 4 h. The reaction was quenched with water (5 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=9%) to obtain 10 mg of a white solid with a yield of 10%.

[0264] 1 H NMR(400MHz,Chloroform-d)δ(ppm):9.14(brs,1H),7.39–7.34(m,3H),7.12(td,J 1=9.2Hz,J2=4.4Hz,1H),5.13(d,J=47.6Hz,2H),4.91(s,2H),3.55–3.27(m,3H),3 .10(brs,0.5H),2.94–2.74(m,2.5H),2.58–2.29(m,3H),1.75–1.48(m,2H),1.06( t,J=7.2Hz,3H),1.00(t,J=7.6Hz,2H),0.68(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd ForC 21 H 27 O3N4F2[M+H] + ,421.2046;Found 421.2148.

[0265] Embodiment 11:

[0266] Synthesis of (R)-6-Chloro-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione

[0267]

[0268] (1) Synthesis of 5-ethylpyrimidine-2,4,6(1H,3H,5H)-trione (Intermediate 27)

[0269]

[0270] Sodium metal (215 mg, 9.35 mmol) was added to ultra-dry methanol (4 mL), and stirred at room temperature until the sodium metal was completely dissolved to obtain a methanol solution of sodium methoxide. Then 2 mL of the methanol solution of sodium methoxide was taken, and diethyl ethylmalonate (540 mg, 3 mmol) was added dropwise at room temperature, and the temperature was raised to reflux reaction for 30 min, cooled to room temperature, urea (180 mg, 3 mmol) was added, and the temperature was continued to be raised to reflux reaction for 3 h, concentrated to dryness, diluted with water (5 mL), and then adjusted to pH = 2 with concentrated hydrochloric acid, and placed in a refrigerator for overnight. The next day, filtered, the filter cake was washed with cold water, and vacuum dried to obtain 156 mg of an off-white solid, with a yield of 34.7%.

[0271] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.22 (s, 2H), 3.52 (t, J = 7.2Hz, 1H), 1.93 (quint, J = 7.6Hz, 2H), 0.83 (t, J = 7.2Hz, 3H).

[0272] (2) Synthesis of 2,4,6-trichloro-5-ethylpyrimidine (Intermediate 28)

[0273]

[0274] The intermediate 27 (2.1 g, 13.4 mol) was added in batches to a mixture of phosphorus oxychloride (5 mL, 53.6 mmol) and N,N-dimethylaniline (2.5 mL, 19.7 mmol), and stirred at room temperature for 10 minutes. The reaction solution was then heated to 110°C and refluxed with stirring to react. The reaction was stopped after 6 hours. After the reaction solution was cooled to room temperature, it was poured into crushed ice, stirred, filtered, and the filter cake was washed with ether to obtain 2.148 g of a white waxy solid with a yield of 76.7%.

[0275] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 2.80 (q, J = 7.6Hz, 2H), 1.14 (t, J = 7.6Hz, 3H).

[0276] (3) Synthesis of 6-chloro-5-ethylpyrimidine-2,4(1H,3H)-dione (Intermediate 29)

[0277]

[0278] Intermediate 28 (2.02 g, 9.55 mmol) was added to 15% aqueous sodium hydroxide solution (13 mL), and the temperature was raised to reflux for reaction. The reaction was stopped after 6 h, and the reaction solution was cooled to room temperature. The reaction solution was acidified to pH = 1 with concentrated hydrochloric acid under ice bath. Solid precipitated, filtered, and the filter cake was washed with cold water to obtain 1.079 g of off-white solid, with a yield of 64.7%.

[0279] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.82 (s, 1H), 11.31 (s, 1H), 2.31 (q, J = 7.2Hz, 2H), 0.96 (t, J = 7.2Hz, 3H).

[0280] (4) Synthesis of (R)-6-chloro-1-(3-(3,4-diethylpiperazine-1-carboxylate)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Compound 11)

[0281]

[0282] Intermediate 7j (145 mg, 0.44 mmol), EDCI (177 mg, 0.92 mmol), HOBt (127 mg, 0.94 mmol), DIEA (0.5 mL, 2.87 mmol) were dissolved in a mixture of anhydrous DMF (2 mL) and anhydrous DCM (3 mL), stirred at room temperature for 10 min, and then intermediate 10a (141 mg, 0.55 mmol) was added, and stirring at room temperature was continued. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl solution (10 mL), dried, filtered, and concentrated over anhydrous MgSO4 to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=6%) and slurried with n-hexane to obtain 131 mg of an off-white solid with a yield of 66.2%.

[0283] 1H NMR(400MHz,Chloroform-d)δ(ppm):8.95(brs,1H),7.41–7.36(m,2H),7.08(td,J1=9.2Hz,J2=4.0Hz,1H),5.24(s,2H),4.14(brs,1H),3.56–3.04(m ,3H),2.93–2.71(m,2H),2.59–2.21(m,5H),1.73–1.45(m,2H),1.14–1.02 (m,6H),0.99(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 22 H 29 O3N4ClF[M+H] + ,451.1907;Found451.1921.

[0284] Embodiment 12:

[0285] Synthesis of (R)-5-cyclopropyl-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 12)

[0286]

[0287] Intermediate 7k (124 mg, 0.4 mmol), EDCI (154 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol), DIEA (0.6 mL, 3.2 mmol) were dissolved in a mixture of anhydrous DMF (1 mL) and anhydrous DCM (3 mL), stirred at room temperature for 10 min, and then intermediate 10a (334 mg, 0.5 mmol) was added, and the reaction was continued to stir at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined. The organic phase was washed with saturated NaCl (10 mL), dried, filtered, and concentrated over anhydrous MgSO4 to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 81 mg of a yellow solid with a yield of 36.7%.

[0288] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.61 (s, 1H), 7.34–7.27 (m, 2H), 7.08 (td, J1=9.2Hz, J2=4.4Hz, 1H ),6.79(dd,J1=3.2Hz,J2=1.2Hz,1H),4.82(s,2H),4.14(brs,1H),3.47–3.26(m,2.5H),3.11(brs,0.5H ),2.90–2.85(m,0.5H),2.78(brs,1.5H),2.53–2.29(m,3H),1.68–1.49(m,2H),1.05(t,J=7.2Hz,3H),0 .99(t,J=7.6Hz,2H),0.85–0.79(m,2H),0.66(t,J=7.6Hz,1H),0.51–0.45(m,2H); HRMS(ESI)m / z:calcd For C 23 H 30 O3N4F[M+H] + ,429.2297;Found 429.2303.

[0289] Embodiment 13:

[0290] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-(1-propen-2-yl)pyrimidine-2,4(1H,3H)-dione (Compound 13)

[0291]

[0292] Intermediate 71 (120 mg, 0.39 mmol), EDCI (154 mg, 0.80 mmol), HOBt (111 mg, 0.8 mmol), DIEA (0.42 mL, 2.4 mmol) were dissolved in anhydrous DCM (4 mL), stirred at room temperature for 10 min, and then intermediate 10a (349 mg, 0.51 mmol) was added, and the reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared, and the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 50 mg of a yellow solid with a yield of 29.6%.

[0293] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.48 (s, 1H), 7.37–7.34 (m, 2H), 7.15 (d, J = 2.8Hz, 1H), 7 .11(dd,J1=9.2Hz,J2=4.0Hz,1H),5.69-5.67(m,1H),5.16–5.12(m,1H),4.90(s,2H),4.13(b rs,1H),3.55–3.02(m,3H),2.97–2.73(m,2H),2.59–2.25(m,3H),1.97(s,3H),1.73–1.48(m, 2H),1.07(t,J=7.2Hz,3H),1.00(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 23 H 30 O3N4F[M+H] + ,429.2297;Found 429.2305.

[0294] Embodiment 14:

[0295] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione

[0296]

[0297] (1) Synthesis of 2,4-dimethoxy-5-(prop-1-en-2-yl)pyrimidine (Intermediate 30)

[0298]

[0299] Intermediate 4b (154 mg, 0.85 mmol) was dissolved in ethanol (4 mL), and platinum dioxide (44 mg, 0.19 mmol) was added. The mixture was stirred at room temperature under hydrogen. After the reaction was completed, the mixture was filtered and concentrated to obtain 155 mg of a yellow oil with a yield of 99.4%.

[0300] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.04 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.01 (sepd, J1 = 6.8Hz, J2 = 0.8Hz, 1H), 1.22 (d, J = 6.8Hz, 6H).

[0301] (2) Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione (Compound 14)

[0302]

[0303] The intermediate 7m (121 mg, 0.40 mmol), EDCI (161 mg, 0.84 mmol), HOBt (110 mg, 0.81 mmol), DIEA (0.42 mL, 2.41 mmol) were dissolved in anhydrous DCM (4 mL), stirred at room temperature for 10 min, and then the intermediate 10a (336 mg, 0.49 mmol) was added, and the reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 48 mg of a yellow solid with a yield of 28.2%.

[0304] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.24 (s, 1H), 7.36–7.32 (m, 2H), 7.11 (td, J1 = 8.8Hz, J2=3.2Hz,1H),6.88(dd,J1=2.4Hz,J2=1.2Hz,1H),4.87(s,2H),4.28–4.05(m,1H),3.60– 3.03(m,3H),2.99–2.72(m,3H),2.65–2.22(m,3H),1.78–1.60(m,2H),1.13(d,J=6.8Hz,6 H),1.12–1.05(m,3H),1.02(t,J=7.2Hz,2H),0.68(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd For C 23 H 32 O3N4F[M+H] + ,431.2453;Found 431.2460.

[0305] Embodiment 15:

[0306] Synthesis of Ethyl (R)-2-(1-ethyl-4-(5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazin-2-yl)acetate

[0307]

[0308] (1) Synthesis of (R)-1-(3-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-ethylpiperazine-1-carboxyl)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Intermediate 24)

[0309]

[0310] Intermediate 7a (199 mg, 0.67 mmol), EDCI (259 mg, 1.35 mmol), HOBt (180 mg, 1.33 mmol), DIEA (0.35 mL, 2.01 mmol) were dissolved in anhydrous DCM (5 mL), stirred at room temperature for 10 min, and then intermediate 23 (217 mg, 0.80 mmol) was added, and stirring at room temperature was continued. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl solution (10 mL), dried, filtered, and concentrated over anhydrous MgSO4 to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=11%) to give 351 mg of a yellow oil with a yield of 95.4%.

[0311] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.47–8.43 (m, 1H), 7.38–7.31 (m, 2H), 7.10 (t, J = 8.8Hz, 1H), 6.92–6. 90(m,1H),4.86(s,2H),4.06(brs,0.5H),3.83–3.68(m,2H),3.62–3.47(m,1.5H),3.36(brs,1.5H),3.14(b rs,0.5H),2.91–2.69(m,2.5H),2.52(brs,2.5H),2.34(qt,J1=7.6Hz,J2=1.6Hz,2H),1.88–1.57(m,2H),1. 22–1.05(m,6H),0.91(s,5H),0.79(s,4H),0.08(s,1.5H),0.08(s,1.5H),-0.08(s,1.5H),-0.09(s,1.5H).

[0312] (2) Synthesis of (R)-5-ethyl-1-(3-(4-ethyl-3-(2-hydroxyethyl)piperazine-1-carboxyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 15)

[0313]

[0314] Intermediate 24 (32 mg, 0.06 mmol) was dissolved in THF (0.25 mL), and then water (0.25 mL) and glacial acetic acid (0.25 mL, 4.37 mmol) were added. The mixture was stirred at room temperature. After 2 h, TLC showed that the raw material had not reacted completely. Glacial acetic acid (1 mL) and a catalytic amount of 2N dilute hydrochloric acid were added. After 5 h, the reaction was complete. The mixture was concentrated and slurried with n-hexane to obtain 29 mg of a white solid with a yield of 100%.

[0315] 1 H NMR(400MHz, Methanol-d4)δ(ppm):7.52–7.47(m,1H),7.46(s,1H),7.44-7.37(m,1H),7.21(t,J=9.2Hz,1H),4.88(s,2H),3.88-3.27(m,9H),3.24-3. 05(m,2H),2.27(qd,J1=7.6Hz,J2=1.2Hz,2H),2.13–1.97(m,1H),1.91–1.6 6(m,1H),1.33(t,J=7.2Hz,3H),1.06(t,J=7.2Hz,3H); HRMS(ESI)m / z:calcd For C 22 H 30 O4N4F[M+H] + ,433.2246;Found433.2249.

[0316] Embodiment 16:

[0317] Synthesis of (R)-6-chloro-5-ethyl-1-(3-(4-ethyl-3-(2-hydroxyethyl)piperazine-1-carboxylic acid)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 16)

[0318]

[0319] Intermediate 7j (49 mg, 0.15 mmol), EDCI (43 mg, 0.22 mmol), HOBt (31 mg, 0.23 mmol) and DIEA (78 μl, 0.45 mmol) were dissolved in anhydrous DCM (2.5 μl). The mixture was stirred at room temperature for 10 min, and then (R)-2-(1-ethylpiperazine-2-yl)ethanol trifluoroacetate (28 mg, 0.18 mmol) was added. The reaction was continued to be stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. After concentration, the crude product was obtained and purified by column chromatography (SiO2, MeOH (5% AcOH) / DCM, MeOH (5% AcOH) = 10%). The mixture was recrystallized from EA to obtain 10 mg of a white solid with a yield of 14.3%.

[0320] 1 H NMR (500MHz, Chloroform-d) δ (ppm): 7.42–7.36 (m, 2H), 7.10 (t, J = 7.6Hz, 1H), 5. 24(s,2H),4.08–3.88(m,1H),3.88–3.61(m,2H),3.53(brs,1H),3.47–3.27(m,1H) ,3.15–2.98(m,2H),2.90–2.98(m,2H),2.53(t,J=6.4Hz,2H),2.03–1.86(m,2H), 1.85–1.64(m,2H),1.17(t,J=6.4Hz,3H),1.10–1.06(m,3H); HRMS(ESI)m / z:calcd For C 22 H 29 O4N4ClF[M+H] + ,467.1856;Found 467.1844.

[0321] Embodiment 17:

[0322] Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione

[0323]

[0324] (1) Synthesis of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid benzyl ester (Intermediate 31)

[0325]

[0326] Take intermediate 13 (1.143 g, 2.77 mmol), add DCM (15 mL), add imidazole (282 mg, 3.15 mmol) under ice bath and stir for 10 min, add TBDMSCl (626 mg, 4.15 mmol), warm to room temperature and stir to react. After the reaction is completed, filter, add DCM (20 mL) to the filtrate, wash with water (10 mL×2), and dry over anhydrous magnesium sulfate to obtain a crude product, which is purified by column chromatography (SiO2, MeOH / DCM, MeOH=8%) to obtain 555 mg of a yellow oil with a yield of 55.5%.

[0327] 1 H NMR(500MHz,Chloroform-d)δ(ppm):7.39-7.30(m,5H),5.14(s,2H),4.05(brs,2H),3.66(s,1H), 3.56(dd,J1=13.2,J2=5.2Hz,1H),3.12–3.02(m,2H),2.90-2.78(m,3H),0.88(s,9H),0.06(s,6H).

[0328] (2) Synthesis of (R)-1-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Intermediate 32)

[0329]

[0330] Intermediate 7a (304 mg, 1.03 mmol), EDCI (336 mg, 1.75 mmol), HOBt (232 mg, 1.72 mmol), and DIEA (0.45 mL, 2.58 mmol) were dissolved in a mixture of anhydrous DMF (0.5 mL) and anhydrous DCM (4.5 mL). After stirring at room temperature for 10 min, intermediate 15 (224 mg, 0.87 mmol) was added. The reaction was stopped after stirring at room temperature for 6 h, and the mixture was concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=3-5%) to obtain 273 mg of a light yellow oil with a yield of 59.2%.

[0331] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.46 (s, 0.4H), 8.41 (s, 0.6H), 7.36-7.32 (m, 2H), 7.07 (q, J=8.8Hz, 1H ),6.89(dt,J1=8.0Hz,J2=1.6Hz,1H),4.80(s,2H),4.38(d,J=10.6Hz,1H),3.84–3.80(m,1H),3.69–3.62(m, 1H),3.41–3.29(m,2H),3.06–2.84(m,2H),2.78–2.66(m,2H),2.54–2.39(m,2H),2.35–2.28(m,2H),1.62(br s,2H),1.12–1.02(m,6H),0.92(s,3H),0.68(s,6H),0.09(s,,1H),0.08(s,1H),-0.06(s,2H),-0.09(s,2H).

[0332] (3) Synthesis of (R)-1-(3-(3,4-diethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione (Compound 17)

[0333]

[0334] The intermediate 32 (87 mg, 0.16 mmol) was dissolved in THF (1 mL), and TBAF (0.32 mL, 0.32 mmol) was added. The reaction was stirred at room temperature for 6 h and then stopped. The crude product was concentrated and purified by column chromatography (SiO2, MeOH / DCM, MeOH=8%). The product was slurried with n-hexane to obtain 44 mg of a light yellow solid with a yield of 65.7%. 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.91 (s, 1H), 7.37–7.32 (m, 2H), 7.11 (t, J = 7.6Hz ,,1H),6.96(d,J=10.8Hz,1H),4.90–4.80(m,2H),4.17–3.99(m,1H),3.93–3.68(m,1H ),3.63(dd,J1=11.6Hz,J2=3.2Hz,1H),3.52–3.27(m,3H),3.05–2.83(m,2H),2.71(br s,1H),2.67–2.40(m,3H),2.39–2.29(m,2H),1.13–1.09(m,6H); HRMS(ESI)m / z:calcd For C 21 H 28O4N4F[M+H] + ,419.2089;Found419.2093.

[0335] Embodiment 18:

[0336] Synthesis of (S)-5-ethyl-1-(3-(4-ethyl-3-(hydroxymethyl)piperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 18)

[0337]

[0338] Intermediate 7a (43 mg, 0.15 mmol), EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol), and DIEA (0.15 mL, 0.87 mmol) were dissolved in anhydrous DCM (1 mL). After stirring at room temperature for 10 min, intermediate 10b (98 mg, 0.17 mmol) was added and the reaction was continued to be stirred at room temperature. The reaction was stopped after 8 h and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=10%) and slurried with n-hexane to obtain 56 mg of a white solid with a yield of 91.8%.

[0339] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 7.34 (ddd, J1=10.8Hz, J2=5.2Hz, J3=2.0Hz, 2H), 7.14–7.08 (m,1H),6.96(d,J=10.6Hz,1H),4.90–4.80(m,2H),4.17–3.99(m,1H),3.93–3.68(m,1H),3.63(dd ,J1=11.6Hz, J2=3.2Hz,1H),3.52–3.27(m,3H),3.05–2.83(m,2H),2.71(s,1H),2.67–2.39(m,3H) ),2.39–2.29(m,2H),1.25–1.15(m,3H),1.11(td,J1=7.6Hz,J2=2.4Hz,3H); HRMS(ESI)m / z:calcd For C 21 H 28 O4N4F[M+H] + ,419.2089;Found419.2089.

[0340] Embodiment 19:

[0341] Synthesis of (R)-1-(3-(4-cyclopropyl-3-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Compound 19)

[0342]

[0343] Intermediate 7a (99 mg, 0.34 mmol), EDCI (134 mg, 0.7 mmol), HOBt (91 mg, 0.67 mmol), and DIEA (300 μL, 1.7 mmol) were dissolved in anhydrous DMF (6 mL). After stirring at room temperature for 10 min, intermediate 10c (149 mg, 0.34 mmol) was added and the reaction was continued to be stirred at room temperature. The reaction was stopped after 6 h and quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined and washed with saturated NaCl solution (10 mL). The crude product was dried, filtered, and concentrated over anhydrous MgSO4 to obtain the crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=3%) and slurried with n-hexane to obtain 117 mg of a white solid with a yield of 80.4%.

[0344] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.68 (s, 1H), 7.36–7.31 (m, 2H), 7.11 (td, J1=8.8Hz, J2=4.4Hz, 1H), 6.94-6.92(m,1H),4.87(s,2H),4.18(brs,1H),3.43–3.26(m,2H),3.05-2.87(m,2H),2.45(brs,2H),2.3 4(qt,J1=7.6Hz,J2=1.6Hz,2H),2.07–1.92(m,1H),1.71-1.44(m,2H),1.10(td,J1=7.6Hz,J2=1.6Hz,3H) ,1.01(t,J=7.6Hz,2H),0.89–0.82(m,1H),0.66(t,J=7.6Hz,2H),0.63–0.34(m,3H); HRMS(ESI)m / z:calcd ForC 23 H 30 O3N4F[M+H] + ,429.2297;Found429.2304.

[0345] Embodiment 20:

[0346] Synthesis of (R)-1-(3-(4-(cyclopropylmethyl)-3-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Compound 20)

[0347]

[0348] Intermediate 7a (97 mg, 0.33 mmol), EDCI (139 mg, 0.73 mmol), HOBt (91 mg, 0.67 mmol), and DIEA (300 μL, 1.7 mmol) were dissolved in anhydrous DMF (5 mL). After stirring for 10 min, intermediate 10d (200 mg, 0.37 mmol) was added and stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 125 mg of a white solid with a yield of 85.6%. 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.69–8.67 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (td, J1=8.8Hz, J2=2.8Hz, 1H ),6.93-6.91(m,1H),4.87(s,2H),4.15(brs,1H),3.52–3.30(m,2H),3.13-2.93(m,2H),2.65-2.42(m,3H),2 .34(qdd,J1=7.2Hz,J2=2.0Hz,J3=0.8Hz,2H),2.29-2.24(m,1H),1.67-1.51(m,2H),1.10(td,J1=7.6Hz,J2= 1.6Hz,3H),1.00(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H),0.54(brs,2H),0.12(brs,2H); HRMS(ESI)m / z:calcd For C 24 H 32 O3N4F[M+H] + ,443.2453;Found 443.2460.

[0349] Embodiment 21:

[0350] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 21)

[0351]

[0352] Intermediate 7a (99 mg, 0.34 mmol), EDCI (131 mg, 0.68 mmol), HOBt (92 mg, 0.68 mmol), and DIEA (300 μL, 1.7 mmol) were dissolved in anhydrous DMF (5 mL). After stirring for 10 min, intermediate 10e (157 mg, 0.34 mmol) was added and stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 104 mg of a light yellow solid with a yield of 65.4%.

[0353] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.63 (s, 1H), 7.36–7.32 (m, 2H), 7.11 (td, J1=7.6Hz, J1= 3.6Hz,1H),6.93–6.91(m,1H),4.87(s,2H),3.94(brs,1H),3.69–3.42(m,1H),3.33(brs,1H), 3.24–2.99(m,3H),2.98–2.71(m,1H),2.69–2.48(m,2H),2.34(q,J=7.2Hz,2H),1.70–1.36(m, 2H),1.10(t,J=7.2Hz,3H),1.01(t,J=7.2Hz,2H),0.67(t,J=7.2Hz,1H); HRMS(ESI)m / z:calcd For C 22 H 27 O3N4F4[M+H] + ,471.2014;Found 471.2020.

[0354] Embodiment 22:

[0355] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-isopropylpiperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione

[0356]

[0357] (1) Synthesis of isopropyl 4-nitrobenzenesulfonate (Intermediate 33)

[0358]

[0359] Under ice bath, isopropanol (314 μL, 4.1 mmol), p-nitrobenzenesulfonyl chloride (1.443 g, 6.47 mmol), DMAP (1.047 g, 8.57 mmol) and pyridine (950 μL, 11.7 mmol) were added to DCM (21 mL) and stirred for reaction. After 1 h, the temperature was raised to room temperature and the reaction was continued with stirring. After 2 h of reaction, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, EA / PE, EA=8%) to obtain 81 mg of a green oil with a yield of 41.3%.

[0360] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.46 (d, J=9.2Hz, 1H), 8.25–8.14 (m, 2H), 7.84 (d ,J=8.8Hz,1H),4.86–4.70(m,1H),1.35(d,J=6.4Hz,3H),1.24(d,J=6.4Hz,3H).

[0361] (2) Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-isopropylpiperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 22)

[0362]

[0363] Intermediate 7a (97 mg, 0.34 mmol), EDCI (134 mg, 0.68 mmol), HOBt (92 mg, 0.68 mmol), and DIEA (360 μL, 2 mmol) were dissolved in anhydrous DMF (5 mL). After stirring for 10 min, intermediate 10f (212 mg, 0.35 mmol) was added and stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 77 mg of a light yellow solid with a yield of 52.7%. 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.59 (s, 1H), 7.36–7.32 (m, 2H), 7.10 (td, J1=8.8 Hz,J2=4.4Hz,1H),6.97–6.88(m,1H),4.87(s,2H),4.18(brs,1H),3.39–3.00(m,4H), 2.83–2.44(m,2H),2.36–2.28(m,3H),1.68–1.40(m,2H),1.10(td,J1=7.6,J2=1.6Hz, 6H),0.99(t,J=7.6Hz,2H),0.92(brs,3H),0.68(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 23 H 32 O3N4F[M+H] + ,431.2453;Found431.2459.

[0364] Embodiment 23:

[0365] Synthesis of (R)-4-(2-ethyl-4-(5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazin-1-yl)-N-methylbenzamide

[0366]

[0367] (1) Synthesis of tert-butyl (R)-3-ethyl-4-(4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (Intermediate 34)

[0368]

[0369] (R)-1-Boc-2-ethylpiperazine (43 mg, 0.22 mmol), N-methyl-4-bromobenzamide (54 mg, 0.25 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Ruphos (11 mg, 0.02 mmol) and tBuONa (59 mg, 0.61 mmol) were dissolved in 1,4-dioxane at room temperature. The mixture was protected by argon and heated to 120°C with stirring under reflux. The reaction was stopped after 8 h and quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, EA / DCM, MeOH=36%) to obtain 22 mg of a light yellow oil with a yield of 28.0%.

[0370] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.70(d,J=8.8Hz,2H),6.79(d,J=8.4Hz,2H),6.31(s,1H),4.17–4.10(m,2H),3.68(brs, 1H),3.40(d,J=11.6Hz,1H),3.16–3.09(m,3H),2.97(d,J=4.8Hz,3H),1.72-1.57(m,2H),1.48(s,9H),0.92(t,J=7.6Hz,3H).

[0371] (2) Synthesis of (R)-4-(2-ethyl-4-(5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazin-1-yl)-N-methylbenzamide (Compound 23)

[0372]

[0373] Intermediate 7a (164 mg, 0.55 mmol), EDCI (212 mg, 1.1 mmol), HOBt (149 mg, 1.1 mmol), and DIEA (800 μL, 4.4 mmol) were dissolved in anhydrous DMF (4 mL). After stirring for 10 min, intermediate 10 g (452 ​​mg, 0.6 mmol) was added and stirred at room temperature. The reaction was stopped after TLC showed that the starting material disappeared. The reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 195 mg of a light yellow solid with a yield of 68.0%.

[0374] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.82 (s, 0.6H), 8.77 (s, 0.4H), 7.69 (d, J = 8.4Hz, 2H), 7.40-7.35 (m, 2H), 7.14 (td, J 1=8.8Hz,J2=2.0Hz,1H),6.94(dt,J1=9.6Hz,J2=1.2Hz,1H),6.82(s,2H),6.09(s,1H),4.90–4.85(m,2H),4.73–4.59(m, 1H),3.88(s,0.5H),3.63–3.51(m,2H),3.41–3.19(m,3H),2.99(d,J=4.8Hz,3H),2.39–2.29(m,2H),1.72–1.65(m,1H),1 .53–1.45(m,1H),1.10(td,J1=7.6Hz,J2=4.4Hz,3H),0.97(t,J=7.6Hz,2H),0.57(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 28 H 33 O4N5F[M+H] + ,522.2511;Found 522.2516.

[0375] Embodiment 24:

[0376] Synthesis of (R)-5-(2-ethyl-4-(5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazin-1-yl)-N-methylpicolinamide

[0377]

[0378] (1) Synthesis of (R)-tert-butyl 3-ethyl-4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 35)

[0379]

[0380] Under argon protection at room temperature, (R)-1-Boc-2-ethylpiperazine (23 mg, 0.1 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (24 mg, 0.1 mmol), Pd2(dba)3 (3 mg, 0.0025 mmol), Ruphos (5 mg, 0.01 mmol) and Cs2CO3 (97 mg, 0.3 mmol) were dissolved in toluene (1.5 mL), sealed, heated to 130°C and refluxed with stirring for reaction. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 25 mg of a light yellow oil with a yield of 71.6%.

[0381] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.26 (d, J = 3.2Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.04 (dd, J1 = 8.8Hz, J2 = 3.2Hz, 1H),4.17–4.09(m,2H),3.93(s,3H),3.74(brs,1H),3.48(dt,J1=12.0Hz,J2=3.2Hz,1H),3.20-3.02(m,3H),1.67–

[0382] 1.58(m,2H),1.46(s,9H),0.93(t,J=7.6Hz,3H).

[0383] (2) Synthesis of (R)-tert-butyl 3-ethyl-4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 36)

[0384]

[0385] The intermediate 35 (25 mg, 0.07 mmol) and 6 M methylamine aqueous solution (2.4 mL, 2.2 mmol) were dissolved in methanol (1 mL) at room temperature, and the reaction was stirred at room temperature. The reaction was stopped after 8 h and quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) to obtain 12 mg of a light yellow oil with a yield of 48.2%.

[0386] 1H NMR(500MHz,Chloroform-d)δ(ppm):8.07(s,1H),8.04(d,J=9.0Hz,1H),7.77(brs,1H),7.13(dd,J1=9.0Hz,J2=3.0Hz,1H),4.19–4.03(m ,2H),3.70(brs,1H),3.44(d,J=11.5Hz,1H),3.20–3.11(m,3H),3.00(d,J=5.0Hz,3H),1.63(brs,2H),1.49(s,9H),0.95(t,J=7.5Hz,3H).

[0387] (3) Synthesis of (R)-5-(2-ethyl-4-(5-((5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazin-1-yl)-N-methylpicolinamide (Compound 24)

[0388]

[0389] Intermediate 7a (89 mg, 0.3 mmol), EDCI (99 mg, 0.5 mmol), HOBt (67 mg, 0.5 mmol), and DIEA (400 μL, 2 mmol) were dissolved in anhydrous DMF (3 mL). After stirring for 10 min, intermediate 10h (166 mg, 0.25 mmol) was added and stirred at room temperature. The reaction was stopped after 6 h and quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=6%) and slurried with n-hexane to obtain 43 mg of a light yellow solid with a yield of 34.4%. 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.55 (s, 0.6H), 8.52 (s, 0.4H), 8.13–8.05 (m, 2H), 7.86 (brs, 1H), 7. 41–7.37(m,2H),7.16(q,J=9.6Hz,2H),6.93(d,J=9.6Hz,1H),4.92–4.85(m,2H),3.92(brs,1H),3.68–3. 39(m,3H),3.39–3.16(m,3H),3.01(d,J=5.2Hz,3H),2.37–2.30(m,2H),1.77–1.69(m,1H),1.58–1.49(m, 1H),1.11(td,J1=7.6Hz,J2=4.4Hz,3H),1.00(t,J=7.6Hz,2H),0.60t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 27 H 32 O4N6F[M+H] + ,523.2464;Found523.2471.

[0390] Embodiment 25:

[0391] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-phenylpiperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione

[0392]

[0393] (1) Synthesis of (R)-tert-butyl 3-ethyl-4-phenylpiperazine-1-carboxylate (Intermediate 37)

[0394]

[0395] At room temperature, (R)-1-Boc-2-ethylpiperazine (28 mg, 0.13 mmol), bromobenzene (45 mg, 0.29 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Davephos (12 mg, 0.03 mmol) and Cs2CO3 (141 mg, 0.43 mmol) were dissolved in toluene (1 mL). Under argon protection, the tube was sealed and heated to 110°C with stirring for reaction. After the reaction, the reaction was quenched with saturated NH4Cl solution (10 mL), extracted with DCM (10 mL×3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=0%) and slurried with n-hexane to obtain 22 mg of a light yellow solid with a yield of 59.5%.

[0396] 1 H NMR(500MHz,Chloroform-d)δ(ppm):7.26–7.23(m,2H),6.89–6.78(m,3H),4.20–3.85(m,2H),3.52(b rs,1H),3.30–3.17(m,2H),3.13–3.04(m,2H),1.63–1.51(m,2H),1.48(s,9H),0.88(t,J=7.6Hz,3H).

[0397] (2) Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-phenylpiperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 25)

[0398]

[0399] Intermediate 7a (174 mg, 0.59 mmol), EDCI (226 mg, 1.18 mmol), HOBt (159 mg, 1.18 mmol), and DIEA (0.6 mL, 3.5 mmol) were dissolved in a mixture of anhydrous DMF (0.5 mL) and anhydrous DCM (5.5 mL). After stirring for 10 min, intermediate 10i (141 mg, 0.55 mmol) was added and stirred at room temperature. The reaction was stopped after 5 h, and the reaction was quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 120 mg of a light yellow solid with a yield of 43.8%.

[0400] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.51 (s, 1H), 7.39–7.35 (m, 2H), 7.28–7.22 (m, 2H), 7.14 (t, J= 8.8Hz,1H),6.93(d,J=9.6Hz,1H),6.86(t,J=7.6Hz,3H),4.92–4.85(m,2H),4.58(d,J=14.0Hz,1H), 3.71(brs,0.5H),3.60–3.28(m,4H),3.25-3.22(m,1.5H),2.34(quint,J=7.2Hz,2H),1.64–1.41(m, 2H),1.11(td,J1=7.6Hz,J2=4.8Hz,3H),0.96(t,J=7.6Hz,2H),0.53(brs,1H); HRMS(ESI)m / z:calcd For C 26 H 30 O3N4F[M+H] + ,465.2297;Found 465.2304.

[0401] Embodiment 26:

[0402] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-phenylpiperazine-1-carboxylate)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 26)

[0403]

[0404] Intermediate 7a (111 mg, 0.38 mmol), EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), and DIEA (0.4 mL, 2.30 mmol) were dissolved in a mixture of anhydrous DMF (0.5 mL) and anhydrous DCM (3.5 mL). After stirring for 10 min, intermediate 10j (72 mg, 0.45 mmol) was added and stirred at room temperature. The reaction was stopped after 6 h, and the reaction was quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=4%) and slurried with n-hexane to obtain 72 mg of a light yellow solid with a yield of 44.2%.

[0405] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.64 (s, 1H), 7.38–7.32 (m, 2H), 7.11 (td, J1=8.4Hz, J2=4.4Hz, 1H) ,6.94–6.92(m,1H),4.87(s,2H),4.56(d,J=47.6Hz,2H),4.06(s,1H),3.61–3.30(m,2.5H),3.16–2.97(m ,1.5H),2.83-2.65(m,1.5H),2.62-2.41(m,2.5H),2.34(qt,J1=7.6Hz,J2=1.6Hz,2H),1.71–1.48(m,2H ),1.10(td,J1=7.6Hz,J2=1.2Hz,3H),1.00(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd ForC 22 H 29 O3N4F2[M+H] + ,435.2202;Found435.2208.

[0406] Embodiment 27:

[0407] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-(3-fluoro-2-(fluoromethyl)propyl)piperazine-1-carboxyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 27)

[0408]

[0409] Intermediate 7a (137 mg, 0.46 mmol), EDCI (179 mg, 0.93 mmol), HOBt (131 mg, 0.97 mmol), and DIEA (0.48 mL, 2.76 mmol) were dissolved in anhydrous DMF (0.5 mL) and anhydrous DCM (3.5 mL). After stirring for 10 min, intermediate 10k (98 mg, 0.55 mmol) was added and stirred at room temperature. The reaction was stopped after 6 h, and the reaction was quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 90 mg of a light yellow solid with a yield of 42.9%.

[0410] 1H NMR (400MHz, Chloroform-d) δ (ppm): 8.69 (s, 1H), 7.38–7.32 (m, 2H), 7.11 (td, J1=9.2Hz, J2=3.6 Hz,1H),6.95–6.90(m,1H),5.85(t,J=57.2Hz,H),4.84(s,2H),3.95(brs,1H),3.74–3.23(m,2.5 H),3.18–2.97(m,1.5H),2.95-2.72(m,2H),2.72–2.40(m,2H),2.34(q,J=7.6Hz,2H),1.68–1.47 (m,2H),1.10(t,J=7.6Hz,3H),1.01(t,J=7.6Hz,2H),0.67(t,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 22 H 28 O3N4F3[M+H] + ,453.2108;Found453.2112.

[0411] Embodiment 28:

[0412] Synthesis of (R)-5-ethyl-1-(3-(3-ethyl-4-(thiazol-5-ylmethyl)piperazine-1-carboxyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 28)

[0413]

[0414] Intermediate 7a (116 mg, 0.39 mmol), EDCI (151 mg, 0.79 mmol), HOBt (131 mg, 0.97 mmol), and DIEA (105 mg, 0.78 mmol) were dissolved in a mixture of anhydrous DMF (1 mL) and anhydrous DCM (3.5 mL). After stirring for 10 min, intermediate 101 (98 mg, 0.46 mmol) was added and stirred at room temperature. The reaction was stopped after 8 h, and the reaction was quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (SiO2, MeOH / DCM, MeOH=5%) and slurried with n-hexane to obtain 94 mg of a light yellow solid with a yield of 63.3%.

[0415] 1H NMR(400MHz,Chloroform-d)δ(ppm):8.75(s,1H),8.59(s,1H),7.73(s,1H),7.38–7.29(m,2H ),7.10(q,J=8.8Hz,1H),6.92(s,1H),4.86(s,2H),4.08(brs,2H),3.81(brs,1H),3.56-3.08( m,3H),2.84–2.73(m,1H),2.55–2.38(m,2H),2.33(q,J=7.2Hz,2H),1.73(brs,1H),1.53(brs, 1H),1.10(t,J=7.6Hz,3H),1.03(t,J=7.6Hz,2H),0.72(d,J=7.6Hz,1H); HRMS(ESI)m / z:calcd For C 24 H 29 O3N5FS[M+H] + ,486.1970;Found 486.1975.

[0416] Embodiment 29:

[0417] Synthesis of (R)-1-(3-(4-((1H-imidazol-4-yl)methyl)-3-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)-5-ethylpyrimidine-2,4(1H,3H)-dione (Compound 29)

[0418]

[0419] Intermediate 7a (92 mg, 0.13 mmol), TCFH (177 mg, 0.63 mmol) and NMI (120 μL, 1.50 mmol) were dissolved in anhydrous MeCN (1 mL) and stirred for 15 min until the solution was clear. An acetonitrile solution (1 mL) of intermediate 10m (70 mg, 0.36 mmol) and NMI (40 μL, 0.50 mmol) were neutralized and added to the reaction solution. The reaction was stirred at room temperature. The reaction was stopped after 6 h, diluted with DCM, washed with water, and purified by column chromatography (SiO2, MeOH / DCM, MeOH=24%) to obtain 27 mg of a white solid with a yield of 18.5%. 1HNMR (500MHz, Chloroform-d) δ (ppm): 10.06 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.47 (d, J =8.0Hz,1H),7.86(td,J1=7.0Hz,J2=1.5Hz,1H),7.80–7.78(m,3H),7.47(s,1H),3.7 2(s,2H),3.00(s,2H),2.88(d,J=7.0Hz,2H),2.23(s,2H),1.94(s,2H),1.79–1.77(m ,3H),1.62(brs,2H),1.31–1.29(m,3H),0.86(t,J=6.5Hz,3H); HRMS(ESI)m / z:calcd For C 24 H 30 O3N6F[M+H] + ,469.2358;Found 469.2363.

[0420] Embodiment 30:

[0421] Synthesis of (R)-5-ethyl-1-(3-(4-ethyl-3-(fluoromethyl)piperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione

[0422]

[0423] (1) Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (Intermediate 38)

[0424]

[0425] The compound tert-butyl(R)-2-(hydroxymethyl)piperazine-1-carboxylate (648 mg, 3 mmol) was placed in a reaction flask, and EA (10 mL), water (5 mL), and Na2CO3 (636 mg, 6 mmol) were added. Benzyloxycarbonyl chloride (0.63 mL, 4.5 mmol) was added dropwise into the reaction flask under ice bath, and the temperature was gradually raised to room temperature and stirred for reaction. The reaction was stopped the next day, EA (30 mL) was added, and the mixture was washed with water (20 mL), washed with saturated NaCl solution (20 mL×2), dried over anhydrous magnesium sulfate, and purified by column chromatography (E:P, 0-35%, 35% peak) to obtain 890 mg of colorless oil with a yield of 84.7%.

[0426] 1H-NMR(400MHz,Chloroform-d)δ(ppm):7.26-7.37(m,5H),5.16(s,2H),4.18(brs,2H),4. 02(brs,1H),3.87(brs,1H),3.59(brs,2H),2.97–3.09(m,3H),2.08(s,1H),1.46(s,9H).

[0427] (2) Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (Intermediate 39)

[0428]

[0429] Take intermediate 38 (200 mg, 0.57 mmol), add DCM (6 mL), add methanesulfonic anhydride (198 mg, 1.14 mmol) in DCM (3 mL) dropwise into the reaction flask under ice bath, stir for a while under ice bath, then add Et3N (0.25 mL, 1.71 mmol), after addition, continue to react under ice bath, stop the reaction after 1 h, add DCM (30 mL), wash with water (15 mL), wash with saturated NaCl solution (15 mL×2), dry with anhydrous magnesium sulfate, and concentrate to obtain 244 mg of light yellow oil with a yield of 100%.

[0430] (3) Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(fluoromethyl)piperazine-1,4-dicarboxylate (Intermediate 40)

[0431]

[0432] Intermediate 39 (244 mg, 0.57 mmol) was placed in a reaction flask, THF (5 mL) was added, 1 M tetrabutylammonium fluoride solution in THF (1.71 mL, 1.71 mmol) was added, and the reaction was heated to reflux. The reaction was stopped after 4 h, DCM (40 mL) was added, and the mixture was washed with saturated NaCl solution (20 mL × 2), dried over anhydrous magnesium sulfate, and purified by column chromatography (E:P, 0-15%, 15% peak) to give 60 mg of a colorless oil, and the total yield of the previous step was 30%.

[0433] 1H-NMR(400MHz,Chloroform-d)δ(ppm):7.30–7.35(m,5H),5.14–5.16(m,2H),4.47(brs,1H),4.35(brs, 2H),4.18(d,J=13.6Hz,1H),3.91–4.19(m,2H),3.13(td,J1=14.0Hz,J2=4.0Hz,1H),2.93–3.06(m,2H).

[0434] (4) Synthesis of (R)-3-(Fluoromethyl)piperazine-1-carboxylic acid benzyl ester (Intermediate 41)

[0435]

[0436] Intermediate 40 (250 mg, 0.71 mmol) was placed in a reaction bottle, and DCM (5 mL) and TFA (0.536 mL, 7.1 mmol) were added. The mixture was stirred at room temperature for reaction. The reaction was stopped after 4 h, concentrated to dryness, and directly used for the next step.

[0437] (5) Synthesis of (R)-4-ethyl-3-(fluoromethyl)piperazine-1-carboxylic acid benzyl ester (Intermediate 42)

[0438]

[0439] Take intermediate 41 (261 mg, 0.71 mmol), add acetonitrile (8 mL), add DIEA (0.99 mL, 5.68 mmol), add bromoethane (0.11 mL, 1.42 mmol), raise the temperature to 50 ° C for reaction, stop the reaction after two days, concentrate to dryness, and column chromatography (D: M, M, 0-2%, 2% peak) to obtain 105 mg of yellow oil with a yield of 53.57%.

[0440] 1 H-NMR(400MHz,Chloroform-d)δ(ppm):7.26–7.36(m,5H),5.10–5.17(m,2H),4.59(dd,J1=10.0Hz,J2=4.4Hz,0.5H),4.54(brs,0.5H),4.48(dd,J1=10.0 Hz,J2=4.4Hz,0.5H),4.42(brs,0.5H),3.76–3.87(m,2H),3.13–3.31(m,2H) ,2.77–2.85(m,2H),2.55–2.74(m,2H),2.39(brs,1H),1.07(t,J=7.2Hz,3H).

[0441] (6) Synthesis of (R)-1-ethyl-2-(fluoromethyl)piperazine (Intermediate 43)

[0442]

[0443] Intermediate 42 (105 mg, 0.374 mmol) was placed in a reaction bottle, and ethanol (5 mL) and 10% Pd / C (21 mg) were added. Hydrogenation reduction reaction was carried out at room temperature and pressure. The next day, the reaction was stopped, filtered, the filter cake was washed with DCM, and the filtrate was concentrated to obtain 45 mg of a colorless oil with a yield of 82.4%.

[0444] HRMS(ESI)m / z:calcd For C7H 16 N2F[M+H] + ,147.1292;Found 147.1297.

[0445] (7) Synthesis of (R)-5-ethyl-1-(3-(4-ethyl-3-(fluoromethyl)piperazine-1-carbonyl)-4-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (Compound 30)

[0446]

[0447] Take intermediate 7a (104 mg, 0.357 mmol), add DMF (10 mL), EDCI (137 mg, 0.714 mmol), HOBt (96 mg, 0.714 mmol), DIEA (0.25 mL, 1.428 mmol) and the hydrochloride of intermediate 43 (116 mg, 0.536 mmol), stir the reaction at room temperature, stop the reaction the next day, add water, extract with ethyl acetate (30 mL×2), combine the organic layers, wash with saturated NaCl solution (20 mL×2), dry over anhydrous magnesium sulfate, and analyze by column chromatography (D:M, M 0-3%, 3% peak) to obtain 50 mg of an off-white solid with a yield of 33.3%.

[0448] 1 H-NMR (400MHz, Chloroform-d) δ (ppm): 8.91 (s, 0.5H), 8.87 (s, 0.5H), 7.32–7.40 (m, 2H), 7.11 (t, J = 6.8Hz, 1H), 6.93 (s, 1H), 4.87 (s, 2H), 4.60 (d,J=46.4Hz,1H),4.12–4.46(m,1H),3.22-3.55(m,3H),2.33–2.92(m,8H),1.10(t,J=6.8Hz,5H),0.87(t,J=6.4Hz,1H); HRMS(ESI)m / z:calcd For C21 H 27 O3N4F2[M+H] + ,Found 421.2046 421.204

[0449] Pharmacological experiments:

[0450] 1. Materials and Reagents

[0451] 1.1. Protein

[0452] catPARP-1 (PARP-1 catalytic domain structure) or catPARP-2.

[0453] 1.2. Test buffer

[0454] 1×PBS+100nM BSA: 135mM NaCl, 4.7mM KCl, 10mM Na2HPO4, 2mM NaH2PO4, 100nMBSA.

[0455] 1.3. Probe

[0456] ZJ-II-604, molecular weight 870.25Da.

[0457]

[0458] 1.4. Test compounds

[0459] BGB290 and AZD5305.

[0460] 1.5. Test container

[0461] All black 96-well cell culture plates.

[0462] 2. Test Method

[0463] 2.1. K of probe ZJ-II-604 for catPARP-1 / 2 d Value determination

[0464] The K of ZJ-II-604 was measured for catPARP-1 and catPARP-2. d value, setting the concentration of ZJ-II-604 to 0.0125uM, the concentration of catPARP-1 protein (uM): 1, 0.333, 0.1, 0.0333, 0.01, 0.00333, 0.001, 0.000333, 0.0001, 0.0000333, 0.00001, 0 and the concentration of catPARP-2 protein (uM): 0.5, 0.2, 0.1, 0.05, 0.02, 0.01, 0.005, 0.002, 0.001, 0.0005, 0.

[0465] Fluorescence polarization method, excitation wavelength 485nm, emission wavelength 525nm. Place the 96-well plate in a 4℃ refrigerator and incubate overnight in the dark. Complete dynamic equilibrium is achieved in about 14-16 hours. Use formula 1 to fit the data and calculate the probe K d value.

[0466]

[0467] Y = fluorescence anisotropy value (mA); x = PARP-1 or PARP-2 concentration (μM); A0 = Y min ; A max =Y max -Y min ; Cl = probe concentration (μM); K d = probe equilibrium dissociation constant (μM);

[0468] After determination and calculation, the Kd value of ZJ-II-604 for PARP-1 was 0.676 nM R 2 99.89%, K for PARP-2 d The value is 0.6569nM R 2 99.73%.

[0469] Compound K d (K i ) value test

[0470] The probe concentration was 0.0125uM, the protein concentration of catPARP-1 was set to 0.1uM, and the catPARP-2 was set to 0.1uM. Incubate overnight at 4°C in the dark for about 14-16 hours.

[0471] The test concentrations of BGB290 for PARP-1 / 2 were 50uM, 5uM, 0.5uM, 0.05uM, 0,005uM, 0.0005uM; the test concentrations of AZD5305 for PARP-1 were 50uM, 5uM, 0.5uM, 0.05uM, 0,005uM, 0.0005uM, and the test concentrations for PARP-2 were 500uM, 50uM, 5uM, 0.5uM, 0.05uM, 0.005uM. The fitting software GraphPad Prism used the least squares method for nonlinear fitting of Formula 2.

[0472]

[0473] Y = fluorescence anisotropy value (mA); x = Log value of compound concentration (Log μM); A max =Y max -Ymin ; Cl = probe concentration (μM); K d = probe equilibrium dissociation constant (μM); K i = Compound equilibrium dissociation constant (μM), i.e., K of the compound for the target d .

[0474] The test results showed that the Kd values ​​of catPARP-1 for pamiparib and AZD5305 were 3.7 and 3.4 nM, respectively. 50 ) are 1.3nM (J.Med.Chem.2020,63,15541-15563) and 3nM (J.Med.Chem.2021,64,14498-14512), respectively. The Kd values ​​of catPARP-2 for pamiparib and AZD5305 are 0.92nM and 765.8nM, respectively. The data in the literature (IC 50 ) are 0.9nM (J.Med.Chem.2020,63,15541-15563) and 1400nM (J.Med.Chem.2021,64,14498-14512) respectively.

[0475] The experimental results are shown in Table 1

[0476] Table 1. K of compounds inhibiting PARP-1 and PARP-2 d

[0477]

Claims

1. A compound as shown in general formula I or a pharmaceutically acceptable salt thereof In Formula I, R1 is selected from the following atoms, groups or structural fragments, including H, F, Cl, Br, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl, substituted or unsubstituted C2, C3, C4 straight or branched alkenyl, substituted or unsubstituted C2, C3, C4 straight or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; R2 is selected from the following atoms, groups or structural fragments, including H, F, Cl, Br, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl, substituted or unsubstituted C2, C3, C4 straight or branched alkenyl, substituted or unsubstituted C2, C3, C4 straight or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; R3 is selected from the following atoms, groups or structural fragments, including H, F, Cl, Br, CF3, CN, ORj1, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl; wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl; R4 is selected from the following atoms, groups or structural fragments: (1) hydrogen, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom; (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S; (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is shown in general formula IA In Formula IA R1 and R2 are the same as in claim 1; R3 ’ Independently selected from the following atoms, groups or structural fragments, including H, CF3, CN, substituted or unsubstituted C1, C2, C3, C4 straight or branched alkyl; wherein the substituent is selected from F, Cl, Br, CN, CF3, ORj1, NRj2Rk1, SRj3, wherein said Rj1, Rj2, Rk1, Rj3 are independently selected from H, methyl, ethyl; R4 is selected from the following atoms, groups or structural fragments: (1) substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom; (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S; (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is shown in the general formula IB In Formula IB, R1 and R2 are the same as in claim 1; R3' is independently selected from the following atoms, groups or structural fragments, including F, Cl, Br, ORj1, wherein said Rj1 is independently selected from H, methyl, ethyl; R4 is selected from the following atoms, groups or structural fragments: (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom; (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S; (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that The compound is shown in general formula IA-1 In Formula IA-1, R1 and R2 are the same as in claim 1; R4 is selected from the following atoms, groups or structural fragments: (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom; (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S; (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that The compound is shown in general formula IA-2 In Formula IA-2, R1 and R2 are the same as in claim 1; R4 is selected from the following atoms, groups or structural fragments: (1) H, substituted or unsubstituted C1, C2, C3, C4, C5, C6 straight chain or branched alkyl, substituted or unsubstituted C2, C3, C4, C5, C6 straight chain or branched alkenyl; wherein the substituent is selected from F, Cl, Br, CN, ORc1, SRc2, NRc3Rd1, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, Ar, wherein Rc1, Rc2, Rc3, Rd1 are independently selected from H, methyl, ethyl; (2) substituted or unsubstituted C3, C4, C5, C6, C7 cycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered oxacycloalkyl, substituted or unsubstituted C3, C4, C5, C6, C7 ring-membered azacycloalkyl, wherein the substituent is selected from methyl, ethyl, F, ORc1, wherein Rc1 is selected from H, methyl, ethyl; the oxacycloalkyl and azacycloalkyl contain 1 heteroatom; (3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S; (4) CH2Ar, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from methyl, ethyl, methyl substituted with fluorine atom, ethyl, F, Cl, Br, CN, ORa′1, SRa′2, NRa′3Rb′1, COORa′4, CONRa′5Rb′2, wherein Ra′1, Ra′2, Ra′3, Rb′1, Ra′4, Rb′2 are independently selected from H, methyl, ethyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatoms are selected from O, N, and S.

6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following group:

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salts of the compounds are selected from salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases that can provide physiologically acceptable cations and ammonium salts.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that The inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, potassium ion; the alkaline earth metal ion is selected from calcium ion and magnesium ion; the organic base capable of providing physiologically acceptable cations is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

9. A method for preparing a compound according to any one of claims 1 to 6, characterized in that The steps include: The present invention adopts the following method to prepare the compound shown in formula I: 6-R2-5-iodo-2,4-dimethoxypyrimidine is used as a raw material, and a substituent R is introduced by a coupling reaction. 1 , then undergoes a selective alkylation reaction with 5-bromomethyl-2-fluorobenzoic acid methyl ester under the action of HMDS, and after hydrolysis, obtains 5-((2,4-dioxo-uracil-1(2H)-yl)methyl)benzoic acid containing different substitutions of R1 and R2, and then undergoes a condensation reaction with substituted piperazine to obtain uracildione PARP-1 inhibitor (I). The specific description is as follows: Using 2-fluoro-5-methylbenzoic acid methyl ester 1 as the starting material, intermediate 2 was obtained through bromination reaction; Using 5-iodo-2,4-dimethoxypyrimidine 3 with different substitutions at the 6-position as the starting material, the substituents were introduced by coupling reaction to obtain intermediate 4; Intermediate 4 was treated with TMSCl to remove the methyl ether protecting group to obtain intermediate 5; Intermediate 5 undergoes nucleophilic substitution with intermediate 2 to give intermediate 6; Intermediate 6 undergoes hydrolysis reaction under lithium hydroxide conditions to obtain intermediate 7; Using intermediate 8 as the starting material, different substituents were introduced through nucleophilic substitution reaction and coupling reaction to obtain intermediate 9; Intermediate 9 was subjected to trifluoroacetic acid conditions to remove the Boc protecting group to obtain intermediate 10; Intermediate 7 and intermediate 10 undergo acid-amine condensation reaction to obtain a compound of formula I; The definitions of R1, R2, R3 and R4 are the same as those in any one of claims 1-5.

10. A pharmaceutical composition, characterized in that The invention comprises an effective dose of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a PARP-1 inhibitor.

12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and\or treating a disease associated with PARP-1.

13. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug or an antitumor drug sensitizer.

14. Use according to claim 13, characterised in that The tumor is selected from melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, and glioma.

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