Phthalasinone compounds, their preparation methods and uses

Abstract

This invention discloses a phthalazinone compound, its preparation method, and its uses. The structure of this compound is shown in formula (I), and it exhibits excellent PARP14 inhibitory activity, inhibiting IC50 in vitro. 50 The optimal concentration level is nanomolar, which has the potential to become a new drug for the prevention and / or treatment of tumors and inflammatory diseases. When used in combination with existing known antitumor and anti-inflammatory drugs, it can improve the therapeutic effect of existing known antitumor and anti-inflammatory drugs while reducing the side effects of the drugs.

Description

Technical Field

[0001] This invention relates to a phthalazinone compound, its preparation method and uses, and more particularly to a phthalazinone compound with PARP14 inhibitory activity, its preparation method and uses. Background Technology

[0002] The poly(ADP-ribosyltransferase) (PARP) family has 18 members, among which mono-ADP-ribosyltransferase (monoPARP) can utilize nicotinamide adenine dinucleotide (NAD). + PARP14 is a monoPARP that is primarily involved in cellular responses and signal transduction of the immune system. Compared to normal tissues, PARP14 is highly expressed in cancerous and inflamed tissues.

[0003] PARP14 acts as both a negative and positive feedback regulator of IFN-γ / STAT1 and IL-4 / STAT6 transcriptional signaling, participating in the differentiation of macrophages and T helper cells. In human tumor explants, inhibition of PARP14 reduces the expression of IL-4-driven primary tumor genes in macrophages and induces the expression of inflammatory mRNAs similar to those induced by immune checkpoint inhibitor (ICI) therapy. Further studies have shown that inhibition of PARP14 can restore the sensitivity of IFN-γ-induced PD-1 immune checkpoint inhibitor-resistant tumors to PD-1 immune checkpoint inhibitors. In addition, knockout or inhibition of PARP14 affects the survival and proliferation of various tumor cells, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), hepatocellular carcinoma (HCC), and mPCa. In inflammatory responses, PARP14 promotes the differentiation of Th2 and Th17 cells by regulating the IL-4 / STAT6 and IL-6 / STAT3 transcriptional signaling pathways, thereby producing cytokines such as IL-4, IL-5, IL-13, IL-17A, IL-17F, and IL-21, and further driving the aggregation of eosinophils and neutrophils. Upregulation of PARP14 can also stimulate B cells to mature and differentiate into plasma cells to produce IgE antibodies. Studies have demonstrated that knocking out or inhibiting PARP14 has shown superior therapeutic effects in inflammatory disease models such as Th2 cytokine-driven allergic airway inflammation, steroid-resistant allergic pneumonia, HDM-induced asthma, bleomycin-induced idiopathic pulmonary fibrosis, and oxazolone-induced atopic dermatitis.

[0004] Currently, there are no PARP14 inhibitor drugs on the market, and the drugs that have entered clinical trials have shortcomings such as simple structure and limited activity. Therefore, there is an urgent need for drugs to treat cancers or inflammatory diseases characterized by abnormal PARP14 expression. Summary of the Invention

[0005] Objectives of the invention: The first objective of this invention is to provide a novel phthalazinone compound with PARP14 inhibitory activity; the second objective is to provide a method for preparing the compound; the third objective is to provide a pharmaceutical composition containing the compound; and the fourth objective is to provide a pharmaceutical use for the compound and the pharmaceutical composition thereof.

[0006] Technical solution: The phthalazinone compounds of the present invention have the structure shown in formula (I), and further include their stereoisomers, tautomers, solvates, prodrugs, isotope labels, or pharmaceutically acceptable salts.

[0007]

[0008] in:

[0009] R 1 The substituent is selected from H, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocyclic alkyl, substituted phenyl, or substituted 5- to 6-membered heteroaryl; the substituent is selected from H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, phenyl-substituted C1-C8 alkyl, 5- to 6-membered heteroaryl-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C3-C8 halocycloalkyl carbonyl, C3-C8 cycloalkyl carbonyl, hydroxyl, amino, nitro, or cyano;

[0010] R 2 Selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, hydroxy-substituted C1-C8 alkyl or amino-substituted C1-C8 alkyl.

[0011] R 3 The substituent is selected from substituted phenyl groups, substituted 5- to 6-membered heteroaryl groups, substituted C3-C8 cycloalkyl groups, and substituted 3- to 10-membered heterocyclic alkyl groups; the substituent of the phenyl or 5- to 6-membered heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxyl, amino, or C1-C8 alkyl carbonyl-substituted amino groups; the substituent of the C3-C8 cycloalkyl or 3- to 10-membered heterocyclic alkyl group is selected from H, oxo and / or -L1-R. 4 ;

[0012] L1 is selected from a bond or a C1-C4 alkylene group;

[0013] R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR5 R 5 ', substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkyl carbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkyl carbonyl, C3-C8 cycloalkyl carbonyl, C3-C8 halocycloalkyl carbonyl, phenyl carbonyl, 5- to 6-membered heteroaryl carbonyl, or carbamoyl; wherein the substituent of the phenyl or heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, cyano, hydroxyl, amino, or an amino group substituted with C1-C8 alkyl carbonyl; wherein the substituent of the cycloalkyl or heterocycloalkyl group is selected from H, oxo, and / or -L2-R. 4 ';

[0014] L2 is selected from a bond or a C1-C4 alkylene group;

[0015] R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxy carbonyl, C1-C8 alkoxy alkyl carbonyl, C1-C8 alkyl carbamoyl, di(C1-C8 alkyl) carbamoyl, di(C1-C8 alkyl) amino alkyl carbonyl, C3-C8 cycloalkyl carbonyl or C3-C8 halocycloalkyl carbonyl;

[0016] R 5 R 5 Each is independently selected from H or C1-C8 alkyl groups;

[0017] The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S;

[0018] A 1 Selected from -O-, -NH-, -CH2-, or -S-;

[0019] A 2 Selected from -O-, -NH-, -N(CH3)-, -CH2-, -CH2NH-, or -S-;

[0020] A 3Selected from -O-, -NH-, -N(CH3)-, -S-, -(CH2) m1 -or -NH(CH2) m1 -;

[0021] m1 is selected from 1 or 2;

[0022] n is selected from 0, 1, or 2;

[0023] m, p, and q are each independently selected from 0 or 1.

[0024] The term "stereoisomer" refers to compounds that have the same chemical composition and connectivity, but whose atoms have different spatial orientations that cannot be interchanged by single bond rotation. "Stereoisomers" include both "diastereomers" and "enantiomers." A "diastereomer" is a stereoisomer with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as crystallization, electrophoresis, and chromatography. An "enantiomer" is a stereoisomer of a compound that is a non-overlapping mirror image of another compound.

[0025] The term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) active atoms, such as keto-enol tautomers.

[0026] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a given compound, and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be acid addition salts and / or base addition salts. Acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, carbonates, hydrogen sulfates, hydrogen phosphates, dihydrogen phosphates, and bicarbonates. Salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, ferulic acids, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, lactates, nicotinates, lauryl sulfate, naphthalenesulfonates, camphorsulfonates, gluconates, glucuronides, oleates, palmitates, stearates, dihydroxynaphthalates, and trifluoroacetates. Base addition salts can form with inorganic or organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, and aluminum salts; salts derived from organic bases include salts formed with various primary, secondary, and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperazine, piperidine, morpholine, tromethamine, and choline salts.

[0027] The term “pharmaceutical acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or mammals treated with it.

[0028] The term "solvent" refers to an association or complex of one or more solvent molecules with the compounds of this invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, acetonitrile, acetone, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecules are water.

[0029] As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, "prodrugs" can also be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed together with a suitable enzyme or chemical reagent in a transdermal patch reservoir, the prodrug can be slowly converted into the compounds of the present invention.

[0030] Any general formulas or structures given herein are also intended to include isotopically labeled forms of compounds. These isotopically labeled forms of compounds may also be referred to as “isotopic labels” or “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, but not limited to… 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes (e.g. 3 H, 13 C and 14 Those of C) are synthesized by means well known in the art, such as by using one or more starting materials in which hydrogen has been replaced by deuterium.

[0031] The term "alkyl" refers to a monovalent group of a straight or branched saturated hydrocarbon chain having 1 to 8 carbon atoms (more typically 1 to 6 carbon atoms or 1 to 4 carbon atoms). The term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.

[0032] The term "alkylene" refers to a divalent group of a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms (more typically 1 to 4 carbon atoms). Examples of this term include groups such as methylene, ethylene, propylene, butylene, pentylene, and hexylene.

[0033] The term "halogen" refers to fluorine, chlorine, bromine, or iodine (preferably fluorine or chlorine).

[0034] The term "alkoxy" refers to an "alkyl-O-" group, wherein the alkyl group is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein the alkyl group is as defined herein. The term is exemplified by groups such as trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, 2,2,2-trichloroethyl, etc.

[0036] The term "cycloalkyl" refers to a monocyclic saturated or partially unsaturated carbocyclic group having 3 to 8 membered ring atoms (3 to 8) or multiple fused (fused) rings, bridged rings, or spirocyclic rings (7 to 8) as ring atoms. Cycloalkyl groups can be saturated or partially unsaturated and can be fused with another saturated, partially unsaturated, or aromatic carbocyclic ring, provided that the connection point with the target molecule is not on an aromatic carbocyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, etc.

[0037] The term "heteroaryl" refers to a monovalent monocyclic aromatic group having 5 to 6 ring atoms, wherein, in addition to a carbon atom, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. The term "heteroaryl" also includes a second ring fused thereto containing 5 to 6 ring atoms, wherein the second ring can be an aromatic ring or a non-aromatic ring, provided that the connection point with the target molecule is on the heteroaryl portion of the multiple fused system. It should also be understood that the connection point of the heteroaryl can be on any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inzolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzoimidazolyl, thiaindyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-inzolyl and 3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazolyl.

[0038] The term "heterocyclic alkyl" refers to a monomolecular saturated or partially unsaturated group having 3 to 10 ring atoms in a 3- to 10-membered monocyclic ring or multiple fused (fused) rings, bridged rings, or spirocyclic rings having 7 to 10 ring atoms, wherein, in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Heterocyclic alkyl groups can be saturated or partially unsaturated and can be fused with another saturated, partially unsaturated, or aromatic ring, provided that the connection point with the target molecule is not on an aromatic ring. Examples of heterocyclic alkyl groups include, but are not limited to, aziridine propane, aziridine butane, tetrahydropyrrolyl, piperidinyl, aziridine heptane, aziridine octane, oxadiazine, oxadiazine propane, oxadiazine butane, tetrahydrofuranyl, tetrahydropyranyl, oxadiazine heptane, oxadiazine octane, thiohepane propane, thiohepane butane, tetrahydrothiophene, tetrahydrothioranyl, thioheptane heptane, thiohepane octane, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, piperazine, morpholinyl, dioxane, thiazolyl, dithiazolyl, dihydropyridinyl, etc.

[0039] Preferably, in the structure:

[0040] R 1 The substituent is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, substituted C3-C6 cycloalkyl, substituted 3- to 6-membered heterocyclic alkyl, substituted phenyl, or substituted 5- to 6-membered heteroaryl; the substituent is selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic alkyl, phenyl-substituted C1-C6 alkyl, 5- to 6-membered heteroaryl-substituted C1-C6 alkyl, C1-C8 alkyl carbonyl, C3-C8 halocycloalkyl carbonyl, C3-C8 cycloalkyl carbonyl, hydroxyl, amino, nitro, or cyano;

[0041] The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S.

[0042] Preferably, in the structure: R 1 The substituent is selected from H or substituted methyl, ethyl, propyl, methoxyethyl, cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrroleyl or pyrazolyl; the substituent is selected from H, halogen, methyl, trifluoromethyl, acetyl or cyclopropylcarbonyl.

[0043] Preferably, in the structure, R 3 Selected from:

[0044]

[0045] Where X is selected from CR6 R 6 '、NR 6 Or O;

[0046] R 6 R 6 Each independently selected from -L1-R 4 ;

[0047] L1 is selected from a bond or a C1-C4 alkylene group;

[0048] R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkyl carbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkyl carbonyl, C3-C8 cycloalkyl carbonyl, C3-C8 halocycloalkyl carbonyl, phenyl carbonyl, 5- to 6-membered heteroaryl carbonyl, or carbamoyl; wherein the substituent of the phenyl or heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, cyano, hydroxyl, amino, or an amino group substituted with C1-C8 alkyl carbonyl; wherein the substituent of the cycloalkyl or heterocycloalkyl group is selected from H, oxo, and / or -L2-R. 4 ';

[0049] L2 is selected from a bond or a C1-C4 alkylene group;

[0050] R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxy carbonyl, C1-C8 alkoxy alkyl carbonyl, C1-C8 alkyl carbamoyl, di(C1-C8 alkyl) carbamoyl, di(C1-C8 alkyl) amino alkyl carbonyl, C3-C8 cycloalkyl carbonyl, C3-C8 halocycloalkyl carbonyl;

[0051] R 5 R 5 Each is independently selected from H or C1-C6 alkyl groups;

[0052] The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S.

[0053] Preferably, in the structure, R 3 Selected from:

[0054]

[0055] Among them, R 7 It is selected from H, methyl, isopropyl, benzyl, halobenzyl, p-methylbenzyl, oxacyclobutyl, cyclopropylmethyl, tetrahydropyranylmethyl, pyridylmethyl, halopyridylmethyl, N-methylpyrazolylmethyl, N-methylpyrrolithylmethyl, N-methylpyrrolithylformyl, N-cyclopropylpyrazolylmethyl, 2-methylthiazolylmethyl, N-isobutylpyrazolylmethyl, 4-fluoropyrazolyl-1-methyl, 2-methylimidazolyl-1-methyl, 4-trifluoromethylpyrazolyl-1-methyl, cyclopropylcarbonyl, furanylmethyl, pyrimidinylmethyl, oxazolylmethyl, or benzoyl.

[0056] Preferably, in the structure, R 2 It is selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl or amino-substituted C1-C6 alkyl.

[0057] Further optimization, R 2 Selected from H, hydroxyl, or halogen.

[0058] Further optimization, R 2 Selected from H or halogens.

[0059] Preferably, the phthalazinone compounds of the present invention are selected from any one of the following compounds:

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066] Preferably, the pharmaceutically acceptable salt is an acid addition salt formed by a compound of formula (I) and any of the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, malic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid.

[0067] The preparation method of the phthalazinone compounds described in this invention is selected from any of the following methods:

[0068] Method 1: When n=0, p=0, R 1 When selected from H, halogen, methyl, or hydroxyl, compound IV reacts first with R. 3 (A 3 ) q H-condensation, followed by deprotection, yields compound I.

[0069]

[0070] Among them, m, q, A 2 A 3 R 2 R 3 The definition is as stated above;

[0071] Step 1: Compound IV, R 3 (A 3 ) q Compound XIX is prepared by reacting H and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate under alkaline conditions in a suitable solvent, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, and N,N-diisopropylethylamine, preferably, the base is selected from N,N-diisopropylethylamine; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, or any combination thereof, preferably, the suitable reaction solvent is N,N-dimethylformamide.

[0072] Step 2: Compound XIX is reacted under acidic conditions to prepare compound I, wherein the acid is selected from sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, formic acid, oxalic acid, butyric acid or any combination thereof, preferably, the acid is selected from a trifluoroacetic acid / trifluoromethanesulfonic acid mixed acid.

[0073] Method 2: When n=0, p=0, A 2 Selected from -CH2NH-, R 1 When selected from H, halogen, methyl, or hydroxyl, compound X first reacts with R. 3 (A3 ) q COOH condensation followed by deprotection yields compound I.

[0074]

[0075] Among them, m, q, A 3 R 2 R 3 The definition is as stated above;

[0076] Step 1: Compounds X and R 3 (A 3 ) q Compound XX is prepared by reacting COOH and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate under alkaline conditions in a suitable solvent, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, and N,N-diisopropylethylamine, preferably, the base is selected from N,N-diisopropylethylamine; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, or any combination thereof, preferably, the suitable reaction solvent is N,N-dimethylformamide.

[0077] Step 2: Compound XX is reacted under acidic conditions to prepare compound I, wherein the acid is selected from sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, formic acid, oxalic acid, butyric acid or any combination thereof, preferably, the acid is selected from a trifluoroacetic acid / trifluoromethanesulfonic acid mixed acid.

[0078] Method 3: When p = 1, m = 0, A 2 When selected from -CH2-, compounds XVII and R 3 (A 3 ) q H-condensation yields compound I;

[0079]

[0080] Where, n, q, A 1 A 3 R 1 R 2 R 3 The definition is as stated above;

[0081] Compounds XVII and R 3 (A 3 ) qCompound I is prepared by reacting H and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate under alkaline conditions in a suitable solvent, wherein the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, and N,N-diisopropylethylamine, preferably, the base is selected from N,N-diisopropylethylamine; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, dichloromethane, or any combination thereof, preferably, the suitable reaction solvent is N,N-dimethylformamide.

[0082] Method 4: When n=0, p=0, R 1 When the compounds are selected from H, halogen, methyl, or hydroxyl, compound II is N-protected and hydrolyzed to give compound IV, which is then obtained by following method one to obtain compound I.

[0083]

[0084] Among them, m and A 2 R 2 The definition is as stated above;

[0085] Step 1: Compound II is reacted with p-methoxybenzyl chloride (PMB-Cl) under alkaline conditions in a suitable solvent to prepare compound III. The base is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine. Preferably, the base is selected from cesium carbonate. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane, or any combination thereof. Preferably, the suitable solvent is acetonitrile.

[0086] Step 2: Compound III is reacted with a base in a suitable solvent to prepare compound IV, wherein the base is selected from sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from lithium hydroxide; the suitable solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, water or any combination thereof, preferably, the suitable solvent is a methanol / water mixture.

[0087] Method 5: When n=0, p=0, A 2 Selected from -CH2NH-, R 1When selected from H, halogen, methyl, or hydroxyl, compound V undergoes N-protection, reduction, bromination, diazotization, and reduction to obtain compound X, which is then obtained according to method two to obtain compound I.

[0088]

[0089] Wherein, m, R 2 The definition is as stated above;

[0090] Step 1: Compound V is reacted with p-methoxybenzyl chloride (PMB-Cl) under alkaline conditions in a suitable solvent to prepare compound VI. The base is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine. Preferably, the base is selected from cesium carbonate. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane, or any combination thereof. Preferably, the suitable solvent is acetonitrile.

[0091] Step 2: Compound VI is reacted with sodium borohydride (NaBH4) in a suitable solvent to prepare compound VII, wherein the suitable solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane or any combination thereof, preferably, a tetrahydrofuran / methanol mixed solvent.

[0092] Step 3: Compound VII, carbon tetrabromide (CBr4), and triphenylphosphine (PPh3) are reacted in a suitable solvent to prepare compound VIII. The suitable solvent is selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, trichloromethane, carbon tetrachloride, or any combination thereof. Preferably, the suitable solvent is dichloromethane.

[0093] Step 4: Compound VIII is reacted with trimethyl azidosilane (TMSN3) under alkaline conditions in a suitable solvent to prepare compound IX. The base is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, cesium fluoride, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine. Preferably, the base is selected from cesium fluoride. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane, or any combination thereof. Preferably, the suitable solvent is N,N-dimethylformamide.

[0094] Step 5: Compound IX and triphenylphosphine (PPh3) are reacted in a suitable solvent to prepare compound X, wherein the suitable solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, water or any combination thereof, preferably, a tetrahydrofuran / water mixed solvent.

[0095] Method Six: When p=1, m=0, A 2 When selected from -CH2-, compound XI is subjected to substitution, bromination, activation, condensation, reduction and hydrolysis to obtain compound XVII, and then compound I is obtained according to method three;

[0096]

[0097] Where, n, A 1 R 1 R 2 The definition is as stated above;

[0098] Step 1: Compound XI and R 1 (CH2) n Br or R 1 (CH2) n Compound XII is prepared by reacting OMs under alkaline conditions in a suitable solvent, wherein the base is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from potassium carbonate; the suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or any combination thereof, preferably, the suitable solvent is N,N-dimethylformamide.

[0099] Step 2: Compound XII, N-bromosuccinimide (NBS), and azobisisobutyronitrile are reacted in a suitable solvent to prepare compound XIII. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, or any combination thereof. Preferably, the suitable solvent is carbon tetrachloride.

[0100] Step 3: Compound XIII is reacted with triphenylphosphine (PPh3) in a suitable solvent to prepare compound XIV. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or any combination thereof. Preferably, the suitable solvent is acetonitrile.

[0101] Step 4: Compound XIV is reacted with ethyl glyoxylate under alkaline conditions in a suitable solvent to prepare compound XV', wherein the base is selected from triethylamine, pyridine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, preferably, the base is selected from triethylamine; the suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or any combination thereof, preferably, the suitable solvent is dichloromethane.

[0102] Step 5: Compound XV' is reacted with hydrazine hydrate in a suitable solvent to prepare compound XVI. The suitable solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, methanol, ethanol, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or any combination thereof. Preferably, the suitable solvent is ethanol.

[0103] Step 6: Compound XVI is reacted with a base in a suitable solvent to prepare compound XVII, wherein the base is selected from sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, pyridine, N,N-diisopropylethylamine, preferably, the base is selected from lithium hydroxide; the suitable solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, water or any combination thereof, preferably, the suitable solvent is a methanol / water mixture.

[0104] Method 7: When p = 1, compound XV' is hydrolyzed and substituted to obtain compound XV, then compound XVII is obtained according to method 6, and finally compound I is obtained according to method 3;

[0105]

[0106] Where, n, A 1 R 1 R 2 The definition is as stated above;

[0107] Step 1: Compound XV' is reacted under acidic conditions in a suitable solvent to prepare compound XVIII, wherein the acid is selected from sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, formic acid, oxalic acid, butyric acid or any combination thereof, preferably, the acid is selected from a trifluoroacetic acid / trifluoromethanesulfonic acid mixture; the suitable reaction solvent is selected from N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or any combination thereof, preferably, the suitable reaction solvent is dichloromethane.

[0108] Step 2: Compound XVIII and R 1 (CH2) n Compound XV is prepared by reacting OH, triphenylphosphine (PPh3), and diisopropyl azodicarboxylate in a suitable reaction solvent, wherein the suitable reaction solvent is selected from methanol, ethanol, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, chloroform, or any combination thereof, preferably tetrahydrofuran.

[0109] The mixture obtained by the above method is then salted with a pharmaceutically acceptable acid to obtain the pharmaceutically acceptable salt.

[0110] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0111] The pharmaceutical compositions of the present invention comprise the compounds of the present invention and pharmaceutically acceptable carriers.

[0112] Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0113] The term "therapeutic effective amount" refers to an amount sufficient to affect the treatment when administered to a mammal requiring such treatment, as defined below. Therapeutic effective amount will vary depending on factors such as the weight and age of the subject, the type of disease, the severity of the disease condition, and the route of administration, and can be readily determined by a person skilled in the art.

[0114] The compounds of the present invention can be administered in the form of pharmaceutical compositions, wherein the pharmaceutical composition comprises the compounds of the present invention and at least one pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can be prepared according to methods well known in the pharmaceutical field. Depending on the therapeutic need, the compositions of the present invention can be administered via a variety of routes. Routes of administration include, but are not limited to, oral, injection, intravenous infusion, topical (e.g., intranasal, intraocular, oral, rectal, vaginal, percutaneous delivery), etc. Depending on the route of administration, the pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to tablets, capsules (e.g., soft and hard gelatin capsules), pills, granules, powders, lozenges, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups, aerosols).

[0115] When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) a lubricant, such as silica, talc, stearic acid, polyethylene glycol, etc.; c) a binder, such as magnesium aluminosilicate, gelatinized starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) a disintegrant, such as starch, alginic acid, agar, corn starch; e) a stabilizer, such as an antioxidant like ascorbic acid; f) a flow aid, such as silica; g) a flavoring agent, such as peppermint, methyl salicylate; and a sweetener, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerin, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0116] The effective dose of the compounds or pharmaceutical compositions of the present invention administered to an individual or patient will be determined by a clinician based on factors such as the condition and severity of the disease being treated, the individual's or patient's age, weight and general health status, and the route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. In some embodiments, a typical dose range is about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, a typical dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. In some embodiments, a typical dose range is about 0.1 mg / kg body weight to about 50 mg / kg body weight per day. In some embodiments, a typical dose range is about 0.5 mg / kg body weight to about 25 mg / kg body weight per day. In some embodiments, a typical dose range is about 1 mg / kg body weight to about 10 mg / kg body weight per day. Specific doses may vary depending on variables such as the type and progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can also be extrapolated from the dose-response curve obtained from in vitro or animal model testing systems.

[0117] The purpose of the compounds or pharmaceutical compositions thereof described in this invention is to prepare PARP14 inhibitor drugs.

[0118] Preferably, the drug is a drug for the prevention and / or treatment of tumors or inflammatory diseases.

[0119] Further preferably, the drug is a drug for the prevention and / or treatment of leukemia, lymphoma, liver cancer, bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lung cancer, prostate cancer, skin cancer, testicular cancer, thyroid cancer, melanoma, or uterine cancer; or the drug is a drug for the prevention and / or treatment of atopic dermatitis, psoriasis, scleroderma, inflammatory bowel disease, arthritis, inflammatory demyelinating diseases, emphysema, psoriasis, asthma, pulmonary fibrosis, allergies, or lupus.

[0120] The compounds of the present invention have inhibitory activity against PARP14. The activity of PARP14 in an individual or patient can be inhibited by administering a therapeutically effective amount of the compounds of the present invention to the individual or patient in need. As PARP14 inhibitors, the compounds of the present invention can be used to prevent and / or treat various diseases associated with abnormal expression or activity of PARP14. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, the cancers that the compounds of the present invention can prevent and / or treat include:

[0121] i) Malignant tumors of the hematopoietic system, such as leukemia and lymphoma. Exemplary lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, follicular lymphoma, pilocellular lymphoma, and Burkitt lymphoma. Exemplary leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0122] ii) Other cancers, including liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing sarcoma, pancreatic cancer, gallbladder cancer, stomach cancer, gastrointestinal tumors, head and neck cancer, colorectal cancer (e.g., colon cancer, colorectal cancer, rectal cancer), Kaposi's sarcoma, kidney cancer, laryngeal cancer, lung cancer, prostate cancer, skin cancer, testicular cancer, thyroid cancer, melanoma, and uterine cancer, etc.

[0123] Furthermore, the compounds of the present invention can also be used to prevent and / or treat inflammatory diseases, including atopic dermatitis, scleroderma, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), arthritis, inflammatory demyelinating diseases, emphysema, psoriasis, asthma, allergies, lupus, etc.

[0124] The compounds of the present invention can be administered in combination with one or more other pharmaceutical agents or treatment methods. Other pharmaceutical agents or treatment methods suitable for combination with the compounds of the present invention include chemotherapeutic agents, immunotherapeutic agents, radiotherapy, etc. The compounds of the present invention and other pharmaceutical agents can be administered separately via the same or different routes of administration, or simultaneously as a combination agent in a pharmaceutical composition.

[0125] Suitable chemotherapeutic agents include, but are not limited to, aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents, histone deacetylase inhibitors, farnesyltransferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platinum compounds, compounds that reduce protein kinase activity and other anti-angiogenic compounds, gonadotropin-releasing factor agonists, anti-androgens and antiproliferative antibodies, PDE4 inhibitors, aryl hydrocarbon receptor modulators, S1P receptor modulators, JAK inhibitors, glucocorticoids, antifibrotic drugs, leukotriene receptor antagonists, salicylates, theophylline, H1 receptor antagonists, β-receptor agonists, and anti-inflammatory antibodies.

[0126] Aromatase inhibitors include, but are not limited to, exemestane, formestan, aminoglutethimide, vorozole, fastrozole, anatozole, and letrozole. Anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Topoisomerase I inhibitors include, but are not limited to, topotecan, irinotecan, and 9-nitrocamptothecin. Topoisomerase II inhibitors include, but are not limited to, anthracyclines, doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, loxoantrone, etoposide, and teniposide. Microtubule activators include, but are not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinca alkaloids, especially vinca sulfate; vincristine, especially vincristine sulfate; and vinblastines, as well as epothilones such as epothilone B and D. Alkylating agents include, but are not limited to, cyclophosphamide, ifosfamide, and melphalan. Histone deacetylase inhibitors involve compounds that inhibit histone deacetylases and have antiproliferative activity. Farnesyltransferase inhibitors involve compounds that inhibit farnesyltransferase and possess antiproliferative activity. COX-2 inhibitors involve compounds that inhibit cyclooxygenase type 2 (COX-2) and possess antiproliferative activity, such as celecoxib, ibuprofen, coccib, and phenicoxib. MMP inhibitors involve compounds that inhibit matrix metalloproteinases and possess antiproliferative activity. mTOR inhibitors involve compounds that inhibit mammalian rapamycin target (mTOR) and possess antiproliferative activity, such as everolimus. Antitumor antimetabolites include, but are not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouracil nucleoside, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edarax, and salts of these compounds. Platinum compounds include, but are not limited to, carboplatin, cisplatin, and oxaliplatin. Compounds that reduce protein kinase activity and further inhibit angiogenesis include, but are not limited to, compounds that reduce the activity of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), Bcr-Abl, c-Kit, Flt-3, insulin-like growth factor I receptor (IGF-IR), and cyclin-dependent kinases (CDKs). Gonadotropin-releasing factor agonists include, but are not limited to, abalegactam, serotonin, and serotonin acetate. Antiandrogens include, but are not limited to, bicalutamide. Antiproliferative antibodies include, but are not limited to, trastuzumab, trastuzumab-DM1, erlotinib, bevacizumab, rituximab, and 2C4 antibodies. PDE4 inhibitors involve compounds that inhibit phosphodiesterase and have anti-inflammatory activity, such as criborone, roflumilast, defamiclast, and lotalast. Aromatic hydrocarbon receptor modulators include, but are not limited to, benzenemod. S1P receptor modulators involve compounds that regulate the sphingosine 1-phosphate receptor and have anti-inflammatory activity, such as ozamod and ictromod.JAK inhibitors involve compounds that inhibit Janus kinase and have anti-inflammatory activity, such as ruxolitinib, tofacitinib, baricitinib, digotinib, utpatinib, jaktinib, cedutinib, and abuxitinib. Glucocorticoids include, but are not limited to, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, hydrocortisone, and budesonide. Antifibrotic drugs include, but are not limited to, pirfenidone and nintedanib. Leukotriene receptor antagonists involve compounds that inhibit leukotriene receptors and have anti-inflammatory activity, such as montelukast, zafirlukast, and pramlukast. Salicylate derivatives include, but are not limited to, mesalazine, sulfasalazine, and aspirin. Theophylline derivatives include, but are not limited to, aminophylline, dihydroxypropyltheophylline, choline, and theophylline ethanolamine. H1 receptor antagonists involve compounds that inhibit histamine H1 receptors and have anti-inflammatory activity, such as chlorpheniramine, cetirizine, loratadine, and desloratadine. Beta-receptor agonists involve compounds that activate adrenaline beta receptors and possess anti-inflammatory activity, such as salbutamol, terbutaline, salmeterol, and formoterol. Anti-inflammatory antibodies include, but are not limited to, dopamine, leblizumab, trastuzumab, nimotuzumab, vedolizumab, ustekinumab, infliximab, adalimumab, golimumab, and omalizumab.

[0127] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0128] The compound designed in this invention exhibits excellent PARP14 inhibitory activity, and in vitro inhibition of IC50... 50 The optimal concentration can reach nanomolar levels, even below 50 nM, which has the potential to become a new drug for the prevention and / or treatment of tumors and inflammatory diseases. When used in combination with existing known antitumor and anti-inflammatory drugs, it can improve the therapeutic effect of existing known antitumor and anti-inflammatory drugs while reducing the side effects of the drugs. Detailed Implementation

[0129] The technical solution of the present invention will be further described below with reference to the embodiments.

[0130] Example 1: Synthesis of 4-(2-(8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one (I-1)

[0131] Step 1: Synthesis of methyl 2-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)acetate (III-1)

[0132] 2-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl acetate (II-1, 4.20 g, 19.26 mmol) and cesium carbonate (15.69 g, 48.15 mmol) were mixed with acetonitrile (40 mL), followed by the slow dropwise addition of p-methoxybenzyl chloride (3.62 g, 23.11 mmol). After the addition was complete, the mixture was heated to 60 °C and reacted for approximately 3 h. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate = 3:1) to ensure complete reaction. The reaction was then stopped and cooled to room temperature. Water (80 mL) was added to the reaction mixture, and the mixture was stirred for 5 min. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to give 4.36 g of a pale yellow solid, with a yield of 67.0%. MS-ESI: [M+H] + 339.1; 1 ¹H NMR (300MHz, chloroform-d) δ (ppm): 8.48–8.45 (m, 1H), 7.82–7.65 (m, 2H), 7.46–7.41 (m, 1H), 7.49–7.38 (m, 2H), 6.87–6.82 (m, 2H), 5.32 (s, 2H), 3.98 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H).

[0133] Step 2: Synthesis of 2-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid (IV-1)

[0134] Compound III-1 (4.20 g, 12.42 mmol) was mixed with a methanol / water mixture (1:1, 40 mL), followed by the addition of lithium hydroxide monohydrate (1.30 g, 31.05 mmol). After the addition was complete, the mixture was heated to 40 °C and reacted for approximately 2 h. The reaction was monitored by TLC (dichloromethane:methanol = 30:1) to ensure complete reaction of the starting materials, at which point the reaction was stopped. The solvent was removed by concentration under reduced pressure, and water (30 mL) was added to the residue. The pH of the reaction solution was adjusted to 2-3 with dilute hydrochloric acid (2 mol / L) under ice bath conditions, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 3.89 g of a white solid, with a yield of 96.6%. MS-ESI: [M+H] + 325.1; 1 H-NMR(300MHz,DMSO-d6)δ(ppm):12.74(s,1H),8.32-8.29(m,1H),7.97-7.85(m, 3H),7.30-7.27(m,2H),6.89-6.85(m,2H),5.24(s,2H),3.99(s,2H),3.71(s,3H).

[0135] Step 3: Synthesis of 4-(2-(-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)-2-(4-methoxybenzyl)phthalazine-1(2H)-one (XIX-1)

[0136] Compound IV-1 (200 mg, 0.62 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (354 mg, 0.93 mmol), and N,N-dimethylformamide (6 mL) were mixed, followed by the addition of a mixture of N,N-diisopropylethylamine (321 mg, 2.48 mmol) and 8-benzyl-3,8-diazabicyclo[3.2.1]octane hydrochloride (162 mg, 0.68 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for approximately 1.5 h. The reaction was stopped once the starting material was completely reacted by TLC (dichloromethane:methanol = 10:1). Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:1) to give 283 mg of a pale yellow oil, yield 89.8%. MS-ESI: [M+H] + 509.2.

[0137] Step 4: Synthesis of 4-(2-(8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one (I-1)

[0138] Compound XIX-1 (270 mg, 0.53 mmol) was dissolved in trifluoroacetic acid (3 mL), followed by the addition of trifluoromethanesulfonic acid (159 mg, 1.06 mmol). After the addition was complete, the mixture was heated to 60 °C and reacted for approximately 2 h. The reaction was monitored by TLC (dichloromethane:methanol = 10:1) to ensure complete reaction of the starting material, at which point the reaction was stopped. The solvent was removed by concentration under reduced pressure. The residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL × 3), and the organic layers were combined. The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 80:1) to give 150 mg of a brown solid, with a yield of 72.9%. MS-ESI: [M+H] + 389.2; 1H-NMR (300MHz, chloroform-d) δ (ppm): 10.49 (s, 1H), 8.49-8.46 (m, 1H), 8.01-7.97 (m, 1 H),7.89(td,J=7.6,1.6Hz,1H),7.82(td,J=7.5,1.4Hz,1H),7.44-7.34(m,5H), 4.28-4.24(m,1H),4.03(s,2H),3.88-3.84(m,1H),3.79-3.71(m,2H),3.67-3.6 1(m,1H),3.44(s,2H),3.20-3.12(m,1H),2.11-2.02(m,2H),1.73-1.62(m,2H).

[0139] Following the preparation method of compound I-1, the following compounds were prepared:

[0140]

[0141]

[0142]

[0143] Example 2: Synthesis of 1-benzyl-N-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)piperidine-4-carboxamide (I-15)

[0144] Step 1: Synthesis of methyl 3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylate (VI-1)

[0145] Using methyl 4-oxo-3,4-dihydrophthalazine-1-carboxylate (V-1, 5.98 g, 29.31 mmol) and p-methoxybenzyl chloride (5.51 g, 35.17 mmol) as starting materials, the procedure was the same as that for the synthesis of compound III-1, yielding 7.28 g of a white solid in 76.6% yield. MS-ESI: [M+H] + 325.1; 1 ¹H NMR (300MHz, chloroform-d) δ (ppm): 8.64–8.60 (m, 1H), 8.48–8.45 (m, 1H), 7.88–7.76 (m, 2H), 7.51–7.45 (m, 2H), 6.90–6.84 (m, 2H), 5.43 (s, 2H), 4.05 (s, 3H), 3.79 (s, 3H).

[0146] Step 2: Synthesis of 4-hydroxymethyl-2-(4-methoxybenzyl)phthalazine-1(2H)-one (VII-1)

[0147] Compound VI-1 (7.28 g, 22.46 mmol) and lithium chloride (1.43 g, 33.69 mmol) were dissolved in a tetrahydrofuran / methanol mixture (4:1, 75 mL). Sodium borohydride (1.27 g, 33.69 mmol) was then added in portions at 0 °C. After the addition was complete, the mixture was allowed to return to room temperature and reacted for approximately 2 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1) until complete, at which point the reaction was stopped. The solvent was removed by concentration under reduced pressure. Water (50 mL) was added to the residue, and the pH was adjusted to 6 with dilute hydrochloric acid (1 mol / L) in an ice bath. A white solid precipitated. The precipitate was filtered, and the filter cake was dried under vacuum to give 6.12 g of a white solid, with a yield of 92.0%. MS-ESI: [M+H] + 297.1; 1 HNMR(300MHz,DMSO-d6)δ(ppm):δ8.33-8.30(m,1H),8.17-8.14(m,1H),7.99-7.85(m,2H),7.34-7.2 9(m,2H),6.92-6.87(m,2H),5.60(t,J=5.7Hz,1H),5.25(s,2H),4.73(d,J=5.7Hz,2H),3.72(s,3H).

[0148] Step 3: Synthesis of 4-bromomethyl-2-(4-methoxybenzyl)phthalazine-1(2H)-one (VIII-1)

[0149] Compound VII-1 (6.00 g, 20.26 mmol), carbon tetrabromide (20.16 g, 60.78 mmol), and triphenylphosphine (15.94 g, 60.78 mmol) were dissolved in dichloromethane (60 mL), and the reaction was allowed to proceed at room temperature for approximately 0.5 h. The reaction was stopped after the starting material was completely reacted by TLC (petroleum ether:ethyl acetate = 3:1). The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 4.62 g of a white solid, yield 63.7%, MS-ESI: [M+H]. + 359.0.

[0150] Step 4: Synthesis of 4-azidomethyl-2-(4-methoxybenzyl)phthalazin-1(2H)-one (IX-1)

[0151] Compound VIII-1 (4.62 g, 12.90 mmol), azidotrimethylsilane (2.23 g, 19.35 mmol), and cesium fluoride (5.88 g, 38.70 mmol) were mixed with N,N-dimethylformamide (50 mL), and the mixture was heated to 60 °C and reacted for approximately 1.5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) until complete. The reaction was then stopped and cooled to room temperature. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 5). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 2.78 g of a white solid, yield 67.1%, MS-ESI: [M+H]. + 322.1.

[0152] Step 5: Synthesis of 4-(aminomethyl)-2-(4-methoxybenzyl)phthalazine-1(2H)-one (X-1)

[0153] Compound IX-1 (2.70 g, 8.41 mmol) and triphenylphosphine (3.31 g, 12.62 mmol) were dissolved in a tetrahydrofuran / water mixture (4:1, 30 mL), and after replacing with N2, the reaction was carried out at room temperature for about 5 h. The reaction was stopped when the starting material was completely reacted by TLC (petroleum ether:ethyl acetate = 3:1). The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 1.95 g of a white solid, yield 78.6%. MS-ESI: [M+H] + 296.1; 1 ¹H NMR (300MHz, chloroform-d) δ (ppm): 8.50–8.47 (m, 1H), 7.82–7.73 (m, 3H), 7.49–7.44 (m, 2H), 6.89–6.84 (m, 2H), 5.36 (s, 2H), 4.20 (s, 2H), 3.79 (s, 3H).

[0154] Step 6: Synthesis of 1-benzyl-N-((3-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)piperidine-4-carboxamide (XX-1)

[0155] Using compound X-1 (200 mg, 0.68 mmol) and 1-benzylpiperidine-4-carboxylic acid (178 mg, 0.81 mmol) as starting materials, the procedure was the same as that for the synthesis of compound XIX-1, yielding 293 mg of a white solid in 86.8% yield. MS-ESI: [M+H] + 497.2.

[0156] Step 7: Synthesis of 1-benzyl-N-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)piperidine-4-carboxamide (I-15)

[0157] Using compound XX-1 (293 mg, 0.59 mmol) as the starting material, the synthesis procedure was the same as that for compound I-1, yielding 152 mg of a white solid in 68.5% yield. MS-ESI: [M+H] + 377.2; 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 12.61 (s, 1H), 8.32 (t, J = 5.6Hz, 1H), 8.26 (dd, J = 7.8, 1.2Hz, 1H), 7.94-7.92 (m, 2H), 7.88-7.83 (m, 1 H),7.33-7.21(m,5H),4.56(d,J=5.6Hz,2H),3.42(s,2H),2.80-2.76(m,2H),2.16-2.08(m,1H),1.90-1.83(m,2H),1.62-1.57(m,4H).

[0158] Following the preparation method of compound I-15, the following compounds were prepared:

[0159]

[0160] Example 3: Synthesis of N-(1-benzylpiperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide (I-19)

[0161] Step 1: Synthesis of 5-(cyclopropylmethoxy)isobenzofuran-1(3H)-one (XII-1)

[0162] 5-Hydroxyisobenzofuran-1(3H)-one (XI-1, 5.80 g, 38.66 mmol), bromomethylcyclopropane (6.26 g, 46.39 mmol), and potassium carbonate (13.36 g, 96.65 mmol) were mixed with N,N-dimethylformamide (60 mL), and the mixture was heated to 60 °C and reacted for approximately 5 h. The reaction was monitored by TLC (dichloromethane:methanol = 30:1) to ensure complete reaction. The reaction was then stopped and cooled to room temperature. Water (240 mL) was added to the reaction mixture, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 6.25 g of a brown solid, with a yield of 79.2%. 1H-NMR (300MHz, chloroform-d) δ (ppm): 7.82 (d, J = 8.5Hz, 1H), 7.05 (dd, J = 8.5, 2.1Hz, 1H), 6.92-6.91 (m, 1 H),5.25(s,2H),3.90(d,J=6.9Hz,2H),1.39-1.25(m,1H),0.74-0.68(m,2H),0.42-0.37(m,2H).

[0163] Step 2: Synthesis of 3-bromo-5-(cyclopropylmethoxy)isobenzofuran-1(3H)-one (XIII-1)

[0164] Compound XII-1 (6.20 g, 30.38 mmol) was dissolved in carbon tetrachloride (60 mL), followed by the sequential addition of N-bromosuccinimide (5.57 g, 31.29 mmol) and azobisisobutyronitrile (499 mg, 3.04 mmol). After the addition was complete, the mixture was heated to 80 °C and reacted for approximately 6 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1) to ensure complete reaction of the starting material, at which point the reaction was stopped. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 60:1) to give 4.00 g of a pale yellow solid, with a yield of 46.7%. 1 ¹H-NMR (300MHz, chloroform-d) δ (ppm): 7.82 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.12 (dd, J = 8.5, 2.1 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 3.95 (d, J = 7.0 Hz, 2H), 1.40–1.27 (m, 1H), 0.76–0.69 (m, 2H), 0.44–0.39 (m, 2H).

[0165] Step 3: Synthesis of (6-(cyclopropylmethoxy)-3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphine (XIV-1)

[0166] Compound XIII-1 (4.00 g, 14.18 mmol) and triphenylphosphine (4.09 g, 15.60 mmol) were dissolved in acetonitrile (40 mL), and the mixture was then heated to 60 °C and reacted for approximately 6 h. The reaction was stopped by TLC (petroleum ether:ethyl acetate = 15:1) to monitor the reaction until complete. The solvent was removed by concentration under reduced pressure, and the residue was slurryed with a 10:1 mixture of ethyl acetate and dichloromethane to give 6.63 g of a white solid, yielding 85.9%. MS-ESI: [M+H] + 545.1; 1¹H-NMR (300MHz, chloroform-d) δ (ppm): 7.91–7.83 (m, 9H), 7.72–7.64 (m, 8H), 7.07 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 3.70–3.64 (m, 1H), 3.48–3.42 (m, 1H), 1.14–1.04 (m, 1H), 0.65–0.60 (m, 2H), 0.31–0.28 (m, 2H).

[0167] Step 4: Synthesis of ethyl 2-(6-(cyclopropylmethoxy)-3-oxoisobenzofuran-1(3H)-ylidene)ethyl acetate (XV'-1) Compound XIV-1 (6.60 g, 12.13 mmol) and ethyl glyoxylate (1.61 g, 15.77 mmol) were dissolved in dichloromethane (65 mL). After replacing with N2, triethylamine (1.47 g, 14.56 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and the reaction was allowed to proceed for approximately 6 h. The reaction was stopped when the starting material was completely reacted by TLC (petroleum ether:ethyl acetate = 10:1). The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1) to give 2.12 g of a white solid, yield 60.7%. 1 ¹H-NMR (300MHz, chloroform-d) δ (ppm): 8.52 (d, J = 2.2Hz, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.13 (dd, J = 8.5, 2.2Hz, 1H), 6.03 (s, 1H), 4.21 (q, J = 7.1Hz, 2H), 3.92 (d, J = 7.0Hz, 2H), 1.29 (t, J = 7.1Hz, 3H), 1.24–1.18 (m, 1H), 0.66–0.59 (m, 2H), 0.38–0.33 (m, 2H).

[0168] Step 5: Synthesis of ethyl 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazine-1-yl)ethyl acetate (XVI-1)

[0169] Compound XV'-1 (2.11 g, 7.32 mmol) was dissolved in anhydrous ethanol (20 mL), followed by the addition of hydrazine hydrate (80%, 481 mg, 7.69 mmol). After the addition was complete, the mixture was heated to 85 °C and reacted for approximately 0.5 h. The reaction was monitored by TLC (dichloromethane:methanol = 20:1) to ensure complete reaction. The reaction was then stopped and cooled to room temperature. A white solid precipitated, which was filtered, and the filter cake was dried under vacuum. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 80:1), yielding a total of 1.80 g of white solid, with a yield of 81.4%. MS-ESI: [M+H] + 303.1; 1H-NMR (300MHz, chloroform-d) δ (ppm): 10.70 (s, 1H), 8.40 (d, J = 8.8Hz, 1H), 7.35 (dd, J = 8.8, 2.4Hz, 1H), 7.09 (d, J = 2.4Hz, 1H), 4 .21(q,J=7.1Hz,2H),3.97-3.94(m,4H),1.39-1.32(m,1H),1.26(t,J=7.1Hz,3H),0.76-0.69(m,2H),0.45-0.40(m,2H).

[0170] Step 6: Synthesis of 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid (XVII-1)

[0171] Compound XVI-1 (1.80 g, 5.96 mmol) was mixed with a methanol / water mixture (1:1, 20 mL), followed by the addition of lithium hydroxide monohydrate (625 mg, 14.89 mmol). The reaction was allowed to proceed at room temperature for approximately 3 h. The reaction was stopped by TLC (dichloromethane:methanol = 10:1) to monitor the reaction progress. The solvent was removed by concentration under reduced pressure. Water (15 mL) was added to the residue, and the pH was adjusted to 3-4 with dilute hydrochloric acid (2 mol / L) in an ice bath. A white solid precipitated. The precipitate was filtered, and the filter cake was dried under vacuum to give 1.50 g of a white solid, with a yield of 91.8%. MS-ESI: [M+H] + 275.1; 1 ¹H-NMR (300MHz, chloroform-d) δ 11.69 (s, 1H), 10.73 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.9, 2.4 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 3.98 (d, J = 7.0 Hz, 2H), 3.87 (s, 2H), 1.36–1.22 (m, 1H), 0.67–0.53 (m, 2H), 0.43–0.32 (m, 2H).

[0172] Step 7: Synthesis of N-(1-benzylpiperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide (I-19)

[0173] Compound XVII-1 (60 mg, 0.22 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (354 mg, 0.93 mmol), and N,N-dimethylformamide (3 mL) were mixed, followed by the addition of a mixture of N,N-diisopropylethylamine (321 mg, 2.48 mmol) and 1-benzylpiperidin-4-amine (46 mg, 0.24 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for approximately 6 h. The reaction was stopped when the starting material was completely reacted by TLC (dichloromethane:methanol = 10:1). Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 30:1) to give 62 mg of a white solid, with a yield of 63.3%. MS-ESI: [M+H] + 447.2; 1 H-NMR (300MHz, DMSO-d6) δ (ppm): 12.40 (s, 1H), 8.44 (s, 1H), 8.13 (d, J = 8.8Hz, 1H) ,7.39(dd,J=8.8,2.3Hz,1H),7.32-7.26(m,6H),3.98(d,J=7.1Hz,2H),3.77(s,2H) ,3.59-3.49(m,1H),3.44(s,2H),2.77-2.70(m,2H),2.03-1.95(m,2H),1.73-1.69( m,2H),1.51-1.39(m,2H),1.31-1.23(m,1H),0.63-0.55(m,2H),0.36-0.30(m,2H).

[0174] Following the preparation method of compound I-19, the following compounds were prepared:

[0175]

[0176]

[0177]

[0178]

[0179] Example 4: Synthesis of 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)acetamide (I-31)

[0180] Step 1: Synthesis of tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)carbamate

[0181] Piperidin-4-ylcarbamate tert-butyl ester (500 mg, 2.50 mmol) and 1-methyl-1H-pyrazole-4-carboxaldehyde (358 mg, 3.25 mmol) were dissolved in tetrahydrofuran (8 mL), followed by the addition of acetic acid (300 mg, 5.00 mmol). The mixture was stirred at room temperature for about 1 h. Sodium triacetoxyborohydride (848 mg, 4.00 mmol) was added to the reaction solution under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and the reaction was allowed to proceed overnight. The reaction was stopped when the starting materials were completely reacted by TLC (dichloromethane:methanol = 10:1). Add 15 mL of ice water to the reaction solution, adjust the pH to 8-9 with saturated sodium bicarbonate solution, extract with a dichloromethane / methanol mixed solvent (10:1, 10 mL × 3), combine the organic layers, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 50:1) to give 711 mg of white solid, yield 96.7%, MS-ESI: [M+H] + 295.2.

[0182] Step 2: Synthesis of 1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-amine hydrochloride

[0183] 500 mg (1.70 mmol) of tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)carbamate was dissolved in 3 mL of dichloromethane. Then, a solution of dioxane (4 mol / L) of hydrogen chloride was slowly added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted overnight. The reaction was monitored by TLC (dichloromethane:methanol = 10:1) to ensure complete reaction. The solvent was removed by concentration under reduced pressure. The residue was slurryed with 5 mL of ethyl acetate, filtered, and the filter cake was dried under vacuum to give 346 mg of a white solid, yield 76.5%. MS-ESI: [M+H] + 195.2.

[0184] Step 3: Synthesis of 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)acetamide (I-31)

[0185] Using compound XVII-1 (80 mg, 0.29 mmol) and 1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-amine hydrochloride (85 mg, 0.32 mmol) as starting materials, the procedure was the same as that for the synthesis of compound I-19, yielding 87 mg of white solid in 66.6% yield.

[0186] Example 5: Synthesis of 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexyl)acetamide (I-45)

[0187] Step 1: Synthesis of tert-butyl (4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexyl)carbamate

[0188] 200 mg (0.68 mmol) of tert-butyl (4-(bromomethyl)cyclohexyl)carbamate, 67 mg (0.82 mmol) of 2-methyl-1H-imidazole, and 189 mg (1.37 mmol) of potassium carbonate were mixed with 2 mL of N,N-dimethylformamide, and the mixture was heated to 80 °C and reacted for approximately 8 h. The reaction was stopped after TLC (dichloromethane:methanol = 15:1) to monitor the reaction progress. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 40:1) to give 168 mg of a colorless oil (yield 84.2%). MS-ESI: [M+H] + 294.2.

[0189] Step 2: Synthesis of 4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexane-1-amine hydrochloride

[0190] Using tert-butyl (4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexyl)carbamate (160 mg, 0.55 mmol) as the starting material, the procedure was the same as the synthesis of 1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-4-amine hydrochloride, yielding 120 mg of a white solid in 82.8% yield. MS-ESI: [M+H] + 194.2.

[0191] Step 3: Synthesis of 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexyl)acetamide (I-45)

[0192] Using compound XVII-1 (80 mg, 0.29 mmol) and 4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexane-1-amine hydrochloride (85 mg, 0.32 mmol) as starting materials, the procedure was the same as that for the synthesis of compound I-19, yielding 95 mg of a white solid in 73.1% yield.

[0193] Example 6: Synthesis of N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(7-((1-methyl-1H-pyrazol-4-yl)methoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide (I-48)

[0194] Step 1: Synthesis of ethyl 2-(6-hydroxy-3-oxoisobenzofuran-1(3H)-ylidene) (XVIII-1)

[0195] Compound XV'-1 (1.72 g, 5.97 mmol) was dissolved in dichloromethane (15 mL). Under ice bath conditions, trifluoroacetic acid (5.45 g, 47.76 mmol) and trifluoromethanesulfonic acid (1.34 g, 8.96 mmol) were slowly added sequentially to the reaction solution. After the addition was complete, the mixture was brought to room temperature and the reaction was allowed to proceed for approximately 0.5 h. The reaction was stopped by TLC (petroleum ether:ethyl acetate = 10:1) to monitor the reaction progress. The pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate solution at -20 °C, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dried under vacuum. The filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1), yielding a total of 1.10 g of white solid (78.7% yield). MS-ESI: [M+H] + 235.1.

[0196] Step 2: Synthesis of ethyl acetate 2-(6-((1-methyl-1H-pyrazol-4-yl)methoxy)-3-oxoisobenzofuran-1(3H)-ylidene) (XV-1)

[0197] Compound XVIII-1 (200 mg, 0.85 mmol), (1-methyl-1H-pyrazole-4-yl)methanol (114 mg, 1.02 mmol), and triphenylphosphine (449 mg, 1.71 mmol) were dissolved in tetrahydrofuran (4 mL). After replacing the nitrogen with nitrogen, diisopropyl azodicarboxylate (346 mg, 1.71 mmol) was slowly added dropwise to the reaction solution under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and the reaction was allowed to proceed overnight. The reaction was stopped by TLC (petroleum ether:ethyl acetate = 3:1) to monitor the reaction until the starting material was completely reacted. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 252 mg of a white solid, yield 90.3%. MS-ESI: [M+H] + 329.1.

[0198] Step 3: Synthesis of N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(7-((1-methyl-1H-pyrazol-4-yl)methoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide (I-48)

[0199] Using compound XV-1 (300 mg, 0.91 mmol) as the starting material, a series of procedures were performed similarly to those for the synthesis of compound I-19, yielding 132 mg of a white solid, with an overall yield of 57.6%. MS-ESI: [M+H] + 505.2; 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 12.43 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.8Hz, 1 H),7.86(s,1H),7.55(s,1H),7.44(d,J=8.8,2.4Hz,1H),7.36-7.30(m,3H),7.21 -7.11(m,2H),5.11(s,2H),3.82(s,3H),3.78(s,2H),3.61-3.52(m,1H),3.39(s, 2H),2.78-2.69(m,2H),2.09-1.91(m,2H),1.82-1.67(m,2H),1.53-1.40(m,2H).

[0200] Following the preparation method of compound I-48, the following compounds were prepared:

[0201]

[0202] Example 7: PARP14 Inhibitory Activity Test

[0203] 1. Experimental reagents

[0204] The PARP14 chemiluminescence assay kit was purchased from BPS Bioscience.

[0205] 2. Experimental Methods

[0206] Compound samples were prepared into a 10 mM stock solution using DMSO and then added to the screening system. The detection range was 0.01 nM–100 nM. The samples were serially diluted 3-fold, with two replicates for each concentration. The IC50 was calculated using nonlinear regression with GraphPad Prism5 based on the experimental results. 50 value.

[0207] Add 100 μL of histone PBS solution (20 μg / mL) to each well of a 96-well plate and incubate overnight at 4°C. Remove the plate and wash twice. Add 30 μL of reaction buffer (100 μM NAD) to each well. + 25 μM biotinylated NAD +Add 200 nM slDNA), then add 5 μL of different concentrations (0.1 nM, 0.33 nM, 1 nM, 3.3 nM, 10 nM, 33 nM, 100 nM, 330 nM, 1000 nM) of compound or solvent control. Next, add 20 μL PARP protein (50 ng / well) and incubate at 30 °C for 1 h. Discard and wash twice. Add 50 μL streptavidin-labeled horseradish peroxidase (HRP) to each well and incubate at 30 °C for 0.5 h. Finally, add 100 μL of chromogenic buffer and measure the luminescence signal using a multi-well spectrophotometer (SpectraMax M5 microplate reader). The inhibition rate of PARP14 enzyme activity = (1 - (RLU) / 200 nM slDNA) cmpd -RLU blank / RLU pos.ctrl -RLU blank The concentration logarithm was plotted on the X-axis, and the percentage inhibition rate on the Y-axis. A dose-response curve was fitted using the log(inhibitor) vs. response-variable slope method in GraphPad Prism 8 software to determine the IC50 of each compound on enzyme activity. 50 value.

[0208] 3. Experimental Results

[0209] The compounds of this invention were screened for in vitro PARP14 inhibitory activity, and the results are shown in Table 1.

[0210] Table 1. Inhibitory activity of compounds against PARP14

[0211]

[0212] Note: A: 0.0001 <IC 50 ≤0.05μM; B: 0.05 <IC 50 ≤0.5μM; C:IC 50 >0.5μM.

[0213] Table 1 shows that the compounds of the present invention have good inhibitory activity against PARP14, and the activities of compounds I-19 to I-20, I-26, I-29, I-31, I-34 to I-43, I-45 and I-48 to I-49 are all no higher than 50 nM.

Claims

1. A phthalazinone compound, characterized in that, Having the structure shown in formula (I), it also includes its stereoisomers, tautomers, solvates, prodrugs, isotopic labels, or pharmaceutically acceptable salts. in: R 1 The substituent is selected from H, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocyclic alkyl, substituted phenyl, or substituted 5- to 6-membered heteroaryl; the substituent is selected from H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic alkyl, phenyl-substituted C1-C8 alkyl, 5- to 6-membered heteroaryl-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C3-C8 halocycloalkyl carbonyl, C3-C8 cycloalkyl carbonyl, hydroxyl, amino, nitro, or cyano; R 2 Selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, hydroxy-substituted C1-C8 alkyl or amino-substituted C1-C8 alkyl. R 3 The substituent is selected from substituted phenyl groups, substituted 5- to 6-membered heteroaryl groups, substituted C3-C8 cycloalkyl groups, and substituted 3- to 10-membered heterocyclic alkyl groups; the substituent of the phenyl or 5- to 6-membered heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxyl, amino, or C1-C8 alkyl carbonyl-substituted amino groups; the substituent of the C3-C8 cycloalkyl or 3- to 10-membered heterocyclic alkyl group is selected from H, oxo and / or -L1-R. 4 ; L1 is selected from a bond or a C1-C4 alkylene group; R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkyl carbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkyl carbonyl, C3-C8 cycloalkyl carbonyl, C3-C8 halocycloalkyl carbonyl, phenyl carbonyl, 5- to 6-membered heteroaryl carbonyl, or carbamoyl; wherein the substituent of the phenyl or heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, cyano, hydroxyl, amino, or an amino group substituted with C1-C8 alkyl carbonyl; wherein the substituent of the cycloalkyl or heterocycloalkyl group is selected from H, oxo, and / or -L2-R. 4 '; L2 is selected from a bond or a C1-C4 alkylene group; R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxy carbonyl, C1-C8 alkoxy alkyl carbonyl, C1-C8 alkyl carbamoyl, di(C1-C8 alkyl) carbamoyl, di(C1-C8 alkyl) amino alkyl carbonyl, C3-C8 cycloalkyl carbonyl or C3-C8 halocycloalkyl carbonyl; R 5 R 5 Each is independently selected from H or C1-C8 alkyl groups; The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S; A 1 Selected from -O-, -NH-, -CH2-, or -S-; A 2 Selected from -O-, -NH-, -N(CH3)-, -CH2-, -CH2NH-, or -S-; A 3 Selected from -O-, -NH-, -N(CH3)-, -S-, -(CH2) m1 -or -NH(CH2) m1 -; m1 is selected from 1 or 2; n is selected from 0, 1, or 2; m, p, and q are each independently selected from 0 or 1.

2. The phthalazinone compound according to claim 1, characterized in that, In the structure: R 1 The substituent is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, substituted C3-C6 cycloalkyl, substituted 3- to 6-membered heterocyclic alkyl, substituted phenyl, or substituted 5- to 6-membered heteroaryl; the substituent is selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic alkyl, phenyl-substituted C1-C6 alkyl, 5- to 6-membered heteroaryl-substituted C1-C6 alkyl, C1-C8 alkyl carbonyl, C3-C8 halocycloalkyl carbonyl, C3-C8 cycloalkyl carbonyl, hydroxyl, amino, nitro, or cyano; The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S.

3. The phthalazinone compound according to claim 1, characterized in that, In the structure: R 1 The substituent is selected from H or substituted methyl, ethyl, propyl, methoxyethyl, cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrroleyl or pyrazolyl; the substituent is selected from H, halogen, methyl, trifluoromethyl, acetyl or cyclopropylcarbonyl.

4. The phthalazinone compound according to claim 1, characterized in that, In the structure: R 3 Selected from: Where X is selected from CR 6 R 6 '、NR 6 Or O; R 6 R 6 Each independently selected from -L1-R 4 ; L1 is selected from a bond or a C1-C4 alkylene group; R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkyl carbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkyl carbonyl, C3-C8 cycloalkyl carbonyl, C3-C8 halocycloalkyl carbonyl, phenyl carbonyl, 5- to 6-membered heteroaryl carbonyl, or carbamoyl; wherein the substituent of the phenyl or heteroaryl group is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, cyano, hydroxyl, amino, or an amino group substituted with C1-C8 alkyl carbonyl; wherein the substituent of the cycloalkyl or heterocycloalkyl group is selected from H, oxo, and / or -L2-R. 4 '; L2 is selected from a bond or a C1-C4 alkylene group; R 4 Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 5 R 5 ', carboxyl, hydroxyl, hydroxy-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, C1-C8 alkyl carbonyl, C1-C8 alkyl sulfonyl, C1-C8 alkoxy carbonyl, C1-C8 alkoxy alkyl carbonyl, C1-C8 alkyl carbamoyl, di(C1-C8 alkyl) carbamoyl, di(C1-C8 alkyl) amino alkyl carbonyl, C3-C8 cycloalkyl carbonyl or C3-C8 halocycloalkyl carbonyl; R 5 R 5 Each is independently selected from H or C1-C6 alkyl groups; The heterocyclic alkyl group contains 1-4 cyclic heteroatoms selected from N, O or S, and the heteroaryl group contains 1-4 cyclic heteroatoms selected from N, O or S.

5. The phthalazinone compound according to claim 1, characterized in that, In the structure: R 3 Selected from: Among them, R 7 It is selected from H, methyl, isopropyl, benzyl, halobenzyl, p-methylbenzyl, oxacyclobutyl, cyclopropylmethyl, tetrahydropyranylmethyl, pyridylmethyl, halopyridylmethyl, N-methylpyrazolylmethyl, N-methylpyrrolithylmethyl, N-methylpyrrolithylformyl, N-cyclopropylpyrazolylmethyl, 2-methylthiazolylmethyl, N-isobutylpyrazolylmethyl, 4-fluoropyrazolyl-1-methyl, 2-methylimidazolyl-1-methyl, 4-trifluoromethylpyrazolyl-1-methyl, cyclopropylcarbonyl, furanylmethyl, pyrimidinylmethyl, oxazolylmethyl, or benzoyl.

6. The phthalazinone compound according to claim 1, characterized in that, In the structure: R 2 Selected from H or halogens.

7. The phthalazinone compound according to claim 1, characterized in that, Selected from any one of the following compounds: 4-(2-(8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 4-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)phthalazin-1(2H)-one; N-(1-benzoylpiperidin-4-yl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; N-((1-benzylpiperidin-4-yl)methyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 4-(2-(7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-oxoethyl)phthalazine-1(2H)-one; N-(1-Benzylpiperidin-4-yl)-N-methyl-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 4-(2-(8-(cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; 4-(2-(8-benzoyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; 4-(2-(8-(cyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; 4-(2-(8-(4-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; 4-(2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-oxoethyl)phthalazine-1(2H)-one; 4-(2-(3-benzyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-oxoethyl)phthalazine-1(2H)-one; 1-Benzyl-N-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)piperidine-4-carboxamide; 1-Benzoyl-N-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)piperidine-4-carboxamide; 1-Benzoyl-N-(2-(4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)piperidine-4-carboxamide; 1-Benzyl-N-(2-(4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)piperidine-4-carboxamide; N-(1-benzylpiperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)acetamide; N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; N-(1-benzoylpiperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(1-methyl-1H-pyrrolo-3-carbonyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide; 6-(cyclopropylmethoxy)-4-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethyl)phthalazin-1(2H)-one; N-(1-(4-chlorobenzyl)piperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(oxecyclobutane-3-yl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(4-methylbenzyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)acetamide; 6-(cyclopropylmethoxy)-4-(2-oxo-2-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)phthalazin-1(2H)-one; N-(3-acetamidophenyl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-ethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)acetamide; N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(7-(2-methoxyethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-(cyclopentylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(4-fluorobenzyl)azacyclobutane-3-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-methyl-1H-pyrrolo-3-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(2-(4-fluorobenzyl)-2-azaspiro[3.3]heptane-6-yl)acetamide; N-(1-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((2-methylthiazo-4-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(1-((1-isobutyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)cyclohexyl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-((2-methyl-1H-imidazol-1-yl)methyl)cyclohexyl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)acetamide; 2-(7-(cyclopropylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)-N-(6-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)spiro[3.3]heptane-2-yl)acetamide; N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(7-((1-methyl-1H-pyrazol-4-yl)methoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide; N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(7-(oxecyclobutane-3-ylmethoxy)-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide.

8. A method for preparing the phthalazinone compound according to claim 1, characterized in that, Choose from any of the following methods: Method 1: When n=0, p=0, R 1 When selected from H, halogen, methyl, or hydroxyl, compound IV reacts first with R. 3 (A 3 ) q H-condensation, followed by deprotection, yields compound I. Among them, m, q, A 2 A 3 R 2 R 3 The definition is as described in claim 1; Method 2: When n=0, p=0, A 2 Selected from -CH2NH-, R 1 When selected from H, halogen, methyl, or hydroxyl, compound X first reacts with R. 3 (A 3 ) q COOH condensation followed by deprotection yields compound I. Among them, m, q, A 3 R 2 R 3 The definition is as described in claim 1; Method 3: When p = 1, m = 0, A 2 When selected from -CH2-, compounds XVII and R 3 (A 3 ) q H-condensation yields compound I; Where, n, q, A 1 A 3 R 1 R 2 R 3 The definition is as described in claim 1; Method 4: When n=0, p=0, R 1 When the compounds are selected from H, halogen, methyl, or hydroxyl, compound II is N-protected and hydrolyzed to give compound IV, which is then obtained by following method one to obtain compound I. Among them, m and A 2 R 2 The definition is as described in claim 1; Method 5: When n=0, p=0, A 2 Selected from -CH2NH-, R 1 When selected from H, halogen, methyl, or hydroxyl, compound V undergoes N-protection, reduction, bromination, diazotization, and reduction to obtain compound X, which is then obtained according to method two to obtain compound I. Wherein, m, R 2 The definition is as described in claim 1; Method Six: When p=1, m=0, A 2 When selected from -CH2-, compound XI is subjected to substitution, bromination, activation, condensation, reduction and hydrolysis to obtain compound XVII, and then compound I is obtained according to method three; Where, n, A 1 R 1 R 2 The definition is as described in claim 1; Method 7: When p = 1, compound XV' is hydrolyzed and substituted to obtain compound XV, then compound XVII is obtained according to method 6, and finally compound I is obtained according to method 3; Where, n, A 1 R 1 R 2 The definition is as described in claim 1.

9. A pharmaceutical composition, characterized in that, It comprises the compound according to claim 1 and a pharmaceutically acceptable carrier.

10. Use of a compound of claim 1 or a pharmaceutical composition of claim 9 in the preparation of a medicament for a PARP14 inhibitor.

11. The use according to claim 10, characterized in that, The drug is a drug for the prevention and / or treatment of tumors or inflammatory diseases.

12. The use according to claim 10, characterized in that, The stated medication is for the prevention and / or treatment of leukemia, lymphoma, liver cancer, bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing sarcoma, pancreatic cancer, gallbladder cancer, stomach cancer, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lung cancer, prostate cancer, skin cancer, testicular cancer, thyroid cancer, melanoma, or uterine cancer; or the stated medication is for the prevention and / or treatment of atopic dermatitis, psoriasis, scleroderma, inflammatory bowel disease, arthritis, inflammatory demyelinating diseases, emphysema, psoriasis, asthma, pulmonary fibrosis, allergies, or lupus.

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