Quinazolinone derivative as well as preparation method and application thereof

Abstract

The invention relates to a quinazolinone derivative as shown in a formula (I) as well as a preparation method and application of the quinazolinone derivative. The quinazolinone derivative shown in the formula (I) has PARP14 inhibiting activity and can be used for preventing and / or treating cancers and inflammatory diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a quinazolinone derivative, a preparation method thereof, and uses thereof. Background Art

[0002] Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme that can regulate gene expression, protein degradation, and various cellular stress responses within cells. The PARP family has 18 members, which can be divided into mono(ADP-ribosyl)transferases (monoPARP) and poly(ADP-ribosyl)transferases (polyPARP) according to different catalytic activities, and they use nicotinamide adenine dinucleotide (NAD + ) as a substrate to perform mono- or poly-ADP-ribosylation modification on target proteins. (Nizi MG et al, J Med Chem. 2022, 65, 7532-7560). Among them, PARP-14 is a monoPARP that is mainly involved in cellular responses and signal transduction in the immune system (Qin W et al, Front Pharmacol. 2019, 10, 172).

[0003] Studies have shown that PARP14 is a negative downstream regulator of IFN-γ / STAT1 transcription and a positive regulator of IL-4 / STAT6 transcription, and is involved in the differentiation process of macrophages and T helper cells (Iwata H et al, Nat Commun. 2016, 7, 12849; Mehrotra P et al, J Biol Chem. 2010, 286(3), 1767–1776). Knockout of the PARP14 gene drives macrophages towards the IFN-γ-driven M1 phenotype, while reducing the IL-4-driven M2 phenotype and the Th2 phenotype of 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 in immune checkpoint inhibitor (ICI) therapy (Schenkel LB et al, Cell Chem Biol. 2021, 28, 1-11). Recent 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 (Wong CW et al, Nat Commun. 2023, 14, 5983). In addition, the non-immune anti-tumor effects of PARP14 are also being studied simultaneously. For example, knockout or inhibition of PARP14 affects the survival and proliferation of diffuse large B-cell lymphoma (DLBCL) (Aguiar RCT et al, J Biol Chem. 2005, 280(40), 33756-33765), multiple myeloma (MM) (Barbarulo A et al, Oncogene. 2013, 32(36), 4231-4242), hepatocellular carcinoma (HCC) (Iansante V et al, Nat Commun. 2015, 6(1), 7882), and metastatic prostate cancer (mPCa) (Bachmann SB et al, Mol Cancer. 2014, 13(1), 125-149). These studies confirm the potential application value of PARP14 inhibitors as monotherapy and / or in combination with ICI in cancer treatment.

[0004] In the inflammatory response, PARP14 promotes the differentiation of Th2 cells by regulating the binding process of STAT6 to the GATA3 promoter, thereby generating cytokines such as IL-4, IL-5, and IL-13. Among them, IL-4 / STAT6 further regulates the expression of eosinophil chemotactic factor 3 (eotaxin 3) to cause the aggregation of eosinophils, and stimulates B cells to mature and differentiate into plasma cells to produce IgE antibodies. In addition, as a member of the IL-6 / STAT3 signaling cascade, PARP14 can promote the differentiation of T helper 17 (Th17) cells and follicular T helper (Tfh) cells, thereby upregulating the secretion of cytokines IL-17A, IL-17F, and IL-21, ultimately leading to the recruitment of neutrophils (Eddie AM et al, bioRxiv 2021; Niepel M et al, ERS International Congress 2022). Studies have confirmed that knocking out or inhibiting PARP14 shows 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 contact dermatitis (Mehrotra P et al, J Allergy Clin Immunol. 2013, 131(2):521; Niepel M et al, ERS International Congress 2022; Niepel M et al, ISID 2023 Meeting). Therefore, compared with existing therapies, regulating multiple inflammatory pathways by inhibiting PARP14 is expected to improve the therapeutic effect of related inflammation.

[0005] Currently, the clinical need for drugs to treat cancers or inflammatory diseases characterized by abnormal expression of PARP14 remains extremely urgent. The research and development of such drugs have received increasing attention. For example, PCT / US2018 / 066700 discloses a quinazolinone compound as a PARP14 inhibitor.

[0006] The object of the present invention is to provide a compound with inhibitory activity against PARP14, which can be used for the prevention and / or treatment of tumors and inflammatory diseases with abnormal expression of PARP14. Summary of the Invention

[0007] The present invention discloses a compound represented by formula (I):

[0008]

[0009] or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, wherein

[0010] X is selected from CH2, O, NH or S;

[0011] R 1 is selected from H, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl-C1-C8 alkyl, 5- to 6-membered heteroaryl-C1-C8 alkyl, C1-C8 alkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, hydroxy, amino, nitro or cyano;

[0012] R 2 is selected from H, halogen, hydroxy, cyano, nitro, amino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, hydroxy C1-C8 alkyl, or amino C1-C8 alkyl;

[0013] R 3 is selected from:

[0014] a. wherein R 4 and R 5 together with the carbon atom to which they are attached form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with an oxo group and / or -L1-R 6 ; wherein L1 is selected from a bond or C1-C4 alkylene, and R 6 is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxy, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl; wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; the cycloalkyl or heterocycloalkyl is optionally substituted with oxo and / or -L2-R 6 ’ is substituted, L2 is selected from a bond or C1-C4 alkylene, R 6 ’ is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, carboxyl, hydroxy, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl, wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; Y is selected from N or CR 8 ;

[0015] b. -Z-(CH2) m1 -Q, where Q is selected from optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl; wherein the phenyl or 5- to 6-membered heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; the C3-C8 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with oxo and / or -L1-R 6 is substituted, where L1 is selected from a bond or C1-C4 alkylene, R 6Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl; wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxyl, amino, C1-C8 alkylcarbonylamino; the cycloalkyl or heterocycloalkyl is optionally substituted with an oxo group and / or -L2-R 6 ’, L2 is selected from a bond or C1-C4 alkylene, and R 6 ’ is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, carboxyl, hydroxyl, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl; Z is selected from CR 8 R 8 ’, NR 8 , O or Se;

[0016] R 7 and R 7 ’ are each independently selected from H or C1-C8 alkyl;

[0017] R 8 and R 8 ’ are each independently selected from H or C1-C6 alkyl;

[0018] p and q are each independently selected from 1, 2 or 3;

[0019] n and m are each independently selected from 0, 1 or 2;

[0020] m1 is selected from 0, 1, 2 or 3;

[0021] The condition is that when X is O, n is 1, m is 0, and R 1 is cyclopropyl and R 2 is F, R 3 is not any of the following groups:

[0022]

[0023] When X is O, n is 1, m is 0, and R 1 is phenyl and R 2 is F, R 3 is not

[0024] When X is O, n is 1, m is 0, and R 1 is methyl and R 2 is F, R 3 is not

[0025] When X is O, n is 1, m is 0, and R 2 is F and R 3 is R 1 is not cyclobutyl, cyclopentyl or tetrahydropyranyl;

[0026] When X is O, n is 0, m is 0, and R 1 is cyclopentyl and R 2 is F, R 3 is not

[0027] When X is O, n is 1, m is 0, and R 1 is and R 2 is F, R 3 is not

[0028] In some embodiments, R in the compound represented by formula (I) 1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted with groups selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl-C1-C6 alkyl, 5- to 6-membered heteroaryl-C1-C6 alkyl, C1-C8 alkylcarbonyl, C3-C8 halocycloalkylcarbonyl, C3-C8 cycloalkylcarbonyl, hydroxy, amino, nitro or cyano.

[0029] In some embodiments, R 1selected from ethyl, propyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl; said groups are optionally substituted with groups selected from the following: halogen, methyl, trifluoromethyl, acetyl, cyclopropylcarbonyl.

[0030] In some embodiments, R in the compound of formula (I) 3 is selected from:

[0031]

[0032] wherein:

[0033] W represents CR 9 R 9 ’, NR 9 or O, R 9 and R 9 ’ are each independently selected from -L1-R 6 , wherein L1 is selected from a bond or a C1-C4 alkylene, and R 6 is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxyl, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl; wherein said phenyl or heteroaryl is optionally substituted with groups selected from the following: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxyl, amino, C1-C8 alkylcarbonylamino; said cycloalkyl or heterocycloalkyl is optionally substituted with an oxo group and / or -L2-R 6 ’, L2 is selected from a bond or a C1-C4 alkylene, and R 6 ’ is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, carboxyl, hydroxyl, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminoalkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl, wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxyl, amino, C1-C8 alkylcarbonylamino;

[0034] m1 is selected from 0, 1, 2 or 3; p is selected from 1, 2 or 3; q is selected from 1, 2 or 3.

[0035] In some embodiments, R in the compound of formula (I) 3 is selected from:

[0036]

[0037] wherein:

[0038] R 10 is selected from H, methyl, oxetanyl, propionyl, acetyl, isopropionyl, isobutyryl, methoxycarbonyl, cyclopropylcarbonyl, halocyclopropylcarbonyl, benzoyl, benzyl, halobenzyl, p-methylbenzyl, p-trifluoromethylbenzyl, pyridylmethyl, pyrazolylmethyl, pyridinecarbonyl, halopyridinecarbonyl, N-methylpyrrolecarbonyl, N-methylpyrazolecarbonyl, furancarbonyl, C1-C3 alkylsulfonyl or N,N-dimethylformamido.

[0039] In some embodiments, R in the compound of formula (I) 2 is selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, hydroxy C1-C8 alkyl, or amino C1-C8 alkyl. In a preferred embodiment, R 2 is selected from H, hydroxyl or halogen. In a more preferred embodiment, R 2 is selected from H, fluorine or chlorine.

[0040] In a more preferred embodiment, the compound of formula (I) is selected from:

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] or a stereoisomer, tautomer, solvate, prodrug, isotopically labeled compound, and pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the present invention provides a method for preparing a compound represented by formula (I).

[0052] In some embodiments, the present invention further provides a pharmaceutical composition comprising a compound represented by formula (I) of the present invention or a stereoisomer, tautomer, solvate, prodrug, isotopically labeled compound, and pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0053] In some embodiments, the present invention further provides a pharmaceutical use of the compound represented by formula (I) of the present invention, particularly for use in the preparation of a drug for preventing and / or treating cancer and inflammatory diseases.

[0054] Advantages: Compared with the prior art, the compounds of the present invention exhibit significantly better biological activity of inhibiting PARP14, and have a bright prospect of being developed into a new drug for preventing and / or treating tumors and inflammatory diseases. Moreover, when the compounds of the present invention are used in combination with known anti-tumor and anti-inflammatory drugs, the therapeutic effect of the known anti-tumor and anti-inflammatory drugs can be improved, and at the same time, the side effects of the drugs can be reduced. Detailed Embodiments

[0055] Definitions

[0056] As used in this specification, unless the context in which they are used indicates otherwise, the following words and phrases are generally intended to have the meanings set forth below.

[0057] As used herein, the term "alkyl" refers to a monovalent group of a straight-chain or branched-chain saturated hydrocarbon chain having 1 to 8 carbon atoms (more typically 1 to 6 carbon atoms or 1 to 4 carbon atoms). Illustrative examples of this term are 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, and the like.

[0058] As used herein, the term "alkylene" refers to a divalent group of a straight-chain or branched-chain saturated hydrocarbon chain having 1 to 8 carbon atoms (more typically 1 to 6 carbon atoms or 1 to 4 carbon atoms). Illustrative examples of this term are groups such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0059] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine (preferably fluorine or chlorine).

[0060] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, where alkyl is as defined herein. Illustrative examples of this term are groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0061] As used herein, the term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen, where alkyl is as defined herein. Illustrative examples of this term are groups such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 2,2,2-trichloroethyl, and the like.

[0062] As used herein, the term "cycloalkyl" refers to a monocyclic 3- to 8-membered ring having 3 to 8 carbon atoms as ring atoms or a single saturated or partially unsaturated carbocyclic group of multiple fused (condensed), bridged, or spiro rings having 7 to 8 carbon atoms as ring atoms. The cycloalkyl can be saturated or partially unsaturated and can be fused to another saturated, partially unsaturated, or aromatic carbocyclic ring, provided that the point of attachment to the target molecule is not on the aromatic carbocyclic ring. Examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, and the like.

[0063] As used herein, the term "heteroaryl" refers to a monovalent monocyclic aromatic group having 5 to 6 ring atoms, wherein in addition to carbon atoms, the ring atoms further comprise at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. The term "heteroaryl" also includes a ring having 5 to 6 ring atoms fused thereto secondarily, wherein the second ring may be an aromatic ring or a non-aromatic ring, provided that the point of attachment to the target molecule is in the heteroaryl moiety of the multiple fused system. It should also be understood that the point of attachment of the heteroaryl can be on any suitable atom of the heteroaryl, including carbon atoms and heteroatoms (such as nitrogen). Exemplary heteroaryls include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuryl, benzimidazolyl, thianthrenyl, pyrrolo[2,3-b]pyridyl, quinazolin-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazolyl.

[0064] As used herein, the term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated group of a 3- to 8-membered monocyclic ring having 3 to 8 ring atoms or a multiple fused (fused), bridged, or spiro ring having 7 to 10 ring atoms, wherein in addition to carbon atoms, the ring atoms further comprise at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. The heterocycloalkyl can be saturated or partially unsaturated and can be fused to another saturated, partially unsaturated, or aromatic ring, provided that the point of attachment to the target molecule is not on the aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, oxiranyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, oxocanyl, thiiranyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiepanyl, thicocanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, piperazinyl, morpholinyl, dioxolanyl, thioxolanyl, dithiolanyl, dihydropyridyl, and the like.

[0065] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to effect treatment as defined below when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on factors such as the weight and age of the subject being treated, the type of disease, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0066] As used herein, the term "stereoisomer" refers to compounds having the same chemical composition and connectivity, but differing in the orientation of their atoms in space, which orientation cannot be interchanged by rotation about a single bond. "Stereoisomers" include "diastereoisomers" and "enantiomers". "Diastereoisomers" are stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties such as melting point, boiling point, spectral characteristics and reactivity. Diastereoisomer mixtures can be separated by high-resolution analytical procedures such as crystallization, electrophoresis and chromatography. "Enantiomers" are two stereoisomers that are non-superimposable mirror images of each other.

[0067] As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electronic distribution of one (or more) mobile atoms, such as keto-enol tautomers.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the given compound and that are 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 acids and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, etc.; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, ferulate, mandelate, mesylate, esylate, tosylate, salicylate, lactate, nicotinate, lauryl sulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucuronate, oleate, palmitate, stearate, pamoate, trifluoroacetate, etc. Base addition salts can be formed with inorganic bases or organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts, etc.; salts derived from organic bases include salts formed with various primary, secondary and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, glucosamine, lysine, piperazine, piperidine, morpholine, tromethamine, choline, etc.

[0069] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0070] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, acetonitrile, acetone, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0071] As used in the text, the term "prodrug" refers to those compounds that are readily subject to chemical change under physiological conditions to provide the compounds of the invention. Additionally, a "prodrug" can also be converted to the compounds of the invention by chemical or biochemical means in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compounds of the invention.

[0072] Any general formula or structure given herein is also intended to include isotopically labeled forms of the compounds. These isotopically labeled forms of the compounds may also be referred to as "isotope labels", or "isotope-enriched analogs". Isotopically labeled compounds have the structures depicted 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 invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, 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 isotopically labeled compounds of the invention, such as those incorporating a radioactive isotope (e.g., 3 H, 13 C, and 14 C), are synthesized by means well known in the art, such as by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0073] Pharmaceutical Formulations and Dosage

[0074] The compounds of the present invention can be administered in the form of pharmaceutical compositions, wherein the pharmaceutical compositions comprise the compounds of the present invention and at least one pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical art. Depending on the therapeutic need, the compositions of the present invention can be administered by various routes. The routes of administration include, but are not limited to, oral, injection, intravenous drip, topical (such as intranasal, intraocular, oral, rectal, vaginal, transdermal delivery), etc. Depending on the route of administration, the pharmaceutical compositions of the present invention can be in solid form (including but not limited to tablets, capsules (such as soft and hard gelatin capsules), pills, granules, powders, dusting powders, lozenges, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups, aerosols).

[0075] When the pharmaceutical compositions of the present invention are in solid form, the pharmaceutically acceptable carriers generally include one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silica, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants like ascorbic acid; f) glidants, such as silica; g) flavoring agents, such as peppermint, methyl salicylate; sweetening agents, such as sucrose, saccharin. When the pharmaceutical compositions of the present invention are in liquid form, the pharmaceutically acceptable carriers generally include one or more of the following: a) diluents, such as water for injection, normal saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) antioxidants, such as ascorbic acid or sodium bisulfite; c) buffers, such as acetates, phosphates, etc.

[0076] 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 disease condition and severity being treated, the age, weight, and general health of the individual or patient, the route of administration, etc. For example, the compounds of the present invention can be provided for parenteral administration in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w / v of the compound. In some embodiments, typical dose ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, typical dose ranges are from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. In some embodiments, typical dose ranges are from about 0.1 mg / kg body weight to about 50 mg / kg body weight per day. In some embodiments, typical dose ranges are from about 0.5 mg / kg body weight to about 25 mg / kg body weight per day. In some embodiments, typical dose ranges are from about 1 mg / kg body weight to about 10 mg / kg body weight per day. The specific dose may vary depending on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and the route of its administration. The effective dose can also be extrapolated from dose-response curves obtained from in vitro or animal model test systems.

[0077] Indications

[0078] The compounds of the present invention have the activity of inhibiting PARP14. By administering a therapeutically effective amount of the compounds of the present invention to an individual or patient in need, the activity of PARP14 in the individual or patient can be inhibited. As a PARP14 inhibitor, the compounds of the present invention can be used for the prevention and / or treatment of various diseases associated with the abnormal expression or activity of PARP14. For example, the compounds of the present invention can be used for the treatment of cancer. In some embodiments, the cancers that can be prevented and / or treated according to the compounds of the present invention include:

[0079] i) Hematopoietic system malignancies such as leukemia and lymphoma. Exemplary lymphomas include Hodgkin lymphoma or non-Hodgkin lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic leukemia (CLL), T-cell lymphoma, follicular lymphoma, hairy cell lymphoma, and Burkitt lymphoma. Exemplary leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0080] 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's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, bowel 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.

[0081] In addition, the compounds of the present invention can also be used for preventing and / or treating inflammatory diseases, including atopic dermatitis, scleroderma, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), arthritis, inflammatory demyelinating diseases, emphysema, psoriasis, asthma, allergy, lupus, etc.

[0082] Combined medication

[0083] The compounds of the present invention can be administered in combination with one or more additional agents or treatment methods. The additional 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 the additional agents can be administered separately by the same or different routes of administration, or simultaneously administered as a combined reagent in a pharmaceutical composition.

[0084] Suitable chemotherapeutic agents include aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase 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, antiandrogens, antiproliferative antibodies, PDE4 inhibitors, aryl hydrocarbon receptor modulators, S1P receptor modulators, JAK inhibitors, glucocorticoids, antifibrotic agents, leukotriene receptor antagonists, salicylic acids, theophyllines, H1 receptor antagonists, β receptor agonists, and anti-inflammatory antibodies, etc.

[0085] Aromatase inhibitors include, but are not limited to, exemestane, formestane, aminoglutethimide, vorozole, letrozole, anastrozole, and letrozole. Antiestrogens 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, losoxantrone, etoposide, and teniposide. Microtubule activators include, but are not limited to, paclitaxel and docetaxel of the taxanes; vinca alkaloids such as vinblastine, especially vinblastine sulfate; vincristine, especially vincristine sulfate, and vinflunine, and epothilones such as epothilone B and D. Alkylating agents include, but are not limited to, cyclophosphamide, ifosfamide, and melphalan. Histone deacetylase inhibitors relate to compounds that inhibit histone deacetylases and have antiproliferative activity. Farnesyltransferase inhibitors relate to compounds that inhibit farnesyltransferase and have antiproliferative activity. COX-2 inhibitors relate to compounds that inhibit cyclooxygenase type 2 enzyme (COX-2) and have antiproliferative activity, such as celecoxib, rofecoxib, and lumiracoxib. MMP inhibitors relate to compounds that inhibit matrix metalloproteinases and have antiproliferative activity. mTOR inhibitors relate to compounds that inhibit mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as everolimus. Antitumor antimetabolites include, but are not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, floxuridine, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate, 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 antiangiogenic compounds include, but are not limited to, compounds that reduce the activity of, such as 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, abarelix, goserelin, and goserelin 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 antibody. PDE4 inhibitors relate to compounds that inhibit phosphodiesterase and have anti-inflammatory activity, such as crisaborole, roflumilast, deflazacort, loteprednol etabonate. Aryl hydrocarbon receptor modulators include, but are not limited to, bexarotene. S1P receptor modulators relate to compounds that regulate sphingosine 1-phosphate receptor and have anti-inflammatory activity, such as ozanimod, itraconazole.JAK inhibitors refer to compounds that inhibit Janus kinases and have anti-inflammatory activity, such as ruxolitinib, tofacitinib, baricitinib, deucravacitinib, upadacitinib, jackitinib, sedacitinib, abrocitinib. Glucocorticoids include but are not limited to prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone acetonide, hydrocortisone, budesonide. Anti-fibrotic drugs include but are not limited to pirfenidone, nintedanib. Leukotriene receptor antagonists refer to compounds that inhibit leukotriene receptors and have anti-inflammatory activity, such as montelukast, zafirlukast, pranlukast. Salicylic acid drugs include but are not limited to mesalazine, sulfasalazine, aspirin. Theophylline drugs include but are not limited to aminophylline, diprophylline, choline theophyllinate, theophylline ethanolamine. H1 receptor antagonists refer to compounds that inhibit histamine H1 receptors and have anti-inflammatory activity, such as chlorpheniramine, cetirizine, loratadine, desloratadine. β receptor agonists refer to compounds that activate adrenaline β receptors and have anti-inflammatory activity, such as salbutamol, terbutaline, salmeterol, formoterol. Anti-inflammatory antibodies include but are not limited to dupilumab, lebrikizumab, trastuzumab, nimotuzumab, vedolizumab, ustekinumab, infliximab, adalimumab, golimumab, omalizumab.

[0086] General synthetic method

[0087] The compounds of the present invention can be prepared using the methods disclosed herein and their modified routes, as well as methods well-known in the art. Typical embodiments of the compounds according to the present invention can be synthesized using the following general reaction procedures. It is obvious from the description herein that corresponding different products can be obtained by using other materials with similar structures to replace the reaction raw materials. The reaction raw materials are typically obtained from commercial sources or synthesized using disclosed methods.

[0088] Reaction Scheme I:

[0089]

[0090] Wherein, n, X, R 1 , R 2 , R 3 are as defined herein.

[0091] Compound V reacts with R 3 H in a solvent suitable for the reaction to prepare Compound I, wherein the solvent suitable for the reaction is selected from methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, acetone, toluene, dichloromethane, N-methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is isopropanol.

[0092] Reaction Scheme II:

[0093]

[0094] wherein, n, X, R 1 , R 2 , R 3 are as defined herein.

[0095] Compound VI reacts with R 3 H in a solvent suitable for the reaction to prepare Compound I. Among them, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine. Preferably, the base is selected from triethylamine; the solvent suitable for the reaction is selected from dichloromethane, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, acetone, toluene, N-methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is dichloromethane.

[0096] Reaction Process III:

[0097]

[0098] wherein, n, X, R 1 , R 2 , R 3 are as defined herein.

[0099] Step 1: Compound IX reacts with R 1 -(CH2) n -Br or R 1 -(CH2) n -OMs in a solvent suitable for the reaction to prepare Compound XIII. Among them, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, pyridine, N,N-diisopropylethylamine. Preferably, the base is selected from potassium carbonate; 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 solvent suitable for the reaction is dimethyl sulfoxide.

[0100] Step 2: Compound XIII reacts under acidic conditions in a solvent suitable for the reaction to prepare Compound I. Among them, the acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, formic acid, hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, butyric acid. Preferably, the acid is selected from trifluoroformic acid; the solvent is selected from water, dichloromethane, methanol, ethanol, 1,4-dioxane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or any combination thereof. Preferably, the solvent suitable for the reaction is dichloromethane.

[0101] Reaction Scheme IV:

[0102]

[0103] wherein n, X, R 1 , R 2 , R 3 are as defined herein.

[0104] Compound XI reacts with an excess of R 1 -(CH2) n -XH in a solvent suitable for the reaction to prepare Compound I. Preferably, the solvent suitable for the reaction is an excess of R 1 -(CH2) n -XH.

[0105] Reaction Scheme V:

[0106]

[0107] wherein n, X, R 1 , R 2 , R 3 are as defined herein.

[0108] Step 1: Compound XII reacts with R 3 COCl in a solvent suitable for the reaction to prepare Compound XIV. Among them, the base is selected from sodium hydride, triethylamine, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine. Preferably, the base is selected from triethylamine; the solvent suitable for the reaction is selected from N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, acetone, toluene, dichloromethane, N-methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is dichloromethane.

[0109] Step 2: Compound XIV reacts with acetic anhydride in a solvent suitable for the reaction to prepare Compound XV. Preferably, the solvent suitable for the reaction is acetic anhydride.

[0110] Step 3: Compound XV reacts with ammonia water in a solvent suitable for the reaction to prepare Compound I. Among them, the solvent suitable for the reaction is selected from methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, water or any combination thereof. Preferably, the solvent suitable for the reaction is ethanol.

[0111] Reaction Scheme VI:

[0112]

[0113] wherein n, X, R 1 , R 2, R 3 As defined herein.

[0114] Compound II reacts with R 3 CN in a suitable reaction solvent to prepare Compound I, wherein the acid is selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, butyric acid, oxalic acid, trifluoroacetic acid, and preferably, the acid is selected from hydrochloric acid; the suitable reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, methanol, ethanol, dichloromethane or any combination thereof, and preferably, the suitable reaction solvent for the reaction is 1,4-dioxane.

[0115] Reaction Scheme VII:

[0116]

[0117] wherein n, X, R 1 , R 2 As defined herein.

[0118] Step 1: Compound II reacts with sodium cyanate in a suitable reaction solvent to prepare Compound III, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, pyridine, N,N-diisopropylethylamine, and preferably, the base is selected from sodium hydroxide; the suitable reaction solvent is selected from water, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, formic acid, acetic acid, hydrochloric acid, sulfuric acid or any combination thereof, and preferably, the suitable reaction solvent for the reaction is a water / acetic acid mixed solvent.

[0119] Step 2: Compound III reacts with phosphorus oxychloride in a suitable reaction solvent to prepare Compound IV, wherein the base is selected from dimethylamine, diethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and preferably, the base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the suitable reaction solvent is selected from toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, acetone, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran or any combination thereof, and preferably, the suitable reaction solvent for the reaction is toluene.

[0120] Step 3: Compound IV reacts with a base in a suitable reaction solvent to prepare Compound V, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or cesium carbonate, triethylamine, N,N - diisopropylethylamine. Preferably, the base is selected from sodium hydroxide; the suitable reaction solvent is selected from methanol, tetrahydrofuran, 1,4 - dioxane, acetonitrile, acetone, N,N - dimethylformamide, dichloromethane, water or any combination thereof. Preferably, the solvent suitable for the reaction is a water / tetrahydrofuran mixed solvent.

[0121] Reaction Scheme VIII:

[0122]

[0123] Wherein, n, X, R 1 、R 2 are as defined herein.

[0124] Compound II reacts with chloroacetonitrile in a suitable reaction solvent to prepare Compound VI, wherein the acid is selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, butyric acid, oxalic acid, trifluoroacetic acid. Preferably, the acid is selected from hydrochloric acid; the suitable reaction solvent is selected from tetrahydrofuran, dichloromethane, ethyl acetate, 1,4 - dioxane, acetonitrile, acetone, methanol, ethanol, N,N - dimethylformamide, dimethyl sulfoxide, water or any combination thereof. Preferably, the solvent suitable for the reaction is 1,4 - dioxane.

[0125] Reaction Scheme IX:

[0126]

[0127] Wherein, X, R 2 、R 3 are as defined herein.

[0128] Step 1: Compound V reacts with 2 - (trimethylsilyl)ethoxymethyl chloride (SEM - Cl) in a suitable reaction solvent to prepare Compound VII, wherein the base is selected from sodium hydroxide, sodium hydride, potassium hydroxide, sodium methoxide, potassium tert - butoxide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium (trimethylsilyl)amide, n - butyllithium, lithium diisopropylamide. Preferably, the base is selected from lithium bis(trimethylsilyl)amide; the suitable reaction solvent is selected from N,N - dimethylformamide, tetrahydrofuran, 1,4 - dioxane, dimethyl sulfoxide, acetonitrile, acetone, toluene, dichloromethane, N - methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is tetrahydrofuran.

[0129] Step 2: Compound VII reacts with R 3Compound VIII is prepared by reacting in a solvent suitable for the reaction, wherein the solvent suitable for the reaction is selected from methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, acetone, toluene, dichloromethane, N-methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is isopropanol.

[0130] Step 3: Compound VIII reacts with H2 / palladium-carbon in a solvent suitable for the reaction to prepare compound IX, wherein the solvent suitable for the reaction is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, ethyl acetate or any combination thereof. Preferably, the solvent suitable for the reaction is a methanol / tetrahydrofuran mixed solvent.

[0131] Reaction Scheme X:

[0132]

[0133] wherein n, R 2 、R 3 are as defined herein.

[0134] Compound X reacts with R 3 H in a solvent suitable for the reaction to prepare compound XI, wherein the solvent suitable for the reaction is selected from methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, acetone, toluene, dichloromethane, N-methylpyrrolidone or any combination thereof. Preferably, the solvent suitable for the reaction is isopropanol.

[0135] Reaction Scheme XI:

[0136]

[0137] wherein n, X, R 1 、R 2 are as defined herein.

[0138] Compound II reacts with a base in a solvent suitable for the reaction to prepare compound XII, wherein the base is selected from sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine. Preferably, the base is selected from sodium hydroxide; the solvent suitable for the reaction is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, dichloromethane, water or any combination thereof. Preferably, the solvent suitable for the reaction is a methanol / water mixed solvent.

[0139] The present invention will be further described below by way of specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or adjustments according to the teachings of the present invention, which do not depart from the spirit and scope of the present invention.

[0140] The abbreviations used in the embodiments of the present invention have the following respective meanings:

[0141] Abbreviation Name h hour g gram L liter mg milligram min minute mL milliliter mol mole mmol millimole <![CDATA[N2]]> nitrogen TLC thin layer chromatography

[0142] Example 1 Synthesis of 2-(((1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)amino)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (I-1)

[0143] Step 1: Synthesis of 7-(cyclopropylmethoxy)-5-fluoroquinazoline-2,4(1H,3H)-dione (III-1)

[0144] Methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate (II-1, 12.68 g, 53.03 mmol) was mixed with an acetic acid / water mixed solvent (2:1, 120 mL), and after stirring for 15 min, sodium cyanate solid (10.34 g, 159.09 mmol) was added. After the addition was complete, the temperature was raised to 35 °C and the reaction was carried out for about 4 h. Thin layer chromatography (TLC) (petroleum ether:ethyl acetate = 8:1) was used to monitor the complete reaction of the raw materials, and the reaction was stopped. The solvent was removed by reduced pressure concentration. Water (60 mL) was added to the residue, and then sodium hydroxide solid was added in batches to adjust the pH of the reaction solution to 12 - 13. After the addition was complete, the temperature was raised to 70 °C and the reaction was carried out for about 1 h. TLC (dichloromethane:methanol = 20:1) was used to monitor the complete reaction of the intermediate, the heating was stopped, and it was cooled to room temperature. The pH of the reaction solution was adjusted to 3 - 4 with dilute hydrochloric acid (6 mol / L) under an ice bath, filtered by suction, and the filter cake was dried in vacuo to obtain 8.56 g of a brown solid with a yield of 64.6%, MS-ESI: [M+H] + 251.1.

[0145] Step 2: Synthesis of 2,4-dichloro-7-(cyclopropylmethoxy)-5-fluoroquinazoline (IⅤ-1)

[0146] Compound III-1 (2.60 g, 10.40 mmol) was mixed with toluene (30 mL) and heated to 50 °C. Subsequently, phosphorus oxychloride (11.96 g, 78.00 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.17 g, 20.80 mmol) were slowly added dropwise to the reaction solution in sequence. After addition, the temperature was raised to 110 °C and the reaction was carried out for about 6 h. The reaction of the raw materials was monitored by TLC (petroleum ether:ethyl acetate = 10:1) until completion, and then the reaction was stopped and cooled to room temperature. Under vigorous stirring, the reaction solution was slowly added dropwise to ice water (60 mL), and yellow flocculates precipitated. After stirring for 0.5 h, filtration was carried out, and the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined, washed twice with water and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 40:1) to obtain 1.25 g of a white solid with a yield of 42.0%. 1 1H-NMR (300 MHz, chloroform-d6) δ (ppm): 7.07–6.98 (m, 1H), 6.87–6.82 (m, 1H), 3.97 (d, J = 7.1 Hz, 2H), 1.29–1.25 (m, 1H), 0.75–0.66 (m, 2H), 0.44–0.37 (m, 2H).

[0147] Step 3: Synthesis of 2-chloro-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (V-1)

[0148] Compound IV-1 (1.25 g, 4.37 mmol) was dissolved in tetrahydrofuran (6 mL), and then an aqueous sodium hydroxide solution (1 mol / L, 10 mL) was added. After addition, the reaction was carried out at room temperature for about 2 h. The reaction of the raw materials was monitored by TLC (dichloromethane:methanol = 30:1) until completion, and then the reaction was stopped. The reaction solution was diluted with water (20 mL), and the pH of the reaction solution was adjusted to 5 with dilute acetic acid (6 mol / L) under an ice bath. A large amount of white solid precipitated. After continuous stirring for 20 min, filtration was carried out, and the filter cake was dried in vacuo to obtain 1 g of a white solid with a yield of 85.4%, MS-ESI: [M+H] + 269.0

[0149] Step 4: Synthesis of 2-(((1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)amino)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one (I-1)

[0150] Compound V-1 (100 mg, 0.37 mmol) and 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)methanamine (102 mg, 0.56 mmol) were dissolved in isopropanol (4 mL), and then refluxed for about 6 h. The reaction was monitored by TLC (dichloromethane:methanol = 20:1). When the raw materials were completely reacted, the reaction was stopped. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1) to obtain 70 mg of a white solid with a yield of 45.7%. MS-ESI: [M+H] + 415.2; 1 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 6.47–6.42 (m, 2H), 6.37 (bs, 1H), 4.38–4.24 (m, 2H), 3.89 (d, J = 7.0 Hz, 2H), 3.25–3.22 (m, 2H), 3.10–3.03 (m, 1H), 2.59–2.56 (m, 1H), 2.00–1.93 (m, 1H), 1.86–1.80 (m, 1H), 1.77–1.65 (m, 2H), 1.25–1.20 (m, 1H), 1.18–1.00 (m, 2H), 0.72–0.66 (m, 4H), 0.60–0.55 (m, 2H), 0.35–0.31 (m, 2H).

[0151] Referring to the preparation method of compound I-1, the following compounds were prepared:

[0152]

[0153]

[0154]

[0155] Example 2 Synthesis of 4-(((7-(cyclopentylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)amino)methyl)cyclohexane-1-carboxylic acid (I-4)

[0156] Step 1: Synthesis of 2-chloro-7-(cyclopentylmethoxy)-5-fluoroquinazolin-4(3H)-one (V-2)

[0157] Using methyl 2-amino-4-(cyclopentylmethoxy)-6-fluorobenzoate (II-2, 4.00 g, 15.00 mmol) as the raw material, a series of operations were the same as those for the synthesis of compound V-1, and 1.69 g of a white solid was obtained with a total yield of 38.1%. MS-ESI: [M+H] + 297.1.

[0158] Step 2: Synthesis of 4-(((7-(Cyclopentylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)amino)methyl)cyclohexane-1-carboxylic acid (I-4)

[0159] Dissolve compound V-2 (120 mg, 0.41 mmol) and 4-(Aminomethyl)cyclohexane-1-carboxylic acid (97 mg, 0.62 mmol) in isopropanol (5 mL), and then reflux the reaction overnight. Monitor the reaction by TLC (dichloromethane:methanol = 10:1) until the raw materials are completely reacted, and then stop the reaction. Concentrate the solvent under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 40:1) and preparative thin-layer plate (dichloromethane:methanol = 20:1) in turn. Then slurry it with a mixed solvent of isopropyl ether / isopropanol (20:1), filter it by suction, and dry the filter cake under vacuum to obtain 30 mg of white solid, with a yield of 17.5%.

[0160] Example 3 Synthesis of 7-((1-Acetylpiperidin-4-yl)methoxy)-2-((7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-5-fluoroquinazolin-4(3H)-one (I-22)

[0161] Step 1: Synthesis of 7-(1-Acetylpiperidin-4-yl)methoxy)-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one (VI-1)

[0162] Dissolve methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (II-3, 3.00 g, 9.25 mmol) and chloroacetonitrile (2.10 g, 27.75 mmol) in a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 30 mL), heat up to 80 °C, and react for about 3 h. Monitor the reaction by TLC (dichloromethane:methanol = 30:1) until the raw materials are completely reacted, then stop the reaction and cool it to room temperature. Filter it by suction, dry the filter cake, and then slurry it with water (10 mL) and a mixed solvent of dichloromethane / methanol (60:1, 10 mL) in turn, filter it by suction, and dry the filter cake under vacuum to obtain 1.81 g of pale yellow solid, with a yield of 53.3%, MS-ESI: [M+H] + 368.1.

[0163] Step 2: Synthesis of tert-Butyl 7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0164] Dissolve 2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane (300 mg, 1.33 mmol) and triethylamine (337 mg, 3.33 mmol) in dichloromethane (5 mL). Slowly add cyclopropylcarbonyl chloride (153 mg, 1.46 mmol) dropwise under an ice bath. After addition, transfer to room temperature and react for about 2 h. Monitor the reaction by TLC (dichloromethane:methanol = 15:1) until the raw materials are completely reacted, then stop the reaction. Add ice water (10 mL) to the reaction solution, separate the organic layer, extract the aqueous layer with dichloromethane (5 mL × 2), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 50:1) to obtain 330 mg of a colorless oil, with a yield of 84.4%, MS-ESI: [M+H] + 295.2.

[0165] Step 3: Synthesis of cyclopropyl(2,7-diazaspiro[3.5]nonan-7-yl)methanone

[0166] Dissolve tert-butyl 7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, 1.02 mmol) in dichloromethane (3 mL), then add trifluoroacetic acid (582 mg, 5.10 mmol). After addition, react at room temperature for about 2 h. Monitor the reaction by TLC (dichloromethane:methanol = 15:1) until the raw materials are completely reacted, then stop the reaction. Concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 7 - 8 with saturated sodium bicarbonate solution, extract with a dichloromethane / methanol mixed solvent (8:1, 10 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure to obtain 144 mg of a yellow solid, with a yield of 72.7%, MS-ESI: [M+H] + 195.1.

[0167] Step 4: Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-2-((7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-5-fluoroquinazolin-4(3H)-one (I-22)

[0168] Dissolve compound VI-1 (200 mg, 0.55 mmol) in dichloromethane (5 mL), then successively add triethylamine (167 mg, 1.65 mmol) and cyclopropyl(2,7-diazaspiro[3.5]nonan-7-yl)methanone (128 mg, 0.66 mmol). After addition, reflux the reaction overnight. Monitor the reaction by TLC (dichloromethane:methanol = 30:1) until the raw materials are completely reacted, and then stop the reaction. Concentrate and remove the solvent under reduced pressure. The residue is separated and purified by column chromatography (dichloromethane:methanol = 80:1) and preparative thin-layer plate (dichloromethane:methanol = 35:1) to obtain 45 mg of white solid with a yield of 15.6%. MS-ESI: [M+H] + 526.3; 1 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.78 (bs, 1H), 6.92–6.86 (m, 2H), 4.43–4.38 (m, 1H), 4.00 (d, J = 6.4 Hz, 2H), 3.86–3.82 (m, 1H), 3.62–3.56 (m, 2H), 3.53 (s, 2H), 3.43–3.38 (m, 2H), 3.15 (s, 4H), 3.09–3.02 (m, 1H), 2.59–2.55 (m, 1H), 2.05–2.02 (m, 1H), 2.00 (s, 3H), 1.97–1.92 (m, 1H), 1.82–1.71 (m, 4H), 1.64–1.57 (m, 2H), 1.30–1.03 (m, 2H), 0.72–0.64 (m, 4H).

[0169] Refer to the preparation method of compound I-22 to prepare the following compounds:

[0170]

[0171]

[0172] Example 4 Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)selanyl)methyl)quinazolin-4(3H)-one (Ⅰ-25)

[0173] Step 1: Synthesis of 1,2-bis(tetrahydro-2H-pyran-4-yl)diselenide

[0174] Selenium (246 mg, 3.12 mmol) and sodium hydroxide (47 mg, 4.68 mmol) were added to N,N-dimethylformamide (10 mL). Subsequently, hydrazine hydrate (1.2 mL) was slowly added dropwise under a N2 atmosphere. After addition, the temperature was raised to 100 °C, and the reaction was carried out for about 15 min. Then the heating was stopped and it was cooled to room temperature. 4-Methylbenzenesulfonic acid oxolan-4-yl ester (800 mg, 3.12 mmol) was added to the above reaction solution. After addition, the temperature was raised to 100 °C, and the reaction was carried out for about 2 h. TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor the complete reaction of the raw materials, and then the reaction was stopped and cooled to room temperature. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain 435 mg of a yellow oil, with a yield of 42.2%, MS-ESI: [M+H] + 331.0。

[0175] Step 2: Synthesis of tetrahydro-2H-pyran-4-selenol

[0176] 1,2-Bis(tetrahydro-2H-pyran-4-yl) diselenide (433 mg, 1.31 mmol) was dissolved in absolute ethanol (6 mL). At 0 °C, sodium borohydride (248 mg, 6.55 mmol) was added under a N2 atmosphere. After addition, it was transferred to room temperature and the reaction was carried out for about 1.5 h. TLC (petroleum ether:ethyl acetate = 8:1) was used to monitor the complete reaction of the raw materials, and then the reaction was stopped. Water (10 mL) was added to the reaction solution under an ice bath, and the pH of the reaction solution was adjusted to 1-2 with dilute hydrochloric acid (2 mol / L). It was extracted with ethyl acetate (8 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain 176 mg of a yellow solid, with a yield of 80.9%, MS-ESI: [M+H] + 167.0。

[0177] Step 3: Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)selanyl)methyl)quinazolin-4(3H)-one (I-25)

[0178] Compound VI-1 (200 mg, 0.55 mmol) was dissolved in dichloromethane (5 mL). Subsequently, triethylamine (167 mg, 1.65 mmol) and tetrahydro-2H-pyran-4-selenol (109 mg, 0.66 mmol) were added in sequence. After addition, the reaction was refluxed overnight. TLC (dichloromethane:methanol = 30:1) was used to monitor the complete reaction of the raw materials, and then the reaction was stopped. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane:methanol = 80:1) to obtain 38 mg of a white solid, with a yield of 13.9%.

[0179] Example 5 Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one (I-30)

[0180] Step 1: Synthesis of 7-(benzyloxy)-2-chloro-5-fluoroquinazolin-4(3H)-one (V-4)

[0181] Using methyl 2-amino-4-(benzyloxy)-6-fluorobenzoate (II-4, 5.82 g, 21.16 mmol) as the raw material, through a series of operations same as the synthesis of compound V-1, 830 mg of white solid was obtained, with an overall yield of 14.2%, MS-ESI: [M+H] + 305.0

[0182] Step 2: Synthesis of 7-(benzyloxy)-2-chloro-5-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (VII-1)

[0183] Dissolve compound V-4 (1.40 g, 4.60 mmol) in tetrahydrofuran (15 mL), then at 0 °C under N2 atmosphere, add lithium bis(trimethylsilyl)amide (1.0 mol / L THF solution, 1.54 g, 9.20 mmol), continuously react at low temperature for about 1 h, then add 2-(trimethylsilyl)ethoxymethyl chloride (1.15 g, 6.90 mmol). After addition, transfer to room temperature and react for about 3 h. Monitor the reaction of the raw materials to completion by TLC (dichloromethane:methanol = 30:1), and stop the reaction. Add ice water (15 mL) to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 80:1) to obtain 1.88 g of white solid, with a yield of 94.2%, MS-ESI: [M+H] + 435.1

[0184] Step 3: Synthesis of 7-(benzyloxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (VIII-1)

[0185] Using compound VII-1 (118 mg, 0.27 mmol) and 4-aminomethyltetrahydro pyran (47 mg, 0.41 mmol) as the raw materials, through the operation process same as the synthesis of compound I-1, 134 mg of white solid was obtained, with a yield of 96.7%, MS-ESI: [M+H] + 514.2

[0186] Step 4: Synthesis of 5-Fluoro-7-hydroxy-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((2-(trimethylsilyl)ethoxymethyl)quinazolin-4(3H)-one (IX-1)

[0187] Dissolve compound VIII-1 (130 mg, 0.25 mmol) in a mixed solvent of methanol / tetrahydrofuran (1:1, 3 mL), then add palladium on carbon (10%, 80 mg, 0.75 mmol), displace H2, and react at room temperature for about 3 h. Monitor the reaction of the raw materials to completion by TLC (dichloromethane:methanol = 30:1), and stop the reaction. Filter by suction, concentrate the filtrate under reduced pressure to obtain 100 mg of a yellow oil, with a yield of 93.5%, MS-ESI: [M+H] + 424.2

[0188] Step 5: Synthesis of (1-Acetylpiperidin-4-yl)methyl methanesulfonate

[0189] Dissolve 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (6.93 g, 44.11 mmol) and pyridine (6.98 g, 88.22 mmol) in dichloromethane (70 mL), and add methanesulfonic anhydride (11.53 g, 66.16 mmol) in batches under an ice bath. After addition, transfer to room temperature and react overnight. Monitor the reaction of the raw materials to completion by TLC (dichloromethane:methanol = 15:1), and stop the reaction. Add ice water (50 mL), separate the organic layer, wash it twice with water and saturated brine respectively, dry it over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to obtain 9.48 g of a brown solid, with a yield of 91.4%, MS-ESI: [M+H] + 236.1

[0190] Step 6: Synthesis of 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (XIII-1)

[0191] Compound IX-1 (100 mg, 0.24 mmol), potassium carbonate (83 mg, 0.6 mmol) and (1-acetylpiperidin-4-yl)methyl methanesulfonate (68 mg, 0.29 mmol) were mixed with dimethyl sulfoxide (5 mL), and the temperature was raised to 80 °C. The reaction was carried out for about 3 h. The reaction of the raw materials was monitored by TLC (methylene chloride:methanol = 30:1). The reaction was stopped and cooled to room temperature. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (8 mL × 3). The organic layers were combined, washed 5 times with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 60:1) to obtain 125 mg of a colorless oil, with a yield of 92.6%. MS-ESI: [M+H] + 563.3.

[0192] Step 7: Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one (I-30)

[0193] Compound XIII-1 (96 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (97 mg, 0.85 mmol) was added. After the addition, the reaction was carried out overnight at room temperature. The reaction of the raw materials was monitored by TLC (dichloromethane:methanol = 20:1). The reaction was stopped. The solvent was removed by concentration under reduced pressure. The pH of the residue was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with a dichloromethane / methanol mixed solvent (10:1, 8 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 30:1) and slurried with an isopropyl ether / isopropyl alcohol mixed solvent (20:1, 3 mL), filtered by suction, and the filter cake was dried in vacuo to obtain 43 mg of a white solid, with a yield of 58.5%. MS-ESI: [M+H] + 433.2; 1 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 6.51–6.42 (m, 2H), 6.36 (bs, 1H), 4.41–4.37 (m, 1H), 3.92 (d, J = 6.3 Hz, 2H), 3.89–3.81 (m, 3H), 3.32–3.27 (m, 2H), 3.24–3.20 (m, 2H), 3.08–3.00 (m, 1H), 2.59–2.54 (m, 1H), 1.99 (s, 3H), 1.96–1.94 (m, 1H), 1.81–1.72 (m, 3H), 1.61–1.56 (m, 2H), 1.28–1.07 (m, 4H).

[0194] Referring to the preparation method of reference compound I-30, the following compounds were prepared:

[0195]

[0196]

[0197]

[0198] Example 6 Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((1-(pyridin-2-ylmethyl)piperidin-4-ylmethyl)amino)quinazolin-4(3H)-one (I-32)

[0199] Step 1: Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((piperidin-4-ylmethyl)amino)quinazolin-4(3H)-one trifluoroacetate (I-32-1)

[0200] Using compound VI-1 (400 mg, 0.92 mmol) and 1-tert-butoxycarbonyl-4-aminomethylpiperidine (296 mg, 0.38 mmol) as raw materials, the operation process was the same as the synthesis of compound I-30, and 457 mg of yellow oil was obtained, with an overall yield of 76.5%. MS-ESI: [M+H] + 432.2.

[0201] Step 2: Synthesis of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((1-(pyridin-2-ylmethyl)piperidin-4-ylmethyl)amino)quinazolin-4(3H)-one (I-32)

[0202] Compound I-32-1 (265 mg, 0.40 mmol), cesium carbonate (521 mg, 1.60 mmol) and 2-(bromomethyl)pyridine hydrobromide (111 mg, 0.44 mmol) were added to acetonitrile (6 mL), and the temperature was raised to 60 °C, and the reaction was carried out for about 3.5 h. TLC (dichloromethane:methanol = 10:1) was used to monitor the complete reaction of the raw materials, the reaction was stopped, and it was cooled to room temperature. Water (15 mL) was added, and it was extracted with ethyl acetate (8 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane:methanol = 10:1) and preparative thin layer plate (dichloromethane:methanol = 25:1) to obtain 52 mg of white solid, with a yield of 24.9%.

[0203] Example 7 Synthesis of 7-((cyclopropylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one (I-49)

[0204] Step 1: Synthesis of 7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one (XI-1)

[0205] Using 2-chloro-4-oxo-7-fluoroquinazoline (X-1, 256 mg, 1.29 mmol) and 4-aminomethyltetrahydropyran (178 mg, 1.55 mmol) as raw materials, the operation process was the same as that for the synthesis of compound I-1, and 254 mg of white solid was obtained, with a yield of 71.0%, MS-ESI: [M+H] + 278.1

[0206] Step 2: Synthesis of 7-((cyclopropylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one (I-49)

[0207] Compound XI-1 (200 mg, 0.72 mmol) was mixed with cyclopropylmethylamine (1.02 g, 14.40 mmol), and the reaction was carried out in a sealed tube at 120 °C for about 2 d. TLC (methylene chloride:methanol = 20:1) was used to monitor the complete reaction of the raw materials, and the reaction was stopped and cooled to room temperature. The reaction solution was separated and purified by column chromatography (methylene chloride:methanol = 30:1) and preparative thin-layer plate (methylene chloride:methanol = 20:1) to obtain 80 mg of pale yellow solid, with a yield of 33.9%. MS-ESI: [M+H] + 329.2 1 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.45–6.38 (m, 2H), 6.18 (d, J = 2.2 Hz, 1H), 6.10 (bs, 1H), 3.89–3.83 (m, 2H), 3.31–3.24 (m, 2H), 3.21–3.17 (m, 2H), 2.96–2.92 (m, 2H), 1.81–1.74 (m, 1H), 1.62–1.57 (m, 2H), 1.28–1.15 (m, 2H), 1.07–1.03 (m, 1H), 0.51–0.45 (m, 2H), 0.24–0.19 (m, 2H).

[0208] Refer to the preparation method of compound I-49 to prepare the following compounds:

[0209]

[0210] Example 8 Synthesis of 5-fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonan-2-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one (I-52)

[0211] Step 1: Synthesis of 2-Amino-6-fluoro-4-(2-morpholinoethoxy)benzoic acid (XII-1)

[0212] Mix methyl 2-amino-6-fluoro-4-(2-morpholinoethoxy)benzoate (II-5, 500 mg, 1.68 mmol) with methanol (8 mL), then add aqueous sodium hydroxide solution (5 mol / L, 1.68 mL). After addition, heat the mixture to 50 °C and react for about 5 h. Monitor the reaction by TLC (dichloromethane:methanol = 20:1) until the raw materials are completely reacted, then stop the reaction. Concentrate the solvent under reduced pressure. Add water (10 mL) to the residue, adjust the pH of the reaction solution to 6 - 7 with dilute hydrochloric acid (2 mol / L) under ice bath, extract with dichloromethane / methanol mixed solvent (10:1, 10 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to obtain 250 mg of yellow solid with a yield of 52.5%, MS-ESI: [M+H] + 286.1

[0213] Step 2: Synthesis of methyl 7-isobutyryl-7-azaspiro[3.5]nonane-2-carboxylate

[0214] Using methyl 7-azaspiro[3.5]nonane-2-carboxylate hydrochloride (500 mg, 2.28 mmol) and isobutyryl chloride (267 mg, 2.51 mmol) as raw materials, the operation process is the same as that for the synthesis of tert-butyl 7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, to obtain 506 mg of colorless oily substance with a yield of 87.6%, MS-ESI: [M+H] + 254.2

[0215] Step 3: Synthesis of 7-isobutyryl-7-azaspiro[3.5]nonane-2-carboxylic acid

[0216] Mix methyl 7-isobutyryl-7-azaspiro[3.5]nonane-2-carboxylate (500 mg, 1.97 mmol) with methanol / water mixed solvent (1:1, 6 mL), then add lithium hydroxide monohydrate (250 mg, 5.91 mmol). After addition, react at room temperature for about 2 h. Monitor the reaction by TLC (dichloromethane:methanol = 25:1) until the raw materials are completely reacted, then stop the reaction. Concentrate the solvent under reduced pressure. Add water (10 mL) to the residue, adjust the pH of the reaction solution to 3 - 4 with dilute hydrochloric acid (2 mol / L) under ice bath, extract with ethyl acetate (8 mL × 3), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to obtain 453 mg of white solid with a yield of 96.1%, MS-ESI: [M+H] + 240.2

[0217] Step 4: Synthesis of 7-isobutyryl-7-azaspiro[3.5]nonane-2-carbonyl chloride

[0218] Dissolve 7-isobutyryl-7-azaspiro[3.5]nonane-2-carboxylic acid (450 mg, 1.88 mmol) in dichloromethane (4 mL), then add thionyl chloride (3 mL). After addition, reflux the reaction mixture for about 1 h. Monitor the reaction by TLC (dichloromethane:methanol = 25:1) until the raw materials are completely reacted, and then stop the reaction. Concentrate the solvent under reduced pressure to obtain 470 mg of a yellow oil, with a yield of 97.3%.

[0219] Step 5: Synthesis of 2-fluoro-6-(7-isobutyryl-7-azaspiro[3.5]nonane-2-carboxamido)-4-(2-morpholinoethoxy)benzoic acid (XIV-1)

[0220] Dissolve compound XII-1 (110 mg, 0.39 mmol) in dichloromethane (3 mL). Under ice bath, add triethylamine (79 mg, 0.78 mmol) and 7-isobutyryl-7-azaspiro[3.5]nonane-2-carbonyl chloride (121 mg, 0.47 mmol) successively. After addition, transfer the reaction mixture to room temperature and react for about 3 h. Monitor the reaction by TLC (dichloromethane:methanol = 10:1) until the raw materials are completely reacted, and then stop the reaction. Add ice water (5 mL) to the reaction solution, extract with dichloromethane / methanol mixed solvent (10:1, 8 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 20:1) to obtain 100 mg of a yellow solid, with a yield of 50.8%, MS-ESI: [M+H] + 506.3。

[0221] Step 6: Synthesis of 5-fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonane-2-yl)-7-(2-morpholinoethoxy)-4H-benzo[d][1,3]oxazin-4-one (XV-1)

[0222] Mix compound XIV-1 (80 mg, 0.16 mmol) with acetic anhydride (2 mL) and reflux the reaction mixture for about 8 h. Monitor the reaction by TLC (dichloromethane:methanol = 15:1) until the raw materials are completely reacted, then stop the reaction and cool to room temperature. Add ice water (5 mL) to the reaction solution, adjust the pH to 6 - 7 with saturated sodium bicarbonate solution, extract with ethyl acetate (5 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 40:1) to obtain 45 mg of a brown oil, with a yield of 57.7%, MS-ESI: [M+H] + 488.2。

[0223] Step 7: Synthesis of 5-Fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonan-2-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one (I-52)

[0224] Dissolve compound XV-1 (42 mg, 0.086 mmol) in ethanol (2 mL), then add ammonia water (16 mg, 0.45 mmol). After addition, react in a sealed tube at 80 °C for about 3 h. Monitor the reaction of the raw material by TLC (methylene chloride:methanol = 20:1). Stop the reaction when the raw material reaction is complete, and cool to room temperature. Concentrate under reduced pressure to remove the solvent. The residue is separated and purified by column chromatography (methylene chloride:methanol = 30:1) and slurried with isopropyl ether, then filtered by suction. The filter cake is dried in vacuo to obtain 25 mg of a white solid with a yield of 59.8%. MS-ESI: [M+H] + 487.3; 1 H NMR (300 MHz, chloroform-d) δ (ppm): 11.19 (s, 1H), 6.93 (s, 1H), 6.74–6.69 (m, 1H), 4.32–4.20 (m, 2H), 3.78 (s, 4H), 3.69–3.52 (m, 4H), 3.43–3.39 (m, 1H), 2.92–2.82 (m, 3H), 2.70–2.59 (m, 4H), 2.35 (d, J = 8.91 Hz, 4H), 1.81–1.74 (m, 2H), 1.69–1.67 (m, 2H), 1.17–1.13 (m, 6H).

[0225] Refer to the preparation method of compound I-52 to prepare the following compounds:

[0226]

[0227]

[0228] Example 9 Synthesis of 2-(2-(1-Acetylpiperidin-4-yl)ethyl)-5-fluoro-7-(2-morpholinoethoxy)quinazolin-4(3H)-one (I-56)

[0229] Step 1: Synthesis of 3-(Piperidin-4-yl)propionitrile Hydrochloride

[0230] Dissolve tert-butyl 4-(2-cyanoethyl)piperidine-1-carboxylate (700 mg, 2.94 mmol) in dichloromethane (3 mL), and then add a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 10 mL). After the addition, react at room temperature overnight. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 3:1) until the raw materials are completely reacted, and then stop the reaction. Concentrate under reduced pressure to remove the solvent. The residue is slurried with ethyl acetate, filtered by suction, and the filter cake is dried in vacuo to obtain 456 mg of a white solid with a yield of 89.1%. MS-ESI: [M+H] + 139.1.

[0231] Step 2: Synthesis of 3-(1-acetylpiperidin-4-yl)propanenitrile

[0232] Using 3-(piperidin-4-yl)propanenitrile hydrochloride (350 mg, 2.01 mmol) and acetyl chloride (173 mg, 2.21 mmol) as raw materials, the operation process is the same as the synthesis of tert-butyl 7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain 334 mg of a colorless oil with a yield of 92.3%. MS-ESI: [M+H] + 181.1.

[0233] Step 3: Synthesis of 2-(2-(1-acetylpiperidin-4-yl)ethyl)-5-fluoro-7-(2-morpholinoethoxy)quinazolin-4(3H)-one (I-56)

[0234] Mix compound II-5 (100 mg, 0.33 mmol), 3-(1-acetylpiperidin-4-yl)propanenitrile (238 mg, 1.32 mmol) with a 1,4-dioxane solution of hydrogen chloride (4 mol / L, 3 mL), and react in a sealed tube at 80 °C overnight. Monitor the reaction by TLC (dichloromethane:methanol = 20:1) until the raw materials are completely reacted, stop the reaction, and cool to room temperature. Concentrate under reduced pressure to remove the solvent. Adjust the pH of the residue to 7-8 with saturated sodium carbonate solution, extract with a dichloromethane / methanol mixed solvent (10:1, 8 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 20:1) and preparative thin-layer plate (dichloromethane:methanol = 25:1) to obtain 25 mg of a white solid with a yield of 17.0%. MS-ESI: [M+H] + 447.2; 11H NMR (300 MHz, DMSO-d6) δ (ppm): 12.09 (s, 1H), 6.93–6.85 (m, 2H), 4.39–4.35 (m, 1H), 4.26 (t, J = 5.6 Hz, 2H), 3.83–3.78 (m, 1H), 3.61–3.59 (m, 4H), 3.04–2.96 (m, 1H), 2.79–2.71 (m, 2H), 2.63–2.58 (m, 2H), 2.51–2.46 (m, 5H), 2.00 (s, 3H), 1.77–1.64 (m, 4H), 1.52–1.45 (m, 1H), 1.17–0.96 (m, 2H).

[0235] Referring to the preparation method of reference compound I-56, the following compounds were prepared:

[0236]

[0237] Example 10 PARP14 Inhibitory Activity Test

[0238] Experimental reagents:

[0239] The PARP14 chemiluminescence assay kit was purchased from BPS Bioscience.

[0240] Experimental method:

[0241] The compound sample was prepared into a 10 mM stock solution with DMSO, and then added to the screening system. The detection range was 0.01 nM - 100 nM, diluted with a 3-fold concentration gradient, and two replicates were made for each concentration. For the experimental results, the IC 50 value was calculated by non-linear regression using GraphPad Prism5.

[0242] Add 100 μL of the PBS solution of histone (20 μg / mL) to a 96-well plate and incubate overnight at 4 °C in the refrigerator. Take it out and wash the plate twice. Add 30 μL of reaction buffer (100 μM NAD + , 25 μM biotinylated NAD +and 200 nM slDNA), and then 5 μL of compounds at different concentrations (0.01 nM, 0.03 nM, 0.1 nM, 0.33 nM, 1 nM, 3.3 nM, 10 nM, 33 nM, 100 nM) or solvent control was added. Subsequently, 20 μL of PARP protein (50 ng / well) was added, and the mixture was incubated at 30 °C for 1 h. The supernatant was poured out, and the plate was washed twice. 50 μL of streptavidin-labeled horseradish peroxidase (HRP) was added to each well, and the mixture was incubated at 30 °C for 0.5 h. Finally, 100 μL of chromogenic solution was added, and the luminescence signal was measured using a multi-well spectrophotometer (Molecular Devices SpectraMax M5 microplate reader). Inhibition rate of PARP14 enzyme activity = (1 - (RLU cmpd –RLU blank / RLU pos.ctrl –RLU blank )) × 100%. Using the Log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, a log(inhibitor) vs. response-variable slope fitting dose-effect curve was used with the analysis software GraphPad Prism 8 to obtain the IC 50 value of each compound for enzyme activity.

[0243] Experimental results:

[0244] The in vitro PARP14 inhibitory activity of some compounds of the present invention was screened, and the results are shown in Table 1.

[0245] Table 1. Inhibitory activity of some compounds on PARP14

[0246]

[0247]

[0248] Note: A: 0.1 < IC 50 ≤ 1.5 nM; B: 1.5 < IC 50 ≤ 15 nM; C: IC 50 > 15 nM.

[0249] The results in Table 1 show that the compounds of the present invention all have good inhibitory activity on PARP14.

[0250] Pharmacokinetic study of the compound of Example 11 in rats

[0251] Experimental method:

[0252] Eight male SD rats were selected and administered intravenously (four rats each with RBN-3143 and I-1). 200 μL of blood was collected from the eyeballs before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The whole blood samples were placed in anticoagulant tubes containing 1% sodium heparin, centrifuged (3500 revolutions / min for 10 minutes), and the upper plasma samples were collected into sample tubes. 20 μL of plasma was taken, 200 μL of methanol (containing 100 ng / mL of internal standard) was added, vortexed for 5 min, then centrifuged at 14500 rmp for 10 min at 4°C. 200 μL of the supernatant was taken and centrifuged at 14500 rmp for 10 min at 4°C. 150 μL of the supernatant was taken, 50 μL of ultrapure water was added, vortexed and mixed evenly, 100 μL was taken and placed in an injection vial, and then LC-MS / MS determination was carried out. The PK parameters were calculated using Phoenix software, and the specific results are shown in Table 2 below.

[0253] Table 2. Pharmacokinetic data of the test compound in SD rats

[0254]

[0255] The results in Table 2 show that the compound I-1 of the present invention has good pharmacokinetic properties in SD rats.

Claims

1. The compound of formula (I): or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, wherein X is selected from CH2, O, NH or S; R 1 selected from H, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, phenyl-C1-C8 alkyl, 5- to 6-membered heteroaryl-C1-C8 alkyl, C1-C8 alkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, hydroxy, amino, nitro or cyano; R 2 selected from H, halogen, hydroxyl, cyano, nitro, amino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, hydroxy C1-C8 alkyl, or amino C1-C8 alkyl; R 3 Selected from: a. wherein R 4 and R 5 together with the carbon atom to which they are attached form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heteroalkyl, wherein the C3-C8 cycloalkyl or 3- to 8-membered heteroalkyl is optionally substituted with an oxo group and / or -L1-R 6 ; wherein L1 is selected from a bond or a C1-C4 alkylene, and R 6 is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ', an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted 3- to 8-membered heteroalkyl, carboxyl, hydroxy, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminocarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl; wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; the cycloalkyl or heteroalkyl is optionally substituted with an oxo group and / or -L2-R 6 '; L2 is selected from a bond or a C1-C4 alkylene, and R 6 ' is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ', an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, carboxyl, hydroxy, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminocarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl, wherein the phenyl or heteroaryl is optionally substituted with a group selected from: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; Y is selected from N or CR 8 ; b.-Z-(CH2) m1 -Q, where Q is selected from optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl; wherein said phenyl or 5- to 6-membered heteroaryl is optionally substituted with a group selected from the following: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; said C3-C8 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with oxo and / or -L1-R 6 substituted, where L1 is selected from a bond or C1-C4 alkylene, R 6 is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, carboxyl, hydroxy, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminocarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl, phenylcarbonyl, 5- to 6-membered heteroarylcarbonyl or carbamoyl; wherein said phenyl or heteroaryl is optionally substituted with a group selected from the following: halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, hydroxy, amino, C1-C8 alkylcarbonylamino; said cycloalkyl or heterocycloalkyl is optionally substituted with an oxo group and / or -L2-R 6 ’ substituted, L2 is selected from a bond or C1-C4 alkylene, R 6 ’ is selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, amino, NR 7 R 7 ’, carboxyl, hydroxy, hydroxy C1-C8 alkyl, amino C1-C8 alkyl, C1-C8 alkylcarbonyl, C1-C8 alkylsulfonyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxyalkylcarbonyl, C1-C8 alkylcarbamoyl, di(C1-C8 alkyl)carbamoyl, di(C1-C8 alkyl)aminocarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylcarbonyl; Z is selected from CR 8 R 8 ’, NR 8 , O or Se; R 7 and R 7 ' are each independently selected from H or C1-C8 alkyl; R 8 and R 8 ' are each independently selected from H or C1-C6 alkyl; p and q are each independently selected from 1, 2 or 3; n and m are each independently selected from 0, 1 or 2; m1 is selected from 0, 1, 2 or 3; Provided that when X is O, n is 1, m is 0, R 1 is cyclopropyl and R 2 is F, R 3 is not the following group: When X is O, n is 1, m is 0, R 1 is phenyl and R 2 is F, R 3 is not When X is O, n is 1, m is 0, R 1 is methyl and R 2 is F, R 3 is not When X is O, n is 1, m is 0, R 2 is F and R 3 is then R 1 is not cyclobutyl, cyclopentyl or tetrahydropyranyl; When X is O, n is 0, m is 0, R 1 is cyclopentyl and R 2 is F, R 3 is not When X is O, n is 1, m is 0, R 1 is and R 2 is F, then R 3 is not 2. The compound or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts according to claim 1, wherein: R 1 selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted by a group selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl-C1-C6 alkyl, 5- to 6-membered heteroaryl-C1-C6 alkyl, C1-C8 alkylcarbonyl, C3-C8 halocycloalkylcarbonyl, C3-C8 cycloalkylcarbonyl, hydroxy, amino, nitro or cyano.

3. The compound or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts according to claim 1, wherein: R 1 selected from ethyl, propyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl; said groups are optionally substituted with groups selected from: halogen, methyl, trifluoromethyl, acetyl, cyclopropylcarbonyl.

4. The compound or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts according to claim 1, wherein: R 3 Selected from: wherein: W represents CR 9 R 9 ’, NR 9 or O, R 9 and R 9 ’ are each independently selected from -L1-R 6 , where L1 is selected from a bond or a C1-C4 alkylene group, and R 6 is selected from H, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, an amino group, NR 7 R 7 ’, an optionally substituted phenyl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted 3- to 8-membered heterocycloalkyl group, a carboxyl group, a hydroxyl group, a hydroxy C1-C8 alkyl group, an amino C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, a C1-C8 alkylsulfonyl group, a C1-C8 alkoxycarbonyl group, a C1-C8 alkoxyalkylcarbonyl group, a C1-C8 alkylcarbamoyl group, a di(C1-C8 alkyl)carbamoyl group, a di(C1-C8 alkyl)aminocarbonylalkyl group, a C3-C8 cycloalkylcarbonyl group, a C3-C8 halocycloalkylcarbonyl group, a phenylcarbonyl group, a 5- to 6-membered heteroarylcarbonyl group or a carbamoyl group; wherein the phenyl or heteroaryl group is optionally substituted with a group selected from the following: halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a C1-C8 alkylcarbonylamino group; the cycloalkyl or heterocycloalkyl group is optionally substituted with an oxo group and / or -L2-R 6 ’, where L2 is selected from a bond or a C1-C4 alkylene group, and R 6 ’ is selected from H, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, an amino group, NR 7 R 7 ’, an optionally substituted phenyl group, an optionally substituted 5- to 6-membered heteroaryl group, a carboxyl group, a hydroxyl group, a hydroxy C1-C8 alkyl group, an amino C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, a C1-C8 alkylsulfonyl group, a C1-C8 alkoxycarbonyl group, a C1-C8 alkoxyalkylcarbonyl group, a C1-C8 alkylcarbamoyl group, a di(C1-C8 alkyl)carbamoyl group, a di(C1-C8 alkyl)aminocarbonylalkyl group, a C3-C8 cycloalkylcarbonyl group, a C3-C8 halocycloalkylcarbonyl group, a phenylcarbonyl group, a 5- to 6-membered heteroarylcarbonyl group or a carbamoyl group, wherein the phenyl or heteroaryl group is optionally substituted with a group selected from the following: halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a C1-C8 alkylcarbonylamino group; m1 is selected from 0, 1, 2 or 3; p is selected from 1, 2 or 3; q is selected from 1, 2 or 3.

5. The compound or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts according to claim 1, wherein: R 3 Selected from: wherein: R 10 selected from H, methyl, oxetanyl, propionyl, acetyl, isopropylcarbonyl, isobutyryl, methoxycarbonyl, cyclopropylcarbonyl, halocyclopropylcarbonyl, benzoyl, benzyl, halobenzyl, p-methylbenzyl, p-trifluoromethylbenzyl, pyridylmethyl, pyrazolylmethyl, pyridinecarbonyl, halopyridinecarbonyl, N-methylpyrrolecarbonyl, N-methylpyrazolecarbonyl, furancarbonyl, C1-C3 alkylsulfonyl or N,N-dimethylformamido.

6. The compound or its stereoisomers, tautomers, solvates, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts according to claim 1, wherein: R 2 selected from H or a halogen.

7. The compound according to claim 1, selected from: 2-(((1-(Cyclopropanecarbonyl)piperidin-4-yl)methyl)amino)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one; 7-(7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-2-carboxylic acid; 7-(Cyclopropylmethoxy)-5-fluoro-2-(methyl(piperidin-4-ylmethyl)amino)quinazolin-4(3H)-one; 4-(((7-(Cyclopentylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)amino)methyl)cyclohexane-1-carboxylic acid; 4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)amino)methyl)cyclohexane-1-carboxylic acid; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-pyridylpiperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(furan-3-carbonyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 5-Fluoro-2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 5-Fluoro-2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one; 2-(((1-benzylpiperidin-4-yl)methyl)amino)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one; 2-(((1-(4-Chlorobenzyl)piperidin-4-yl)methyl)amino)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(4-fluorobenzyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(4-methylbenzyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(5-fluoropyridinyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(7-oxo-2,6-diazaspiro[3.4]octan-2-yl)quinazolin-4(3H)-one; 5-Fluoro-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 5-Fluoro-2-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(methyl((1-(pyridin-2-ylmethyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 2-(7-Acetyl-2,7-diazaspiro[3.5]nonan-2-yl)-5-fluoro-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 7-(Cyclopropylmethoxy)-5-fluoro-2-(((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-((1-Acetylpiperidin-4-yl)methoxy)-2-((7-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-5-fluoroquinazolin-4(3H)-one; 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)quinazolin-4(3H)-one; 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)methyl)quinazolin-4(3H)-one; 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((tetrahydro-2H-pyran-4-yl)selanyl)methyl)quinazolin-4(3H)-one; 7-((1-Acetylpiperidin-4-yl)methoxy)-2-(((1-(cyclopropanecarbonyl)piperidin-4-yl)(methyl)amino)methyl)-5-fluoroquinazolin-4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((methyl(1-(1 - methyl - 1H - pyrazole - 4 - carbonyl)piperidine - 4 - acyl)amino)methyl)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-2 - ((6-(Cyclopropanecarbonyl)-2,6 - diazaspiro[3.3]heptan - 2 - yl)methyl)-5 - fluoroquinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 -(morpholinomethyl)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((tetrahydro - 2H - pyran - 4 - yl)methyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-2 - (((1-(Cyclopropanecarbonyl)piperidin - 4 - ylmethyl)amino)-5 - fluoroquinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((1-(pyridin - 2 - ylmethyl)piperidin - 4 - ylmethyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - (((1 - pyridylpiperidin4 - yl)methyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-2 -(7-(Cyclopropanecarbonyl)-2,7 - diazaspiro[3.5]non - 2 - yl)-5 - fluoroquinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((1-(oxetan - 3 - yl)piperidin - 4 - ylmethyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((1-(1 - methyl - 1H - pyrrole - 3 - carbonyl)piperidin - 4 - ylmethyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((1-(5 - fluoropyridinoyl)piperidin - 4 - ylmethyl)amino)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - (((1 - methyl - 1H - pyrazol - 4 - yl)methyl)amino)quinazolin - 4(3H)-one; 5 - Fluoro - 2 - (((1-(pyridin - 2 - ylmethyl)piperidin - 4 - yl)methyl)amino)-7 -(2-(tetrahydro - 2H - pyran - 4 - yl)ethoxy)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 -(2 - oxa - 7 - azaspiro[3.5]non - 7 - yl)quinazolin - 4(3H)-one; 7 - ((1 - Acetylpiperidin - 4 - yl)methoxy)-5 - fluoro - 2 - ((1-(1 - fluorocyclopropane - 1 - carbonyl)piperidin - 4 - ylmethyl)amino)quinazolin - 4(3H)-one; 7-((2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-(((1-pyridylpiperidin-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-2-(((1-(ethylsulfonyl)piperidin-4-ylmethyl)amino)-5-fluoroquinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((1-methylpiperidin-4-ylmethyl)amino)quinazolin-4(3H)-one; 7-(((1-(cyclopropanecarbonyl)piperidin-4-yl)methoxy)-2-(((-1-(cyclopropanecarbonyl)piperidin-4-yl)methyl)amino)-5-fluoroquinazolin-4(3H)-one; 4-(((7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)amino)methyl)-N,N-dimethylpiperidine-1-carboxamide; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-2-(((1-acetylpiperidin-4-yl)methyl)amino)-5-fluoroquinazolin-4(3H)-one; 7-((cyclopropylmethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(cyclopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 7-(benzylamino)-2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-4(3H)-one; 5-fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonan-2-yl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 5-fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonan-2-yl)-7-((1-methyl-1H-pyrazol-4-yl)methoxy)quinazolin-4(3H)-one; 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7-isobutyryl-7-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one; 2-(7-acetyl-7-azaspiro[3.5]nonan-2-yl)-5-fluoro-7-((1-methyl-1H-pyrazol-4-yl)methoxy)quinazolin-4(3H)-one; 2-(2-(1-acetylpiperidin-4-yl)ethyl)-5-fluoro-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; 5-fluoro-2-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-7-(2-morpholinoethoxy)quinazolin-4(3H)-one; or a stereoisomer, tautomer, solvate, prodrug, isotopically labeled compound, and pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled compound, and pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled compound, and pharmaceutically acceptable salt in the preparation of a drug for inhibiting PARP14.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled compound, and pharmaceutically acceptable salt in the preparation of a drug for preventing and / or treating tumors and inflammatory diseases.

11. The use according to claim 10, wherein the tumor is selected from leukemia, lymphoma, liver cancer, bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer, intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lung cancer, prostate cancer, skin cancer, testicular cancer, thyroid cancer, melanoma and uterine cancer; and the inflammatory disease is selected from atopic dermatitis, scleroderma, inflammatory bowel disease, arthritis, inflammatory demyelinating diseases, emphysema, psoriasis, asthma, allergy and lupus.

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