Compound for regulating PARP enzyme activity, preparation method therefor, and use thereof

Abstract

The present disclosure relates to a compound represented by formula (I) for regulating PARP enzyme activity, a preparation method therefor, and the use thereof. Specifically, the compound relates to a compound that can be used as a drug to regulate PARP14 enzyme activity, a pharmacologically acceptable salt thereof, a composition containing the compound or the salt thereof, and the use thereof in the preparation of a drug, and belongs to the field of pharmaceutical chemistry.

Description

A compound for regulating PARP enzyme activity, a preparation method thereof and use thereof TECHNICAL FIELD

[0001] The present disclosure relates to a compound for regulating PARP enzyme activity, a preparation method thereof and use thereof, in particular to a compound for regulating PARP14 enzyme activity, a pharmacologically acceptable salt thereof, a composition containing the compound or the salt thereof, and use thereof for preparing a medicament, belonging to the field of medicinal chemistry. BACKGROUND

[0002] Atopic dermatitis is one of the most common skin inflammatory diseases, which usually occurs in childhood of individuals and can last into adulthood, and a small number of individuals develop the disease after adulthood or later. The disease is characterized by recurrent episodes, pruritus, and local eczema, usually accompanied by seasonal fluctuations. Patients with the disease often have other allergic diseases such as allergic asthma, allergic rhinoconjunctivitis, food allergy, etc. (N Engl J Med. 2021 Mar 25; 384(12): 1136-1143). The prevalence and incidence of atopic dermatitis have gradually increased over the past few decades, and the current prevalence of the disease is 15%, up to 20% in children and 10% in adults, making it the 15th ranked non-fatal disease (Br J Dermatol 2021; 184:304-9).

[0003] The pathophysiology of atopic dermatitis is complex and caused by multiple factors, involving skin barrier dysfunction, immune response changes, IgE-mediated hypersensitivity, and environmental factors. Recent studies have found that Th2-type cytokines such as KIF3A, IL-4, and IL-13 play a key role in the development of atopic dermatitis (J Dermatol. 2014; 41(3): 213-20). Therefore, for Th2-type inflammation, macromolecular drugs such as Dupilumab and tralokinumab have been developed, and small molecule drugs such as JAK and PDE4 inhibitors have been marketed. In a head-to-head clinical study of upadacitinib (JAK inhibitor) and Dupilumab, it was found that upadacitinib had a significant advantage in efficacy (JAMA Dermatol. 2021 Sep; 157(9): 1047-1055). This suggests that the development of small molecule drugs targeting intracellular downstream signals has the opportunity to be better than antibody drugs, and based on the safety problems of JAK inhibitors, the development of other targets of Th2-type inflammation may achieve better efficacy and safety.

[0004] Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme, there are 17 members, PARP1-PARP17, which is believed to play an important role in protein homeostasis, gene expression and cellular emergency response (Nat. Rev. Cancer. 2014, 14, 502-509). The development of drugs against the PARP family is mainly concentrated in the field of cancer, but in recent years, some studies have found that the family member PARP14 plays a key role in the STAT6 signaling pathway closely related to Th2 type inflammation. STAT6, as a transcriptional regulator, mainly mediates the expression of Th2 type inflammatory factors such as IL-4 / 13. PARP14 inhibitors can inhibit LPS-induced STAT6 target gene expression at the cellular level (PLoS One. 2013 Dec 20; 8(12): e83127, J Biol Chem. 2007 Jun 29; 282(26): 18732), suggesting that the development of inhibitors against PARP14 has potential in the treatment of Th2 type inflammation-related diseases, for example, in the allergic airway disease model, genetic depletion of PARP14 and its enzymatic activity leads to reduced lung inflammation and IgE levels, which is a key indicator of the asthma process in this model (J Allergy Clin Immunol. 2012 July 25; 131(2): 521). Therefore, inhibiting the catalytic activity of PARP14 can also be a potential new therapy for Th2 type inflammatory diseases, including allergic airway diseases.

[0005] Currently, only a few companies (such as Ribon Therapeutics) are developing inhibitors against PARP14, and their preclinical research data shows that they are good in selectivity and safety, slightly better than IL-5 mAb in animal models of asthma and better than Dupilumab in animal models of atopic dermatitis. There is still an urgent need for drugs that can treat cancers or inflammatory diseases characterized by abnormal expression of PARP14 in the clinic.

[0006] The compounds provided by the present disclosure and their pharmaceutically acceptable salts further meet the need for small molecules that inhibit the activity of PARP14. SUMMARY

[0007] The present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof,

[0008] Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, -NH-,

[0009] X is CR X wherein RX each independently selected from the group consisting of hydrogen, deuterium, tritium, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl,

[0010] m, n, o, p, t are each independently selected from 0, 1, 2, 3, 4, and at most one of m, n, o, p is 0,

[0011] each R 2 each independently selected from the group consisting of deuterium, tritium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, nitro, hydroxyl, thiol, halogen, cyano, amine, or when t is 2 or more, two R 2 together form =0 or imine,

[0012] Y 1 , Y 2 , Y 3 each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl,

[0013] L 1 is selected from the group consisting of *—(CH2) q O—, *—(CH2) q S—, *—(CH2) q NH—, *—(CD2) q O—, *—(CD2) q S—, *—(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, and * indicates that said group is attached to R 1 (i.e., said group is attached to R 1 via the bond shown by *),

[0014] R 1 is selected from the group consisting of 3-10 membered cycloalkyl optionally substituted with one or more substituents, 3-10 membered heterocycloalkyl optionally substituted with one or more substituents, 3-10 membered heteroaryl optionally substituted with one or more substituents, each of said heterocycloalkyl, heteroaryl independently comprising 1-2 heteroatoms selected from N, O, S, wherein said substituents are selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3-10 membered heterocycloalkyl.

[0015] In certain embodiments of the present disclosure, Z is preferably -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)-, more preferably -O-, -S-.

[0016] In certain embodiments of the present disclosure, X is CR X , R X is selected from the group consisting of hydrogen, deuterium, tritium, C1-C5 alkyl (e.g., C1-C4 alkyl, C1-C3 alkyl), C1-C5 alkoxy (e.g., C1-C4 alkoxy, C1-C3 alkoxy), hydroxyl. In certain embodiments of the present disclosure, X is CR X , R X is selected from the group consisting of hydrogen, deuterium, tritium, C1-C5 alkyl (e.g., C1-C4 alkyl, C1-C3 alkyl), hydroxyl. In certain embodiments of the present disclosure, X is CR X , R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, ethyl, methoxy, ethoxy, hydroxyl; in certain specific embodiments of the present disclosure, X is CR X , R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, hydroxyl, preferably hydrogen, deuterium, tritium, methyl.

[0017] In certain embodiments of the present disclosure, n, o, m, p are each independently selected from 0, 1, 2, 3, 4, and the sum of n, o is 2-4, the sum of m, p is 2-4; in certain specific embodiments of the present disclosure, n, o, m, p are each independently selected from 1, 2 (e.g., in certain embodiments of the present disclosure, n, o are 1, m, p are 2).

[0018] In certain embodiments of the present disclosure, t is 0, 1, 2, each R 2 is independently selected from the group consisting of deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, or when t is 2, 2 R 2 together form =O or =NH. In certain embodiments of the present disclosure, t is 0, 1, preferably t is 0.

[0019] In certain embodiments of the present disclosure, Y 1 , Y 2 and Y 3each independently selected from hydrogen, deuterium, tritium, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, C1-C5 alkyl (e.g., C1-C4 alkyl, C1-C3 alkyl), C1-C5 alkoxy (e.g., C1-C4 alkoxy, C1-C3 alkoxy), C1-C5 haloalkyl (e.g., C1-C4 haloalkyl, C1-C3 haloalkyl), 3-5 membered cycloalkyl (e.g., 3-4 membered cycloalkyl). In certain embodiments of the disclosure, the Y 1 , Y 2 , Y 3 each independently selected from hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl.

[0020] In certain embodiments of the disclosure, the L 1 is selected from—O—, —S—, —NH—, —CH2—, —(CH2)2—, —(CH2)3—, —CH=CH—, —(CH=CH)2—, —(CH=CH)3—, *—CH2O—, *—(CH2)2O—, *—(CH2)3O—, *—CH2S—, *—(CH2)2S—, *—(CH2)3S—, *—CH2NH—, *—(CH2)2NH—, *—(CH2)3NH—, *—CD2O—, *—(CD2)2O—, *—(CD2)3O—, *—CD2S—, *—(CD2)2S—, *—(CD2)3S—, *—CD2NH—, *—(CD2)2NH—, *—(CD2)3NH—, —CD2—, —(CD2)2—, —(CD2)3—, —CD=CD—, —(CD=CD)2—, —(CD=CD)3—, wherein * indicates that the group is attached to R 1 ; in certain specific embodiments of the disclosure, the L 1 is selected from—(CH2)2—, —CH=CH—, —(CD2)2—, —CD=CD—, *—CH2O—, *—(CH2)2O—, *—(CD2)2O—, *—CD2O—, *—(CH2)2NH—, *—(CD2)2NH—, *—CH2NH—, *—CD2NH—, *—(CH2)2S—, *—CH2S—, *—(CD2)2S—, *—CD2S—, wherein * indicates that the group is attached to R 1 .

[0021] In certain embodiments of the disclosure, R 1selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3-10 membered heterocycloalkyl (the substituents specifically, for example, deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -COCH(CH2)2, -COCD3, -CO-cycloalkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, cyanomethyl, cyanoethyl, cyano-n-propyl, cyano-i-propyl, oxetanyl, oxiranyl, oxolanyl).

[0022] In certain embodiments of the disclosure, R 1 selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3-10 membered heterocycloalkyl (the substituents specifically, for example, deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -COCH(CH2)2, -COCD3, -CO-cycloalkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, cyanomethyl, cyanoethyl, cyano-n-propyl, cyano-i-propyl, oxetanyl, oxiranyl, oxolanyl).

[0023] In certain embodiments of the disclosure, R 1 selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3-10 membered heterocycloalkyl (the substituents specifically, for example, deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -COCH(CH2)2, -COCD3, -CO-cycloalkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, cyanomethyl, cyanoethyl, cyano-n-propyl, cyano-i-propyl, oxetanyl, oxiranyl, oxolanyl).

[0024] Group (i): Preferably, group (i) can be selected from More preferably, group (i) can be selected from

[0025] In certain embodiments of the present disclosure, R 1 is selected from wherein R 1A is selected from C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, a is selected from 0, 1, 2, each R 1B is each independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, aminyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3-10 membered heterocycloalkyl containing 1-2 heteroatoms selected from O or S (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-5 membered heterocycloalkyl, 3-4 membered heterocycloalkyl); preferably, R 1A is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated i-propyl, deuterated cyclopropyl, a is selected from 0, 1, 2, each R 1B is each independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, oxiranyl, oxetanyl, oxolanyl.

[0026] In certain embodiments of the present disclosure, Z is selected from -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)- (preferably -O-, -S-), X is selected from CH, CD, CT, CCH3, COH (preferably CH, CD, CT, CCH3), n, o, m, p are each independently selected from 1, 2 (e.g., n, o are 1, m, p are 2), t is 0, Y 1 , Y 2 , Y 3each independently selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl (particularly, each of R1to R4is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, ethyl, cyclopropyl, trifluoromethyl), L 1 is selected from the group consisting of— (CH2)2—,— (CD2)2—, *— CH2O—, *— CD2O—, *— (CH2)2O—, *— (CD2)2O—, *— (CH2)2S—, *— (CD2)2S—, *— (CH2)2NH—, *— (CD2)2NH—, *— CH2NH—, *— CD2NH—, *— CH2S—, *— CD2S—,— CH=CH—,— CD=CD—, wherein * indicates that the group is attached to R 1 is connected to R 1 is selected from the group consisting of wherein R 1A is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, a is selected from 0, 1, 2, each R 1B each independently selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-10 membered heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-5 membered heterocycloalkyl, 3-4 membered heterocycloalkyl) containing 1-2 heteroatoms selected from O or S; preferably, R 1A is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated i-propyl, deuterated cyclopropyl, a is selected from 0, 1, 2, each R 1B each independently selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, oxetanyl.

[0027] The present disclosure also provides a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof,

[0028] R A is selected from the group consisting of cyano, 3-10 membered heterocycloalkyl, C1-C6 cyanoalkyl, wherein R 1A is selected from C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl,

[0029] R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, said R 1C is attached to any one or both ring carbon atoms of the piperidinyl group,

[0030] a is selected from 0, 1, 2,

[0031] each R 1B is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, aminyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,

[0032] L 1 is selected from *—(CH2) q O—, *—(CH2) q S—, *—(CH2) q NH—, *—(CD2) q O—, *—(CD2) q S—, *—(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * indicates that the group is attached to the piperidinyl group,

[0033] Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, preferably -O-, -S-;

[0034] X is CR X wherein R X is independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl,

[0035] m, n, o, p, t are each independently selected from 0, 1, 2, 3, 4, and at most one of m, n, o, p is 0,

[0036] each R 2each independently selected from the group consisting of deuterium, tritium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, nitro, hydroxy, thiol, halogen, cyano, amine, or when t is 2 or more, 2 R 2 together form =0 or imine group,

[0037] Y 1 , Y 2 , Y 3 each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3- to 8-membered cycloalkyl.

[0038] In certain embodiments of the present disclosure, R A is selected from the group consisting of cyano, cyanomethyl, cyanoethyl, cyanon-propyl, cyanoisopropyl, oxetanyl, wherein R 1A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl.

[0039] In certain embodiments of the present disclosure, R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, said R 1C is attached to the piperidinyl ring carbon position 2 / 2, 2 / 3, 2 / 4, 2 / 5, 2 / 6, 3 / 3, 3 / 4, 3 / 5 or 3 / 6; in certain embodiments of the present disclosure, R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, said R 1C is attached to the piperidinyl ring carbon position 2 / 2, 2 / 3 or 2 / 5, preferably, R 1C is absent; the position of the piperidinyl ring carbon atom in the present disclosure is made according to the rules of chemical nomenclature (IUPAC nomenclature of organic chemistry), for example, the numbering sequence of the piperidinyl ring carbon atoms is

[0040] In certain embodiments of the present disclosure, a is selected from 0, 1, 2, each R 1B each independently selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxy, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoroisopropyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloroisopropyl.

[0041] In certain embodiments of the present disclosure, the L 1 is selected from the group consisting of—O—, —S—, —NH—, —CH2—, —(CH2)2—, —(CH2)3—, —CH=CH—, —(CH=CH)2—, —(CH=CH)3—, *—CH2O—, *—(CH2)2O—, *—(CH2)3O—, *—CH2S—, *—(CH2)2S—, *—(CH2)3S—, *—CH2NH—, *—(CH2)2NH—, *—(CH2)3NH—, *—CD2O—, *—(CD2)2O—, *—(CD2)3O—, *—CD2S—, *—(CD2)2S—, *—(CD2)3S—, *—CD2NH—, *—(CD2)2NH—, *—(CD2)3NH—, —CD2—, —(CD2)2—, —(CD2)3—, —CD=CD—, —(CD=CD)2—, —(CD=CD)3—, wherein * denotes that the group is attached to the piperidinyl group; in certain specific embodiments of the present disclosure, the L 1 is selected from the group consisting of—(CH2)2—, —CH=CH—, *—CH2O—, *—(CH2)2O—, *—(CD2)2O—, *—CD2O—, —(CD2)2—, —CD=CD—, *—(CH2)2NH—, *—(CD2)2NH—, *—CH2NH—, *—CD2NH—, *—(CH2)2S—, *—CH2S—, *—(CD2)2S—, *—CD2S—, wherein * denotes that the group is attached to the piperidinyl group.

[0042] In certain embodiments of the present disclosure, the Y 1 , Y 2 , Y 3 are each independently selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl.

[0043] In certain embodiments of the present disclosure, the R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, ethyl, methoxy, ethoxy, hydroxy; in certain specific embodiments of the present disclosure, the R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, hydroxy, preferably hydrogen, deuterium, tritium, methyl.

[0044] In certain embodiments of the present disclosure, n, o, m, p are each independently selected from 0, 1, 2, 3, 4, and the sum of n, o is 2-4, the sum of m, p is 2-4; in certain specific embodiments of the present disclosure, n, o, m, p are each independently selected from 1, 2 (for example, in certain specific embodiments of the present disclosure, n, o are 1, m, p are 2).

[0045] In certain embodiments of the present disclosure, t is 0, 1, 2, each R 2 is each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, or when t is 2, 2 R 2 together form =O or =NH.

[0046] In certain specific embodiments of the present disclosure, Z is selected from -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)- (preferably -O-, -S-), X is selected from CH, CD, CT, CCH3, COH (preferably CH, CD, CT, CCH3), n, o, m, p are each independently selected from 1, 2 (for example, n, o are 1, m, p are 2), t is 0, Y 1 , Y 2 , Y 3 is each independently selected from hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl (for example, selected from hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, ethyl, cyclopropyl, trifluoromethyl), L 1 is selected from —(CH2)2—, —(CD2)2—, *—CH2O—, *—CD2O—, *—(CH2)2O—, *—(CD2)2O—, *—(CH2)2S—, *—(CD2)2S—, *—(CH2)2NH—, *—(CD2)2NH—, *—CH2NH—, *—CD2NH—, *—CH2S—, *—CD2S—, —CH=CH—, —CD=CD—, wherein * indicates that the group is attached to the piperidinyl group, R A is selected from cyano, cyanomethyl, oxetanyl, wherein R 1Aselected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl, R 1C is absent, a is selected from 0, 1, 2, each R 1B is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-isopropyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-isopropyl.

[0047] The present disclosure also provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof,

[0048] R 1 is selected from wherein R 1A is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, a is selected from 0, 1, 2, each R 1B is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-10 membered heterocycloalkyl,

[0049] L 1 is selected from *—(CH2) q O—, *—(CH2) q S—, *—(CH2) q NH—, *—(CD2) q O—, *—(CD2) q S—, *—(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * represents said group is connected to R 1 ,

[0050] Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-,

[0051] X is CR X , wherein R Xeach independently selected from the group consisting of hydrogen, deuterium, tritium, Ci-C6-alkyl, Ci-C6-alkoxy, hydroxy, halogen, cyano, nitro, amine,

[0052] t is selected from 0, 1, 2, 3, 4,

[0053] each R 2 each independently selected from the group consisting of deuterium, tritium, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, Ci-C6-haloalkyl, Ci-C6-haloalkoxy, nitro, hydroxy, thiol, halogen, cyano, amine, or, when t is 2 or more, 2 R 2 together form =0 or imine,

[0054] Y 1 , Y 2 , Y 3 each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl, 3- to 8-membered cycloalkyl.

[0055] In certain embodiments of the present disclosure, the Z is preferably -0-, -S-.

[0056] In certain embodiments of the present disclosure, the R 1A is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, cyclopropyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated i-propyl, deuterated cyclopropyl, a is selected from 0, 1, 2, each R 1B each independently selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxy, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, oxiranyl, oxetanyl, oxolanyl.

[0057] In certain embodiments of the present disclosure, the L 1—(CH2)2—, —CH=CH—, —(CD2)2—, —CD=CD—, *—CH2O—, *—(CH2)2O—, *—(CD2)2O—, *—CD2O—, *—(CH2)2NH—, *—(CD2)2NH—, *—CH2NH—, *—CD2NH—, *—(CH2)2S—, *—CH2S—, *—(CD2)2S—, *—CD2S—, wherein * indicates that the group is attached to R 1 ; in certain embodiments of the disclosure, the L 1 —(CH2)2—, —CH=CH—, —(CD2)2—, —CD=CD—, *—CH2O—, *—(CH2)2O—, *—(CD2)2O—, *—CD2O—, *—(CH2)2NH—, *—(CD2)2NH—, *—CH2NH—, *—CD2NH—, *—(CH2)2S—, *—CH2S—, *—(CD2)2S—, *—CD2S—, wherein * indicates that the group is attached to R 1 .

[0058] In certain embodiments of the disclosure, the Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl.

[0059] In certain embodiments of the disclosure, the R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, ethyl, methoxy, ethoxy, hydroxy; in certain embodiments of the disclosure, the R X is selected from the group consisting of hydrogen, deuterium, tritium, methyl, hydroxy, preferably hydrogen, deuterium, tritium, methyl.

[0060] In certain embodiments of the disclosure, t is 0, 1, 2, each R 2each independently is selected from the group consisting of deuterium, tritium, nitro, hydroxy, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, or, when t is 2, 2 R 2 together form =0 or =NH.

[0061] In certain embodiments of the present disclosure, Z is selected from the group consisting of -0-, -S-, -S(0)2-, -S(O)-, -S(0)(NH)- (preferably -0-, -S-), X is selected from the group consisting of CH, CD, CT, CCH3, COH (preferably CH, CD, CT, CH3), t is 0, Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl (in particular, for example, selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, ethyl, cyclopropyl, trifluoromethyl), L 1 is selected from the group consisting of— (CH2)2—,— (CD2)2—, *— CH2O—, *— CD2O—, *— (CH2)20—, *— (CD2)20—, *— (CH2)2S—, *— (CD2)2S—, *— (CH2)2NH—, *— (CD2)2NH—, *— CH2NH—, *— CD2NH—, *— CH2S—, *— CD2S—,— CH=CH—,— CD=CD—, wherein * denotes that the group is attached to R 1 , R 1 is selected from the group consisting of wherein R 1A is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated i-propyl, deuterated cyclopropyl, a is selected from the group consisting of 0, 1, 2, each R 1Beach independently is selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, oxiranyl, oxetanyl, oxolanyl.

[0062] For the compounds of Formula (I), Formula (II), Formula (III), or pharmaceutically acceptable salts thereof, solvates (e.g., hydrates) thereof, or prodrugs thereof provided by the present disclosure, in some preferred embodiments, Y 1 , Y 2 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, Y 3 is selected from the group consisting of hydrogen, deuterium, tritium, and Y 1 , Y 2 at least one is not hydrogen, deuterium, tritium; in certain specific preferred embodiments of the present disclosure, Y 1 , Y 2 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, cyclopropyl, Y 3 is selected from the group consisting of hydrogen, deuterium, tritium, and Y 1 , Y 2 at least one is not hydrogen, deuterium, tritium.

[0063] For the compounds of Formula (I), Formula (II), Formula (III), or pharmaceutically acceptable salts thereof, solvates (e.g., hydrates) thereof, or prodrugs thereof provided by the present disclosure, in some preferred embodiments, Z is selected from the group consisting of -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)- (preferably -O-, -S-), X is selected from the group consisting of CH, CD, CT, CCH3, COH (preferably CH, CD, CT, CCH3), t is 0, Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, cyclopropyl, Y 1 , Y 2 at least one is not hydrogen, deuterium, tritium, and Y 3 is hydrogen, deuterium, tritium), L 1selected from - (CH2) 2-, -CH=CH-, *-CH2S-, *-CH2O-, *-CD2O-, *- (CH2) 2O-, *-CH2NH-, wherein * indicates the position where the group is attached to R 1 or piperidinyl.

[0064] In some embodiments, the present disclosure also provides a compound represented by Formula (IV), or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof,

[0065] wherein Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, -NH-, preferably -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)-;

[0066] R X each independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl), hydroxyl;

[0067] Y 1 , Y 2 , and Y 3 each independently selected from hydrogen, deuterium, tritium, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl), C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy), C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl), 3-6 membered cycloalkyl (e.g., 3-5 membered cycloalkyl, 3-4 membered cycloalkyl);

[0068] L 1 selected from *— (CH2) q O—, *— (CH2) q S—, *— (CH2) q NH—, *— (CD2) q O—, *— (CD2) q S—, *— (CD2) q NH—, — (CH=CH) r —, — (CH2) r —, — (CD=CD) r —, — (CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * indicates the position where L 1 is attached to R 1 ;

[0069] R 1 selected from wherein R 1A is selected from C1-C6alkyl (e.g., C1-C5alkyl, C1-C4alkyl, C1-C3alkyl), 3-6 membered cycloalkyl (e.g., 3-5 membered cycloalkyl, 3-4 membered cycloalkyl), C1-C6haloalkyl, C1-C6deuteroalkyl (e.g., C1-C5deuteroalkyl, C1-C4deuteroalkyl, C1-C3deuteroalkyl), a is selected from 0, 1, 2, each R 1B is each independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, aminyl, C1-C6alkyl (e.g., C1-C5alkyl, C1-C4alkyl, C1-C3alkyl), C1-C6alkoxy (e.g., C1-C5alkoxy, C1-C4alkoxy, C1-C3alkoxy), C1-C6haloalkyl (e.g., C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl), 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from O or S (e.g., 3-5 membered heterocycloalkyl, 3-4 membered heterocycloalkyl);

[0070] is preferably R 1A is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, deutero-methyl, deutero-ethyl, deutero-n-propyl, deutero-i-propyl, deutero-cyclopropyl, deutero-cyclobutyl, a is 0 or 1, R 1B is selected from deuterium, tritium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, tribromomethyl, tribromoethyl, tribromo-n-propyl, tribromo-i-propyl, oxiranyl, oxetanyl, oxolanyl.

[0071] In some embodiments, in the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), Y 1 is selected from hydrogen, deuterium, tritium, halogen (e.g., fluorine, chlorine, bromine, iodine). Preferably, Y 1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine.

[0072] In some embodiments, in the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), Y 2selected from hydrogen, deuterium, tritium, halogen (e.g. fluorine, chlorine, bromine, iodine), Ci-C6-alkyl (e.g. Ci-C5-alkyl, Ci-C4-alkyl, Ci-C3-alkyl, methyl, ethyl, propyl), Ci-C6-haloalkyl (Ci-C5-haloalkyl, Ci-C4-haloalkyl, Ci-C3-haloalkyl, Ci-C5-fluoroalkyl, Ci-C4-fluoroalkyl, Ci-C3-fluoroalkyl, Ci-C5-chloroalkyl, Ci-C4-chloroalkyl, Ci-C3-chloroalkyl, Ci-C5-bromoalkyl, Ci-C4-bromoalkyl, Ci-C3-bromoalkyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trichloromethyl, trichloroethyl, trichloropropyl, tribromomethyl, tribromoethyl, tribromopropyl), 3- to 6-membered cycloalkyl (e.g. 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl, cyclopropyl, cyclobutyl). Preferably, Y 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, Ci-C5-alkyl (e.g. methyl, ethyl, propyl), Ci-C5-haloalkyl (e.g. Ci-C5-fluoroalkyl, Ci-C5-chloroalkyl, Ci-C5-bromoalkyl), 3- to 5-membered cycloalkyl (e.g. cyclopropyl, cyclobutyl).

[0073] In some embodiments, in the compounds of formula (I), (II), (III) and (IV), Y 3 selected from hydrogen, deuterium, tritium, halogen (e.g. fluorine, chlorine, bromine, iodine). Preferably, Y 1 selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine.

[0074] In some embodiments, in the compounds of formula (I), (II), (III) and (IV), L 1 selected from *—(CH2) q O—, *—(CH2) q S—, *—(CH2) q NH—, *—(CD2) q O—, *—(CD2) q S—, —(CH=CH) r —, —(CH2) r —, wherein said q is selected from 0, 1, 2 (preferably q is 1 or 2), r is selected from 1, 2, 3 (preferably r is 1 or 2), * indicates the position of L 1 attached to R 1 In some specific embodiments, said L 1 selected from *—CH2O—, *—(CH2)2O—, *—CH2NH—, *—(CH2)2NH—, *—CD2O—, *—(CD2)2O—, —(CH2)2—, —CH=CH—, *—CH2S—, *—(CH2)2S—, *—CD2S—, *—(CD2)2S—, wherein * indicates the position of L1 R 1 position.

[0075] In some embodiments, in the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), R 1 is selected from wherein R 1A is selected from C1-C5 alkyl, 3-5 membered cycloalkyl, C1-C5 deuterated alkyl, a is 0 or 1, and R 1B are each independently selected from fluorine, chlorine, bromine, iodine, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, and 3-5 membered heterocycloalkyl containing 1-2 heteroatoms selected from O or S. In some embodiments, R 1A is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated i-propyl, deuterated cyclopropyl, and deuterated cyclobutyl, a is 0 or 1, and R 1B is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, tribromomethyl, tribromoethyl, tribromo-n-propyl, tribromo-i-propyl, oxiranyl, oxetanyl, and oxolanyl.

[0076] In some embodiments, in the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), R 1 is selected from

[0077] In some embodiments of the present disclosure, the present disclosure provides a compound as shown below, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof:

[0078] The present disclosure also encompasses schemes obtained by any combination, deletion, or alternation of the above embodiments.

[0079] Another aspect of the present disclosure is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0080] Another aspect of the present disclosure provides use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof, for the preparation of a medicament, wherein the medicament is a PARP14 inhibitor, for treating or preventing a disease associated with PARP14 or a Th2-type inflammatory cytokine in a cell. Alternatively, the present disclosure provides a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament, wherein the medicament is a PARP14 inhibitor, for treating or preventing a disease associated with PARP14 or a Th2-type inflammatory cytokine in a cell. Alternatively, the present disclosure provides a method of inhibiting PARP14 activity or reducing a Th2-type inflammatory cytokine in a cell, comprising administering to a subject in need thereof a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof. Alternatively, the present disclosure provides a method of treating or preventing a disease associated with PARP14 or a Th2-type inflammatory cytokine in a cell in a subject in need thereof, comprising administering to the subject a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof. Alternatively, the present disclosure provides use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof, for treating or preventing a disease associated with PARP14 or a Th2-type inflammatory cytokine in a cell. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof is administered in a therapeutically effective amount. In some embodiments, the therapeutically effective amount can be determined by a clinician based on the age, sex, weight, severity of disease, family history, health status, etc. of the patient. The compound, or a pharmaceutically acceptable salt thereof, or a solvate (e.g., hydrate) thereof, or a prodrug thereof, or a pharmaceutical composition thereof can be administered by a conventional route.

[0081] The disease associated with PARP14 or a Th2-type inflammatory cytokine in the present disclosure refers to a disease or its complications that achieves a clinically beneficial effect such as remission, improvement, stop of progression, alleviation, or no longer worsening by inhibiting PARP14 activity and down-regulating the expression of a Th2-type inflammatory cytokine. In some embodiments, the disease in the present disclosure includes cancer and inflammation, the cancer includes multiple myeloma, DLBCL (diffuse large B-cell lymphoma), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer, or melanoma, and the inflammation includes atopic dermatitis, pneumonia, allergic airway disease, asthma, etc.

[0082] Definitions

[0083] Unless otherwise indicated, the following terms have the following meanings in the specification and claims.

[0084] "Chain hydrocarbon group" refers to a group consisting of only carbon and hydrogen atoms, which is connected in a chain shape. The hydrocarbon group can be a saturated hydrocarbon group or an unsaturated hydrocarbon group; the chain shape can be a straight chain or a branched chain. The C1-C10 chain hydrocarbon group used in the present disclosure refers to a straight chain hydrocarbon group or a branched chain hydrocarbon group consisting of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range of any two of the aforementioned values) carbon atoms, including saturated hydrocarbon groups and unsaturated hydrocarbon groups. 10 Chain hydrocarbon group refers to a straight chain hydrocarbon group or a branched chain hydrocarbon group consisting of 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range of any two of the aforementioned values) carbon atoms, including saturated hydrocarbon groups and unsaturated hydrocarbon groups.

[0085] "Alkyl" refers to a saturated aliphatic chain hydrocarbon group, including straight chain alkyl and branched chain alkyl. For example, the C1-C6 alkyl used in the present disclosure refers to a straight chain alkyl or a branched chain alkyl consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6, or a range of any two of the aforementioned values) carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, n-hexyl, and the like.

[0086] "Alkoxy" refers to -O-alkyl; the C1-C6 alkoxy used in the present disclosure refers to a straight chain alkoxy or a branched chain alkoxy consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6, or a range of any two of the aforementioned values) carbon atoms. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, t-pentoxy, n-hexoxy, and the like.

[0087] "Ring" refers to any cyclic covalently closed structure, including, for example, carbocyclic (e.g., aromatic or alicyclic) and heterocyclic (e.g., aromatic or alicyclic). Carbocyclic refers to a ring consisting of only carbon atoms, and heterocyclic refers to a closed structure covalently bonded by carbon atoms and heteroatoms. Depending on the number of rings, "ring" can be monocyclic, bicyclic, tricyclic, or polycyclic. When the ring is bicyclic, tricyclic, or polycyclic, the relationship between the rings can include fused, spiro, or bridged.

[0088] "Heteroatom" refers to any atom other than carbon that can be covalently bonded to carbon. Common heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0089] "Member" refers to the number of skeletal atoms that make up a ring. Typical 5-membered rings include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene, and the like; typical 6-membered rings include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like.

[0090] "Alicyclic" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. A saturated aliphatic carbocyclic group is called, for example, a saturated alicyclic group, or a "cycloalkyl group"; a partially unsaturated carbocyclic group is called, for example, an unsaturated alicyclic group. Alicyclic groups can be monocyclic, spirocyclic, fused, or bridged. For example, a 3- to 8-membered alicyclic group refers to an aliphatic carbocyclic group composed of 3 to 8 skeletal carbon atoms. Typical alicyclic structures include, but are not limited to: wait.

[0091] "Alicyclic" or "alicyclic group" refers to a non-aromatic cyclic group formed by replacing carbon atoms in an alicyclic ring with one or more heteroatoms. Alicyclic or alicyclic groups can include saturated and unsaturated alicyclic rings. For example, a 3- to 12-membered alicyclic group refers to a non-aromatic cyclic group consisting of 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or any range of two of the aforementioned values) skeletal atoms containing one or more heteroatoms (e.g., 1-3, 1-2 N, O, or S atoms). It can be a saturated or unsaturated alicyclic group.

[0092] "Saturated alicyclic" or "cycloalkyl" refers to an aliphatic cyclic group with a saturated carbon atom as its backbone. This cyclic group can be monocyclic, spirocyclic, fused, or bridged. In this disclosure, 3- to 10-membered cycloalkyl refers to a cyclic alkyl group composed of 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values). Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclic [2,1,1]hexyl. wait.

[0093] "Saturated alicyclic heterocycles," also known as "heterocyclic alkyl groups," refer to alicyclic heterocycles in which all carbon atoms constituting the cyclic skeleton are saturated. For example, the 3- to 10-membered heterocyclic alkyl groups used in this disclosure refer to non-aromatic cyclic groups formed by a cyclic skeleton composed of 3 to 10 atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values), wherein the atoms constituting the cyclic skeleton consist of saturated carbon atoms and heteroatoms (e.g., 1-3, 1-2 N, O, or S atoms). Typical saturated alicyclic heterocycles include, but are not limited to: wait.

[0094] "unsaturated aliphatic heterocycle" or "unsaturated aliphatic heterocyclyl" refers to a cyclic structure that is not aromatic and contains part of the unsaturated atoms as a ring backbone in the aliphatic heterocycle. For example, in certain embodiments of the present disclosure, "unsaturated aliphatic heterocycle" refers to a ring backbone that contains unsaturated carbon atoms. A 3-12 membered unsaturated aliphatic heterocycle as used in the present disclosure refers to a non-aromatic cyclic group composed of 3-12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or a range defined by any two of the aforementioned values) backbone atoms, wherein the atoms comprising the ring backbone include saturated carbon atoms, unsaturated carbon atoms, and heteroatoms (e.g., 1-3, 1-2 N, O, or S atoms), and typical unsaturated aliphatic heterocycles include, but are not limited to:

[0095] "aromatic ring" or "aryl" refers to a fully unsaturated carbocyclic ring having a planar ring with a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer. An aromatic ring can be composed of six, eight, ten, or more than ten carbon atoms, and an aromatic ring can be monocyclic, bicyclic, tricyclic, or polycyclic. Common aromatic rings include, but are not limited to, benzene rings, naphthalene rings, phenanthrene rings, anthracene rings, tetraphenes, pyrene rings, pentaphenes, and the like. A 6-10 membered aromatic ring or 6-10 membered aryl group as used in the present disclosure refers to an aromatic ring group composed of 6-10 (e.g., 6, 7, 8, 9, 10, or a range defined by any two of the aforementioned values) backbone carbon atoms.

[0096] "aromatic heterocycle" or "heteroaryl" refers to an aromatic cyclic structure formed by replacing carbon atoms in an aromatic ring with one or more heteroatoms (e.g., 1-3, 1-2 N, O, or S atoms), and typical aromatic heterocycles or heteroaryl groups include, but are not limited to: and the like.

[0097] A 5-10 membered aromatic heterocycle or 5-10 membered heteroaryl group as used in the present disclosure refers to an aromatic ring group composed of 5-10 backbone atoms (e.g., 5, 6, 7, 8, 9, 10, or a range defined by any two of the aforementioned values) containing heteroatoms (e.g., 1-3, 1-2 N, O, or S atoms).

[0098] "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0099] "haloalkyl" refers to a group in which at least one hydrogen atom of an alkyl group is replaced with a halogen atom, and a C1-C6 haloalkyl group as used in the present disclosure refers to a straight-chain alkyl group or a branched-chain alkyl group composed of 1-6 carbon atoms, and a group in which at least one hydrogen atom of the alkyl group is optionally substituted with a halogen atom.

[0100] ​"Cyanoalkyl" refers to a group formed by replacing at least one hydrogen atom in an alkyl group with a cyano group. In this disclosure, C1 to C6 cyanoalkyl refers to a straight-chain alkyl or branched alkyl group consisting of 1 to 6 carbon atoms, and a group formed by arbitrarily replacing at least one hydrogen atom in the alkyl group with a cyano group.

[0101] "Haloalkoxy" refers to a group in which at least one hydrogen atom in an alkoxy group is replaced by a halogen atom. The C1 to C6 haloalkoxy groups used in this disclosure refer to straight-chain alkyl or branched alkyl groups composed of 1 to 6 carbon atoms, and at least one hydrogen atom on the alkyl group is arbitrarily replaced by a halogen atom.

[0102] "Deuterium" or "deuterium atom" refers to an isotope of hydrogen, also known as heavy hydrogen, which consists of one proton, one neutron, and one electron. Its chemical symbol is commonly the letter D or 6. 2 H represents...

[0103] "Tritium" or "tritium atom" refers to an isotope of hydrogen, also known as superheavy hydrogen, which consists of one proton, two neutrons, and one electron. Its chemical symbol is commonly the letter T or t. 3 H represents

[0104] "Deuterated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a deuterium atom. In this disclosure, C1-C6 deuterated alkyl refers to a straight-chain alkyl or branched alkyl group consisting of 1-6 carbon atoms, and at least one hydrogen atom on the alkyl group is arbitrarily replaced by a deuterium atom. For example, in this disclosure, a deuterated methyl group can be a monodeuterated methyl group, a dideuterated methyl group, or a trideuterated methyl group.

[0105] "Amine" or "amine" refers to a substance with the -NR group. S R T The chemical structure of R, where R S R T Each group is independently selected from hydrogen, deuterium, tritium, alkyl, and cycloalkyl groups. Common "amino groups" include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, and -N(CH2CH3)2.

[0106] "Imine" or "imine" refers to a group with the radical NR. W The chemical structure of R, where R W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, common imino groups include, but are not limited to, =NH, =NCH3, =CH2CH3, =NCH(CH3)2.

[0107] "Carbonyl" or "acyl" refers to a group with -COR c The chemical structure of R, where R cCommon carbonyl or acyl groups include, but are not limited to, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -COCH(CH2)2, -COCD3.

[0108] "Amide" or "amido" refers to a chemical group having the structure -C(O)NR U R V or -NR U C(O)R V wherein R U , R V are each independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, heterocycloalkyl, common amido groups include, but are not limited to, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3.

[0109] "Ester" refers to a chemical group having the structure -C(O)OR a or -OC(O)R b wherein R a , R b may each independently be selected from alkyl (e.g., C1-C6 alkyl), cycloalkyl (e.g., 3-8 membered cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl), common ester groups include, but are not limited to, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2.

[0110] "Substituted" means that one or more hydrogen atoms of a group are independently replaced with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) by one skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond. Each and independently is selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0111] "Inhibitor" refers to a substance that decreases the activity of an enzyme.

[0112] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. "Optionally substituted" means unsubstituted and substituted, for example, "an optionally substituted heterocyclic group" means that an alkyl group can or can not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0113] The term "independently" means that when the number of substituents on a group designated by the same symbol is more than one, the substituents can be the same or different at each occurrence.

[0114] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0115] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0116] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned.

[0117] "Tautomer" or "tautomer forms" means different energy structural isomers that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerization. A specific example of a prototropic tautomer is the imidazole moiety, wherein a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by the reorganization of some bonding electrons. Non-limiting examples of tautomers include, but are not limited to

[0118] "Stereoisomer" means isomers that have the same order of attachment of atoms but differ in the spatial arrangement of atoms. It can be divided into several categories, such as conformational isomers, cis-trans isomers, chiral isomers, which can be further divided into enantiomers and diastereomers. The spatial arrangement of atoms in the structure of a "stereoisomer" is usually represented by a wedge-shaped covalent bond (bold wedge-shaped bond dashed wedge-shaped bond ) indicates, wherein the bold wedge indicates out of the plane of the paper and the dashed wedge indicates into the plane of the paper.

[0119] "Enantiomer" refers to a compound having the same molecular formula and functional groups, the same atomic connectivity, but whose stereochemical configurations of atoms are not identical, and which form a stereoisomer that is a mirror image of the other.

[0120] "Diastereomer" refers to a compound having the same molecular formula and functional groups, the same atomic connectivity, but whose stereochemical configurations of atoms are not identical, and which form a stereoisomer that is not a mirror image of the other.

[0121] In the present disclosure, a straight line covalent bond "—" in a structure of a compound can indicate coplanar with the paper. In the present disclosure, when there are stereoisomers of atoms connected by a straight line covalent bond, then the straight line covalent bond indicates that the arrangement of the atoms connected by the straight line covalent bond can include coplanar with the paper, out of the plane of the paper, into the plane of the paper, or a mixture of various arrangements.

[0122] Unless otherwise indicated, the terms "comprise", "comprises", "comprising", "includes", "including", "contain", "contains", "containing", or any other variation thereof, used in this document, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises, includes, contains or contains elements or steps not recited in the list of elements or steps is not excluded.

[0123] Unless otherwise indicated, all numbers expressing quantities of ingredients, measurement of properties and reaction conditions used herein are to be understood as being modified in all instances by the term "about". The term "about" when used in connection with a percentage, can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0124] Unless the context clearly indicates otherwise, singular terms used herein shall encompass the plural, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" as used herein shall be understood to encompass both "and / or".

[0125] Obviously, according to the above content of the present disclosure, according to the ordinary technical knowledge and means in the art, other various forms of modifications, replacements or changes can also be made without departing from the above basic technical ideas of the present disclosure.

[0126] The abbreviations in the present disclosure have the following meanings: DETAILED DESCRIPTION

[0127] Synthetic methods

[0128] The present disclosure also provides a synthesis method of the above-mentioned compound, which is mainly prepared from a method reported in the chemical literature or a related synthesis starting from a commercially available chemical reagent.

[0129] Method 1

[0130] The compound represented by formula (i) is subjected to a ring-closing reaction with the compound represented by formula (ii) under the action of a condensing agent (such as HATU, etc.) to obtain the compound represented by formula (I). Among them, R 1 , L 1 , Y 1 , Y 2 , Y 3 , X, R 2 , n, m, o, p, t are defined as consistent with the foregoing of the present disclosure, and Z is selected from -O-, -S-, -N(Boc)-; when Z is selected from -S-, further oxidation reaction can occur after the ring-closing reaction by the action of an oxidizing agent (such as m-CPBA, hydrogen peroxide, manganese dioxide, tert-butyl hydroperoxide, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -S(O)2- or -S(O)-, or further oxidative amination reaction can occur by the action of an iodo-oxidizing agent (such as iodobenzene diacetate) and an ammonia source (such as ammonium carbamate, ammonia, ammonium nitrate, ammonium fluoride, ammonium carbonate, ammonium acetate, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -S(O)(NH)-; when Z is selected from -N(Boc)-, further deprotection reaction can occur after the ring-closing reaction by the action of a Boc deprotection reagent (such as hydrochloric acid, trifluoroacetic acid, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -NH-.

[0131] Method 2

[0132] The compound represented by formula (i-1) is subjected to a ring-closing reaction with the compound represented by formula (ii-1) under the action of an acidic reagent (such as hydrochloric acid, dilute sulfuric acid, etc.) to obtain the compound represented by formula (I). Among them, R 1 , L 1 , Y 1 , Y 2 , Y 3 , X, R 2, n, m, o, p, t are defined as previously described in the present disclosure, Z is selected from -0-, -S-, -N(Boc)-; when Z is selected from -S-, further oxidation reaction can occur after the ring-closing reaction by the action of an oxidizing agent (such as m-CPBA, hydrogen peroxide, manganese dioxide, tert-butyl hydroperoxide, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -S(O)2- or -S(O)-, or further oxidative amination reaction can occur by the action of an iodo-oxidizing agent (such as iodo-benzene diacetate) and an ammonia source (such as ammonium carbamate, ammonia, ammonium nitrate, ammonium fluoride, ammonium carbonate, ammonium acetate, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -S(O)(NH)-; when Z is selected from -N(Boc)-, further deprotection reaction can occur after the ring-closing reaction by the action of a de-Boc protecting agent (such as hydrochloric acid, trifluoroacetic acid, etc.) to obtain the target compound of the present disclosure represented by formula (I) with Z being -NH-.

[0133] Method 3

[0134] The compound represented by formula (i-2) is subjected to ring-closing reaction with the compound represented by formula (ii) under the action of a condensing agent (such as HATU, etc.) to obtain the compound represented by formula (iii), then amine protection (such as trimethylsilyl ethoxymethyl (SEM) and the like) is performed to obtain the compound represented by formula (iv), then coupling reaction is performed with the compound represented by formula (a-2) under the action of a coupling reagent (such as Pd2(dba)3, BINAP, t-BuXphos, PdCl2(dppf).DCM, etc.) to obtain the compound represented by formula (v), and finally deprotection is performed under the action of a deprotection reagent (such as trifluoroacetic acid, HCl / dioxane, etc.) to obtain the compound represented by formula (I). Wherein, L 3 is selected from — (CH2) q OH, — (CH2) q SH, — (CH2) q SC(O)CH3, — (CH2) q NH2, — (CD2) q OH, — (CD2) q SH, — (CD2) q NH2, — (CH=CH) r B(OH)2, — (CH2) r B(OH)2, — (CD=CD) r B(OH)2, — (CD2) r B(OH)2, when the L 3 is a boronic acid derivative, it can also be a pinacol boronate compound formed by esterification with pinacol, Z 1selected from -0-, -S-, -N(Boc)-, Z is selected from -0-, -S-, -NH-, R 1 1 1 2 3 2 5 The definitions of n, m, o, p, t are consistent with the foregoing of the present disclosure. When Z is selected from -S-, further oxidation reaction can be occurred by the action of oxidizing agent (such as m-CPBA, hydrogen peroxide, manganese dioxide, tert-butyl hydroperoxide, etc.) to obtain the target compounds of the present disclosure represented by formula (I) with Z being -S(O)2-, -S(O)-, or further oxidative amination reaction can be occurred by the action of iodo-oxidizing agent (such as iodobenzene diacetate) and ammonia source (such as ammonium carbamate, ammonia, ammonium nitrate, ammonium fluoride, ammonium carbonate, ammonium acetate, etc.) to obtain the target compounds of the present disclosure represented by formula (I) with Z being -S(O)(NH)-.

[0135] Method 4

[0136] The compound represented by formula (i-3) and the compound represented by formula (ii) undergo ring-closing reaction under the action of condensing agent (such as HATU, etc.) to obtain the compound represented by formula (iii-3), then amine protection (such as trimethylsilyl ethoxy (SEM) and the like) is carried out to obtain the compound represented by formula (iv-3), then hydrogenation is carried out to remove L 5 to obtain the compound represented by formula (v-3), then substitution reaction or reductive amination reaction is carried out with the compound represented by formula (b-2) to obtain the compound represented by formula (vi-3), and finally deprotection is carried out under the action of deprotection reagent (such as trifluoroacetic acid, HCl / dioxane, etc.) to obtain the compound represented by formula (I). Wherein, L 4 is selected from -0-, -S-, -NH-, L 5 is an acid-stable protecting group (preferably a protecting group suitable for catalytic hydrogenolysis removal, such as benzyl, p-methoxybenzyl, etc.), L 0 is selected from -OH, -SH, -NH2, L 2 is selected from chlorine, bromine, iodine, =0 or active ester (such as mesylate), L is selected from —(CH2) q —, —(CD2) q —, L 1 is selected from *—(CH2) q O—, *—(CH2) q S—, *—(CH2) q NH—, —(CD2) q O—, —(CD2) q S—, —(CD2) q NH—, Z 1 ​​​​selected from -0-, -S-, -N(Boc)-, Z is selected from -0-, -S-, -NH-, R 1 , Y 1 , Y 2 , Y 3 , X, R 2 , n, m, o, p, q, t are defined as consistent with the foregoing of the present disclosure. When Z is selected from -S-, further oxidation reaction can occur by the action of oxidizing agents (such as m-CPBA, hydrogen peroxide, manganese dioxide, tert-butyl hydroperoxide, etc.) to obtain the target compounds of the present disclosure represented by formula (I) with Z being -S(O)2-, -S(O)-, or further oxidative amination reaction can occur by the action of iodo-oxidizing agents (such as iodobenzene diacetate) and ammonia sources (such as ammonium carbamate, ammonia, ammonium nitrate, ammonium fluoride, ammonium carbonate, ammonium acetate, etc.) to obtain the target compounds of the present disclosure represented by formula (I) with Z being -S(O)(NH)-.

[0137] In the foregoing method 1, method 2, method 3, and method 4, the compounds represented by formula (i), formula (ii), formula (i-1), formula (ii-1), formula (i-2), formula (i-3), formula (a-2), and formula (b-2) can be commercially available products or can be prepared by the preparation methods disclosed in the prior art by those skilled in the art. For example, the compounds represented by formula (i) and formula (i-1) can be prepared by the following method a and method b; the compounds represented by formula (ii) and formula (ii-1) can be prepared by method c; and the compounds represented by formula (i-3) can be prepared by the following method d.

[0138] Method a

[0139] a) the compound represented by formula (a-1) is coupled with the compound represented by formula (a-2) under the action of a coupling reagent (such as Pd2(dba)3, BINAP, t-BuXphos, PdCl2(dppf).DCM, etc.) to obtain the compound represented by formula (a-3);

[0140] b) substitution reaction of the compound represented by formula (a-3) with 2,4-dimethoxyphenylmethylamine to obtain the compound represented by formula (a-4);

[0141] c) reaction of the compound represented by formula (a-4) under the action of a deprotection reagent (such as trifluoroacetic acid, etc.) to remove the dimethoxyphenyl group to obtain the compound represented by formula (i-1);

[0142] d) ester hydrolysis reaction of the compound represented by formula (i-1) to obtain the compound represented by formula (i);

[0143] wherein L 3 is selected from -(CH2)q OH,—(CH2) q SH,—(CH2) q SC(O)CH3,—(CH2) q NH2,—(CD2) q OH,—(CD2) q SH,—(CD2) q NH2,—(CH=CH) r B(OH)2,—(CH2) r B(OH)2,—(CD=CD) r B(OH)2,—(CD2) r B(OH)2,R 1 ,Y 1 ,Y 2 ,Y 3 ,L 1 ,q,r are defined as previously described in the present disclosure. The compound represented by the aforementioned formula (a-1), formula (a-2), and 2,4-dimethoxyphenylmethylamine can be commercially available or can be prepared by the preparation method disclosed in the prior art by those skilled in the art. The compound represented by the aforementioned formula (a-1) in which the bromine atom at the 4-position is replaced by a hydroxyl group can be obtained by Mitsunobu reaction to obtain the compound represented by formula (a-3), and at this time, L 3 is selected from—(CH2) q OH,—(CH2) q SH,—(CD2) q OH,—(CD2) q SH. The aforementioned L 3 is a boronic acid derivative, or a pinacol boronic ester compound formed by esterification with pinacol.

[0144] Method b

[0145] The compound represented by formula (b-1) is subjected to substitution reaction or reductive amination reaction with the compound represented by formula (b-2) to obtain the compound represented by formula (a-3); the method of steps b) to d) in method a is repeated to obtain the compound represented by formula (i-1), and the compound represented by formula (i). Wherein L 0 is selected from—OH,—SH,—NH2, and L is selected from—(CH2) q ,—(CD2) q ,—, L 2 is selected from chlorine, bromine, iodine, =O, or an active ester (such as mesylate), and L 1 is selected from—(CH2) q O—,—(CH2) q S—,—(CH2) q NH—,—(CD2)q O—, —(CD2) q S—, —(CD2) q NH—, R 1 , Y 1 , Y 2 , Y 3 , q, * are defined as previously described in the present disclosure. The compounds of formula (b-1), formula (b-2) and 2,4-dimethoxyphenylmethylamine can be commercially available or can be prepared by those skilled in the art by using the methods disclosed in the prior art.

[0146] Method c

[0147] a) reacting a compound of formula (c-1) with methanesulfonyl chloride to obtain a compound of formula (c-2);

[0148] b) reacting a compound of formula (c-2) with a cyanating agent (e.g. tetrabutylammonium cyanide) to obtain a compound of formula (ii-1);

[0149] c) reacting a compound of formula (ii-1) in an alcohol (e.g. methanol, etc.), an acidic agent (e.g. hydrochloric acid / dioxane solution, etc.) to obtain a compound of formula (c-3);

[0150] d) reacting a compound of formula (c-3) in the presence of an aminating agent (e.g. ammonium formate, etc.) to obtain a compound of formula (ii);

[0151] wherein X, R 2 , n, m, o, p, t are defined as previously described in the present disclosure, Z is selected from -O-, -S-, -N(Boc)-. The compound of formula (c-1) can be commercially available or can be prepared by those skilled in the art by using the methods disclosed in the prior art; in some cases (e.g. when X is CH), the compound of formula (c-1) can also be obtained from a compound of formula (c) by the action of a reducing agent (e.g. sodium borohydride, borane, etc.), said compound of formula (c) having the structure wherein R 2 , n, m, o, p, t are defined as previously described in the present disclosure. The compound of formula (c) can be commercially available or can be prepared by those skilled in the art by using the methods disclosed in the prior art.

[0152] Method d

[0153] reacting a compound of formula (d-1) with a protecting group L 5The compound shown as formula (d-2) is protected, and then reacted with 2,4-dimethoxyphenylmethylamine to obtain a compound shown as formula (d-3) or a similar derivative, and then reacted in trifluoroacetic acid to obtain a compound shown as formula (d-4), and finally hydrolyzed in a basic environment to obtain a compound shown as formula (i-3). Wherein, L 0 , L 4 , L 5 , Y 1 , Y 2 , Y 3 , the definitions of which are consistent with the foregoing of the present disclosure.

[0154] Preparation Example 1: Preparation of 7-oxaspiro[3.5]nonane-2-carboxamide

[0155] 7-oxaspiro[3.5]nonan-2-one (0.77 g) was dissolved in methanol (15 mL), and sodium borohydride (0.27 g) was added in portions, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, a proper amount of water was added for quenching, excess methanol was removed by concentration, ethyl acetate was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain compound 7-oxaspiro[3.5]nonan-2-ol. MS (ESI) m / z (M+H) + = 143.1.

[0156] Under the condition of ice water bath, 7-oxaspiro[3.5]nonan-2-ol (0.62 g) was dissolved in dry dichloromethane (10 mL), and N,N-diisopropylethylamine (1.13 g) was added. Methylsulfonyl chloride (0.65 g) was dissolved in dichloromethane (1 mL), and slowly added dropwise into the above reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, a proper amount of water was added for quenching, dichloromethane was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain compound 7-oxaspiro[3.5]nonan-2-yl methanesulfonate.

[0157] 7-oxaspiro[3.5]nonan-2-yl methanesulfonate (0.54 g) and tetrabutylammonium cyanide (0.99 g) were dissolved in acetonitrile (10 mL), and the reaction was initiated by microwave under heating at 110°C for 1 hour. After the reaction was completed, a proper amount of water was added for quenching, ethyl acetate was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain compound 7-oxaspiro[3.5]nonan-2-carbonitrile. MS (ESI) m / z (M+H) + = 152.1.

[0158] Dissolve 7-oxaspiro[3.5]nonane-2-carbonimidate hydrochloride (0.36 g) in a solution of ammonia in methanol (5 mL, 7 N) and react at room temperature for 3 hours. After completion of the reaction, concentrate and purify the crude product by preparative HPLC to give the title compound 7-oxaspiro[3.5]nonane-2-carbamimidate. MS (ESI) m / z (M+H) + = 184.1.

[0159] Dissolve 7-oxaspiro[3.5]nonane-2-carbonimidate hydrochloride (0.36 g) in a solution of ammonia in methanol (5 mL, 7 N) and react at room temperature for 3 hours. After completion of the reaction, concentrate and purify the crude product by preparative HPLC to give the title compound 7-oxaspiro[3.5]nonane-2-carbamimidate. MS (ESI) m / z (M+H) + = 169.1.

[0160] Preparation Example 2: Preparation of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid

[0161] Step 1: Preparation of methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluorobenzoate

[0162] Dissolve methyl 2,6-difluoro-4-hydroxybenzoate (0.50 g), (1-acetylpiperidin-4-yl)methyl methanesulfonate (0.75 g) and potassium carbonate (0.73 g) in N,N-dimethylformamide (15 mL) and react at 100 °C for 4 hours. After completion of the reaction, quench with an appropriate amount of water, filter, collect the filtrate, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to give the crude product.

[0163] MS (ESI) m / z (M+H) + = 328.1.

[0164] Step 2: Preparation of methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

[0165] Dissolve methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluorobenzoate (0.25 g), (2,4-dimethoxyphenyl)methanamine (0.26 g) and potassium carbonate (0.26 g) in N,N-dimethylacetamide (5 mL) and react at 100 °C for 4 hours. After completion of the reaction, quench with an appropriate amount of water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and purify the crude product by preparative HPLC to give the title compound.

[0166] MS (ESI) m / z (M+H) + = 475.2.

[0167] Step 3: Preparation of methyl 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino-6- fluorobenzoate

[0168] Methyl 4-((l-acetylpiperidin-4-yl)methoxy)-2-((2,4-dimethoxybenzyl)amino)-6- fluorobenzoate (0.2 g) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) and reacted at room temperature for 2 hours. After the reaction was completed, it was concentrated, the crude product was dissolved in an appropriate amount of methanol, an appropriate amount of potassium carbonate was added to adjust the pH of the system to 8-9, concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain the title compound.

[0169] MS (ESI) m / z (M+H) + = 325.1.

[0170] Step 4: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid

[0171] Methyl 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (0.12 g) was dissolved in methanol (5 mL) and water (1 mL), sodium hydroxide (89.00 mg) was added, and reacted at 50°C overnight. After the reaction was completed, an appropriate amount of hydrochloric acid solution (1 N) was added to adjust the pH of the system to about 5, a solid was precipitated, suction filtration was performed, the filter cake was washed with an appropriate amount of water, the solid was collected, and dried under reduced pressure to obtain the title compound.

[0172] MS (ESI) m / z (M+H) + = 311.1.

[0173] Preparation Example 3: Preparation of 7-thiaspiro[3.5]nonane-2-carboxamidine

[0174] The title compound was prepared by using the corresponding commercially available reagent as a raw material, using a similar preparation method to Preparation Example 1 described above. MS (ESI) m / z (M+H) + = 185.1.

[0175] Preparation Example 4: Preparation of 2-amino-4-(cyclobutylmethoxy)-6-fluorobenzoic acid

[0176] The title compound was prepared by using the corresponding commercially available reagent as a raw material, using a similar preparation method to Preparation Example 2 described above, according to Method b described above. MS (ESI) m / z (M+H) + = 240.1.

[0177] Preparation Example 5: Preparation of 2-amino-4-(cyclopentylmethoxy)-6-fluorobenzoic acid

[0178] The title compound was prepared in accordance with the similar method of Preparation 2 by using the corresponding commercially available reagents as starting materials, and by referring to Method b above. MS (ESI) m / z (M+H) + = 254.1.

[0179] Preparation 6: Preparation of 2-amino-4-(benzyloxy)-6-fluorobenzoic acid

[0180] Step 1: Preparation of 4-(benzyloxy)-2,6-difluorobenzoic acid benzyl ester

[0181] 2,6-difluoro-4-hydroxybenzoic acid (2.0 g) and potassium carbonate (6.3 g) were added to a solution of anhydrous N,N-dimethylformamide (20 mL). Benzyl bromide (5.89 g) was slowly added dropwise into the reaction system, and the reaction was carried out at room temperature. After the reaction was completed, the system was diluted with an appropriate amount of ethyl acetate, filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 354.9.

[0182] Step 2: Preparation of 4-(benzyloxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoic acid benzyl ester

[0183] 4-(benzyloxy)-2,6-difluorobenzoic acid benzyl ester (4.0 g), potassium carbonate (3.12 g), and (2,4-dimethoxyphenyl)methanamine (2.08 g) were added to N-methylpyrrolidone (20 mL), and the reaction was carried out at 90°C for 16 h. After the reaction was completed, the system was diluted with an appropriate amount of ethyl acetate, filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 501.9.

[0184] Step 3: Preparation of 2-amino-4-(benzyloxy)-6-fluorobenzoic acid benzyl ester

[0185] 4-(benzyloxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoic acid benzyl ester (5.2 g) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (10 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the system was concentrated to obtain a crude product. MS (ESI) m / z (M+H) + = 351.9. Step 4: Preparation of 2-amino-4-(benzyloxy)-6-fluorobenzoic acid

[0186] Dissolve 2-amino-4-(benzyloxy)-6-fluorobenzoic acid benzyl ester (3.5 g) in methanol (20 mL) and water (10 mL), and add sodium hydroxide solid (1.99 g) portionwise. React at 60 °C for 20 h. After the reaction is completed, concentrate the system to about 10 mL of solution, and adjust the pH of the system to about 5 with 2 N dilute hydrochloric acid. A large amount of solid precipitates out of the system. Filter the solid under suction, wash the solid with water, and dry to obtain the title compound. MS (ESI) m / z (M+H) + = 261.9.

[0187] Preparation Example 7: Preparation of tert-butyl 2-carbamoyl-7-azaspiro[3.5]nonane-7- carboxylate

[0188] Dissolve 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (4.0 g), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (6.21 g), and N,N-diisopropylethylamine (3.84 g) in dichloromethane (40 mL), and react at room temperature for 1 h. Add 7 M ammonium methanol solution (10 mL) to the system, and react at room temperature for 1 h. After the reaction is completed, concentrate the system to obtain a crude product. Purify the crude product by silica gel column chromatography to obtain tert-butyl 2-carbamoyl-7-azaspiro[3.5]nonane-7-carboxylate. MS (ESI) m / z (M+H) + = 268.9. Dissolve tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (3.8 g) in dichloromethane (20 mL), and add trimethylsulfoxonium tetrafluoroborate (4.19 g) portionwise to the reaction system. React at room temperature for 4 h. Add 7 M ammonium methanol solution (20 mL) to the system, and continue to react for 10 h. After the reaction is completed, concentrate the system to obtain a crude product. Purify the crude product by preparative HPLC to obtain the title compound. MS (ESI) m / z (M+H) + = 267.9.

[0189] Preparation Example 8: Preparation of S-((l-acetylpiperidin-4-yl)methyl)ethanethiol

[0190] Add (l-acetylpiperidin-4-yl)methyl methanesulfonate (400 mg), potassium thioacetate (582.4 mg), and potassium carbonate (704.8 mg) to tetrahydrofuran (4 mL) and water (2 mL), and react at 60 °C for 20 h. After the reaction is completed, dry the system under suction to obtain a crude product. Purify the crude product by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 216.1.

[0191] Preparation 9: Preparation of 2-hydroxy-7-thia[3.5]nonane-2-carboximidate

[0192] Step 1: Preparation of 2-((trimethylsilyl)oxy)-7-thiaspiro[3.5]non-2-carbonitrile

[0193] Under nitrogen atmosphere, 7-thiaspiro[3.5]non-2-one (50 mg) and ZnI2(10 mg) were dissolved in dichloromethane (2 mL), to the system was added dropwise TMSCN (63.5 mg), the reaction was carried out at room temperature for 6 h, after the reaction was completed, the system was quenched with saturated NaHCO3(2 mL), extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. MS (ESI) m / z (M+H) + = 256.1.

[0194] Step 2: Preparation of 2-hydroxy-7-thiazino[3.5]non-2-imidate methyl ester

[0195] 2-((trimethylsilyl)oxy)-7-thiaspiro[3.5]non-2-carbonitrile (40 mg) was dissolved in methanol (1 mL), 4N hydrochloric acid dioxane solution (1 mL) was added, and the reaction was carried out at room temperature for 3 h, and then concentrated to obtain the crude product. MS (ESI) m / z (M+H) + = 216.1.

[0196] Step 3: Preparation of 2-hydroxy-7-thia[3.5]nonane-2-carboximidate

[0197] 2-hydroxy-7-thiazino[3.5]non-2-imidate methyl ester (40 mg) was dissolved in 7N ammonium methanol solution (1 mL), and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the system was concentrated to obtain the crude product, and the crude product was separated and purified by preparative HPLC to obtain the title compound.

[0198] MS (ESI) m / z (M+H) + = 201.1.

[0199] Preparation 10: Preparation of 2-hydroxy-7-oxaspiro[3.5]nonane-2-carboximidate

[0200] Using the corresponding general commercially available reagent as the raw material, the title compound was prepared by using the similar preparation method of Preparation 9 described above. MS (ESI) m / z (M+H) + = 185.1.

[0201] Preparation 11: Preparation of 2-amino-6-fluoro-4-((5-methylthiazol-2-yl)methoxy)benzoic acid

[0202] The title compound was prepared by a similar method to that described in Preparation 2, using the appropriate commercially available starting materials, according to the methods described above in Method b. MS (ESI) m / z (M+H) + = 283.0.

[0203] Preparation 12: Preparation of 2-amino-6-fluoro-4-((2-methylpyridin-4- yl)methoxy)benzoic acid

[0204] The title compound was prepared by a similar method to that described in Preparation 2, using the appropriate commercially available starting materials, according to the methods described above in Method b. MS (ESI) m / z (M+H) + = 277.1.

[0205] Preparation 13: Preparation of 2-amino-6-fluoro-4-((2-methoxypyridin-4- yl)methoxy)benzoic acid

[0206] (2-methoxypyridin-4-yl)methanol (148 mg), 2,6-difluoro-4-hydroxybenzoic acid methyl ester (200 mg), triphenylphosphine (417 mg) were added to anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere, and diisopropyl azodicarboxylate (321 mg) was added to the reaction system, which was allowed to react at room temperature for 1 h. After the reaction was completed, the system was rotary evaporated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 2,6-difluoro-4-(2-methoxypyridin-4-yl)methoxy)benzoic acid methyl ester. MS (ESI) m / z (M+H) + = 310.0.

[0207] The title compound was prepared by a similar method to that described in Preparation 2, using the appropriate commercially available starting materials, according to the methods described above in Method b. MS (ESI) m / z (M+H) + = 293.0.

[0208] Preparation 14: Preparation of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6- chlorobenzoic acid

[0209] The title compound was prepared by a similar method to that described in Preparation 2, using the appropriate commercially available starting materials (for example 2-chloro-4-hydroxy-6-fluorobenzoic acid methyl ester or 2-chloro-4-bromo-6-fluorobenzoic acid methyl ester, etc.), according to the methods described above in Method a or Method b. MS (ESI) m / z (M+H) + = 327.1.

[0210] Preparation 15: Preparation of 2-amino-6-chloro-4-((2-methoxypyridin-4- yl)methoxy)benzoic acid

[0211] The title compound was prepared by the similar method to that described in Preparation 2 or Preparation 13, using the corresponding commercially available reagent (for example, methyl 2-chloro-4-hydroxy-6-fluorobenzoate or methyl 2-chloro-4-bromo-6-fluorobenzoate, etc.) as starting material, according to the above described Method a or Method b. MS (ESI) m / z (M+H) + = 309.0.

[0212] Preparation 16: Preparation of 2-amino-4-((2-methoxypyridin-4-yl)methoxy)-6- methylbenzoic acid

[0213] The title compound was prepared by the similar method to that described in Preparation 2 or Preparation 13, using the corresponding commercially available reagent (for example, methyl 2-chloro-4-hydroxy-6-fluorobenzoate or methyl 2-chloro-4-bromo-6-fluorobenzoate, etc.) as starting material, according to the above described Method a or Method b. MS (ESI) m / z (M+H) + = 309.0.

[0214] Preparation 17: Preparation of (E)-4-(2-(l-acetylpiperidin-4-yl)vinyl)-2-amino-6- fluorobenzoic acid

[0215] The title compound was prepared by the similar method to that described in Preparation 13, using the corresponding commercially available reagent as starting material, according to the above described Method a. MS (ESI) m / z (M+H) + = 307.1.

[0216] Preparation 18: Preparation of 4-(2-(l-acetylpiperidin-4-yl)ethyl)-2-amino-6- fluorobenzoic acid

[0217] Under hydrogen atmosphere, methyl (E)-4-(2-(l-acetylpiperidin-4-yl)vinyl)-2-((2,4- dimethoxybenzyl)amino)-6-fluorobenzoate (150 mg) was dissolved in methanol (15 mL), then 10% Pd / C (15 mg) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated to give methyl 4-(2-(l-acetylpiperidin-4-yl)ethyl)-2-((2,4-dimethoxybenzyl)amino)-6- fluorobenzoate as a crude product. MS (ESI) m / z (M+H) + = 473.2.

[0218] The title compound was prepared by a similar method to that described in Preparation 2, Step 3-4, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 309.1.

[0219] In the present disclosure, Preparation 18 can also be prepared by a similar method to that described in Preparation 13, using the corresponding commercially available reagents as starting materials, according to Method a described above.

[0220] Preparation 19: Preparation of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-5- chlorobenzoic acid

[0221] The title compound was prepared by a similar method to that described in Preparation 13, using the corresponding commercially available reagents as starting materials, according to Method a described above. MS (ESI) m / z (M+H) + = 327.1.

[0222] Preparation 20: Preparation of (1-(acetyl-d3)piperidin-4-yl)methyl methanesulfonate

[0223] Step 1: Preparation of 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one 2,2,2-d3

[0224] Under ice water bath condition, piperidin-4-ylmethanol (141.2 mg) was dissolved in dry dichloromethane (2 mL), N,N-diisopropylethylamine (476.0 mg) and deuterated acetyl chloride (150.0 mg) were added successively into the system, and the mixture was reacted at 0 °C for 30 min. After the reaction was completed, the system was quenched by adding appropriate amount of water, extracted with dichloromethane, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain the crude product. MS (ESI) m / z (M+H) + = 161.1. Step 2: Preparation of (1-(acetyl-d3)piperidin-4-yl)methyl methanesulfonate

[0225] Under ice water bath condition, 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one 2,2,2-d3 crude product (250.0 mg) was dissolved in dry dichloromethane (2 mL), N,N- diisopropylethylamine (476.0 mg) and methylsulfonyl chloride (211.0 mg) were added successively into the system, and the mixture was reacted at 0 °C for 30 min. After the reaction was completed, the system was quenched by adding appropriate amount of water, extracted with dichloromethane, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain the title compound. MS (ESI) m / z (M+H) + = 239.1.

[0226] Preparation 21: Preparation of 4-((l-(acetyl-d3)piperidin-4-yl)methoxy)-2-amino-6- fluorobenzoic acid

[0227] The title compound was prepared in accordance with the procedures described in Preparation 2, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 314.2.

[0228] Preparation 22: Preparation of 6-oxaspiro[3.4]octane-2-carboxamide

[0229] The title compound was prepared in accordance with the procedures described in Preparation 1, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 155.1.

[0230] Preparation 23: Preparation of 2-methyl-7-thiaspiro[3.5]nonane-2-carboximide

[0231] The title compound was prepared in accordance with the procedures described in Preparation 2, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 182.0.

[0232] The title compound was prepared in accordance with the procedures described in Preparation 1, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 199.1.

[0233] Preparation 24: 2-methyl-7-oxaspiro[3.5]nonane-2-carboxamide

[0234] The title compound was prepared in accordance with the procedures described in Preparation 2, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 183.1.

[0235] Preparation 25: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino-3,5,6- trifluorobenzoic acid

[0236] The title compound was prepared by a similar procedure to that described in Preparation 2 above, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 347.1.

[0237] Preparation 26: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino benzoic acid

[0238] The title compound was prepared by a similar procedure to that described in Preparation 2 or Preparation 13 above, using the corresponding commercially available reagents as starting materials (for example methyl 4-hydroxy-2-fluorobenzoate or methyl 4-bromo-2-fluorobenzoate, etc.), by a similar procedure to that described in Method a or Method b above. MS (ESI) m / z (M+H) + = 293.1.

[0239] Preparation 27: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2-amino-6- cyclopropylbenzoic acid

[0240] The title compound was prepared by a similar procedure to that described in Preparation 13 above, using the corresponding commercially available reagents as starting materials (for example methyl 2-cyclopropyl-4-bromo-6-fluorobenzoate, etc.), by a similar procedure to that described in Method a above. MS (ESI) m / z (M+H) + = 333.1.

[0241] Preparation 28: Preparation of 2-amino-6-chloro-4-((2-(trifluoromethyl)pyridin-4- yl)methoxy)benzoic acid

[0242] The title compound was prepared by a similar procedure to that described in Preparation 2 or Preparation 13 above, using the corresponding commercially available reagents as starting materials, by a similar procedure to that described in Method a or Method b above. MS (ESI) m / z (M+H) + = 347.0.

[0243] Preparation 29: Preparation of 4-(((l-acetylpiperidin-4-yl)methyl)thio)-2-amino-6- fluorobenzoic acid

[0244] The title compound was prepared by a similar method to that described in Preparation 2, using the appropriate commercially available starting material (e.g. 4- hydroxymethylpiperidine, 4-bromomethylpiperidine, etc.). MS (ESI) m / z (M+H) + = 327.1.

[0245] Preparation 30: Preparation of 4-(((1-acetylpiperidin-4-yl)methyl)amino)-2- amino-6-fluorobenzoic acid

[0246] The title compound was prepared by a similar method to that described in Preparation 13, using the appropriate commercially available starting material. MS (ESI) m / z (M+H) + = 310.1.

[0247] Preparation 31: Preparation of 2-amino-6-fluoro-4-((1-propionylpiperidin-4- yl)methoxy)benzoic acid

[0248] The title compound was prepared by a similar method to that described in Preparation 2 or Preparation 13, using the appropriate commercially available starting material (e.g. 1-propionyl-4-hydroxymethylpiperidine, 1-propionyl-4- bromomethylpiperidine, etc.), with reference to Method a, Method b. MS (ESI) m / z (M+H) + = 325.1.

[0249] Preparation 32: Preparation of 2-amino-4-((1-(cyclopropanecarbonyl)piperidin-4- yl)methoxy)-6-fluorobenzoic acid

[0250] The title compound was prepared by a similar method to that described in Preparation 2 or Preparation 13, using the appropriate commercially available starting material (e.g. 1-cyclopropanecarbonyl-4-hydroxymethylpiperidine, 1- cyclopropanecarbonyl-4-bromomethylpiperidine, etc.), with reference to Method a, Method b. MS (ESI) m / z (M+H) + = 337.1.

[0251] Preparation 33: Preparation of 4-((1-acetylpiperidin-4-yl)methoxy)-6-amino-2,3- difluorobenzoic acid

[0252] Step 1: Preparation of 6-bromo-2,3,4-trifluorobenzoic acid

[0253] A solution of lithium diisopropylamide in tetrahydrofuran (50 mL) was cooled to -78 °C under ice water bath, and a solution of 5-bromo-1,2,3-trifluorobenzene (5 g) in tetrahydrofuran (5 mL) was added dropwise into the system, and the reaction was carried out at -78 °C for 3 h; then the reaction system was poured into dry ice, and stirred for 1 h; after the system returned to room temperature, 1N hydrochloric acid solution was used to adjust the pH of the system to about 1, and extracted with ethyl acetate; the obtained organic phase was adjusted to about 10 with 2N sodium hydroxide solution; the separated aqueous phase was adjusted to about 1 with 2N hydrochloric acid, and extracted with ethyl acetate; the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. MS (ESI) m / z (M+H) + = 254.9.

[0254] Step 2: Preparation of tert-butyl 6-bromo-2,3,4-trifluorobenzoate

[0255] A solution of 6-bromo-2,3,4-trifluorobenzoic acid (1 g) in tetrahydrofuran (15 mL) was prepared, and 4-dimethylaminopyridine (95.1 mg), di-tert-butyl dicarbonate (2.57 g) were added into the system in turn, and the reaction was carried out at 70 °C for 4 h. After the reaction was completed, the system was concentrated to give a crude product, which was separated and purified by silica gel column chromatography to give the title compound. MS (ESI) m / z (M+H) + = 310.9.

[0256] Step 3: Preparation of tert-butyl 4-((1-acetylpiperidin-4-yl)methoxy)-6-bromo-2,3- difluorobenzoate

[0257] Tert-butyl 6-bromo-2,3,4-trifluorobenzoate (700 mg) and 1-(4- (hydroxymethyl)piperidin-1-yl)ethan-1-one (354 mg), potassium carbonate (931 mg) were added into N,N-dimethylformamide (7 mL) in turn, and the reaction was carried out at 70 °C for 12 h. After the reaction was completed, the system was diluted with ethyl acetate, filtered, and the filtrate was washed with saturated brine; the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by silica gel column chromatography to give the title compound. MS (ESI) m / z (M+H) + = 448.0.

[0258] Step 4: Preparation of tert-butyl 4-((1-acetylpiperidin-4-yl)methoxy)-6-((tert- butoxycarbonyl)amino)-2,3-difluorobenzoate

[0259] In nitrogen atmosphere, tert-butyl 4-((l-acetylpiperidin-4-yl)methoxy)-6- bromo-2,3-difluorobenzoate (200 mg) and tert-butyl carbamate (104 mg), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (21.2 mg), tris(dibenzylideneacetone)dipalladium (10 mg), cesium carbonate (435 mg) were added to 1,4- dioxane (5 mL) and reacted at 110 °C for 2 h. After the reaction was completed, the system was diluted with an appropriate amount of ethyl acetate, filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 485.2.

[0260] Step 5: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-6-amino-2,3- difluorobenzoic acid

[0261] Tert-butyl 4-((l-acetylpiperidin-4-yl)methoxy)-6-((tert-butoxycarbonyl)amino)- 2,3-difluorobenzoate (220 mg) was dissolved in a mixture of dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and reacted at room temperature for 2 h. After the reaction was completed, the system was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 329.1.

[0262] Preparation Example 34: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2- amino-6-(trifluoromethyl)benzoic acid

[0263] Using the corresponding commercially available reagents as starting materials (for example, 2-trifluoromethyl-4-hydroxy-6-fluorobenzoic acid methyl ester or 2- trifluoromethyl-4-bromo-6-fluorobenzoic acid methyl ester, etc.), the title compound was prepared by a method similar to that of Preparation Example 2 or Preparation Example 13 according to the above-described Method a, Method b. MS (ESI) m / z (M+H) + = 361.1.

[0264] Preparation Example 35: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy)-2- amino-3,6-difluorobenzoic acid

[0265] Methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (125 mg) was dissolved in N,N-dimethylformamide (1 mL), 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane ditetrafluoroborate (136 mg) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was quenched with an appropriate amount of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-3,6-difluorobenzoate. MS (ESI) m / z (M+H) + = 343.1.

[0266] The title compound was prepared according to the procedure described in Preparation Example 2, Step 5, using the corresponding commercially available reagents. MS (ESI) m / z (M+H) + = 329.1.

[0267] Preparation Example 36: Preparation of 4-((1-acetyl-4-fluoropiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid

[0268] Under an ice water bath, 1-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (900 mg) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (1.31 g) and methylsulfonyl chloride (581 mg) were added successively, and the mixture was reacted at 0°C for 2 h. After the reaction was completed, the mixture was quenched with an appropriate amount of water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl (1-acetyl-4-fluoropiperidin-4-yl)methanesulfonate. MS (ESI) m / z (M+H) + = 254.0.

[0269] The title compound was prepared according to the procedure described in Preparation Example 2, Step 5, using the corresponding commercially available reagents. MS (ESI) m / z (M+H) + = 329.1.

[0270] Preparation Example 37: Preparation of 2-amino-6-fluoro-4-(imidazo[1,2-a]pyridin-7-methoxy)benzoic acid

[0271] The title compound was prepared according to the procedure described in Preparation Example 2, Step 5, using the corresponding commercially available reagents. MS (ESI) m / z (M+H) + = 302.0.

[0272] Preparation 38: Preparation of 2-amino-4-((2-methoxypyridin-4-yl)methoxy)-6- (trifluoromethyl)benzoic acid

[0273] Using the corresponding commercially available reagents as starting material (for example 2-trifluoromethyl-4-hydroxy-6-fluorobenzoic acid methyl ester or 2-trifluoromethyl-4-bromo-6-fluorobenzoic acid methyl ester, etc.), the title compound was prepared by a similar procedure to that described in Preparation 2 or Preparation 13, according to Method a or Method b described above. MS (ESI) m / z (M+H) + = 343.1.

[0274] Preparation 39: Preparation of 2-amino-6-fluoro-4-((1-(oxetan-3-yl)piperidin-4- yl)methoxy)benzoic acid

[0275] Using the corresponding commercially available reagents as starting material (for example 2,6-difluoro-4-hydroxybenzoic acid methyl ester or 2,6-difluoro-4-bromobenzoic acid methyl ester, N-(3-oxetanyl)piperidin-4-methanol, etc.), the title compound was prepared by a similar procedure to that described in Preparation 2 or Preparation 13, according to Method a or Method b described above. MS (ESI) m / z (M+H) + = 325.1.

[0276] Preparation 40: Preparation of 2-amino-4-((1-cyanopiperidin-4-yl)methoxy)-6- fluorobenzoic acid

[0277] Step 1: Preparation of methyl 4-((1-cyanopiperidin-4-yl)methoxy)-2,6-difluorobenzoate

[0278] Methyl 2,6-difluoro-4-(piperidin-4-ylmethoxy)benzoate hydrochloride (900 mg), potassium carbonate (772 mg), cyanogen bromide (436 mg) were added into acetonitrile (10 mL) at room temperature, and the mixture was stirred for 2 h. After the reaction was completed, the system was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography to give the title compound. MS (ESI) m / z (M+H) + = 311.1.

[0279] Step 2: Preparation of methyl 4-((1-cyanopiperidin-4-yl)methoxy)-2-((2,4- dimethoxybenzyl)amino)-6-fluorobenzoate

[0280] The title compound was prepared by following the similar method described in Step 2 of Preparation 2 using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 458.2.

[0281] Step 3: Preparation of methyl 2-amino-4-((l-cyanopiperidin-4-yl)methoxy)-6- fluorobenzoate

[0282] Methyl 4-((l-cyanopiperidin-4-yl)methoxy)-2-((2,4-dimethoxybenzyl)amino)-6- fluorobenzoate (910 mg) was dissolved in dichloromethane (10 mL), 2,3-dichloro-5,6- dicyanobenzoquinone (894 mg) was added to the system, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the system was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + = 308.1.

[0283] Step 4: Preparation of 2-amino-4-((l-cyanopiperidin-4-yl)methoxy)-6-fluorobenzoic acid

[0284] Methyl 2-amino-4-((l-cyanopiperidin-4-yl)methoxy)-6-fluorobenzoate (80 mg) and potassium trimethylsilanolate (66 mg) were sequentially added to acetonitrile (2 mL), and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 2N dilute hydrochloric acid, and a solid was precipitated. The solid was suction filtered and dried under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + = 294.1.

[0285] Preparation 41: Preparation of 4-((l-acetylpiperidin-4-yl)methoxy-d2)-2-amino-6- fluorobenzoic acid

[0286] Methyl 1-acetylpiperidine-4-carboxylate (2.0 g) was dissolved in tetrahydrofuran (20 mL) under ice-salt bath conditions, and deuterated lithium aluminum hydride (273 mg) was added portionwise to the system. The reaction was carried out at -10 °C for 1 h. After the reaction was completed, the system was quenched with water (0.25 mL), and 15% sodium hydroxide solution (0.25 mL), water (0.75 mL), and an appropriate amount of anhydrous sodium sulfate were sequentially added to the system. After sufficient stirring, the system was suction filtered, and the filtrate was concentrated to obtain 1-(4-(hydroxymethyl-d2)piperidin-1-yl)ethan-1-one. MS (ESI) m / z (M+H) + = 160.1.

[0287] The title compound was prepared by a similar method to that described in Preparation 2, using the corresponding commercially available reagent as starting material. MS (ESI) m / z (M+H) + = 313.1.

[0288] Preparation 42: Preparation of 2-amino-4-((1-(cyanomethyl)piperidin-4-yl)methoxy)-6- fluorobenzoic acid

[0289] The title compound was prepared by a similar method to that described in Preparation 2 or Preparation 13, using the corresponding commercially available reagent (e.g. tert-butyl 2,6-difluoro-4- hydroxybenzoate, 2-(4-(hydroxymethyl)piperidin-1-yl)acetonitrile, etc.) as starting material. MS (ESI) m / z (M+H) + = 308.1.

[0290] Preparation 43: Preparation of 7-oxaspiro[3.5]nonane-2-d-2-carboxamide

[0291] Under nitrogen atmosphere, 7-oxaspiro[3.5]nonane-2-carbonitrile (200.0 mg) was dissolved in dry tetrahydrofuran (2 mL), the system was cooled to -78 °C, 1M lithium bis(trimethylsilyl)amide (1.6 mL) was added dropwise, and the system was reacted at -78 °C for 30 min. Then 0.5 mL of deuterated methanol was added, and the system was naturally warmed to room temperature and reacted for 1 h. After the reaction was completed, the system was quenched by adding an appropriate amount of water, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by silica gel column chromatography to give 7-oxaspiro[3.5]nonane-2-d-2-carbonitrile. MS (ESI) m / z (M+H) + = 153.1.

[0292] The title compound was prepared by a similar method to that described in Preparation 1, using the corresponding commercially available reagent as starting material. MS (ESI) m / z (M+H) + = 170.1.

[0293] Preparation 44: Preparation of 2-amino-6-fluoro-4-((2-(oxetan-3-yl)pyridin-4-yl)methoxy)benzoic acid

[0294] Under ice water bath condition, ethyl isonicotinate (2.26 g) and concentrated sulfuric acid (1.6 mL), 3-iodohomocyclobutane (5.5 g), ferrous sulfate heptahydrate (1.2 g) were added into dimethyl sulfoxide (22 mL) in turn, hydrogen peroxide (4.5 mL) was added dropwise into the system, after reaction at room temperature for 10 min, ferrous sulfate heptahydrate (1.2 g) was added into the reaction system, reaction was carried out at 40 °C for 0.5 h; then ferrous sulfate heptahydrate (1.2 g) was added into the system, the system was cooled to 0 °C, hydrogen peroxide (4.5 mL) was added dropwise, after dropwise addition was completed, the system was continuously reacted at 40 °C for 2 h, after reaction was completed, the system was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, the crude product was separated and purified by silica gel column chromatography to obtain ethyl 2-(oxetan-3-yl)isonicotinate. MS (ESI) m / z (M+H) + = 208.2.

[0295] Under ice water bath condition, ethyl 2-(oxetan-3-yl)isonicotinate (560 mg) was dissolved in tetrahydrofuran (6 mL), lithium aluminum hydride (257 mg) was added into the system in batches, reaction was carried out at room temperature for 0.5 h, after reaction was completed, 0.25 mL of water, 0.25 mL of 15% sodium hydroxide aqueous solution, 0.75 mL of water and appropriate amount of anhydrous sodium sulfate were added into the system in turn, filtered, the filtrate was concentrated to obtain compound (2-(oxetan-3-yl)pyridin-4-yl)methanol. MS (ESI) m / z (M+H) + = 166.1.

[0296] The title compound was prepared by adopting the corresponding general commercially available reagent as raw material, referring to the above-mentioned method b, and following the similar preparation method of Preparation Example 2. MS (ESI) m / z (M+H) + = 319.1.

[0297] Preparation Example 45: Preparation of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-bromobenzoic acid

[0298] The title compound was prepared by adopting the corresponding general commercially available reagent (for example, methyl 2-bromo-4-hydroxy-6-fluorobenzoate, etc.) as raw material, referring to the above-mentioned method a or method b, and following the similar preparation method of Preparation Example 2 or Preparation Example 13. MS (ESI) m / z (M+H) + = 371.0.

[0299] Example 1: Preparation of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7-oxaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one

[0300] To a solution of 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoic acid (10 mg) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (12.50 mg) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12.20 mg) successively. The mixture was stirred at room temperature for 30 min. 7-Oxaspiro[3.5]non-2-ylcarbamidine (5.40 mg) was added and the mixture was stirred at room temperature for another 2 h. After the reaction was completed, the reaction mixture was separated and purified by preparative HPLC to give the title compound.

[0301] MS (ESI) m / z (M+H) + = 444.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 12.6, 2.4 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.00 (d, J = 6.4 Hz, 2H), 3.84 (d, J = 13.6 Hz, 1H), 3.54 (t, J = 5.2 Hz, 2H), 3.47 - 3.36 (m, 3H), 3.09-3.00 (m, 1H), 2.60-2.51 (m, 1H), 2.16 (s, 2H), 2.14 (s, 2H), 2.07-1.95 (m, 4H), 1.84-1.71 (m, 2H), 1.62 (t, J = 5.2 Hz, 2H), 1.50 (t, J = 5.2 Hz, 2H), 1.30-1.18 (m, 1H), 1.17-1.05 (m, 1H).

[0302] Example 2: Preparation of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7- thiaspiro[3.5]non-2-yl)quinazolin-4(3H)-one

[0303] The title compound was prepared by the similar method of Example 1 using the corresponding commercially available reagents and the product in the previous example as starting material according to the previous synthetic method 1 of the present disclosure. MS (ESI) m / z (M+H) + = 444.2. 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 12.6, 2.4 Hz, 1H), 4.45 - 4.33 (m, 1H), 4.00 (d, J = 6.4 Hz, 2H), 3.89 - 3.79 (m, 1H), 3.42-3.34 (m, 1H), 3.10 - 2.99 (m, 1H), 2.60 - 2.52 (m, 3H), 2.47 - 2.41 (m, 2H), 2.11 - 1.97 (m, 8H), 1.87 - 1.70 (m, 6H), 1.30-1.05 (m, 2H).

[0304] Example 3: Preparation of 7-(cyclopentylmethoxy)-5-fluoro-2-(7-thiaspiro[3.5]non-2- yl)quinazolin-4(3H)-one, Example 4: Preparation of 7-(cyclopentylmethoxy)-2-(7,7-dioxo-7- thiaspiro[3.5]non-2-yl)-5-fluoroquinazolin-4(3H)-one

[0305] Step 1: Preparation of 7-(cyclopentylmethoxy)-5-fluoro-2-(7-thiaspiro[3.5]non-2-yl)quinazolin- 4(3H)-one (Example 3)

[0306] To a solution of 2-amino-4-(cyclopentylmethoxy)-6-fluorobenzoic acid (23.00 mg) in N,N- dimethylformamide (2 mL) was added N,N-diisopropylethylamine (34.80 mg) and N,N,N',N'- tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (34.22 mg) successively. After the reaction mixture was stirred at room temperature for 30 min, 7-thiaspiro[3.5]nonane-2- carboxamidine (16.50 mg) was added and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was separated and purified by preparative HPLC to give the title compound. MS (ESI) m / z (M+H) + = 403.1.

[0307] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 6.91 - 6.86 (m, 1H), 6.80 (dd, J = 12.7, 2.4 Hz, 1H), 3.98 (d, J = 7.0 Hz, 2H), 3.42 - 3.35 (m, 1H), 2.59 - 2.53 (m, 2H), 2.47 - 2.42 (m, 2H), 2.35 - 2.27 (m, 1H), 2.08 (s, 2H), 2.05 (s, 2H), 1.87 - 1.82 (m, 2H), 1.81 - 1.68 (m, 4H), 1.66 - 1.48 (m, 4H), 1.38 - 1.27 (m, 2H).

[0308] Step 2: Preparation of 7-(cyclopentylmethoxy)-2-(7,7-dioxo-7-thiasprio[3.5]non-2-yl)-5- fluoroquinazolin-4(3H)-one (Example 4)

[0309] 7-(cyclopentylmethoxy)-5-fluoro-2-(7-thiasprio[3.5]non-2-yl)quinazolin-4(3H)-one (15.00 mg) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (22.73 mg) was added, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, N,N-dimethylformamide (2 mL) was added to the system, and the dichloromethane was removed. The crude product was separated and purified by preparative HPLC to give the title compound.

[0310] MS (ESI) m / z (M+H) + = 435.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 12.7, 2.3 Hz, 1H), 3.99 (d, J = 7.0 Hz, 2H), 3.47 - 3.37 (m, 1H), 3.07 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.37 - 2.26 (m, 1H), 2.22 (s, 2H), 2.20 (s, 2H), 2.14 - 2.04 (m, 2H), 2.03 - 1.93 (m, 2H), 1.82 - 1.71 (m, 2H), 1.68 - 1.47 (m, 4H), 1.39 - 1.28 (m, 2H).

[0311] Example 5: Preparation of 7-(cyclopentylmethoxy)-5-fluoro-2-(7-imino-7-oxo-7 6 thiasprio[3.5]non-2-yl)quinazolin-4(3H)-one

[0312] To a solution of 7-(cyclopentylmethoxy)-5-fluoro-2-(7-thiaspiro[3.5]non-2-yl)quinazolin-4(3H)-one (15.00 mg) in methanol (2 mL) was added ammonium carbamate (4.37 mg) and iodoacetic acid benzyl ester (25.23 mg) and the reaction was allowed to proceed open to the air for 2 h. After the reaction was completed, the reaction mixture was separated and purified by preparative HPLC to give the title compound. MS (ESI) m / z (M+H) + = 434.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 12.6, 2.4 Hz, 1H), 3.99 (d, J = 7.0 Hz, 2H), 3.51 (s, 1H), 3.45 - 3.36 (m, 1H), 2.99 - 2.93 (m, 2H), 2.89 - 2.83 (m, 2H), 2.38 - 2.26 (m, 1H), 2.25 - 2.12 (m, 4H), 2.06 - 1.99 (m, 2H), 1.96 - 1.90 (m, 2H), 1.82 - 1.72 (m, 2H), 1.67 - 1.48 (m, 4H), 1.38 - 1.28 (m, 2H).

[0313] Example 6: Preparation of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7- azaspiro[3.5]non-2-yl)quinazolin-4(3H)-one

[0314] To a solution of methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (50 mg) in 1,4-dioxane (1 mL) was added tert-butyl 2-cyano-7-azaspiro[3.5]nonane-7- carboxylate (57 mg) and aqueous hydrogen chloride (2 N, 1 mL) and the reaction was allowed to proceed at 100 °C overnight. LCMS showed the reaction was complete. The pH of the system was adjusted to neutral by adding saturated sodium bicarbonate solution, and the organic phase was extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography to give the title compound. MS (ESI) m / z (M+H) + = 443.2. 1H NMR (400 MHz, DMSO-d6) δ 6.90 (s, 1H), 6.83 (dd, J = 12.5, 2.4 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.01 (d, J = 6.5 Hz, 2H), 3.87 - 3.72 (m, 2H), 3.07 (d, J = 12.7 Hz, 1H), 2.70 (s, 2H), 2.60 (s, 2H), 2.10 (s, 2H), 2.09 (s, 2H), 2.00 (s, 3H), 1.78 (t, J = 15.5 Hz, 2H), 1.57 (s, 2H), 1.45 (s, 2H), 1.30 - 1.21 (m, 4H).

[0315] Example 7: Preparation of 7-((cyclobutylmethyl)amino)-5-fluoro-2-(7- azaspiro[3.5]non-2-yl)quinazolin-4(3H)-one

[0316] Step 1: Preparation of tert-butyl 2-(7-bromo-5-fluoro-4-oxo-3,4-dihydroquinazolin- 2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0317] To a solution of tert-butyl 2-(7-bromo-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7- azaspiro[3.5]nonane-7-carboxylate (0.5 g) in N,N-dimethylformamide (5 mL) was added 2-aminomethyl-7-azaspiro[3.5]nonane (0.3 g) and N,N-diisopropylethylamine (0.5 g) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The organic phase was separated and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with dichloromethane and methanol) to give the title compound. MS (ESI) m / z (M+H) + = 465.9.

[0318] Step 2: Preparation of tert-butyl 2-(7-bromo-5-fluoro-4-oxo-3-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7- carboxylate

[0319] To a solution of 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7- azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.1 g) and potassium carbonate (978 mg) in N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (590 mg) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel to give the title compound. MS (ESI) m / z (M+H) + = 595.8.

[0320] Step 3: Preparation of 2-(7-((cyclobutylmethyl)amino)-5-fluoro-4-oxo-3-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7- carboxylic acid tert-butyl ester

[0321] To a solution of 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7- azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.1 g) and potassium carbonate (978 mg) in N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (590 mg) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel to give the title compound. MS (ESI) m / z (M+H) + = 595.8.

[0322] Step 4: Preparation of 7-((cyclobutylmethyl)amino)-5-fluoro-2-(7-azaspiro[3.5]nonan-2- yl)quinazolin-4(3H)-one

[0323] To a solution of 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7- azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.1 g) and potassium carbonate (978 mg) in N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (590 mg) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel to give the title compound. MS (ESI) m / z (M+H) + = 595.8. 1H NMR (400 MHz, DMSO-d6) δ 6.71 (t, J = 5.3 Hz, 1H), 6.44 - 6.33 (m, 2H), 3.35-3.25 (m, 1H), 3.16-3.10 (m, 2H), 2.70 - 2.58 (m, 2H), 2.57 - 2.52 (m, 2H), 2.09 - 2.01 (m, 6H), 1.96-1.81 (m, 2H), 1.80 - 1.63 (m, 2H), 1.57-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.31 - 1.18 (m, 1H).

[0324] Example 8: Preparation of 7-(((l-acetylpiperidin-4-yl)methyl)thio)-5-fluoro-2-(7- azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one

[0325] The title compound was prepared by following a similar procedure described in Example 7, using the corresponding commercially available reagents as starting materials. MS (ESI) m / z (M+H) + = 459.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 1.8 Hz, 1H), 7.18 - 7.11 (m, 1H), 4.35 (d, J = 13.0 Hz, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.09 (d, J = 6.4 Hz, 2H), 3.05 - 2.93 (m, 2H), 2.71 - 2.51 (m, 4H), 2.10 (s, 2H), 2.08 (s, 2H), 1.98 (s, 3H), 1.87 - 1.77 (m, 3H), 1.55 (t, J = 5.4 Hz, 2H), 1.42 (t, J = 5.5 Hz, 2H), 1.29 - 1.16 (m, 1H), 1.14 - 1.04 (m, 1H).

[0326] Example 9: Preparation of 7-(cyclopropylmethoxy)-5-fluoro-2-(7-azaspiro[3.5]nonan-2- yl)quinazolin-4(3H)-one

[0327] Step 1: Preparation of tert-butyl 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)- 7-azaspiro[3.5]nonanoate

[0328] To a solution of 2-amino-4-(benzyloxy)-6-fluorobenzoic acid (1.5 g), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (2.19 g) and N,N-diisopropylethylamine (2.03 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 0.5 h. Then tert-butyl 2-aminocarbonyl-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g) was added to the reaction system, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the system was diluted with an appropriate amount of ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by silica gel column chromatography to give the title compound.

[0329] MS (ESI) m / z (M+H) + = 493.9.

[0330] Step 2: Preparation of tert-butyl 2-(7-(benzyloxy)-5-fluoro-4-oxo-3-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7- carboxylate

[0331] To a solution of tert-butyl 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-7- azaspiro[3.5]nonane-7-carboxylate (1.2 g) in anhydrous tetrahydrofuran (10 mL), the system was placed in an ice bath, and 2M lithium bis(trimethylsilyl)amide (3.65 mL) was slowly added dropwise. The reaction was carried out at 0°C for 0.5 h. Then 2- (trimethylsilyl)ethoxymethyl chloride (0.81 g) was added to the reaction system, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was quenched with methanol, and the crude product was concentrated. The crude product was separated and purified by silica gel column chromatography to give the title compound. MS (ESI) m / z (M+H) + = 624.3.

[0332] Step 3: Preparation of tert-butyl 2-(5-fluoro-7-hydroxy-4-oxo-3-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7- carboxylate

[0333] tert-Butyl 2-(7-(benzyloxy)-5-fluoro-4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)- 3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.5 g) and 10% palladium on carbon (150 mg) were added to methanol (15 mL) and stirred at room temperature under a hydrogen atmosphere for 16 h. After the reaction was completed, the reaction mixture was filtered through celite and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel to give the title compound. MS (ESI) m / z (M+H) + = 533.9.

[0334] Step 4: Preparation of tert-Butyl 2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3-((2- (trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7- carboxylate

[0335] tert-Butyl 2-(5-fluoro-7-hydroxy-4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4- dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (50.0 mg) was dissolved in N,N-dimethylformamide (1 mL), and potassium carbonate (25.9 mg) and bromomethylcyclopropane (15.2 mg) were sequentially added to the system, which was then stirred at 80°C for 2 h. After the reaction was completed, the system was diluted with an appropriate amount of ethyl acetate, filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product.

[0336] MS (ESI) m / z (M+H) + = 533.9.

[0337] Step 5: Preparation of 7-(cyclopropylmethoxy)-5-fluoro-2-(7-azaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one

[0338] tert-Butyl 2-(7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)- 3,4-dihydroquinazolin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (53.0 mg) was dissolved in a 4N hydrochloric acid solution in dioxane (1 mL) and stirred at 40°C for 2 h. After the reaction was completed, the system was concentrated to give a crude product, which was dissolved in methanol (2 mL) and the pH of the system was adjusted to 7-8 with potassium carbonate. The mixture was filtered, and the filtrate was purified by preparative HPLC to give the title compound. MS (ESI) m / z (M+H) + = 533.9.

[0339] 1H NMR (400 MHz, DMSO-d6) δ 6.86 - 6.79 (m, 2H), 3.97 (d, J = 7.1 Hz, 2H), 3.42 - 3.40 (m, 1H), 2.68 - 2.61 (m, 2H), 2.59 - 2.52 (m, 2H), 2.09 (s, 2H), 2.07 (s, 2H), 1.54 - 1.39 (m, 4H), 1.25 - 1.22 (m, 1H), 0.62 - 0.56 (m, 2H), 0.37 - 0.32 (m, 2H).

[0340] Using the corresponding commercial reagents and the products in the preceding Preparation Examples and Examples as raw materials, using the similar preparation method in the above Examples, a class of compounds were prepared, the structures and characterization data of the compounds are shown in Table 1,

[0341] Table 1

[0342] Preparation of 7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(7-oxa-2- azaspiro[3.5]non-2-yl)quinazolin-4(3H)-one

[0343] 7-oxa-2-azaspiro[3.5]nonane hydrochloride (500.0 mg) was dissolved in N,N- dimethylformamide (5 mL), N,N-diisopropylethylamine (1.2 g) and 1H-pyrazole-1- carboxamidine hydrochloride (470.0 mg) were added to the system in turn, and the reaction was carried out at 60°C for 1 h. After the reaction was completed, a large amount of white solid was precipitated in the system, and the solid was extracted by filtration. The solid was washed with a small amount of ethyl acetate and dried under reduced pressure to obtain compound 7-oxa-2-azaspiro[3.5]nonane-2-carboxamide. MS (ESI) m / z (M+H)+= 170.1.

[0344] To anhydrous N,N-dimethylformamide (2 mL) were added 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluorobenzoic acid (70 mg), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (85.0 mg) and N,N-diisopropylethylamine (78.8 mg) sequentially, after stirring at room temperature for 0.5 h, 7-oxa-2-azaspiro[3.5]nonane-2-carboximidamide (45.0 mg) was added, and the reaction was carried out at room temperature for 1.5 h. After the reaction was completed, the system was quenched with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by preparative silica gel plate separation to obtain compound 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluoro-N-(imino(7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)benzamide. MS (ESI) m / z (M+H) + = 465.2.

[0345] To anhydrous tetrahydrofuran (2 mL) were added 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluoro-N-(imino(7-thia-2-azaspiro[3.5]nonan-2-yl)methyl)benzamide (50.0 mg) and potassium tert-butoxide (23.3 mg) sequentially, and the reaction was carried out at 50°C for 0.5 h. After the reaction was completed, the system was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the title compound.

[0346] MS (ESI) m / z (M+H) + = 445.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 6.53-6.41 (m, 2H), 4.44-4.35 (m, 1H), 3.92 (d, J = 6.5 Hz, 2H), 3.85 (s, 1H), 3.82 (s, 4H), 3.52 (t, J = 5.1 Hz, 4H), 3.07-2.99 (m, 1H), 2.58-2.54 (m, 1H), 1.99 (s, 4H), 1.81-1.73 (m, 2H), 1.72 (t, J = 5.1 Hz, 4H), 1.26-1.21 (m, 1H), 1.14-1.04 (m, 1H).

[0347] Using the corresponding commercial reagents and the products in the preceding preparation examples and examples as raw materials, and using the similar preparation method of Comparative Example 1 and / or Example 7, a class of comparative example compounds were prepared, the structures and characterization data of which are shown in Table 2,

[0348] Table 2

[0349] Based on the prior art and the disclosure of the prior art, the applicant also prepared the following Comparative Examples 1-4.

[0350] Comparative Example 1: 7-(Cyclopentylmethoxy)-5-fluoro-2-(2,7-diazaspiro[3.5]nonan-2- yl)quinazolin-4(3H)-one hydrochloride

[0351] Step 1: Synthesis of tert-butyl 2-(5-fluoro-7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate

[0352] The compound tert-butyl 2-(7-(benzyloxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (480 mg) was dissolved in a mixture solvent of dichloromethane and methanol (1:2), 10% palladium on carbon (41 mg) was added, hydrogen was replaced, and then the reaction was carried out at room temperature overnight. TLC (dichloromethane:methanol = 15:1) was used to monitor the completion of the reaction, and the reaction was stopped. Silica was used to filter, methanol (5 mL x 3) was used to wash, and the filtrate was concentrated under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + = 405.2.

[0353] Step 2: Synthesis of tert-butyl 2-(7-(cyclopentylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0354] The compound obtained in Step 1 (180 mg), bromomethylcyclopentane (88 mg), and potassium carbonate (124 mg) were dissolved in dichlorosulfoxide (5 mL), and the temperature was raised to 60°C, and the reaction was carried out for 6 h. TLC (dichloromethane:methanol = 15:1) was used to monitor the completion of the reaction, and the reaction was stopped. The temperature was lowered to room temperature, water (20 mL) was added for dilution, ethyl acetate (10 mL x 3) was used for extraction, the combined organic layers were washed with water and saturated sodium chloride solution, and anhydrous sodium sulfate was used for drying. Filtration was carried out under suction, and the filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (dichloromethane:methanol = 100:1) to obtain the title compound. MS (ESI) m / z (M+H) + = 487.2.

[0355] Step 3: Synthesis of 7-(cyclopentylmethoxy)-5-fluoro-2-(2,7-diazaspiro[3.5]nonan-2-yl)quinazolin- 4(3H)-one hydrochloride

[0356] At 0°C, the compound obtained in step 2 (140 mg) was dissolved in an ethyl acetate solution of hydrogen chloride (4 mol / L, 2 mL), and the reaction was carried out at room temperature for 3 h, during which a solid precipitated. The reaction was stopped after TLC (dichloromethane:methanol = 5:1) monitoring showed that the reaction proceeded completely. The mixture was filtered, washed with ethyl acetate, and the filter cake was dried under vacuum to give the title compound. MS (ESI) m / z (M+H) + =387.2. 1 H-NMR(300MHz,DMSO-d6)δ9.21(s,2H),7.29(s,1H),6.83-6.78(m,1H),4.15(s,4H),3.95(d,J=7.0Hz,2H),3.0 5-2.97(m,4H),2.37-2.28(m,1H),2.04-1.96(m,4H),1.83-1.73(m,2H),1.65-1.54(m,4H),1.37-1.26(m,2H).

[0357] Comparative Example 2: Preparation of 7-(cyclopropylmethoxy)-5-fluoro-2-(2,7-diazaspiro[3.5]nonane-2-yl)quinazolin-4(3H)-one

[0358] Step 1: Preparation of intermediates

[0359] 7-(cyclopropylmethoxy)-5-fluoroquinazoline-2,4(1H,3H)-dione (80 mg) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (81 mg) were dissolved in isopropanol (5 mL), and then refluxed for 5 h. The reaction was stopped after the starting material was completely reacted by TLC (dichloromethane:methanol = 15:1). The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 40:1) to obtain the intermediate. MS (ESI) m / z (M+H) + =459.2.

[0360] Step 2: Synthesis of 7-(cyclopropylmethoxy)-5-fluoro-2-(2,7-diazaspiro[3.5]nonane-2-yl)quinazolin-4(3H)-one hydrochloride

[0361] The intermediate (70 mg) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of hydrogen chloride (4.5 mol / L, 2 mL) was added. The reaction was carried out overnight at room temperature under nitrogen protection. The reaction was monitored by TLC (dichloromethane:methanol = 10:1) until complete, at which point the reaction was stopped. The mixture was filtered, washed with ethyl acetate, and the filter cake was dried under vacuum to give a white solid. MS (ESI) m / z (M+H) + =359.2. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 7.30 (s, 1H), 6.83-6.78 (m, 1H), 4.15 (s, 4H), 3.94 (d, J = 7.1 Hz, 2H), 3.06-3.00 (m, 4H), 2.05-2.01 (m, 4H), 1.30-1.22 (m, 1H), 0.64-0.57 (m, 2H), 0.39-0.34 (m, 2H).

[0362] Synthesis of 7-(cyclobutylmethoxy)-5-fluoro-2-(2,7-diazaspiro[3.5]nonan-2-yl)quinazolin-4(3H)-one hydrochloride

[0363] The compound obtained in Step 1 of Comparative Example 1 and bromomethylcyclobutane were used as raw materials, and the operation process was the same as the synthesis of Comparative Example 1 to obtain a white solid. MS (ESI) m / z (M+H) + = 373.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 2H), 7.30 (s, 1H), 6.83-6.78 (m, 1H), 4.15 (s, 4H), 3.94 (d, J = 7.1 Hz, 2H), 3.06-3.00 (m, 4H), 2.05-2.01 (m, 4H), 1.30-1.22 (m, 1H), 0.64-0.57 (m, 2H), 0.39-0.34 (m, 2H).

[0364] Synthesis of 5-fluoro-2-(2,7-diazaspiro[3.5]nonan-2-yl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one hydrochloride

[0365] The compound obtained in Step 1 of Comparative Example 1 and 4-bromomethyltetrahydropyran were used as raw materials, and the operation process was the same as the synthesis of Comparative Example 1 to obtain the title compound. MS (ESI) m / z (M+H) + = 403.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 2H), 7.30 (s, 1H), 6.83-6.78 (m, 1H), 4.15 (s, 4H), 3.94 (d, J = 7.1 Hz, 2H), 3.06-3.00 (m, 4H), 2.05-2.01 (m, 4H), 1.30-1.22 (m, 1H), 0.64-0.57 (m, 2H), 0.39-0.34 (m, 2H).

[0366] Biological test

[0367] Unless otherwise specified, the experimental materials, reagents, operations and methods used in the following activity test examples can be obtained from commercial channels or easily known or prepared based on the prior art.

[0368] Test Example 1: Enzymatic inhibition test

[0369] 1. Purpose of experiment

[0370] To determine the inhibitory activity of the compounds of the present application on PARP14.

[0371] 2. Experimental materials

[0372] 2.1 Main reagents

[0373] 3. Experimental method (Unless otherwise specified, the following reagents are reagents in the PARP14 Chemiluminescent assay kit)

[0374] 3.1 Mix 5x Histone mix with 1x PARP14 buffer to make 25 μL of 1x Histone mix, add 1x Histone mix to assay plate and incubate at 4°C overnight (plate coating).

[0375] 3.2 Remove liquid from 3.1 assay plate, wash plate 3 times with 100 μL PBST for 5 min each, then add 25 μL blocking solution per well and incubate at room temperature for 90 min.

[0376] 3.3 After incubation, remove blocking solution from plate and wash plate 3 times with 100 μL PBST for 5 min each.

[0377] 3.4 Add 100 nL of pre-diluted test compound solution per well and centrifuge at 1000 rpm for 1 min.

[0378] 3.5 Add 5 μL of PARP14 enzyme solution per well and centrifuge at 1000 rpm for 1 min.

[0379] 3.6 Add 5 μL of substrate solution per well and centrifuge at 1000 rpm for 1 min, then incubate at 25°C for 1 h.

[0380] 3.7 Remove liquid from plate, then wash plate 3 times with 100 μL PBST per well for 5 min each.

[0381] 3.8 Add St-HRP diluted with blocking solution (1:2000) per well and incubate at 25°C for 30 min.

[0382] 3.9 Remove liquid from plate and wash plate 3 times with 100 μL PBST per well for 5 min.

[0383] 3.10 Add 25 μL of ELISA ECL A and B solution mixture (1:1) per well and read plate using BMG microplate reader.

[0384] 4. Data analysis

[0385] Data analysis was performed using the equation Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*Hillslope)), where X is the concentration of the compound to be tested and Y is the inhibition rate.

[0386] 5. Experimental results:

[0387] It was found that the IC50 value of the compound of the present disclosure for PARP14 inhibitory activity was less than 20 nM, the IC50 value of some compounds of the present disclosure (for example, Examples 1, 19, 43, etc.) for PARP14 inhibitory activity was greater than or equal to 5 nM and less than 10 nM, the IC50 value of some compounds of the present disclosure (for example, Examples 6, 10, 12, etc.) for PARP14 inhibitory activity was less than 5 nM. It was found that the IC50 value of Comparative Example 15, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4 for PARP14 inhibitory activity was greater than or equal to 20 nM and less than 50 nM in the parallel test of the present disclosure. 50 50 50 50

[0388] Test Example 2: NanoBRET assay

[0389] 1 Purpose of experiment

[0390] To determine the competitive binding activity of the compound of the present application to PARP14 in cells.

[0391] 2 Experimental materials

[0392] 2.1 Main reagents / cells

[0393] 3 Experimental method

[0394] 3.1 Transfect H293T cells with Nanoluc-PARP14 fusion vector (purchased from Promega; item number: CS3489A40) in a constant temperature incubator for 20-30 h. After incubation, discard the supernatant, digest, centrifuge, resuspend with Opti-MEM medium, count, adjust the cell density to 2E5 / mL, and add 85 μL of cell suspension per well to a white 96-well plate.​​​​

[0395] 3.2 Add test compound: Prepare 10x test compound solution with Opti-MEM medium, 4-fold serial dilution for 9 gradients. Add 10 μL test compound of different concentrations to each well.

[0396] 3.3 Add Tracer: Prepare 20x Tracer with Opti-MEM fresh medium in the dark, add 5 μL Tracer to each well. Set up blank control group (containing only cells) and Tracer group (containing cells and Tracer) at the same time.

[0397] 3.4 Mix well, and incubate the plate in the incubator for 2 h.

[0398] 3.5 Take out the cell culture plate at the end of incubation and equilibrate at room temperature, add appropriate amount of Intracellular TE Nano-Glo Substrate / Inhibitor mixture to each well, and incubate and detect at room temperature.

[0399] 3.6 Detect the fluorescence signals at donor emission wavelength 460 nm and acceptor emission wavelength 610 nm by using a microplate reader.

[0400] 4 Data analysis

[0401] Fit the dose-effect curve by using the log(inhibitor) vs. response-Variable slope(four parameters) in the analysis software GraphPad Prism, so as to obtain the IC 50 value of the compound.

[0402] Wherein Acceptor(610 nm) represents the fluorescence signal at acceptor emission wavelength 610 nm, and Donor(460 nm) represents the fluorescence signal at donor emission wavelength 460 nm. Convert the BRET ratio x 1000 into milliBRET units mBU.

[0403] 5. Experimental results:

[0404] The intracellular binding activity of the compound in the embodiments of the present disclosure is shown in Table 3 below,

[0405] Table 3

[0406] In the table, “A+” represents that the IC 50 range of intracellular binding activity is less than 3 nM; “A” represents that the IC 50 range of intracellular binding activity is greater than or equal to 3 nM and less than or equal to 10 nM; and “B” represents that the IC 50IC50values greater than 10 nM and less than 30 nM; "C" represents the IC50values of the intracellular binding activity 50 IC50values greater than 30 nM and less than 100 nM; "D" represents the IC50values of the intracellular binding activity 50 IC50values greater than 100 nM and less than 500 nM; "E" represents the IC50values of the intracellular binding activity 50 IC50values greater than 500 nM and less than 1 μM; "F" represents the IC50values of the intracellular binding activity 50 IC50values greater than 1 μM and less than 10 μM.

[0407] It is found that the IC50values of the intracellular binding activity of the compounds of the present disclosure 50 are less than 500 nM, the IC50values of the intracellular binding activity of certain compounds of the present disclosure 50 are greater than or equal to 30 nM and less than 100 nM, the IC50values of the intracellular binding activity of certain compounds of the present disclosure 50 are greater than or equal to 10 nM and less than 30 nM, the IC50values of the intracellular binding activity of certain compounds of the present disclosure 50 are greater than or equal to 3 nM and less than 10 nM, the IC50values of the intracellular binding activity of certain compounds of the present disclosure 50 are less than 3 nM. It is found that the compounds of the present disclosure have greatly improved intracellular binding activity, and the intracellular binding activity of the compounds of the present disclosure is at least 5 times or even about 10 times or more than that of the control or prior art compounds, for example, the intracellular binding activity of PARP14, Example 27 is 9 times that of Control Example 27, and Example 64 is 30 times that of Control Example 64.

[0408] Test Example 3: Liver microsomal stability test

[0409] 1. Purpose of the experiment

[0410] To determine the stability of the compound in rat and human liver microsomes.

[0411] 2. Reagents and consumables

[0412] 3. Experimental procedure

[0413] 3.1 Incubation system of the test

[0414] 3.2 Pipette an appropriate amount of liver microsomal solution into 1 mL 96-deep well plate, add the test drug solution, i.e. test group (or positive substrate solution, i.e. control group), pre-incubate for 5 min at 37℃ in a thermomixer. Take out two aliquots of the mixture from the system, add 1xPBS instead of NADPH, and take out the mixture at 0, 60 min, add methanol (containing internal standard) to terminate the reaction. Add NADPH to start the reaction in the remaining mixture, take out the mixture from the system at 0, 5, 15, 30, 45, 60 min for the test group, and at 0, 30, 60 min for the control group, add methanol (containing internal standard) to terminate the reaction. Mix all the samples after termination of the reaction, centrifuge at 3800 rpm for 15 min in a centrifuge, and take the supernatant for LC-MS / MS analysis.

[0415] 3.3 Data analysis

[0416] The peak area is determined from the extracted ion chromatogram. The slope value k is determined by linear regression of the natural logarithm of the remaining percentage of parent drug versus incubation time. The in vitro half-life (t 1 / 2 ) is calculated according to the slope, and the in vitro intrinsic clearance (CL int ) is calculated, expressed in μL / min / mg protein. The calculation formula is as follows:

[0417] t 1 / 2 = ln2 / k = 0.693 / k; CL int = 0.693 / T 1 / 2 / microsome protein content

[0418] It has been found through experiments that the compound (e.g. Example 1, Example 27, Example 43) of the present disclosure can have good liver microsomal stability, and can be more stable in liver microsomal metabolism than existing compounds or control compounds, and the half-life in human liver microsomes can be prolonged by about 3-4 times.

[0419] Test Example 4: Patch-clamp technique for detecting the effect of a compound on hERG channel current

[0420] 1. Purpose of the experiment

[0421] The patch-clamp technique is used to investigate the potential inhibitory effect of the compound of the present application on the hERG channel.

[0422] 2. Test method

[0423] 2.1. Cell culture

[0424] HEK-293 cell line stably expressing hERG potassium channel (hERG potassium channel cells purchased from Creacell company, item number: A-0320) was used. 1) The HEK-293 cell line stably expressing hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418, and the culture temperature was 37°C and the carbon dioxide concentration was 5%.

[0425] 2) Cell passage: remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Express solution, incubate at 37°C for about 0.5 min. When the cells are detached from the bottom of the dish, add about 5 mL of 37°C preheated complete culture medium (purchased from Gibco). Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min to collect the cells. Expand or maintain the culture by inoculating the cells in a 6 cm cell culture dish, and the amount of cells inoculated in each cell culture dish is 2.5 x 10 5 cells (final volume: 5 mL).

[0426] 3) To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0427] 4) Patch clamp detection, before the test, the cells were separated by TrypLE TM Express, 4 x 10 3 cells were plated on coverslips and cultured in a 24-well plate (final volume: 500 μL), and after 18 hours, the test was performed.

[0428] 2.2. Patch clamp detection

[0429] The voltage stimulation protocol for recording hERG potassium current by whole-cell patch clamp is as follows: after forming a whole-cell seal, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV for 0.5 s (as a leakage current detection), then stepped to 30 mV for 2.5 s, and then quickly restored to -50 mV for 4 s to induce the tail current of hERG channel. The data was collected every 10 s to observe the effect of drugs on hERG tail current. The 0.5 s -50 mV stimulation was used as a leakage current detection. The test data was collected by an IPA amplifier (Sutter Instrument) and stored in Sutter Patch software.

[0430] Patch-clamp operation: First, the capillary glass tube was drawn into a recording electrode by a microelectrode puller. Then the electrode filled with intracellular solution was mounted into a microelectrode holder. Under the inverted microscope, the microelectrode manipulator was operated to immerse the electrode into extracellular solution and record the electrode resistance (Rpip). Then the electrode was slowly contacted to the cell surface and a negative pressure was applied to form a GΩ high resistance seal. At this time, fast capacitance compensation was performed. The negative pressure was continuously applied to break the cell membrane and form a whole-cell recording mode. Finally, slow capacitance compensation was performed and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was given.

[0431] When the hERG current of the whole-cell recording was stable, the drug administration was started. Each drug concentration was detected for 5 min (or the current was stable) before the next concentration was detected. Each test compound was detected at low and high concentrations. The cell-covered coverslips were placed in the recording bath of the inverted microscope, and the test compound working solution and the external solution without the compound were sequentially flowed through the recording bath to act on the cells by gravity perfusion from low concentration to high concentration, while liquid displacement was performed in the recording by using a peristaltic pump. The current detected in each cell in the external solution without the compound was used as its own control group. At least two cells were used for independent repeated detection twice at each concentration. All electrophysiological tests were performed at room temperature.

[0432] 2.3. Data analysis

[0433] First, the tail current (Peak tail current compound ) after each drug concentration was normalized to the control tail current (Peak tail current Control ) of the blank solvent treatment group as “Peak tail current compound / Peak tail current Control ”, and then the inhibition rate corresponding to each drug concentration was calculated as 1-(Peak tail current compound / Peak tail current Control ).

[0434] It was found through experiments that the hERG inhibition rate of the compound of the present disclosure can be only 20% of that of the existing compound (for example, Comparative Example 1), that is, the compound of the present disclosure can have a smaller effect on hERG than the existing compound or the control compound, and can have a more obvious safety advantage. Test Example 5: In vivo pharmacokinetic study of intravenous and oral administration of test compounds in SD rats

[0435] 1. Experimental animals

[0436] Species: SD rats, male, SPF level. Source: purchased from Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd., Experimental Animal Production License No.: SCXK (Chuan) 2023-0040.

[0437] 2. Preparation of test samples

[0438] 2.1. Accurately weigh an appropriate amount of the test compound, first add 5% DMA to prepare the final volume, vortex to dissolve, then add 5% HS-15, 90% normal saline (Normal Saline) in turn, ultrasonic, vortex to mix, get 0.2 mg / mL of transparent and clear drug solution, for intravenous injection administration.

[0439] 2.2. Accurately weigh an appropriate amount of the test compound, first add 5% DMA to prepare the final volume, vortex to dissolve, then add 95vol% of 0.5% MC, ultrasonic, vortex to mix, get 0.5 mg / mL of transparent and clear drug solution, for intragastric administration.

[0440] 3. Test design

[0441] 4. Blood sampling time points

[0442] 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration.

[0443] 5. Sample collection and disposal

[0444] Blood was collected through the jugular vein, about 0.2 mL of each sample was collected, EDTA-K2 anticoagulation, blood samples were placed on ice after collection, and centrifuged to separate plasma within 2 hours (centrifugation conditions: 6000g, 5min, 2-8℃). The collected plasma samples were stored in a -80℃ refrigerator before analysis, and the remaining plasma samples were stored in a -70℃ refrigerator after analysis.

[0445] 6. Bioanalysis and data processing

[0446] LC-MS / MS method was used to determine the drug concentration of the specified compound in plasma, and Winnolin 8.3 non-compartment model was used to calculate the main pharmacokinetic parameters. When calculating the pharmacokinetic parameters, C max BLQ (including "No peak") before was calculated as 0; C max BLQ (including "No peak") after was not involved in the calculation.

[0447] Experiments show that the compound of the present embodiment has obvious advantages in pharmacokinetics and pharmacodynamics compared with existing compounds or control compounds, and can have higher blood drug concentration, lower apparent clearance rate and higher oral bioavailability. The apparent clearance rate of the compound of the present embodiment by intravenous route can be 30% of that of the control example 1, and the blood drug concentration (AUC) can be more than about 3.5 times that of the control example 1; the apparent clearance rate of the compound of the present embodiment by oral route can be only 10% of that of the control example 1, the blood drug concentration (AUC) can be more than about 10 times that of the control example 1, and the bioavailability can be more than 3 times that of the control example 1. The compound of the present embodiment can have better pharmacodynamics and better oral bioavailability compared with the control example 1.

[0448] The present disclosure is not limited to the above-mentioned optional embodiments, and anyone can derive other various forms of products under the inspiration of the present disclosure. The above-mentioned specific embodiments should not be understood as limiting the protection scope of the present disclosure, and the protection scope of the present disclosure should be defined by the claims, and the specification can be used to interpret the claims. According to the above-mentioned content, those skilled in the art can also make other various forms of modifications, replacements or changes without departing from the concept and spirit of the present disclosure, and all fall within the protection scope of the present disclosure.

[0449] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents. Moreover, in any country, any reference in this application to any document is not intended to constitute an admission that such document is part of the state of the art in that country.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, ###0001### (I) Z is selected from -0-, -S-, -S(0)2-, -S(0)(NH)-, -S(O)-, -NH-, preferably -0-, -S-, -S(0)2-, -S(O)-, -S(0)(NH)-, X is CR X wherein R X each independently selected from hydrogen, deuterium, tritium, Ci-C6alkyl, Ci-C6alkoxy, hydroxyl, each of m, n, o, p, t is independently selected from 0, 1, 2, 3, 4, and at most one of m, n, o, p is 0, each R 2 each independently selected from deuterium, tritium, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, nitro, hydroxy, mercapto, halogen, cyano, amine, or when t is 2 or more, two R 2 together form =0 or imine group, Y 1 , Y 2 , Y 3 each independently is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3- to 8-membered cycloalkyl, L 1 —(CH2) q O—, —(CH2) q S—, —(CH2) q NH—, —(CD2) q O—, —(CD2) q S—, —(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * indicates that said group is attached to R 1 , R 1 selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3- to 10-membered heterocycloalkyl, wherein each of said heterocycloalkyl independently comprises 1-2 heteroatoms selected from the group consisting of N, O, S, and wherein each of said substituents is optionally substituted with one or more substituents selected from the group consisting of deuterium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3- to 10-membered heterocycloalkyl, wherein each of said heterocycloalkyl independently comprises 1-2 heteroatoms selected from the group consisting of N, O, S, and wherein each of said substituents is optionally substituted with one or more substituents selected from the group consisting of deuterium, cyano, nitro, hydroxyl, thiol, halogen, amine, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 cyanoalkyl, 3- to 10-membered heterocycloalkyl, wherein each of said heterocycloalkyl independently comprises 1-2 heteroatoms selected from the group consisting of N, O, S, and wherein each of said substituents is optionally substituted with one or more substituents selected from the group consisting of deuterium, cyano, nit 2. The compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, of claim 1, wherein, said R 1 a group selected from group (i) optionally substituted with one or more substituents selected from deuterium, tritium, cyano, nitro, hydroxy, thiol, halogen, aminyl, carbonyl, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6cyanoalkyl, 3-10 membered heterocycloalkyl, preferably the substituents are selected from deuterium, tritium, cyano, nitro, hydroxy, thiol, fluorine, chlorine, bromine, iodine, -NH2, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -COCH(CH2)2, -COCD3, -CO-cycloalkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl, cyanomethyl, cyanoethyl, cyano-n-propyl, cyano-i-propyl, oxetanyl, oxetanyl and oxolanyl, group (i), Preferably, group (i) is selected from More preferably, group (i) is selected from 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, wherein, The R 1 Selected from Where R 1A Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, where a is selected from 0, 1, or 2, and each R 1B Each is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, mercapto, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or 3- to 10-membered heterocyclic alkyl containing 1-2 heteroatoms selected from O or S; preferably, R 1A Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl, a selected from 0, 1, 2, each R 1B Each is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoron-propyl, trifluoroisopropyl, trichloromethyl, trichloroethyl, trichloron-propyl, trichloroisopropyl, oxecyclopropyl, oxecyclobutyl, and oxecyclopentyl.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, wherein, The compound is a compound of formula (II), R A selected from cyano, 3-10 membered heterocycloalkyl, Ci-C6cyanoalkyl, wherein R 1A selected from Ci-C6alkyl, 3- to 6-membered cycloalkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, said R 1C is attached to any one or both ring carbon atoms of the piperidinyl group, a is selected from 0, 1, 2, Each R 1B Each group is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, mercapto, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. L 1 —(CH2) q O—, —(CH2) q S—, —(CH2) q NH—, —(CD2) q O—, —(CD2) q S—, —(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, and * indicates that the group is attached to the piperidinyl group, Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, preferably -O-, -S-; X is CR X wherein R X each independently is selected from the group consisting of hydrogen, deuterium, tritium, Ci-C6alkyl, Ci-C6alkoxy, hydroxyl, each of m, n, o, p, t is independently selected from 0, 1, 2, 3, 4, and at most one of m, n, o, p is 0, each R 2 each independently selected from deuterium, tritium, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, nitro, hydroxy, mercapto, halogen, cyano, amine, or when t is 2 or more, two R 2 together form =0 or imine group, Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3- to 8-membered cycloalkyl.

5. The compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, of claim 4, wherein, said R A selected from cyano, cyanomethyl, cyanoethyl, cyanon-propyl, cyanoisopropyl, oxetanyl, wherein R 1A selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl; and / or R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, R 1C is attached at piperidinyl ring carbon atom positions 2 / 2, 2 / 3, 2 / 4, 2 / 5, 2 / 6, 3 / 3, 3 / 4, 3 / 5 or 3 / 6; preferably, R 1C is absent, -CH2- or -CH2CH2-, and when R 1C is present, R 1C is attached at piperidinyl ring carbon atom positions 2 / 2, 2 / 3 or 2 / 5, more preferably, R 1C is absent; and / or said a is selected from 0, 1, 2, each R 1B each independently is selected from the group consisting of deuterium, tritium, cyano, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-i-propyl, trichloromethyl, trichloroethyl, trichloro-n-propyl, trichloro-i-propyl.

6. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, according to any one of claims 1 to 5, wherein, each of n, o, m, p is independently selected from 0, 1, 2, 3, 4, and the sum of n, o is 2-4, the sum of m, p is 2-4; preferably, each of n, o, m, p is independently selected from 1, 2.

7. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, of any one of claims 1-3, wherein The compound is a compound of formula (III), R 1 selected from wherein R 1A is selected from C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, a is selected from 0, 1, 2, each R 1B is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, amine, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3-10 membered heterocycloalkyl, L 1 —(CH2) q O—, —(CH2) q S—, —(CH2) q NH—, —(CD2) q O—, —(CD2) q S—, —(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * indicates that said group is attached to R 1 , Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, preferably -O-, -S-. X is CR X wherein R X each independently is selected from the group consisting of hydrogen, deuterium, tritium, Ci-C6alkyl, Ci-C6alkoxy, hydroxyl, t is selected from 0, 1, 2, 3, 4, each R 2 each independently selected from deuterium, tritium, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, nitro, hydroxy, mercapto, halogen, cyano, amine, or when t is 2 or more, two R 2 together form =0 or imine group, Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3- to 8-membered cycloalkyl.

8. The compound or its pharmaceutically acceptable salt, or solvate thereof, or prodrug thereof according to claim 3 or 7, wherein, The R 1A Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl, a selected from 0, 1, 2, each R 1B Each is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoron-propyl, trifluoroisopropyl, trichloromethyl, trichloroethyl, trichloron-propyl, trichloroisopropyl, oxecyclopropyl, oxecyclobutyl, and oxecyclopentyl.

9. The compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, according to any one of claims 1 to 8, wherein, said R X selected from the group consisting of hydrogen, deuterium, tritium, methyl, ethyl, methoxy, ethoxy, hydroxy; preferably from the group consisting of hydrogen, deuterium, tritium, methyl, hydroxy, more preferably from the group consisting of hydrogen, deuterium, tritium, methyl.

10. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, of any one of claims 1-9, wherein, said L 1 is selected from the group consisting of—O—,—S—,—NH—,—CH2—,—(CH2)2—,—(CH2)3—,—CH=CH—,—(CH=CH)2—,—(CH=CH)3—,—CH2O—,—(CH2)2O—,—(CH2)3O—,—CH2S—,—(CH2)2S—,—(CH2)3S—,—CH2NH—,—(CH2)2NH—,—(CH2)3NH—,—CD2O—,—(CD2)2O—,—(CD2)3O—,—CD2S—,—(CD2)2S—,—(CD2)3S—,—CD2NH—,—(CD2)2NH—,—(CD2)3NH—,—CD2—,—(CD2)2—,—(CD2)3—,—CD=CD—,—(CD=CD)2—,—(CD=CD)3—, wherein * denotes that the group is attached to R 1 or piperidinyl; preferably, said L 1 is selected from the group consisting of—(CH2)2—,—CH=CH—,—(CD2)2—,—CD=CD—,—CH2O—,—(CH2)2O—,—(CD2)2O—,—CD2O—,—(CH2)2NH—,—(CD2)2NH—,—CH2NH—,—CD2NH—,—(CH2)2S—,—CH2S—,—(CD2)2S—,—CD2S—, wherein * denotes that the group is attached to R 1 or piperidinyl; more preferably, said L 1 is selected from the group consisting of—(CH2)2—,—CH=CH—,—CH2O—,—(CH2)2O—,—CD2O—,—CH2NH—,—CH2S—, wherein * denotes that the group is attached to R 1 or piperidinyl.

11. The compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, according to any one of claims 1 to 10, wherein, said Y 1 , Y 2 , Y 3 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl; preferably, Y 1 , Y 2 at least one is not hydrogen, deuterium, tritium, Y 3 is selected from the group consisting of hydrogen, deuterium, tritium; more preferably, said Y 1 , Y 2 each independently is selected from the group consisting of hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, methyl, ethyl, cyclopropyl, trifluoromethyl, and Y 1 , Y 2 at least one is not hydrogen, deuterium, tritium; and / or said t is 0, 1, 2, each R 2 each independently selected from the group consisting of deuterium, tritium, nitro, hydroxy, thioxy, fluorine, chlorine, bromine, iodine, cyano, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, or, when t is 2, 2 R 2 together form =0 or =NH; preferably, said t is 0.

12. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, of any one of claims 1-3 and 7, wherein, The compound is a compound of formula (IV), Z is selected from -O-, -S-, -S(O)2-, -S(O)(NH)-, -S(O)-, -NH-, preferably -O-, -S-, -S(O)2-, -S(O)-, -S(O)(NH)-; R X each independently is selected from the group consisting of hydrogen, deuterium, tritium, Ci-C6alkyl, hydroxyl; Y 1 , Y 2 and Y 3 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl, 3- to 6-membered cycloalkyl; L 1 —(CH2) q O—, —(CH2) q S—, —(CH2) q NH—, —(CD2) q O—, —(CD2) q S—, —(CD2) q NH—, —(CH=CH) r —, —(CH2) r —, —(CD=CD) r —, —(CD2) r —, wherein said q is selected from 0, 1, 2, 3, r is selected from 1, 2, 3, * indicates the position of L 1 attached to R 1 . R 1 selected from wherein R 1A is selected from C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, a is selected from 0, 1, 2, each R 1B is independently selected from deuterium, tritium, cyano, nitro, hydroxyl, thiol, halogen, aminyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from O or S.

13. The compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug thereof, of any one of claims 1 to 12, wherein, selected from the group consisting of 14. A pharmaceutical composition comprising at least one compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition according to claim 14, for use as a medicament; preferably, the medicament is a PARP14 inhibitor; preferably, the medicament is for treating or preventing a disease associated with PARP14 or a cellular Th2-type inflammatory factor; preferably, the disease comprises a cancer and an inflammation; preferably, the cancer comprises multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, breast cancer, glioma, follicular lymphoma, pancreatic cancer, lung cancer, colon cancer or melanoma, the inflammation comprises atopic dermatitis, pneumonia, allergic airway disease, asthma.

Images