Nucleoside compounds, methods of making and using the same

Abstract

The present application provides nucleoside compounds, and a preparation method and application thereof. Specifically, the present application provides a compound or a pharmaceutically acceptable salt, isomer, mixture, solvate, crystal form or prodrug thereof, wherein the compound is a compound of formula A or a multimer derived from the compound of formula A. The nucleoside compound provided by the present application has excellent antitumor effect and regulation effect on the partial editing function of ADAR1, and has great application potential in the treatment of related diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to nucleoside compounds, their preparation methods, and applications. Background Technology

[0002] Human RNA is subject to strict modification and regulation in order to perform its biological functions. More than 100 RNA modification methods have been discovered, among which adenosine deaminase-dependent RNA editing is the most common. Through the deamination action of RNA-specific adenosine deaminases (ADARs), adenosine (A) in RNA molecules is converted to inosine (I). ADARs are classified into three subtypes based on their structure and function: ADAR1, ADAR2, and ADAR3. The human ADAR1 protein is expressed by the ADAR1 gene located in the q21 region of chromosome 1. This gene can encode two subtypes through different promoters: constitutive P110 located in the cell nucleus and interferon-inducible P150 located in both the cell nucleus and cytoplasm. ADAR1 proteins all contain 2-3 dsRNA-binding domains (dsRBD), deaminase domains (CDD), and a nuclear localization signal (NLS). The ADAR1 p150 isoform contains a nuclear export signal (NES) to facilitate its movement between the cytoplasm and nucleus, as well as a Zα domain that specifically binds to Z-NDA / RNA. ADAR1 affects the amino acid sequence, localization, stability, and function of proteins by performing A-to-I editing on the editing regions, introns, and 3'-UTRs of coding genes, as well as some non-coding RNAs (such as miRNAs, circRNAs, and lncRNAs). The influence of ADAR1 on the activity / efficiency of downstream substrate RNA editing is associated with many diseases, primarily in oncology, virology, and neurology. Studies have shown that ADAR1 overexpression or abnormal function in various tumor cells plays an important regulatory role in tumor cell proliferation inhibition and immunotherapy resistance. When ADAR1 function is suppressed, unedited dsRNA is recognized as immunogenic by MDA5, activating the MDA5-mediated interferon signaling pathway and thus triggering an autoimmune response. On the other hand, suppression of ADAR1 function leads to the accumulation of dsRNA in the body, which competitively binds to PKR, causing downstream PKR phosphorylation and eIF2α phosphorylation, resulting in the arrest of protein transcription and translation.

[0003] In summary, there is an urgent need in this field to develop a class of modifiers for ADAR1 editing functions. Summary of the Invention

[0004] The purpose of this invention is to provide a class of nucleoside compounds that target ADAR1.

[0005] In a first aspect of the invention, a compound or a pharmaceutically acceptable salt, isomer or mixture thereof, solvate, crystal form or prodrug is provided, said compound being a compound of formula A or a polymer derived from a compound of formula A;

[0006]

[0007] in,

[0008] X is a halogen;

[0009] R is selected from the following group: hydrogen, C1-C6 alkyl, OR1, NR 2 R 3 ;

[0010] R1 is -R 1a -R 1b ;in,

[0011] R 1a It is either free of single bonds or C1-C3 alkylene groups;

[0012] R 1b Selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkylamino, unsubstituted or with n1 R 4 The substituted C3-C10 carbocyclic group, unsubstituted or replaced by n1 R groups 4 The substituted 4 to 10-membered heterocyclic groups, unsubstituted or replaced by n1 R groups 4 The substituted C6-C12 aryl group, unsubstituted or replaced by n1 R groups 4 The 5 to 10 heteroaryl groups that are replaced;

[0013] n1 is 1, 2, 3, 4, 5 or 6;

[0014] R 2 and R 3Each of the following is independently selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynoxy, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted C3-C10 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C6-C12 aryl, optionally substituted 5- to 10-membered heteroaryl. The group may contain: a carbocyclic group, optionally substituted -C1-C2 alkylene-C3-C10 carbocyclic group, optionally substituted -C1-C2 alkylene-4 to 10-membered heterocyclic group, optionally substituted -C1-C2 alkylene-C6-C12 aryl group, optionally substituted -C1-C2 alkylene-5 to 10-membered heteroaryl group; and, as a whole or as part of a group, the carbocyclic group, heterocyclic group, aryl group, and heteroaryl group may optionally be further substituted with one or more (e.g., 1, 2, 3, or 4) R groups. 5 Replaced;

[0015] R 4 and R 5 Each independently as R S Alternatively, groups selected from the group consisting of: -CN, -NO2, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynoxy, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, R 6 -OR 6 -NH-R 6 -NHC(O)-R 6 -NHS(O)-R 6 and -NHS(O)2-R 6 Or, two R atoms located on the same or adjacent atoms. 4 Or two Rs 5 Together with the attached atoms, they form rings selected from the group consisting of: optionally substituted C3-C10 carbocyclic groups, optionally substituted 4- to 10-membered heterocyclic groups, optionally substituted C6-C12 aryl groups, and optionally substituted 5- to 10-membered heteroaryl groups.

[0016] R 6 Selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C6-C12 aryl and optionally substituted 5- to 10-membered heteroaryl, optionally substituted -C1-C2 alkylene-C3-C10 carbocyclic, optionally substituted -C1-C2 alkylene-4- to 10-membered heterocyclic, optionally substituted -C1-C2 alkylene-C6-C12 aryl and optionally substituted -C1-C2 alkylene-5- to 10-membered heteroaryl;

[0017] The term "optionally substituted" means that the group is unsubstituted or that the H in the group is replaced by one or more (e.g., 1, 2, 3, or 4) R groups. S Replaced;

[0018] Each R S Independently selected from the group consisting of: D, CN, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, and benzyl; or, two Rs. S (such as two R atoms located on the same or adjacent atoms) S Together they form groups selected from the following group: oxo (=O), C1-C6 alkylene, 2 to 6 heteroalkylene.

[0019] In another preferred embodiment, the carbocyclic group includes: cycloalkyl or cycloalkenyl.

[0020] In another preferred embodiment, the heterocyclic group includes heterocyclic alkyl or heterocyclic alkenyl groups.

[0021] In another preferred embodiment, the aryl group includes: phenyl.

[0022] In another preferred embodiment, X is selected from the group consisting of F, Cl, and Br.

[0023] In another preferred example, X is F.

[0024] In another preferred embodiment, the compound of formula A is a compound of formula I;

[0025]

[0026] Wherein, R is defined as in Equation I.

[0027] In another preferred example, R is -OR 1 .

[0028] In another preferred embodiment, R 1a It is a C1-C3 alkylene group; preferably a C1-C2 alkylene group; more preferably -CH2- or -CH(CH3)-.

[0029] In another preferred example, R is -OR 1b or -O-C1-C3 alkylene-R 1b .

[0030] In another preferred example, R is -OR 1b -O-CH2-R 1b or -O-CH(CH3)-R 1b .

[0031] In another preferred embodiment, R1b Selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 ynyl, unsubstituted or substituted with one or more (e.g., n1) R 4 The substituted C3-C10 carbocyclic group, unsubstituted or replaced by one or more (e.g., n1) R groups 4 The substituted heterocyclic group, unsubstituted or substituted by one or more (e.g., n1) R 4 The substituted C6-C12 aryl group, unsubstituted or substituted with one or more (e.g., n1) R 4 The 5 to 10 heteroaryl groups that are replaced.

[0032] In another preferred embodiment, R 1b Selected from the following group: C1-C6 alkyl, C2-C6 ynyl, C3-C10 carbocyclic, unsubstituted or modified by one or more (e.g., n1) R 4 The substituted C6-C12 aryl group, unsubstituted or substituted with one or more (e.g., n1) R 4 The 5 to 10 heteroaryl groups that are replaced.

[0033] In another preferred embodiment, R 1b Selected from the group consisting of: methyl, ethyl, ethynyl, cyclopropyl, cyclobutyl, unsubstituted or modified by one or more R groups. 4 The substituted phenyl, unsubstituted, or substituted with one or more (e.g., n1) R 4 The 5- or 6-membered heteroaryl group that is replaced.

[0034] In another preferred embodiment, R 4 Each is independently selected from the following group: -CN, halogen, C1-C6 alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, R 6 -OR 6 and -NHS(O)2-R 6 .

[0035] In another preferred embodiment, R 4 Each is independently selected from the following group: -CN, halogen, C1-C6 alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, R 6 -OR 6 and -NHS(O)2-R 6 .

[0036] In another preferred embodiment, R 6Selected from the group consisting of: C1-C6 alkyl, optionally substituted C6-C12 aryl (e.g., optionally substituted phenyl), optionally substituted 5- to 10-membered heteroaryl (e.g., optionally substituted 5 or 6-membered heteroaryl, preferably substituted 6-membered nitrogen-containing heteroaryl, more preferably substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl), optionally substituted -C1-C2 alkylene-C6-C12 aryl (e.g., optionally substituted benzyl), and optionally substituted -C1-C2 alkylene-5 to 10-membered heteroaryl (e.g., optionally substituted -methylene-5 or 6-membered heteroaryl, preferably substituted -methylene-6-membered nitrogen-containing heteroaryl, more preferably substituted -methylene-pyridinyl, optionally substituted -methylene-pyrimidinyl, optionally substituted -methylene-pyridazinyl).

[0037] In another preferred embodiment, R 4 Each is independently selected from the group consisting of: -O-benzyl, -O-methylene-5 or 6-membered heteroaryl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, halogen, CN, -NHS(O)2-C1-C6 alkyl, phenyl, 5 or 6-membered heteroaryl.

[0038] In another preferred embodiment, n1 is 1 or 2.

[0039] In another preferred example, R is -OR 1b -O-CH2-R 1b or -O-CH(CH3)-R 1b .

[0040] In another preferred embodiment, R 1b Selected from the following group: C1-C6 alkyl, C2-C6 ynyl, C3-C10 carbocyclic, unsubstituted or modified by one or more (e.g., n1) R 4 The substituted C6-C12 aryl group, unsubstituted or replaced by one or more (e.g., n1) R 4 The 5 to 10 heteroaryl groups that are replaced.

[0041] In another preferred embodiment, R 2 Selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl groups; preferably, selected from the group consisting of hydrogen and C1-C6 alkyl groups.

[0042] In another preferred embodiment, R 2 Selected from the following group: hydrogen, methyl, ethyl.

[0043] In another preferred embodiment, R 3Selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynoxy, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted C3-C10 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C6-C12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted -C1-C2 alkylene-C3-C10 carbocyclic, optionally substituted -C1-C2 alkylene-4- to 10-membered heterocyclic, optionally substituted -C1-C2 alkylene-C6-C12 aryl, optionally substituted -C1-C2 alkylene-5- to 10-membered heteroaryl; and, as a whole or as part of a group, the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally further constituting one or more (e.g., 1, 2, 3, or 4) R 5 What it replaced.

[0044] In another preferred embodiment, R 3 Selected from the group consisting of: hydrogen, optionally substituted C6-C12 aryl (such as optionally substituted phenyl), optionally substituted 5- to 10-membered heteroaryl (such as optionally substituted 5 or 6-membered heteroaryl, preferably such as optionally substituted 6-membered nitrogen-containing heteroaryl, more preferably such as optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl), optionally substituted -C1-C2 alkylene-C6-C12 aryl (such as optionally substituted benzyl), optionally substituted -C1-C2 alkylene-5 to 10-membered heteroaryl (such as optionally substituted -methylene-5 or 6-membered heteroaryl, preferably such as optionally substituted -methylene-6-membered nitrogen-containing heteroaryl, more preferably such as optionally substituted -methylene-pyridinyl, optionally substituted -methylene-pyrazinyl, optionally substituted -methylene-pyrimidinyl, optionally substituted -methylene-pyridazinyl).

[0045] In another preferred embodiment, R 3 Selected from the following group: hydrogen, phenyl, 5 or 6 heteroaryl, benzyl, -methylene-5 or 6 heteroaryl.

[0046] In another preferred embodiment, the polymer derived from compound A includes at least a portion formed by the loss of a H atom from the R group of compound A.

[0047] In another preferred embodiment, the portion formed by the loss of a H atom from the R group of compound A is shown below:

[0048]

[0049] Among them, R i X is a divalent group derived from R, and X and R are defined as in formula A or I.

[0050] In another preferred embodiment, Ri For -OR i 1 Among them, R i 1 Derived from R 1 divalent groups (i.e., R) 1 (a divalent group formed by a group losing one hydrogen atom); where R 1 As defined in equation A or I.

[0051] In another preferred embodiment, R i For -OR i 1a -R i 1b Among them, R i 1a For R 1a R i 1b For is derived from R 1b divalent groups (i.e., R) 1b (A divalent group formed by the loss of one hydrogen atom by a radical) where R 1a and R 1b As defined in equation A or I.

[0052] In another preferred embodiment, the polymer derived from compound A includes at least a portion formed by the loss of a H atom from the R group of compound A.

[0053] In another preferred embodiment, the portion formed by the loss of a H atom from the R group of compound A is shown below:

[0054]

[0055] Among them, R i X is a divalent group derived from R, and X and R are defined as in formula A.

[0056] In another preferred embodiment, the polymer derived from compound A is a dimer derived from compound A.

[0057] In another preferred embodiment, the polymer derived from compound A is a polymer as shown in formula B;

[0058]

[0059] in,

[0060] L represents no or a divalent linker;

[0061] R i 1a and R ii 1a Each independently as R1a Or none; and R i 1a and R ii 1a At least one of them is not zero;

[0062] R i 1b and R ii 1b Each is independently derived from R 1b divalent groups or none; and R i 1b and R ii 1b At least one of them is not zero;

[0063] X, R 1a and R 1b Defined in compound A of the same formula.

[0064] In another preferred embodiment, R i 1a For R 1a R i 1b For is derived from R 1b The divalent group.

[0065] In another preferred embodiment, R ii 1a For R 1a Or none, R ii 1b Derived from R 1b It may contain or not contain divalent groups.

[0066] In another preferred embodiment, derived from R 1b The divalent group refers to the group composed of R 1b A divalent group is formed by losing a hydrogen atom.

[0067] In another preferred embodiment, the divalent linking group is selected from the group consisting of: optionally substituted C2-C6 alkenyl groups, optionally substituted C2-C6 alkyne groups, and optionally substituted C1-C6 alkylene groups.

[0068] In another preferred embodiment, the divalent linking group is selected from the group consisting of C2-C6 ynylene and C1-C6 alkylene.

[0069] In another preferred embodiment, L is either absent or C2-C6 ynylene.

[0070] In another preferred embodiment, L is either non-acetylenic or non-acetylenic (i.e., ... ).

[0071] In another preferred embodiment, R i 1a and Rii 1a Each is independently a C1-C5 alkylene group; preferably, it is a methylene group.

[0072] In another preferred embodiment, R i 1b and R ii 1b Each is independently derived from or not replaced by one or more (e.g., n1) R 4 The substituted C6-C12 aryl group may be unsubstituted or replaced by one or more (e.g., n1) R groups. 4 The substituted 5 to 10-membered heteroaryl divalent group is absent; and R i 1b and R ii 1b At least one of them is not zero; where R 4 Defined in compound A of the same formula.

[0073] In another preferred embodiment, R i 1b and R ii 1b Each is independently derived from or not replaced by one or more (e.g., n1) R 4 The substituted phenyl, unsubstituted, or substituted with one or more (e.g., n1) R 4 The substituted 5- or 6-membered heteroaryl divalent group may or may not be present; and R i 1b and R ii 1b At least one of them is not zero; where R 4 Defined in compound A of the same formula.

[0074] In another preferred embodiment, "derived from" means derived from R 4 A divalent group is formed by losing a hydrogen atom on a C6-C12 aryl (phenyl) or 5 to 10 heteroaryl (5 or 6 heteroaryl).

[0075] In another preferred embodiment, "derived from" means derived from R 4 A divalent group is formed by losing a hydrogen atom at the meta or para position of the phenyl or 5- or 6-membered heteroaryl group.

[0076] In another preferred embodiment, the compounds are selected from the following table:

[0077]

[0078]

[0079]

[0080] In another preferred embodiment, the compound of formula A or the compound of formula I is selected from compounds 1 to 43 in the table above.

[0081] In another preferred embodiment, the polymer derived from compound A is selected from compounds 44 to 47 in the table above.

[0082] In another preferred embodiment, the isomer or mixture thereof includes: optical isomers (such as diastereomers and enantiomers), depolarized isomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, and mixtures thereof (such as racemates).

[0083] In a second aspect of the invention, a pharmaceutical composition is provided, comprising:

[0084] (i) the compound as described in the first aspect or its pharmaceutically acceptable salt, isomer or mixture thereof, solvate, crystal form or prodrug; and

[0085] (ii) Pharmaceutically acceptable carriers.

[0086] In a third aspect of the invention, the use of the compound as described in the first aspect or a pharmaceutically acceptable salt, isomer or mixture thereof, solvate, crystal form or prodrug, or pharmaceutical composition as described in the second aspect, in the preparation of (i) an inhibitor of RNA A-to-I editing of APOBEC3D and / or (ii) a medicament for the treatment or prevention of tumors.

[0087] In another preferred embodiment, the tumor includes cancer.

[0088] In another preferred embodiment, the inhibitor of RNA A-to-I editing of APOBEC3D is a selective inhibitor of RNA A-to-I editing of APOBEC3D.

[0089] In another preferred embodiment, the tumor is selected from the group consisting of: prostate cancer, leukemia, breast cancer, multiple myeloma, lung cancer, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma, or combinations thereof.

[0090] In a fourth aspect of the invention, a method for preparing a compound as described in the first aspect is provided, wherein R is -OR 1 The compound is as shown in Formula A1; and the preparation method includes the following steps:

[0091]

[0092] (S1) React the intermediate of formula INT2 with N,N-dimethylformamide dimethyl acetal to form the intermediate of formula INT1-3;

[0093] (S2) Make the intermediate of formula INT3 and IR 1 The reaction yields the intermediate INT4; and

[0094] (S3) Deprotect the intermediate of formula INT4 to obtain the compound.

[0095] In a fifth aspect of the invention, an intermediate is provided, wherein the intermediate is as shown in formula INT3 or INT4;

[0096]

[0097] Among them, X and R 1 As defined in equation A.

[0098] In another preferred embodiment, the intermediate is used to prepare a compound as defined in the first aspect.

[0099] In another preferred example, X is F.

[0100] In a sixth aspect of the invention, a method for inhibiting cell proliferation is provided, comprising the step of contacting cells with a compound as described in the first aspect or a pharmaceutically acceptable salt, isomer, or mixture thereof, solvate, crystal form, or prodrug thereof, thereby inhibiting cell proliferation.

[0101] In another preferred embodiment, the cells are tumor cells, more preferably cancer cells.

[0102] In another preferred embodiment, the cells are selected from the group consisting of prostate cancer cells.

[0103] In another preferred embodiment, the cells are selected from the group consisting of PC-3.

[0104] In another preferred embodiment, the method is non-therapeutic in vitro.

[0105] In a sixth aspect of the invention, a method for inhibiting A-to-I editing of APOBEC3D RNA is provided, comprising the step of contacting a subject with a compound as described in the first aspect or a pharmaceutically acceptable salt, isomer, or mixture thereof, solvate, crystal form, or prodrug thereof, thereby inhibiting A-to-I editing of APOBEC3D.

[0106] In another preferred embodiment, the method is selective.

[0107] In another preferred embodiment, the object is a cell.

[0108] In another preferred embodiment, the cells are tumor cells, more preferably cancer cells.

[0109] In another preferred embodiment, the cells are selected from the group consisting of prostate cancer cells.

[0110] In another preferred embodiment, the cells are selected from the group consisting of PC-3.

[0111] In another preferred embodiment, the method is non-therapeutic in vitro.

[0112] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0113] Figure 1 The effects of some compounds of the present invention on the RNA A-to-I editing level of APOBEC3D are shown.

[0114] Figure 2 The effects of some compounds of the present invention on the RNA A-to-I editing level of MDM2 are shown.

[0115] Figure 3 The results of PKR activation induced by combining some of the compounds of this invention with IFNβ are shown. Detailed Implementation

[0116] Through extensive and in-depth research, the inventors have discovered a class of nucleoside analogs targeting ADAR1. These compounds affect some of the editing functions of ADAR1, selectively inhibiting the editing efficiency of the substrate APOBEC, while having little effect on the phosphorylation of another substrate, MDM2, and the downstream pathway PKR. Currently, no compounds have been found that definitively target ADAR1 and selectively inhibit its editing function, suggesting that selective editing has significant potential applications in the treatment of related diseases. Based on this, the inventors have completed this invention.

[0117] the term

[0118] Unless otherwise specified, the terms or abbreviations herein have the conventional meanings as understood by those skilled in the art.

[0119] Unless otherwise stated, the term "alkyl," either on its own or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C1-C6 represents 1 to 6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0120] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with other terms refers to a stable straight-chain or branched or cyclic hydrocarbon group or a combination thereof, consisting of a specified number of chain atoms containing 1 to 3 heterochain atoms selected from O, N, Si, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroatoms O, N, and S can be located at any internal position of the heteroalkyl group. Heteroatoms Si can be located at any position of the heteroalkyl group, including positions where the alkyl group is attached to the remainder of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, and -CH2-CH2. Up to two heterochain atoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0121] As used herein, the term "alkylene," either itself or as part of another substituent, refers to a divalent group derived from an alkyl group as defined above. Alkylenes typically have 1-6, 1-4, 1-3, or 1-2 carbon atoms (i.e., C1-C6 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene). Examples of alkylenes include, for example, methylene (-CH2-) and ethylene (e.g., -CH(CH3)-, -(CH2)2-). Similarly, the term "heteroalkylene," either itself or as part of another substituent, refers to a divalent group derived from a heteroalkyl group as defined above. When two linkages of an alkylene or heteroalkylene are attached to the same or different ring atoms on a ring, the alkylene or heteroalkylene, together with the attached ring, forms a spirocyclic, bridged, or fused ring structure.

[0122] Unless otherwise stated, the term "alkynyl" refers to an unsaturated alkyl group having one or more (e.g., 1 or 2) triple bonds. Generally, alkynyl groups have 2-6 carbon atoms, i.e., C2-C6 alkynyl groups. Examples of such alkynyl groups include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, etc.

[0123] As used herein, the term "carbocyclic" refers to a non-aromatic hydrocarbon ring having a specified number of ring atoms (e.g., 3 to 10 ring atoms, i.e., C3-C10 carbocyclic) and being fully saturated or having one or more (e.g., 1 or 2) double bonds between the ring apexes. "Cycloalkyl" can be a monocyclic (e.g., cyclopropyl, cyclobutyl, cyclohexyl, etc.) or a bicyclic and polycyclic hydrocarbon ring, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. When a "carbocyclic" is fully saturated (i.e., contains no double bonds), it is a cycloalkyl group; when a "carbocyclic" has one or more (e.g., 1 or 2) double bonds between the ring apexes and is non-aromatic, it is a cycloalkenyl group.

[0124] Similarly, the term "heterocyclic group" refers to a carbocyclic group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heterocyclic groups can be monocyclic, bicyclic, or polycyclic systems. Generally, heterocyclic groups typically comprise 4 to 10 ring atoms (i.e., 4 to 10-membered heterocyclic groups), preferably 4 to 6 ring atoms (i.e., 4 to 6-membered heterocyclic groups) and contain 1, 2, 3, or 4 heterocyclic atoms. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valproic acid, imidazolidinone, hydantoin, dioxolane, benzodiimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinine ring, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or a cyclic heteroatom.

[0125] As used in this article, "alkoxy" refers to R i O- group, where R i Alkyl groups are those defined above. C1-C6 alkoxy groups are those containing 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, etc. "Haloalkoxy" refers to the group obtained by substituting at least one hydrogen atom of the alkoxy group as described above with a halogen; specific examples include trifluoromethoxy, etc.

[0126] As used in this article, "alkynyloxy group" refers to R i O- group, where R i This refers to the alkyne as defined above. C2-C6 alkynyloxy groups are those containing 2 to 6 carbon atoms. Specific examples of alkynyloxy groups include acetylenyloxy and propynylenyloxy.

[0127] Unless otherwise stated, the term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which can be monocyclic, fused together, or covalently linked polycyclic (up to three-cyclic) rings. Generally, aryl groups have 6-12 ring atoms, i.e., C6-C12 aryl groups. The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Generally, heteroaryl groups have 5-10 ring atoms, i.e., 5-10-membered heteroaryl groups, preferably 5-6 ring atoms, i.e., 5-6-membered heteroaryl groups, and contain 1, 2, 3, or 4 heteroatoms (preferably N). Heteroaryl groups can be linked to the rest of the molecule via heteroatoms. Non-limiting examples of aryl groups include phenyl and naphthyl, while non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, and isobenzofuranyl. ryl), isoindolyl, indene, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc. The substituents in each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents listed below.

[0128] As used in this article, "amino" refers to -NH2.

[0129] As used herein, “C1-C6 alkylamino” refers to a group obtained by substituting one or two hydrogens of -NH2 with a C1-C6 alkyl group as described above, and can be represented as R. i R ii N-, where R i and R ii Each is independently H or C1-C6 alkyl, and R i and R ii At most one is H. Specific examples of C1-C6 alkylamino groups include methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, sec-butylamino, n-pentamino, isopentamino, neopentamino, n-hexylamino, isopentamino, 3-methylpentamino, 3,3-dimethylbutylamino, 2-ethylbutylamino, etc.

[0130] "C1-C6 alkoxyamino" refers to a group obtained by replacing the two hydrogens of -NH2 with C1-C6 alkyl and oxygen as described above; specific examples of C1-C6 alkoxyamino include methoxyamine, dimethoxyamine, ethoxyamine, n-propoxyamine, and isopropoxyamine.

[0131] In some embodiments, the terms above (such as “alkyl,” “aryl,” and “heteroaryl”) will include substituted and unsubstituted forms of the specified group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted forms provided below, while the term “alkyl” and the associated aliphatic group refer to the unsubstituted form unless specified otherwise.

[0132] Unless otherwise defined, substituents of alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be a variety of groups selected from the group consisting of: -halogen, -OR a -NR a R b -SR a -SiR a R b R c -OC(O)R a -C(O)R a -CO2R a -CONR a R b -OC(O)NR a R b -NR b C(O)R a -NR a -C(O)NR b R c -NR b C(O)2R a -NH-C(NH2)=NH, -NR a C(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -CN and -NO2, in quantities ranging from zero to (2M+1), where M is the total number of carbon atoms in this group. R a R b and R c Each independently represents hydrogen and unsubstituted C. 1-8Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted -C 1-4 Alkylene-aryl. When R a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR a R b It refers to the combination of 1-pyrrolidinyl and 4-morpholinyl.

[0133] Similarly, unless otherwise defined, the substituents of aryl and heteroaryl groups are diverse and are generally selected from: -halogen, -OR a -OC(O)R a -NR a R b -SR a -R a -CN, -NO2, -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NR b C(O)R a -NR b C(O)2R a -NR a -C(O)NR b R c -NH-C(NH2)=NH, -NR a C(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in quantities ranging from zero to the total number of open valences on the aromatic ring system; where R a R b and R c Independently selected from hydrogen, C 1-8 Alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, unsubstituted -C 1-4alkylene-aryl or heteroaryl and unsubstituted -C 1-4 Alkylene-aryloxy group.

[0134] The two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CH2). q The substituents of -U- are used, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -A-(CH2). r -B-, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or single bonds, and r is an integer from 1 to 3. One single bond in the resulting new ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CH2). s -X-(CH2) t The substituents are substituted, where s and t are independent integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0135] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0136] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0137] In this document, unless otherwise specified, the term “substitution” means that one or more (e.g., 1, 2, 3 or 4) hydrogen atoms on a group are substituted by a substituent selected from the group consisting of: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-OH.

[0138] As used herein, the terms “containing,” “comprising,” or “including” indicate that various ingredients may be used together in mixtures or compositions of the present invention. Therefore, the terms “consistent with…” and “composed of…” are included in the term “containing.”

[0139] As used herein, the term "pharmaceuticalally acceptable" means a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0140] As used herein, the term "therapeutic effective dose" refers to any amount of a drug as described below, which, when used alone or in combination with another therapeutic agent, promotes disease regression, manifested as a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of impairment or disability caused by the disease. The "therapeutic effective dose" of the drug of this invention also includes a "preventive effective dose," which is any amount of a drug as described below, which, when administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or suffering from a relapse of the disease, inhibits the occurrence or recurrence of the disease.

[0141] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0142] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0143] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0144] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0145] nucleoside compounds

[0146] As used herein, the terms “compound of the present invention,” “nucleoside analog,” and “nucleoside analog targeting ADAR1” are used interchangeably to refer to compounds of the general formulas described in the first aspect of the present invention (such as compounds represented by formulas A, I, II, and III). The term also includes compounds of formula (I) or isomers thereof or mixtures thereof, as well as their various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0147] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0148] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this invention, those salts are equivalent to the parent form of the compound.

[0149] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with a solvent molecule in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water. The solvate form is generally equivalent to the non-solvate form and should be included within the scope of the present invention. Some compounds of the present invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent for the applications contemplated by the present invention and should be included within the scope of the present invention.

[0150] Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention. When the compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), it will be understood by those skilled in the art that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).

[0151] The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds. A non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C), 2 H) or carbon-13 ( 13 C). In addition to the uses described in this application, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of this invention.

[0152] Furthermore, the compounds of this invention also include prodrugs of compounds represented by formula (I). The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of formula (I), or salts or solutions of compounds of formula (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0153] One object of the present invention is to provide a nucleoside analog that has activity that affects the partial editing function of ADAR1.

[0154] To achieve the above-mentioned objectives of this invention, this application provides the following technical solutions:

[0155] In one embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt or prodrug thereof; said compound is a compound of formula A or a polymer derived from compound A.

[0156]

[0157] X and R are as defined above.

[0158] In another embodiment, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt or prodrug thereof;

[0159]

[0160] Wherein, R is as defined above. In some embodiments, R is selected from hydrogen, alkyl, amino, OR 1 NR 2 R 3 .

[0161] In some implementation schemes, R 1 It is selected from C1-C6 alkyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C12 aryl, substituted or unsubstituted benzene ring, substituted or unsubstituted C3-C8 heterocyclic group, substituted or unsubstituted benzyl, and substituted or unsubstituted C5-C10 heteroaryl.

[0162] In some implementation schemes, R 2 and R 3 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkynoxy, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C12 aryl, substituted or unsubstituted benzyl ring, substituted or unsubstituted C3-C8 heterocyclic group, substituted or unsubstituted benzyl, substituted or unsubstituted C5-C10 heteroaryl.

[0163] In another embodiment, the compound is a polymer as shown in Formula B;

[0164]

[0165] The variables are as defined above.

[0166] In some embodiments, the compound is preferably from formula II and formula III.

[0167]

[0168] Among them, R 1 R2 and R 3 As defined above.

[0169] In some implementation schemes, X, R, R 1 R 1a R 1b R 2 R 3 R 4 R 5 R 6 R S n1 and n1 are each independently the corresponding groups in the specific compounds prepared in the preparation examples (such as Examples 1 to 43).

[0170] In some implementation schemes, X, L, R i 1a R i 1b R ii 1a R ii 1b and R 4 Each is an independent corresponding group in the specific compound prepared in the preparation examples (such as Examples 44 to 47).

[0171] In some embodiments, the compound is selected from the following compounds:

[0172]

[0173]

[0174] In some embodiments, the compounds or polymers involved in this application and their pharmaceutically acceptable salts may have isomers or racemates, such as optical isomers (including diastereomers and enantiomers), transisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, and mixtures thereof, but are not limited thereto. These isomers are also included within the scope defined by the claims of this invention.

[0175] Pharmaceutical Compositions and Administration

[0176] Another object of the present invention is to provide a pharmaceutical composition comprising the nucleoside compound.

[0177] Another object of the present invention is to provide the use of the nucleoside compound or pharmaceutical composition in the preparation of an ADAR1 inhibitor or in the preparation of a medicament for the treatment, prevention or control of ADAR1-related diseases or symptoms.

[0178] Specifically, the compounds of this invention possess excellent anti-tumor cell proliferation activity and the ability to selectively inhibit the RNA A-to-I editing level of APOBEC by targeting ADAR1. Therefore, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat, prevent, and alleviate tumors or ADAR1-related diseases. According to the prior art, the compounds of this invention can be used to treat the following diseases: tumors (or cancers), such as prostate cancer, leukemia, breast cancer, multiple myeloma, lung cancer, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma, etc.

[0179] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-500 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0180] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0181] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0182] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0183] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0184] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0185] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0186] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0187] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0188] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0189] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0190] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0191] Preparation method

[0192] Another object of the present invention is to provide a method for preparing the nucleoside compounds of the present invention.

[0193] In one specific embodiment, the present invention provides a method for preparing the compound described in the first aspect of the present invention when R is OR1, and the synthetic route is as follows:

[0194]

[0195] In some embodiments, the preparation method includes the steps of:

[0196] (S1) React the intermediate of formula INT2 with N,N-dimethylformamide dimethyl acetal to form the intermediate of formula INT1-3;

[0197] (S2) Make the intermediate of formula INT3 and IR 1 The reaction yields the intermediate INT4;

[0198] (S3) Deprotect the intermediate of formula INT4 to obtain the compound.

[0199] In some embodiments, the present invention also provides an intermediate for synthesizing the compounds of the present invention, said intermediate being...

[0200]

[0201] This invention provides another method for preparing the compound, the synthetic route of which is shown below.

[0202]

[0203] In some embodiments, the preparation method includes the steps of:

[0204] (S1) React the intermediate of formula INT2 with TBSCl to form the intermediate of formula INT5;

[0205] (S2) React the intermediate of formula INT5 with MMTrCl to form the intermediate of formula INT6;

[0206] (S3) Deprotects INT6 to form intermediate INT7;

[0207] (S4) Makes the intermediate of formula INT7 and IR 1 The reaction yields the intermediate INT8;

[0208] (S5) Deprotect the intermediate of formula INT8 to obtain the compound.

[0209] In each formula, X and R 1 As defined in the first aspect.

[0210] The main advantages of this invention include:

[0211] (a) The compounds of the present invention have excellent ability to inhibit the proliferation of tumor cells.

[0212] (b) The compounds of the present invention have excellent selective ability to inhibit the RNA A-to-I editing level of APOBEC3D.

[0213] (c) The compounds of the present invention inhibit the RNA A-to-I editing level of APOBEC3D while having almost no inhibition of the RNA A-to-I editing level of MDM2.

[0214] (d) The compounds of the present invention have no significant effect on PKR phosphorylation in the downstream PKR pathway.

[0215] (e) Preferred compounds of the present invention have excellent pharmacokinetic properties.

[0216] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0217] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0218] The Chinese names of reagents represented by chemical formulas or English letter abbreviations are as follows: ℃ represents degrees Celsius; g represents grams; s represents singlet, d represents doublet, t represents triplet, m represents multiplet; min represents minutes; ml represents milliliters; mmol represents millimoles; h represents hours; TLC represents thin-layer chromatography.

[0219] In the following examples, the proton NMR spectra were recorded using a Bruker AMX-600 NMR spectrometer, and the chemical shift δ was expressed in ppm.

[0220] Unless otherwise specified, all reaction solvents were purified using standard methods.

[0221] Thin-layer chromatography used GF254 high-efficiency plates, which were produced by Yantai Chemical Research Institute.

[0222] Unless otherwise specified, all solvents are analytical grade reagents.

[0223] Color development was performed using methods such as ultraviolet fluorescence.

[0224] The removal of organic solvents under reduced pressure is carried out in a rotary evaporator.

[0225] Preparation Examples

[0226] Example 1: Synthesis of Compound 1

[0227] Synthesis route:

[0228]

[0229] Synthesis of intermediate 1-2 in step one: 2-Fluoroadenosine (25g, 87.65mmol) was added to 600ml of acetone to form a suspension, and placed in an ice bath. Then, 11ml of perchloric acid was slowly added dropwise to form a clear solution. After reacting at 0℃ for 3h, TLC monitoring showed that the starting material was basically consumed. Ammonium hydroxide solution was slowly added to adjust the pH to about 7-8. After cooling and standing for 1h, a large amount of crystals precipitated. After filtration, the filter cake was dried under vacuum to obtain a white powder intermediate 1-2 (27.5g, 96%). 1 H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.92(s,2H),6.03(d,J=2.9Hz,1H),5.29(dd,J=6.2,2.9Hz,1H),5.09(m ,1H),4.93(dd,J=6.2,2.6Hz,1H),4.20(td,J=5.0,2.6Hz,1H),3.58-3.48(m,2H),1.54(s,3H),1.33(s,3H).

[0230] Synthesis of intermediate 1-3 in step 2: Intermediate 1-2 (17 g, 52.26 mmol) was dissolved in 200 ml DMF, and N,N-dimethylformamide dimethyl acetal (34.71 ml, 261.3 mmol) was added. The mixture was stirred at 50 °C for 2 h. The starting material was completely consumed by TLC monitoring. The mixture was cooled to room temperature, diluted with water, extracted with DCM, and the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white foamy solid compound 1-3 (16.17 g, 81%). 1 HNMR(600MHz,DMSO-d6)δ8.91(s,1H),8.43(s,1H),6.08(d,J=2.8Hz,1H),5.32(dd,J=6.2,2.9Hz,1H),5.10(t,J=5.4Hz,1H),4 .94(dd,J=6.2,2.6Hz,1H),4.22(td,J=5.0,2.6Hz,1H),3.59-3.51(m,3H),3.24(s,3H),3.16(s,3H),1.55(s,3H),1.33(s,3H).

[0231] The third step involved the synthesis of intermediates 1-4: Intermediate 1-3 (60 mg, 0.16 mmol) was dissolved in 5 ml of DMF and placed in an ice bath. Sodium hydride (10 mg, 0.24 mmol) was added, and the mixture was stirred in an ice bath for 0.5 h. Then, iodomethane (34 mg, 0.24 mmol) was added, and the mixture was stirred for 2 h. TLC analysis showed that the reaction of the starting material was basically complete. The reaction was quenched by adding a saturated sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white foamy solid compound 1-4 (69 mg, 73%). 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),6.07(d,J=2.6Hz,1H),5.32(dd,J=6.2,2.6Hz,1H),4.93(dd,J=6.2,2.7Hz,1H),4 .33(td,J=5.1,2.7Hz,1H),3.49(qd,J=10.5,5.1Hz,2H),3.24(s,3H),3.18(d,J=5.2Hz,2H),1.54(s,3H),1.33(s,3H).

[0232] The fourth step, synthesis of compound 1: Intermediates 1-4 were dissolved in 2 ml of methanol, and 0.2 ml of hydrazine hydrate was added. The mixture was stirred at room temperature for 2 h, and the reaction was confirmed to be complete by TLC. The reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate and water, and the organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was directly proceeded to the next step without purification. The crude product from the previous step was dissolved in tetrahydrofuran / water (2 / 1), and approximately 1 ml of trifluoroacetic acid was added. The mixture was reacted overnight at 40 °C. The reaction was confirmed to be almost complete by TLC. The reaction solution was concentrated under reduced pressure and purified by reversed-phase silica gel column chromatography to obtain a white solid, compound 1. 1 H NMR (600MHz, DMSO-d6) δ8.27(s,1H),7.84(s,2H),5.78(d,J=5.3Hz,1H),5.51(d,J=5.9Hz,1H),5.28(d,J=5.3Hz,1H),4.52(q,J= 5.4Hz,1H),4.11(q,J=4.9Hz,1H),4.01(q,J=4.5Hz,1H),3.58(dd,J=10.8,3.9Hz,1H),3.52(dd,J=10.8,5.4Hz,1H),3.29(s,3H).

[0233] Example 2: Synthesis of Compound 2

[0234]

[0235] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with benzyl bromide to obtain compound 2. 1 HNMR (600MHz, DMSO-d6) δ8.31 (s, 1H), 7.86 (d, J = 43.4Hz, 2H), 7.32-7.27 (m, 2H), 6.99-6.92 (m, 3H), 5.85 (d, J = 5.1Hz, 1H), 5. 61(d,J=5.9Hz,1H),5.41(d,J=5.4Hz,1H),4.64(q,J=5.3Hz,1H),4.30(q,J=4.9Hz,1H),4.27-4.22(m,2H),4.20-4.16(m,1H).

[0236] Example 3: Synthesis of Compound 3:

[0237]

[0238] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-benzyloxybenzyl bromide to obtain compound 3. 1 H NMR (600MHz, DMSO-d6) δ8.25 (s, 1H), 7.86 (s, 2H), 7.44-7.41 (m, 2H), 7.38 (dd, J = 8.4, 6.7Hz, 2H), 7.34-7. 30(m,1H),7.26(t,J=7.9Hz,1H),6.98(dd,J=2.5,1.5Hz,1H),6.94-6.91(m,1H),6.91-6.88(m,1H),5.80( d,J=5.3Hz,1H),5.54(d,J=5.9Hz,1H),5.30(d,J=5.3Hz,1H),5.06(s,2H),4.55-4.52(m,1H),4.52(s,2H) ,4.18(q,J=4.6Hz,1H),4.07(q,J=4.3Hz,1H),3.71(dd,J=10.8,3.7Hz,1H),3.63(dd,J=10.8,5.0Hz,1H).

[0239] Example 4: Synthesis of Compound 4

[0240]

[0241] Synthesis of intermediate 4-1 (Step 1): Intermediate 3-1 (0.2 g, 0.39 mmol) was dissolved in 5 mL of ethanol, followed by the dropwise addition of hydrazine hydrate (0.11 mL, 2.36 mmol). The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow solid product 4-1 (0.06 g, 47%). 1 H NMR (600MHz, DMSO-d6) δ8.36(s,1H),7.89(s,2H),6.01(d,J=3.3Hz,1H),5.52(dd,J=6.3,2.9Hz,1H),5.36(dd,J=6.3,3 .2Hz,1H),4.96(dd,J=6.3,2.8Hz,1H),4.09(dtd,J=33.2,5.8,2.8Hz,2H),2.79-2.70(m,2H),1.54(s,5H),1.33(s,3H).

[0242] The synthesis of compound 4 in the second step: intermediate 4-1 (60 mg, 0.19 mmol) was dissolved in tetrahydrofuran / water (2 / 1), and about 1 ml of trifluoroacetic acid was added. The reaction was carried out overnight at 40 °C. The reaction was found to be almost complete by TLC. The reaction solution was concentrated under reduced pressure and purified by reverse silica gel column chromatography to obtain a white solid compound 4. 1 H NMR (600MHz, DMSO-d6) δ8.36(s,1H),7.84(s,2H),5.76(d,J=6.1Hz,1H),5.46(s,1H),5.20(s,1H),4.60(t,J=5.7Hz,1H ), 4.12 (t, J = 4.4Hz, 1H), 3.89 (q, J = 4.8Hz, 1H), 2.86 (dd, J = 13.4, 4.7Hz, 1H), 2.79 (dd, J = 13.4, 5.9Hz, 1H), 1.23 (s, 2H).

[0243] Example 5: Synthesis of Compound 5

[0244]

[0245] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 3-(trifluoromethyl)bromobenzyl to obtain compound 5. 1H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.86(s,2H),7.72-7.50(m,4H),5.81(d,J=5.2Hz,1H),5.53(d,J=5.9Hz,1H),5.31(d,J=5.3Hz,1H),4 .64(s,2H),4.55(q,J=5.4Hz,1H),4.19(q,J=4.9Hz,1H),4.08(q,J=4.5Hz,1H),3.75(dd,J=10.8,3.7Hz,1H),3.68(dd,J=10.8,5.4Hz,1H).

[0246] Example 6: Synthesis of Compound 6

[0247]

[0248] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 4-(trifluoromethyl)bromobenzyl to obtain compound 6. 1 H NMR (600MHz, DMSO-d6) δ8.25(s,1H),7.83(s,2H),7.69(d,J=8.2Hz,1H),7.53(d,J=8.1Hz,1H),5.80(d,J=5.3Hz,1H),5.53(d,J=6.4Hz,1H),5.33 -5.28(m,1H),4.64(s,1H),4.55(d,J=5.0Hz,1H),4.21(s,1H),4.09(p,J=4.9Hz,1H),3.75(dd,J=10.6,3.6Hz,1H),3.68(dd,J=10.9,5.3Hz,1H).

[0249] Example 7: Synthesis of Compound 7

[0250]

[0251] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-(trifluoromethyl)bromobenzyl to obtain compound 7. 1H NMR (600MHz, DMSO-d6) δ8.21 (s, 1H), 7.84 (d, J = 41.7Hz, 2H), 7.72 (d, J = 7.9Hz, 1H), 7. 66(dd,J=16.2,7.6Hz,2H),7.51(t,J=7.6Hz,1H),5.80(d,J=5.4Hz,1H),5.53(d,J=6. 0Hz,1H),5.31(d,J=5.4Hz,1H),4.70(s,2H),4.55(q,J=5.5Hz,1H),4.20(q,J=4.9Hz, 1H), 4.09 (q, J=4.5Hz, 1H), 3.78 (dd, J=11.0, 3.7Hz, 1H), 3.72 (dd, J=10.9, 5.2Hz, 1H).

[0252] Example 8: Synthesis of Compound 8

[0253]

[0254] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-methoxybenzyl bromide to obtain compound 8. 1 H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.85(s,2H),7.25(t,J=8.1Hz,1H),6.91-6.87(m,2H),6.86-6.83(m,1H),5.80(d,J=5.3Hz,1H),5.52(d,J= 5.9Hz,1H),5.29(d,J=5.3Hz,1H),4.52(d,J=7.9Hz,3H),4.17(q,J=4.7Hz,1H),3.72(s,3H),3.70(d,J=3.7Hz,1H),3.63(dd,J=10.8,4.9Hz,1H).

[0255] Example 9: Synthesis of Compound 9

[0256]

[0257] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 4-tert-butylbenzyl bromide to obtain compound 9. 1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.85(s,2H),7.37-7.33(m,2H),7.23 (d,J=8.1Hz,2H),5.79(d,J=5.3Hz,1H),5.51(d,J=5.9Hz,1H),5.28(d,J=5 .2Hz,1H),4.54(d,J=5.3Hz,1H),4.49(s,2H),4.16(q,J=4.5Hz,1H),4.05( d,J=4.3Hz,1H),3.68(d,J=3.8Hz,1H),3.62(d,J=5.1Hz,1H),1.27(s,9H).

[0258] Example 10: Synthesis of Compound 10

[0259]

[0260] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-fluorobenzyl bromide to obtain compound 10. 1 HNMR (600MHz, Methanol-d4) δ7.17(d,J=7.6Hz,1H),7.11(dd,J=9.6,2.4Hz,1H),7.03(td,J=8.6,2.6Hz,1H),5.96(d,J=4.7Hz,1H ), 4.63 (d, J = 2.9Hz, 3H), 4.40 (t, J = 4.8Hz, 1H), 4.24 (q, J = 3.8Hz, 1H), 3.86 (dd, J = 10.9, 3.1Hz, 1H), 3.78 (dd, J = 10.9, 3.8Hz, 1H).

[0261] Example 11: Synthesis of Compound 11

[0262]

[0263] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 4-fluorobenzyl bromide to obtain compound 11. 1HNMR (600MHz, DMSO-d6) δ8.22(s,1H),7.86(s,2H),7.37(dd,J=8.4,5.7Hz,2H),7.16(t,J=8.8Hz,2H),5.80(d,J=5.2Hz,1H),5.52(d,J=6.0Hz 1H), 5.29 (d, J = 5.3Hz, 1H), 4.52 (s, 2H), 4.18 (m, 1H), 4.06 (q, J = 4.4Hz, 1H), 3.71 (dd, J = 10.8, 3.7Hz, 1H), 3.63 (dd, J = 10.8, 5.0Hz, 1H).

[0264] Example 12: Synthesis of Compound 12

[0265]

[0266] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 2-fluorobenzyl bromide to obtain compound 12. 1 HNMR(600MHz,DMSO-d6)δ8.22(s,1H),7.83(s,2H),7.47-7.42(m,1H),7.40-7 .35(m,1H),7.22-7.17(m,2H),5.79(d,J=5.3Hz,1H),5.52(d,J=6.0Hz,1H),5 .29(d,J=5.3Hz,1H),4.59(s,2H),4.54-4.50(m,1H),4.18-4.16(m,1H),4.06 (q,J=4.3Hz,1H),3.74(dd,J=10.7,3.7Hz,1H),3.67(dd,J=10.7,4.9Hz,1H).

[0267] Example 13: Synthesis of Compound 13

[0268]

[0269] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with (1-bromoethyl)benzene to obtain compound 13. 1HNMR (600MHz, Methanol-d4) δ8.34(d,J=27.3Hz,1H),7.34-7.28(m,4H),7.28-7.24(m,1H),5.95(dd,J=7.7,4.6Hz,1H),4.60(dt,J=21. 6,4.8Hz,1H),4.53(p,J=6.5Hz,1H),4.35(dt,J=47.4,4.8Hz,1H),4.15(td,J=4.9,2.7Hz,1H),3.71-3.46(m,2H),1.47(t,J=6.3Hz,3H).

[0270] Example 14: Synthesis of Compound 14

[0271]

[0272] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 2-chlorobenzyl bromide to obtain compound 14.

[0273] 1 H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.84(s,2H),7.49(dd,J=6.8,2.6Hz,1H), 7.46-7.44(m,1H),7.36-7.31(m,2H),5.81(d,J=5.3Hz,1H),5.53(d,J=6.0Hz, 1H),5.30(d,J=5.3Hz,1H),4.61(s,2H),4.55(q,J=5.4Hz,1H),4.20(q,J=4.9H z,1H),4.09(q,J=4.3Hz,1H),3.82-3.78(m,1H),3.72(dd,J=10.7,5.0Hz,1H).

[0274] Example 15: Synthesis of Compound 15

[0275]

[0276] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-chlorobenzyl bromide to obtain compound 15.

[0277] 1H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.82(s,2H),7.39-7.33(m,3H),7.28(dt,J=7.4,1.7Hz,1H),5.80(d,J=5.2Hz,1H),5.53( d,1H),5.30(d,1H),4.55(s,2H),4.18(d,J=5.0Hz,1H),4.07(q,J=4.4Hz,1H),3.75-3.71(m,1H),3.65(dd,J=10.8,5.2Hz,1H).

[0278] Example 16: Synthesis of Compound 16

[0279]

[0280] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 4-chlorobenzyl bromide to obtain compound 16.

[0281] 1 H NMR (600MHz, DMSO-d6) δ8.23(s,1H),7.85(s,2H),7.41-7.38(m,2H),7.34(d,J=8.4Hz,2H),5.79(d,J=5.2Hz,1H),5.52(s,1H),5 .29(s,1H),4.52(s,3H),4.18(t,J=4.7Hz,1H),4.06(q,J=4.4Hz,1H),3.71(dd,J=10.8,3.7Hz,1H),3.64(dd,J=10.8,5.0Hz,1H).

[0282] Example 17: Synthesis of Compound 17

[0283]

[0284] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-methylbenzyl bromide to obtain compound 17. 1HNMR(600MHz,DMSO-d6)δ8.19(s,1H),7.85(d,J=39.4Hz,2H),7.29(dd,J=7.4,1.4Hz,1H),7.21-7.12(m,3H),5.80(d,J=5.3Hz,1H),5.56-5.48(m,1 H),5.29(s,1H),4.52(s,2H),4.17(t,J=4.5Hz,1H),4.07(q,J=4.3Hz,1H) ,3.72(dd,J=10.7,3.8Hz,1H),3.65(dd,J=10.7,4.9Hz,1H),2.25(s,3H).

[0285] Example 18: Synthesis of Compound 18

[0286]

[0287] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 3-(bromomethyl)pyridine to obtain compound 18. 1 H NMR(600MHz,DMSO-d6)δ8.58-8.53(m,1H),8.51(dd,J=4.7,1.6Hz,1H),8.23(s,1H),7.85(d, J=44.0Hz,2H),7.74(dt,J=7.8,2.0Hz,1H),7.37(dd,J=7.8,4.8Hz,1H),5.80(d,J=5.2Hz,1H) ,5.53(d,J=5.9Hz,1H),5.31(d,J=5.3Hz,1H),4.58(s,2H),4.53(q,J=5.4Hz,1H),4.19(q,J= 4.9Hz, 1H), 4.08 (q, J = 4.4Hz, 1H), 3.75 (dd, J = 10.8, 3.7Hz, 1H), 3.67 (dd, J = 10.8, 5.1Hz, 1H).

[0288] Example 19: Synthesis of Compound 19

[0289]

[0290] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3,5-difluorobenzyl bromide to obtain compound 19. 1HNMR(600MHz,DMSO-d6)δ8.24(s,1H),7.85(s,J=39.8Hz,2H),7.13(tt,J=9.4 ,2.4Hz,1H),7.077.00(m,2H),5.81(d,J=5.2Hz,1H),5.53(d,J=5.9Hz,1H),5 .31(d,J=5.3Hz,1H),4.56(s,J=4.2Hz,2H),4.20(q,J=4.8Hz,1H),4.08(dt,J =5.1,3.8Hz,1H),3.74(dd,J=10.8,3.7Hz,1H),3.67(dd,J=10.8,5.2Hz,1H).

[0291] Example 20: Synthesis of Compound 20

[0292]

[0293] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-fluoro-4-methoxybenzyl bromide to obtain compound 20. 1 H NMR (600MHz, DMSO-d6) δ8.23 (s, 1H), 7.84 (s, 2H), 7.16 (dd, J = 12.4, 1.8Hz, 1H), 7. 11(s,1H),7.11-7.09(m,1H),5.79(d,J=5.3Hz,1H),5.51(d,J=6.0Hz,1H),5.28(d ,J=5.2Hz,1H),4.52(q,J=5.3Hz,1H),4.46(s,2H),4.16(d,J=4.7Hz,1H),4.07-4. 04(m,1H),3.83(s,3H),3.68(dd,J=10.8,3.8Hz,1H),3.61(dd,J=10.8,5.0Hz,1H).

[0294] Example 21: Synthesis of Compound 21

[0295]

[0296] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with iodobenzene to obtain compound 21. 1HNMR(600MHz,DMSO-d6)δ8.31(s,1H),7.86(s,2H),7.32-7.27(m,2H),6.99-6.92(m,3H),5.85(d,J=5.1Hz,1H),5.61(d, J=5.9Hz,1H),5.41(d,J=5.4Hz,1H),4.64(q,J=5.3Hz,1H),4.30(q,J=4.9Hz,1H),4.27-4.22(m,2H),4.20-4.16(m,1H).

[0297] Example 22: Synthesis of Compound 22

[0298]

[0299] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 4-methylbenzyl bromide to obtain compound 22. 1 HNMR(600MHz,DMSO-d6)δ8.23(s,1H),7.86(s,J=34.7Hz,2H),7.21(d,J=8.0Hz,2H), 7.15(d,J=7.7Hz,2H),5.79(d,J=5.3Hz,1H),5.51(d,J=5.9Hz,1H),5.28(d,J=5.2Hz 1H),4.52(q,J=5.3Hz,1H),4.48(s,2H),4.16(d,J=4.5Hz,1H),4.06(q,J=4.2H z,1H),3.69(dd,J=10.8,3.7Hz,1H),3.61(dd,J=10.8,4.9Hz,1H),2.29(s,3H).

[0300] Example 23: Synthesis of Compound 23

[0301]

[0302] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-(bromomethyl)pyridine to obtain compound 23. 1H NMR(600MHz,DMSO-d6)δ8.52(ddd,J=4.8,1.8,0.9Hz,1H),8.31(s,1H),7.88(s,2H),7.76( td,J=7.7,1.8Hz,1H),7.40(d,J=7.8Hz,1H),7.32-7.27(m,1H),5.81(d,J=5.3Hz,1H),5.5 2(d,J=5.9Hz,1H),5.30(d,J=5.3Hz,1H),4.61(s,2H),4.56(q,J=5.4Hz,1H),4.21(q,J=4. 8Hz, 1H), 4.09 (q, J = 4.2Hz, 1H), 3.78 (dd, J = 10.8, 3.6Hz, 1H), 3.72 (dd, J = 10.8, 4.9Hz, 1H).

[0303] Example 24: Synthesis of Compound 24

[0304]

[0305] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 4-(bromomethyl)pyridine to obtain compound 23. 1 H NMR (600MHz, DMSO-d6) δ8.53-8.47(m,1H),8.25(s,1H),7.92(s,2H),7.32-7.30(m,1H),5.81(d,J=5.1Hz,1H),5.54(d,J=5.9Hz,1H),5.31(d,J=5 .4Hz,1H),4.59(s,1H),4.56(q,J=5.0Hz,2H),4.23(q,J=4.6Hz,1H),4.0 9(td,J=4.8,3.6Hz,1H),3.76(dd,J=10.8,3.6Hz,1H),3.72-3.66(m,1H).

[0306] Example 25: Synthesis of Compound 25

[0307]

[0308] Synthesis of intermediate 25-1 in step one: Intermediate 3-2 (50 mg, 0.15 mmol) and benzaldehyde (0.02 mL, 0.18 mmol) were dissolved in 4 mL of dichloroethane, followed by the addition of 0.01 mL of acetic acid. After reacting at room temperature for 30 minutes, sodium cyanoborohydride (15 mg, 0.23 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid product 25-1 (30 mg, 47%). 1 H NMR (600MHz, DMSO-d6) δ8.32(s,1H),7.89(s,2H),7.33-7.16(m,5H),6.81(s,1H),6.03(d,J=3.4Hz,1H),5.36(dd,J=6.3 ,2.9Hz,1H),4.95(dd,J=6.3,2.9Hz,1H),4.25(dt,J=7.1,4.1Hz,1H),2.72(d,J=32.8Hz,2H),1.53(s,3H),1.32(3,4H).

[0309] The second step was the synthesis of compound 25: intermediate 25-1 (30 mg, 0.07 mmol) was dissolved in 1 ml of tetrahydrofuran, followed by the addition of 0.5 ml of water and 1 ml of trifluoroacetic acid. The reaction was carried out overnight at 40 °C. The starting material was completely consumed by TLC monitoring. The mixture was concentrated under reduced pressure and purified by reversed-phase column chromatography to obtain a white solid 25 (10 mg, 37%). 1 H NMR(600MHz,DMSO-d6)δ9.01(s,1H),8.34(s,1H),7.89(s,2H),7.47-7.31(m,5H),5.88(d ,J=5.0Hz,1H),5.72-5.69(m,1H),5.53(s,1H),4.63(d,J=5.1Hz,1H),4.26-4.11(m,4H).

[0310] Example 26: Synthesis of Compound 26

[0311]

[0312] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-methylbenzyl bromide to obtain compound 26. 1HNMR(600MHz,DMSO-d6)δ8.24(s,1H),7.84(s,2H),7.23(d,J=7.6Hz,1H),7.16 -7.10(m,3H),5.80(d,J=5.3Hz,1H),5.52(d,J=6.0Hz,1H),5.29(d,J=5.3Hz,1 H),4.53(q,J=5.5Hz,1H),4.50(s,2H),4.17(q,J=4.9Hz,1H),4.06(q,J=4.2Hz ,1H),3.70(dd,J=10.7,3.7Hz,1H),3.62(dd,J=10.7,5.0Hz,1H),2.29(s,3H).

[0313] Example 27: Synthesis of Compound 27

[0314]

[0315] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-bromomethylthiophene to obtain compound 27. 1 HNMR(600MHz,DMSO-d6)δ8.24(s,1H),7.84(s,2H),7.52(dd,J=4.9,3.0Hz,1H),7.42 (dd,J=3.0,1.2Hz,1H),7.08(dd,J=4.9,1.3Hz,1H),5.79(d,J=5.3Hz,1H),5.51(d,J= 6.0Hz,1H),5.28(d,J=5.3Hz,1H),4.53(s,2H),4.52-4.50(m,1H),4.15(q,J=4.9Hz,1 H), 4.05 (q, J = 4.2Hz, 1H), 3.70 (dd, J = 10.8, 3.7Hz, 1H), 3.62 (dd, J = 10.8, 4.9Hz, 1H).

[0316] Example 28: Synthesis of Compound 28

[0317]

[0318] Synthesis of intermediate 28-1 in step one: Intermediate 1-2 (0.5 g, 1.54 mmol) and 2-iodobenzoic acid (1.7 g, 6.15 mmol) were dissolved in 20 mL of acetonitrile and reacted at 60 °C for 4 h under N2 protection. The starting material was completely consumed by TLC monitoring. After filtration, the filtrate was washed with saturated sodium thiosulfate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light yellow solid 4-1 (0.3 g crude product).

[0319] The synthesis of intermediate 28-2 in step two: Intermediate 28-1 (0.18 g, 0.55 mmol) and aniline (0.06 mL, 0.67 mmol) were dissolved in 5 mL of dichloroethane, followed by the addition of 0.1 mL of acetic acid. The reaction was carried out at room temperature for 30 minutes, then sodium cyanoborohydride (0.05 g, 0.83 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow oily product 28-2 (50 mg, 23%). 1 H NMR (600MHz, DMSO-d6) δ8.30(s,1H),7.82(s,3H),7.59-7.56(m,2H),7.33-7.29(m,2H),7.07-7.02(m,1H),6.08(d,J=2.8Hz, 1H),5.41(dd,J=6.3,2.9Hz,1H),5.02-4.96(m,1H),4.30(td,J=6.2,3.0Hz,1H),3.27-3.20(m,2H),1.53(s,3H),1.32(s,3H).

[0320] The third step was the synthesis of compound 28: intermediate 28-2 (30 mg, 0.07 mmol) was dissolved in 1 ml of tetrahydrofuran, followed by the addition of 0.5 ml of water and 1 ml of trifluoroacetic acid. The reaction was carried out overnight at 40 °C. The reaction was monitored by TLC until the starting material was completely consumed. The mixture was concentrated under reduced pressure and purified by reversed-phase column chromatography to obtain a white solid, 28. 1 H NMR (600MHz, DMSO-d6) δ8.28(s,1H),7.87(s,2H),7.09-7.03(m,2H),6.63(d,J=8.0Hz,2H),6.53(t,J=7.3Hz,1H),5.79(d,J=5.9Hz,1H) ,5.73(t,J=6.2Hz,1H),5.50(d,J=6.1Hz,1H),5.27(d,J=5.0Hz,1H),4.64(q,J=5.8Hz,1H),4.13(q,J=4.7Hz,1H),4.07(q,J=5.0Hz,1H).

[0321] Example 29: Synthesis of Compound 29

[0322]

[0323] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-bromomethylpyrazine to obtain compound 29. 1HNMR(600MHz,DMSO-d6)δ8.68(d,J=1.5Hz,1H),8.61(dd,J=2.6,1.5Hz,1H),8.5 9(d,J=2.6Hz,1H),8.30(s,1H),7.82(s,2H),5.81(d,J=5.3Hz,1H),5.53(d,J=5 .9Hz,1H),5.31(d,J=5.3Hz,1H),4.70(s,2H),4.58-4.54(m,1H),4.21(q,J=4.9 Hz, 1H), 4.10 (q, J = 4.3Hz, 1H), 3.83 (dd, J = 10.8, 3.6Hz, 1H), 3.79-3.76 (m, 1H).

[0324] Example 30: Synthesis of Compound 30

[0325]

[0326] Following the methods in steps 2 and 3 of Example 28, the benzene ring was replaced with N-ethylaniline to obtain compound 30. 1 HNMR(600MHz,Methanol-d4)δ8.06(s,1H),7.15-7.08(m,2H),6.80-6.75(m,2H),6.6 0(tt,J=7.3,1.0Hz,1H),5.88(d,J=4.4Hz,1H),4.79-4.74(m,1H),4.33(t,J=5.3Hz,1 H),4.26(ddd,J=6.4,5.2,4.0Hz,1H),3.81(dd,J=15.6,4.1Hz,1H),3.58(dd,J=15.6, 6.5Hz, 1H), 3.42 (qd, J = 7.1, 2.0Hz, 2H), 3.31 (p, J = 1.7Hz, 2H), 1.08 (t, J = 7.0Hz, 3H).

[0327] Example 31: Synthesis of Compound 31

[0328]

[0329] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 2-bromomethyl-6-fluoropyridine to obtain compound 31. 1H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 7.95 (td, J = 8.3, 7.4Hz, 1H), 7.88 (s, 2H), 7. 35(dd,J=7.3,2.5Hz,1H),7.08(dd,J=8.1,2.5Hz,1H),5.81(d,J=5.3Hz,1H),5.54 (d,J=6.0Hz,1H),5.32(d,J=5.3Hz,1H),4.58-4.56(m,3H),4.21(q,J=4.9Hz,1H), 4.09(q,J=4.4Hz,1H), 3.79(dd,J=10.8,3.6Hz,1H), 3.73(dd,J=10.8,5.1Hz,1H).

[0330] Example 32: Synthesis of Compound 32

[0331]

[0332] Synthesis of intermediate 32-1 in step one: Intermediate 1-2 (150 mg, 0.46 mmol) was dissolved in dichloromethane (10 ml), DMAP (56 mg, 0.46 mmol) and triethylamine (232 mg, 2.3 mmol) were added, and the reaction solution was placed in an ice bath. p-Toluenesulfonyl chloride (354 mg, 1.86 mmol) was added. After reacting for 2 h under these conditions, the reaction was found to be almost complete by TLC. The reaction solution was extracted with dichloromethane and water, and the organic layers were combined. The organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 32-1 (180 mg, 82%). 1 H NMR (600MHz, DMSO-d6) δ8.19(s,1H),7.99-7.85(m,2H),7.60-7.55(m,2H),7.25(d,J=8.0Hz,2H),6.10(d,J=2.1Hz,1H),5.27(dd,J= 6.2,2.2Hz,1H),4.92(dd,J=6.2,3.1Hz,1H),4.36-4.29(m,2H),4.23(dd,J=10.4,7.2Hz,1H),2.36(s,3H),1.51(s,3H),1.29(s,3H).

[0333] The second step involved the synthesis of intermediate 32-2: Intermediate 32-1 (150 mg, 0.31 mmol) was added to a two-necked reaction flask, and the mixture was purged three times with nitrogen. A tetrahydrofuran solution of triethyl borohydride (1 M, 3.1 ml) was then added. The reaction was carried out at room temperature for approximately 1 hour. TLC analysis indicated that the reaction was nearly complete. The reaction was quenched by slow addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 32-2 (60 mg, 61%). 1 H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.89(d,J=30.3Hz,2H),6.00(d,J=2.6Hz,1H),5.41(dd,J=6.3,2.6Hz,1 H),4.76(dd,J=6.3,3.4Hz,1H),4.24(dq,J=6.6,3.2Hz,1H),1.53(s,3H),1.32(s,3H),1.26(d,J=6.6Hz,3H).

[0334] The third step was the synthesis of compound 32: intermediate 32-2 (60 mg, 0.19 mmol) was dissolved in tetrahydrofuran / water (2 / 1), and 0.5 ml of trifluoroacetic acid was added. The reaction solution was heated to 40 °C and reacted overnight. TLC showed that the reaction was basically complete. The reaction solution was concentrated under reduced pressure and purified by reverse column chromatography to obtain compound 32. 1 H NMR (600MHz, DMSO-d6) δ8.31 (s, 1H), 7.84 (d, J = 29.6Hz, 2H), 5.74 (d, J = 5.0Hz, 1H), 4.60 (t, J = 5.0Hz, 1H), 4.00-3.92 (m, 4H), 1.30 (d, J = 6.3Hz, 3H).

[0335] Example 33: Synthesis of Compound 33

[0336]

[0337] Synthesis of intermediate 33-1 in step one: Intermediate 1-2 (4 g, 12.3 mmol) was dissolved in 60 mL of ultra-dry DMF. Imidazole (2.51 g, 36.89 mmol) and tert-butyldimethylchlorosilane (2.41 g, 15.99 mmol) were added sequentially under nitrogen protection in an ice bath. The mixture was then moved to room temperature and reacted for 3 h. TLC was used to monitor the complete consumption of the starting materials. The reaction solution was diluted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was washed twice with water and then washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 34-1 (5 g, 92%).

[0338] The synthesis of intermediate 33-2 in step 2: Intermediate 33-1 (5 g, 11.37 mmol) was dissolved in 60 mL of ultra-dry dichloromethane and placed in an ice bath. Under nitrogen protection, 2,4,6-trimethylpyridine (4.51 mL, 34.12 mmol), silver nitrate (3.86 g, 22.75 mmol), and 4-methoxytriphenylchloromethane (7.03 g, 22.75 mmol) were added sequentially. The mixture was then moved to room temperature and reacted for 2 h. TLC was used to monitor the complete consumption of the starting materials. The reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was extracted with DCM. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 33-2 (7.8 g, 96%). 1 H NMR(600MHz,DMSO-d6)δ8.33(s,1H),8.07(s,1H),7.36-7.26(m,8H),7.26 -7.19(m,4H),6.88-6.80(m,2H),6.10(d,J=2.1Hz,1H),5.33(dd,J=6.2,2. 1Hz,1H),4.89(dd,J=6.1,2.8Hz,1H),4.22(td,J=5.3,2.7Hz,1H),3.76-3 .61(m,5H),1.51(s,3H),1.31(s,3H),0.76(s,9H),-0.09(d,J=9.0Hz,6H).

[0339] The third step involved the synthesis of intermediate 33-3: Intermediate 33-2 (7.8 g, 10.96 mmol) was dissolved in 60 mL of tetrahydrofuran, and 4.5 mL of tetrabutylammonium fluoride solution (13.15 mL, 13.15 mmol) was added. The mixture was reacted at room temperature for 1 h. TLC was used to monitor the complete consumption of the starting material. Ethyl acetate was added to dilute the reaction solution, followed by extraction. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid product 33-3 (4.56 g, 69%). 1H NMR(600MHz,DMSO-d6)δ8.41(s,1H),8.08(s,1H),7.33-7.27(m,8H),7.23(dt d,J=6.5,3.5,1.9Hz,4H),6.88-6.84(m,2H),6.03(d,J=2.7Hz,1H),5.28(dd,J =6.2,2.8Hz,1H),5.06(t,J=5.4Hz,1H),4.90(dd,J=6.2,2.7Hz,1H),4.19(td ,J=5.1,2.7Hz,1H),3.73(s,3H),3.55-3.48(m,2H),1.52(s,3H),1.31(s,3H).

[0340] The fourth step was the synthesis of intermediate 33-4: Intermediate 33-3 (0.2 g, 0.335 mmol) was dissolved in 8 ml of DMF, and sodium hydride (0.030 g, 0.770 mmol) was added under ice bath conditions and stirred for 10 min. Then, iodopropane (0.039 ml, 0.402 mmol) was added, and the mixture was moved to room temperature for 8 h. TLC monitoring showed that some of the starting material remained, which was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 33-4 (80 mg, 37%). 1 H NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.08(s,1H),7.32-7.28(m,8H),7.24-7.20(m,4H),6. 88-6.84(m,2H),6.05(d,J=2.3Hz,1H),5.32(dd,J=6.1,2.3Hz,1H),4.89(dd,J=6.1,2.7Hz, 1H),4.32(td,J=4.9,2.7Hz,1H),3.52(dd,J=10.6,4.6Hz,1H),3.46(dd,J=10.6,5.4Hz,1H) ,3.28(t,J=6.6Hz,2H),1.51(s,3H),1.44-1.36(m,3H),1.31(s,3H),0.76(t,J=7.4Hz,3H).

[0341] The fifth step was the synthesis of compound 33: intermediate 33-4 (100 mg, 0.156 mmol) was dissolved in 1 ml of tetrahydrofuran, followed by the addition of 0.5 ml of water and 1 ml of trifluoroacetic acid. The reaction was carried out overnight at 40 °C. The starting material was completely consumed by TLC monitoring. The mixture was concentrated under reduced pressure and purified by reversed-phase column chromatography to obtain a white solid 33 (17 mg, 33%). 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.85(s,J=45.9Hz,2H),5.79(d,J=5.0Hz,1H),5.53(d,1H),5.27(d,1H),4.49(t,J=5.0Hz,1H),4.15(d,J=4.7Hz ,1H),4.02(q,J=4.3Hz,1H),3.65(dd,J=10.8,3.8Hz,1H),3.56(dd,J=4.7H z,1H),3.40(t,J=6.5Hz,2H),1.53(h,J=7.1Hz,2H),0.87(t,J=7.4Hz,3H).

[0342] Example 34: Synthesis of Compound 34

[0343]

[0344] Following the synthesis method of Example 33, the raw material iodopropane was replaced with bromomethylcyclopropane to obtain compound 34. 1 HNMR(600MHz,DMSO-d6)δ8.35(s,1H),7.86(s,J=47.5Hz,2H),5.80(d,J=5.2Hz,1H),5.5 2(d,J=6.0Hz,1H),5.27(d,J=5.3Hz,1H),4.51(q,J=5.3Hz,1H),4.15(q,J=4.8Hz,1H),4. 03(q,J=4.2Hz,1H),3.66(dd,J=10.8,3.8Hz,1H),3.57(dd,J=10.8,4.6Hz,1H),3.28-3.2 5(m,1H),1.02(dddd,J=14.9,6.8,3.2,2.0Hz,1H),0.51-0.47(m,2H),0.22-0.17(m,2H).

[0345] Example 35: Synthesis of Compound 35

[0346]

[0347] Following the synthesis method of Example 33, the raw material iodopropane was replaced with iodoethane to obtain compound 35. 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.83(s,2H),5.79(d,J=5.1Hz,1H),5.52(d,1H),5.26(d,1H),4.50(t,J=5.1Hz,1H),4.14(t,J=4 .7Hz,1H),4.04-4.00(m,1H),3.64(dd,J=10.8,3.8Hz,1H),3.55(dd,J=10.8,4.9Hz,1H),3.49(q,J=7.0Hz,2H),1.13(t,J=7.0Hz,3H).

[0348] Example 36: Synthesis of Compound 36

[0349]

[0350] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with N-(3-(bromomethyl)phenylmethanesulfonamide to obtain compound 36. 1 H NMR (600MHz, DMSO-d6) δ9.74(s,1H),8.24(s,1H),7.84(s,2H),7.30(t,J=7.8Hz,1H),7.19(t,J=2.0Hz,1H),7.14(ddd ,J=8.1,2.4,1.1Hz,1H),7.06(dt,J=7.7,1.3Hz,1H),5.80(d,J=5.3Hz,1H),5.54(d,J=6.0Hz,1H),5.31(d,J=5.3Hz,1H 1H),4.53-4.50(m,3H),4.18(t,J=4.7Hz,1H),4.09-4.06(m,1H),3.72(dd,J=10.8,3.8Hz,1H),3.64(dd,J=10.8,5.1Hz,1H),2.97(s,3H).

[0351] Example 37: Synthesis of Compound 37

[0352]

[0353] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-cyanobenzyl bromide to obtain compound 37. 1HNMR(600MHz,DMSO-d6)δ8.23(s,1H),7.84(s,2H),7.79-7.75(m,2H),7.66(dd, J=7.9,1.5Hz,1H),7.55(td,J=7.6,0.8Hz,1H),5.80(d,J=5.2Hz,1H),5.53(d,J= 5.9Hz,1H),5.31(d,J=5.4Hz,1H),4.60(s,2H),4.55(q,J=5.4Hz,1H),4.20(q,J =4.9Hz,1H),4.11-4.06(m,1H),3.79-3.74(m,1H),3.67(dd,J=10.8,5.3Hz,1H).

[0354] Example 38: Synthesis of Compound 38

[0355]

[0356] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 4-cyanobenzyl bromide to obtain compound 38. 1 HNMR(600MHz,DMSO-d6)δ8.24(s,1H),7.84(s,2H),7.80(d,J=8.3Hz,2H),7.5 1(d,J=8.3Hz,2H),5.81(d,J=5.1Hz,1H),5.54(d,J=5.9Hz,1H),5.31(d,J=5. 4Hz,1H),4.63(s,2H),4.55(q,J=5.3Hz,1H),4.21(q,J=4.9Hz,1H),4.08(td, J=4.9,3.7Hz,1H),3.75(dd,J=10.8,3.7Hz,1H),3.68(dd,J=10.8,5.2Hz,1H).

[0357] Example 39: Synthesis of Compound 39

[0358]

[0359] Following the method of Example 33, iodomethane was replaced with 3-bromo-1-trimethylsilyl-1-propyne to obtain compound 39. 1H NMR (600MHz, DMSO-d6) δ8.29(s,1H),7.85(s,2H),5.79(d,J=5.4Hz,1H),5.53(d,1H),5.31(d,1H),4.51(t,J=5.3Hz,1H),4.20(dd,J=4.0, 2.4Hz,2H),4.12(t,J=4.6Hz,1H),4.04(q,J=4.2Hz,1H),3.72(dd,J=10.6,3.7Hz,1H),3.62(dd,J=10.6,5.1Hz,1H),3.47(t,J=2.4Hz,1H).

[0360] Example 40: Synthesis of Compound 40

[0361]

[0362] Synthesis of intermediate 40-1 in step one: Following the synthesis method in step 3 of Example 1, the raw material was replaced with 4-iodobenzyl bromide to obtain intermediate 40-1.

[0363] The second step was the synthesis of intermediate 40-2: intermediate 40-1 (400 mg, 0.671 mmol) was dissolved in 2 ml of anhydrous methanol, and 2 ml of ammonia methanol solution was added. The mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the starting material was completely consumed. The solvent was removed by concentration under reduced pressure, and the product 40-2 (360 mg, 99%) was purified by silica gel column chromatography.

[0364] The third step involved the synthesis of intermediate 40-3: Intermediate 40-2 (360 mg, 0.665 mmol) was dissolved in 6 mL of ultra-dry DMF. Under nitrogen protection, cuprous iodide (0.025 g, 0.133 mmol), bis(triphenylphosphine)palladium dichloride (0.047 g, 0.067 mmol), trimethylsilylacetylene (0.113 mL, 0.798 mmol), and 1.5 mL of triethylamine were added sequentially. The reaction was carried out at room temperature for 1 h. LC-MS was used to monitor the complete consumption of the starting materials. The reaction solution was diluted with ethyl acetate, extracted with water, and the organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 40-3 (220 mg, 65%).

[0365] The fourth step was the synthesis of compound 40: intermediate 40-3 (220 mg, 0.430 mmol) was dissolved in 2 ml of tetrahydrofuran, followed by the addition of 1 ml of water and 2 ml of trifluoroacetic acid. The reaction was carried out overnight at 40 °C. The starting material was completely consumed by TLC monitoring. The mixture was concentrated under reduced pressure and purified by reversed-phase column chromatography to obtain a white solid 40 (20 mg, 12%). 1H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.89(s,2H),7.48-7.44(m,2H),7.33(d, J=8.0Hz,2H),5.80(d,J=5.2Hz,1H),5.53(d,J=5.9Hz,1H),5.30(d,J=5.4Hz, 1H),4.56(s,2H),4.53(q,J=5.3Hz,1H),4.21-4.18(m,1H),4.18(s,1H),4.07 (q,J=4.3Hz,1H),3.73(dd,J=10.8,3.7Hz,1H),3.65(dd,J=10.8,4.9Hz,1H).

[0366] Example 41: Synthesis of Compound 41

[0367]

[0368] Following the synthesis method of Example 40, 4-iodobenzyl bromide was replaced with 3-iodobenzyl bromide to obtain compound 41. 1 HNMR(600MHz,DMSO-d6)δ8.23(s,1H),7.87(s,2H),7.43(s,1H),7.41-7.39(m,1H),7.36(d,J=4.9Hz,2H),5.80(d,J=5.2Hz,1H),5.52(d,J=5.9Hz,1H 1H), 5.30 (d, J = 5.4Hz, 1H), 4.54 (s, 2H), 4.19-4.17 (m, 2H), 4.07 (q, J = 4.4Hz, 1H), 3.72 (dd, J = 10.8, 3.8Hz, 1H), 3.64 (dd, J = 10.7, 5.1Hz, 1H).

[0369] Example 42: Synthesis of Compound 42

[0370]

[0371] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 3-phenylbenzyl bromide to obtain compound 42. 1HNMR(600MHz,DMSO-d6)δ8.27(s,1H),7.84(s,2H),7.64-7.60(m,3H),7.58(dt,J=7.7,1.5Hz,1H ),7.44(t,J=7.6Hz,3H),7.38-7.34(m,1H),7.32(dt,J=7.6,1.4Hz,1H),5.81(d,J=5.3Hz,1H),5 .54(d,J=6.0Hz,1H),5.31(d,J=5.3Hz,1H),4.63(d,J=3.3Hz,2H),4.55(q,J=5.4Hz,1H),4.20(q ,J=4.9Hz,1H),4.09(q,J=4.3Hz,1H),3.75(dd,J=10.8,3.7Hz,1H),3.68(dd,J=10.8,5.0Hz,1H).

[0372] Example 43: Synthesis of Compound 43

[0373]

[0374] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 1-bromomethyl-3-phenoxybenzene to obtain compound 43. 1 H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.83(s,2H),7.39-7.33(m,3H),7.12(tt,J=7.3,1.1Hz,1H), 7.10-7.08(m,1H),7.02-6.98(m,2H),6.96(t,J=2.0Hz,1H),6.92(ddd,J=8.1,2.6,1.0Hz,1H),5.7 9(d,J=5.2Hz,1H),5.53(d,J=6.0Hz,1H),5.30(d,J=5.4Hz,1H),4.53(s,2H),4.52-4.49(m,1H),4. 15(q,J=4.9Hz,1H),4.07-4.04(m,1H),3.71(dd,J=10.8,3.7Hz,1H),3.63(dd,J=10.8,5.1Hz,1H).

[0375] Example 44: Synthesis of Compound 44

[0376]

[0377] Following the method in steps 3 and 4 of Example 1, iodomethane was replaced with 1,4-di(bromomethyl)benzene to obtain compound 44. 1H NMR (600MHz, DMSO-d6) δ8.24(s,2H),7.85(s,4H),7.30(s,4H),5.80(d,J=5.3Hz,2H),5.54(d,J=5.9Hz,2H),5.30(d,J=5.3H z,2H),4.53(s,6H),4.18(t,J=4.6Hz,2H),4.07(q,J=4.3Hz,2H),3.72(dd,J=10.8,3.8Hz,2H),3.64(dd,J=10.7,5.0Hz,2H).

[0378] Example 45: Synthesis of Compound 45

[0379]

[0380] Following the methods in steps 3 and 4 of Example 1, iodomethane was replaced with 1,3-di(bromomethyl)benzene to obtain compound 45. 1 H NMR (600MHz, DMSO-d6) δ8.24(s,2H),7.85(s,4H),7.32(dd,J=8.3,6.5Hz,1H),7.27-7.24(m,3H),5.80(d,J=5.3Hz,2H),5.54(d,J=5.9 Hz, 2H), 5.30 (d, J = 5.3Hz, 2H), 4.18 (t, J = 4.6Hz, 2H), 4.07 (q, J = 4.3Hz, 2H), 3.72 (dd, J = 10.8, 3.8Hz, 2H), 3.64 (dd, J = 10.7, 5.0Hz, 2H).

[0381] Example 46: Synthesis of Compound 46

[0382]

[0383] Synthesis of intermediate 46-3 (Step 1): Intermediates 46-1 (0.116 g, 0.215 mmol), 46-2 (0.110 g, 0.215 mmol), Pd(PPh3)2Cl2 (0.008 g, 0.011 mmol), CuI (0.004 g, 0.022 mmol), and CsF (0.033 g, 0.215 mmol) were added to a two-necked flask, dissolved in 4 ml of DMF, and 1 ml of triethylamine were added. The mixture was reacted at room temperature for 6 hours. LC-MS was used to monitor complete consumption of the starting materials. The reaction mixture was diluted with ethyl acetate, extracted with water, and the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 46-3 (0.138 g, 75%).

[0384] The second step involved the synthesis of compound 46: intermediate 46-3 (138 mg, 0.162 mmol) was dissolved in 2 ml of tetrahydrofuran, and 1 ml of water and 2 ml of trifluoroacetic acid were added. The mixture was reacted overnight at 40 °C. The reaction was monitored by TLC until the starting material was completely consumed. The solvent was removed by concentration under reduced pressure, and the product 46 was obtained by preparative high performance liquid chromatography. 1 H NMR (600MHz, DMSO-d6) δ8.25(d,J=6.3Hz,2H),7.83(s,4H),7.69(d,J=1.7Hz,1H),7.67-7.64(m,1H),7.51(d,J=2. 1Hz,1H),7.47(dt,J=7.4,1.7Hz,1H),7.41(t,J=7.5Hz,1H),7.39-7.37(m,1H),7.34(d,J=7.7Hz,1H),7.15(t,J=7. 7Hz,1H),5.81(t,J=4.9Hz,2H),5.53(dd,J=6.0,2.8Hz,2H),5.31(dd,J=5.4,4.2Hz,2H),4.57(s,2H),4.55-4.53(m ,2H),4.51(s,2H),4.18(dq,J=9.9,4.9Hz,2H),4.08(dq,J=13.0,4.3Hz,2H),3.75-3.69(m,2H),3.68-3.62(m,2H).

[0385] Example 47: Synthesis of Compound 47

[0386]

[0387] Following the synthetic steps of Example 46, intermediate 46-2 was replaced with intermediate 47-1 to obtain intermediate 47-2. Intermediate 47-2 (155 mg, 0.148 mmol) was dissolved in 2 ml of tetrahydrofuran, and 1 ml of water and 2 ml of trifluoroacetic acid were added. The mixture was reacted overnight at 40°C. After the starting material was completely consumed by TLC monitoring, the solvent was removed by concentration under reduced pressure, and the product 47 was obtained by preparative high-performance liquid chromatography. 1HNMR (600MHz, DMSO-d6) δ8.32(s,1H),8.24(s,1H),7.85(s,4H),7.40(d,J=1.7Hz,1H),7.36(ddd,J= 11.9,4.7,1.4Hz,3H),5.80(t,J=5.3Hz,2H),5.54(dd,J=9.5,6.0Hz,2H),5.32(dd,J=15.0,5.3Hz,2 H),4.54(d,J=7.8Hz,4H),4.45(d,J=2.7Hz,2H),4.17(dq,J=9.0,4.7Hz,2H),4.07(ddd,J=9.5,5.4, 4.0Hz, 2H), 3.79 (dd, J=10.7, 3.8Hz, 1H), 3.71 (dt, J=10.6, 4.1Hz, 2H), 3.64 (dd, J=10.8, 5.2Hz, 1H).

[0388] Biological evaluation experiments:

[0389] Test Example 1: Assay for In Vitro Proliferation Inhibition

[0390] The inhibitory effect of the compound on the proliferation of the prostate cancer cell line PC-3 was tested using the following methods.

[0391] Experimental steps:

[0392] The inhibitory effect of the compound on PC-3 cell proliferation was determined using the CCK-8 assay, and the half-maximal inhibitory concentration (IC50) of the compound was obtained. 50 value:

[0393] 1) Seed 3,000-10,000 cells / well in logarithmic growth phase into 96-well plates and incubate at 37°C and 5% CO2 for 12-24 hours.

[0394] 2) Add serially diluted solutions of the test compound of different concentrations to the culture plate and incubate at 37°C and 5% CO2 for 72 hours;

[0395] 3) 2-4 hours before the end of incubation, discard the culture medium in the well plate and add 100 μL of 10% CCK-8 solution to each well;

[0396] 4) After incubation, measure the OD using a microplate reader. 450 Inhibition rate = (OD value of control group - OD value of experimental group) / OD value of control group × 100%;

[0397] 5) After obtaining the data, GraphPad Prism 9.0.0 is used to fit and obtain the IC. 50 .

[0398] The experimental results show that the compounds in this invention have a strong inhibitory effect on the prostate cancer PC-3 cell line, as detailed in Table 1. Furthermore, Examples 37, 106, and 152 also show strong inhibitory effects on various other cancer cell lines, with the measured IC50 values ​​shown in Table 2. It can be seen that the compounds have a strong inhibitory effect on the proliferation of hepatocellular carcinoma cell lines JHH-7 and HEP3B, colorectal carcinoma cell line HCT116, non-small cell lung cancer cell lines H23 and H2030, cholangiocarcinoma cell line HUCCT1, pancreatic carcinoma cell line PANC04.03, and thyroid carcinoma cell line TPC1.

[0399] Table 1. Inhibitory effects of compounds on the proliferation activity of prostate cancer PC-3 cells.

[0400]

[0401]

[0402] Table 2 shows the IC50 values ​​of compounds inhibiting the proliferation of various cancer cells.

[0403]

[0404] Test Example 2: ADAR1 Deaminase Activity Detection

[0405] The effect of the compound on the binding of ADAR1 to dsRNA in the PC-3 cell line was tested by RESS-qPCR.

[0406] The experimental steps are as follows:

[0407] 1) Generate logarithmic growth phase cells at a rate of 2-4 * 10 5 Cells / wells were seeded into 6-well plates and incubated at 37°C and 5% CO2 for 12-24 hours.

[0408] 2) Add DMSO and different concentrations of the test compound solution to each well of the culture plate, and incubate at 37°C and 5% CO2 for 48 hours.

[0409] 3) After incubation, RNA was extracted and reverse transcribed into cDNA;

[0410] 4) The Ato I editing efficiency of ADAR1 downstream target molecules MDM2 and APOBEC3D was detected using RESS-qPCR. The relative RNA editing level (edit / WT RNA ratio) was 2. -(Ct Edit-Ct WT) ;

[0411] 5) After obtaining the data, use GraphPad Prism 9.0.0 to perform a significance analysis of the difference between the drug-treated group and the DMSO control group.

[0412] Experimental results are as follows Figure 1 and 2 As shown in the figure. The experimental results show that compounds 2, 31 and 40 of the present invention can selectively inhibit the RNA A-to-I editing level of APOBEC3D without affecting MDM2, suggesting that the embodiments may have inhibited part of the ADAR1 editing function.

[0413] Test Example 3: Detection of ADAR1 binding to dsRNA

[0414] This experiment used the BPS Bioscience ADAR1:RNA TR-FRET Assay Kit (cat. 82252) for detection; inhibition rate = 1 - (FRET) S -FRET neg ) / (FRET P -FRET neg )×100%. FRET S FRET value of the compound to be tested. P FRET value for DMSO group, FRET neg The FRET value represents the negative control group.

[0415] The experimental results are shown in Table 3. The results show that Examples 2, 31, 40, and 43 of this invention do not affect the binding of ADAR1 and dsRNA, indicating that Examples 2, 31, 40, and 43 do not competitively bind to the ADAR1 RBDs domain with the dsRNA substrate, thus not affecting its A to I editing function.

[0416] Table 3. Effects of compounds on ADAR1 binding to dsRNA

[0417]

[0418] Test Example 4: Detection of PKR activation in downstream molecules of ADAR1

[0419] PKR was found to competitively bind to dsRNA with ADAR1. Unedited double-stranded RNA resulting from ADAR1 deletion is recognized by PKR as abnormal RNA, thereby inducing PKR activation and leading to a series of downstream stress responses and growth inhibition. The effect of the compound on PKR activation, a downstream molecule of ADAR1, in the PC-3 cell line was tested using Western blotting.

[0420] The experimental steps are as follows:

[0421] 1) Generate logarithmic growth phase cells at a rate of 2-4 * 10 5 Cells / wells were seeded into 6-well plates and incubated at 37°C and 5% CO2 for 12-24 hours.

[0422] 2) Add DMSO and different concentrations of the test compound solution to each well of the culture plate, set up 2 replicates for each well, add 5 nM IFNβ to one replicate well, and incubate at 37℃ and 5% CO2 for 48 hours.

[0423] 3) After incubation, the samples were collected and the expression levels of ADAR1, PKR and p-PKR were detected by Western blotting.

[0424] Experimental results are as follows Figure 3 As shown in the figure. The experimental results show that the combination of IFNβ in Examples 2, 31, 40 and 43 of the present invention did not induce PKR activation, further clarifying that Examples 2, 31, 40 and 43 do not competitively bind to the ADAR1RBDs domain with the dsRNA substrate.

[0425] Test Example 5: Pharmacokinetics of the Compound in Mice

[0426] 1. Experimental animals: Healthy male ICR mice, weighing 18-20g, in groups of 3.

[0427] 2. Experimental drugs: Compound 2 and control compound (Example 1 of Patent CN113549076A) in this invention.

[0428] 3. Drug Preparation: Weigh a certain amount of the drug and prepare the solution using different solvents according to the route of administration. For gavage administration: 0.5% MC; for intravenous administration: 5% DMSO + 5% ethanol.

[0429] +40% PEG300 +50% Saline.

[0430] 4. ICR mice were fasted for 12 hours before administration, but had free access to water. The intravenous dose was 5 mg / kg, and the gavage dose was 10 mg / kg.

[0431] 5. Sampling and Measurement: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 h and 24 h after intravenous administration; 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after gavage administration; 30-40 μL of whole blood was collected from mice via intravenous administration at the above-mentioned time points and placed in EDTA-K2 tubes. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11,000 rpm for 5 min within 30 min to separate the plasma. The plasma was then frozen at -70℃ for analysis.

[0432] 6. Pharmacokinetic Parameters Results The pharmacokinetic parameters of the compounds of this invention and the control compounds are shown in Tables 3 to 5 below.

[0433] Table 3 Pharmacokinetic parameters of Example 2 of the present invention Table 4. Plasma concentrations (ng / mL) of the control compound administered by gavage to mice (n=3, males)

[0434]

[0435]

[0436] BLQ in the table:Below LLOQ (LLOQ=1ng / mL) Table 5. Plasma concentrations (ng / mL) of the control compound administered intravenously to mice (n=3, males)

[0437] Time(h) 4 5 6 Mean SD 0.083 620 78.7 167 289 10.9 0.25 BQL BQL BQL 0.5 BQL BQL BQL 1 BQL BQL BQL 2 BQL BQL BQL 4 BQL BQL BQL 6 BQL BQL BQL 8 BQL BQL BQL 24 BQL BQL BQL

[0438] BLQ in the table:Below LLOQ (LLOQ=1ng / mL) Conclusion: The concentrations of the control compound were too low after administration (po) and (iv) to calculate pharmacokinetic parameters. Therefore, the compound of this invention exhibits significantly superior pharmacokinetic properties to the control compound in mice. All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug, characterized in that, The compound is a compound of formula A or a polymer derived from compound A; in, X is a halogen; R is selected from the following group: hydrogen, C1-C6 alkyl, OR 1 NR 2 R 3 ; R1 is -R 1a -R 1b ;in, R 1a It is either free of single bonds or C1-C3 alkylene groups; R 1b Selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkylamino, unsubstituted or with n1 R 4 The substituted C3-C10 carbocyclic group, unsubstituted or replaced by n1 R groups 4 The substituted 4 to 10-membered heterocyclic groups, unsubstituted or replaced by n1 R groups 4 The substituted C6-C12 aryl group, unsubstituted or replaced by n1 R groups 4 The 5 to 10 heteroaryl groups that are replaced; n1 is 1, 2, 3, 4, 5 or 6; R 2 and R 3 Each is independently selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynoxy, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted C3-C10 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C6-C12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted -C1-C2 alkylene-C3-C10 carbocyclic, optionally substituted -C1-C2 alkylene-4- to 10-membered heterocyclic, optionally substituted -C1-C2 alkylene-C6-C12 aryl, optionally substituted -C1-C2 alkylene-5- to 10-membered heteroaryl; and, as a whole or as part of a group, the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally further construed as being influenced by one or more R groups. 5 Replaced; R 4 and R 5 Each independently as R S Alternatively, groups selected from the group consisting of: -CN, -NO2, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynoxy, optionally substituted halo-C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, R 6 -OR 6 -NH-R 6 -NHC(O)-R 6 -NHS(O)-R 6 and -NHS(O)2-R 6 Or, two R atoms located on the same or adjacent atoms. 4 Or two Rs 5 Together with the attached atoms, they form rings selected from the group consisting of: optionally substituted C3-C10 carbocyclic groups, optionally substituted 4- to 10-membered heterocyclic groups, optionally substituted C6-C12 aryl groups, and optionally substituted 5- to 10-membered heteroaryl groups. R 6 Selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C6-C12 aryl and optionally substituted 5- to 10-membered heteroaryl, optionally substituted -C1-C2 alkylene-C3-C10 carbocyclic, optionally substituted -C1-C2 alkylene-4- to 10-membered heterocyclic, optionally substituted -C1-C2 alkylene-C6-C12 aryl and optionally substituted -C1-C2 alkylene-5- to 10-membered heteroaryl; The term "optionally substituted" means that the group is unsubstituted or that the H in the group is replaced by one or more R groups. S Replaced; Each R S Independently selected from the group consisting of: D, CN, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl, and benzyl; or, two Rs. S (such as two R atoms located on the same or adjacent atoms) S Together they form groups selected from the following group: oxo (=O), C1-C6 alkylene, 2 to 6 heteroalkylene.

2. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug, characterized in that, The compound of formula A is a compound of formula I; Wherein, R is defined as in Equation I.

3. The compound as described in claim 1 or 2, or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug, characterized in that, R is -OR 1b -O-CH2-R 1b or -O-CH(CH3)-R 1b ;and R 1b Selected from the group consisting of: C1-C6 alkyl, C2-C6 ynyl, C3-C10 carbocyclic, unsubstituted or modified by one or more R groups. 4 The substituted C6-C12 aryl group, unsubstituted or substituted with one or more R 4 The 5 to 10 heteroaryl groups that are replaced.

4. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug, characterized in that, The polymer derived from compound A is a polymer as shown in formula B; in, L represents no or a divalent linker; R i 1a and R ii 1a Each independently as R 1a Or none; and R i 1a and R ii 1a At least one of them is not zero; R i 1b and R ii 1b Each is independently derived from R 1b Divalent groups or none; and R i 1b and R ii 1b At least one of them is not zero; X, R 1a and R 1b Defined in compound A of the same formula.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug, characterized in that, The compounds are selected from the following table:

6. A pharmaceutical composition, characterized in that, include (i) the compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, mixture thereof, solvate, crystal form, or prodrug thereof; and (ii) Pharmaceutically acceptable carriers.

7. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer or mixture thereof, solvate, crystal form or prodrug, or the pharmaceutical composition of claim 6 in the preparation of (i) an inhibitor of RNAA-to-I editing of APOBEC3D and / or (ii) a medicament for the treatment or prevention of tumors.

8. The use as described in claim 7, characterized in that, The tumor is selected from the group consisting of: prostate cancer, leukemia, breast cancer, multiple myeloma, lung cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma, or a combination thereof.

9. A method for preparing the compound as described in claim 1, characterized in that, R is -OR 1 The compound is as shown in Formula A1; and the preparation method includes the following steps: (S1) React the intermediate of formula INT2 with N,N-dimethylformamide dimethyl acetal to form the intermediate of formula INT1-3; (S2) Make the intermediate of formula INT3 and IR 1 The reaction yields the intermediate INT4; and (S3) Deprotect the intermediate of formula INT4 to obtain the compound.

10. An intermediate, characterized in that, The intermediate is shown in formula INT3 or INT4; Among them, X and R 1 As defined in equation A.

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