ADAR1 small-molecule inhibitor, pharmaceutical composition and application of ADAR1 small-molecule inhibitor and pharmaceutical composition

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to an ADAR1 small-molecule inhibitor, a pharmaceutical composition and application. The ADAR1 small-molecule inhibitor disclosed by the invention comprises a compound shown as a general formula (I ') or (I), or pharmaceutically acceptable salt, solvate, hydrate, deuterated compound, stereoisomer, tautomer, isotope label, metabolite or prodrug of the compound, and further discloses a pharmaceutical composition comprising the ADAR1 small-molecule inhibitor and medical application of the pharmaceutical composition.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to an ADAR1 small molecule inhibitor, a pharmaceutical composition and uses thereof. Background Art

[0002] RNA editing mediated by ADARs (adenosine to inosine acting on RNA enzymes) is a widespread post-transcriptional modification in mammals, with three different members: ADAR1, ADAR2, and ADAR3. [1-3] . ADAR1 and ADAR2 are expressed in most tissues of the human body and have RAN editing activity, while ADAR3 is only expressed in the brain and has no editing function. ADAR1 is a specific adenosine deaminase that acts on double-stranded RNA (dsRNA) to hydrolyze and deaminate adenosine (A) to inosine (I), referred to as A-to-I editing. ADAR1 has two different subtypes: interferon-induced p150 and constitutively expressed p110. p110 lacks a nuclear export signal (NES) and is localized in the cell nucleus, while p150 has an additional Zα domain compared to p110, which can bind to Z-DNA / Z-RNA and contains NES, so p150 is localized in the cytoplasm.

[0003] ADAR1 editing can effectively neutralize the immunogenicity of endogenous dsRNA and modulate immune responses [1,4] . Endogenous dsRNA that has not been edited by ADAR1 will be recognized by the immune sensor MDA5 (Melanoma differentiation associated gene-5) as "non-self" pathogenic dsRNA, triggering an innate immune response. Therefore, ADAR1 editing of dsRNA plays an important role in preventing abnormal and chronic activation of innate immune responses. ADAR1 activity and expression have been found to be upregulated in a variety of cancers, resulting in excessive editing of dsRNA and causing immune escape. Multiple studies have found that ADAR1 loss makes tumors sensitive to immunotherapy and overcomes resistance to immunotherapy. The experiment used CRISPR genome editing technology to prepare an ADAR1-deficient B16 mouse melanoma model [5], found that compared with the wild-type B16 tumor immune microenvironment, the ADAR1-null group had a significant increase in cytotoxic T cells (CD8+T cells), a significant decrease in myeloid-derived suppressor cells (MDSC) and tumor-associated neutrophils, a change in the balance of chemokines expressed by immune cells, and an increase in IFNβ and IFNγ (intergeron) protein levels. Moreover, ADAR1-null wild-type B16 tumors and ADAR1-null tumor cell lines of three other transplanted tumor models were more sensitive to PD-1 (Programmed cell death protein 1) immunotherapy. In addition, the loss of ADAR1 can eliminate immune resistance caused by B2m gene mutation or loss and restore sensitivity to immunotherapy. Combined with these studies, ADAR1 is confirmed to be a new target for anticancer immunotherapy. Therefore, ADAR1 inhibitors are promising anticancer drug candidates. Summary of the invention

[0004] In view of this, the object of the present invention is to provide an ADAR1 small molecule inhibitor for use in the preparation of anti-cancer immunotherapy drugs.

[0005] In a first aspect, the present invention provides an ADAR1 small molecule inhibitor, comprising: a compound as shown in general formula (I') or general formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, deuterated compound, stereoisomer, tautomer, isotope-labeled compound, metabolite or prodrug thereof:

[0006]

[0007] Among them, m is an integer between 0 and 5.

[0008] w selects 0, 1, 2, or 3;

[0009] R 1 Selected from hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 One of the amine groups,

[0010] R 2 , R 3 , R 4 Each is independently selected from one of hydrogen, halogen, and C1-C5 alkyl,

[0011] R 5 , R 6 , R 7Each is independently selected from hydrogen, halogen, hydroxyl, amino, C1-C6 alkoxy, cyano, nitro, trifluoroalkyl, acyl, ester, carbamoyl, C1-C6 alkyl, C1-C6 heteroalkyl, aryl, heteroaryl, C5-C 10 Aromatic ring, C5-C 10 A heteroaromatic ring,

[0012] Cy1, Cy2, and Cy3 are each independently selected from C3-C 10 One of an aliphatic ring, a heteroaliphatic ring, an aromatic ring, and a heteroaromatic ring, wherein the Cy1 is replaced by one or more of the R 5 The Cy2 is replaced by one or more of the R 6 The Cy3 is replaced by one or more of the R 7 replace.

[0013] It can be understood that in the embodiments of the present invention, m can be 0, 1, 2, 3, 4 or 5; the alkyl group can be a saturated alkyl group, an unsaturated alkyl group, a chain alkyl group and a cyclic alkyl group; the alkoxy group can be a chain or cyclic saturated or unsaturated alkoxy group; the amine group can be a chain or cyclic saturated or unsaturated amine group; the halogen is a halogen atom, including but not limited to fluorine, chlorine, bromine, iodine, etc.; the heteroalkyl group is an alkyl group containing heteroatoms, including but not limited to N, O, P, S, etc.; the aryl group is a group with a conjugated structure, including but not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.; the heteroaryl group is an aryl group containing heteroatoms, including but not limited to N, O, P, S, etc.

[0014] The heteroaliphatic ring, aromatic ring, and heteroaromatic ring can be C2-C9 heteroaliphatic ring, C6-C 10 Aromatic ring, C1-C9 heteroaromatic ring.

[0015] Aryl and heteroaryl can be C6-C 10 Aryl, C1-C9 heteroaryl.

[0016] The present invention provides an ADAR1 small molecule inhibitor, including: a compound as shown in general formula (I'), or a pharmaceutically acceptable salt, solvate, hydrate, deuterated compound, stereoisomer, tautomer, isotope-labeled compound, metabolite or prodrug thereof:

[0017]

[0018] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Cy 1 , Cy 2 , Cy3 , m, and w have the definitions described in the present invention.

[0019] The present invention provides an ADAR1 small molecule inhibitor, comprising: a compound as shown in the general formula (I'-1) or (I'-2), or a pharmaceutically acceptable salt, solvate, hydrate, deuterated product, stereoisomer, tautomer, isotope-labeled product, metabolite or prodrug thereof:

[0020]

[0021] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Cy 1 , Cy 2 , Cy 3 , m, and w have the definitions described in the present invention.

[0022] The present invention provides an ADAR1 small molecule inhibitor, comprising: a compound as shown in general formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, deuterated compound, stereoisomer, tautomer, isotope-labeled compound, metabolite or prodrug thereof:

[0023]

[0024] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Cy 1 , Cy 2 , Cy 3 , m, and w have the definitions described in the present invention.

[0025] In some embodiments, the ADAR1 small molecule inhibitors of the present invention include compounds represented by general formula (II), or pharmaceutically acceptable salts, solvates, hydrates, deuterated compounds, stereoisomers, tautomers, isotope-labeled compounds, metabolites or prodrugs thereof:

[0026]

[0027] Among them, X 1 , X 2 and X 3 Each independently is CH or N;

[0028] x is 0, 1, 2, 3, 4, or 5;

[0029] z is 0, 1, 2, 3, or 4;

[0030] y is 0, 1, 2, 3, 4, or 5;

[0031] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and w have the definitions described in the present invention.

[0032] In some embodiments, the ADAR1 small molecule inhibitors described in the present invention include compounds represented by general formula (II-1) or (II-2), or pharmaceutically acceptable salts, solvates, hydrates, deuterated compounds, stereoisomers, tautomers, isotope-labeled compounds, metabolites or prodrugs thereof:

[0033]

[0034] Among them, X 1 , X 2 , X 3 , x, y, z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and w have the definitions described in the present invention.

[0035] In some embodiments, the ADAR1 small molecule inhibitors of the present invention include compounds represented by general formula (III) or (IV), or pharmaceutically acceptable salts, solvates, hydrates, deuterated compounds, stereoisomers, tautomers, isotope-labeled compounds, metabolites or prodrugs thereof:

[0036]

[0037] Among them, X 1 , X 2 , X 3 , x, y, z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and w have the definitions described in the present invention.

[0038] In some embodiments, the ADAR1 small molecule inhibitors of the present invention include compounds represented by general formula (III-1), (III-2), (IV-1) or (IV-2), or pharmaceutically acceptable salts, solvates, hydrates, deuterated compounds, stereoisomers, tautomers, isotope-labeled compounds, metabolites or prodrugs thereof:

[0039]

[0040] Among them, X 1 , X 2 , X 3 , x, y, z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and w have the definitions described in the present invention.

[0041] In some embodiments, the alkyl group includes one of a saturated alkyl group, an unsaturated alkyl group, a chain alkyl group and a cyclic alkyl group; and / or

[0042] The R 2 , the R 3 , the R 4 Each is independently selected from one of hydrogen, halogen, C1-C3 alkyl; and / or

[0043] The halogen is selected from one of fluorine, chlorine, bromine and iodine.

[0044] In some embodiments, the R 1 One selected from hydroxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methylamino and ethylamino; and / or

[0045] The aliphatic ring, the heteroaliphatic ring, the aromatic ring, and the heteroaromatic ring are each independently selected from a monocyclic ring, a condensed ring, and a spirocyclic ring.

[0046] In some embodiments, the ADAR1 small molecule inhibitor comprises at least one of the following compounds:

[0047]

[0048] Experimental tests have shown that the above ADAR1 small molecule inhibitors provided by the present invention have good ADAR1 inhibitory activity and are expected to be used in the preparation of anti-cancer immunotherapy drugs.

[0049] In a second aspect, the present invention also protects a pharmaceutical composition, comprising: a pharmaceutical ingredient, wherein the pharmaceutical ingredient comprises the above-mentioned ADAR1 small molecule inhibitor.

[0050] In some embodiments, the drug component further includes: a drug molecule that can act synergistically with the ADAR1 small molecule inhibitor, wherein the drug molecule includes at least one of a chemotherapeutic agent, an antibody, and a nucleic acid.

[0051] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0052] In a third aspect, the present invention also protects the use of the aforementioned ADAR1 small molecule inhibitor or the aforementioned pharmaceutical composition in the preparation of drugs for treating ADAR1-related diseases.

[0053] In some embodiments, the ADAR1-related disease comprises a cancer or a tumor selected from at least one of melanoma, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma, and testicular seminoma.

[0054] Herein, if a group is introduced into the center of a ring through a bond, it means that the group can be substituted at a substitutable position on the ring. 5 , R 6 , R 7 and Substitutions can be made at substitutable positions on the ring to which it is attached:

[0055]

[0056] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0057] The term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0058] The terms "optional", "optionally" or "arbitrarily", "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with..." means that the substitution may or may not occur.

[0059] When the term "each independently" is used in combination with "arbitrarily", for example, "each independently arbitrarily replaced by..." means that the specific options are replaced by... or not by... without affecting each other.

[0060] Unless explicitly stated otherwise, the descriptions used in the present invention such as "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense, which may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0061] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, isopropylbenzene or a mixture thereof, etc.

[0062] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0063] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed by compounds and bases, including but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, choline salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts and tromethamine salts.

[0064] The term "isotopically labeled" means that the compounds of the present invention are isotopically labeled. They are identical to those compounds described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl. DETAILED DESCRIPTION

[0065] Those skilled in the art can easily perceive other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the specification of the present application is merely exemplary and not restrictive.

[0066] DNA-Encoded Library (DEL) technology is an emerging small molecule drug screening technology that combines DNA technology with combinatorial chemistry to efficiently construct a compound library with a capacity of billions. DEL has huge advantages in compound library capacity, library construction difficulty, and screening time, shortening the cycle of lead compound discovery in new drug research and development (especially in the discovery of lead compounds for difficult-to-drug targets). The embodiment of the present invention mainly uses DNA-encoded compound library technology to screen and obtain a series of small molecule compounds with ADAR1 inhibitory activity.

[0067] The embodiments of the present invention are represented by compound I1, compound I2, compound I3, compound I4 and compound I5, which specifically show the specific preparation process and ADAR1 inhibitory activity of such ADAR1 small molecule inhibitors. These embodiments are only used to illustrate the present invention, but do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.

[0068]

[0069]

[0070] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0071] 1 H NMR was performed using Bruker AVⅢ400 or Bruker AVⅢ500.

[0072] LCMS was performed using Agilent 1200HPLC / 6100SQ under the following conditions:

[0073] Mobile phase: A: water (10 mM NH4HCO3); B: acetonitrile (CAN);

[0074] Elution gradient: 5% increase to 95% B in 1.4 min, 95% B for 1.6 min;

[0075] Flow rate: 1.8ml / min;

[0076] Chromatographic column: XBridge C18 4.6*50mm, 3.5um;

[0077] Column temperature: 45°C;

[0078] Detection wavelength: UV (214nm);

[0079] MS (ESI, pos mode, 110 to 1000 amu).

[0080] Example 1

[0081] In this example, compound I1 was synthesized, and its Chinese chemical name is: methyl (S)-2-(5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propanoate. The specific synthesis process is as follows:

[0082] Step 1, synthesis of methyl 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate:

[0083]

[0084] In a 100mL round-bottom flask, 5-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (1.50g, 8.00mmol, 1.00eq), K2CO3 (2.67g, 19.35mmol, 2.42eq), TBAI (9.33g, 25.27mmol, 3.16eq) and THF (40.0mL) were added, and 4-chlorobenzyl bromide (2.42g, 11.75mmol, 1.47eq) was added dropwise under stirring at room temperature, and then stirred at room temperature for 12h. After the reaction was completed, the reaction solution was diluted with water, the aqueous phase was extracted with EtOAc, the organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc (v / v) = 1: 1) to obtain 1.80g of the product as a white solid with a yield of 72%. LCMS (ESI + ):m / z=312(M+H + ).

[0085] Step 2, synthesis of 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid:

[0086]

[0087] In a 100 mL round-bottom flask, methyl 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.80 g, 5.77 mmol, 1.00 eq), THF (15.0 mL), H2O (15.0 mL) and MeOH (15.0 mL) were added, and then LiOH (450 mg, 18.79 mmol, 3.26 eq) was added and stirred at room temperature for 2 h. After the reaction was completed, 3 M dilute hydrochloric acid was used to adjust the mixture to neutrality, and the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE: EtOAc (v / v) = 1: 1) to obtain 1.15 g of the product as a light yellow solid with a yield of 64%. LCMS (ESI + ):m / z=298(M+H + ).

[0088] Step 3, synthesis of methyl (S)-2-((tert-butyloxycarbonyl)amino)-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propionate:

[0089]

[0090] Under nitrogen protection, in a 100 mL round-bottom flask, (S)-3-(2-bromophenyl)-2-((tert-butyloxycarbonyl)amino)propionic acid methyl ester (600 mg, 1.67 mmol, 1 eq), (6-chloro-4-methylpyridin-3-yl)boric acid (1.20 g, 7.00 mmol, 4.18 eq), K2CO3 (702 mg, 5.08 mmol, 3.03 eq), Pd(dppf)Cl2 (240 mg, 328 μmol, 0.2 eq), dioxane (30.0 mL) and H2O (6.0 mL) were added, and the mixture was heated to 90°C and stirred for 12 h. After the reaction was completed, the mixture was filtered and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC (Phenomenex luna C18 150×25mm×10um; mobile phase: [water(FA)-ACN]; B%: 18%-48%, 8min) to obtain 580 mg of the product as a yellow solid with a yield of 85%. LCMS (ESI + ):m / z=405(M+H + ).

[0091] Step 4, synthesis of methyl (S)-2-amino-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propionate:

[0092]

[0093] Methyl (S)-2-((tert-butyloxycarbonyl)amino)-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propanoate (580 mg, 1.43 mmol, 1 eq) was dissolved in CH2Cl2 (10.0 mL), cooled in an ice-water bath, and HCl / dioxane (4.00 M, 35 mL) was added. The mixture was allowed to react at room temperature for 2 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain 600 mg of the hydrochloride salt of the product as a yellow solid, which was directly used in the next step. LCMS (ESI + ):m / z=305(M+H + ).

[0094] Step 5, synthesis of methyl (S)-2-(5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propanoate:

[0095]

[0096] In a 25 mL round-bottom flask, 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (489 mg, 1.64 mmol, 1 eq), DMF (10.0 mL), DIEA (930 mg, 7.20 mmol, 1.25 mL, 4.39 eq) and methyl (S)-2-amino-3-(2-(6-chloro-4-methylpyridin-3-yl)phenyl)propanoate hydrochloride (500 mg, 1.64 mmol, 1 eq) were added, and HATU (750.00 mg, 1.97 mmol, 1.2 eq) was added after stirring to dissolve, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was directly separated and purified by preparative HPLC (Welch Xtimate C18 150×25mm×5um, mobile phase: [water(NH3H2O)-ACN]; B%: 35%-65%, 15min) to obtain 58 mg of the product as a yellow solid with a yield of 6%. LCMS (ESI + ):m / z=584(M+H + ). 1 HNMR(400MHz,CD3OD)δ8.30-8.24(m,1H),8.22-8.17(m,1H),8.11-7.98(m,1H),7.46-7.27(m,8H),7.15-7 .07(m,1H),5.31-5.17(m,2H),4.77-4.53(m,1H),3.72-3.60(m,3H),3.16-2.78(m,2H),2.14-1.99(m,3H).

[0097] Example 2

[0098] In this example, compound I2 was synthesized, and its Chinese chemical name is: (S)-5-chloro-1-(4-chlorobenzyl)-N-(1-(methylamino)-1-oxo-3-(2-(6-phenylpyridin-3-yl)phenyl)propan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide. The specific synthesis process is as follows:

[0099] Step 1, synthesis of tert-butyl (S)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropane-2-yl)carbamate:

[0100]

[0101] Under nitrogen protection, in a 50 mL round-bottom flask, (S)-3-(2-bromophenyl)-2-((tert-butyloxycarbonyl)amino)propionic acid (1.20 g, 3.49 mmol, 1.00 eq), DMF (12.0 mL), DIEA (2.25 g, 17.4 mmol, 3.04 mL, 5.00 eq) and methylamine hydrochloride (706 mg, 10.4 mmol, 3.00 eq) were added, and HATU (2.65 g, 6.97 mmol, 2.00 eq) was added after stirring to dissolve, and the mixture was reacted at room temperature for 1.5 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc (v / v) = 1: 1) to obtain 1.1 g of the product as a white solid with a yield of 88%. LCMS (ESI + ): m / z = 357, 359 (M+H + ).

[0102] Step 2, synthesis of tert-butyl (S)-(1-(methylamino)-1-oxo-3-(2-(6-phenylpyridin-3-yl)phenyl)propane-2-yl)carbamate:

[0103]

[0104] Under nitrogen protection, in a 100 mL round-bottom flask, tert-butyl (S)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (1.1 g, 3.09 mmol, 1 eq), (6-phenylpyridin-3-yl)boric acid (727 mg, 3.65 mmol, 1.18 eq), K2CO3 (1.07 g, 7.74 mmol, 2.5 eq), Pd(dppf)Cl2 (449 mg, 0.62 mmol, 0.2 eq), dioxane (25.0 mL) and H2O (5.0 mL) were added, and the reaction was heated to 100°C and stirred for 2 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with EtOAc. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The residue was separated by silica gel column chromatography (PE: EtOAc (v / v) = 1: 1) to obtain 1.1 g of the product as a white solid with a yield of 84%. LCMS (ESI + ):m / z=432(M+H + ).

[0105] Step 3, synthesis of (S)-2-amino-N-methyl-3-(2-(6-phenylpyridin-3-yl)phenyl)propionamide:

[0106]

[0107] Tert-butyl (S)-(1-(methylamino)-1-oxo-3-(2-(6-phenylpyridin-3-yl)phenyl)propan-2-yl)carbamate (1.1 g, 2.55 mmol, 1 eq) was dissolved in EtOAc (10.0 mL), cooled in an ice-water bath, and HCl / EtOAc (2.00 M, 20 mL) was added. The mixture was allowed to react at room temperature for 17 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain 860 mg of the hydrochloride salt of the product as a pink solid, which was used directly in the next step. LCMS (ESI + ):m / z=332(M+H + ).

[0108] Step 4, synthesis of (S)-5-chloro-1-(4-chlorobenzyl)-N-(1-(methylamino)-1-oxo-3-(2-(6-phenylpyridin-3-yl)phenyl)propane-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide:

[0109]

[0110] In a 50 mL round-bottom flask, 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (295 mg, 0.99 mmol, 1.1 eq), DMF (20.0 mL), DIEA (384 mg, 2.97 mmol, 3.3 eq) and (S)-2-amino-N-methyl-3-(2-(6-phenylpyridin-3-yl)phenyl)propanamide hydrochloride (328 mg, 0.89 mmol, 1 eq) were added, and HATU (489 mg, 1.29 mmol, 1.5 eq) was added after stirring to dissolve, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, the reaction solution was directly separated and purified by preparative HPLC (Welch Xtimate C18 150×25mm×5um, mobile phase: [water(NH3H2O)-ACN]; B%: 35%-65%, 15min) to obtain 100 mg of the product as a white solid with a yield of 18%. LCMS (ESI + ):m / z=611(M+H + ). 1H NMR(400MHz, DMSO-d6)δ9.69(d,J=7.9Hz,1H),8.55-8.48(m,2H),8.12-8.06(m, 2H),8.05-7.98(m,2H),7.87(d,J=8.1Hz,1H),7.75(dd,J=8.2,2.4Hz,1H),7.56 -7.48(m,2H),7.48-7.38(m,5H),7.36-7.27(m,3H),7.23-7.16(m,1H),5.15(s, 2H),4.68-4.58(m,1H),3.25-3.15(m,1H),3.00-2.90(m,1H),2.52-2.51(m,3H).

[0111] Example 3

[0112] In this example, compound I3 was synthesized, and its Chinese chemical name is: (R)-5-chloro-1-(4-chlorobenzyl)-N-(4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide. The specific synthesis process is as follows:

[0113] Step 1, synthesis of tert-butyl (R)-(1-(4-bromophenyl)-4-(methylamino)-4-oxobutan-2-yl)carbamate:

[0114]

[0115] In a 500 ml round-bottom flask, (R)-4-(4-bromophenyl)-3-((tert-butyloxycarbonyl)amino)butyric acid (2.0 g, 5.58 mmol), HATU (3.18 g, 8.38 mmol) and DIEA (2.88 g, 22.3 mmol) were added. After stirring at room temperature for 0.5 hours in DMF (20 mL) solvent, CH3NH2.HCl (456 mg, 6.68 mmol) was added. The reaction was stirred at room temperature for 3 hours. After adding water (40 mL), a solid was precipitated, which was filtered and washed with water. The solid was dried in vacuo to obtain tert-butyl (R)-(1-(4-bromophenyl)-4-(methylamino)-4-oxobutan-2-yl)carbamate (1.32 g, 63.9%) as a white solid.

[0116] Step 2, synthesis of tert-butyl (R)-(4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butyl-2-yl)carbamate:

[0117]

[0118] Tert-butyl (R)-(1-(4-bromophenyl)-4-(methylamino)-4-oxobutan-2-yl)carbamate (1.8 g, 4.86 mmol), (2,3,6-trifluorophenyl)boric acid (1.71 g, 9.72 mmol), Cs2CO3 (4.75 g, 14.58 mmol) and RuPhos-Pd-G4 (1.65 g, 1.944 mmol) were added to a 250 ml reactor, and 1,4-dioxane / H2O (v / v=4:1) (50 mL) was added. The reaction solution was heated to 100° C. and stirred overnight. After the reaction was completed, the mixture was cooled and filtered to remove undissolved material. EA (100 mL) was added to extract and the organic layer was washed with water and brine, and then the organic phase was dried over Na2SO4. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=1:1) to give tert-butyl (R)-(4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butan-2-yl)carbamate (510 mg, 24.9%) as a white solid.

[0119] Step 3, synthesis of (R)-3-amino-N-methyl-4-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butanamide:

[0120]

[0121] To a 50 ml round bottom flask, add (R)-tert-butyl (4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butyl-2-yl)carbamate (510 mg, 1.21 mmol) and dissolve in 1,4-dioxane (2 mL), and add HCl / 1,4-dioxane (10 mL). The reaction system was stirred at room temperature for 2 hours. The mixture was dried under vacuum to obtain (R)-3-amino-N-methyl-4-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butanamide (433 mg, 100%) as a colorless oil, which was directly used in the next step.

[0122] Step 4, synthesis of (R)-5-chloro-1-(4-chlorobenzyl)-N-(4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide:

[0123]

[0124] DMF (10 mL), (R)-3-amino-N-methyl-4-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butanamide (433 mg, 1.21 mmol), 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (359 mg, 1.21 mmol), EDCI (465 mg, 2.42 mmol), HOBt (622 mg, 2.42 mol) and DIEA (780 mg, 6.05 mmol) were added to a 50 ml reaction bottle, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated and purified by Pre-HPLC (XtimatePrep C1810um 21.2*250mm 150A, phase A: water (10mmNH4HCO3), phase B: acetonitrile, 55-85% in 8 minutes, stop at 16 minutes, 30mL / min, retention time: 11.5 minutes) to obtain a white solid (R)-5-chloro-1-(4-chlorobenzyl)-N-(4-(methylamino)-4-oxo-1-(2',3',6'-trifluoro-[1,1'-biphenyl]-4-yl)butan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (135mg, 18%). LCMS (ESI + ): m / z = 603.44 (M + H + ). 1 H NMR (400MHz, DMSO-d6): δ9.72(d,J=8.0Hz,1H)8.57(d,J=4.0Hz,1H),8.22(d,J=4Hz,1H),7.87(m,1H),7.53(m,1H), 7.41-7.22(m,9H),5.23-5.14(m,2H),4.53-4.48(m,1H),2.96-2.86(m,2H),2.54(d,J=8Hz,3H),2.34(d,J=8Hz,2H).

[0125] Example 4

[0126] This example synthesizes compound I4, whose Chinese chemical name is: (R)-5-chloro-2'-(2-(5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(methylamino)-3-oxopropyl)-[1,1'-biphenyl]-3-carboxylic acid methyl ester. The specific synthesis process is as follows:

[0127] Step 1: Synthesis of tert-butyl (R)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate

[0128]

[0129] To a 50 ml round-bottom flask were added (R)-3-(2-bromophenyl)-2-(tert-butoxycarbonyl)amino)propionic acid (3.0 g, 8.72 mmol), HATU (4.97 g, 13.1 mmol), DIEA (4.5 g, 34.9 mmol) and DMF (20 mL) in sequence. The reaction was stirred at room temperature for 0.5 hours. Then CH3NH2.HCl (711 mg, 10.4 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (40 mL) was added to quench the reaction. A solid precipitated out, and the solid was separated by filtration and washed with water. After the solid was dried in vacuo, tert-butyl (R)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (1.32 g, 42.6%) was obtained as a white solid.

[0130] Step 2, synthesis of (R)-2'-(2-(tert-butyloxycarbonyl)amino)-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylic acid methyl ester:

[0131]

[0132] To a 50 ml round bottom flask was added tert-butyl (R)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (1.32 g, 3.71 mmol), (3-chloro-5-(methoxycarbonyl)phenyl)boric acid (952 mg, 4.45 mmol), K2CO3 (1.02 g, 7.42 mmol), Pd(dppf)Cl2 (271 g, 0.371 mmol) and 1,4-dioxane / H2O (v / v=5:1) (24 mL). The reaction was heated to 100°C and stirred overnight. After the reaction was completed, the mixture was cooled and filtered to remove undissolved material. EA (100 mL) was added for extraction and the organic layer was washed with water and brine, and then dried over Na2SO4. The organic phase was collected, concentrated and purified by silica gel column chromatography (PE:EA=2:3) to give (R)-methyl 2'-(2-(tert-butoxycarbonyl)amino)-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylate (400 mg, 24%) as a white solid.

[0133] Step 3, synthesis of (R)-2'-(2-amino-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylic acid methyl ester hydrochloride:

[0134]

[0135] To a 25 ml round bottom flask, add (R)-2'-(2-(tert-butyloxycarbonyl)amino)-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylic acid methyl ester (399 mg, 0.89 mmol) and 1,4-dioxane (2 mL). Add HCl / 1,4-dioxane (10 mL) during stirring and stir at room temperature for 2 hours. After the reaction is completed, spin dry directly to obtain (R)-2'-(2-amino-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylic acid methyl ester hydrochloride (343 mg, 100%) in the form of a colorless oily HCl salt.

[0136] Step 4, synthesis of (R)-5-chloro-2'-(2-(5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(methylamino)-3-oxopropyl)-[1,1'-biphenyl]-3-carboxylic acid methyl ester:

[0137]

[0138] DMF (10 mL), (R)-2'-(2-amino-3-(methylamino)-3-oxopropyl)-5-chloro-[1,1'-biphenyl]-3-carboxylic acid methyl ester hydrochloride (343 mg, 0.89 mmol) and 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (264 mg, 0.89 mmol), HATU (509 mg, 1.34 mmol) and DIEA (574 mg, 4.45 mmol) were added to a 25 ml round-bottom flask at room temperature and stirred for 3 hours. The mixture was concentrated and purified by Pre-HPLC to give (R)-5-chloro-2'-(2-(5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(methylamino)-3-oxopropyl)-[1,1'-biphenyl]-3-carboxylic acid methyl ester (111 mg, 20%) as a white solid. LCMS (ESI + ): m / z = 627.92 (M + H + ). 1HNMR (400MHz, DMSO-d6): 1H NMR (400MHz, DMSO-d6) δ9.61(d,J=8.0Hz,1H),8.57(d,J=8.0Hz,1H),8.04-8.01(m,2H),7. 82(t,J=8.0,1.5Hz,1H),7.68(t,J=2Hz,1H),7.58(t,J=2.0Hz,1H),7.44–7.37(m,4H),7.3 2–7.26(m,3H),7.13(dt,J=6.4,1.6Hz,1H),5.24–4.08(m,2H),4.54(q,J=4.0Hz,1H),3.84 (s, 3H), 3.16 (dd, J = 12.0, 4.0 Hz, 1H), 2.92 ( dd, J = 12.0, 4.0 Hz, 1H), 3.51 ( d, J = 4.0 Hz, 3H).

[0139] Example 5

[0140] In this example, compound I5 was synthesized, and its Chinese chemical name is: (S)-5-chloro-1-(4-chlorobenzyl)-N-(3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide. The specific synthesis process is as follows:

[0141] Step 1, synthesis of tert-butyl (S)-(3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1-(methylamino)-1-oxopropan-2-yl)carbamate:

[0142]

[0143] A 50 ml round-bottom flask was added with solvent dioxane / H2O (10 mL / 2 mL), followed by tert-butyl (S)-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (700 mg, 2 mmol), (4-methoxy-2-(trifluoromethyl)phenyl)boric acid (433 mg, 2 mmol), Pd(dppf)Cl2 (220 mg, 0.3 mmol) and K2CO3 (820 mg, 6 mmol). The reaction was stirred at 90°C for 3 hours. After the reaction was completed, water was added to quench and EA (100 mL) was added for extraction. After washing with water (30 mL*3), the product was purified by silica gel column (EA in PE: 20%) to obtain a yellow solid product (400 mg, 44%).

[0144] Step 2, synthesis of (S)-2-amino-3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-N-methylpropionamide:

[0145]

[0146] To a 25 ml round-bottom flask was added tert-butyl (S)-(3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1-(methylamino)-1-oxopropyl-2-yl)carbamate (400 mg, 1 mmol) and DCM (6 mL), and HCl was added during stirring. The reaction system was stirred at room temperature for 1 hour. When LCMS showed that the reaction was complete. It was concentrated to remove the solvent. The crude product (300 mg, yellow oil) was used directly in the next step without purification, with a yield of 96%.

[0147] Step 3, synthesis of (S)-5-chloro-1-(4-chlorobenzyl)-N-(3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0148]

[0149] Add 10 ml of DMF to a 25 ml round-bottom flask. Then add (S)-2-amino-3-(4'-methoxy-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-N-methylpropionamide (300 mg, 0.85 mmol), 5-chloro-1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (253 mg, 0.85 mmol), EDCI (253 mg, 1.3 mmol), HOBT (176 mg, 1.3 mmol) and DIPEA (256 mg, 2 mmol). The reaction system was stirred at room temperature for 16 hours. After quenching the reaction with water, EA was added for extraction, and water and brine (30 ml) were added for washing. The collected organic phase was spin-dried and concentrated and purified by preparative high performance liquid chromatography. A white solid product (80 mg, 15%) was obtained. LCMS (ESI + ):m / z=633.46(M+H +). 1H NMR(400MHz,DMSO-d6)1H NMR(500MHz,Methanol-d4)δ8.25–8.16(m,2H),7.41-7.34(m,5H),7.27-7.19(m,4H),7.16-7.01(m,2H),5.19(m,2H),4.57 -4.51(m,1H),3.77(d,J=12.0Hz,3H),3.15-3.05(m,1H),2.93-2.88(m,0.5H),2.76-2.71(m,0.5H),2.62(d,J=8.0Hz,3H).

[0150] Example 6

[0151] This embodiment uses surface plasmon resonance (SPR) to detect the interaction between ADAR1 and compounds. Specifically, the Cytiva Biacore 8K system is used for analysis, the S series CM7 chip, and the amino coupling program is used to fix the ligand protein ADAR1, with a fixed amount of 10,000 RU. The running buffer starts with 100uM of the compound to be analyzed and dilutes it downward by 2 times to obtain 7 concentration gradients, with 2 zero concentrations set at intervals for multi-cycle kinetic detection. The test results are shown in Table 1. The example compounds I1, I2, I3, I4, and I5 of the present invention have good binding to the ADAR1 protein, indicating that the compounds provided in the embodiments of the present invention have good ADAR1 inhibitory activity. Among them, 0μmol <A≤30μmol,30μmol<B≤100μmol,100μmol<C。

[0152] Table 1 ADAR1 inhibitory activity of compounds

[0153]

[0154]

[0155] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

[0156] References:

[0157] 1.Rajendra Karki, Thirumala-Devi Kanneganti, Trends Immunol, 2023, 44(3), 201-216.

[0158] 2.Alan Herbert,Trends Cancer,2019,5(5),272-282.

[0159] 3.Rohini Datta,Julia Z Adamska,Amruta Bhate,Jin Billy Lee,WileyInterdiscip Rev RNA.2023,17:e1817.

[0160] 4.Rajendra Karki,Balamurugan Sundaram,Bhesh Raj Sharma,SangJoon Lee,RK Subbarao Malireddi,Lam Nhat Nguyen,Shelby Christgen,Min Zheng,Yaqiu Wang,Parimal Samir,Geoffrey Neale,Peter Vogel,Thirumala-Devi Kanneganti Cell Rep.,2021,;37(3):109858.

[0161] 5.Jeffrey J Ishizuka,Robert T Manguso,Collins K Cheruiyot,Kevin Bee,Arpit Panda,Arvin Iracheta-Vellve,Brian C Miller,Peter P Du,Kathleen B Yates,Juan Dubrot,Ilana Buchumenski,Dawn E Comstock,Flavian D Brown,Austin Ahn,Ian Wyern,Hans Pope,Margaret DZimmer,Debattama R Sen,Sarah K Lane-Reticker,Emily J Robitschek,Gabriel K Griffin,Natalie B Collins,Adrienne H Long,John GDoench,David Kozono,Erez Y Levanon,WNicholas Haining,Nature,2019,563–48.

Claims

1. An ADAR1 small molecule inhibitor, comprising: A compound represented by general formula (I') or general formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, deuterated compound, stereoisomer, tautomer, isotope-labeled compound, metabolite or prodrug thereof: Among them, m is an integer between 0 and 5. w selects 0, 1, 2, or 3; R 1 Selected from hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 One of the amine groups, R 2 , R 3 , R 4 Each is independently selected from one of hydrogen, halogen, and C1-C5 alkyl, R 5 , R 6 , R 7 Each is independently selected from hydrogen, halogen, hydroxyl, amino, C1-C6 alkoxy, cyano, nitro, trifluoroalkyl, acyl, ester, carbamoyl, C1-C6 alkyl, C1-C6 heteroalkyl, aryl, heteroaryl, C5-C 10 Aromatic ring, C5-C 10 A heteroaromatic ring, Cy1, Cy2, and Cy3 are each independently selected from C3-C 10 One of an aliphatic ring, a heteroaliphatic ring, an aromatic ring, and a heteroaromatic ring, wherein the Cy1 is replaced by one or more of the R 5 The Cy2 is replaced by one or more of the R 6 The Cy3 is replaced by one or more of the R 7 replace.

2. The ADAR1 small molecule inhibitor according to claim 1, characterized in that Including compounds represented by general formula (II), or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, isotope-labeled substances, metabolites or prodrugs thereof: Among them, X 1 , X 2 and X 3 Each independently is CH or N; x is 0, 1, 2, 3, 4, or 5; z is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, 4, or 5.

3. The ADAR1 small molecule inhibitor according to claim 1 or 2, characterized in that The alkyl group includes one of a saturated alkyl group, an unsaturated alkyl group, a chain alkyl group and a cyclic alkyl group; and / or The R 2 , the R 3 , the R 4 Each is independently selected from one of hydrogen, halogen, C1-C3 alkyl; and / or The halogen is selected from one of fluorine, chlorine, bromine and iodine.

4. The ADAR1 small molecule inhibitor according to claim 1 or 2, characterized in that The R 1 One selected from hydroxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methylamino and ethylamino; and / or The aliphatic ring, the heteroaliphatic ring, the aromatic ring, and the heteroaromatic ring are each independently selected from a monocyclic ring, a condensed ring, and a spirocyclic ring.

5. The ADAR1 small molecule inhibitor according to any one of claims 1 to 4, characterized in that The ADAR1 small molecule inhibitor comprises at least one of the following compounds:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a pharmaceutical component, wherein the pharmaceutical component comprises the ADAR1 small molecule inhibitor according to any one of claims 1-5.

7. The pharmaceutical composition according to claim 6, characterized in that The drug component also includes: a drug molecule that can act synergistically with the ADAR1 small molecule inhibitor, and the drug molecule includes at least one of a chemotherapeutic agent, an antibody, and a nucleic acid.

8. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition also includes pharmaceutically acceptable excipients.

9. Use of the ADAR1 small molecule inhibitor according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 6 to 8 in the preparation of a drug for treating ADAR1-related diseases.

10. The use according to claim 9, characterized in that: The ADAR1-related disease includes cancer or tumor, and the cancer or tumor is selected from at least one of melanoma, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer, adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, epidermal basal cell carcinoma, and testicular seminoma.

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