Heterocyclic compound and application thereof in medicine

Abstract

The invention relates to a heterocyclic compound and application thereof in medicine, in particular to a heterocyclic compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a deuterated substance, a pharmaceutically acceptable salt or a co-crystal thereof, and a pharmaceutical composition containing the heterocyclic compound or the stereoisomer, the solvate, the prodrug, the metabolite, the deuterated substance, the pharmaceutically acceptable salt or the co-crystal thereof. The invention also discloses application of the heterocyclic compound or the pharmaceutical composition in preparation of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a heterocyclic compound or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, a pharmaceutical composition thereof and its application in medicine. Background Art

[0002] DNA damage can be caused by a variety of factors, which can be divided into endogenous and exogenous factors. Endogenous damage includes replication fork arrest, reactive oxygen species, etc., while exogenous damage includes ultraviolet rays, ionizing radiation, chemicals, etc. DNA damage will further induce DNA damage response (DDR) in cells to counteract the effects of damage, avoid the occurrence of damage-induced diseases such as cancer, and maintain genome integrity. DDR involves multiple mechanisms and pathways, including the activation of various checkpoint pathways, such as G1, S, G2, and M checkpoints, which regulate specific DNA repair mechanisms at different stages of the cell cycle. The CCNE1 gene encodes cyclin El protein, which forms a complex with cyclin-dependent kinase 2 (CDK2) to regulate the G1-S phase transition of cells. Gene amplification of CCNE1 and / or abnormal expression of cyclin El have been observed in many tumors. CCNE1 gene amplification and / or high expression of cyclin El force cancer cells to enter the S phase prematurely, causing cell replication stress.

[0003] The WEE kinase family is an important kinase family involved in cell cycle regulation, and its members include WEE1 (WEE1A and WEE1B) and PKMYT1. The two differ in biological function and cellular localization. WEE1 is located in the nucleus and mainly participates in phosphorylation of the Tyr15 residue of cyclin-dependent kinase 1 (CDK1) and CDK2, regulating the activity of CDK1 and CDK2. PKMYT1 is membrane-associated and mainly located in the endoplasmic reticulum. Its main function is to participate in phosphorylation of Thr14 and Tyr15 of CDK1, regulate the activity of CDK1, and thus regulate the cell G2-M checkpoint and affect the progression of the cell cycle. For DNA repair, many cancer cells are completely dependent on the G2 checkpoint due to defects in the G1 checkpoint mechanism caused by p53 mutations. Therefore, inhibiting PKMYT1 and intervening in the G2 checkpoint have a good inhibitory effect on various tumors, especially tumors with cell cycle disorders and DDR caused by gene mutations such as CCNE1 amplification. PKMYT1 inhibitors are expected to become new strategies and approaches for DDR therapy. Summary of the invention

[0004] The purpose of the present invention is to provide a heterocyclic compound capable of inhibiting the overexpression of PKMYT1, a pharmaceutical composition thereof and an application thereof in preparing an anti-tumor drug.

[0005] One or more embodiments of the present invention provide a compound represented by formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

[0006]

[0007] in:

[0008] A is selected from a 5- to 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O or S;

[0009] B is selected from a benzene ring or a naphthalene ring;

[0010] C is selected from a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring; preferably, when C is a carbocyclic ring, it is a monocyclic ring;

[0011] R1 may be the same or different and are each independently selected from -C(=O)NH2 or -NH2;

[0012] R2 may be the same or different and are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or 3 to 8 membered heterocyclic ring; or any two R1 and the connected carbon atom form a 3 to 8 membered heterocyclic ring; the 3 to 8 membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;

[0013] R3 may be the same or different and are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl;

[0014] L1 is selected from -NH-, -O- or -C(=O)-;

[0015] L2 is absent or selected from -NH-, -O-, -C(=O)- or

[0016] p is selected from 0, 1 or 2;

[0017] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0018] k is selected from 0, 1, 2 or 3;

[0019] t is selected from 1, 2, 3 or 4.

[0020] One or more embodiments of the present invention provide a compound represented by formula (I-1) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

[0021]

[0022] in:

[0023] R 1-1 are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or 3 to 8 membered heterocyclic ring; or any two R1 and the connected carbon atom form a 3 to 8 membered heterocyclic ring; the 3 to 8 membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;

[0024] n is selected from 0, 1, 2 or 3.

[0025] One or more embodiments of the present invention provide a compound represented by formula (I-2) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

[0026]

[0027] in:

[0028] R 2-1 Selected from

[0029] R 2-2 Not present or selected from -NH-, -O- or y is a natural number selected from 1 to 4;

[0030] D is selected from a 6-10 membered carbocyclic ring or a 6-10 membered heterocyclic ring;

[0031] R 2-3 may be the same or different and are selected from H, halogen, C 1-3 Alkyl, m is a natural number selected from 1-6.

[0032] In one or more embodiments of the present invention, the compound represented by formula (I-2) of the present invention, wherein,

[0033] When D is a 6-10 membered carbon ring, D is a monocyclic ring, preferably, D is a benzene ring;

[0034] When D is a 6-10 membered heterocyclic ring, D is a monocyclic ring or a bicyclic ring.

[0035] In one or more embodiments of the present invention, the compound represented by formula (I-2) of the present invention, wherein,

[0036] R 2-1 Selected from

[0037] In one or more embodiments of the present invention, the compound of the present invention is selected from the following structures:

[0038]

[0039]

[0040] One or more embodiments of the present invention provide a pharmaceutical composition, comprising:

[0041] (1) a compound of the present invention or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof;

[0042] (2) optionally one or more other active ingredients; and

[0043] (3) Pharmaceutically acceptable carriers and / or excipients.

[0044] One or more embodiments of the present invention provide the use of the pharmaceutical composition of the present invention or the compound or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal in the preparation of anti-tumor drugs.

[0045] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0046] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0047] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0048] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0049] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5-8 membered heteroaryl, and the 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. The "heteroaryl" or "heteroaromatic ring" may be further substituted with one or more substituents.

[0050] "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl" above; when it is a non-aromatic ring, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclic group" or "carbocycle" is optionally further substituted by one or more substituents.

[0051] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thiidine, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiazole, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyrazinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" may be further substituted with one or more substituents.

[0052] When the above-mentioned "alkyl", "alkoxy", "heteroaryl", "heteroaromatic ring", "carbocyclic group", "carbocyclic ring", "heterocyclic group" or "heterocyclic ring" is substituted, it can be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, and wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 , R q3 Select from H or C 1-6 Alkyl; wherein R q4 , R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , where the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0053] Halogens include F, Cl, Br and I.

[0054] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0055] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0056] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0057] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0058] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0059] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0060] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0061] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group. DETAILED DESCRIPTION

[0062] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0063] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

[0064] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0065] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0066] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0067] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0068] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biomedicine Research and Development.

[0069] Intermediate 1

[0070] (E)-4-Cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxylic acid (Intermediate 1)

[0071] (E)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylp henyl)-1H-imidazole-2-carboxylic acid

[0072]

[0073] first step:

[0074] (E)-N'-(4-cyano-1H-imidazol-5-yl)-N,N-dimethylformamide (1-C)

[0075] (E)-N'-(4-cyano-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0076] To a 1L reaction bottle, weighed 1-A (15 g, 138.8 mmol, 1.0 eq) and 1-B (24.8 g, 208.1 mmol, 1.5 eq) were added, and 200 mL of toluene was added for suspension. Subsequently, the reaction was reacted at 60 ° C for 16 h. After the reaction was complete, the reaction solution was concentrated, and then slurried with 50 mL of petroleum ether: ethyl acetate (1:1), stirred for 30 min, filtered and the filter cake was collected. The filter cake was washed with 100 mL of toluene to obtain the product 1-C as a brown solid (11 g, yield 49%).

[0077] LC-MS m / z(ESI)=164.2[M+1].

[0078] Step 2:

[0079] (E)-N'-(4-cyano-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (1-E)

[0080] (E)-N'-(4-cyano-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazol-5-yl)-N,N-dim ethylformimidamide

[0081] Weigh 1-C (3 g, 18.4 mmol, 1.0 eq), 1-D (3.3 g, 18.4 mmol, 1.0 eq), anhydrous copper acetate (5.5 g, 27.6 mmol, 1.5 eq), N,N,N',N'-tetramethylethylenediamine (4.3 g, 36.8 mmol, 2.0 eq) in a 250 ml reaction bottle. Dissolve the mixture in 50 mL of tetrahydrofuran, replace oxygen, and react in an oil bath at 80 ° C and stir for 5 days. Cool the reaction solution to room temperature and filter. Dilute the filtrate with 150 mL of water, extract with ethyl acetate (150 mL × 3), combine the organic phases, and concentrate to obtain a residue. The mixture is purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain the product 1-E as a light yellow solid (1.3 g, yield 24%).

[0082] LC-MS m / z(ESI)=298.16[M+1].

[0083] Step 3:

[0084] (E)-N'-(2-Bromo-4-cyano-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (1-F)

[0085] (E)-N'-(2-bromo-4-cyano-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0086] Weigh 1-E (600 mg, 2.0 mmol, 1.0 eq) in a 100 mL reaction bottle and dissolve it in 10 mL N,N-dimethylformamide. Slowly add N-bromosuccinimide (538.7 mg, 3.0 mmol, 1.5 eq) to the mixture under ice bath, and stir the reaction at room temperature for 3 h. When the reaction is complete, quench the reaction with saturated sodium sulfite aqueous solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, and concentrate to obtain crude 1-F as a yellow solid (530 mg).

[0087] LC-MS m / z(ESI)=376.07[M+1].

[0088] Step 4:

[0089] Phenyl (E)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxylate (1-H)

[0090] Phenyl(E)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-di methylphenyl)-1H-imidazole-2-carboxylate

[0091] Weigh the crude product 1-F (520 mg, 1.4 mmol, 1.0 eq), 1-G (2.5 g, 20.7 mmol, 15.0 eq), palladium acetate (62.1 mg, 0.3 mmol, 0.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (159.9 mg, 0.3 mmol, 0.2 eq) in a 100 mL reaction bottle, and then add 10 mL of anhydrous acetonitrile to suspend. After the addition, the reaction was stirred at 100 ° C for 16 h. The reaction solution was added to 50 mL of water, extracted with ethyl acetate (50 mL × 3), separated, and concentrated. Purification on a silica gel column (petroleum ether: ethyl acetate = 1:1.5) gave the product 1-H as a yellow solid (500 mg, yield 87%).

[0092] LC-MS m / z(ESI)=418.17[M+1].

[0093] Step 5:

[0094] (E)-4-Cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxylic acid (Intermediate 1)

[0095] (E)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylp henyl)-1H-imidazole-2-carboxylic acid

[0096] 1-H (530 mg, 1.3 mmol, 1.0 eq) and sodium hydroxide (203.1 mg, 5.1 mmol, 4.0 eq) were weighed into a 100 mL reaction bottle. The reaction mixture was dissolved with 5 mL of methanol and 5 mL of water, and then stirred at room temperature for 2 h. 1N HCl solution was used to adjust the pH of the reaction solution to 5, and the precipitated solid was observed. The filter cake was collected by filtration and dried to obtain the intermediate 1 as a white solid (380 mg, yield 88%).

[0097] LC-MS m / z(ESI)=342.1[M+1].

[0098] Intermediate 2

[0099] (E)-4-Cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxylic acid (Intermediate 2)

[0100] (E)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylp henyl)-1H-imidazole-2-carboxylic acid

[0101]

[0102]

[0103] first step:

[0104] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (2-B)

[0105] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0106] 1-C (1.7 g, 10.42 mmol, 1.0 eq), 2-A (3.09 g, 10.42 mmol, 1.0 eq), anhydrous copper acetate (3.12 g, 15.63 mmol, 1.5 eq), N,N,N',N'-tetramethylethylenediamine (2.42 g, 20.84 mmol, 2.0 eq) were weighed separately in a 250 ml reaction bottle. The mixture was dissolved in 30 mL of tetrahydrofuran. After fully replacing oxygen three times, the reaction was stirred at 80 ° C for 5 days. After the reaction was complete, the reaction solution was naturally cooled to room temperature, filtered and the filtrate was collected. The filtrate was combined, added to 120 mL of water, extracted three times with ethyl acetate (120 mL), separated, and the organic phase was concentrated. Purification on a silica gel column (petroleum ether: ethyl acetate = 1:1) gave the product 2-B as a light yellow solid (1.7 g, yield 39.45%).

[0107] LC-MS m / z(ESI)=414.22[M+1].

[0108] Step 2:

[0109] (E)-N'-(2-bromo-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (2-C)

[0110] (E)-N'-(2-bromo-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0111] Weigh 2-B (1.70 mg, 4.11 mmol, 1.0 eq) in a 100 mL reaction bottle and dissolve it in 20 mL N, N-dimethylformamide. Cool the reaction system in an ice bath, then slowly add N-bromosuccinimide (1.10 mg, 6.17 mmol, 1.5 eq) to the mixed system. After the addition, remove the ice bath and stir at room temperature for 3 h. When the reaction is complete, dilute the reaction with 70 mL of ethyl acetate, quench with saturated sodium sulfite aqueous solution, and separate the liquids. Combine the organic phases and concentrate to obtain the crude product 2-C as a yellow solid (1.7 g, yield 83.98%).

[0112] LC-MS m / z(ESI)=492.14[M+1].

[0113] Step 3:

[0114] Phenyl (E)-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-((((dimethylamino)methylene)amino)-1H-imidazole-2-carboxylate (2-E)

[0115] pheny(E)-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)pheny l)-5-(((dimethylamino)methylene)amino)-1H-imidazole-2-carboxylate

[0116] Weigh 2-C (1.7 g, 3.45 mmol, 1.0 eq), 2-D (6.32 g, 51.78 mmol, 15.0 eq), triethylamine (1.05 g, 10.36 mmol, 3 eq), palladium acetate (154.99 mg, 0.69 mmol, 0.2 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (399.47 mg, 0.69 mmol, 0.2 eq) in a 100 mL reaction bottle, then add 30 mL of anhydrous acetonitrile to the system to fully replace nitrogen. Stir the reaction at 100 ° C for 16 h. After the reaction is complete, cool the reaction solution to room temperature naturally, add the reaction solution to 120 mL of water, extract with ethyl acetate (120 mL × 3), separate the liquids, and concentrate. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:1.5) to give the product 2-E as a yellow solid (1.4 g, yield 75.9%).

[0117] LC-MS m / z(ESI)=534.25[M+1].

[0118] Step 4:

[0119] (E)-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-(((dimethylamino)methylene)amino)-1H-imidazole-2-carboxylic acid (Intermediate 2)

[0120] (E)-4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-(((dimethylamino)methylene)amino)-1H-imidazole-2-carboxylic acid

[0121] Weigh 2-E (1.40 g, 2.62 mmol, 1.0 eq) and sodium hydroxide (419.67 mg, 10.49 mmol, 4.0 eq) in a 100 mL reaction flask, and then add 30 mL (methanol: water: tetrahydrofuran = 1:1:1) mixed solvent to dissolve. Stir the reaction at room temperature for 2 h. When the reaction is complete, add the reaction solution to 50 mL of water, adjust the pH to 5 with 1 M HCl solution, observe the precipitated solid, and collect the filter cake by filtration to obtain intermediate 2 as a white solid (1.2 g, yield 99.7%).

[0122] LC-MS m / z(ESI)=458.21[M+1].

[0123] Example 1

[0124] 4-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-phenoxynicotinamide (Compound 1)

[0125] 4-amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-phenoxynicotinamide

[0126]

[0127] first step:

[0128] 4-Amino-5-bromo-6-chloronicotinic acid ethyl ester (1b)

[0129] ethyl 4-amino-5-bromo-6-chloronicotinate

[0130] 1a (3.0 g, 15.0 mmol, 1.0 eq) and N,N-dimethylformamide (50 mL) were weighed and suspended in a 250 mL reaction bottle. N-bromosuccinimide (1.25 g, 22.4 mmol, 1.5 eq) was slowly added to the system under an ice bath; then, the reaction was allowed to react at room temperature for 16 h. After the reaction was complete, the reaction solution was slowly added to 100 mL of ice water, stirred for 15 min, filtered and the filter cake was collected, and the filter cake was washed with 100 mL of toluene to obtain 1b as a white solid (3.7 g, yield 88%).

[0131] LC-MS m / z(ESI)=278.9[M+1].

[0132] Step 2:

[0133] 4-Amino-5-bromo-6-phenoxynicotinate ethyl ester (1d)

[0134] ethyl 4-amino-5-bromo-6-phenoxynicotinate

[0135] Weigh 1b (3.5 g, 12.5 mmol, 1.0 eq), phenol (1.2 g, 12.5 mmol, 1.0 eq), potassium carbonate (2.6 g, 18.8 mmol, 1.5 eq) in a 250 mL reaction bottle, and then add N-methylpyrrolidone (50 mL) to the system. After the addition, the reaction was refluxed and stirred at 140 ° C for 3 h. After the reaction was complete, the reaction solution was naturally cooled to room temperature, and then poured into 100 mL of ice water, stirred for 15 min, filtered and collected the filter cake, and the filter cake was dried with 100 mL of toluene to obtain 1d as a white solid (3.1 g, yield 73%).

[0136] LC-MS m / z(ESI)=337.01[M+1].

[0137] Step 3:

[0138] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinate ethyl ester (1f)

[0139] ethyl 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinate

[0140] 1d (1.5 g, 4.5 mmol, 1.0 eq), 1e (1.6 g, 8.9 mmol, 1.2 eq), sodium tert-butoxide (1.3 g, 13.4 mmol, 3 eq), palladium acetate (99.9 mg, 0.5 mmol, 0.1 eq), tri-tert-butylphosphine tetrafluoroborate (129.1 mg, 0.5 mmol, 0.1 eq) were weighed into a 100 mL three-necked flask, and 30 mL of tert-butanol was added to the system. After the addition, the reaction was stirred under reflux at 80 ° C for 4 h under nitrogen protection. After the reaction was complete, the reaction solution was naturally cooled to room temperature, the reaction solution was added to 100 mL of water, extracted with ethyl acetate (100 mL × 3), separated, the organic phase was concentrated, and purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain 1f as a brown solid (500 mg, yield 29%).

[0141] LC-MS m / z(ESI)=393.46[M+1].

[0142] Step 4:

[0143] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinic acid (1g)

[0144] 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinic acid

[0145] Weigh 1f (370 mg, 0.9 mmol, 1.0 eq) and sodium hydroxide (150.8 mg, 3.8 mmol, 4.0 eq) separately in a 100 mL reaction bottle, and then add 10 mL of tetrahydrofuran and 10 mL of water to the system. After the addition, stir the reaction at 80 ° C for 48 h. After the reaction is complete, cool the reaction solution to room temperature naturally, add the reaction solution to 20 mL of water, adjust the pH to 5 with 1N HCl, filter and collect the filter cake, and use 20 mL of toluene to dry the filter cake to obtain 1g as a white solid (300 mg, yield 87%).

[0146] LC-MS m / z(ESI)=365.40[M+1].

[0147] Step 5:

[0148] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinamide (1h)

[0149] 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-phenoxynicotinamide

[0150] Weigh 1g (300mg, 0.8mmol, 1.0eq), ammonium chloride (220.2mg, 4.1mmol, 5.0eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (344.4mg, 0.9mmol, 1.1eq), N,N-diisopropylethylamine (266.0mg, 2.1mmol, 2.5eq) in a 100mL three-necked flask, and then add N,N-dimethylformamide (10mL) to the system. After the addition, stir the reaction at room temperature for 4h. After the reaction is complete, add the reaction solution into 50mL of water, extract with ethyl acetate (50mL×3), separate the liquids, concentrate the organic phase, and purify it on a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain 1h as a brown-yellow oil (250mg, yield 83%).

[0151] LC-MS m / z(ESI)=364.4[M+1].

[0152] Step 6:

[0153] 4-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-phenoxynicotinamide (Compound 1)

[0154] 4-amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-phenoxynicotinamide

[0155] Weigh 1h (250 mg, 0.7 mmol, 1.0 eq) and 10 mL of dichloromethane in a 100 mL reaction bottle, and then add boron tribromide (1M) in dichloromethane (2.1 mL, 2.1 mmol, 3.0 eq) to the system. After the addition, stir the reaction at room temperature for 8 h. After the reaction is complete, cool the reaction solution to room temperature naturally, add 20 mL of methanol to the reaction solution under an ice bath to quench, concentrate, and purify by reverse column (water: acetonitrile = 40:60) to obtain the product compound 1 as a white solid (110 mg, yield 45%).

[0156] LC-MS m / z(ESI)=350.3[M+1].

[0157] 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.27(s,1H),7.34–7.30(m,2H),7.16–7.09 (m,1H),6.97(d,1H),6.94–6.89(m,2H),6.75(d,1H),1.95(s,3H),1.88(s,3H).

[0158] Example 2

[0159] 4-Amino-6-(2,3-dimethylphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 2)

[0160] 4-amino-6-(2,3-dimethylphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide

[0161]

[0162]

[0163] first step:

[0164] 4-Amino-5-bromo-6-(2,3-dimethylphenoxy)nicotinate ethyl ester (2b)

[0165] ethyl 4-amino-5-bromo-6-(2,3-dimethylphenoxy)nicotinate

[0166] Weigh 1b (2 g, 7.2 mmol, 1.0 eq), 2a (866 mg, 7.2 mmol, 1.0 eq) and potassium carbonate (1.5 g, 10.7 mmol, 1.5 eq) in a 250 mL reaction bottle, add 50 mL of N-methylpyrrolidone to suspend. After the addition, the reaction was refluxed and stirred at 140 ° C for 3 h. After the reaction was complete, the reaction solution was naturally cooled to room temperature, poured into 100 mL of ice water, stirred for 15 min, filtered and collected the filter cake to obtain the product 2b as a white solid (1.5 g, yield 58%).

[0167] LC-MS m / z(ESI)=365.01[M+1].

[0168] Step 2:

[0169] 4-Amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinate ethyl ester (2c)

[0170] ethyl 4-amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinate

[0171] 2b (500 mg, 1.37 mmol, 1.0 eq), 1e (369.7 mg, 2.05 mmol, 1.5 eq), sodium tert-butoxide (328.9 mg, 3.42 mmol, 2.5 eq), palladium acetate (30.7 mg, 0.14 mmol, 0.1 eq) and tri-tert-butylphosphine tetrafluoroborate (39.7 mg, 0.14 mmol, 0.1 eq) were weighed and dissolved in a 100 mL three-necked flask, and 10 mL of tert-butanol was added. After the addition, the reaction was carried out at 80 ° C. and nitrogen was protected for 4 h. After the reaction was complete, the reaction solution was naturally cooled to room temperature, the reaction solution was added to 100 mL of water, extracted with ethyl acetate (100 mL×3), the organic phases were combined, and purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain 2c as a brown-yellow solid (250 mg, yield 43%).

[0172] LC-MS m / z(ESI)=421.2[M+1].

[0173] Step 3:

[0174] 4-Amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid (2d)

[0175] 4-amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid

[0176] Weigh 2c (250 mg, 0.68 mmol, 1.0 eq) and sodium hydroxide (109.5 mg, 2.7 mmol, 4.0 eq) in a 100 ml reaction bottle, add 5 mL of tetrahydrofuran to dissolve the mixture. After the addition, stir the reaction at 80 ° C for 48 h. After the reaction is complete, naturally cool the reaction solution to room temperature, add the reaction solution to 20 mL of water, adjust the pH value to 5 with 1N HCl, filter and collect the filter cake to obtain the product 2d as a white solid (100 mg, yield 37%).

[0177] LC-MS m / z(ESI)=393.1[M+1].

[0178] Step 4:

[0179] 4-Amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide (2e)

[0180] 4-amino-6-(2,3-dimethylphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)

[0181] Nicotinamide

[0182] Weigh compound 2d (100 mg, 0.3 mmol, 1.0 eq), ammonium chloride (54.5 mg, 1.0 mmol, 4.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106.6 mg, 0.3 mmol, 1.1 eq) in a 100 mL three-necked flask, add 3 mL of N,N-dimethylformamide to dissolve the mixture, and slowly drop N,N-diisopropylethylamine (82.3 mg, 0.6 mmol, 2.5 eq) into the system. After the addition, the reaction was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was added to 20 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 2e as a brown-yellow oil (30 mg, yield 31%).

[0183] LC-MS m / z(ESI)=392.19[M+1].

[0184] Step 5:

[0185] 4-Amino-6-(2,3-dimethylphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 2)

[0186] 4-amino-6-(2,3-dimethylphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)

[0187] Nicotinamide

[0188] Weigh compound 2e (30 mg, 0.1 mmol, 1.0 eq) in a 100 mL reaction bottle, add 2 mL of dichloromethane to dissolve. Add a dichloromethane solution of boron tribromide (1 M) (0.3 mL, 0.3 mmol, 4.0 eq) under ice bath. After addition, stir the reaction at room temperature for 8 h. After the reaction is complete, naturally cool the reaction solution to room temperature, slowly add 10 mL of methanol to the reaction solution under ice bath, concentrate, and purify by reverse column (water: acetonitrile = 30:70) to obtain the product compound 2 as a white solid (3 mg, yield 10%).

[0189] LC-MS m / z(ESI)=378.17[M+1].

[0190] 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.19(s,1H),7.88(s,1H),7.29(s,1H),7.06–6.93 (m,4H),6.76(d,1H),6.66(d,1H),2.21(s,3H),1.98(s,3H),1.90(s,3H),1.88(s,3H).

[0191] Example 3

[0192] 4-Amino-6-(3,4-dichlorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 3)

[0193] 4-amino-6-(3,4-dichlorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)

[0194] Nicotinamide

[0195]

[0196] first step

[0197] 4-Amino-5-bromo-6-(3,4-dichlorophenoxy)nicotinate ethyl ester (3b)

[0198] ethyl 4-amino-5-bromo-6-(3,4-dichlorophenoxy)nicotinate

[0199] 1b (1.8 g, 6.43 mmol, 1.0 eq) was weighed into a 100 mL three-necked flask, dissolved with 18 mL of N-methylpyrrolidone, and compound 3a (1.05 g, 6.43 mmol, 1.0 eq) and potassium carbonate (1.33 g, 9.64 mmol, 1.5 eq) were added, and the temperature was raised to 140°C for reaction for 2 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, 50 mL of water was added, and extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain compound 3b as a yellow solid (1.8 g, yield 70%).

[0200] LC-MS m / z(ESI)=404.92[M+1].

[0201] Step 2

[0202] 4-Amino-6-(3,4-dichlorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid (3c)

[0203] 4-amino-6-(3,4-dichlorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinate

[0204] Compound 3b (500 mg, 1.2 mmol, 1.0 eq), compound 1e (267 mg, 1.5 mmol, 1.2 eq), palladium acetate (28 mg, 0.1 mmol, 0.1 eq), tri-tert-butylphosphine tetrafluoroborate (536 mg, 0.1 mmol, 0.1 eq) and sodium tert-butoxide (356 mg, 3.7 mmol, 3.0 eq) were weighed into a 100 mL three-necked flask, 5 mL of tert-butanol was added to dissolve, nitrogen was replaced three times, and the reaction solution was heated to 80 ° C for 4 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by reverse column (water: acetonitrile = 45:55) to obtain compound 3c as a white solid (260 mg, yield 37%).

[0205] LC-MS m / z(ESI)=433.06[M+1].

[0206] Step 3

[0207] 4-Amino-6-(3,4-dichlorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide (3d)

[0208] 4-amino-6-(3,4-dichlorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide

[0209] Compound 3c (260 mg, 0.5 mmol, 1.0 eq) was weighed into a 100 mL three-necked flask, dissolved with 4 mL of N,N-dimethylformamide, and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (342 mg, 0.9 mmol, 2.0 eq) and N,N-diisopropylethylamine (145 mg, 1.1 mmol, 2.5 eq) were added to the reaction solution, stirred at room temperature for 10 min, and then ammonium chloride (49 mg, 0.9 mmol, 2.0 eq) was added to the reaction solution, and the reaction was continued at room temperature for 2 h. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 3d as a white solid (50 mg, yield 26%).

[0210] LC-MS m / z(ESI)=432.06[M+1].

[0211] Step 4

[0212] 4-Amino-6-(3,4-dichlorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 3)

[0213] 4-amino-6-(3,4-dichlorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide

[0214] Compound 3d (50 mg, 0.1 mmol, 1.0 eq) was weighed into a 50 mL three-necked flask and dissolved with 2 mL of dichloromethane. Boron tribromide (1 M) dichloromethane solution (0.5 mL, 0.5 mmol, 4.0 eq) was added dropwise to the reaction solution under an ice bath, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, methanol was added dropwise under an ice bath to quench the reaction. The reaction solution was concentrated and purified by a reverse column (water: acetonitrile = 40:60) to obtain compound 3 as a white solid (21 mg, yield 44%).

[0215] LC-MS m / z(ESI)=418.06[M+1].

[0216] 1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.31(s,1H),7.95(s,1H),7.58(d,1H),7.37(s,1H), 7.26(d,1H),7.01–6.96(m,1H),6.96–6.91(m,1H),6.75(d,1H),1.93(s,3H),1.86(s,3H).

[0217] Example 4

[0218] 4-Amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 4)

[0219] 4-amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide

[0220]

[0221] first step

[0222] 4-Amino-5-bromo-6-(4-cyano-2-methoxyphenoxy)nicotinate ethyl ester (4b)

[0223] ethyl 4-amino-5-bromo-6-(4-cyano-2-methoxyphenoxy)nicotinate

[0224] 1b (2.0 g, 7.2 mmol, 1.0 eq) was weighed into a 100 mL three-necked flask, dissolved with 20 mL of N-methylpyrrolidone, and then compound 4a (1.1 g, 7.2 mmol, 1.0 eq) and potassium carbonate (1.5 g, 10.8 mmol, 1.5 eq) were added to the reaction solution, and the reaction solution was heated to 140 ° C for 5 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, 50 mL of water was added, and extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated salt, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate = 10: 1) to obtain compound 4b as a yellow solid (1.9 g, yield 64%).

[0225] LC-MS m / z(ESI)=392.02[M+1].

[0226] Step 2

[0227] 4-Amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinate (4c)

[0228] 4-amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinate

[0229] Compound 4b (300 mg, 0.8 mmol, 1.0 eq), compound 1e (272 mg, 0.9 mmol, 1.2 eq), palladium acetate (17 mg, 0.1 mmol, 0.1 eq), tri-tert-butylphosphine tetrafluoroborate (22 mg, 0.1 mmol, 0.1 eq) and sodium tert-butoxide (220 mg, 2.3 mmol, 3.0 eq) were weighed in a 100 mL three-necked flask, 3 mL of tert-butanol was added to dissolve, nitrogen was replaced three times, and the reaction solution was heated to 80 ° C for 4 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (20 mL×3), the organic phases were combined, anhydrous sodium sulfate was added, concentrated, and purified by reverse column (water: acetonitrile = 50:50) to obtain compound 4c as a white solid (70 mg, yield 16%).

[0230] LC-MS m / z(ESI)=448.18[M+1].

[0231] Step 3

[0232] 4-Amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid (4d)

[0233] 4-amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nico tinic acid

[0234] Compound 4c (70 mg, 0.2 mmol, 1.0 eq) was weighed into a 50 mL reaction bottle, 2.5 mL of ethanol and 1 mL of water were added to dissolve, and lithium hydroxide (15 mg, 0.6 mmol, 4.0 eq) was added to the reaction solution, and the reaction solution was heated to 50 ° C for 2 h. After the reaction was completed, the reaction solution was naturally cooled to room temperature, and pH was adjusted to 3 with 1N hydrochloric acid, and then extracted with 10 mL of ethyl acetate, the organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase (water: acetonitrile = 35:65) to obtain compound 4d as a white solid (53 mg, yield 81%).

[0235] LC-MS m / z(ESI)=420.15[M+1].

[0236] Step 4

[0237] 4-Amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide (4e)

[0238] 4-amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide

[0239] Compound 4d (53 mg, 0.1 mmol, 1.0 eq) was weighed into a 50 mL three-necked flask, dissolved with 2 mL of N, N-dimethylformamide, and then N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (96 mg, 0.3 mmol, 2.0 eq) and N, N-diisopropylethylamine (41 mg, 0.3 mmol, 2.5 eq) were added to the reaction solution, stirred at room temperature for 10 min, and then ammonium chloride (14 mg, 0.3 mmol, 2.0 eq) was added to the reaction solution, and the reaction was continued at room temperature for 2 h. After the reaction was completed, 15 mL of water was added, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate = 2:3) to obtain compound 4e as a white solid (28 mg, yield 53%).

[0240] LC-MS m / z(ESI)=419.16[M+1].

[0241] Step 5

[0242] 5-Amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 4)

[0243] 4-amino-6-(4-cyano-2-methoxyphenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide

[0244] Compound 4e (28 mg, 0.067 mmol, 1.0 eq) was weighed into a 50 mL three-necked flask and dissolved with 2 mL of dichloromethane. Then, a dichloromethane solution of boron tribromide (1 M) (0.3 mL, 0.3 mmol, 4.0 eq) was added dropwise to the reaction solution under an ice bath, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction was quenched with methanol, the reaction solution was concentrated, and the reaction solution was purified by reverse phase column (water: acetonitrile = 40:60) to obtain compound 4 as a white solid (5 mg, yield 18%).

[0245] LC-MS m / z(ESI)=405.15[M+1].

[0246] 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.28(d,1H),7.15(d,1H),7.10(d,1H),7.07(d,1H),6. 78(d,1H),6.16(s,2H),5.63(s,2H),4.70(s,1H),3.74(s,3H),2.10(s,3H),2.07(s,3H).

[0247] Example 5

[0248] 4-Amino-6-(3-chloro-4-fluorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 5)

[0249] 4-amino-6-(3-chloro-4-fluorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)

[0250] Nicotinamide

[0251]

[0252] first step:

[0253] 4-Amino-5-bromo-6-(3-chloro-4-fluorophenoxy)nicotinate ethyl ester (5b)

[0254] ethyl 4-amino-5-bromo-6-(3-chloro-4-fluorophenoxy)nicotinate

[0255] Weigh 1b (2 g, 7.2 mmol, 1.0 eq), compound 5a (1.1 g, 7.2 mmol, 1.0 eq) and potassium carbonate (1.5 g, 10.8 mmol, 1.5 eq) in a 100 ml reaction bottle, add 50 ml N-methylpyrrolidone to suspend. After addition, reflux and stir at 140 ° C for 3 h. After the reaction is complete, cool the reaction solution to room temperature naturally, pour it into 100 ml ice water, stir for 15 min, filter and collect the filter cake to obtain product 5b as a white solid (2.5 g, yield 92%).

[0256] LC-MS m / z(ESI)=378.96[M+1].

[0257] Step 2:

[0258] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinate ethyl ester (5c)

[0259] ethyl 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)-nic otinate

[0260] Compound 5b (1.5 g, 4.0 mmol, 1.0 eq), 1e (855 mg, 4.8 mmol, 1.2 eq), sodium tert-butoxide (1.1 g, 11.9 mmol, 3 eq), palladium acetate (90.4 mg, 0.4 mmol, 0.1 eq) and tri-tert-butylphosphine tetrafluoroborate (11.6 mg, 0.4 mmol, 0.1 eq) were weighed into a 100 mL three-necked flask, and 30 mL of tert-butanol was added to dissolve. After the addition, the reaction was stirred at 80 ° C. and refluxed under nitrogen for 4 h. After the reaction was complete, the reaction solution was naturally cooled to room temperature, the reaction solution was added to 100 mL of water, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain compound 5c as a brown solid (200 mg, yield 11%).

[0261] LC-MS m / z(ESI)=444.13[M+1].

[0262] Step 3:

[0263] 4-Amino-6-(3-chloro-4-fluorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid (5d)

[0264] 4-amino-6-(3-chloro-4-fluorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinic acid

[0265] Weigh compound 5c (100 mg, 0.22 mmol, 1.0 eq) and sodium hydroxide (35.2 mg, 0.9 mmol, 4.0 eq) in a 100 ml reaction bottle, add 10 ml tetrahydrofuran and 10 ml water to dissolve. After the addition, stir the reaction at 80 ° C for 48 h. After the reaction is complete, naturally cool the reaction solution to room temperature, add the reaction solution to 20 ml water, adjust pH ≈ 5 with 1 N HCl, filter and collect the filter cake to obtain compound 5d as a white solid (81 mg, yield 88%).

[0266] LC-MS m / z(ESI)=416.09[M+1].

[0267] Step 4:

[0268] 4-Amino-6-(3-chloro-4-fluorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide (5e)

[0269] 4-amino-6-(3-chloro-4-fluorophenoxy)-5-(3-methoxy-2,6-dimethylphenyl)nicotinamide

[0270] Compound 5d (81 mg, 0.2 mmol, 1.0 eq), ammonium chloride (50.8 mg, 1.0 mmol, 5.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.4 mg, 0.2 mmol, 1.1 eq) were weighed in a 100 ml three-necked flask, 10 mL of N,N-dimethylformamide was added to dissolve, and N,N-diisopropylethylamine (61.3 mg, 2.1 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was added to 50 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 5e as a brown-yellow oil (75 mg, yield 95%).

[0271] LC-MS m / z(ESI)=415.11[M+1].

[0272] Step 5:

[0273] 4-Amino-6-(3-chloro-4-fluorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)nicotinamide (Compound 5)

[0274] 4-amino-6-(3-chloro-4-fluorophenoxy)-5-(3-hydroxy-2,6-dimethylphenyl)-nicoti namide

[0275] Weigh compound 5e (75 mg, 0.2 mmol, 1.0 eq) in a 100 mL reaction bottle, add 10 mL of dichloromethane solvent, and slowly drop boron tribromide (1M) dichloromethane solution (0.5 mL, 0.5 mmol, 3.0 eq) into the system. After the addition, stir the reaction at room temperature for 8 h. After the reaction is complete, cool the reaction solution to room temperature naturally. Under an ice bath, slowly add 20 mL of methanol to the reaction solution, concentrate, and purify by reverse column (water: acetonitrile = 30:70) to obtain compound 5 as a white solid (63 mg, yield 87%).

[0276] LC-MS m / z(ESI)=401.09[M+1].

[0277] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.29(s,1H),7.92(s,1H),7.39-7.35(m,2 H),7.227.19(m,1H),6.98-6.93(m,2H),6.76(d,1H),1.94(s,3H),1.87(s,3H).

[0278] Example 6

[0279] 4-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinamide (Compound 6)

[0280] 4-amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinami de

[0281]

[0282]

[0283] first step:

[0284] 4-Amino-5-bromo-6-(4-morpholinophenoxy)nicotinate ethyl ester (6b)

[0285] ethyl 4-amino-5-bromo-6-(4-morpholinophenoxy)nicotinate

[0286] Weigh 1b (2 g, 7.2 mmol, 1.0 eq), compound 6a (1.3 g, 7.2 mmol, 1.0 eq), potassium carbonate (1.5 g, 10.8 mmol, 1.5 eq) in a 100 mL reaction bottle, add 50 mL of N-methylpyrrolidone to suspend. After the addition, reflux and stir at 140 ° C for 3 h. After the reaction is complete, cool the reaction solution to room temperature naturally, pour the reaction solution into 100 mL of ice water, stir for 15 min, filter and collect the filter cake to obtain product 6b as a white solid (2.1 g, yield 69%).

[0287] LC-MS m / z(ESI)=421.06[M+1].

[0288] Step 2:

[0289] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinate ethyl ester (6c)

[0290] 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)-nicotinate

[0291] Weigh compound 6b (1.5 g, 3.1 mmol, 1.0 eq), 1e (676 mg, 3.8 mmol, 1.2 eq), sodium tert-butoxide (898 mg, 9.4 mmol, 3 eq), palladium acetate (67.2 mg, 0.3 mmol, 0.1 eq) and tri-tert-butylphosphine tetrafluoroborate (87 mg, 0.3 mmol, 0.1 eq) in a 100 mL three-necked flask, and add 30 mL of tert-butanol to dissolve. After the addition, react at 80 ° C, reflux and stir under nitrogen for 4 h. After the reaction is complete, cool the reaction solution to room temperature naturally, add the reaction solution to 100 mL of water, extract with ethyl acetate (100 mL × 3), combine the organic phases, and purify on a silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain compound 6c as a brown solid (100 mg, yield 7%).

[0292] LC-MS m / z(ESI)=477.23[M+1].

[0293] Step 3:

[0294] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinic acid (6d)

[0295] 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinic acid

[0296] Weigh compound 6c (100 mg, 0.2 mmol, 1.0 eq) and sodium hydroxide (33.6 mg, 0.8 mmol, 4.0 eq) in a 100 mL reaction bottle, add 10 mL of tetrahydrofuran and 10 mL of water to dissolve. After the addition, stir the reaction at 80 ° C for 48 h. After the reaction is complete, cool the reaction solution to room temperature naturally, add the reaction solution to 20 mL of water, adjust the pH to 5 with 1N HCl, filter and collect the filter cake to obtain compound 6d as a white solid (87 mg, yield 92%).

[0297] LC-MS m / z(ESI)=449.20[M+1].

[0298] Step 4:

[0299] 4-Amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinamide (6e)

[0300] 4-amino-5-(3-methoxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinamide

[0301] Compound 6d (87 mg, 0.2 mmol, 1.0 eq), ammonium chloride (50.8 mg, 1.0 mmol, 5.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.4 mg, 0.2 mmol, 1.1 eq) were weighed in a 100 mL three-necked flask, 10 mL of N,N-dimethylformamide was added to dissolve, and N,N-diisopropylethylamine (61.3 mg, 2.1 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was added to 50 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 6e as a brown-yellow oil (62 mg, yield 72%).

[0302] LC-MS m / z(ESI)=448.12[M+1].

[0303] Step 5:

[0304] 4-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)nicotinamide (Compound 6)

[0305] 4-amino-5-(3-hydroxy-2,6-dimethylphenyl)-6-(4-morpholinophenoxy)-nicotina mide

[0306] Weigh compound 6e (62 mg, 0.1 mmol, 1.0 eq) in a 100 mL reaction bottle, add 10 mL of dichloromethane to dissolve, and then add a dichloromethane solution of boron tribromide (1 M) (0.4 mL, 0.4 mmol, 3.0 eq) to the system. After the addition, stir the reaction at room temperature for 8 h. After the reaction is complete, slowly add 20 mL of methanol to the reaction solution under an ice bath, concentrate, and purify with a reverse column (acetonitrile: water = 40:60) to obtain the product compound 6 as a white solid (42 mg, yield 74%).

[0307] LC-MS m / z(ESI)=434.2[M+1].

[0308] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.24(s,1H),7.27(s,2H),7.14(s,1H),7.01(s,1H),6.9 7(d,1H),6.89(d,2H),6.81–6.76(m,3H),3.72(s,4H),3.04(s,4H),1.94(s,3H),1.87(s,3H).

[0309] Example 7

[0310] 5-amino-N2-(4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 7)

[0311] 5-amino-N2-(4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide

[0312]

[0313] first step:

[0314] (E)-4-Cyano-5-(((dimethylamino)methylene)amino)-N-(4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (7b)

[0315] (E)-4-cyano-5-(((dimethylamino)methylene)amino)-N-(4-fluorophenyl)-1-(3-met hoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide

[0316] Intermediate 1 (100 mg, 0.3 mmol, 1.0 eq), 7a (39.1 mg, 0.4 mmol, 1.2 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122.5 mg, 0.3 mmol, 1.1 eq), N,N-diisopropylethylamine (94.7 mg, 0.7 mmol, 2.5 eq) were weighed and placed in a 100 mL reaction bottle, and then 3 mL of N,N-dimethylformamide was added to the system. After the addition, the reaction was stirred at room temperature for 3 h. 20 mL of the reaction solution was added to quench the reaction, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel plate (PE:EA=1:1) to obtain the product 7b as a white solid (60 mg, yield 47%).

[0317] LC-MS m / z(ESI)=425.19[M+1].

[0318] Step 2:

[0319] 5-Amino-4-cyano-N-(4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (7c)

[0320] 5-amino-4-cyano-N-(4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imi dazole-2-carboxamide

[0321] Weigh 7b (60 mg, 0.1 mmol, 1.0 eq) into a 50 mL reaction bottle, and then add 1 mL of tetrahydrofuran and 1 mL of 2N hydrochloric acid solution to the system. After the addition, stir the reaction at 65 ° C for 16 h. After the reaction is complete, cool naturally to room temperature, concentrate and freeze-dry to obtain the product 7c as a white solid (35 mg, yield 67%).

[0322] LC-MS m / z(ESI)=380.14[M+1].

[0323] Step 3:

[0324] 5-Amino-N2-(4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (7d)

[0325] 5-amino-N2-(4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide

[0326] 7c (30 mg, 0.1 mmol, 1.0 eq), potassium carbonate (43.7 mg, 0.3 mmol, 4.0 eq), and 2 mL of dimethyl sulfoxide were weighed and placed in a 50 mL reaction bottle and stirred under an ice bath. Then, 30% hydrogen peroxide (35.8 mg, 0.3 mmol, 4.0 eq) was slowly added to the system. After the addition, the reaction was stirred at room temperature for 3 h. 20 mL of saturated sodium sulfite aqueous solution was added to quench the reaction, and 20 mL of ethyl acetate (20 mL×3) was added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, and concentrated to obtain crude product 7d as a white solid (30 mg, yield 95%).

[0327] LC-MS m / z(ESI)=398.16[M+1].

[0328] Step 4:

[0329] 5-amino-N2-(4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 7)

[0330] 5-amino-N2-(4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide

[0331] Weigh 7d (30 mg, 0.1 mmol, 1.0 eq) and 2 mL of dichloromethane and place them in a 50 mL reaction bottle. Slowly add a dichloromethane solution of boron tribromide (1 M) (76.6 mg, 0.3 mmol, 4.0 eq) to the system under ice bath stirring. After the addition, the reaction was stirred at room temperature for 3 h. When the reaction was complete, the reaction was quenched with excess methanol and concentrated. The residue was purified on a silica gel plate (DCM: MeOH = 12: 1) to obtain the product compound 7 as a white solid (28 mg, yield 97%).

[0332] LC-MS m / z(ESI)=384.1[M+1].

[0333] 1 H NMR(DMSO-d6,400MHz)δ10.03(s,1H),9.47(s,1H),7.60–7.69(m,2H),7.05–7 .15(m,4H),6.99(d,1H),6.84(d,1H),5.74(s,2H),1.83(s,3H),1.74(s,3H).

[0334] Example 8

[0335] 5-amino-N2-(2,4-difluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 8)

[0336] 5-amino-N2-(2,4-difluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidaz ole-2,4-dicarboxamide

[0337]

[0338] first step:

[0339] (E)-4-Cyano-N-(2,4-difluorophenyl)-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (8b)

[0340] (E)-4-cyano-N-(2,4-difluorophenyl)-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide

[0341] Weigh intermediate 1 (130 mg, 0.381 mmol, 1.0 eq), 8a (59.0 mg, 0.457 mmol, 1.2 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (159.3 mg, 418.9 mmol, 1.1 eq), N,N-diisopropylethylamine (123.1 mg, 952.0 mmol, 2.5 eq) respectively and place them in a 100 ml reaction bottle, then add 3 mL of N,N-dimethylformamide to the system. After the addition, stir the reaction at room temperature for 3 h. After the reaction is complete, add 20 mL of ethyl acetate to the reaction solution, extract the organic phase twice with water, then extract the organic phase once with saturated sodium chloride aqueous solution, separate the liquids, concentrate the organic phase, and purify it on a silica gel plate (PE:EA=1:1) to obtain the product 8b as a white solid (80 mg, yield 58.6%).

[0342] LC-MS m / z(ESI)=453.1[M+1].

[0343] Step 2:

[0344] 5-Amino-4-cyano-N-(2,4-difluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (8c)

[0345] 5-amino-4-cyano-N-(2,4-difluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide

[0346] 8b (80 mg, 0.177 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and then 1 ml of tetrahydrofuran and 1 ml of 2M hydrochloric acid aqueous solution were added to the system. After the addition, the reaction was stirred at 65 ° C for 16 h. After the reaction was complete, it was naturally cooled to room temperature, concentrated and freeze-dried to obtain the product 8c, a white solid (65 mg, yield 92.51%).

[0347] LC-MS m / z(ESI)=398.1[M+1].

[0348] Step 3:

[0349] 5-Amino-N2-(2,4-difluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (8d)

[0350] 5-amino-N2-(2,4-difluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidaz ole-2,4-dicarboxamide

[0351] Weigh 8c (65 mg, 0.164 mmol, 1.0 eq), potassium carbonate (90.4 mg, 0.654 mmol, 4.0 eq), and 2 mL of dimethyl sulfoxide into a 50 ml reaction bottle and stir under an ice bath. Then slowly add 30% hydrogen peroxide (74.18 mg, 0.316 mmol, 4.0 eq) to the system. After the addition, stir the reaction at room temperature for 3 h. Add 20 mL of ethyl acetate to the reaction solution, extract and wash the organic phase twice with sodium sulfite aqueous solution (20 mL), and then extract and wash the organic phase once with saturated sodium chloride aqueous solution (20 mL), separate the liquids, and concentrate the organic phase. The crude product 8d is obtained as a white solid (55 mg, yield 80.95%).

[0352] LC-MS m / z(ESI)=416.1[M+1].

[0353] Step 4:

[0354] 5-amino-N2-(2,4-difluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 8)

[0355] 5-amino-N2-(2,4-difluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidaz ole-2,4-dicarboxamide

[0356] Weigh 8d (55 mg, 0.132 mmol, 1.0 eq) and 2 mL of dichloromethane respectively into a 50 ml reaction bottle and stir under an ice bath. Then slowly add 1 M dichloromethane solution of boron tribromide (132.7 mg, 0.529 mmol, 4.0 eq) to the system. After the addition, stir the reaction at room temperature for 3 h. After the reaction is complete, quench the reaction solution with excess methanol, concentrate, and purify on a silica gel plate (DCM: MeOH = 12: 1) to obtain the product compound 8 as a white solid (38 mg, yield 71.51%).

[0357] LC-MS m / z(ESI)=402.1[M+1].

[0358] 1H NMR(DMSO-d6,400MHz)δ9.58(s,1H),9.47(s,1H),7.73(td,1H),7.35–3.32(m,1H),7.17 (s,1H),7.08(s,1H),7.01(dd,2H),6.83(d,1H),5.80(s,2H),1.82(s,3H),1.73(s,3H).

[0359] Example 9

[0360] 5-amino-N2-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 9)

[0361] 5-amino-N2-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarbox

[0362]

[0363]

[0364] first step:

[0365] (E)-N-(3-chloro-4-fluorophenyl)-4-cyano-5-((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (9b)

[0366] (E)-N-(3-chloro-4-fluorophenyl)-4-cyano-5-(((dimethylamino)methylene)amino)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide

[0367] Weigh the intermediate 1 (130 mg, 0.381 mmol, 1.0 eq), 9a (66.5 mg, 0.457 mmol, 1.2 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (159.3 mg, 418.9 mmol, 1.1 eq), N,N-diisopropylethylamine (123.1 mg, 952.0 mmol, 2.5 eq) respectively and place them in a 100 ml reaction bottle, then add 3 mL of N,N-dimethylformamide to the system. After the addition, stir the reaction at room temperature for 3 h. After the reaction is complete, add 20 mL of ethyl acetate to the reaction solution, wash the organic phase twice with water, and then wash the organic phase once with a saturated sodium chloride aqueous solution, separate the liquids, concentrate the organic phase, and purify it on a silica gel plate (PE:EA=1:1) to obtain the product 9b as a white solid (70 mg, yield 30.2%).

[0368] LC-MS m / z(ESI)=469.1[M+1].

[0369] Step 2:

[0370] 5-Amino-N-(3-chloro-4-fluorophenyl)-4-cyano-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2-carboxamide (9c)

[0371] 5-amino-N-(3-chloro-4-fluorophenyl)-4-cyano-1-(3-methoxy-2,6-dimethylpheny l)-1H-imidazole-2-carboxamide

[0372] 9b (65 mg, 0.138 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and then 1 ml of tetrahydrofuran and 1 ml of 2M hydrochloric acid aqueous solution were added to the system. After the addition, the reaction was stirred at 65 ° C for 16 h. After the reaction was complete, it was naturally cooled to room temperature, concentrated and freeze-dried to obtain the product 9c, a white solid (50 mg, yield 87.16%).

[0373] LC-MS m / z(ESI)=414.1[M+1].

[0374] Step 3:

[0375] 5-Amino-N2-(3-chloro-4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (9d)

[0376] 5-amino-N2-(3-chloro-4-fluorophenyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide

[0377] Weigh 9c (45 mg, 0.108 mmol, 1.0 eq), potassium carbonate (60.1 mg, 0.435 mmol, 4.0 eq), and 2 mL of dimethyl sulfoxide into a 50 ml reaction bottle and stir under an ice bath. Then slowly add 30% hydrogen peroxide (49.3 mg, 0.435 mmol, 4.0 eq) to the system. After the addition, stir the reaction at room temperature for 3 h. Add 20 mL of ethyl acetate to the reaction solution, extract and wash the organic phase twice with sodium sulfite aqueous solution (20 mL), and then extract and wash the organic phase once with saturated sodium chloride aqueous solution (20 mL), separate the liquids, and concentrate the organic phase. The crude product 9d is obtained as a white solid (40 mg, yield 88.18%).

[0378] LC-MS m / z(ESI)=432.1[M+1].

[0379] Step 4:

[0380] 5-amino-N2-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide (Compound 9)

[0381] 5-amino-N2-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-2,4-dicarboxamide

[0382] Weigh 9d (45 mg, 0.104 mmol, 1.0 eq) and 2 mL of dichloromethane respectively into a 50 ml reaction bottle and stir under an ice bath. Then slowly add 1 M dichloromethane solution of boron tribromide (104.4 mg, 0.416 mmol, 4.0 eq) to the system. After the addition, stir the reaction at room temperature for 3 h. After the reaction is complete, quench the reaction solution with excess methanol, concentrate, and purify on a silica gel plate (DCM: MeOH = 12: 1) to obtain the product compound 9 as a white solid (41 mg, yield 91.87%).

[0383] LC-MS m / z(ESI)=418.1[M+1].

[0384] 1H NMR(DMSO-d6,400MHz)δ10.20(s,1H),9.50(s,1H),7.94(dd,1H),7.57–7.53(m,1H),7.3 4(t,1H),7.11(d,2H),7.00(d,1H),6.85(d,1H),5.79(s,2H),1.83(s,3H),1.74(s,3H).

[0385] Example 10

[0386] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imidazole-4-carboxamide (Compound 10)

[0387] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imid azole-4-carboxamide

[0388]

[0389] first step:

[0390] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(morpholine-4-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (10b)

[0391] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(morpholine-4-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0392] Weigh intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 10a (27.42 mg, 0.315 mmol, 1.2 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.68 mg, 0.288 mmol, 1.1 eq) in a 100 ml reaction bottle. After the mixture was dissolved with 3 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (84.73 mg, 0.656 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution, washed twice with water, and then washed with saturated sodium chloride aqueous solution. The organic phases were combined and purified on a silica gel plate (PE:EA=1:1) to obtain the product 10b as a white solid (80 mg, yield 57.92%).

[0393] LC-MS m / z(ESI)=527.27[M+1].

[0394] Step 2:

[0395] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imidazole-4-carbonitrile (10c)

[0396] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imid azole-4-carbonitrile

[0397] Weigh 10b (80 mg, 0.152 mmol, 1.0 eq) into a 50 ml reaction bottle, then add 1 mL of tetrahydrofuran and 1 mL of 6 M hydrochloric acid. After the addition, stir the reaction at 65 °C for 16 h. After the reaction is complete, cool to room temperature naturally and concentrate to obtain the product 10c as a white solid (40 mg, yield 77.15%).

[0398] LC-MS m / z(ESI)=342.15[M+1].

[0399] Step 3:

[0400] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imidazole-4-carboxamide (Compound 10)

[0401] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(morpholine-4-carbonyl)-1H-imid azole-4-carboxamide

[0402] Weigh 10c (40 mg, 0.117 mmol, 1.0 eq) and potassium carbonate (64.78 mg, 0.468 mmol, 4.0 eq) into a 50 ml reaction bottle. Dissolve the mixture in 2 mL of dimethyl sulfoxide, and cool the reaction solution in an ice bath. Slowly drop 30% hydrogen peroxide (0.468 mL, 0.468 mmol, 4.0 eq) into the system, and after the addition, stir the reaction at room temperature for 3 h. The reaction solution is quenched with sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases are combined, concentrated, and purified on a silica gel plate to obtain compound 10 as a white solid (17 mg, yield 40.37%).

[0403] LC-MS m / z(ESI)=360.16[M+1].

[0404] 1 HNMR(DMSO-d6,400MHz)δ9.47(s,1H),6.93–7.11(m,3H),6.80(d,1H),5.6 2(s,2H),4.01(s,2H),3.59(s,4H),3.42(s,2H),1.83(s,3H),1.73(s,3H).

[0405] Embodiment 11

[0406] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 11)

[0407] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imid azole-4-carboxamide

[0408]

[0409] first step:

[0410] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(isoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (11b)

[0411] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(isoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0412] Weigh intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 11a (37.5 mg, 0.314 mmol, 1.2 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.68 mg, 0.288 mmol, 1.1 eq) respectively and place them in a 100 ml reaction bottle, add 3 mL of N,N-dimethylformamide, and slowly drop N,N-diisopropylethylamine (84.7 mg, 0.655 mmol, 2.5 eq). After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution, washed twice with water, the organic phases were combined, and purified on a silica gel plate (PE:EA=1:1) to obtain the product 11b as a white solid (78 mg, yield 53.2%).

[0413] LC-MS m / z(ESI)=558.28[M+1].

[0414] Step 2:

[0415] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imidazole-4-carbonitrile (11c)

[0416] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imid azole-4-carbonitrile

[0417] Weigh 11b (78 mg, 0.139 mmol, 1.0 eq) into a 50 ml reaction bottle, then add 1 ml tetrahydrofuran and 1 ml 6 M hydrochloric acid to suspend the system. After the addition, stir the reaction at 65 ° C for 16 h. After the reaction is complete, cool to room temperature naturally and concentrate to obtain the product 11c, a white solid (30 g, yield 57.55%).

[0418] LC-MS m / z(ESI)=374.15[M+1].

[0419] Step 3:

[0420] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 11)

[0421] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(isoindoline-2-carbonyl)-1H-imid azole-4-carboxamide

[0422] Weigh 11c (30 mg, 0.08 mmol, 1.0 eq) and potassium carbonate (44.4 mg, 0.324 mmol, 4.0 eq) in a 50 ml reaction bottle, suspend with 3 mL of dimethyl sulfoxide, and drop 30% hydrogen peroxide (0.32 mL, 0.321 mmol, 4.0 eq) under ice bath. After addition, stir the reaction at room temperature for 3 h. Add 20 mL of ethyl acetate to the reaction solution, wash with sodium sulfite aqueous solution, combine the organic phases, and concentrate. Purify on silica gel plate to obtain compound 11 as a white solid (8.1 mg, yield 25.76%).

[0423] LC-MS m / z(ESI)=392.16[M+1].

[0424] 1 H NMR(DMSO-d6,400MHz)δ9.47(s,1H),7.85(d,1H),7.25(d,1H),7.21(s,1H),7.07(t,1H),6.9 4–7.03(m,3H),6.82(d,1H),5.73(s,2H),4.62(d,2H),3.16(d,2H),1.86(s,3H),1.77(s,3H).

[0425] Example 12

[0426] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carboxamide (Compound 12)

[0427] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carboxamide

[0428]

[0429]

[0430] first step:

[0431] (E)-N-(4-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (12b)

[0432] (E)-N'-(4-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0433] Intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 12a (35.81 mg, 0.288 mmol, 1.2 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (119.55 mg, 0.314 mmol, 1.1 eq) were weighed into a 100 mL reaction bottle. After the mixture was dissolved with 3 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (84.73 mg, 0.655 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution, washed with water twice, and then washed with saturated sodium chloride aqueous solution. The organic phases were combined and purified on a silica gel plate (PE:EA=1:1) to obtain the product 12b as a white solid (77 mg, yield 50.09%).

[0434] LC-MS m / z(ESI)=564.28[M+1].

[0435] Step 2:

[0436] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carbonitrile (12c)

[0437] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carbonitrile

[0438] 12b (77 mg, 0.136 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and 1 ml of tetrahydrofuran and 1 ml of 2 M hydrochloric acid were added to the system. After the addition, the reaction was stirred at 65 ° C for 16 h. After the reaction was complete, it was naturally cooled to room temperature and concentrated to obtain the product 12c as a white solid (40 mg, yield 77.39%).

[0439] LC-MS m / z(ESI)=379.16[M+1].

[0440] Step 3:

[0441] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carboxamide (Compound 12)

[0442] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-1H-imidazole-4-carboxamide

[0443] 12c (40 mg, 0.105 mmol, 1.0 eq) and potassium carbonate (58.4 mg, 0.422 mmol, 4.0 eq) were weighed into a 50 ml reaction bottle. 2 mL of dimethyl sulfoxide was added to dissolve the mixture, and 30% hydrogen peroxide (0.42 mL, 0.422 mmol, 4.0 eq) was slowly added under ice bath. After the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was quenched with sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, concentrated, and purified on a silica gel plate to obtain compound 12 as a white solid (5.2 mg, yield 12.41%).

[0444] LC-MS m / z(ESI)=397.17[M+1].

[0445] 1H NMR(DMSO-d6,400MHz)δ7.97(s,1H),7.26(s,1H),6.93–7.03(m,2H),6.84(d,1H) ),5.84(s,1H),5.73(s,2H),4.71(s,2H),4.45(d,4H),1.82(s,3H),1.72(s,3H).

[0446] Embodiment 13

[0447] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 13)

[0448] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide

[0449]

[0450]

[0451] first step:

[0452] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (13b)

[0453] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0454] Intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 13a (41.91 mg, 0.314 mmol, 1.2 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.28 mg, 0.288 mmol, 1.1 eq) were weighed into a 100 ml reaction bottle. The mixture was dissolved in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (84.73 mg, 0.655 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution, washed twice with water, and then washed with saturated sodium chloride aqueous solution. The organic phases were combined and purified on a silica gel plate (PE:EA=1:1) to obtain the product 13b as a white solid (80 mg, yield 53.26%).

[0455] LC-MS m / z(ESI)=573.29[M+1].

[0456] Step 2:

[0457] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carbonitrile (13c)

[0458] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carbonitrile

[0459] 13b (80 mg, 0.139 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and 1 ml of tetrahydrofuran and 1 ml of 2 M hydrochloric acid were added to the system. After the addition, the reaction was stirred at 65 °C for 16 h. After the reaction was complete, the mixture was naturally cooled to room temperature and concentrated to obtain the product 13c as a white solid (40 mg, yield 73.92%).

[0460] LC-MS m / z(ESI)=388.17[M+1].

[0461] Step 3:

[0462] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 13)

[0463] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(5-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide

[0464] 13c (40 mg, 0.103 mmol, 1.0 eq) and potassium carbonate (57.07 mg, 0.412 mmol, 4.0 eq) were weighed separately in a 50 ml reaction bottle. 2 mL of dimethyl sulfoxide was added to dissolve the mixture, and the reaction solution was cooled in an ice bath. 30% hydrogen peroxide (0.41 mL, 0.412 mmol, 4.0 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was quenched with sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, concentrated, and purified on a silica gel plate to obtain compound 13 as a white solid (21 mg, yield 50.17%).

[0465] LC-MS m / z(ESI)=406.18[M+1].

[0466] 1 H NMR(DMSO-d6,400MHz)δ9.47(s,1H),7.74(d,1H),7.20(s,1H),7.06(s,1H),6.97(d,2H),6.86–6.90 (m,1H),6.81(d,1H),5.71(s,2H),4.61(s,2H),3.10(t,2H),2.23(s,3H),1.85(s,3H),1.76(s,3H).

[0467] Embodiment 14

[0468] 5-amino-2-(hexahydro-1H-furano[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-4-carboxamide (Compound 14)

[0469] 5-amino-2-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dim ethylphenyl)-1H-imidazole-4-carboxamide

[0470]

[0471]

[0472] first step:

[0473] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (14b)

[0474] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylform imidamide

[0475] Intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 14a (35.6 mg, 0.314 mmol, 1.2 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.68 mg, 0.288 mmol, 1.1 eq) were weighed into a 100 ml reaction bottle. After the mixture was dissolved with 3 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (84.73 mg, 0.655 mmol, 2.5 eq) was slowly added dropwise to the system, and then 3 mL of N,N-dimethylformamide was added to the system. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution. The mixture was washed twice with water and then with a saturated sodium chloride aqueous solution. The organic phases were combined and purified on a silica gel plate (PE:EA=1:1) to obtain the product 14b as a white solid (50 mg, yield 34.49%).

[0476] LC-MS m / z(ESI)=553.29[M+1].

[0477] Step 2

[0478] 5-Amino-2-(hexahydro-1H-furano[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-4-carbonitrile (14c)

[0479] 5-amino-2-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dim ethylphenyl)-1H-imidazole-4-carbonitrile

[0480] 14b (50 mg, 0.09 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and 1 ml of tetrahydrofuran and 1 ml of 2 M hydrochloric acid were added to the system. After the addition, the reaction was stirred at 65 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature naturally, and the product 14c was concentrated to a white solid (25 mg, yield 75.22%).

[0481] LC-MS m / z(ESI)=368.16[M+1].

[0482] Step 3:

[0483] 5-amino-2-(hexahydro-1H-furano[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazole-4-carboxamide (Compound 14)

[0484] 5-amino-2-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-1-(3-hydroxy-2,6-dim ethylphenyl)-1H-imidazole-4-carboxamid

[0485] Weigh 14c (25 mg, 0.068 mmol, 1.0 eq) and potassium carbonate (37.62 mg, 0.272 mmol, 4.0 eq) in a 50 ml reaction bottle. Dissolve the mixture in 2 mL of dimethyl sulfoxide, and cool the reaction solution in an ice bath. Slowly drop 30% hydrogen peroxide (0.27 mL, 0.272 mmol, 4.0 eq) into the system. After the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was quenched with sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, concentrated, and purified on a silica gel plate to obtain compound 14 as a white solid (6.2 mg, yield 23.64%).

[0486] LC-MS m / z(ESI)=406.18[M+1].

[0487] 1 H NMR(DMSO-d6,400MHz)δ9.43(s,1H),7.09(s,1H),6.95(d,2H),6.79(d,1H),5.58(s,2H),4.12(dd,1H ),3.96(dd,1H),3.75(q,2H),3.54(dd,2H),3.50–3.44(m,1H),2.89(d,3H),1.80(d,3H),1.70(d,3H).

[0488] Embodiment 15

[0489] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 15)

[0490] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide

[0491]

[0492]

[0493] first step:

[0494] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformamide (15b)

[0495] (E)-N'-(4-cyano-1-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazol-5-yl)-N,N-dimethylformimidamide

[0496] Intermediate 2 (120 mg, 0.262 mmol, 1.0 eq), 15a (41.91 mg, 0.314 mmol, 1.2 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.28 mg, 0.288 mmol, 1.1 eq) were weighed into a 100 ml reaction bottle. After the mixture was dissolved with 3 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (84.73 mg, 0.655 mmol, 2.5 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was complete, 20 mL of ethyl acetate was added to the reaction solution, washed twice with water, and then washed with saturated sodium chloride aqueous solution. The organic phases were combined and purified on a silica gel plate (PE:EA=1:1) to obtain the product 15b as a white solid (80 mg, yield 53.26%).

[0497] LC-MS m / z(ESI)=573.29[M+1].

[0498] Step 2:

[0499] 5-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carbonitrile (15c)

[0500] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carbonitrile

[0501] 15b (80 mg, 0.139 mmol, 1.0 eq) was weighed and placed in a 50 ml reaction bottle, and 1 ml of tetrahydrofuran and 1 ml of 2 M hydrochloric acid were added to the system. After the addition, the reaction was stirred at 65 ° C for 16 h. After the reaction was complete, it was naturally cooled to room temperature and concentrated to obtain the product 15c as a white solid (40 mg, yield 73.92%).

[0502] LC-MS m / z(ESI)=388.17[M+1].

[0503] Step 3:

[0504] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide (Compound 15)

[0505] 5-amino-1-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylisoindoline-2-carbonyl)-1H-imidazole-4-carboxamide

[0506] 15c (40 mg, 0.103 mmol, 1.0 eq) and potassium carbonate (57.07 mg, 0.412 mmol, 4.0 eq) were weighed into a 50 ml reaction bottle. 2 mL of dimethyl sulfoxide was added to dissolve the mixture, and the reaction solution was cooled in an ice bath. 30% hydrogen peroxide (0.41 mL, 0.412 mmol, 4.0 eq) was slowly added dropwise to the system. After the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was quenched with sodium sulfite aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, concentrated, and purified on a silica gel plate to obtain compound 15 as a white solid (21 mg, yield 50.17%).

[0507] LC-MS m / z(ESI)=406.18[M+1].

[0508] 1 H NMR(DMSO-d6,400MHz)δ9.46(s,1H),7.15(s,1H),7.10(d,1H),6.98(td,4H),6.79(d ,1H),5.77(s,2H),4.35(t,2H),2.97(t,2H),2.00(s,3H),1.87(s,3H),1.77(s,3H).

[0509] Biological tests

[0510] PKMYT1 kinase inhibition assay

[0511] Experimental steps:

[0512] 1. Using ADP-Glo TM KinaseAssay (Promega) was used to detect the inhibitory activity of the compounds on PKMYT1 kinase, and the ADP-fluorescence standard curves of different concentrations were constructed according to the instructions of the kit;

[0513] 2. Perform the experiment in a 384-well white plate. Add 1 μL of the test compound of different concentrations, 2 μL of PKMYT1 kinase, 2 μL of substrate and ATP mixture to each well, set up a control group (without compound) and a solvent blank group, mix well, centrifuge (1000 rpm, 30 s), and incubate the reaction at 37°C for 60 min;

[0514] 3. Add 5 μL ADPrGlo TM Reagent to terminate the reaction, mix well, centrifuge (1000 rpm, 30 s), and incubate at 25°C for 40 min;

[0515] 4. Add 10 μL Kinase Detection Reagent, shake and mix, centrifuge (1000 rpm, 30 s), and incubate at 25°C for 30 min;

[0516] 5. Use a microplate reader to measure the fluorescence value and calculate the enzyme activity inhibition rate. The formula is inhibition rate = (fluorescence value of the experimental well - fluorescence value of the solvent blank well) / (fluorescence value of the control well - fluorescence value of the solvent blank well) × 100%.

[0517] GraphPad Prism 8 was used for fitting and calculation of IC 50 value.

[0518] Table 1 Inhibitory activity of the compounds of the present invention on PKMYT1 enzyme

[0519] Compound No. <![CDATA[PKMYT1 inhibitory activity (IC 50 , nM)]]> Compound 1 A Compound 2 C Compound 3 B Compound 4 B Compound 5 A Compound 6 C

[0520] Note: A: IC 50<10nM; B:10nM<IC 50 <100nM; C:100nM<IC 50 <500nM. The results show that the compound of the present invention has significant PKMYT1 kinase inhibitory activity.

[0521] Cell proliferation inhibition assay-CTG

[0522] Experimental steps:

[0523] 1. Take OVCAR-3 cells in the logarithmic growth phase, add trypsin to digest into single cells, count after centrifugation and resuspend, adjust the cell density, inoculate in a 96-well cell culture plate (1500 cells / well), set experimental wells, control wells and solvent control wells, and incubate in a 37°C, 5% CO2 incubator overnight after inoculation.

[0524] 2. Prepare the compound to be tested into a 10 mM stock solution with DMSO, dilute the compound stock solution with RPMI-1640 medium, and dilute it by 3-fold gradient to obtain 9 concentrations of the compound, add it to a 96-well plate to make the final concentration of 4 nM-30 μM, and place it in a 37°C, 5% CO2 incubator for further culturing for 4 days.

[0525] 3. Take out the 96-well plate from the incubator, add CellTiter-Glo (Promega) working solution, put it on a constant temperature oscillator for 2 minutes, incubate it at room temperature in the dark for 10 minutes, put it into the microplate reader, and read the chemiluminescence after shaking for 5 seconds.

[0526] 4. Calculate cell survival rate = (luminescence value of experimental well + luminescence value of solvent control well) / (luminescence value of control well + luminescence value of solvent control well) × 100%

[0527] 5. Data analysis: GraphPad Prism 8 software was used to calculate the half-maximal inhibitory concentration (IC) by curve fitting. 50 ), draw the compound effect-dose curve:

[0528] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0529] X: Compound concentration

[0530] Y: Cell viability (%Viability)

[0531] The results show that the compound of the present invention has a significant cell proliferation inhibitory effect.

[0532] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound represented by formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in: A is selected from a 5- to 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O or S; B is selected from a benzene ring or a naphthalene ring; C is selected from a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring; R1 may be the same or different and are each independently selected from -C(=O)NH2 or -NH2; R2 may be the same or different and are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or 3 to 8 membered heterocyclic ring; or any two R1 and the connected carbon atom form a 3 to 8 membered heterocyclic ring; the 3 to 8 membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S; R3 may be the same or different and are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl; L1 is selected from -NH-, -O- or -C(=O)-; L2 is absent or selected from -NH-, -O-, -C(=O)- or p is selected from 0, 1 or 2; q is selected from 0, 1, 2, 3, 4, 5 or 6; k is selected from 0, 1, 2 or 3; t is selected from 1, 2, 3 or 4.

2. The compound according to claim 1 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by formula (I-1): in: R 1-1 are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or 3 to 8 membered heterocyclic ring; or any two R1 and the connected carbon atom form a 3 to 8 membered heterocyclic ring; the 3 to 8 membered heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S; n is selected from 0, 1, 2 or 3.

3. The compound according to claim 1 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by formula (I-2): in: R 2-1 Selected from R 2-2 Not present or selected from -NH-, -O- or y is a natural number selected from 1 to 4; D is selected from a 6-10 membered carbocyclic ring or a 6-10 membered heterocyclic ring; R 2-3 may be the same or different and are selected from H, halogen, C 1-3 Alkyl, m is a natural number selected from 1-6.

4. The compound of formula (I-2) according to claim 3, or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: When D is a 6-10 membered carbon ring, D is a monocyclic ring, preferably, D is a benzene ring; When D is a 6-10 membered heterocyclic ring, D is a monocyclic ring or a bicyclic ring.

5. The compound of formula (I-2) according to claim 3 or 4, or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 2-1 Selected from 6. The compound according to claim 1 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following structures:

7. A pharmaceutical composition, comprising: (1) The compound according to any one of claims 1 to 6, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 7 in the preparation of an anti-tumor drug.

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