Pyrimidinone derivative and application thereof in medicine

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a pyrimidinone derivative or its stereoisomer, solvate, prodrug, metabolite, deuterated compound, pharmaceutically acceptable salt or co-crystal, and its application in medicine. Background Art

[0002] Multiple factors can cause DNA damage. The damage factors can be divided into endogenous and exogenous. Among them, endogenous damage includes replication fork stalling, reactive oxygen species, etc., and exogenous damage includes ultraviolet rays, ionizing radiation, chemical substances, etc. DNA damage will further induce cells to undergo DNA damage response (DDR) to counter the impact of damage, avoid the occurrence of diseases caused by damage such as cancer, and maintain genomic integrity. DDR involves multiple mechanisms and pathways, including the activation of various checkpoint pathways, such as G1, S, G2, and M-phase checkpoints, which regulate specific DNA repair mechanisms at different cell cycle stages. The CCNE1 gene encodes the cyclin E1 protein. Cyclin E1 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 E1 have been observed in various tumors. Gene amplification of CCNE1 and / or high expression of cyclin E1 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. There are differences in their biological functions and cell localization. WEE1 is located in the nucleus and is mainly involved in phosphorylating the Tyr15 residues of cyclin-dependent kinase 1 (CDK1) and CDK2 to regulate the activities of CDK1 and CDK2. PKMYT1 has membrane association and is mainly located in the endoplasmic reticulum. Its main function is to participate in phosphorylating Thr14 and Tyr15 of CDK1 to regulate the activity of CDK1, thereby regulating the G2-M phase checkpoint of cells and affecting cell cycle progression. For DNA repair, many cancer cells have defects in the G1 checkpoint mechanism due to p53 mutations and thus completely rely on the G2 checkpoint. Therefore, inhibiting PKMYT1 and intervening in the G2 checkpoint have good inhibitory effects on various tumors, especially on tumors with gene mutations such as CCNE1 amplification that cause cell cycle disorders and DDR. PKMYT1 inhibitors are expected to become new strategies and approaches for DDR therapy. Summary of the Invention

[0004] The object of the present invention is to provide a pyrimidinone derivative capable of inhibiting the overexpression of PKMYT1 and its application in the preparation of anti-tumor drugs.

[0005] The present invention provides a compound of formula (I) capable of inhibiting the overexpression of PKMYT1, or a stereoisomer, solvate, prodrug, metabolite, deuterated compound, pharmaceutically acceptable salt or cocrystal thereof. The compound of formula (I) is:

[0006]

[0007] Wherein, R 1 and R 2 each independently selected from halogen, C 1-6 alkyl or 3- to 6-membered cycloalkyl;

[0008] A is selected from phenyl, naphthyl or 4- to 10-membered heteroaryl, and the 4- to 10-membered heteroaryl contains at least 1 N;

[0009] R 3 each independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, and the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocycloalkyl are optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl, halogen or hydroxy;

[0010] R 4 is selected from H, halogen or C 1-6 alkyl;

[0011] n is selected from 0, 1, 2 or 3.

[0012] In one or more embodiments of the present application, the compound, or all of its stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or cocrystals, has the structure shown in formula (I-1):

[0013]

[0014] Wherein, R 1 and R 2 each independently selected from C 1-6 alkyl or 3- to 6-membered cycloalkyl;

[0015] A is 4- to 8-membered heteroaryl, and the 4- to 8-membered heteroaryl contains at least 1 N;

[0016] R 3 each independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered cycloalkyl, C 1-6A haloalkyl group or a 3- to 8-membered heterocycloalkyl group, where the 3- to 8-membered cycloalkyl group and the 3- to 8-membered heterocycloalkyl group are optionally substituted with a C 1-6 alkyl group, a halogen, or a hydroxyl group;

[0017] n is selected from 0, 1, 2, or 3.

[0018] In one or more embodiments of the present application, the compound, or all of its stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts, or cocrystals, has the structure shown in formula (I-2):

[0019]

[0020] Wherein, R 1 and R 2 are each independently selected from a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group;

[0021] A is a 4- to 8-membered heteroaryl group, and the 4- to 8-membered heteroaryl group contains at least 1 N;

[0022] R 3 is selected from a C 1-3 alkyl group, a 3- to 6-membered cycloalkyl group, a C 1-3 haloalkyl group, or a 3- to 6-membered heterocycloalkyl group, and the 3- to 6-membered heterocycloalkyl group is optionally substituted with a C 1-3 alkyl group, a halogen, or a hydroxyl group.

[0023] In one or more embodiments of the present application, the compound, or its stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts, or cocrystals, wherein,

[0024] A is selected from a phenyl group,

[0025] In one or more embodiments of the present application, the compound, or all of its stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts, or cocrystals, is selected from, but not limited to, the following structures:

[0026]

[0027]

[0028]

[0029] One or more embodiments of the present application provide a pharmaceutical composition, and the pharmaceutical composition includes:

[0030] (1) The compound of the present application or its stereoisomers, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts, or cocrystals;

[0031] (2) One or more optional other active ingredients; and

[0032] (3) A pharmaceutically acceptable carrier and / or excipient.

[0033] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application, or the compound or its stereoisomer, solvate, prodrug, metabolite, deuterated compound, pharmaceutically acceptable salt or cocrystal thereof in the preparation of an anti-tumor drug.

[0034] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0035] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further substituted by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0036] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and still more preferably an alkyl group having 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 a substituent, it may optionally be further substituted by one or more substituents. "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-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy. The definition of the alkyl group is the same as the definition of "alkyl" described above.

[0037] "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-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy. The definition of the alkyl group is the same as the definition of "alkyl" described above.

[0038] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which may be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heteroaryl, and 1 to 4 (e.g., 1, 2, 3, 4) N, S which are selectively substituted in the ring of the heteroaryl may be oxidized to various oxidation states. The heteroaryl may be linked to a heteroatom or a carbon atom, and the heteroaryl may be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. The heteroaryl is optionally further substituted by one or more substituents.

[0039] "Cycloalkyl" refers to a saturated cycloalkyl group, the ring of which can be a monocyclic ring of 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring of 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or a polycyclic system of 10 to 20 members (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 members). The ring carbon atoms preferably have 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, cycloheptatrienyl, etc. When the cycloalkyl is substituted, it may optionally be further substituted by one or more substituents.

[0040] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a monocyclic ring of 3 to 8 members (such as 3, 4, 5, 6, 7, 8 members), a bicyclic ring of 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or a tricyclic system of 10 to 15 members (such as 10, 11, 12, 13, 14, 15 members), and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably a heterocyclic group of 3 to 8 members. One, two or three N, S optionally substituted in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be linked to a heteroatom or a carbon atom; "heterocycloalkyl" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, adamantylamine and oxaspiro[3.3]heptanyl.

[0041] When the above-mentioned "alkyl", "alkoxy", "heteroaryl", "cycloalkyl" or "heterocycloalkyl" is substituted, it may optionally be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituents 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)OC1-6 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 alkynyl, and wherein said 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 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O)C 3-8 cycloalkyl is optionally further substituted by 1 to 3 substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O; R q1 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-10 aryl; R q2 , R q3 is selected from H or C1-6 alkyl; wherein, R q4 , R q5 is selected from H, C 1-6 alkyl, -NH(C=NR q1 )NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 alkyl is optionally further substituted by one or more substituents 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 heterocycloalkyl; or R q4 and R q5 together with the N atom form a 3- to 8-membered heterocycle, which heterocycle may contain one or more heteroatoms selected from N, O or S.

[0042] Halogen includes F, Cl, Br and I.

[0043] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt of the compound of the present invention that retains the biological effectiveness and characteristics of the free acid or free base, and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, and the free base with a non-toxic inorganic acid or organic acid.

[0044] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, its pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" means a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents.

[0045] "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0046] "Excipient" means an inert substance added to a pharmaceutical composition to facilitate the administration of the 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.

[0047] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compounds of the present invention, and such 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 individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0048] "Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including binary co-crystals formed between two neutral solids, as well as multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0049] "Stereoisomer" refers to an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0050] "Optional" or "optionally" or "selective" or "selectively" means that the subsequent event or condition may or may not occur, and this description includes the cases where the event or condition occurs and the cases where it does not occur. For example, "heterocyclic group optionally substituted by alkyl" means that the alkyl may or may not be present, and this description includes the cases where the heterocyclic group is substituted by alkyl and the cases where the heterocyclic group is not substituted by alkyl. Detailed Description of the Invention

[0051] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0052] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR measurement is performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0053] The MS measurement is performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0054] The HPLC measurement is performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

[0055] The thin-layer chromatography silica gel plate uses the Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15 mm - 0.20 mm, and the specification of the silica gel plate used for thin-layer chromatography separation and purification of products is 0.4 mm - 0.5 mm;

[0056] Column chromatography generally uses Yantai Huanghai silica gel 200 - 300 mesh silica gel as the carrier;

[0057] The known starting materials of the present invention can be synthesized by adopting or according to the methods known in the art, or can be purchased from companies such as Titan Technology, Aladdin Chemistry, Shanghai Dermachem, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, J&K Scientific, Jiangsu ApexBio Technology, etc.

[0058] Intermediate 1

[0059] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate 1)

[0060] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0061]

[0062] The first step:

[0063] (E)-2-(((dimethylamino)methylene)amino)-1H-pyrrole-3-carboxylate (1-B) Weigh 1-A (25 g, 162.15 mmol, 1.0 eq) into a 1000 mL reaction flask, add 300 mL of toluene for suspension, add N,N-dimethylformamide dimethyl acetal (28.92 g, 243.22 mmol, 1.5 eq) at room temperature, and heat up to 60 °C for reaction for 2 h. After the reaction is complete, naturally cool the reaction solution to room temperature and concentrate to obtain the crude product 1-B, which is a black oily substance (59 g).

[0064] LC-MS m / z (ESI) = 210.1 [M + 1].

[0065] The second step:

[0066] (E)-2-(((Dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxylate ethyl ester (1-C)

[0067] (E)-2-(((Dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxylate ethyl ester

[0068] Weigh 1-B (59 g, 280.93 mmol, 1.0 eq) into a 1000 mL reaction flask, add 600 mL of N,N-dimethylformamide to dissolve it, displace the air with nitrogen three times, and cool the system to 0 °C in an ice bath. Add sodium hydride (16.84 g, 421.39 mmol, 60% purity, 1.5 eq) portionwise under a nitrogen stream. After the addition is complete, stir the reaction at 0 °C for 1 h. Under a nitrogen stream, add tosyl chloride (106.74 g, 561.86 mmol, 2.0 eq) portionwise to the reaction system. The reaction solution is allowed to warm to room temperature naturally and stirred for another 1 h. After the reaction is complete, pour the reaction solution into 2000 mL of ice-cold saturated ammonium chloride aqueous solution to quench it under a nitrogen stream. The mixture is extracted with ethyl acetate (500 mL × 3), the organic phases are combined, dried over anhydrous sodium sulfate, and the organic phase is concentrated to obtain a residue. Purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain 1-C, a yellow solid (38 g, 64% of the product).

[0069] LC-MS m / z (ESI) = 364.1 [M+1].[[]END]]

[0070] The third step:

[0071] (E)-2-(((Dimethylamino)methylene)amino)-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide (1-E)

[0072] (E)-2-(((Dimethylamino)methylene)amino)-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide

[0073] Weigh 1-C (33 g, 90.91 mmol, 1.0 eq) and 1-D (33 g, 181.82 mmol, 2.0 eq) separately and place them in a 1000 mL reaction flask. Immediately add 400 mL of toluene to the system. Replace the air with nitrogen three times and protect the system with nitrogen. Slowly add trimethylaluminum (19.66 g, 272.73 mmol, 3.0 eq) dropwise to the system. After addition, transfer the reaction to 110 °C and stir for 1 h. When the reaction is complete, allow the reaction solution to cool naturally to room temperature and quench it with 2 L of ice water. Extract the system with ethyl acetate (500 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a residue. Purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 1-E, a yellow solid (42 g, 93% of the product).

[0074] LC-MS m / z (ESI) = 499.20 [M+1].

[0075] Step 4:

[0076] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1-F)

[0077] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0078] Weigh 1-E (40 g, 80.32 mmol, 1.0 eq) and place it in a 1000 mL reaction flask. Add 400 mL of dichloromethane to suspend it and cool the system to -30 °C. Add pyridinium tribromide (28 g, 88.35 mmol, 1.1 eq) and react at -30 °C for 2 h. When the reaction is complete, allow the reaction solution to cool naturally to room temperature and quench it with 1 L of ice water. Extract the system with dichloromethane (500 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product 1-F, a yellow solid (59 g).

[0079] LC-MS m / z (ESI) = 577.10 [M+1].

[0080] Step 5:

[0081] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate 1)

[0082] 6-bromo-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0083] Weigh 1-F (57 g, 98.78 mmol, 1.0 eq) into a 1000 mL reaction flask, add 200 mL of methanol and 200 mL of ethanol and suspend. Add 200 mL of 2 M hydrochloric acid at room temperature; after adding, transfer the reaction to 65 °C and stir for 2 h. When the reaction is complete, adjust the pH of the reaction solution to 6 - 7 with saturated aqueous sodium bicarbonate, concentrate, extract the system with ethyl acetate (500 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a residue. Purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 1, a pink solid (28 g, 58% of the product).

[0084] LC-MS m / z (ESI) = 488.10 [M + 1].

[0085] Example 1

[0086] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 1)

[0087] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0088]

[0089] The first step:

[0090] (E)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxylic acid (1a)

[0091] (E)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxylic acid

[0092] Weigh 1-C (2.1 g, 5.78 mmol, 1.0 eq) and sodium hydroxide (0.35 g, 8.68 mmol, 1.5 eq) separately into a 100 mL reaction flask. Immediately add 15 mL of ethanol and 15 mL of water to the system. Heat to 105 °C and react for 2 h. After the reaction is complete, cool to room temperature, rotary evaporate to remove ethanol from the reaction solution, wash away impurities in the reaction solution with ethyl acetate, adjust the pH of the aqueous phase to 6 - 7 with dilute hydrochloric acid, freeze-dry, and then purify by reverse-phase column chromatography to obtain 1a as a purple solid (980 mg, yield 52%).

[0093] LC-MS m / z(ESI) = 336.1[M + 1].

[0094] Step 2:

[0095] (E)-2-(((dimethylamino)methylene)amino)-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide (1c)

[0096] (E)-2-(((dimethylamino)methylene)amino)-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide

[0097] Weigh 1a (980 mg, 2.92 mmol, 1.0 eq) into a 100 mL reaction flask, add 1 drop of N,N-dimethylformamide and 10 mL of dichloromethane. After cooling to 0 °C, add oxalyl chloride (560 mg, 4.38 mmol, 1.5 eq) dropwise and react at room temperature for 1 h. After the reaction is completed, rotary evaporate the reaction solution to dryness, dissolve it with dichloromethane, and then add it dropwise to a reaction system containing 1b (888 mg, 5.84 mmol, 2.0 eq), triethylamine (884 mg, 8.76 mmol, 3.0 eq) and 10 mL of dichloromethane at 0 °C. React at room temperature for 1 h. After the reaction is complete, add water to quench the reaction system, extract with dichloromethane, rotary evaporate to dryness, and then purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1c as a yellow solid (330 mg, yield 24%).

[0098] LC-MS m / z(ESI) = 469.20[M + 1].

[0099] Step 3:

[0100] (E)-5-bromo-2-(((dimethylamino)methylene)amino)-N-(3-methoxy-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide (1d)

[0101] (E)-5-bromo-2-(((dimethylamino)methylene)amino)-N-(3-methoxy-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide

[0102] Weigh 1c (330 mg, 0.70 mmol, 1.0 eq) into a 100 mL reaction flask, and add 5 mL of dichloromethane to the system. Add pyridinium tribromide (225 mg, 0.70 mmol, 1.0 eq) under an ice bath. After addition, stir the reaction at room temperature for 2 h. After the reaction is complete, quench the reaction solution by adding it to 50 mL of saturated aqueous sodium sulfite solution, extract with dichloromethane (50 mL × 3), separate the layers, and concentrate the organic phase to obtain 1d as a black oil (460 mg, crude product).

[0103] LC-MS m / z (ESI) = 547.10 [M+1].

[0104] Step 4:

[0105] 6-bromo-3-(3-methoxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1e)

[0106] 6-bromo-3-(3-methoxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0107] Weigh 1d (460 mg, 0.84 mmol, 1.0 eq) into a 100 mL reaction flask, and add 3 mL of tetrahydrofuran to the system. Add 3 mL of hydrochloric acid (1 M) aqueous solution at room temperature, and stir the reaction at 60 °C for 2 h. After the reaction is complete, quench the reaction solution by adding it to 50 mL of saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (50 mL × 3), separate the layers, and concentrate the organic phase. Purify it by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1e as a yellow solid (270 mg, yield 77%).

[0108] LC-MS m / z (ESI) = 502.20 [M+1].

[0109] Step 5:

[0110] 3-(3-Methoxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1 g)

[0111] 3-(3-methoxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0112] Weigh 1e (270 mg, 0.54 mmol, 1.0 eq), 1f (177 mg, 0.81 mmol, 1.5 eq), bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.05 mmol, 0.1 eq), triphenylphosphine (28 mg, 0.11 mmol, 0.2 eq), and sodium bicarbonate (136 mg, 1.62 mmol, 3.0 eq) into a 100 mL reaction flask. Immediately add 10 mL of 1,2-dimethoxyethane and 2 mL of water to the system. After adding, displace the air with nitrogen three times at room temperature, and stir the reaction at 90 °C for 3 h. After the reaction is complete, allow the reaction solution to cool naturally to room temperature, quench with water, extract with ethyl acetate, separate the layers, concentrate the organic phase, and purify by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1 g as a yellow solid (70 mg, yield 25%).

[0113] LC-MS m / z (ESI) = 516.10 [M+1].

[0114] Step 6:

[0115] 3-(3-Methoxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1 h)

[0116] 3-(3-methoxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0117] Weigh 1 g (70 mg, 0.14 mmol, 1.0 eq) into a 100 mL reaction flask. Immediately add 1 mL of aqueous sodium hydroxide (1 M), 1 mL of methanol, and 1 mL of ethanol to the system. After addition, the reaction is stirred at 60 °C for 1 h. After the reaction is complete, the reaction solution is naturally cooled to room temperature, quenched with water, extracted with ethyl acetate, separated, the organic phase is concentrated, and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to obtain 1 h as a yellow solid (21 mg, yield 42%).

[0118] LC-MS m / z (ESI) = 362.10 [M+1].

[0119] Step 7:

[0120] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 1)

[0121] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0122] Weigh 1 h (21 mg, 0.06 mmol, 1.0 eq) into a 100 mL reaction flask. Immediately add 3 mL of dichloromethane to the system. Dropwise add boron tribromide (75 mg, 0.3 mmol, 5 eq) to the system under an ice bath. After addition, the reaction is stirred at room temperature for 24 h. After the reaction is complete, the reaction solution is dropped into methanol under an ice bath to quench it. After rotary evaporation of the reaction solution, it is purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain Compound 1 as a yellow solid (2.9 mg, yield 15%).

[0123] LC-MS m / z (ESI) = 348.10 [M+1].

[0124] Example 2

[0125] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-cyclopropylpyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 2)

[0126] 6-(2-cyclopropylpyrimidin-5-yl)-3-(3-hydroxy-2,6-dimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0127]

[0128] Step 1:

[0129] 6-(2-Cyclopropylpyrimidin-5-yl)-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (2b)

[0130] 6-(2-cyclopropylpyrimidin-5-yl)-3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0131] Weigh intermediate 1 (200 mg, 0.41 mmol, 1.0 eq), 2a (134 mg, 0.82 mmol, 2.0 eq), [n-Butyldi(1-adamantyl)phosphine]palladium(II) (2-amino-1,1'-biphenyl-2-yl) methanesulfonate (30 mg, 0.04 mmol, 0.1 eq), and potassium phosphate (260 mg, 1.23 mmol, 3.0 eq) into a 50 mL reaction flask, add 5 mL of ethylene glycol dimethyl ether and 2 mL of water for suspension. After addition, displace with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain the crude product 2b as a yellow solid (600 mg).

[0132] LC-MS m / z (ESI) = 528.10 [M+1].

[0133] Step 2:

[0134] 6-(2-Cyclopropylpyrimidin-5-yl)-3-(3-hydroxy-2,6-dimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 2)

[0135] 6-(2-cyclopropylpyrimidin-5-yl)-3-(3-hydroxy-2,6-dimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0136] Weigh 2b (600 mg, 0.06 mmol, 1.0 eq) into a 50 mL reaction flask, add 3 mL of methanol and 3 mL of ethanol and suspend. Add 3 mL of 1 M aqueous sodium hydroxide solution at room temperature; after addition, transfer the reaction to 65 °C and stir for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: pure water = 25:75) to obtain compound 2, a white solid (36 mg, yield 9%).

[0137] LC-MS m / z (ESI) = 374.10 [M+1].[[]END]]

[0138] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.60 (s, 1H), 9.62 (s, 1H), 9.10 (s, 2H), 8.00 (s, 1H), 7.24 (s, 1H), 7.03 (d, 1H), 6.87 (d, 1H), 2.23 (m, 1H), 1.88 (s, 3H), 1.79 (s, 3H), 1.10–1.01 (m, 4H).

[0139] Example 3

[0140] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 3)

[0141] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0142]

[0143] Using intermediate 1 as the starting material, compound 3 was obtained by referring to the similar synthesis method described for compound 2, as a white solid (49 mg, yield 18%).

[0144] LC-MS m / z (ESI) = 336.10 [M+1].[[]END]]

[0145] 11H NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 9.57 (s, 1H), 8.09 (s, 1H), 7.89 (d, 2H), 7.02–6.98 (m, 1H), 6.86 (d, 1H), 6.66 (s, 1H), 3.88 (s, 3H), 1.88 (s, 3H), 1.78 (s, 3H).

[0146] Example 4

[0147] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 4)

[0148] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0149]

[0150]

[0151] Using Intermediate 1 as the starting material, Compound 4 was obtained by referring to the similar synthesis method described for Compound 2. It was a white solid (22 mg, yield 9%).

[0152] LC-MS m / z (ESI) = 406.10 [M+1].

[0153] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.94 (d, 1H), 7.85 (s, 1H), 7.00 (d, 1H), 6.87 (d, 1H), 6.67 (s, 1H), 4.50–4.36 (m, 1H), 4.01–3.94 (m, 2H), 3.49 (dd, 2H), 2.54–2.45 (m, 6H), 1.99–1.95 (m, 4H), 1.87 (s, 3H), 1.78 (s, 3H).

[0154] Example 5

[0155] 5-(3-(3-(Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxypyridinecarbonitrile (Compound 5)

[0156] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxypicolinonitrile

[0157]

[0158]

[0159] Step 1:

[0160] 3-Fluoro-5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-7-tosyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)picolinonitrile (5b)

[0161] 3-fluoro-5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-7-tosyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)picolinonitrile

[0162] Weigh intermediate 1 (200 mg, 0.41 mmol, 1.0 eq), 5a (203 mg, 0.82 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (30 mg, 0.04 mmol, 0.1 eq), and potassium phosphate (260 mg, 1.23 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of ethylene glycol dimethyl ether and 2 mL of water and suspend. After addition, displace with nitrogen three times at room temperature. Transfer the reaction to 90 °C and stir for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain the crude product 5b, which is a yellow solid (400 mg).

[0163] LC-MS m / z (ESI) = 530.10 [M+1].

[0164] Step 2:

[0165] 5-(3-(3-(Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxypicolinonitrile (Compound 5)

[0166] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxypicolinonitrile

[0167] Weigh 5b (400 mg, 0.75 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol suspension to the system. At room temperature, add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system. After addition, transfer the reaction to 65 °C and stir for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: pure water = 25:75) to obtain compound 5 as a yellow solid (34 mg, yield 15%).

[0168] LC-MS m / z (ESI) = 388.10 [M+1].

[0169] 1 1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 9.59 (s, 1H), 8.86 (d, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.58 (s, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 4.05 (s, 3H), 1.89 (s, 3H), 1.80 (s, 3H).

[0170] Example 6

[0171] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 6)

[0172] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0173]

[0174] The first step

[0175] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (6b)

[0176] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0177] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 6a (270 mg, 1.23 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (45 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (390 mg, 1.85 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of ethylene glycol dimethyl ether and 2 mL of water and suspend. After addition, displace the air with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, allow the reaction solution to cool naturally to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain the crude product 6b as a yellow solid (450 mg).

[0178] LC-MS m / z (ESI) = 501.20 [M+1].

[0179] The second step

[0180] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 6)

[0181] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0182] Weigh 6b (450 mg, 0.37 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to the system and suspend. Add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system at room temperature. After addition, transfer the reaction to 65 °C and stir the reaction for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (water:acetonitrile = 40:60) to obtain Compound 6 as a white solid (55.0 mg, yield 42%).

[0183] LC-MS m / z (ESI) = 347.20 [M+1].

[0184] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.64 (s, 1H), 9.56 (s, 1H), 8.96 (d, 1H), 8.12 (d, 1H), 7.97 (s, 1H), 7.32 (d, 1H), 7.03 (d, 1H), 6.87 (d, 1H), 2.51 (s, 3H), 1.89 (s, 3H), 1.79 (s, 3H).

[0185] Example 7

[0186] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 7)

[0187] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0188]

[0189]

[0190] The first step

[0191] 3-(3-Hydroxy-2,6-dimethylphenyl)-7-tosyl-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (7b)

[0192] 3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0193] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 7a (337 mg, 1.23 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (45 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (390 mg, 1.85 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of 1,2-dimethoxyethane and 2 mL of water and suspend. After addition, displace with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir for 3 h. When the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 7b as a yellow solid (470 mg).

[0194] LC-MS m / z (ESI) = 556.20 [M+1].

[0195] The second step

[0196] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 7)

[0197] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0198] Weigh 7b (470 mg, 0.54 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to the system and suspend. At room temperature, add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system. After addition, transfer the reaction to 65 °C and stir for 2 h. When the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (water:acetonitrile = 45:55) to obtain Compound 7 as a white solid (45.0 mg, yield 21%).

[0199] LC-MS m / z (ESI) = 402.10 [M+1].

[0200] 1 H NMR (400 MHz, DMSO-d 6) δ 13.03 (s, 1H), 9.60 (s, 1H), 9.52 (s, 2H), 8.08 (s, 1H), 7.58 (s, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 1.90 (s, 3H), 1.81 (s, 3H).

[0201] 19 F NMR (377 MHz, DMSO-d 6 ) δ -68.73.

[0202] Example 8

[0203] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile (Compound 8)

[0204] 5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile

[0205]

[0206] The first step

[0207] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-7-tosyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile (8b)

[0208] 5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-7-tosyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile

[0209] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 8a (300 mg, 1.23 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine]palladium(II) (2-amino-1,1'-biphenyl-2-yl) methanesulfonate (45 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (390 mg, 1.85 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of 1,2-dimethoxyethane and 2 mL of water to suspend. After adding, displace with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 8b, which is a yellow solid (510 mg).

[0210] LC-MS m / z (ESI) = 526.20 [M+1].

[0211] The second step

[0212] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile (Compound 8)

[0213] 5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylpicolinonitrile

[0214] Weigh 8b (510 mg, 0.60 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to suspend the system. Add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system at room temperature. After adding, transfer the reaction to 65 °C and stir the reaction for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (water:acetonitrile = 40:60) to obtain Compound 8, which is a white solid (75.0 mg, yield 34%).

[0215] LC-MS m / z (ESI) = 372.10 [M+1].

[0216] 1 H NMR (400 MHz, DMSO-d 6)δ12.84(s,1H),9.59(s,1H),9.08(d,1H),8.35(d,1H),7.92(s,1H),7.39(s,1H),7.02(d,1H),6.86(d,1H),2.52(s,3H),1.89(s,3H),1.79(s,3H).

[0217] Example 9

[0218] 5-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)picolinonitrile (Compound 9)

[0219] 5-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)picolinonitrile

[0220]

[0221]

[0222] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 9a (282 mg, 1.23 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (45 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (390 mg, 1.85 mmol, 3.0 eq) into a 15 mL microwave tube. Add 5 mL of ethylene glycol dimethyl ether and 1 mL of water suspension to the microwave tube. After adding, displace with nitrogen three times at room temperature and react in a microwave at 110 °C for 1.5 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a residue. Purify by normal-phase column chromatography (dichloromethane:methanol = 25:1) to obtain Compound 9, a white solid (15 mg, yield 7%).

[0223] LC-MS m / z (ESI) = 358.10 [M+1].

[0224] 1 H NMR (400 MHz, DMSO-d 6)δ12.92(s,1H),9.59(s,1H),9.29(d,1H),8.45(dd,1H),8.11(d,1H),8.05(s,1H),7.50(s,1H),7.04(d,1H),6.88(d,1H),1.89(s,3H),1.80(s,3H).

[0225] Example 10

[0226] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 10)

[0227] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0228]

[0229]

[0230] The first step

[0231] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (10b)

[0232] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0233] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 10a (190 mg, 1.23 mmol, 2.0 eq), bis(1-adamantyl)(n-butyl)phosphonium mesylate palladium(II) (2-amino-1,1'-biphenyl-2-yl) (45 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (390 mg, 1.85 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of 1,2-dimethoxyethane and 2 mL of water and suspend. After adding, displace with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir for 3 h. When the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 10b, a yellow solid (510 mg).

[0234] LC-MS m / z (ESI) = 518.20 [M+1].

[0235] The second step

[0236] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 10)

[0237] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methoxypyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0238] Weigh 10b (510 mg, 0.63 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to the system and suspend. At room temperature, add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system. After adding, transfer the reaction to 65 °C and stir for 2 h. When the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 10, a white solid (25.0 mg, yield 12%).

[0239] LC-MS m / z (ESI) = 364.10 [M+1].

[0240] 1 H NMR (400 MHz, DMSO-d 6)δ12.70(s,1H),9.57(s,1H),9.09(s,2H),7.99(s,1H),7.18(d,1H),7.04(d,1H),6.87(d,1H),3.96(s,3H),1.88(s,3H),1.79(s,3H).

[0241] Example 11

[0242] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 11)

[0243] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0244]

[0245] The first step

[0246] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (11b)

[0247] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0248] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 11a (252 mg, 1.23 mmol, 2.0 eq), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (45 mg, 0.06 mmol, 0.1 eq), and sodium bicarbonate (198 mg, 1.85 mmol, 3.0 eq) into a 50 mL reaction flask. Add 5 mL of 1,4-dioxane and 1 mL of water to make a suspension. After adding, displace with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude 11b as a yellow solid (450 mg).

[0249] LC-MS m / z (ESI) = 501.20 [M+1].

[0250] The second step

[0251] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 11)

[0252] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(pyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0253] Weigh 11b (450 mg, 0.37 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol suspension to the system. At room temperature, add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system. After addition, transfer the reaction to 65 °C and stir for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by normal-phase column chromatography (dichloromethane:methanol = 15:1) to obtain Compound 11, a white solid (13.0 mg, yield 6%).

[0254] LC-MS m / z (ESI) = 347.20 [M+1].

[0255] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 9.76 (dd, 1H), 9.59 (s, 1H), 9.22 (dd, 1H), 8.07 (s, 1H), 8.04 (dd, 1H), 7.63 (s, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 1.89 (s, 3H), 1.80 (s, 3H).

[0256] Example 12

[0257] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 12)

[0258] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0259]

[0260]

[0261] Step 1:

[0262] 3-(3-Hydroxy-2,6-dimethylphenyl)-7-tosyl-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (12b)

[0263] 3-(3-hydroxy-2,6-dimethylphenyl)-7-tosyl-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0264] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 12a (338 mg, 1.24 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (43.68 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (487 mg, 1.86 mmol, 3 eq) respectively, and add them to a suspension of 5 mL of ethylene glycol dimethyl ether and 2 mL of water. After addition, replace the gas with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench it with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 12b as a yellow solid (326 mg).

[0265] LC-MS m / z (ESI) = 554.1 [M+1].

[0266] Step 2:

[0267] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 12)

[0268] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0269] Weigh 12b (326 mg, 0.82 mmol, 1.0 eq) into a 50 mL reaction flask, and then add 3 mL of methanol and 3 mL of ethanol suspension to the system. At room temperature, 3 mL of 1 M aqueous sodium hydroxide solution was added dropwise to the system. After addition, the reaction was transferred to 65 °C and stirred for 2 h. After the reaction was complete, the reaction solution was directly concentrated to obtain a residue, which was purified by reverse-phase column chromatography (acetonitrile: water = 25:75) to obtain compound 12 as a white solid (52 mg, yield 21%).

[0270] LC-MS m / z (ESI) = 401.1 [M+1].[

[0271] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.87 (s, 1H), 9.59 (s, 1H), 9.29 (d, 1H), 8.49 (d, 1H), 8.04 (s, 1H), 7.98 (d, 1H), 7.44 (s, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 1.89 (s, 3H), 1.80 (s, 3H).

[0272] 19 19F NMR (377 MHz, DMSO-d 6 ) δ -66.19.

[0273] Example 13

[0274] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 13)

[0275] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0276]

[0277] The first step:

[0278] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (13b)

[0279] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0280] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 13a (272 mg, 1.24 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (43.68 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (487 mg, 1.86 mmol, 3 eq) respectively, and add them to a suspension of 5 mL of ethylene glycol dimethyl ether and 2 mL of water. After addition, displace the air with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, allow the reaction solution to cool naturally to room temperature, quench it with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 13b as a yellow solid (311 mg, crude product).

[0281] LC-MS m / z (ESI) = 502.1 [M+1].

[0282] Step 2:

[0283] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 13)

[0284] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridazin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0285] Weigh 13b (400 mg, 0.82 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to the system to form a suspension. Add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system at room temperature. After addition, transfer the reaction to 65 °C and stir the reaction for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile:water = 25:75) to obtain Compound 13 (19 mg, yield 9%).

[0286] LC-MS m / z (ESI) = 348.2 [M+1].

[0287] 11H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 9.60 (s, 2H), 8.07 (s, 1H), 7.96 (s, 1H), 7.59 (d, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 2.64 (s, 3H), 1.89 (s, 3H), 1.80 (s, 3H).

[0288] Example 14

[0289] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 14)

[0290] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0291]

[0292] The first step:

[0293] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (14b)

[0294] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0295] Weigh intermediate 1 (300 mg, 0.62 mmol, 1.0 eq), 14a (360 mg, 1.24 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (43.68 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (487 mg, 1.86 mmol, 3 eq) respectively, and add them to a suspension of 5 mL of ethylene glycol dimethyl ether and 2 mL of water. After addition, displace the air with nitrogen three times at room temperature, transfer the reaction to 90 °C, and stir the reaction for 3 h. After the reaction is complete, allow the reaction solution to cool naturally to room temperature, quench it with 50 mL of water, extract the system with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain crude product 14b, which is a yellow solid (311 mg).

[0296] LC-MS m / z (ESI) = 573.2 [M+1].

[0297] Step 2:

[0298] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 14)

[0299] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-morpholinopyrimidin-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0300] Weigh 14b (311 mg, 0.82 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of methanol and 3 mL of ethanol to the system for suspension. At room temperature, add 3 mL of 1 M aqueous sodium hydroxide solution dropwise to the system. After addition, transfer the reaction to 65 °C and stir the reaction for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile:water = 25:75) to obtain Compound 14, which is a white solid (23 mg, yield 10%).

[0301] LC-MS m / z (ESI) = 419.2 [M+1].

[0302] 1 HNMR (400 MHz, DMSO-d 6) δ 12.54 (s, 1H), 9.57 (s, 1H), 8.88 (d, 2H), 7.94 (d, 1H), 7.06–6.99 (m, 2H), 6.90–6.84 (m, 1H), 3.76–3.66 (m, 8H), 1.88 (s, 3H), 1.79 (s, 3H).

[0303] Example 15

[0304] 4-(3-(3-Hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile (Compound 15)

[0305] 4-(3-(3-hydroxy-2,6-dimethylphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile

[0306]

[0307] Using Intermediate 1 as the starting material, Compound 14 was obtained by referring to the similar synthesis method described for Compound 2. It was a white solid (46 mg, yield 21%).

[0308] LC-MS m / z (ESI) = 357.1 [M+1].

[0309] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.54 (s, 1H), 9.57 (s, 1H), 8.06 (d, 2H), 7.99 (s, 1H), 7.88 (d, 2H), 7.31 (s, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 1.89 (s, 3H), 1.80 (s, 3H).

[0310] Example 16

[0311] 6-(4-Fluorophenyl)-3-(3-hydroxy-2,6-dimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 16)

[0312] 6-(4-fluorophenyl)-3-(3-hydroxy-2,6-dimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0313]

[0314] Using Intermediate 1 as the starting material, Compound 16 was obtained by referring to the similar synthesis method described for Compound 2. It was a white solid (28 mg, yield 14%).

[0315] LC-MS m / z (ESI) = 350.12 [M+1].

[0316] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.54 (s, 1H), 9.56 (s, 1H), 7.95 (s, 1H), 7.93–7.88 (m, 2H), 7.33–7.26 (m, 2H), 7.06–7.01 (m, 2H), 6.87 (d, 1H), 1.89 (s, 3H), 1.80 (s, 3H).

[0317] Example 17

[0318] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(p-tolyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 17)

[0319] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(p-tolyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0320]

[0321] Using Intermediate 1 as the starting material, Compound 17 was obtained by referring to the similar synthesis method described for Compound 2. It was a white solid (23 mg, yield 15%).

[0322] LC-MS m / z (ESI) = 346.1 [M+1].

[0323] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 7.75 (d, 2H), 7.20 (d, 2H), 7.00 (d, 1H), 6.89 (s, 1H), 6.85 (d, 1H), 2.32 (s, 3H), 1.88 (s, 3H), 1.79 (s, 3H).

[0324] Example 18

[0325] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 18)

[0326] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0327]

[0328]

[0329] Using Intermediate 1 as the starting material, Compound 18 was obtained by referring to the similar synthesis method described for Compound 2. It is a white solid (52 mg, yield 26%).

[0330] LC-MS m / z (ESI) = 418.1 [M+1].

[0331] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 9.53 (s, 1H), 8.65 (d, 1H), 8.02 (dd, 1H), 7.85 (s, 1H), 7.02 (d, 1H), 6.91 (d, 1H), 6.89 (d, 1H), 6.85 (d, 1H), 3.75–3.68 (m, 4H), 3.52–3.45 (m, 4H), 1.88 (s, 3H), 1.79 (s, 3H).

[0332] Example 19

[0333] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 19)

[0334] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0335]

[0336]

[0337] The first step

[0338] 1,5-Difluoro-2,4-dimethyl-3-nitrobenzene (19b)

[0339] 1,5-difluoro-2,4-dimethyl-3-nitrobenzene

[0340] Weigh 19a (9 g, 29 mmol, 1.0 eq), trimethylcyclotriboroxane (55.8 mL, 200 mmol, 7.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.08 g, 2.9 mmol, 0.1 eq), potassium phosphate (15.66 g, 112 mmol, 4 eq), and add them to a suspension of 180 mL of 1,4-dioxane and 36 mL of water. After addition, displace the air with nitrogen three times at room temperature, transfer the reaction to 80 °C, and react in an oil bath for 2 h. After the reaction is complete, naturally cool the reaction solution to room temperature, quench it with 200 mL of water, extract the system with ethyl acetate (400 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate the organic phase, and purify by normal-phase column chromatography (petroleum ether:dichloromethane = 19:1) to obtain 19b as a yellow solid (4 g, yield 75%).

[0341] LC-MS m / z (ESI) = 187.25 [M+1].

[0342] The second step

[0343] 1-Fluoro-5-methoxy-2,4-dimethyl-3-nitrobenzene (19c)

[0344] 1-fluoro-5-methoxy-2,4-dimethyl-3-nitrobenzene

[0345] Weigh 19b (4 g, 22 mmol, 1.0 eq) into a 100 mL reaction flask, and immediately add 40 mL of methanol to form a suspension. Cool the reaction solution to 0 °C, and add sodium methoxide solution (9.4 g, 220 mmol, 10 eq) (sodium methoxide is prepared as a 30% solution in methanol) in three portions; after addition, transfer the reaction to 80 °C and stir for 2 h. After the reaction is complete, quench it with 400 mL of water, extract the system with ethyl acetate (600 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate the organic phase, and obtain 19c as a yellow solid (2.8 g, yield 66%).

[0346] LC-MS m / z (ESI) = 200.18 [M+1].

[0347] The third step

[0348] 3-Fluoro-5-methoxy-2,6-dimethylaniline (19d)

[0349] 3-fluoro-5-methoxy-2,6-dimethylaniline

[0350] Weigh 19c (2.8 g, 14 mmol, 1.0 eq), ammonium chloride (10.9 g, 140 mmol, 10 eq) and acetic acid (630 mg, 7 mmol, 0.5 eq)) into a 100 mL reaction flask. Heat the reaction solution to 50 °C, then add iron powder (5.7 g, 126 mmol, 9.0 eq) to the reaction solution, and heat the reaction solution to 80 °C for 0.5 h. After the reaction is complete, filter while it is hot, and then wash with ethanol. Collect the filtrate, concentrate it, and purify it by normal-phase column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 19d as a yellow solid (1.6 g, yield 70%).

[0351] LC-MS m / z (ESI) = 170.20 [M+1].

[0352] The fourth step

[0353] (E)-2-(((dimethylamino)methylene)amino)-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide (19e)

[0354] -2-(((dimethylamino)methylene)amino)-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide

[0355] Weigh 1-C (1.5 g, 3.95 mmol, 1.0 eq) and 19d (870 mg, 5.1 mmol, 1.3 eq) into a 100 mL reaction flask, and then immediately add 15 mL of toluene to the system. Replace the gas with nitrogen three times and protect it with nitrogen. Slowly add trimethylaluminum solution (3.95 mL, 7.9 mmol, 2.0 eq) (2 M toluene solution) to the system dropwise; after addition, transfer the reaction to 110 °C and stir for 1 h. After the reaction is complete, naturally cool the reaction solution to room temperature and quench it with 100 mL of ice water. Extract the system with ethyl acetate (200 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate the organic phase to obtain a residue. Purify it by normal-phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 19e as a yellow solid (1.2 g, product 60%).

[0356] LC-MS m / z (ESI) = 487.56 [M+1].

[0357] Step 5

[0358] (E)-5-Bromo-2-((dimethylamino)methylene)amino)-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-p-tolyl-1H-pyrrole-3-carboxamide (19f)

[0359] (E)-5-bromo-2-(((dimethylamino)methylene)amino)-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-tosyl-1H-pyrrole-3-carboxamide

[0360] 19e (1.15 g, 2.4 mmol, 1.0 eq) was weighed into a 100 mL reaction bottle, and 20 mL of dichloromethane was added to the system for suspension. The reaction solution was cooled to -78 °C, and pyridinium tribromide (908 mg, 2.6 mmol, 1.2 eq) was added. After the addition was completed, the reaction was stirred at -78 °C for 1 h. After the reaction was complete, 80 mL of sodium sulfite aqueous solution was added at low temperature to quench the reaction. The system was extracted with dichloromethane (150 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phases were concentrated to obtain 19f as a yellow solid (1.0 g, yield 75%).

[0361] LC-MSm / z(ESI)=565.46[M+1].

[0362] Step 6

[0363] 6-Bromo-3-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-p-tolyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (19g)

[0364] bromo-3-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0365] Weigh 19f (1.0 g, 1.8 mmol, 1.0 eq) in a 100 mL reaction bottle and add 5 mL of methanol to suspend the system. Add 5 mL of hydrogen chloride in ethyl acetate (4 M) to the reaction solution. After the addition, transfer the reaction to 60 ° C and stir for 1 h. After the reaction is complete, concentrate the reaction solution and purify it by normal phase column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 19g as a white solid (550 mg, yield 59%).

[0366] LC-MS m / z (ESI) = 521.37 [M+1].

[0367] The seventh step

[0368] 3-(3-Fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (19h)

[0369] (3-Fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0370] Weigh 19g (200mg, 0.38 mmol, 1.0 eq), 18a (223mg, 0.76 mmol, 2.0 eq), [n-Butyldi(1-adamantyl)phosphine]palladium(II) (2-aminobiphenyl-2-yl) methanesulfonate (28mg, 0.04 mmol, 0.1 eq), and potassium phosphate (244mg, 1.14 mmol, 3.0 eq) into a 30 mL microwave tube. Add 3 mL of ethylene glycol dimethyl ether and 0.6 mL of water suspension. After adding, displace with nitrogen three times at room temperature and react at 110 °C in the microwave for 1 h. After the reaction is complete, naturally cool the reaction solution to room temperature, add 20 mL of water, and extract the system with ethyl acetate (40 mL × 3); combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain the crude product 19h, which is a yellow solid (280mg, yield 63%).

[0371] LC-MS m / z (ESI) = 604.67 [M+1].

[0372] The eighth step

[0373] 3-(3-Fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (19i)

[0374] (3-Fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0375] Weigh 19h (280 mg, 0.29 mmol, 1.0 eq) into a 50 mL reaction flask. Immediately add 3 mL of methanol and 3 mL of ethanol to the system and suspend. At room temperature, add 3 mL of sodium hydroxide aqueous solution (1 M) dropwise to the system. After addition, transfer the reaction to 65 °C and stir for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: pure water = 25:75) to obtain 19i, which is a white solid (130 mg, yield 89%).

[0376] LC-MS m / z (ESI) = 450.49 [M+1].

[0377] The ninth step

[0378] 3-(3-Fluoro-5-hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 19)

[0379] 3-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0380] Weigh 19i (130 mg, 0.28 mmol, 1.0 eq) into a 50 mL reaction flask. Immediately add 3 mL of dichloromethane to the system and suspend. Under an ice bath, add boron tribromide solution (1.15 mL, 1.12 mmol, 4 eq) (1 M dichloromethane solution) dropwise to the system. After addition, remove the ice bath and stir at room temperature overnight. After the reaction is complete, add methanol dropwise to quench the reaction at low temperature, concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: pure water = 35:65) to obtain Compound 19, which is a white solid (40 mg, yield 32%).

[0381] LC-MS m / z (ESI) = 435.46 [M+1].

[0382] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (d, 1H), 10.08 (s, 1H), 8.69 (d, 1H), 8.44 (dd, 1H), 8.04 (s, 1H), 7.38 (d, 1H), 7.14–7.09 (m, 1H), 6.78 (d, 1H), 4.78–4.68 (t, 2H), 4.05 (t, 2H), 3.67 (d, 2H), 3.64 (t, 2H), 1.79 (t, 3H), 1.76 (s, 3H).

[0383] 19 F NMR (377 MHz, DMSO-d 6 ) δ -118.56。

[0384] Example 20

[0385] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 20)

[0386] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0387]

[0388] First and second steps

[0389] 3-(3-Fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (20b)

[0390] 3-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0391] Refer to the similar synthetic method of Compound 19h and 19i above to obtain 20b, which is a white solid (110 mg, yield 95%).

[0392] LC-MS m / z (ESI) = 379.41 [M+1].

[0393] Third step

[0394] 3-(3-Fluoro-5-hydroxy-2,6-dimethylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 20)

[0395] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0396] Weigh 20b (110 mg, 0.29 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of dichloromethane to suspend it. Dropwise add boron tribromide solution (1.16 mL, 1.16 mmol, 4 eq) (1 M dichloromethane solution) to the system under an ice bath. After addition, remove the ice bath and stir the reaction at room temperature overnight. When the reaction is complete, dropwise add methanol to quench the reaction at low temperature. Concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: pure water = 35:65) to obtain compound 20 as a white solid (27 mg, yield 26%).

[0397] LC-MS m / z (ESI) = 365.38 [M+1].

[0398] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (d, 1H), 10.08 (s, 1H), 8.97 (d, 1H), 8.15 (dd, 1H), 8.02 (s, 1H), 7.36 (d, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 2.52 (s, 3H), 1.80 (d, 3H), 1.77 (s, 3H).

[0399] 19 19F NMR (377 MHz, DMSO-d 6 ) δ -118.61.

[0400] Example 21

[0401] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 21)

[0402] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0403]

[0404] Starting from intermediate 1 and referring to the similar synthesis method described for compound 2, compound 21 was obtained as a white solid (35 mg, yield 22%).

[0405] LC-MS m / z (ESI) = 347.39 [M+1].[[]END]]

[0406] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.45 (s, 1H), 9.56 (s, 1H), 8.45 (dd, 1H), 7.97 (s, 1H), 7.91 (dd, 1H), 7.34 (dd, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 6.79 (s, 1H), 2.67 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H).

[0407] Example 22

[0408] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 22)

[0409] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0410]

[0411] First step:

[0412] 6-chloro-3-methoxy-2-methylaniline (22b)

[0413] 6-chloro-3-methoxy-2-methylaniline

[0414] Weighed 22a (8 g, 58.3 mmol, 1.0 eq) into a 250 mL reaction flask, and then added 80 mL of dichloromethane to the system to suspend. Under an ice bath, N-chlorosuccinimide (8.2 g, 61.3 mmol, 1.1 eq) was added to the system in three batches. After addition, the mixture was stirred at 0 °C for 1 h. After the reaction was complete, the reaction solution was directly concentrated to obtain a residue, which was purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 22b as a white solid (2.5 g, yield 25%).

[0415] LC-MS m / z (ESI) = 172.62 [M+1].

[0416] The second step

[0417] (E)-N-(6-chloro-3-methoxy-2-methylphenyl)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxamide (22c)

[0418] (E)-N-(6-chloro-3-methoxy-2-methylphenyl)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxamide

[0419] Weigh 1-C (1.0 g, 2.6 mmol, 1.0 eq) and 22b (685 mg, 3.9 mmol, 1.5 eq) into a 100 mL reaction flask, and then add 15 mL of toluene to the system. Replace the gas with nitrogen three times, protect the system with nitrogen, and slowly add trimethylaluminum solution (2.6 mL, 5.2 mmol, 2.0 eq) (2M toluene solution) dropwise to the system. After the addition, transfer the reaction to 110 °C and stir for 0.5 h. When the reaction is complete, naturally cool the reaction solution to room temperature and quench it with 100 mL of ice water. Extract with ethyl acetate (200 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain a residue. Purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 22c, which is a white solid (1.15 g, yield 89%).

[0420] LC-MS m / z (ESI) = 489.99 [M+1].

[0421] The third step

[0422] (E)-5-bromo-N-(6-chloro-3-methoxy-2-methylphenyl)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxamide (22d)

[0423] (E)-5-bromo-N-(6-chloro-3-methoxy-2-methylphenyl)-2-(((dimethylamino)methylene)amino)-1-tosyl-1H-pyrrole-3-carboxamide

[0424] Weigh 22c (1.15 g, 2.3 mmol, 1.0 eq) into a 100 mL reaction flask. Immediately add 20 mL of dichloromethane to the system to form a suspension. Cool the reaction solution to -78 °C, and add pyridinium tribromide (901 mg, 2.9 mmol, 1.2 eq). After addition, stir the reaction at -78 °C for 1 h. When the reaction is complete, quench the system with 80 mL of aqueous sodium sulfite solution at low temperature. Extract the system with dichloromethane (150 mL × 2). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain 22d as a yellow solid (1.25 g, yield 55%).

[0425] LC-MS m / z (ESI) = 568.88 [M+1].

[0426] The fourth step

[0427] 6-bromo-3-(6-chloro-3-methoxy-2-methylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (22e)

[0428] 6-bromo-3-(6-chloro-3-methoxy-2-methylphenyl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0429] Weigh 22d (1.25 g, 1.2 mmol, 1.0 eq) into a 100 mL reaction flask. Add 5 mL of methanol to the system to form a suspension. Add 5 mL of ethyl acetate solution of hydrogen chloride (4 M) to the reaction solution. After addition, transfer the reaction to 60 °C and stir the reaction for 1 h. When the reaction is complete, concentrate the reaction solution and purify it by normal-phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 22e as a white solid (550 mg, yield 87%).

[0430] LC-MS m / z (ESI) = 523.98 [M+1].

[0431] The fifth step

[0432] 3-(6-chloro-3-methoxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (22f)

[0433] 3-(6-chloro-3-methoxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-7-tosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0434] Weigh 22e (300 mg, 0.58 mmol, 1.0 eq), 18a (340 mg, 1.16 mmol, 2.0 eq), [n-butylbis(1-adamantyl)phosphine]palladium(II) (2-amino-1,1'-biphenyl-2-yl) methanesulfonate (42 mg, 0.06 mmol, 0.1 eq), and potassium phosphate (380 mg, 1.74 mmol, 3.0 eq) into a 50 mL reaction flask. Add 3 mL of ethylene glycol dimethyl ether and 0.6 mL of water and suspend. After addition, displace with nitrogen three times at room temperature and react at 90 °C by microwave for 3 h. After the reaction is complete, naturally cool the reaction solution to room temperature, add 20 mL of water to the reaction system, extract with ethyl acetate (40 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain the crude product 22f, which is a yellow solid (380 mg, yield 55%).

[0435] LC-MS m / z (ESI) = 607.09 [M+1].

[0436] The sixth step

[0437] 3-(6-chloro-3-methoxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (22g)

[0438] 3-(6-chloro-3-methoxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0439] Weigh 22f (380 mg, 0.34 mmol, 1.0 eq) into a 50 mL reaction flask. Immediately add 3 mL of methanol and 3 mL of ethanol to the system and suspend. Dropwise add 3 mL of 1 M aqueous sodium hydroxide solution to the system at room temperature. After addition, transfer the reaction to 65 °C and stir for 2 h. After the reaction is complete, directly concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: water = 38:65) to obtain 22g, which is a white solid (110 mg, yield 71%).

[0440] LC-MS m / z (ESI) = 452.91 [M+1].

[0441] The seventh step

[0442] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 22)

[0443] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0444] Weigh 22 g (110 mg, 0.24 mmol, 1.0 eq) into a 50 mL reaction flask, and immediately add 3 mL of dichloromethane to suspend it. Dropwise add boron tribromide solution (1.15 mL, 1.12 mmol, 1 M dichloromethane solution) to the system under an ice bath. After addition, remove the ice bath and stir the reaction at room temperature overnight. When the reaction is complete, quench the reaction by dropwise adding methanol at low temperature, concentrate the reaction solution to obtain a residue, and purify it by reverse-phase column chromatography (acetonitrile: water = 28:72) to obtain compound 22 as a white solid (17 mg, yield 16%).

[0445] LC-MS m / z (ESI) = 438.88 [M+1].

[0446] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.53 (s, 1H), 10.11 (s, 1H), 8.62 (d, 1H), 8.09 (dd, 1H), 7.97 (d, 1H), 7.32 (d, 1H), 7.03 (d, 1H), 7.01–6.95 (m, 2H), 3.72 (t, 4H), 3.53 (t, 4H), 1.87 (s, 3H).

[0447] Example 23

[0448] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 23)

[0449] 3-(6-chloro-3-hydroxy-2-methylphenyl)-6-(6-methylpyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0450]

[0451]

[0452] Compound 23 was obtained according to a similar synthetic method described in the fifth, sixth, and seventh steps of the above-mentioned compound 22, as a white solid (45 mg, yield 42%).

[0453] LC-MS m / z (ESI) = 367.81 [M+1].

[0454] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.84 (d, 1H), 10.14 (s, 1H), 9.07 (d, 1H), 8.47 (d, 1H), 8.09 (s, 1H), 7.64 (d, 1H), 7.33 (d, 2H), 7.00 (d, 1H), 2.60 (s, 3H), 1.88 (s, 3H).

[0455] Example 24

[0456] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(2-methyl-6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 24)

[0457] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(2-methyl-6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0458]

[0459]

[0460] The first step:

[0461] 4-(6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (24b)

[0462] 4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine

[0463] Weigh 24a (500 mg, 1.95 mmol, 1.0 eq), bis(pinacolato)diboron (741 mg, 2.92 mmol, 1.5 eq), bis(triphenylphosphine)palladium(II) dichloride (136 mg, 0.2 mmol, 0.1 eq), and potassium acetate (571 mg, 5.85 mmol, 3 eq) respectively, and suspend them in 5 mL of triethylamine. After adding, replace the air with nitrogen three times at room temperature, transfer the reaction solution to 90 °C, and react for 2 h. After the reaction is complete, naturally cool the reaction solution to room temperature, add 30 mL of water, extract the system with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate the organic phase, and purify by normal-phase column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 24b, which is a pale yellow solid (550 mg, yield 93%).

[0464] Second and third steps:

[0465] Refer to the similar synthesis method described in Compound 2 to obtain Compound 24, which is a white solid (25 mg, yield 17%).

[0466] LC-MS m / z (ESI) = 432.50 [M+1].

[0467] 1H NMR (400 MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 9.55 (s, 1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.03 (d, 1H), 6.90 (s, 1H), 6.88 (d, 1H), 6.63 (t, 1H), 3.72 (t, 4H), 3.54 (t, 4H), 2.56 (d, 3H), 1.89 (s, 3H), 1.80 (s, 3H).

[0468] Example 25

[0469] 3-(3-Hydroxy-2,6-dimethylphenyl)-6-(4-methyl-6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Compound 25)

[0470] 3-(3-hydroxy-2,6-dimethylphenyl)-6-(4-methyl-6-morpholinopyridin-3-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[0471]

[0472] First step:

[0473] 4-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (25b)

[0474] 4-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine

[0475] 25b was obtained by a similar synthetic method to that of the above-mentioned compound 24b, and it was a pale yellow solid (500 mg, yield 85%).

[0476] Steps two and three:

[0477] Compound 25 was obtained by a similar synthetic method to that described for compound 2, and it was a white solid (30 mg, yield 25%).

[0478] LC-MS m / z (ESI) = 432.50 [M+1].

[0479] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.34 (s, 1H), 9.55 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.04 (d, 1H), 7.01 (s, 1H), 6.87 (d, 1H), 6.67 (d, 1H), 3.73 (t, 4H), 3.55 (t, 4H), 2.45 (s, 3H), 1.89 (s, 3H), 1.80 (s, 3H).

[0480] Biological assays

[0481] PKMYT1 kinase inhibition assay

[0482] 1) The ADP-Glo TM Kinase Assay (Promega) was used to detect the inhibitory activity of the compound against PKMYT1 kinase, and different concentration ADP-fluorescence standard curves were constructed according to the kit instructions;

[0483] 2) Experiments were carried out in a 384-well white plate. 1 μL of the test compound at different concentrations, 2 μL of PKMYT1 kinase, 2 μL of the mixed solution of substrate and ATP were added to each well respectively. A control group (without the compound) and a solvent blank group were set up, mixed well, centrifuged (1000 rpm, 30 s), and incubated at 37 °C for 60 min;

[0484] 3) Add 5 μL of ADPrGlo TMThe reaction was terminated with the reagent, mixed well, centrifuged (1000 rpm, 30 s), and incubated at 25 °C for 40 min;

[0485] 4) Add 10 μL of Kinase Detection Reagent, mix well by shaking, centrifuge (1000 rpm, 30 s), and incubate at 25 °C for 30 min;

[0486] 5) Measure the fluorescence value using a microplate reader, calculate the enzyme activity inhibition rate. The formula is inhibition rate = (fluorescence value of experimental wells - fluorescence value of solvent blank wells) / (fluorescence value of control wells - fluorescence value of solvent blank wells) × 100%. Use GraphPad Prism 8 for fitting and calculate the IC 50 value. The results are shown in Table 1:

[0487] Table 1 Inhibitory activity of the compounds of the present invention against PKMYT1 enzyme

[0488]

[0489]

[0490] Note: A: IC 50 <10 nM; B: 10 nM < IC 50 <100 nM; C: 100 nM < IC 50 <1000 nM.

[0491] The experimental results show that the compounds of the present invention have significant inhibitory activity against PKMYT1 kinase.

[0492] Cell proliferation inhibition experiment - CTG

[0493] 1) Take OVCAR-3 cells in the logarithmic growth phase, add trypsin to digest them into single cells, centrifuge, resuspend and count, adjust the cell density, and inoculate them into a 96-well cell culture plate (1500 cells / well). Set up experimental wells, control wells, and solvent control wells. After inoculation, incubate overnight in an incubator at 37 °C and 5% CO 2 .

[0494] 2) Prepare a 10 mM stock solution of the test compound with DMSO, dilute the compound stock solution with RPMI-1640 medium, and obtain 9 concentrations of the compound by 3-fold serial dilution. Add them to the 96-well plate so that the final concentration is 4 nM - 30 μM, and place them in an incubator at 37 °C and 5% CO 2 and continue to culture for 4 days.

[0495] 3) Remove the 96-well plate from the incubator, add the working solution of CellTiter-Glo (Promega), place it on a thermostatic shaker and shake for 2 min, incubate in the dark at room temperature for 10 min, put it into a microplate reader, and perform chemiluminescence reading after shaking for 5 s.

[0496] 4) Calculate the cell survival rate = (luminescence value of experimental wells - luminescence value of solvent control wells) / (luminescence value of control wells - luminescence value of solvent control wells) × 100%

[0497] 5) Data analysis: Use GraphPad Prism 8 software to calculate the half-maximal inhibitory concentration (IC 50 ) by curve fitting, and plot the compound effect-dose curve:

[0498] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0499] X: Compound concentration

[0500] Y: Cell survival rate (% Viability)

[0501] The experimental results show that the compounds of the present invention have a significant inhibitory effect on cell proliferation.

[0502] The description of the specific implementation methods in the specification of the present invention has been detailed. Those skilled in the art should recognize that the above implementation methods are exemplary and should not be construed as limitations on 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 protection scope of the claims of the present invention.

Claims

1. A pyrimidone derivative represented by formula (I), or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound of formula (I) is: in, R1 and R2 are each independently selected from halogen, C 1-6 Alkyl or 3-6 membered cycloalkyl; A is selected from phenyl, naphthyl or 4-10 membered heteroaryl, wherein the 4-10 membered heteroaryl contains at least 1 N; R3 are each independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, wherein the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by 1 to 3 members selected from C 1-6 Alkyl, halogen or hydroxy substituent substitution; R4 is selected from H, halogen or C 1-6 alkyl; n is selected from 0, 1, 2 or 3.

2. The pyrimidone derivative according to claim 1, or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound has the structure shown in formula (I-1): in, R1 and R2 are each independently selected from C 1-6 Alkyl or 3-6 membered cycloalkyl; A is a 4-8 membered heteroaryl group, wherein the 4-8 membered heteroaryl group contains at least 1 N; R3 are each independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, C 1-6 haloalkyl or 3-8 membered heterocycloalkyl, wherein the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by C 1-6 Alkyl, halogen or hydroxy substitution; n is selected from 0, 1, 2 or 3.

3. The pyrimidone derivative according to claim 2, or any stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound has a structure shown in formula (I-2): in, R1 and R2 are each independently selected from C 1-6 Alkyl or 3-6 membered cycloalkyl; A is a 4-8 membered heteroaryl group, wherein the 4-8 membered heteroaryl group contains at least 1 N; R3 is selected from C 1-3 Alkyl, 3-6 membered cycloalkyl, C 1-3 haloalkyl or 3-6 membered heterocycloalkyl, the 3-6 membered heterocycloalkyl is optionally substituted by C 1-3 Alkyl, halogen or hydroxyl substituted.

4. The pyrimidone derivative according to any one of claims 1 to 3, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or cocrystals thereof, wherein: A is selected from phenyl, 5. The pyrimidone derivative according to any one of claims 1 to 4, or any stereoisomers, solvates, prodrugs, metabolites, deuterated substances, pharmaceutically acceptable salts or co-crystals thereof, wherein the compound is selected from the following structures:

6. A pharmaceutical composition, comprising: (1) The pyrimidone derivative according to any one of claims 1 to 5, or a stereoisomer, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable salt or cocrystal thereof; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

7. Use of the pyrimidone derivative or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 in the preparation of an anti-tumor drug.

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