Tricyclic quinazoline or dihydroquinazoline compounds as inhibitors of AKT

Abstract

The application discloses a tricyclic quinazoline or dihydroquinazoline compound as an AKT inhibitor, a structure of the tricyclic quinazoline compound is shown in general formula I, definitions of various substituents are shown in the specification, and a preparation method of the tricyclic quinazoline compound is provided. The tricyclic quinazoline compound has significant AKT inhibiting activity and can be used as an AKT inhibitor.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to AKT inhibitors, their preparation methods, and their pharmaceutical uses. Background Technology

[0002] The PI3K / AKT / mTOR pathway, composed of phosphatidylinositol 3-kinase (PI3K), its downstream protein AKT (also known as protein kinase B, PKB), and mammalian target of rapamycin (mTOR), is a crucial intracellular signal transduction pathway that plays a vital biological role in cell growth, survival, proliferation, apoptosis, angiogenesis, and autophagy. Abnormal activation of this pathway can lead to a range of diseases, including cancer, neuropathies, autoimmune diseases, and hematologic / lymphatic disorders.

[0003] AKT has three isoforms: AKT1, AKT2, and AKT3. As typical protein kinases, each isoform consists of an N-terminal PH domain (Pleckstrin homology domain), a central ATP-binding kinase domain, and a C-terminal regulatory domain. The three isoforms share approximately 80% amino acid sequence homology, with significant variations only in the PH domain and kinase domain junction regions.

[0004] Currently, targeted drugs against the PI3K / AKT / mTOR signaling pathway are mainly PI3K inhibitors and mTOR inhibitors, while AKT is located at the core of this signal transduction pathway. Inhibiting AKT activity can avoid the serious side effects caused by inhibiting upstream PI3K, and also avoid the negative feedback mechanism that affects drug efficacy caused by inhibiting downstream mTOR. Therefore, finding effective and selective AKT inhibitors is an important direction in the current research and development of targeted cancer drugs. Summary of the Invention

[0005] On the one hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0006]

[0007] in:

[0008] R 1 and R 5 Each is independently selected from H, amino, or -NH (C1-C6 alkyl);

[0009] R 2 Selected from hydrogen or C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with a heterocyclic group, halogen, OH, NH2 or NH (C1-C3 alkyl);

[0010] R 3 and R4 Each is independently selected from H, halogens or C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally substituted with halogens;

[0011] X is selected from CH, O, or S, and Y is selected from CH, O, or S. When X is selected from O or S, Y is selected from CH; when X is selected from CH, Y is selected from S or O.

[0012] n is selected from 0, 1, 2, or 3;

[0013] Dashed lines can represent single or double bonds.

[0014] In some implementation schemes, R 1 and R 5 Each is independently selected from H, amino, or methylamino; preferably R 5 Selected from amino and R 1 Selected from H; more preferably, R 5 Selected from H and R 1 Selected from amino or methylamino; most preferably, R 5 Selected from H and R 1 Selected from methylamino.

[0015] In some implementation schemes, R 2 Selected from hydrogen, methyl, hydroxyethyl, aminomethyl or Preferred, R 2 Selected from hydroxyethyl, aminomethyl or More preferably, R 2 Selected from aminomethyl.

[0016] In some implementation schemes, R 3 and R 4 Each is independently selected from H, trifluoromethyl, F, or Cl.

[0017] In some implementation schemes, R 3 It can be F, Cl, or H.

[0018] In some implementation schemes, R 4 It can be H, Cl, or trifluoromethyl.

[0019] In some implementation schemes, R 3 For H and R 4 It is Cl.

[0020] In some implementation schemes, R 3 Selected from F and R 4 Selected from H.

[0021] In some implementations, X is selected from S, and Y is selected from CH.

[0022] In some implementations, n is selected from 0 or 1; preferably, n is selected from 0.

[0023] In some embodiments, the aforementioned compound of formula I has a structure as shown in formula II.

[0024]

[0025] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of , n and the dashed line are as defined in the compound of formula I, and X is selected from S or O.

[0026] In some implementations, dashed lines represent single bonds.

[0027] In some implementations, X is selected from S.

[0028] In some embodiments, the aforementioned compound of formula I has a structure as shown in formula III.

[0029]

[0030] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of , n and the dashed line are as defined in the compound of formula I, and Y is selected from S or O.

[0031] In some implementations, dashed lines represent double bonds.

[0032] In some implementations, Y is selected from S.

[0033] On the other hand, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0034]

[0035] On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III or a pharmaceutically acceptable salt thereof.

[0036] The pharmaceutical compositions of the present invention can be administered by any suitable route or method, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of compounds of formulas I, II, and III is from about 0.001 mg to 20 mg / kg body weight / day, preferably from 0.01 mg to 10 mg / kg body weight / day.

[0037] For oral administration, the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules, or solutions. Tablets may contain the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. These carriers include, but are not limited to, diluents, disintegrants, binders, lubricants, colorants, or preservatives. Capsules include hard capsules and soft capsules.

[0038] For parenteral administration, the pharmaceutical compositions of the present invention can be administered via intravenous, intramuscular, or subcutaneous injection. They are typically provided as sterile aqueous solutions, suspensions, or lyophilized powders, adjusted to a suitable pH and isotonicity.

[0039] On the other hand, the present invention also provides the use of compounds of formulas I, II, and III in the preparation of medicaments for the prevention and / or treatment of AKT protein kinase-mediated diseases or disease states.

[0040] On the other hand, the present invention also provides methods for preventing and / or treating AKT protein kinase-mediated diseases or disease states, comprising administering compounds of formula I, II, III of the present invention or pharmaceutical compositions of the present invention to an individual in need.

[0041] On the other hand, the present invention also provides compounds of formula I, II, III or pharmaceutical compositions of the present invention for the prevention and / or treatment of AKT protein kinase-mediated diseases or disease states.

[0042] Examples of diseases or disease states mediated by the AKT protein kinase include, but are not limited to, breast cancer, prostate cancer, or ovarian cancer.

[0043] In another aspect, the present invention provides a method for preparing compound of formula I, including but not limited to the following synthetic schemes:

[0044] Synthesis Scheme 1

[0045]

[0046] Among them, R 2 R 3 R 4 As defined above, Y is selected from S or O; in some implementations, Y is selected from S.

[0047] Compound 1-1 is reacted with an oxidant (e.g., cerium ammonium nitrate) and a solvent (e.g., acetic acid and water) to prepare compound 1-2. Compound 1-2 is reacted with a condensation reaction to prepare compound 1-3. Compound 1-3 is reacted with N,N-dimethylformamide-dimethyl acetal and acetic acid to prepare compound 1-4. Compound 1-4 is reacted with 1-methylguanidine hydrochloride in the presence of sodium ethoxide and ethanol to further generate compound 1-5. Compound 1-5 is reacted with an oxidant (e.g., 2,3-dichloro-5,6-dicyanobenzoquinone) to prepare compound 1-6. Compound 1-6 is hydrolyzed to give compound 1-7. Compound 1-7 is reacted with compound 1-11 to prepare compound 1-8. Compound 1-5 is hydrolyzed to give compound 1-9. Compound 1-7 is reacted with compound 1-11 to prepare compound 1-10.

[0048] Synthesis Scheme 2

[0049]

[0050] Among them, R 1 R 2 R 3 R 4 As defined above, X is selected from S or O; in some implementations, X is selected from S.

[0051] Compound 2-1 is reacted with a brominating agent (e.g., bromine) and a solvent (e.g., acetic acid, water) to prepare compound 2-2. Compound 2-2 is reacted with a catalyst (e.g., palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene) to prepare compound 2-3. Compound 2-3 is reacted with N,N-dimethylformamide-dimethyl acetal to prepare compound 2-4. Compound 2-4 is reacted with 1-methylguanidine hydrochloride or guanidine hydrochloride in the presence of sodium ethoxide and ethanol to further generate compound 2-5. Compound 2-5 is hydrolyzed to give compound 2-6. Compound 2-6 is reacted with compound 1-11 to prepare compound 2-7. Compound 2-5 is reacted with an oxidizing agent (e.g., 2,3-dichloro-5,6-dicyanobenzoquinone) to prepare compound 2-8. Compound 2-8 is hydrolyzed to give compound 2-9. Compound 2-9 is reacted with compound 1-11 to prepare compound 2-10.

[0052] The asterisk (*) indicates a chiral center. The compound can be in its optically pure form or a mixture of stereoisomers in any proportion thereof. Detailed Implementation

[0053] Related definitions

[0054] Unless otherwise specified, the following terms used in the specification and claims shall have the following meanings:

[0055] The "compounds" described in this invention include all stereoisomers and tautomers.

[0056] The compounds of this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of this invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomers, and enantiomers are all included within the scope of this invention.

[0057] The compounds of this invention also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0058] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0059] The term “selected from” means that the event or situation described below must happen.

[0060] The numerical ranges used in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.

[0061] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the particular atom or group is normal and the substituted compound is stable. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0062] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and each case has independent options for R. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0063] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups having the indicated number of carbon atoms. For example, the term "C1-C4 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, and C4 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0064] The term heterocyclic group refers to a saturated or unsaturated (but not aromatic) four-, five-, six-, or seven-membered ring containing one or two nitrogen, oxygen, or sulfur atoms. Examples include, but are not limited to, tetrahydrofuranyl, pyrrolyl, or piperazineyl.

[0065] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0066] The term "hydroxyl group" refers to -OH.

[0067] The term "amino" refers to -NH2.

[0068] The term "methylamino" refers to -NHCH3.

[0069] and Both refer to the junction of chemical bonds and have the same chemical meaning. Unless otherwise specified, and The only difference is in the position or order of the connections.

[0070] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid or base of a particular compound without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases). The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acid radical or base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0071] The term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.

[0072] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the body and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration for use in humans or animals.

[0073] Unless otherwise specified, the abbreviation of this invention has the following meanings:

[0074] M: mol / L

[0075] mM: mmol / L

[0076] nM: nmol / L

[0077] h: hours

[0078] min: minutes

[0079] 1 1H NMR: Proton NMR spectrum

[0080] LC / MS: Liquid Chromatography / Mass Spectrometry

[0081] DCM: Dichloromethane

[0082] Boc: tert-Butoxycarbonyl

[0083] Preparation method:

[0084] The preparation methods of the compounds of the present invention are described in more detail below, but these specific preparation methods do not constitute any limitation on the scope of the present invention. Furthermore, reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times are not limited to the examples below.

[0085] The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0086] Example 1: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)thiopheno[3,2-H]quinazolin-8-carboxamide

[0087]

[0088] a) 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid

[0089] Under nitrogen protection, 240 mg of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid, 36.3 mL of acetic acid, and 36.3 mL of water were added to a 250 mL three-necked flask and stirred. A solution of 3.3 g of cerium ammonium nitrate in 36.3 mL of acetic acid was added dropwise at 15 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 6 hours. When the reaction was complete, 50 mL of water and 100 mL of dichloromethane were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined and concentrated to dryness under reduced pressure to give 2.2 g of the yellow title product.

[0090] b) Ethyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate

[0091] 150 mg of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid, 2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 500 mg of 4-dimethylaminopyridine, 20 mL of dichloromethane, and 1.38 g of ethanol were placed in a reaction flask and stirred at 5 °C for 30 minutes. The reaction mixture was then allowed to react at room temperature for 6 hours. The reaction mixture was then concentrated to dryness, and the residue was purified by column chromatography to give 2.0 g of the white title product.

[0092] c) 6-((dimethylamino)methylene)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester

[0093] Ethyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (2 g), N,N-dimethylformamide-dimethyl acetal (10 mL), and acetic acid (2 drops) were placed in a sealed glass tube and reacted at 130 °C for 2 hours. The reaction mixture was then stirred at 0 °C, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with methyl tert-butyl ether (10 mL) to give 2.0 g of the yellow title product.

[0094] d) Ethyl 2-(methylamino)-5,6-dihydrothiopheno[3,2-h]quinazolin-8-carboxylate

[0095] Ethyl 6-((dimethylamino)methylene)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (2 g), 1-methylguanidine hydrochloride (1.21 g), sodium ethoxide (1.7 g), and ethanol (20 mL) were placed in a 100 mL single-necked flask and stirred at room temperature for 5 minutes. The reaction mixture was then heated to reflux and reacted for 2 hours. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography to give 1.2 g of the yellow title product.

[0096] e) 2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxylic acid ethyl ester

[0097] Ethyl 2-(methylamino)-5,6-dihydrothieno[3,2-h]quinazolin-8-carboxylate (900 mg) and toluene (25 mL) were added to a 100 mL single-necked flask and stirred. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (1.5 g) was added, and the mixture was heated to 100 °C and reacted for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography to give 276 mg of the white title product.

[0098] f) 2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxylic acid

[0099] Ethyl 2-(methylamino)thieno[3,2-h]quinazoline-8-carboxylate (90 mg), tetrahydrofuran (4 mL), and methanol (4 mL) were added to a 10 mL single-necked flask and stirred until dissolved. Then, 1 mL of 2N sodium hydroxide was added dropwise, and the mixture was stirred at room temperature for 10 hours. The pH of the reaction solution was then adjusted to 7 with 2N hydrochloric acid, and the solution was concentrated to dryness under reduced pressure. The pH of the residue was adjusted to 1–2 with 2N hydrochloric acid, resulting in the precipitation of a large amount of solid. The residue was filtered and the filter cake was dried to obtain 72 mg of the yellow title product.

[0100] g)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxamide

[0101] 2-(methylamino)thieno[3,2-h]quinazoline-8-carboxylic acid (80 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg), and N,N-dimethylformamide (20 mL) were placed in a 100 mL sealed single-necked flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (60 mg) and (S)-3-amino-3-(4-chlorophenyl)prop-1-ol (55 mg) were added, and the mixture was gradually brought to room temperature and reacted for 6 hours. Water (30 mL) was then added, and the mixture was extracted twice with ethyl acetate (30 mL x 2). The organic layer was concentrated to dryness, and the residue was purified by column chromatography to give 100 mg of the yellow title product.

[0102] 1 H NMR (300MHz, DMSO-d6) δ9.26-9.11(m,2H),8.29(s,1H),7.71(dd,J=18.4,8.4Hz,2H),7.61(d,J=5.0Hz,1H),7.50–7.38(m,4H),5.17(dd,J=14.8,8 .0Hz,1H),4.63(t,J=4.8Hz,1H),3.53–3.39(m,2H),2.95(d,J=4.7Hz,3H) ,2.14–2.02(m,1H),1.91(dd,J=13.5,6.7Hz,1H).MS(ESI+):427.1(M+H).

[0103] Example 2: Synthesis of (S)-N-(1-amino-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxamide

[0104]

[0105] a)(S)-N-(1-(1-(1,3-dioxoisoindol-2-yl)-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxamide

[0106] 2-(methylamino)thieno[3,2-h]quinazoline-8-carboxylic acid (90 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg), and N,N-dimethylformamide (20 mL) were placed in a 100 mL reaction flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (70 mg), (S)-2-(2-amino-3-(3-fluorophenyl)propyl)isoindoline-1,3-dione (110 mg), and triethylamine (60 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. The reaction was stopped when complete. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The organic phase was concentrated to dryness, and the residue was subjected to column chromatography to give 173 mg of the yellow title product.

[0107] b)(S)-N-(1-amino-3-(3-fluorophenyl)propyl-2-yl)-2-(methylamino)thiopheno[3,2-h]quinazolin-8-carboxamide

[0108] (S)-N-(1-(1-(1,3-dioxoisoindol-2-yl)-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)thieno[3,2-h]quinazolin-8-carboxamide (173 mg), ethanol (20 mL), and hydrazine hydrate (30 mg, 80% w / t) were placed in a reaction flask and reacted at 60 °C for 8 hours. The reaction solution was then concentrated to dryness, and the residue was purified by column chromatography to give 121 mg of the yellow title product.

[0109] 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.85(s,1H),8.23(s,1H),7.74(d,J=8.5Hz,1H),7.67(d,J=8.4Hz,1H),7.61(s,1H),7.32 (dd,J=14.5,7.4Hz,1H),7.13(d,J=7.9Hz,2H),7.02(t,J=8.4Hz,1H),4.34(br1H),3.10–2.84(m,8H).MS(ESI+):410.95(M+H).

[0110] Example 3: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothieno[3,2-h]quinazolin-8-carboxamide

[0111]

[0112] a) 2-(methylamino)-5,6-dihydrothieno[3,2-h]quinazolin-8-carboxylic acid

[0113] Ethyl 2-(methylamino)-5,6-dihydrothieno[3,2-h]quinazoline-8-carboxylate (145 mg) and methanol (5 mL) were added to a reaction flask, stirred, and dissolved. Then, 2 N sodium hydroxide (2 mL) was added dropwise, and the mixture was stirred at room temperature for 10 h. The reaction was stopped when the reactants had completely reacted. The pH of the reaction solution was adjusted to 7 with 2 N hydrochloric acid, and the solution was concentrated to dryness. The pH of the residue was adjusted to 1–2 with 2 N hydrochloric acid, resulting in the precipitation of a large amount of the title product. The product was filtered and dried to obtain 90 mg of the yellow title product.

[0114] b)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiopheno[3,2-h]quinazolin-8-carboxamide

[0115] 100 mg of 2-(methylamino)-5,6-dihydrothieno[3,2-h]quinazoline-8-carboxylic acid, 140 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 20 mL of N,N-dimethylformamide were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 70 mg of 1-hydroxybenzotriazole and 73 mg of (S)-3-amino-3-(4-chlorophenyl)prop-1-ol were added, and the mixture was gradually brought to room temperature and reacted for 6 hours. The reaction was stopped when complete. 30 mL of ethyl acetate and 30 mL of water were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was subjected to silica gel column chromatography to give 108 mg of the title product.

[0116] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=8.1Hz,1H),8.17(s,1H),7.80(s,1H),7.44–7.35(m,4H),6.97(d,J=4.6Hz,1H),5.10(dd,J=14.5,8.5Hz,1H) ,4.60(t,J=4.9Hz,1H),3.51–3.39(m,2H),2.89–2.84(m,2H),2.84-2.7 6(m,5H),2.08-1.97(m,1H),1.91-1.82(m,1H).MS(ESI+):429.1(M+H).

[0117] Example 4: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0118]

[0119] a) 2-Bromo-6,7-dihydrobenzo[b]thiophene-4-(5H)-one

[0120] 1 g of 6,7-dihydrobenzo[b]thiophene-4-(5H)-one, 5 mL of acetic acid, and 5 mL of water were added to a 50 mL three-necked flask and stirred. A solution of 1 g of bromine in 10 mL of acetic acid was added dropwise at -10°C. After the addition was complete, the reaction was maintained at this temperature for 1 h, followed by 6 h at room temperature. Once the reaction was complete, the mixture was concentrated, and the pH was adjusted to 5-6 with sodium acetate solution. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted again with 20 mL of ethyl acetate. The organic layers were combined, concentrated to dryness, and the residue was purified by column chromatography to give 1.33 g of the brown title product.

[0121] b) Ethyl 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate

[0122] 680 mg of 2-bromo-6,7-dihydrobenzo[b]thiophene-4-(5H)-one, 60 mg of palladium acetate, 35 mg of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 504 mg of triethylamine, 20 mL of N,N-dimethylformamide, and 5 mL of ethanol were placed in a 100 mL three-necked flask and filled with carbon monoxide gas. The reaction solution was placed at 70°C and reacted for 4 hours. The reaction solution was then concentrated to dryness, and the residue was purified by column chromatography to give 240 mg of the white title product.

[0123] c) 5-((dimethylamino)methylene)-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid ethyl ester

[0124] Ethyl 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (230 mg), N,N-dimethylformamide-dimethyl acetal (4 mL), and acetic acid (1 drop) were placed in a sealed reaction flask and reacted in an oil bath at 130 °C for 2 hours. The reaction solution was then concentrated to dryness to obtain a crude brown title product, which was directly added to the next step.

[0125] d) Ethyl 2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxylate

[0126] Ethyl 5-((dimethylamino)methylene)-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate (300 mg), 1-methylguanidine hydrochloride (190 mg), sodium ethoxide (270 mg), and ethanol (20 mL) were placed in a 100 mL single-necked flask and stirred at room temperature for 5 minutes. The reaction mixture was then heated to reflux and reacted for 2 hours. The reaction solution was then concentrated to dryness, and the residue was purified by column chromatography to give 67 mg of the yellow title product.

[0127] e)2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazolin-8-carboxylic acid

[0128] Ethyl 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylate (67 mg), tetrahydrofuran (5 mL), and methanol (5 mL) were added to a 50 mL single-necked flask. The mixture was stirred and dissolved. Then, 1 mL of 2N sodium hydroxide was added dropwise, and the mixture was stirred at room temperature for 10 hours. The reaction was stopped when the reactants had completely reacted. The pH of the reaction solution was adjusted to 7 with 2N hydrochloric acid, and the solution was concentrated to dryness. The residue was adjusted to pH 1-2 with 2N hydrochloric acid, resulting in the precipitation of a large amount of the title product. The product was filtered and dried to obtain 40 mg of the yellow title product.

[0129] f)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0130] 40 mg of 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid, 66 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 10 mL of N,N-dimethylformamide were placed in a 100 mL reaction flask and stirred at 5 °C for 5 minutes. Then, 30 mg of 1-hydroxybenzotriazole and 35 mg of (S)-3-amino-3-(4-chlorophenyl)prop-1-ol were added, and the mixture was gradually brought to room temperature for 6 hours. The reaction was stopped after completion. 20 mL of ethyl acetate and 20 mL of water were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was subjected to column chromatography to give 50 mg of the yellow title product.

[0131] 1H NMR (300MHz, DMSO-d6) δ9.04(d,J=8.3Hz,1H),8.25(s,1H),8.16(s,1H),7.40(s,4H),6.79(br,1H),5.10(m,1H),4.60( m,1H),3.51–3.37(m,2H),3.05-2.95(m,2H),2.91–2.79(m,5H),2.10–1.99(m,1H),1.88(m,1H).MS(ESI+):429.1(M+H).

[0132] Example 5: Synthesis of N-(4-chlorobenzyl)-2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxamide

[0133]

[0134] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid (80 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg), and N,N-dimethylformamide (10 mL) were placed in a 100 mL sealed single-necked flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (70 mg) and (4-chlorophenyl)methylamine (60 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, stirred, and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography to give 80 mg of the title product.

[0135] 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.20(s,1H),8.15(s,1H),7.46-7.30(m,4H),6.76(s,1 H),4.44(d,J=5.6Hz,2H),3.01(t,J=7.4Hz,2H),2.90-2.78(m,5H).MS(ESI+):385.1(M+H).

[0136] Example 6: Synthesis of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0137]

[0138] 120 mg of 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid, 80 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 10 mL of N,N-dimethylformamide were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 40 mg of 1-hydroxybenzotriazole and 60 mg of (S)-1-(4-chlorophenyl)ethyl-1-amine were added, and the mixture was gradually brought to room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, and the residue was subjected to column chromatography to give 76 mg of the title product.

[0139] 1 H NMR(400MHz, DMSO-d6)δ9.09(d,J=7.9Hz,1H),8.27(s,1H),8.16(s,1H),7.41(s,4H),6.76(s,1H),5.15–5.06(m,1H ),3.00(t,J=7.6Hz,2H),2.88(d,J=4.7Hz,3H),2.83(t,J=7.6Hz,2H),1.48(d,J=7.1Hz,3H).MS(ESI+):399.1(M+H).

[0140] Example 7: Synthesis of (S)-N-(1-amino-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0141]

[0142] a)(S)-N-(1-(1,3-dioxoisoindol-2-yl)-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0143] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazolin-8-carboxylic acid (130 mg), (S)-2-(2-amino-3-(3-fluorophenyl)propyl)isoindoline-1,3-dione (160 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (300 mg), and N,N-dimethylformamide (20 mL) were placed in a reaction flask and stirred at room temperature. Then, N,N-diisopropylethylamine (300 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction was stopped after completion. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, and the residue was subjected to column chromatography to obtain 245 mg of the title product.

[0144] b)(S)-N-(1-amino-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0145] (S)-N-(1-(1,3-dioxoisoindol-2-yl)-3-(3-fluorophenyl)prop-2-yl)-2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxamide (245 mg), ethanol (20 mL), and hydrazine hydrate (50 mg, 80% w / t) were placed in a reaction flask and heated to reflux for 16 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to column chromatography to give 148 mg of the white title product.

[0146] 1 H NMR(400MHz, DMSO)δ8.90(d,J=8.5Hz,1H),8.25(s,2H),8.13(br,3H),7.33(dd,J=14.4,7.9Hz,1H),7.13-7.09(m,2H),7 .03(t,J=8.4Hz,1H),4.43–4.35(m,1H),3.09(t,J=7.4Hz,2H),3.01(br,5H),2.97–2.83(m,4H).MS(ESI+):412.2(M+H).

[0147] Example 8: Synthesis of N-(3-hydroxy-1-(4-(trifluoromethyl)phenyl)propyl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0148]

[0149] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid (50 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg), and N,N-dimethylformamide (20 mL) were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (40 mg), 3-amino-3-(4-(trifluoromethyl)phenyl)prop-1-ol (50 mg), and triethylamine (40 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, stirred, and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, and the residue was subjected to column chromatography to give 81 mg of the title product.

[0150] 1 H NMR(400MHz,DMSO-d6)δ9.13(d,J=8.1Hz,1H),8.27(s,1H),8.16(s,1H),7.72(d,J=8 .3Hz,2H),7.59(d,J=8.1Hz,2H),6.78(s,1H),5.21–5.14(m,1H),4.66(t,J=4.9Hz,1H ),3.52–3.47(m,1H),3.47–3.43(m,1H),2.99(t,J=7.6Hz,2H),2.88(d,J=4.5Hz,3H) ,2.83(t,J=7.6Hz,2H),2.11–2.04(m,1H),1.95-1.85(m,1H).MS(ESI+):463.1(M+H).

[0151] Example 9: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)thiopheno[2,3-h]quinazolin-8-carboxamide

[0152]

[0153] a) Ethyl 2-(methylamino)thiopheno[2,3-h]quinazolin-8-carboxylic acid ester

[0154] Ethyl 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazolin-8-carboxylate (200 mg) and dioxane (20 mL) were added to a 25 mL single-necked flask and stirred. Then, 2,3-dichloro-5,6-dicyanobenzoquinone (300 mg) was added, and the mixture was heated to 100 °C for 4 hours. The reaction solution was then concentrated to dryness, and the residue was purified by column chromatography to give 95 mg of the white title product.

[0155] b) 2-(methylamino)thiopheno[2,3-h]quinazolin-8-carboxylic acid

[0156] Ethyl 2-(methylamino)thieno[2,3-h]quinazoline-8-carboxylate (95 mg) and methanol (5 mL) were added to a reaction flask, and 1 mL of 2N sodium hydroxide was added dropwise with stirring. The mixture was stirred at room temperature for 10 hours. The pH of the reaction solution was adjusted to approximately 7 with 2N hydrochloric acid, and the solution was concentrated to dryness. Then, the pH of the residue was adjusted to 1–2 with 2N hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered and the filter cake was dried to obtain 66 mg of the yellow title product.

[0157] c)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)thiopheno[2,3-h]quinazolin-8-carboxamide

[0158] 2-(methylamino)thieno[2,3-h]quinazoline-8-carboxylic acid (65 mg), (S)-3-amino-3-(4-chlorophenyl)prop-1-ol (50 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg), and N,N-dimethylformamide (20 mL) were placed in a 100 mL reaction flask and stirred at room temperature. Then, N,N-diisopropylethylamine (100 mg) was added, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was subjected to column chromatography to give 84 mg of the title product.

[0159] 1 H NMR (400MHz, DMSO-d6) δ9.31 (d, J = 7.9Hz, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 7. 83–7.71(m,2H),7.58(br,1H),7.43(q,J=8.7Hz,4H),5.16(dd,J=14.7,8.3H z,1H),4.63(t,J=4.8Hz,1H),3.57–3.48(m,1H),3.48–3.42(m,1H),3.06(d, J=2.9Hz,3H),2.19–2.05(m,1H),1.99–1.85(m,1H).MS(ESI+):427.1(M+H).

[0160] Example 10: Synthesis of (S)-2-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0161]

[0162] a) 2-Bromo-5-((dimethylamino)methylene)-6,7-dihydrobenzothiophene-4(5H)-one

[0163] 2-Bromo-6,7-dihydrobenzo[b]thiophene-4-(5H)-one (230 mg), N,N-dimethylformamide-dimethyl acetal (4 mL), and acetic acid (1 drop) were placed in a sealed reaction flask and reacted at 130 °C for 2 h. The reaction solution was then concentrated to dryness to obtain 300 mg of the brown title product crude, which was directly added to the next step.

[0164] b) 8-Bromo-5,6-dihydrothiophene[2,3-h]quinazolin-2-amine

[0165] 300 mg of 2-bromo-5-((dimethylamino)methylene)-6,7-dihydrobenzothiophene-4(5H)-one, 150 mg of guanidine hydrochloride, 270 mg of sodium ethoxide, and 20 mL of ethanol were placed in a 100 mL single-necked flask and stirred at room temperature for 5 minutes. The reaction mixture was then heated to reflux and reacted for 2 hours. The reaction mixture was then concentrated to dryness, and the residue was purified by column chromatography to give 120 mg of the yellow title product.

[0166] c) 2-Amino-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxylic acid

[0167] 8-Bromo-5,6-dihydrothiophene[2,3-h]quinazolin-2-amine (120 mg), oxalic acid (70 mg), palladium acetate (30 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (45 mg), N,N-diisopropylethylamine (100 mg), N,N-dimethylformamide (20 mL), and acetic anhydride (75 mg) were placed in a 100 mL three-necked flask and stirred at 100 °C for 6 h. The reaction solution was then concentrated to dryness, and the residue was purified by column chromatography to give 90 mg of the white title product.

[0168] d)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxamide

[0169] 40 mg of 2-amino-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid, 66 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 10 mL of N,N-dimethylformamide were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 30 mg of 1-hydroxybenzotriazole and 35 mg of (S)-3-amino-3-(4-chlorophenyl)prop-1-ol were added, and the mixture was gradually heated to room temperature for 6 hours. Ethyl acetate (30 mL) and water (30 mL) were then added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted again with 20 mL of ethyl acetate. The organic layers were combined, washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography to give 50 mg of the yellow title product.

[0170] 1 H NMR(400MHz,DMSO-d6)δ9.07(d,J=8.1Hz,1H),8.25(s,1H),8.12(s,1H),7.39(m,4H),6.36(s,2H),5.09(td,J=8.6,5.9Hz,1H),4.59 (t,J=4.9Hz,1H),3.44(m,2H),2.99(t,J=7.6Hz,2H),2.82(t,J=7.7Hz,2H),2.13–1.95(m,1H),1.86(m,1H).MS(ESI+):415.1(M+H).

[0171] Example 11: Synthesis of (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0172]

[0173] a) Methyl 4-oxo-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate

[0174] Under nitrogen protection, 110 mg of 6,7-dihydrobenzothiophene-4(5H)-one was dissolved in 5 ml of dimethyl carbonate. Sodium hydroxide (35 mg, 60% w / w) was added in portions with stirring, and the mixture was refluxed at 85 °C for 3 hours. The mixture was then cooled to 10 °C, quenched with 20 ml of water, and extracted with 50 ml of ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography to give 125 mg of the title product.

[0175] b) 4-Hydroxy-5,6-dihydrothiopheno[2,3-h]quinazolin

[0176] Under nitrogen protection, methyl 4-oxo-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid (125 mg) and formamidine acetate (600 mg) were added to a reaction flask and reacted at 170 °C for 3 hours. The mixture was then cooled to 20 °C and extracted with water (50 mL) and ethyl acetate (50 mL). The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography to give 42 mg of the title product.

[0177] c) 4-Chloro-5,6-dihydrothieno[2,3-h]quinazolin

[0178] Under nitrogen protection, 4-hydroxy-5,6-dihydrothieno[2,3-h]quinazoline (42 mg) was dissolved in anhydrous acetonitrile (8 ml), and phosphorus oxychloride (330 mg) was added dropwise. The reaction was carried out at 85 °C for 8 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography to give 65 mg of the title product.

[0179] d) 8-Bromo-4-chloro-5,6-dihydrothiopheno[2,3-h]quinazolino

[0180] 65 mg of 4-chloro-5,6-dihydrothieno[2,3-h]quinazoline was dissolved in glacial acetic acid (6 ml), and 52 mg of bromine was added dropwise at -15 °C. After the addition was complete, the reaction was allowed to proceed for 3 hours. The reaction was then quenched with 5 ml of 1 M sodium acetate solution. The reaction mixture was concentrated to dryness, and the residue was extracted with 30 ml of water and 50 ml of ethyl acetate. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The organic phase was then subjected to silica gel column chromatography to obtain 55 mg of the title product.

[0181] e) 8-Bromo-5,6-dihydrothiophene[2,3-h]quinazolin-4-amine

[0182] 550 mg of 8-bromo-4-chloro-5,6-dihydrothieno[2,3-h]quinazoline, 5 ml of isopropanol, and 5 ml of ammonia (25% w / w) were added to a sealed reaction tube and reacted at 130 °C for 8 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography to obtain 50 mg of the title product.

[0183] f) Tert-butyl(8-bromo-5,6-dihydrothiophene[2,3-h]quinazolin-4-yl)carbamate

[0184] 8-Bromo-5,6-dihydrothiophene[2,3-h]quinazolin-4-amine (50 mg), triethylamine (100 mg), and 4-dimethylaminopyridine (10 mg) were dissolved in tetrahydrofuran (10 ml), and di-tert-butyl dicarbonate (160 mg) was added dropwise at room temperature. The reaction mixture was then concentrated to dryness, and the residue was purified by silica gel column chromatography to give 50 mg of the title product.

[0185] g)4-((tert-Butoxycarbonyl)amino)-5,6-dihydrothiopheno[2,3-h]quinazolin-8-carboxylic acid

[0186] 50 mg of tert-butyl(8-bromo-5,6-dihydrothiophene[2,3-h]quinazolin-4-yl)carbamate, 65 mg of oxalic acid, 4 mg of palladium acetate, 13 mg of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 67 mg of N,N-diisopropylethylamine, 5 mL of N,N-dimethylformamide, and 50 mg of acetic anhydride were placed in a reaction flask, purged with nitrogen three times, and stirred at 100 °C for 5 hours. The reaction solution was then concentrated to dryness to obtain 66 mg of the white title product.

[0187] h) tert-butyl(S)-(8-((1-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-5,6-dihydrothiophene[2,3-h]quinazolin-4-yl)carbamate

[0188] 4-((tert-Butoxycarbonyl)amino)-5,6-dihydrothieno[2,3-h]quinazolin-8-carboxylic acid (60 mg), N,N-diisopropylethylamine (129 mg), and (S)-3-amino-3-(4-chlorophenyl)prop-1-ol (35 mg) were dissolved in N,N-dimethylformamide (3 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg) was added at room temperature, and the reaction was carried out for 3 hours at room temperature. The reaction solution was then concentrated to dryness, and the residue was subjected to column chromatography to give 42 mg of the title product.

[0189] i)(S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0190] 42 mg of tert-butyl(S)-(8-((1-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-5,6-dihydrothiophene[2,3-h]quinazolin-4-yl)carbamate was dissolved in 3 mL of dioxane. 2 mL of 4 M hydrogen chloride / dioxane solution was added dropwise at 10 °C, and the reaction was allowed to proceed for 1 hour. The reaction solution was then concentrated to dryness, and the residue was adjusted to pH 8 with saturated sodium bicarbonate solution. After concentration under reduced pressure, column chromatography yielded 12 mg of the yellow title product.

[0191] 1H NMR (300MHz, DMSO-d6) δ9.02(d,J=8.1Hz,1H),8.23(s,1H),8.10(s,1H),7.38(m,4H),6.31(s,2H),5.07(q,J=8.3Hz,1H),4. 55(t,J=4.9Hz,1H),3.42(m,2H),2.97(m,J=7.6Hz,2H),2.80(m,2H),2.01(m,1H),1.90–1.80(m,1H).MS(ESI+):415.1(M+H).

[0192] Example 12: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-(pyrrolidone-1-yl)propyl)-2-(methylamino)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0193]

[0194] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid (65 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg), and N,N-dimethylformamide (5 mL) were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (50 mg), (S)-1-(4-chlorophenyl)-3-(pyrrolidine-1-yl)propyl-1-amine (60 mg), and triethylamine (100 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, stirred, and separated. The organic layer was concentrated to dryness, and the residue was subjected to column chromatography to give 90 mg of the title product.

[0195] 1 H NMR(300MHz,DMSO-d6)δ9.12(d,J=8.1Hz,1H),8.22(s,1H),8.16(s,1H),7.44(m,4H),6.69(s,2H),5.08 (m,1H),2.98(m,5H),2.87(m,4H),2.82(m,3H),2.15(m,2H),1.90–1.80(m,4H).MS(ESI+):482.2(M+H).

[0196] Example 13: Synthesis of N-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0197]

[0198] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid (65 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg), and N,N-dimethylformamide (5 mL) were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (50 mg), 3-amino-3-(4-chloro-3-fluorophenyl)prop-1-ol (60 mg), and triethylamine (100 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, stirred, and separated. The organic layer was concentrated to dryness, and the residue was subjected to column chromatography to give 80 mg of the title product.

[0199] 1 H NMR (300MHz, DMSO-d6) δ9.01 (d, J = 7.5 Hz, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.55 (m, 1H), 7.40 (m, 1H), 7.24 (m, 1H), 6.73 (s, 1H) ),5.11(m,1H),4.58(m,1H),3.45(m,2H),3.00(m,2H),2.88(m,3H),2.83(m,2H),2.06–1.87(m,2H).MS(ESI+):447.1(M+H).

[0200] Example 14: Synthesis of N-(1-(3,4-dichlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrothiophene[2,3-h]quinazolin-8-carboxamide

[0201]

[0202] 2-(methylamino)-5,6-dihydrothieno[2,3-h]quinazoline-8-carboxylic acid (65 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg), and N,N-dimethylformamide (5 mL) were placed in a reaction flask and stirred at 5 °C for 5 minutes. Then, 1-hydroxybenzotriazole (50 mg), 3-amino-3-(3,4-dichlorophenyl)prop-1-ol (65 mg), and triethylamine (100 mg) were added, and the mixture was gradually heated to room temperature for 6 hours. The reaction was stopped when complete. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture, and the mixture was stirred and separated. The organic layer was concentrated to dryness, and the residue was purified by silica gel column chromatography to give 60 mg of the title product.

[0203] 1H NMR(300MHz,DMSO-d6)δ9.02(d,J=8.0Hz,1H),8.23(s,1H),8.15(s,1H),7.61(m,2H),7.37(m,1H),6.73(s,1H),5.11 (m,1H),4.58(m,1H),3.44(m,2H),2.99(m,1H),2.88(m,2H),2.83(m,4H),2.06–1.88(m,2H).MS(ESI+):463.1(M+H).

[0204] Example 15: Synthesis of (S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazolin-8-carboxamide

[0205]

[0206] a) 2-Bromo-6,7-dihydrobenzofuran-4(5H)-one

[0207] At 0°C, N-bromosuccinimide (580 mg) was added to a solution of 440 mg of 6,7-dihydrobenzofuran-4(5H)-one in N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL). The organic layer was concentrated to dryness, and the residue was purified by column chromatography to give 200 mg of the yellow title product.

[0208] b) 2-Bromo-5-((dimethylamino)methylene)-6,7-dihydrobenzofuran-4(5H)-one

[0209] 2-Bromo-6,7-dihydrobenzofuran-4(5H)-one (300 mg) and N,N-dimethylformamide-dimethyl acetal (3 ml) were added sequentially to the reaction flask, and the mixture was heated to 130 °C and reacted for 4 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography to give 200 mg of a yellow solid product.

[0210] c) 8-Bromo-N-methyl-5,6-dihydrofuran[2,3-h]quinazolin-2-amine

[0211] 2-Bromo-5-((dimethylamino)methylene)-6,7-dihydrobenzofuran-4(5H)-one (280 mg), methylguanidine hydrochloride (210 mg), and sodium hydroxide (76 mg) were added sequentially to the reaction flask, and the mixture was heated under reflux for 3 hours. After the reaction was complete, the solid was removed by suction filtration, and the filter cake was washed twice with ethyl acetate. The mother liquor was concentrated to dryness, and the residue was purified by column chromatography to give 200 mg of the yellow title product.

[0212] d) Ethyl 2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazolin-8-carboxylic acid

[0213] 8-Bromo-N-methyl-5,6-dihydrofuran[2,3-h]quinazolin-2-amine (200 mg), sodium acetate (285 mg), bis(triphenylphosphine)palladium dichloride (100 mg), ethyl formate (310 mg), and tetrahydrofuran (10 ml) were added sequentially to the reaction flask. The mixture was then purged with nitrogen three times and heated under reflux for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography to give 185 mg of the yellow title product.

[0214] e)2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazolin-8-carboxylic acid

[0215] Ethyl 2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazoline-8-carboxylate (185 mg) and 2M lithium hydroxide (2 mL) were added sequentially to the reaction flask, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was quenched dropwise with 1M hydrochloric acid (4 mL) at 5 °C. The mixture was then extracted with dichloromethane (40 mL), and the dichloromethane phase was concentrated to dryness. The residue was purified by column chromatography to give 150 mg of the white title product.

[0216] f)(S)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazolin-8-carboxamide

[0217] At 0°C, (S)-3-amino-3-(4-chlorophenyl)prop-1-ol (170 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (275 mg), and N,N-diisopropylethylamine (236 mg) were added sequentially to a solution of 150 mg of 2-(methylamino)-5,6-dihydrofuran[2,3-h]quinazolino-8-carboxylic acid in N,N-dimethylformamide (5 ml). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (30 ml) and extracted with ethyl acetate (15 ml). The organic phase was concentrated to dryness, and the residue was purified by column chromatography to give 85 mg of the white title product.

[0218] 1H NMR (400MHz, DMSO-d6) δ8.84(d,J=8.2Hz,1H),8.09(s,1H),7.44(m,1H),7.39(m,4H),6.83(d,J=4.6Hz,1H),5.11( m,1H),4.60(m,1H),3.45(m,2H),3.00(m,2H),2.90(m,3H),2.83(m,2H),2.05–1.83(m,2H).MS(ESI+):413.2(M+H).

[0219] Example 16 In vitro enzyme activity test

[0220] 1. Experimental Procedure

[0221] A mobility shift assay was used to establish a platform for detecting AKT1, AKT2, and AKT3 kinase activities. Compounds were serially diluted 3-fold (total of 10 concentrations) starting at 100 μM with 100% DMSO (Sigma, Cat: D8418-1L). For each concentration, 250 nL of the compound was transferred to the target plate OptiPlate-384F (PerkinElmer, Cat: 6007290) using an Echo550 dispenser. 250 nL of DMSO was added to the positive and negative control wells. Add 10 μL of AKT kinase solution (purchased from Carna, AKT1 Cat: 01-101, AKT2 Cat: 01-102, AKT3 Cat: 01-103; final concentration of AKT1 kinase 0.5 nM, AKT2 kinase 0.05 nM, and AKT3 kinase 0.25 nM) to each compound well and positive control well, respectively; add 10 μL of 1×Kinase buffer (containing 50 mM HEPES, 10 mM MgCl2, and 2 mM DTT) to each negative control well. Then centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 10 minutes. Add 15 μL of ATP (purchased from Sigma, Cat. A7699-5G, Lot. SLBT6850; final ATP concentration for AKT1 was 120 μM, for AKT2 it was 500 μM, and for AKT3 it was 29.3 μM) and Caliper substrate 6 (purchased from GL, Cat: 116368; final substrate concentration was 3 μM) to start the reaction, for a total reaction volume of 25 μL. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for the corresponding times (60 min for AKT1, 30 min for AKT2, and 10 min for AKT3). Add 30 μL of stop assay solution (containing 50 mM EDTA) to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. The conversion rate was read using a Caliper EZ Reader II (device parameters: -1.2 PSI, upstream voltage -500, downstream voltage -2250, reading interval 45 s). The IC50 of the compound was obtained by fitting a dose-response curve using GraphPad Prism 5 software with a log(inhibitor) vs. response-variable slope. 50 value.

[0222] Inhibition rate calculation formula: in:

[0223] Conversion%_sample: This is the conversion rate reading for the sample.

[0224] Conversion%_min: Mean value of negative control wells, representing the conversion rate reading of wells without enzyme activity;

[0225] Conversion%_max: Mean value of positive control wells, representing the conversion rate reading of wells without compound inhibition.

Claims

1. A compound having a structure according to Formula I: ###0001### or a pharmaceutically acceptable salt thereof, wherein: X is selected from CH or S, Y is selected from CH or S, and when X is S, Y is selected from CH; and when X is CH, Y is selected from S; n is selected from 0 or 1 ; and the dotted line can represent a single or double bond.

2. The compound of claim 1, wherein n is 0. R 5 selected from H and R 1 selected from -NH(C1-C6alkyl); R 2 selected from hydrogen or C1-C4alkyl, wherein said C1-C4alkyl is optionally substituted with pyrrolidinyl, halogen, OH, NH2, or NH(C1-C3alkyl); R 3 and R 4 are each independently selected from H, halogen or C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with halogen; 3. The compound of claim 1, wherein n is 1.

4. The compound of claim 1, wherein X is S and Y is CH.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

5. The compound of claim 1, wherein X is CH and Y is S.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 5 selected from H and R 1 selected from methylamino.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 2 selected from hydrogen, methyl, hydroxyethyl, aminomethyl or 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 2 selected from hydroxyethyl, aminomethyl or 6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 2 selected from amino methyl.

7. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 2 selected from hydroxyethyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are each independently selected from H, trifluoromethyl, F or CI.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: R 3 is F, Cl or H; R 4 is H, Cl or trifluoromethyl.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: R 3 is H and R 4 is Cl.

11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: R 3 selected from F and R 4 selected from H.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

6. The compound of claim 1, wherein the compound has a structure according to Formula II: ###0002### 7. The compound of claim 1, wherein the compound has a structure according to Formula III: ###0003### wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and the dotted line are defined as in the compounds of formula I, X is selected from S.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein:

8. The compound of claim 1, wherein the compound has a structure according to Formula IV: ###0004### 9. The compound of claim 1, wherein the compound has a structure according to Formula V: ###0005### wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and the dotted line are defined as in the compounds of formula I, Y is selected from S.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein:

10. The compound of claim 1, wherein the compound has a structure according to Formula VI: ###0006### 11. The compound of claim 1, wherein the compound has a structure according to Formula VII: ###0007### 12. The compound of claim 1, wherein the compound has a structure according to Formula VIII: ###0008### 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula II: ###0009### 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula III: ###0010### 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula IV: ###0011### 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula V: ###0012### 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula VI: ###0013### Among them, R 2 Selected from hydrogen or C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with pyrroleyl, halogen, OH, NH2, or NH (C1-C3 alkyl); R 3 and R 4 Each is independently selected from H, halogen, or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with a halogen; Y is selected from S; 18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein:

19. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

20. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18 or 19, for the manufacture of a medicament for the prevention and / or treatment of a disease or condition mediated by AKT protein kinase.

21. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18 or 19, for the manufacture of a medicament for the prevention and / or treatment of a cancer mediated by AKT protein kinase.

22. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18 or 19, for the manufacture of a medicament for the prevention and / or treatment of a breast cancer, prostate cancer, or ovarian cancer mediated by AKT protein kinase.

23. A method of preparing a compound, comprising: preparing a compound of Formula 1-2 in the presence of an oxidizing agent A and a solvent, condensing the compound of Formula 1-2 to prepare a compound of Formula 1-3, preparing the compound of Formula 1-3 in the presence of N,N-dimethylformamide-dimethyl acetal and acetic acid to prepare a compound of Formula 1-4, further reacting the compound of Formula 1-4 with 1-methylguanidine hydrochloride in the presence of sodium ethoxide and ethanol to form a compound of Formula 1-5, reacting the compound of Formula 1-5 with an oxidizing agent B to prepare a compound of Formula 1-6, hydrolyzing the compound of Formula 1-6 to prepare a compound of Formula 1-7, reacting the compound of Formula 1-7 with a compound of Formula 1-11 to prepare a compound of Formula 1-8, hydrolyzing the compound of Formula 1-5 to prepare a compound of Formula 1-9, and reacting the compound of Formula 1-9 with a compound of Formula 1-11 to prepare a compound of Formula 1-10.

24. The method of claim 23, wherein the oxidizing agent A is cerium ammonium nitrate; the solvent is acetic acid and water; and the oxidizing agent B is 2,3-dichloro-5,6-dicyano-p-benzoquinone.

25. A method of preparing a compound, comprising: wherein R is selected from the group consisting of -NH(Ci-C6alkyl); R 1 is selected from the group consisting of -NH(Ci-C6alkyl); R 2 is selected from the group consisting of hydrogen or Ci-C4alkyl, wherein said Ci-C4alkyl is optionally substituted with pyrrolidinyl, halogen, OH, NH2, or NH(Ci-C3alkyl); R 3 and R 4 are each independently selected from the group consisting of H, halogen, or Ci-C3alkyl, wherein said Ci-C3alkyl is optionally substituted with halogen; X is selected from S; The compound of formula 2-1 is prepared to the compound of formula 2-2 in the presence of a brominating agent and a solvent, the compound of formula 2-2 is prepared to the compound of formula 2-3 in the presence of a catalyst, the compound of formula 2-3 is reacted with N,N-dimethylformamide-dimethyl acetal to prepare the compound of formula 2-4, the compound of formula 2-4 is further reacted with 1-methylguanidine hydrochloride or guanidine hydrochloride in the presence of sodium ethoxide and ethanol to form the compound of formula 2-5, the compound of formula 2-5 is hydrolyzed to form the compound of formula 2-6, the compound of formula 2-6 is reacted with the compound of formula 1-11 to prepare the compound of formula 2-7, the compound of formula 2-5 is reacted with an oxidizing agent C to prepare the compound of formula 2-8, the compound of formula 2-8 is hydrolyzed to form the compound of formula 2-9, the compound of formula 2-9 is reacted with the compound of formula 1-11 to prepare the compound of formula 2-10.

26. The method of claim 25, wherein: The brominating agent is bromine; the solvent is acetic acid and water; the oxidizing agent C is 2,3-dichloro-5,6-dicyano-p-benzoquinone.

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