Pyrroloquinoxalinone derivative as BTK inhibitor and application of pyrroloquinoxalinone derivative

Abstract

The invention discloses a compound as shown in a formula I, or an optical isomer or pharmaceutically acceptable salt thereof. The compound provided by the invention has excellent inhibitory activity on BTK protein kinase, and has stronger cell proliferation inhibitory activity and higher oral exposure. Therefore, the compound disclosed by the invention is a high-selectivity non-covalent BTK inhibitor with remarkable oral anti-tumor activity, so that a new material basis is laid for the treatment of BTK protein kinase mediated cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to novel pyrroloquinoxalinone derivatives, methods for their synthesis, and their use as BTK inhibitors in medicaments for treating tumor-related diseases and autoimmune diseases. Background Art

[0002] Hematological malignancies are malignant proliferative diseases caused by abnormal differentiation and development of hematopoietic stem cells, mainly including four subtypes: leukemia, multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Statistical data from the International Agency for Research on Cancer show that in 2022, the number of new cancer cases globally was 19.976 million, and the number of deaths was 9.744 million. Among them, the number of new cases of hematological malignancies was 1.311 million (NHL: 553,000; leukemia: 487,000; MM: 188,000; HL: 82,000), accounting for 6.6%; the number of deaths was 700,000 (NHL: 251,000; leukemia: 305,000; MM: 121,000; HL: 23,000), accounting for 7.2%. Hematological malignancies have relatively high incidence and mortality rates globally and are major diseases that seriously threaten human health.

[0003] B-cell malignancies are the most common hematological malignancies, characterized by abnormal proliferation of malignant B lymphocytes, including most non-Hodgkin lymphomas, several types of leukemia, and multiple myeloma, and are a type of refractory disease that mainly affects middle-aged and elderly people. In the past few decades, the treatment methods for B-cell malignancies have developed significantly, experiencing a leap from chemotherapy to chemoimmunotherapy and then to targeted therapy. In recent years, targeted drugs represented by Bruton's tyrosine kinase (BTK) inhibitors have completely changed the treatment pattern of these diseases. Compared with traditional chemotherapy and chemoimmunotherapy, kinase-targeted therapy has higher efficacy, fewer side effects, and better patient tolerance, and has been widely used in the treatment of various B-cell malignancies.

[0004] BTK belongs to a member of the protein kinase superfamily and plays a central role in the signal transduction of B-cell antigen receptor (BCR) and other multiple B-cell surface receptors, and is crucial for the proliferation, survival, and function of B cells. The abnormal activation of BTK is closely related to the pathogenesis of B-cell malignancies, and the development of BTK inhibitors has significantly improved the treatment of B-cell malignancies. The approved BTK inhibitors mainly act in a covalent mode, and there are problems with covalent binding site drug resistance mutations. Patients are prone to develop drug resistance after taking the drug for a period of time, leading to disease progression. In addition, the off-target toxic side effects of covalent BTK inhibitors also limit their clinical use. Therefore, there is an urgent need to develop novel selective non-covalent BTK inhibitors with higher efficacy and safety to meet the urgent clinical needs of patients. SUMMARY OF THE INVENTION

[0005] The object of the present invention is to provide novel pyrroloquinoxalinone derivatives, which can be used as novel orally administrable selective non-covalent BTK inhibitors.

[0006] Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

[0007] Another object of the present invention is to provide the use of the above compound in the preparation of a drug for treating BTK-related diseases or inhibiting BTK protein kinase.

[0008] In a first aspect, the present invention provides a compound of formula I, or an optical isomer or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R 1 is selected from the group consisting of: hydrogen, hydroxy, substituted or unsubstituted C1-C3 alkyl;

[0011] R 2 is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl;

[0012] R 3 is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl;

[0013] R 4 is selected from the group consisting of: hydrogen or halogen;

[0014] X is selected from the group consisting of: substituted or unsubstituted C1-C2 alkylene, substituted or unsubstituted C0-C3 alkylene carbonyl;

[0015] Y is selected from the group consisting of: imino, oxygen or sulfur;

[0016] Ring A is selected from the group consisting of: substituted or unsubstituted C5-C8 aryl, substituted or unsubstituted five-membered fused six-membered ring;

[0017] The dotted line represents a chemical bond or does not exist;

[0018] Wherein, the compound of formula I does not include the following compounds:

[0019]

[0020] In a specific embodiment, R 1 is selected from the group consisting of: hydrogen, C1-C3 alkyl substituted with hydroxy;

[0021] R 3 is selected from the group consisting of: hydrogen, halogen, hydroxy or C1-C3 alkyl substituted with halogen;

[0022] X is selected from the group consisting of: substituted or unsubstituted C1-C2 alkylene, carbonyl, or substituted or unsubstituted methylene carbonyl;

[0023] Y is selected from the group consisting of: imino or oxygen;

[0024] The A ring is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroaryl-fused phenyl or cyclohexyl containing 1-3 heteroatoms independently selected from N, O or S.

[0025] In a specific embodiment, R 1 is hydrogen;

[0026] R 2 is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl;

[0027] R 3 is selected from the group consisting of: halogen, substituted or unsubstituted C1-C3 alkyl;

[0028] R 4 is selected from the group consisting of: hydrogen or halogen;

[0029] X is selected from the group consisting of: substituted or unsubstituted methylene, or carbonyl;

[0030] Y is selected from the group consisting of: imino;

[0031] The A ring is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted pyrrolo-fused phenyl;

[0032] The dashed line represents a chemical bond or its absence.

[0033] In a specific embodiment, R 3 is halogen, preferably F.

[0034] In a preferred embodiment, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: halogen, C1-C3 alkyl or C1-C3 hydroxyalkyl.

[0035] In a specific embodiment, the compound is a compound selected from the group consisting of:

[0036]

[0037] Preferably, the compound is a compound selected from the group consisting of:

[0038]

[0039]

[0040] More preferably, the compound is the following compound:

[0041]

[0042] In a second aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition contains the compound described in the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0043] In a preferred embodiment, the pharmaceutical composition is used for treating or preventing BTK-mediated diseases.

[0044] In a preferred embodiment, the BTK-mediated disease is cancer or an autoimmune disease;

[0045] Preferably, the cancer is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia / small lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, acute lymphocytic leukemia;

[0046] The autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, psoriasis, urticaria, multiple sclerosis.

[0047] In a third aspect, the present invention provides the use of the compound described in the first aspect in the preparation of a BTK inhibitor.

[0048] In a preferred embodiment, the BTK inhibitor inhibits BTK activity or expression level.

[0049] In a specific embodiment, the BTK inhibitor is a drug for treating or preventing BTK-mediated diseases.

[0050] In a specific embodiment, the BTK-mediated disease is cancer or an autoimmune disease;

[0051] Preferably, the cancer is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia / small lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, acute lymphocytic leukemia;

[0052] The autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, psoriasis, urticaria, multiple sclerosis.

[0053] In a fourth aspect, the present invention provides a method for treating or preventing BTK-mediated diseases, the method comprising administering a therapeutically effective amount of the compound described in the first aspect or the pharmaceutical composition described in the second aspect to a subject in need thereof.

[0054] In a preferred embodiment, the subject is a mammal; preferably, the subject is a human.

[0055] In a preferred embodiment, the BTK-mediated disease is cancer or an autoimmune disease;

[0056] Preferably, the cancer is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia / small lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, acute lymphocytic leukemia;

[0057] The autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, urticaria, multiple sclerosis.

[0058] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 It shows the selectivity of Compound 4 of the present invention against 468 kinases (including 403 non-mutated kinases) at a concentration of 100 nM;

[0060] Figure 2 It shows the anti-tumor efficacy of Compound 4 of the present invention in the U937 xenograft mouse model (n = 6). (A) Changes in relative tumor volume during drug administration; (B) Changes in mouse body weight during drug administration. DETAILED DESCRIPTION OF THE INVENTION

[0061] Through extensive and in-depth research, the inventors of the present invention designed and synthesized a series of pyrroloquinoxalinone compounds not reported in the literature. The obtained compounds were tested for biological activity, and a batch of compounds capable of inhibiting BTK protein kinase were obtained. Some compounds have significant inhibitory activity against the proliferation of lymphoma cell lines (U937 and Ramos cells). Compared with the compound S2 disclosed in the prior art (CN115368362A), the preferred compounds of the present invention have stronger cell proliferation inhibitory activity and higher oral exposure, and show better oral anti-tumor activity in the U937 xenograft mouse model. In addition, the preferred compounds of the present invention have very high selectivity for BTK among 468 kinase targets, which can greatly reduce off-target toxicity. On this basis, the present invention was completed.

[0062] TERM DEFINITION

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention pertains. For ease of understanding the present invention, the relevant terms related to the present invention are defined as follows, but the scope of the present invention is not limited to these specific definitions.

[0064] Some groups involved herein are defined as follows:

[0065] As used herein, "alkyl" refers to a straight-chain or branched-chain saturated group composed of carbon atoms and hydrogen atoms. For example, "C1-C 10 alkyl" refers to a saturated branched-chain or straight-chain alkyl group with a carbon chain length of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. Examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, pentyl, and the like.

[0066] As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine. In a preferred embodiment, the halogen is fluorine or chlorine.

[0067] As used herein, "halogenated" refers to fluorination, chlorination, bromination, and iodination.

[0068] As used herein, a five-membered fused six-membered ring refers to a bicyclic structure composed of a saturated or unsaturated five-membered ring fused with a six-membered ring. Examples of the five-membered fused six-membered ring include, but are not limited to: benzopyrrole, benzofuran, tetrahydrobenzofuran, etc.

[0069] As used herein, "substituted or unsubstituted" or "optionally substituted" means that the group modified by this term can optionally be substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents selected from the following: halogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, halogen-substituted C1-C3 straight-chain or branched-chain alkyl (such as trifluoromethyl), C1-C3 alkoxy, halogen-substituted C1-C3 alkoxy (such as trifluoromethoxy), cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl.

[0070] The compounds of the present invention and their pharmaceutically acceptable salts

[0071] The present invention provides pyrroloquinoxalinone compounds with a completely new structure. The compounds of the present invention not only have significant inhibitory activity against BTK protein kinase, but also show significant inhibitory activity against the proliferation of lymphoma cell lines. The compounds of the present invention have stronger inhibitory activity against cell proliferation and higher oral exposure, and show better oral anti-tumor activity in a xenograft mouse model. In addition, the compounds of the present invention have very high selectivity for BTK, and thus can have excellent safety.

[0072] In a specific embodiment, the present invention provides a compound represented by Formula I, its optical isomers, or its pharmaceutically acceptable salts:

[0073]

[0074] Wherein, R 1 、R 2 、R 3 、R 4 、X, Y and Ring A are as defined above.

[0075] In a preferred embodiment, the compounds of the present invention are compounds selected from the following group:

[0076]

[0077] Preferred are the following compounds:

[0078]

[0079]

[0080] More preferred are the following compounds:

[0081]

[0082] Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS) and N-methylglucamine.

[0083] Pharmaceutical composition

[0084] Based on the compounds of the present invention, the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

[0085] Those skilled in the art can formulate the pharmaceutical composition of the present invention into dosage forms suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical administration routes for the treatment of tumors and other diseases. The dosage administered is the amount of the drug that is effective in ameliorating or eliminating one or more conditions. For the treatment of a specific disease, the effective amount is the amount of the drug sufficient to ameliorate or in some way alleviate the symptoms associated with the disease. Such an amount may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage administered may cure the disease, but administration is usually for ameliorating the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom amelioration. The dosage of the drug will be determined according to the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0086] The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compounds of the present invention. Among these mammals, the most important one is humans.

[0087] The compounds of the present invention or their pharmaceutical compositions can be used to treat various diseases mediated and participated by BTK protein kinase. Herein, the diseases mediated by BTK protein and its mediators are various cancers and autoimmune diseases. The cancers include but are not limited to: multiple myeloma, chronic lymphocytic leukemia / small lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, acute lymphocytic leukemia regulated by BTK; the autoimmune diseases include but are not limited to: rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, psoriasis, urticaria, multiple sclerosis.

[0088] The pharmaceutical preparation of the present invention can be manufactured by known methods. For example, it can be manufactured by traditional mixing, granulation, tabletting, dissolving, or freeze-drying processes. When manufacturing an oral preparation, solid excipients can be combined with the active compound, and the mixture can be selectively ground. After adding an appropriate amount of auxiliary agents if necessary, the granular mixture is processed to obtain a tablet or a tablet core.

[0089] Suitable excipients, especially fillers, such as sugars like lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If necessary, disintegrants can be added, such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. Auxiliaries, especially flow regulators and lubricants, for example, silica, talc, stearates, such as calcium stearate, stearic acid or polyethylene glycol. If necessary, a suitable coating resistant to gastric juice can be provided for the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution can contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. To prepare a coating resistant to gastric juice, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments can be added to the coating of the tablet or tablet core. For example, for identification or to characterize the combination of the active ingredient dose.

[0090] Therapeutic methods and uses

[0091] Based on the compounds and pharmaceutical compositions of the present invention, those skilled in the art can understand that the compounds of the present invention can be used for the treatment of BTK-mediated diseases, or for the preparation of drugs for preventing or treating BTK-mediated diseases or inhibiting BTK activity.

[0092] Therefore, the present invention further provides a method for treating BTK protein-mediated diseases, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

[0093] The administration methods include but are not limited to various administration methods well-known in the art and can be determined according to the actual situation of the patient. These methods include but are not limited to parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical administration routes.

[0094] Advantages of the present invention:

[0095] 1. The compounds of the present invention are novel pyrroloquinoxalinone compounds with a new structure;

[0096] 2. The compounds of the present invention have excellent inhibitory activity against BTK protein kinase;

[0097] 3. Compared with the compounds disclosed in the prior art, the preferred compounds of the present invention have stronger inhibitory activity on cell proliferation and higher oral exposure, and show better oral anti-tumor activity in the U937 xenograft mouse model;

[0098] 4. The preferred compounds of the present invention have very high selectivity for BTK among 468 kinase targets, and can greatly reduce off-target toxicity;

[0099] 5. The compounds of the present invention are highly selective non-covalent BTK inhibitors with significant oral anti-tumor activity;

[0100] 6. The compounds of the present invention lay a new material foundation for the treatment of cancers mediated by BTK protein kinase, and have great prospects for industrialization and commercialization as well as market value, with remarkable economic benefits.

[0101] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following embodiments can be obtained from commercial channels without special instructions.

[0102] The synthesis of the pyrroloquinoxalinone derivatives of the present invention is shown as follows:

[0103] Example 1. Synthesis of 5-fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (1)

[0104]

[0105]

[0106] Step 1: Synthesis of methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate (1-3)

[0107]

[0108] Methyl 2-pyrrolecarboxylate (125 mg, 1 mmol), methyl 4-fluoro-3-nitrobenzoate (199 mg, 1 mmol), cesium carbonate (326 mg, 1.2 mmol) and N,N-dimethylformamide (3 mL) were added to a reaction flask and reacted at 80 °C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water, allowed to stand overnight, and a white solid precipitated. The solid was filtered by suction, and the filter cake was dried at 50 °C in a vacuum drying oven to obtain compound 1-3, a grayish-white solid, with a yield of 91%.

[0109] 11H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.0 Hz, 1H), 8.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 2.8, 1.8 Hz, 1H), 7.10 (dd, J = 3.9, 1.8 Hz, 1H), 6.44 (dd, J = 3.9, 2.8 Hz, 1H), 3.96 (s, 3H), 3.59 (s, 3H).

[0110] Step 2: Synthesis of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate (1-4)

[0111]

[0112] Compound 1-3 (5.84 g, 19.2 mmol), iron powder (4.31 g, 76.8 mmol) and glacial acetic acid (192 mL) were added to a reaction flask and reacted at 110 °C for 3 h. After completion of the reaction, the reaction system was cooled to room temperature. 1 M dilute hydrochloric acid (200 mL) was added to the reaction solution. After addition, the mixture was stirred at room temperature for 10 min and then filtered by suction. The filter cake was slurried with ethanol for 2 h, and then filtered by suction again. The filter cake was dried in a vacuum drying oven at 50 °C to obtain compound 1-4, a grayish-white solid, with a yield of 90%.

[0113] 1 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.29 - 8.16 (m, 2H), 7.93 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 3.7 Hz, 1H), 6.75 (t, J = 3.2 Hz, 1H), 3.88 (s, 3H).

[0114] Step 3: Synthesis of 7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (1-5)

[0115]

[0116] Compound 1-4 (5.84 g, 19.2 mmol) and tetrahydrofuran (192 mL) were added to a reaction flask. The reaction system was cooled to -30 °C, and then a tetrahydrofuran solution of methyllithium (52 mL, 83 mmol) was added dropwise. After the addition, the temperature was slowly raised to 0 °C and the reaction was continued with stirring for 40 minutes. After the reaction was completed, 30 mL of saturated ammonium chloride was added to the reaction solution to quench the reaction. Most of the tetrahydrofuran was removed by rotary evaporation under reduced pressure. The resulting residue was extracted with 200 mL of ethyl acetate. The organic layers were combined and washed three times each with water and saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 1-5 as a white solid in a yield of 79%.

[0117] 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.14 (dd, J = 2.8, 1.5 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.6, 2.0 Hz, 1H), 7.01 (dd, J = 3.8, 1.4 Hz, 1H), 6.66 (dd, J = 3.9, 2.7 Hz, 1H), 5.14 (s, 1H), 1.45 (s, 6H).

[0118] Step 4: Synthesis of 1-bromo-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (1-6)

[0119]

[0120] Compound 1-5 (241 mg, 1 mmol) and N,N-dimethylformamide (4 mL) were added to a reaction flask. At 0 °C, N-bromosuccinimide (178 mg, 1 mmol) was added. After the addition, the temperature was slowly raised to room temperature and the reaction was continued with stirring for 2 hours. After the reaction was completed, the reaction solution was diluted with 40 mL of ethyl acetate. The organic layer was washed five times each with water, saturated aqueous sodium thiosulfate, and saturated sodium chloride, then dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain compound 1-6 as a white solid in a yield of 86%.

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.87 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.29 (dd, J = 8.9, 2.1 Hz, 1H), 7.10 (d, J = 4.2 Hz, 1H), 6.81 (d, J = 4.2 Hz, 1H), 5.18 (s, 1H), 1.45 (s, 6H). LC-MS / ESI [M+H] +321.03.

[0122] Step 5: Synthesis of 1-(3-Amino-2-methylphenyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (1-8)

[0123]

[0124] Compound 1-6 (161 mg, 0.5 mmol), 2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (151 mg, 0.65 mmol), potassium phosphate (320 mg, 1.5 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41 mg, 0.05 mmol), N,N-Dimethylformamide (2.5 mL) and water (0.75 mL) were added to a reaction flask and reacted at 95 °C for 12 h. After completion of the reaction, the reaction system was cooled to room temperature, 30 mL of ethyl acetate was added to the reaction solution for dilution, and the organic layer was washed five times with water and saturated sodium chloride successively. Subsequently, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by normal-phase column chromatography to obtain pure intermediate 1-8, a white solid, with a yield of 81%.

[0125] 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.47 (s, 1H), 7.11 (d, J = 3.9 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.87 - 6.80 (m, 3H), 6.57 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 3.9 Hz, 1H), 5.09 (s, 2H), 5.04 (s, 1H), 1.69 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H). LC-MS / ESI [M+H] + 348.16.

[0126] Step 6: Synthesis of 2-Fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-6-nitrobenzamide (1-9)

[0127]

[0128] Compound 1-8 (191 mg, 0.55 mmol), 2-fluoro-6-nitrobenzoic acid (257 mg, 1.39 mmol) and DIPEA (392 μL, 2.22 mmol) were dissolved in DMF (4 mL). HATU (526 mg, 1.39 mmol) was added at 0 °C, and the mixture was stirred at room temperature. After 15 h, the reaction solution was diluted with 100 mL of ethyl acetate. The organic layer was washed five times with water and brine respectively, then concentrated in vacuo and purified by silica gel column chromatography to obtain white solid 1-9 in 90.3% yield.

[0129] 1 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.49 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.81 (td, J = 8.4, 6.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 3.9 Hz, 1H), 5.07 (s, 1H), 1.94 (s, 3H), 1.35 (s, 6H).

[0130] Step 7: Synthesis of 2-amino-6-fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (1-10)

[0131]

[0132] Compound 1-9 (257 mg, 0.50 mmol), zinc powder (260 mg, 4.00 mmol), NH4Cl (432 mg, 8.00 mmol) and tetrahydrofuran (3.5 mL) were added to a reaction flask and stirred at room temperature. After 12 h, the mixture was filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography to obtain white solid 1-10 in 86.3% yield.

[0133] 11H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.93 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.86 (dd, J = 8.8, 1.6 Hz 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 4.0 Hz, 1H), 6.44 - 6.33 (m, 1H), 5.93 (s, 2H), 5.08 (s, 1H), 1.94 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H).

[0134] Step 8: Synthesis of 5-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (1)

[0135]

[0136] Dissolve compound 1-10 (73 mg, 0.15 mmol) in tetrahydrofuran (1.5 mL), add triphosgene (50 mg, 0.17 mmol) at 0 °C, and stir at room temperature. After 0.5 h, dilute the reaction solution with 50 mL of ethyl acetate. The organic layer was washed with brine several times and then concentrated by rotary evaporation. The residue was purified by silica gel column chromatography to obtain white solid 1, with a yield of 75.3%, melting point: 233.1 - 233.9 °C.

[0137] 1 1H NMR (400 MHz, DMSO-d6) δ 11.75 (br s, 1H), 11.27 (s, 1H), 7.70 (td, J = 8.0, 5.2 Hz, 1H), 7.55 - 7.45 (m, 4H), 7.17 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 0.5H), 7.06 (d, J = 8.0 Hz, 0.5H), 7.02 (d, J = 8.0 Hz, 0.5H), 6.99 (d, J = 8.0 Hz, 0.5H), 6.92 - 6.84 (m, 2H), 6.62 (d, J = 4.0 Hz, 0.5H), 6.60 (d, J = 4.0 Hz, 0.5H), 5.09 (s, 0.5H), 5.07 (s, 0.5H), 1.76 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H). 11H NMR shows a mixture of atropisomers. 13 13C NMR(151MHz,DMSO-d6)δ161.99(d,J=261.2Hz),161.98(d,J=261.2Hz),159.34(d,J=4.5Hz),159.17(d,J=4.5Hz),155.62,155.61,149.99,149.85,148.51,148.47,142.27,142.25,137.18,137.11,136.71(d,J=12.6Hz),136.70(d,J=12.6Hz),135.87,135.85,134.90(d,J=7.6Hz),134.81(d,J=7.6Hz),132.73,132.61,131.36,131.34,131.09,131.03,129.06,129.04,127.55,124.98,124.94,122.31,122.27,119.27,119.23,115.31,115.24,114.88,114.86,113.42(d,J=7.7Hz),113.39(d,J=7.7Hz),111.77(d,J=31.3Hz),111.75(d,J=31.3Hz),110.05,109.91,104.39(d,J=9.8Hz),104.38(d,J=9.8Hz),70.74,70.69,32.23,32.17,32.15,15.14,15.12. 13 13C NMR shows a mixture ofatropisomers.HRMS(ESI)calcd for C 29 H 22 FN4O4[M-H] - m / z:509.1625,found509.1624.HPLC purity:100%,retention time:7.81,7.99min.

[0138] Example 2. Synthesis of 2-Amino-3-fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (2)

[0139]

[0140] Step 1: Synthesis of 3-Fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-2-nitrobenzamide (2-1)

[0141]

[0142] Prepared with reference to 1-9, pale yellow solid, yield 87.2%.

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.59 (s, 1H), 7.90 - 7.77 (m, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H), 5.06 (s, 1H), 1.94 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H). LC-MS / ESI [M+H] + 515.17.

[0144] Step 2: Synthesis of 2-Amino-3-fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (2)

[0145]

[0146] Prepared with reference to 1-10, white solid, yield 89.8%, melting point: 157.8 - 158.3 °C.

[0147] 11H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.98 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (ddd, J = 11.6, 8.0, 1.2 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 6.89 - 6.82 (m, 2H), 6.61 (td, J = 8.0, 5.2 Hz, 1H), 6.54 (d, J = 4.0 Hz, 1H), 6.36 (s, 2H), 5.08 (s, 1H), 1.92 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H); 13 13C NMR (151 MHz, DMSO-d6) δ 167.61 (d, J = 3.5 Hz), 155.65, 151.62 (d, J = 238.1 Hz), 148.54, 139.01 (d, J = 14.3 Hz), 137.54, 134.95, 134.77, 133.10, 129.10, 128.75 (d, J = 23.6 Hz), 126.79, 124.79, 124.76, 122.31, 119.15, 117.68 (d, J = 19.1 Hz), 117.17 (d, J = 4.8 Hz), 115.04, 114.96, 114.42 (d, J = 7.4 Hz), 113.49, 111.65, 70.78, 32.20, 15.75. HRMS (ESI) calcd for C 28 H 24 FN4O3 [M-H] - m / z: 483.1833, found 483.1831. HPLC purity: 99.70%, retention time: 8.87 min.

[0148] Example 3. Synthesis of 1-(3-(8-Fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (3)

[0149]

[0150] Compound 2 (100 mg, 0.21 mmol), NaOH (10 mg, 0.25 mmol), 37% formaldehyde solution (0.42 mL, 5.17 mmol) and ethanol (3 mL) were added to the reaction flask and stirred at 60° C. After 0.5 hours, the ethanol was removed and extracted with 50 mL of ethyl acetate. The organic layer was dried and passed through a silica gel column to obtain a white solid 3 with a yield of 78.1% and a melting point of 262.3-263.5° C.

[0151] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,0.5H),11.27(s,0.5H),7.60(d,J=8.0Hz,1H),7.57-7.54(m,1H),7.50-7.38(m,3H) ,7.34-7.29(m,1H),7.19-7.16(m,1H),7.03(d,J=9.0Hz,1H),6.91(dd,J=9.0,1.8Hz,0.5H),6.89(s,1H),6.83-6.77 (m,1H),6.70(d,J=8.6Hz,0.5H),6.59(d,J=4.0Hz,0.5H),6.56(d,J=4.0Hz,0.5H),5.15-5.12(m,1H),5.09(s,0.5H) ,5.08(s,0.5H),4.75(dd,J=9.5,3.0Hz,0.5H),4.67(dd,J=9.5,3.0Hz,0.5H),1.90(s,3H),1.39(s,3H),1.38(s,3H). 1 H NMR shows a mixture of atropisomers. 13CNMR(151MHz,DMSO-d6)δ162.03(d,J=3.9Hz),161.82(d,J=3.9Hz),155.65,155.63,151.27(d,J=240.7Hz),151.24(d,J=240.7Hz),148.60,148.51,141.29,141.13,137.89,137.79,136.38,135.94,135.16,135.10,132.85,132.64,130.48,130.27,129.30,129.15,129.04,128.53,127.71(d,J=11.8Hz),124.89,124.37,122.30,122.22,119.24,119.19,119.07(d,J=4.9Hz),117.95(d,J=6.6Hz),117.93(d,J=6.6Hz),115.18,114.91(d,J=4.0Hz),113.64,113.43,111.67(d,J=17.1Hz),70.78,70.76,61.89,61.77,32.26,32.24,32.18,32.15,15.85,15.68. 13 C NMR shows a mixture of atropisomers.HRMS(ESI)calcdfor C 29 H 24 FN4O3[M-H] - m / z:495.1833,found495.1833.HPLC purity:98.93%,retentiontime:8.57min.

[0152] Example 4. Synthesis of 8-fluoro-3-(2-fluoro-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)quinazoline-2,4(1H,3H)-dione (4)

[0153]

[0154] Preparation of Reference 1, white solid, yield: 91.5%, melting point: >300 °C.

[0155] 1H NMR(400MHz,DMSO-d6)δ11.97(s,0.5H),11.92(s,0.5H),11.34(s,1H),7.80(d,J=7.8Hz,1H),7.77-7.65(m,3H),7.56(t,J=7.8Hz,1H),7.49-7.44(s,1H),7.29-7.23(m,1H),7.18(d,J=4.0Hz,1H),7.15-7.11(m,1H),6.99(dd,J=8.8,1.6Hz,0.5H),6.95(dd,J=8.8,1.6Hz,0.5H),6.76(d,J=4.0Hz,1H),5.11(s,0.5H),5.10(s,0.5H),1.41(s,1.5H),1.40(s,3H),1.39(s,1.5H). 1 H NMR shows amixture of atropisomers. 13 C NMR(151MHz,DMSO-d6)δ161.40(d,J=3.3Hz),161.21(d,J=3.3Hz),155.98(d,J=250.8Hz),155.93(d,J=250.8Hz),155.51,155.49,150.40,149.65,149.56,149.55(d,J=254.0Hz),148.77,133.03,133.01(d,J=14.7Hz),129.32(d,J=4.8Hz),129.22(d,J=4.8Hz),129.03,126.43,126.36,126.12,125.81,125.79,124.10(d,J=14.7Hz),123.73(d,J=3.5Hz),123.67(d,J=3.5Hz),123.41(d,J=5.0Hz),123.37(d,J=5.0Hz),122.65(d,J=10.2Hz),122.56(d,J=10.2Hz),122.21,122.14,121.46(d,J=17.8Hz),119.39(d,J=12.4Hz),116.68(d,J=10.6Hz),116.60,116.59,115.33(d,J=3.5Hz),113.52(d,J=4.5Hz),111.83,111.82,70.75,70.72,32.29,32.22,32.16. 1313C NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 28 H 19 F2N4O4 [M-H] - m / z: 513.1375, found 513.1373. HPLC purity: 99.89%, retention time: 7.99 min.

[0156] Example 5. Synthesis of 3-(2-(difluoromethyl)-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (5)

[0157]

[0158] Preparation of Reference 1, white solid, yield: 35.3%, melting point: >300 °C.

[0159] 1 1H NMR (600 MHz, DMSO-d6) δ 11.83 (s, 0.5H), 11.81 (s, 0.5H), 11.29 (s, 1H), 7.85 - 7.81 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 - 7.44 (m, 1H), 7.28 - 7.22 (m, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.88 (t, J = 52.4 Hz, 0.5H), 6.86 (t, J = 52.4 Hz, 0.5H), 6.86 (dd, J = 8.8, 2.0 Hz, 0.5H), 6.82 (dd, J = 8.8, 2.0 Hz, 0.5H), 6.65 - 6.61 (m, 2H), 5.09 (s, 0.5H), 5.07 (s, 0.5H), 1.38 (s, 3H), 1.37 (s, 3H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 20 F3N4O4 [M-H] - m / z: 545.1437, found 545.1436. HPLC purity: 100%, retention time: min 7.85, 8.02.

[0160] Synthesis of 6.8-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)quinazoline-2,4(1H,3H)-dione (6)

[0161]

[0162] Preparation of Reference 1, white solid, yield 82.5%, melting point: >300 °C.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.27 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.61 - 7.55 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.22 (td, J = 8.0, 4.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.94 (dd, J = 8.8, 1.8 Hz, 1H), 6.66 (d, J = 4.0 Hz, 1H), 5.06 (br s, 1H), 1.40 (s, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 161.88 (d, J = 4.5 Hz), 155.72, 150.36, 149.46 (d, J = 247.4 Hz), 148.52, 136.47, 134.33, 133.44, 130.79, 130.01, 129.96, 129.92, 129.28, 129.26 (d, J = 15.1 Hz), 125.59, 123.62 (d, J = 4.5 Hz), 122.90 (d, J = 7.6 Hz), 121.95, 120.93 (d, J = 16.6 Hz), 118.88, 117.29 (d, J = 1.5 Hz), 116.66, 115.76, 113.51, 111.85, 70.76, 32.26. HRMS (ESI) calcd for C 28 H 20 FN4O4 [M - H] - m / z: 495.1469, found 495.1470. HPLC purity: 99.47%, retention time: 7.95 min.

[0164] Synthesis of Example 7. 8-Fluoro-3-(5-fluoro-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (7)

[0165]

[0166] Preparation of Reference 1, white solid, yield: 93.6%, melting point: 212.5 - 213.7 °C.

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 0.5H), 11.90 (s, 0.5H), 11.33 (s, 1H), 7.84 (dd, J = 8.0, 2.4 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.60 (dd, J = 9.2, 2.4 Hz, 1H), 7.48 - 7.45 (m, 2H), 7.29 - 7.24 (m, 1H), 7.19 (d, J = 4.0 Hz, 1H), 6.98 (dd, J = 8.8, 2.0 Hz, 0.5H), 6.93 (dd, J = 8.8, 2.0 Hz, 0.5H), 6.91 - 6.87 (m, 1H), 6.69 (d, J = 4.0 Hz, 0.5H), 6.68 (d, J = 4.0 Hz, 0.5H), 5.13 (s, 0.5H), 5.11 (s, 0.5H), 1.74 (s, 3H), 1.42 (s, 1.5H), 1.41 (s, 1.5H), 1.40 (s, 3H). 1 H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 21 F2N4O4[M-H] - m / z: 527.1531, found 527.1531. HPLC purity: 98.96%, retention time: 8.24, 8.46 min.

[0168] Synthesis of Example 8. 8-Fluoro-3-(3-(2-fluoro-7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (8)

[0169]

[0170] Preparation of Reference 1, white solid, yield 71.7%, melting point: >300 °C.

[0171] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 11.51 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.61 - 7.58 (m, 1H), 7.55 - 7.54 (m, 2H), 7.47 - 7.46 (m, 1H), 7.28 - 7.23 (m, 1H), 7.09 (s, 1H), 6.94 (dd, J = 8.9, 1.8 Hz, 0.25H), 6.90 (dd, J = 8.9, 1.8 Hz, 0.25H), 6.88 - 6.84 (m, 1.5H), 5.12 (s, 0.25H), 5.10 (s, 0.75H), 1.83 (s, 3H), 1.39 - 1.37 (m, 6H). 1 H NMR shows a mixture of atropisomers. HRMS (ESI) calcd for C 29 H 22 FN2O4Na [M+Na] + m / z: 551.1508, found 551.1507. HPLC purity: 98.57%, retention time: 8.27, 8.45 min.

[0172] Example 9. Synthesis of 2-fluoro-1-(3-(8-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (9)

[0173]

[0174] Preparation of Reference 3, white solid, yield 62.6%, melting point: >300 °C.

[0175] 11H NMR (600 MHz, DMSO-d6) δ 11.53 (s, 0.5H), 11.51 (s, 0.5H), 7.62 - 7.59 (m, 2H), 7.53 - 7.46 (m, 3H), 7.34 - 7.31 (m, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.06 - 7.04 (m, 1H), 6.95 (dd, J = 8.9, 1.8 Hz, 0.5H), 6.92 (dd, J = 8.9, 1.8 Hz, 0.5H), 6.87 (d, J = 8.9 Hz, 0.5H), 6.83 - 6.78 (m, 1H), 6.72 (d, J = 8.9 Hz, 0.5H), 5.17 - 5.14 (m, 1H), 5.13 (s, 0.5H), 5.11 (s, 0.5H), 4.78 (dd, J = 9.5, 3.1 Hz, 0.5H), 4.71 (dd, J = 9.5, 3.1 Hz, 0.5H), 1.97 (s, 1.5H), 1.96 (s, 1.5H), 1.39 - 1.38 (m, 6H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 24 F2N4O3Na [M+Na] + m / z: 537.1714, found 537.1713. HPLC purity: 96.07%, retention time: 8.81 min.

[0176] Example 10. Synthesis of 3-(3-(2-fluoro-7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (10)

[0177]

[0178] Preparation of Reference 1, white solid, yield: 68.7%, melting point: >300 °C.

[0179] 11H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 0.7H), 11.75 (s, 0.3H), 11.52 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.49 (d, J = 1.2 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.08 (s, 1H), 6.94 (dd, J = 8.8, 1.9 Hz, 0.3H), 6.89 (dd, J = 8.8, 1.9 Hz, 0.7H), 6.89 - 6.85 (m, 1H), 5.13 (s, 0.3H), 5.12 (s, 0.7H), 1.82 (s, 0.9H), 1.81 (s, 2.1H), 1.39 (s, 1.8H), 1.37 (s, 4.2H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 23 FN4O4 [M+H] + m / z: 511.1781, found 511.1781. HPLC purity: 98.06%, retention time: 8.10, 8.30 min.

[0180] Synthesis of Example 11. 8-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-2H-benzo[e][1,3]oxazin-2,4(3H)-dione (11)

[0181]

[0182] Step 1: Synthesis of 3-Fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-2-methoxybenzamide (11-1)

[0183]

[0184] Refer to the preparation of 1-9, white solid, yield 87.6%.

[0185] 11H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.03 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.29 (d, J = 7.9 Hz, 1H), 7.23 (td, J = 7.9, 5.2 Hz, 1H), 7.17 (d, J = 3.8 Hz, 1H), 6.86 (dd, J = 8.8, 1.6 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 3.8 Hz, 1H), 5.06 (s, 1H), 3.96 (s, 3H), 1.99 (s, 3H), 1.36 (s, 6H). LC-MS / ESI [M-H] + 498.15.

[0186] Step 2: Synthesis of 3-Fluoro-2-hydroxy-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (11-2)

[0187]

[0188] Dissolve compound 11-1 (266 mg, 0.53 mmol) in dichloromethane (5 mL), add BBr3 (0.59 mL, 0.59 mmol) dropwise at -70 °C. After addition, react at -70 °C for 2 hours and then at -10 °C for 1 hour. Quench the reaction mixture with 0.5 mL of methanol and 1 mL of NaHCO3 solution, then add 50 mL of dichloromethane for dilution. Wash the organic layer with brine and then evaporate to dryness. Purify by silica gel column chromatography to obtain white solid 11-2 with a yield of 33.4%.

[0189] 1 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.29 (s, 1H), 10.55 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.34 (dd, J = 8.0, 1.0 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 6.98 (td, J = 8.0, 4.9 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 3.9 Hz, 1H), 5.07 (s, 1H), 1.94 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H). LC-MS / ESI [M + H]+ 486.20.

[0190] Step 3: Synthesis of 8-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-2H-benzo[e][1,3]oxazin-2,4(3H)-dione (11)

[0191]

[0192] Preparation of Reference 1, white solid, yield: 35.7%, melting point: >300 °C.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 7.89 - 7.85 (m, 2H), 7.69 - 7.65 (m, 1H), 7.54 - 7.53 (m, 2H), 7.50 - 7.46 (m, 2H), 7.17 (d, J = 3.6 Hz, 1H), 6.91 (dd, J = 8.8, 1.2 Hz, 0.5H), 6.85 - 6.83 (m, 1H), 6.79 (d, J = 8.8 Hz, 0.5H), 6.63 (d, J = 3.6 Hz, 1H), 5.10 (s, 0.5H), 5.09 (s, 0.5H), 1.85 (s, 1.5H), 1.84 (s, 1.5H), 1.39 (s, 3H), 1.38 (s, 3H). 1 H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 22 FN3O5 [M+H] + m / z: 512.1621, found 512.1621. HPLC purity: 95.50%, retention time: 9.07 min.

[0194] Example 12. Synthesis of 9-Fluoro-4-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (12)

[0195]

[0196] Step 1: Synthesis of N-(3-Bromo-2-methylphenyl)-3-fluoro-2-nitrobenzamide (12-3)

[0197]

[0198] Prepared according to Reference 1 - 9, white solid, yield 85.5%.

[0199] 1 H NMR(400MHz, DMSO - d6)δ10.65(s, 1H), 7.90(td, J = 8.0, 5.2Hz, 1H), 7.83 - 7.82(m, 1H), 7.79(dd, J = 8.0, 1.2Hz, 1H), 7.56(d, J = 8.0Hz, 1H), 7.37(d, J = 8.0Hz, 1H), 7.21(t, J = 8.0Hz, 1H), 2.31(s, 3H).

[0200] Step 2: Synthesis of 2 - amino - N - (3 - bromo - 2 - methylphenyl) - 3 - fluorobenzamide (12 - 4)

[0201]

[0202] Prepared according to Reference 1 - 10, white solid, yield 86.9%.

[0203] 1 H NMR(400MHz, DMSO - d6)δ10.05(s, 1H), 7.61(d, J = 8.0Hz, 1H), 7.55(d, J = 8.0Hz, 1H), 7.33(d, J = 8.0, 1H), 7.26(ddd, J = 11.6, 8.0, 0.8Hz, 1H), 7.20(t, J = 8.0Hz, 1H), 6.64(td, J = 8.0, 5.2Hz, 1H), 6.36(s, 2H), 2.29(s, 3H). LC - MS / ESI[M + H] + 323.00.

[0204] Step 3: Synthesis of N - (3 - bromo - 2 - methylphenyl) - 2 - (2 - chloroacetamido) - 3 - fluorobenzamide (12 - 5)

[0205]

[0206] Dissolve compound 12 - 4 (1.61g, 5.00mmol) and triethylamine (690μL, 5.00mmol) in DMF (7mL), add chloroacetyl chloride (678mg, 6.00mmol) dropwise at 0℃, and stir at room temperature after addition. After 1 hour, dilute the reaction solution with 150mL of ethyl acetate. Wash the organic layer with brine multiple times and then concentrate it by rotary evaporation and pass it through a silica gel column to obtain white solid 12 - 5, yield 75.3%.

[0207] 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 10.07 (s, 1H), 7.54 - 7.43 (m, 2H), 7.51 (dd, J = 8.0, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 4.30 (s, 2H), 2.31 (s, 3H).

[0208] Step 4: Synthesis of 4-(3-bromo-2-methylphenyl)-9-fluoro-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (12-6)

[0209]

[0210] Compound 12-5 (398 mg, 1.00 mmol), K2CO3 (207 mg, 1.50 mmol) and DMF (10 mL) were added to a reaction flask and stirred at 60 °C. After 2 hours, 150 mL of ethyl acetate was added. The organic layer was washed with brine several times and then concentrated by rotary evaporation and purified by silica gel column chromatography to obtain white solid 12-6 with a yield of 71.4%.

[0211] 1 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.69 - 7.65 (m, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.55 (ddd, J = 10.5, 8.2, 1.5 Hz, 1H), 7.33 (td, J = 8.0, 5.2 Hz, 1H), 7.29 - 7.27 (m, 2H), 4.45 - 4.01 (m, 2H), 2.19 (s, 3H). LC-MS / ESI [M+H] + 363.00.

[0212] Step 5: Synthesis of 9-fluoro-4-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (12-7)

[0213]

[0214] Compound 12-6 (181 mg, 0.5 mmol), bis(pinacolato)diboron (191 mg, 0.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (41 mg, 0.05 mmol), potassium acetate (147 mg, 1.5 mmol) and 1,4-dioxane (2.5 mL) were added to a reaction flask, and the reaction was carried out at 80 °C for 12 h under nitrogen protection. After completion of the reaction, the reaction solution was diluted with 50 mL of ethyl acetate. The organic layer was washed three times with water and saturated sodium chloride successively, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the residue was purified by normal-phase column chromatography to obtain white solid 20 with a yield of 89.2%.

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.70 - 7.60 (m, 2H), 7.53 (ddd, J = 10.1, 8.2, 1.5 Hz, 1H), 7.38 - 7.24 (m, 3H), 4.51 - 4.04 (m, 2H), 2.29 (s, 3H), 1.32 (s, 12H). LC-MS / ESI [M+H] + 411.20.

[0216] Step 6: Synthesis of 9-fluoro-4-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (12)

[0217]

[0218] Compound 12-7 (340 mg, 0.83 mmol), 1-6 (220 mg, 0.69 mmol), K3PO4 (439 mg, 2.07 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol), DME (13 mL) and water (4 mL) were added to a microwave reaction tube, and the reaction was carried out by microwave at 110 °C for 30 minutes. The reaction solution was diluted with 100 mL of ethyl acetate, the organic layer was washed repeatedly with brine and then concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain white solid 12 with a yield of 81.2% and a melting point of 276.2 - 277.1 °C.

[0219] 11H NMR (600 MHz, DMSO-d6) δ 11.31 (s, 0.4H), 11.28 (s, 0.6H), 10.58 (s, 0.6H), 10.55 (s, 0.4H), 7.66 (t, J = 7.8 Hz, 1H), 7.55 - 7.45 (m, 4.4H), 7.42 (dd, J = 7.0, 1.8 Hz, 0.6H), 7.32 (td, J = 7.8, 4.8 Hz, 1H), 7.17 (d, J = 3.9 Hz, 0.6H), 7.16 (d, J = 3.9 Hz, 0.4H), 6.92 (dd, J = 8.9, 2.0 Hz, 0.6H), 6.89 - 6.87 (m, 1H), 6.71 (d, J = 8.9 Hz, 0.4H), 6.61 (d, J = 3.9 Hz, 0.6H), 6.60 (d, J = 3.9 Hz, 0.4H), 5.09 (s, 1H), 4.54 - 3.99 (m, 2H), 1.84 (s, 1.8H), 1.83 (s, 1.2H), 1.39 - 1.37 (m, 6H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 30 H 24 FN4O4 [M - H] - m / z: 523.1782, found 523.1781. HPLC purity: 99.77%, retention time: 7.73 min.

[0220] Example 13. Synthesis of 8 - fluoro - 3-(2-(hydroxymethyl)-3-(7-(2 - hydroxypropan - 2 - yl)-4 - oxo - 4,5 - dihydropyrrolo[1,2 - a]quinoxalin - 1 - yl)phenyl)quinazoline - 2,4(1H,3H) - dione (13)

[0221]

[0222] Step 1: Synthesis of (2 - bromo - 6 - nitrobenzyl)oxy)(tert - butyl)dimethylsilane (13 - 2)

[0223]

[0224] Compound 13-1 (5.00 g, 21.65 mmol) was dissolved in dichloromethane (43 mL). Imidazole (2.23 g, 32.47 mmol) and TBSCl (3.90 g, 25.97 mmol) were added at 0 °C, and the mixture was stirred at room temperature. After 3 hours, the reaction solution was diluted with 100 mL of dichloromethane. The organic layer was washed with brine and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give a pale yellow liquid 13-2 in a yield of 90.5%.

[0225] 1 H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (dd, J = 8.0, 1.2 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.05 (s, 2H), 0.88 (s, 9H), 0.08 (s, 6H).

[0226] Step 2: Synthesis of 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)aniline (13-3)

[0227]

[0228] Compound 13-2 (345 mg, 1.00 mmol), iron powder (280 mg, 5.00 mmol), NH4Cl (540 mg, 10.00 mmol), water (2 mL) and ethanol (8 mL) were mixed and stirred at 80 °C. After 2 hours, the mixture was filtered while hot. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography to give a pale yellow liquid 13-3 in a yield of 82.3%.

[0229] 1 H NMR (400 MHz, CDCl3) δ 6.94 - 6.89 (m, 2H), 6.62 - 6.34 (m, 1H), 4.96 (s, 2H), 0.90 (s, 9H), 0.10 (s, 6H).

[0230] Step 3: Synthesis of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (13-4)

[0231]

[0232] Referring to the preparation of 12-6, a white solid 13-4 was obtained in a yield of 70.3%.

[0233] 11H NMR (600 MHz, DMSO-d6) δ 7.05 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.06 (br s, 2H), 4.97 (s, 2H), 1.33 (s, 12H), 0.90 (s, 9H), 0.09 (s, 6H).

[0234] Step 4: Synthesis of 1-(3-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (13-5)

[0235]

[0236] With reference to the preparation of 1-8, a pale yellow solid 13-5 was obtained with a yield of 29.1%.

[0237] 1 1H NMR (600 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.45 (s, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.79 (s, 2H), 6.59 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 3.9 Hz, 1H), 5.19 (s, 2H), 5.03 (s, 1H), 4.33 (d, J = 11.5 Hz, 1H), 4.27 (d, J = 11.5 Hz, 1H), 1.34 (s, 6H), 0.62 (s, 9H), -0.26 (s, 3H), -0.43 (s, 3H). LC-MS / ESI [M+H] + 478.25.

[0238] Step 5: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)-3-fluoro-2-nitrobenzamide (13-6)

[0239]

[0240] With reference to the preparation of 1-9, a white solid 13-6 was obtained with a yield of 88.6%.

[0241] 11H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.47 (s, 1H), 7.94 - 7.79 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 3.9 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 3.9 Hz, 1H), 5.05 (s, 1H), 4.56 (s, 2H), 1.34 (s, 6H), 0.50 (s, 9H), -0.35 (s, 3H), -0.46 (s, 3H). LC-MS / ESI [M+H] + 645.30.

[0242] Step 6: Synthesis of 3-Fluoro-N-(2-(hydroxymethyl)-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)-2-nitrobenzamide (13-7)

[0243]

[0244] Dissolve compound 13-6 (132 mg, 0.21 mmol) in tetrahydrofuran (2 mL), add TBAF (0.25 mL, 0.25 mmol) dropwise at 0 °C. After the addition, stir at room temperature. After 1 hour, dilute with 50 mL of ethyl acetate, wash the organic layer with brine, and then concentrate by rotary evaporation and purify by silica gel column chromatography to obtain white solid 13-7 with a yield of 80.5%.

[0245] 1 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.69 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 - 7.81 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 3.9 Hz, 1H), 6.84 (dd, J = 8.9, 1.7 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.60 (d, J = 3.9 Hz, 1H), 5.47 (t, J = 4.7 Hz, 1H), 5.07 (s, 1H), 4.45 - 4.32 (m, 2H), 1.36 (s, 6H). LC-MS / ESI [M+H] + 531.20.

[0246] Step 7: Synthesis of 2-Amino-3-fluoro-N-(2-(hydroxymethyl)-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)benzamide (13-8)

[0247]

[0248] Compound 13-7 (120 mg, 0.23 mmol), 10% Pd / C (24 mg), ethyl acetate (4 mL) and methanol (1 mL) were added to a reaction flask. A hydrogen balloon was inserted on the reaction flask as a hydrogen source and stirred at room temperature. After 5 hours, it was filtered. The filtrate was concentrated by rotary evaporation and then purified by silica gel column chromatography to obtain white solid 13-8 with a yield of 79.3%.

[0249] 1 H NMR (600 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.35 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.25 (ddd, J = 11.4, 7.9, 0.8 Hz, 1H), 7.18 (dd, J = 7.9, 0.8 Hz, 1H), 7.16 (d, J = 3.9 Hz, 1H), 6.86 (dd, J = 8.9, 2.0 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.62 (td J = 7.9, 5.1 Hz, 1H), 6.58 (d, J = 3.9 Hz, 1H), 6.47 (s, 2H), 5.79 - 5.76 (m, 1H), 5.06 (s, 1H), 4.49 (dd, J = 12.6, 5.4 Hz, 1H), 4.41 (dd, J = 12.6, 4.0 Hz, 1H), 1.36 (s, 6H); 13 C NMR (151 MHz, DMSO-d6) δ 166.96 (d, J = 3.6 Hz), 155.61, 151.78 (d, J = 238.6 Hz), 148.54, 139.23 (d, J = 14.3 Hz), 139.08, 133.61, 131.73, 131.57, 129.20, 128.57, 127.19, 124.88, 124.11, 123.53 (d, J = 3.5 Hz), 122.08, 119.01, 117.91 (d, J = 18.4 Hz), 117.25 (d, J = 5.1 Hz), 115.75, 115.66, 114.85 (d, J = 7.1 Hz), 113.47, 111.48, 70.80, 59.39, 32.22. HRMS (ESI) calcd for C 28 H25 FN4O4Na[M+Na] + m / z: 523.1758, found 523.1757.

[0250] Step 8: Synthesis of 8-Fluoro-3-(2-(hydroxymethyl)-3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)phenyl)quinazoline-2,4(1H,3H)-dione (13)

[0251]

[0252] Prepared according to Reference 1, white solid, yield 51.8%, melting point: >300 °C.

[0253] 1 H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 0.5H), 11.73 (s, 0.5H), 11.26 (s, 1H), 7.81 (d, J = 7.8 Hz, 0.5H), 7.80 (d, J = 7.8 Hz, 0.5H), 7.66 - 7.63 (m, 1H), 7.59 - 7.54 (m, 2H), 7.46 - 7.45 (m, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.25 - 7.11 (m, 1H), 7.16 (d, J = 3.9 Hz, 1H), 6.89 (dd, J = 9.0, 1.8 Hz, 0.5H), 6.85 (dd, J = 9.0, 1.8 Hz, 0.5H), 6.82 (d, J = 9.0 Hz, 0.5H), 6.80 (d, J = 9.0 Hz, 0.5H), 6.67 (d, J = 3.9 Hz, 0.5H), 6.66 (d, J = 3.9 Hz, 0.5H), 5.09 (s, 0.5H), 5.07 (s, 0.5H), 4.70 (dd, J = 6.6, 4.2 Hz, 0.5H), 4.67 (dd, J = 6.6, 4.2 Hz, 0.5H), 4.23 - 4.07 (m, 2H), 1.40 (s, 1.5H), 1.39 (s, 1.5H), 1.37 (s, 3H). 1 H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 23 FN4O5Na[M+Na] + m / z: 549.1550, found 549.1549. HPLC purity: 96.71%, retention time: 7.42, 7.49 min.

[0254] Synthesis of Example 14. 8-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-2-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (14)

[0255]

[0256] Step 1: Synthesis of 2-methyl-1-nitro-3-(prop-1-yn-1-yl)benzene (14-2)

[0257]

[0258] Compound 14-1 (263 mg, 1.00 mmol), PdCl2(PPh3)2 (35 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol) and triethylamine (1.5 mL) were added to a reaction flask. A DMF solution of propyne (1.5 mL, 1.50 mmol) was added dropwise at 0 °C. After addition, the mixture was stirred at room temperature. After 12 hours, it was diluted with 30 mL of ethyl acetate. The organic layer was washed with brine and then concentrated by rotary evaporation and purified by silica gel column chromatography to obtain pale yellow solid 14-2 in a yield of 86.5%.

[0259] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.14 (s, 3H).

[0260] Step 2: Synthesis of methyl 4-methyl-5-(2-methyl-3-nitrophenyl)-1H-pyrrole-2-carboxylate (14-3)

[0261] Methyl 2-acetamidoacrylate (116 mg, 0.66 mmol), 14-2 (86 mg, 0.60 mmol), [RuCl2(p-cymene)]2 (18 mg, 0.03 mmol), AgSbF6 (42 mg, 0.12 mmol), copper acetate (240 mg, 0.12 mmol), methanol (2 mL) and DCE (1 mL) were added to a reaction flask and stirred at 100 °C. After 36 hours, it was diluted with 100 mL of ethyl acetate. The organic layer was washed with brine and then concentrated by rotary evaporation and purified by silica gel column chromatography to obtain pale yellow solid 14-3 in a yield of 58.5%.

[0262] 11H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 2.2 Hz, 1H), 3.76 (s, 3H), 2.23 (s, 3H), 1.89 (s, 3H). LC-MS / ESI [M+H] + 275.10.

[0263]

[0264] Step 3: Synthesis of methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-4-methyl-5-(2-methyl-3-nitrophenyl)-1H-pyrrole-2-carboxylate (14-4)

[0265]

[0266] Refer to the preparation of 1-3, pale yellow solid, yield 50.2%.

[0267] 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 1.5 Hz, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H), 3.88 (s, 3H), 3.63 (s, 3H), 2.12 (s, 3H), 1.89 (s, 3H). LC-MS / ESI [M+H] + 454.10.

[0268] Step 4: Synthesis of methyl 1-(3-amino-2-methylphenyl)-2-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate (14-5)

[0269]

[0270] Refer to the preparation of 1-4, grey solid, yield 70.6%.

[0271] 11H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.90 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.93 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.15 (s, 2H), 3.81 (s, 3H), 1.93 (s, 3H), 1.67 (s, 3H). LC-MS / ESI [M+H] + 362.15.

[0272] Step 5: Synthesis of 1-(3-Amino-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-2-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (14-6)

[0273]

[0274] Refer to the preparation of 1-5, white solid, yield 78.8%.

[0275] 1 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.44 (s, 1H), 7.08 (t, J = 7.7 Hz, 1H), 7.00 (s, 1H), 6.87 - 6.73 (m, 3H), 6.50 (d, J = 7.7 Hz, 1H), 5.12 (s, 2H), 5.04 (s, 1H), 1.91 (s, 3H), 1.68 (s, 3H), 1.35 (s, 6H). LC-MS / ESI [M+H] + 362.20.

[0276] Step 6: Synthesis of 3-Fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-2-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-tolyl)-2-nitrobenzamide (14-7)

[0277]

[0278] Refer to the preparation of 1-9, white solid, yield 87.3%.

[0279] 11H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.60 (s, 1H), 7.90 - 7.78 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.29 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J = 8.8, 1.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.05 (s, 1H), 1.93 (s, 3H), 1.92 (s, 3H), 1.35 (s, 6H).

[0280] Step 7: Synthesis of 2-Amino-3-fluoro-N-(3-(7-(2-hydroxypropan-2-yl)-2-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (14-8)

[0281]

[0282] Refer to the preparation of 14-5, white solid, yield 90.5%.

[0283] 1 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.98 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 11.5, 8.1 Hz, 1H), 7.04 (s, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.60 (td, J = 8.1, 5.2 Hz, 1H), 6.36 (s, 2H), 5.04 (s, 1H), 1.94 (s, 3H), 1.89 (s, 3H), 1.36 (s, 6H).

[0284] Step 8: Synthesis of 8-Fluoro-3-(3-(7-(2-hydroxypropan-2-yl)-2-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (14)

[0285]

[0286] Refer to the preparation of 1, white solid, yield 75.7%, melting point: >300 °C.

[0287] 1H NMR(600MHz,DMSO-d6)δ11.83(s,0.5H),11.81(s,0.5H),11.21(s,1H),7.82(d,J=7.2Hz,1H),7.67-7.65(m,1H),7.55-7.51(m,2H),7.43(d,J=2.0Hz,0.5H),7.42(d,J=2.0Hz,0.5H),7.41(dd,J=7.2,2.0Hz,1H),7.27-7.23(m,1H),7.05(s,1H),6.87(dd,J=8.8,2.0Hz,0.5H),6.83(dd,J=8.8,2.0Hz,0.5H),6.80(d,J=8.8Hz,0.5H),6.79(d,J=8.8Hz,0.5H),5.07(s,0.5H),5.05(s,0.5H),1.98(s,1.5H),1.97(s,1.5H),1.75(s,3H),1.39(s,1.5H),1.38(s,1.5H),1.36(s,3H). 1 H NMR shows a mixture ofatropisomers. 13 C NMR(151MHz,DMSO-d6)δ161.52(d,J=3.5Hz),161.46(d,J=3.5Hz),155.37,155.36,149.90,149.83,149.56(d,J=247.1Hz),148.01,147.97,137.41,137.33,136.22,134.06,134.02,131.68,130.94(d,J=6.5Hz),129.95,129.90,129.47,129.38,128.91,128.90,127.78,123.76,123.74,123.08(d,J=7.4Hz),122.38,122.34,122.28,122.24,121.11(d,J=17.6Hz),119.12(d,J=3.9Hz),117.01(d,J=2.0Hz),117.00(d,J=2.0Hz),114.93,113.38,113.35,112.48,112.46,70.73,70.69,32.27,32.25,32.18,32.16,14.85,14.83,11.72. 13 C NMR shows a mixture of atropisomers.HRMS(ESI)calcdfor C 30 H24 FN4O4[M-H] - m / z: 523.1782, found 523.1783. HPLC purity: 98.95%, retention time: 8.17, 8.43 min.

[0288] Example 15. Synthesis of 8-Fluoro-3-(3-(3-(hydroxymethyl)-7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (15)

[0289]

[0290] Step 1: Synthesis of 2-Amino-3-fluoro-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (15-1)

[0291]

[0292] Compound 12-4 (161 mg, 0.50 mmol), bis(pinacolato)diboron (191 mg, 0.75 mmol), PdCl2(dppf)·CH2Cl2 (41 mg, 0.05 mmol), potassium acetate (147 mg, 1.50 mmol) and 1,4-dioxane (2.5 mL) were suspended in a reaction flask and stirred at 80 °C for 12 h. The reaction mixture was extracted with 100 mL of ethyl acetate, the organic layer was washed with brine and dried by evaporation, and then purified by silica gel column chromatography to obtain white solid 15-1 in a yield of 72.9%.

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.36 (dd, J = 7.6, 1,5 Hz, 1H), 7.24 - 7.19 (m, 2H), 6.61 (td, J = 8.1, 5.1 Hz, 1H), 6.31 (s, 2H), 2.37 (s, 3H), 1.31 (s, 12H). LC-MS / ESI [M+H] + 371.20.

[0294] Step 2: Synthesis of 8-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (15-2)

[0295]

[0296] Refer to the preparation of 1, and obtain white solid 15-2 with a yield of 85.6%.

[0297] 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 7.65 (ddd, J = 10.4, 7.8, 1.6 Hz, 1H), 7.38 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.24 (td, J = 7.8, 4.7 Hz, 1H), 2.21 (s, 3H), 1.32 (s, 12H).

[0298] Step 3: Synthesis of ethyl 3-(benzyloxymethyl)-1H-pyrrole-2-carboxylate (15-4)

[0299]

[0300] Add compound 15-3 (220 mg, 1.50 mmol), Ag2CO3 (28 mg, 0.10 mmol) and 1,4-dioxane (4 mL) to a reaction flask. Finally, add ethyl isocyanoacetate (113 mg, 1.00 mmol) at 80 °C and stir at 80 °C for 0.5 h. Rotate to remove the solvent. The residual solid is dissolved in 40 mL of ethyl acetate and washed with brine. After the organic layer is dried by rotation, it is passed through a silica gel column to obtain pale yellow liquid 15-4 with a yield of 70.6%.

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.39 - 7.25 (m, 5H), 6.95 (t, J = 2.8 Hz, 1H), 6.25 (t, J = 2.5 Hz, 1H), 4.68 (s, 2H), 4.52 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). LC-MS / ESI [M+H] + 258.15.

[0302] Step 4: Synthesis of ethyl 3-(benzyloxymethyl)-1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate (15-5)

[0303]

[0304] Refer to the preparation of 1-3, pale yellow liquid, yield 81.5%.

[0305] 1 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 1.9 Hz, 1H), 8.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.45 - 7.24 (m, 6H), 6.53 (d, J = 2.8 Hz, 1H), 4.73 (s, 2H), 4.59 (s, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H).

[0306] Step 5: Synthesis of methyl 3-((benzyloxy)methyl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate (15-6)

[0307]

[0308] Prepared with reference to 1-4, white solid, yield 66.2%.

[0309] 1 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 8.6, 1.8 Hz, 1H), 7.41 - 7.31 (m, 4H), 7.31 - 7.26 (m, 1H), 6.80 (d, J = 2.9 Hz, 1H), 4.96 (s, 2H), 4.58 (s, 2H), 3.87 (s, 3H). LC-MS / ESI [M+H] + 361.12.

[0310] Step 6: Synthesis of 3-(benzyloxy)methyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (15-7)

[0311]

[0312] Prepared with reference to 1-5, white solid, yield 70.3%.

[0313] 11H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.41 - 7.20 (m, 6H), 6.72 (d, J = 2.9 Hz, 1H), 5.13 (s, 1H), 4.96 (s, 2H), 4.58 (s, 2H), 1.44 (s, 6H). LC-MS / ESI [M+H] + 361.10.

[0314] Step 7: Synthesis of 3-(hydroxymethyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (15-8)

[0315]

[0316] Dissolve compound 15-7 (72 mg, 0.21 mmol) in tetrahydrofuran (2 mL), add TBAF (0.25 mL, 0.25 mmol) dropwise at 0 °C. After dropping, stir at room temperature. After 1 hour, dilute with 50 mL of ethyl acetate, wash the organic layer with brine and then spin-dry and pass through a silica gel column to obtain white solid 15-8, with a yield of 62.4%.

[0317] 1 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.5, 1.9 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 5.19 (t, J = 5.9 Hz, 1H), 5.12 (s, 1H), 4.83 (d, J = 5.9 Hz, 2H), 1.44 (s, 6H). LC-MS / ESI [M+H] + 271.05.

[0318] Step 8: Synthesis of 1-bromo-3-(hydroxymethyl)-7-(2-hydroxypropan-2-yl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (15-9)

[0319]

[0320] Refer to the preparation of 1-6, white solid, with a yield of 92.1%.

[0321] 11H NMR (600 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.78 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.22 (dd, J = 8.9, 2.1 Hz, 1H), 6.76 (s, 1H), 5.20 (s, 1H), 5.15 (s, 1H), 4.84 (s, 2H), 1.43 (s, 6H).

[0322] Step 9: Synthesis of 8-Fluoro-3-(3-(3-(hydroxymethyl)-7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (15)

[0323]

[0324] Preparation of Reference 12, white solid, yield 45.6%, melting point: >300 °C.

[0325] 1 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 11.28 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.54 (dd, J = 7.6, 2.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.46 (dd, J = 7.2, 1.6 Hz, 1H), 7.43 - 7.41 (m, 1H), 7.26 - 7.20 (m, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 0.5H), 6.85 - 6.82 (m, 1.5H), 6.61 (s, 0.5H), 6.60 (s, 0.5H), 5.30 (t, J = 5.9 Hz, 0.5H), 5.29 (t, J = 5.9 Hz, 0.5H), 5.10 (s, 0.5H), 5.08 (s, 0.5H), 4.91 (d, J = 5.9 Hz, 2H), 1.77 (s, 3H), 1.39 (s, 1.5H), 1.38 (s, 1.5H), 1.37 (s, 3H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 22 FN3O5Na [M+Na] + m / z: 563.1707, found 563.1708. HPLC purity: 95.52%, retention time: 7.74, 7.85 min.

[0326] Example 16. Synthesis of 6,8-difluoro-3-(3-(7-(2-hydroxypropyl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (16)

[0327]

[0328] Preparation of Reference 1, white solid, yield: 35.5%, melting point: >300 °C.

[0329] 1 H NMR (600 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.27 (s, 1H), 7.82 (t, J = 9.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.54 - 7.54 (m, 1H), 7.51 - 7.49 (m, 2H), 7.44 (s, 1H), 7.17 (d, J = 3.9 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.87 - 6.83 (m, 1H), 6.62 (d, J = 3.9 Hz, 1H), 5.09 (s, 0.5H), 5.08 (s, 0.5H), 1.76 (s, 3H), 1.39 (s, 3H) 1.37 (s, 3H). 1 HNMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 29 H 22 F2N4O4[M + H] + m / z: 529.1687, found 529.1685. HPLC purity: 97.38%, retention time: 8.22, 8.47 min.

[0330] Example 17. Synthesis of 7-cyclopropyl-3-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (17)

[0331]

[0332] Preparation of Reference 1, light yellow solid, yield: 25.4%, melting point: >300 °C.

[0333] 11H NMR (600 MHz, DMSO-d6) δ 11.54 (s, 0.5H), 11.53 (s, 0.5H), 11.26 (s, 1H), 7.83 (dd, J = 8.4, 3.6 Hz, 1H), 7.51 - 7.42 (m, 4H), 7.16 (d, J = 3.6 Hz, 1H), 6.94 - 6.92 (m, 2H), 6.90 - 6.83 (m, 2H), 6.65 (d, J = 3.6 Hz, 0.5H), 6.60 (d, J = 3.6 Hz, 0.5H), 5.09 (s, 0.5H), 5.07 (s, 0.5H), 2.06 - 2.00 (m, 1H), 1.73 (s, 1.5H), 1.72 (s, 1.5H), 1.41 - 1.35 (m, 6H), 1.11 - 1.06 (m, 2H), 0.76 (s, 2H). 1 1H NMR shows a mixture of atropisomers. HRMS(ESI) calcd for C 32 H 28 N4O4 [M+Na] + m / z: 555.2008, found: 555.2009. HPLC purity: 99.37%, retention time: 8.59, 8.84 min.

[0334] Example 18. Synthesis of 4-Cyclopropyl-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzamide (18)

[0335]

[0336] Refer to the preparation of 1 - 9, white solid, yield: 76.4%, melting point: >300 °C.

[0337] 11H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.99 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 3.9 Hz, 1H), 6.89 - 6.81 (m, 2H), 6.53 (d, J = 3.9 Hz, 1H), 5.09 (s, 1H), 2.04 - 1.97 (m, 1H), 1.92 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H), 1.06 - 1.00 (m, 2H), 0.78 - 0.73 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.72, 155.64, 148.59, 148.52, 137.80, 134.76, 134.64, 133.10, 131.67, 129.11, 128.66, 128.48, 128.23, 126.74, 125.60, 124.73, 122.31, 119.12, 115.00, 114.95, 113.51, 111.64, 70.77, 32.23, 32.19, 15.64, 10.66. HRMS (ESI) calcd for C 31 H 28 N3O3 [M - H] - m / z: 490.2131, found 490.2130. HPLC purity: 96.59%, retention time: 9.41 min.

[0338] Example 19. Synthesis of N-(3-(7-(2-Hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-1H-indole-2-carboxamide (19)

[0339]

[0340] Prepared according to the method of Reference 1 - 9, white solid, yield: 77.5%, melting point: 234.7 - 235.9 °C.

[0341] 11H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.31 (s, 1H), 10.09 (s, 1H), 7.69 - 7.61 (m, 2H), 7.51 - 7.43 (m, 3H), 7.40 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.85 - 6.74 (m, 2H), 6.55 (d, J = 3.9 Hz, 1H), 5.10 (s, 1H), 1.96 (s, 3H), 1.38 (s, 6H). 13 13C NMR (151 MHz, DMSO-d6) δ 170.81, 160.46, 155.64, 148.52, 137.22, 134.90, 134.60, 133.05, 131.69, 129.13, 128.77, 128.44, 127.53, 126.88, 124.77, 124.17, 122.34, 122.15, 120.37, 119.11, 114.99, 114.94, 113.54, 112.85, 111.66, 104.27, 70.78, 32.27, 15.74. HRMS (ESI) calcd for C 30 H 25 N4O3 [M - H] - m / z: 489.1927, found 489.1925. HPLC purity: 99.43%, retention time: 9.00 min.

[0342] Example 20. Synthesis of N-(3-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzo[b]thiophene-2-carboxamide (20)

[0343]

[0344] Refer to the preparation of 1 - 9, white solid, yield 90%.

[0345] 11H NMR (600 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.91 (s, 1H), 7.69 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 6.6 Hz, 1H), 7.16 (d, J = 3.9 Hz, 1H), 6.85 (dd, J = 8.4, 1.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 3.9 Hz, 1H), 5.08 (s, 1H), 2.74 (t, J = 5.9 Hz, 2H), 2.59 (t, J = 5.9 Hz, 2H), 1.90 (s, 3H), 1.79 - 1.70 (m, 4H), 1.37 (d, J = 4.2 Hz, 6H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.24, 155.17, 148.08, 141.41, 136.81, 136.00, 135.16, 134.35, 134.08, 132.56, 129.80, 128.65, 128.24, 127.99, 126.32, 124.28, 121.84, 118.65, 114.48, 114.46, 113.07, 111.18, 70.31, 31.76, 31.72, 24.98, 24.70, 22.82, 22.18, 15.20. HRMS (ESI) calcd for C 30 H 29 N3O3S [M+Na] + m / z: 512.2008, found: 512.2009.

[0346] Example 21. Synthesis of N-(3-(7-(2-hydroxypropyl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (21)

[0347]

[0348] Refer to the preparation of 1 - 9, white solid, yield 80%.

[0349] 11H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.42 (s, 1H), 8.37 (s, 1H), 8.10 - 8.04 (m, 1H), 8.00 - 7.98 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.51 - 7.41 (m, 4H), 7.34 (dd, J = 7.2, 0.8 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.55 (d, J = 3.9 Hz, 1H), 5.08 (s, 1H), 1.95 (s, 3H), 1.37 (d, J = 4.2 Hz, 6H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.57, 155.17, 148.10, 140.44, 139.52, 139.13, 136.50, 134.47, 134.20, 132.46, 128.66, 128.60, 128.05, 126.49, 126.46, 125.98, 125.37, 125.06, 124.33, 122.87, 121.83, 118.66, 114.53, 114.44, 113.08, 111.19, 70.31, 31.77, 31.73, 15.25. HRMS (ESI) calcd for C 30 H 25 N3O3S [M + H] + m / z: 508.1695, found 508.1697.

[0350] Example 22. Synthesis of N-(3-(7-(2-Hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxamide (22)

[0351]

[0352] Referring to the preparation of 1 - 9, white solid, yield: 79.6%, melting point: 195.7 - 197.0 °C.

[0353] 11H NMR (600 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.58 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.5, 1.2 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 3.9 Hz, 1H), 6.88 (dd, J = 8.8, 1.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 3.9 Hz, 1H), 5.10 (s, 1H), 1.97 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H); 13 13C NMR (151 MHz, DMSO-d6) δ 160.64, 155.63, 148.57, 144.26, 142.55, 139.33, 136.80, 134.98, 134.77, 132.87, 129.24, 129.13, 128.59, 126.98, 126.49, 126.41 (q, J = 31.7 Hz), 124.99 (q, J = 273.0 Hz), 124.81, 124.73, 122.61 (q, J = 3.3 Hz), 122.63 (q, J = 3.6 Hz), 122.30, 119.12, 115.01, 114.90, 113.55, 111.67, 70.78, 32.18, 15.72. HRMS (ESI) calcd for C 31 H 25 F3N3O3S [M + H] + m / z: 576.1568, found 576.1568. HPLC purity: 97.56%, retention time: 10.43 min.

[0354] Example 23. Synthesis of 5-cyclopropyl-N-(3-(7-(2-hydroxypropan-2-yl)-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)-2-methylphenyl)benzo[b]thiophene-2-carboxamide (23)

[0355]

[0356] Referring to the preparation of 1-9, white solid, yield: 85.0%, melting point: 203.6 - 204.3 °C.

[0357] 11H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 10.36 (s, 1H), 8.25 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.21 (dd, J = 8.5, 1.7 Hz, 1H), 7.18 (d, J = 3.9 Hz, 1H), 6.88 (dd, J = 8.8, 1.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 3.9 Hz, 1H), 5.09 (brs, 1H), 2.10 - 2.05 (m, 1H), 1.96 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.07 - 0.94 (m, 2H), 0.82 - 0.69 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 161.08, 155.64, 148.56, 141.31, 140.15, 139.89, 138.09, 137.00, 134.92, 134.67, 132.93, 129.13, 129.04, 128.53, 126.91, 126.15, 125.21, 124.79, 123.06, 122.30, 122.08, 119.12, 114.99, 114.92, 113.54, 111.66, 70.78, 32.19, 15.71, 15.53, 10.04. HRMS (ESI) calcd for C 33 H 28 N3O3S [M - H] - m / z: 546.1852, found 546.1853. HPLC purity: 98.53%, retention time: 10.50 min.

[0358] Example 24. Activity Detection

[0359] In the present invention, the inhibitory effect of pyrroloquinoxalinone derivatives on BTK protein kinase.

[0360] The pharmacological activity experiments in the present invention include BTK kinase inhibition experiment, cell proliferation inhibition experiment, snapshot PK experiment, in vivo anti-tumor efficacy experiment and kinase profile selectivity experiment.

[0361] 1. BTK Kinase Inhibitory Activity Experiment

[0362] The in vitro inhibitory activity experiment of the compounds provided by the present invention against BTK kinase activity was carried out as follows. The HTRF@ technology of Cisbio company was used to determine the IC of the compounds against BTK kinase. 50 First, a stock solution with a concentration of 10 uM of the compound to be tested was prepared, and then it was serially diluted three-fold. A total of 11 concentrations were prepared. Each test plate was set with positive control wells and negative control wells, and BMS-986142, Ibrutinib, and S2 were used as positive inhibitors of BTK kinase. Finally, the test results obtained were analyzed using XLFIT5 software to calculate the lC 50 value.

[0363] The experimental results are shown in Table 1 below.

[0364] Table 1. BTK kinase inhibitory activity data of Compounds 1-23

[0365]

[0366]

[0367]

[0368]

[0369] The experimental results show that the pyrroloquinoxalinone derivatives provided by the present invention have obvious BTK inhibitory activity.

[0370] 2. Cell proliferation inhibition activity experiment

[0371] The cell proliferation inhibition activity experiments of Compounds 1, 3, 4, 7, 9, 14, and 19 provided by the present invention were carried out as follows. The CCK8 method was used to determine the inhibitory activity of the compounds against the lymphoma cell lines Ramos and U-937 cells with high expression of BTK. After Ramos and U-937 cells were cultured at 37 °C for 2 hours, different concentrations (starting from a concentration of 40 μM and serially diluted three-fold, a total of 8 concentrations) of the compound to be tested were added and incubated for 2 days. Then, the cells were treated with CCK8 and incubated for another 4 hours. Finally, the absorbance (450 nm) of the solution was measured using a microplate reader and the IC 50 value was calculated. BTK inhibitor S2 was used as a control.

[0372] The experimental results are shown in Table 2 below.

[0373] Table 2. Cell proliferation inhibition activity data of Compounds 1, 3, 4, 7, 9, 14, and 19

[0374]

[0375] The experimental results show that compounds 1, 3, 4, 7, 9, 14, and 19 provided by the present invention can significantly inhibit the proliferation of Ramos and U-937 cells. Among them, the cell proliferation inhibitory activity of the preferred compound 4 is better than that of S2.

[0376] 3. Snapshot PK experiment

[0377] In drug research and development, Snapshot PK has been proven to be a rapid and effective in vivo PK property screening method. This method measures the oral exposure (AUC 0-5h ) within 5 hours after intragastric administration of rats or mice to quickly screen potential orally available candidate drugs. The Snapshot PK experiment of compound 4 provided by the present invention was carried out as follows: Male SD rats were divided into two groups (2 rats in each group) and intragastrically administered at a dose of 10 mg / kg (vehicle: 1% DMSO + 50% PEG400 + 49% PBS). At 4 time points (0.5 h, 1 h, 3 h, 5 h) after administration, venous blood samples of rats were collected. An acetonitrile solution of diclofenac (10 ng / mL) was added to the plasma to be measured to precipitate proteins, followed by vortex oscillation and centrifugation at 4 °C in sequence. Finally, the supernatant was taken for LC-MS / MS analysis. The BTK inhibitor S2 was used as a control.

[0378] The experimental results are shown in Table 3 below.

[0379] Table 3. Snapshot PK experimental results of compound 4 and S2

[0380]

[0381] The experimental results show that the oral exposure (AUC 0-5h ) of compound 4 provided by the present invention is 3 times that of S2 (116.08 vs 39.68 h*ng / mL), and the maximum plasma concentration (C max ) is 4 times that of S2 (62.39 vs 14.25 ng / mL).

[0382] 4. In vivo antitumor efficacy experiment

[0383] The in vivo anti-tumor efficacy experiment of Compound 4 provided by the present invention was carried out as follows. The U937 xenograft tumor mouse model was used for evaluation. U-937 cells were subcutaneously injected into BALB / C nude mice to establish a lymphoma model. When the tumors grew to an appropriate size, the mice were divided into 5 groups for intragastric administration: control group (vehicle) + positive drug Ibrutinib group (50 mg / kg) + Compound S2 group (50 mg / kg) + Compound 4 treatment group (50 mg / kg + 100 mg / kg). All mice were continuously intragastrically administered for 14 days, once a day. The tumor volume and body weight of the mice were recorded on the day of administration and every other day thereafter. Ibrutinib and BTK inhibitor S2 were used as controls.

[0384] The experimental results showed that ( Figure 2 A), after intragastric administration at a dose of 50 mg / kg for 14 days, Compound 4 could significantly inhibit tumor growth, with an inhibition rate of 64.4%, significantly superior to S2 (TGI = 28.7%). The anti-tumor activity of 4 showed a dose-dependence, and stronger efficacy was exhibited at a higher dose (100 mg / kg) (TGI = 74.9%). During the administration period, the body weights of all mice did not change significantly ( Figure 2 B), indicating no obvious toxicity. The above experimental results proved that Compound 4 had significant oral anti-tumor efficacy and the efficacy was superior to S2.

[0385] Note: *P < 0.05, **P < 0.01

[0386] 5. Kinase profile selectivity experiment

[0387] The kinase profile selectivity experiment of Compound 4 provided by the present invention was carried out as follows. The KINOMEscan TM platform was used to test the selectivity of Compound 4 for 468 kinases (including 403 non-mutated kinases) at a concentration of 100 nM. The binding ability of the compound to the kinase target was determined by a competitive binding experiment. The principle is as follows: After the test compound binds to the kinase active site, it can prevent the kinase from binding to the ligand immobilized on the solid support, thereby reducing the amount of kinase captured on the solid support; on the contrary, the compound that does not bind to the kinase has no effect on the kinase capture amount. The binding ability of the compound to the kinase is negatively correlated with the kinase capture amount, and finally is represented by "%Ctrl".

[0388] The experimental results ( Figure 1 ) showed that Compound 4 exhibited high kinase selectivity and was only off-target for 3 kinase targets: TEC, PIP5K1A, and RIOK3, proving that Compound 4 is a highly selective non-covalent BTK inhibitor.

[0389] All documents mentioned in this invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula I, or an optical isomer or a pharmaceutically acceptable salt thereof: in, R 1 Selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted C1-C3 alkyl; R 2 Selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl; R 3 Selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl; R 4 Selected from the group consisting of hydrogen or halogen; X is selected from the group consisting of substituted or unsubstituted C1-C2 alkylene, substituted or unsubstituted C0-C3 alkylenecarbonyl; Y is selected from the group consisting of imino, oxygen or sulfur; Ring A is selected from the group consisting of a substituted or unsubstituted C5-C8 aryl group, a substituted or unsubstituted five-membered and six-membered ring; Dashed lines represent chemical bonds or their absence; Wherein, the compound represented by formula I does not include the following compounds:

2. The compound according to claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from the group consisting of hydrogen, hydroxy-substituted C1-C3 alkyl; R 3 Selected from the group consisting of hydrogen, halogen, hydroxyl or halogen-substituted C1-C3 alkyl; X is selected from the group consisting of a substituted or unsubstituted C1-C2 alkylene group, a carbonyl group, or a substituted or unsubstituted methylenecarbonyl group; Y is selected from the group consisting of imino or oxygen; The A ring is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted five-membered heteroarylphenyl containing 1 to 3 heteroatoms independently selected from N, O or S, or cyclohexyl.

3. The compound according to claim 2, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen; R 2 Selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl; R 3 Selected from the group consisting of halogen, substituted or unsubstituted C1-C3 alkyl; R 4 Selected from the group consisting of hydrogen or halogen; X is selected from the group consisting of a substituted or unsubstituted methylene group, or a carbonyl group; Y is selected from the group consisting of: imino; Ring A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyrrolophenyl; Dashed lines represent chemical bonds or their absence.

4. The compound according to claim 3, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 3 is halogen, preferably F.

5. The compound according to any one of claims 1 to 4, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the group consisting of: Preferably, the compound is a compound selected from the group consisting of: More preferably, the compound is the following compound:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. Use of the compound according to any one of claims 1 to 5 in the preparation of a BTK inhibitor.

8. The use according to claim 7, characterized in that The BTK inhibitor is a drug for treating or preventing BTK-mediated diseases.

9. The use according to claim 8, characterized in that The BTK-mediated disease is cancer or autoimmune disease; Preferably, the cancer is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia / small lymphocytic leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and acute lymphocytic leukemia; The autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, urticaria, and multiple sclerosis.

10. A method for treating or preventing a BTK-mediated disease, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 5 or the pharmaceutical composition of claim 6 to a subject in need thereof.

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