Tricyclic compounds as hif2a inhibitors, processes for their preparation and uses thereof

Abstract

A tricyclic compound of formula (I), its preparation method, and its application as an HIF2α inhibitor.

Description

[0001] This invention claims the following priority:

[0002] CN202110203800.3, application date: February 23, 2021;

[0003] CN202210095335.0, application date: January 26, 2022;

[0004] CN202210135655.4, application date: February 14, 2022. Technical Field

[0005] This invention relates to the compound represented by formula (I), its optical isomers and pharmacologically acceptable salts thereof, and the use of the compound as an HIF2α inhibitor. Background Technology

[0006] Renal cell carcinoma accounts for approximately 2%–3% of adult malignant tumors and 80%–90% of adult kidney malignant tumors. Statistics show that in 2018, there were 403,000 newly diagnosed renal cell carcinoma patients worldwide, and 175,000 died from it. The current incidence rate of renal cell carcinoma in my country is around 4.0 / 100,000, while the incidence rate in urban areas is around 6.0 / 100,000. Based on this, it is estimated that approximately 52,000–78,000 new renal cell carcinoma patients are diagnosed in my country each year, with a total estimated number of patients exceeding 460,000. Gliomas account for 40–50% of intracranial tumors and are the most common intracranial malignant tumors. Malignant gliomas originate from glial cells, exhibiting histological heterogeneity and invasiveness, resulting in a poor prognosis. Because renal cell carcinoma is insensitive to radiotherapy and chemotherapy, targeted therapy has become the main treatment for advanced renal cell carcinoma in recent years, significantly prolonging the survival of patients, especially those with metastatic advanced renal cell carcinoma. However, almost all patients receiving targeted therapy develop drug resistance and tumor recurrence, and there are also significant side effects. Therefore, it is necessary to develop drugs targeting different oncogenic genes for different signaling pathways and drug resistance mechanisms, so that clinicians can choose the order and combination of medications. The goal is to gradually achieve precise medication for different patients, different disease subtypes, and different stages of disease progression, thereby maximizing disease control, minimizing side effects, and improving patients' quality of life.

[0007] The VHL / HIF2α pathway is dominant in the development of most renal cell carcinomas. VHL is the target subunit of E3 ligases responsible for protein degradation. The VHL gene is a typical tumor suppressor gene; its dysfunction can lead to central nervous system hemangiomas, renal cell carcinoma / renal cysts, retinal hemangiomas, pheochromocytomas, and pancreatic tumors. In renal cell carcinoma, especially clear cell carcinoma, abnormalities in the VHL / HIF2α signaling pathway account for over 90%. VHL gene mutations, chromosomal deletions, and gene-level methylation modifications can all lead to VHL gene inactivation or reduced activity. HIF2α cannot be degraded in time, accumulates, and enters the nucleus to form a complex with HIF1β, resulting in the transcription of a series of downstream genes, such as angiogenic factor (VEGF), platelet-derived growth factor (PDGF), cyclin D, glucose transporter (GLUT1), oxygen transport and metabolism, cell proliferation and migration, ultimately leading to tumor development and metastasis. Therefore, developing drugs targeting the VHL / HIF2α pathway could provide new and effective treatment options for renal cell carcinoma patients. Peloton's HIF2a inhibitor PT2977 has entered Phase III clinical trials for the treatment of renal cell carcinoma. Based on its mechanism of action, HIF2a inhibitors are also highly anticipated for the treatment of the rare disease VHL syndrome.

[0008] Gliomas are tumors originating from glial cells in the brain, accounting for 40-50% of all intracranial tumors and being the most common primary intracranial tumors. In my country, the annual incidence of gliomas is 5-8 per 100,000, and the 5-year mortality rate is second only to pancreatic and lung cancer among all cancers. Glioblastoma (GBM) is the most common and deadliest primary malignant brain tumor in adults. Currently, the main treatment is surgery, followed by radiotherapy and chemotherapy, but the overall treatment outcome is not ideal. Newly diagnosed patients receiving standard care have a median survival of only 15 months, with a high recurrence rate; after recurrence, the median survival is only 5-7 months. Clinically, patients with high HIF2α expression in glioblastoma have a worse prognosis. In vitro cell experiments have shown that HIF2α expression is closely related to the tumorigenicity of glioma cells. PT2977 is currently in Phase II clinical trials for the treatment of glioblastoma, demonstrating that HIF2a inhibitors have certain efficacy in patients with this type of tumor, and can provide a new treatment strategy for this segment of the treatment options and for patients with limited access to such treatments.

[0009] HIF2α inhibitors can also be used to treat other tumors. Because inhibiting HIF-2α protein reduces the transcription and expression of angiogenesis-related factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), it can inhibit tumor angiogenesis, exhibiting an anti-angiogenic mechanism of action. Therefore, its use alone or in combination with immune checkpoint inhibitors can expand its application to multiple tumor indications for existing anti-angiogenic drugs, including lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, and multiple myeloma, in addition to renal cell carcinoma. Furthermore, studies have shown that HIF2α inhibitors act on immune cell populations in the tumor microenvironment, inhibiting tumor growth by enhancing the tumor-killing effect of T cells or reducing the effect of immunosuppressive cells. This suggests that HIF2α inhibitors, used alone or in combination with other drugs, may have therapeutic effects on liver cancer, pancreatic ductal carcinoma, lung squamous cell carcinoma, and colon cancer. In addition, the application of HIF2α inhibitors in the treatment of hemangiomas is also worth noting.

[0010] Finally, HIF2α also plays an important role in the development of non-tumor diseases such as pulmonary hypertension, reflux esophagitis, and inflammatory bowel disease. The successful development of HIF2α inhibitors will also provide new treatment options for these patients. Summary of the Invention

[0011] This invention proposes a new class of tricyclic compounds. The compounds of this invention exhibit good inhibitory effects in luciferase and VEGFELISA experiments, and can be used to treat various HIF2α-related diseases such as renal cell carcinoma and malignant glioma.

[0012] This invention provides the compound of formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof.

[0013]

[0014] Among them, ring A is selected from C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0015] Ring B is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclic and 5-6 membered cycloalkenyl, wherein C 5-6 Cycloalkyl, 5-6 membered heterocyclic or 5-6 membered cycloalkenyl groups may be substituted with 1, 2, 3 or 4 Rs;

[0016] L1 is selected from single bonds, -O-, -S-, and -N(R). L )-;

[0017] T1 is selected from -C(R)T - and -N-;

[0018] T2 is selected from O, =NR9, and empty;

[0019] T3 is selected from =NR 10 and O;

[0020] D1 is independently selected from -C(R) D1 )2- and -N(R D1 )-;

[0021] R3 and R4 are independently selected from H, F, Cl, Br and I, respectively;

[0022] R5 is selected from H, OH, F, and NH2;

[0023] R8 is independently selected from H, F, Cl, Br, I, CN, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. 8a replace;

[0024] R9 is selected from H, CN, OH, C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0025] R 10 Selected from H, CN, OH, C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2, or 3 Rs; R, R T R D1 R L R 8a Each is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl group may be optionally substituted by 1, 2 or 3 R';

[0026] R' is independently selected from H, halogen, OH, NH2, CN, and C. 1-6 alkyl;

[0027] m can be 0, 1, 2, 3 or 4 independently;

[0028] n can be 0, 1, 2, or 3 independently;

[0029] The 4-6 membered heterocyclic alkyl, 5-6 membered heterocyclic or 5-6 membered heteroaryl groups comprise 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0030] The present invention also provides the compound of formula (II), its optical isomer, or a pharmaceutically acceptable salt thereof.

[0031]

[0032] Among them, ring A is selected from C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0033] L1 is selected from single bonds, -O-, -S-, and -N(R). L )-;

[0034] T1 is selected from -C(R) T - and -N-;

[0035] T2 is selected from O, =NR9, and empty;

[0036] T3 is selected from =NR 10 and O;

[0037] D1 is independently selected from -C(R) D1 )2- and -N(R D1 )-;

[0038] when for In this case, D2 and D3 are independently selected from single bonds, -O-, -N(R)-, and -C(R), respectively. 2- -C (=R) - -C(=O)- and -C(=NR)-, R6 and R7 are independently selected from H, F, Cl, Br and I, respectively;

[0039] when for At that time, D2 and D3 are independently -C(R)- and N, respectively, and R6 and R7 are independently selected from H, F, Cl, Br and I, respectively;

[0040] when for At that time, D2 is independently selected from -C(R)- and N, and D3 is independently selected from single bonds, -O-, -N(R)-, and -C(R). 2- -C (=R) --C(=O)- and -C(=NR)-, R7 is independently selected from H, F, Cl, Br and I;

[0041] R3 and R4 are independently selected from H, F, Cl, Br and I, respectively;

[0042] R5 is selected from H, OH, F, and NH2;

[0043] R8 is independently selected from H, F, Cl, Br, I, CN, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. 8a replace;

[0044] R9 is selected from H, CN, OH, C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0045] R 10 Selected from H, CN, OH, C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2, or 3 Rs; R, R T R D1 R L R 8a Each is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl group may be optionally substituted by 1, 2 or 3 R';

[0046] R' is independently selected from H, halogen, OH, NH2, CN, and C. 1-6 alkyl;

[0047] m can be 0, 1, 2, 3 or 4 independently;

[0048] n can be 0, 1, 2, or 3 independently;

[0049] The 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl comprises 1, 2 or 3 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0050] The present invention also provides compounds of formula (II-A) or (II-B), their optical isomers, or pharmaceutically acceptable salts thereof.

[0051]

[0052] Among them, ring A is selected from C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0053] L1 is selected from single bonds, -O-, -S-, and -N(R). L )-;

[0054] T1 is selected from -C(R) T - and -N-;

[0055] D1 is independently selected from -C(R) D1 )2- and -N(R D1 )-;

[0056] when for In this case, D2 is selected from -O-, -N(R)-, and -C(R). 2- -C (=R) - -C(=O)- and -C(=NR)-, R6 and R7 are independently selected from H, F, Cl, Br and I, respectively;

[0057] when for In this case, D2 is selected from -C(R)- and N, and R7 is selected from H, F, Cl, Br, and I;

[0058] R3 and R4 are independently selected from H, F, Cl, Br and I, respectively;

[0059] R5 is selected from H, OH, F, and NH2;

[0060] R8 is independently selected from H, F, Cl, Br, I, CN, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. 8a replace;

[0061] R9 is selected from H, CN, OH, C 1-6 Alkyl and C 3-6cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0062] R, R T R D1 R L R 8a Each is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl group may be optionally substituted by 1, 2 or 3 R';

[0063] R' is independently selected from H, halogen, OH, NH2, CN, and C. 1-6 alkyl;

[0064] m can be 0, 1, 2, 3 or 4 independently;

[0065] n can be 0, 1, 2, or 3 independently;

[0066] The 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl comprises 1, 2 or 3 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0067] In some embodiments of the present invention, the compound represented by formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof, has the structure shown in formula (III-A).

[0068]

[0069] Among them, ring A is selected from C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0070] L1 is selected from single bonds, -O-, -S-, and -N(R). L )-;

[0071] T1 is selected from -C(R) T - and -N-;

[0072] R7, R 10 They are each independently selected from H, F, Cl, Br, and I;

[0073] R3 and R4 are independently selected from H, F, Cl, Br and I, respectively;

[0074] R5 is selected from H, OH, F, and NH2;

[0075] R8 is independently selected from H, F, Cl, Br, I, CN, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. 8a replace;

[0076] R T R L R 8a Each is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl group may be optionally substituted by 1, 2 or 3 R';

[0077] R' is independently selected from H, halogen, OH, NH2, CN, and C. 1-6 alkyl;

[0078] m can be 0, 1, 2, 3 or 4 independently;

[0079] The 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl comprises 1, 2 or 3 heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0080] In some embodiments of the present invention, R8 is selected from H, F, Cl, Br, I and CN, and other variables are as defined in the present invention.

[0081] In some embodiments of the present invention, R9 is selected from H, CN, OH, Me, Et, The Me, Et, The variable can be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0082] In some embodiments of the present invention, R9 is selected from H, CN, OH, Me, Et, Other variables are as defined in this invention.

[0083] In some embodiments of the present invention, the above-mentioned R 10 Selected from H, CN, OH, Me, Et, The Me, Et, The variable can be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0084] In some embodiments of the present invention, the above-mentioned R 10 Selected from H, CN, OH, Me, Et, Other variables are as defined in this invention.

[0085] In some embodiments of the present invention, the ring A is selected from phenyl, pyridyl, pyridazinyl, cyclobutyl, cyclopentyl, and cyclohexyl, and other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0087] In some embodiments of the present invention, the above-mentioned R, R T R D1 R L R 8a Independently selected from H, F, Cl, Br, I, CN, OH, Other variables are as defined in this invention.

[0088] In some embodiments of the present invention, the aforementioned ring B is selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanone, tetrahydro-2H-pyran-2-one, piperidin-2-one, tetrahydro-2H-pyranyl, and piperidinyl. The cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanone, tetrahydro-2H-pyran-2-one, piperidin-2-one, tetrahydro-2H-pyranyl, or piperidinyl may optionally be substituted with 1, 2, 3, or 4 Rs, and other variables are as defined in the present invention.

[0089] In some embodiments of the present invention, the ring B is selected from... Other variables are as defined in this invention.

[0090] In some embodiments of the present invention, the ring B is selected from... Other variables are as defined in this invention.

[0091] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0092] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0093] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0094] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0095] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0096] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0097] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0098] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0099] The present invention also provides compounds of the following formula, their optical isomers or pharmaceutically acceptable salts thereof, selected from:

[0100]

[0101]

[0102] The present invention also provides compounds of the following formula, their optical isomers or pharmaceutically acceptable salts thereof, selected from:

[0103]

[0104] The present invention also provides the use of the above-described compounds or their pharmaceutically acceptable salts or the above-described pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of HIF2α-mediated diseases.

[0105] In some embodiments of the present invention, the HIF2α-mediated diseases include those selected from renal cell carcinoma, glioma, Von Hippel-Lindau (VHL) syndrome, lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, multiple myeloma, pancreatic ductal carcinoma, squamous cell carcinoma of the lung, colon cancer, hemangioma, pulmonary hypertension, and inflammatory bowel disease (IBD).

[0106] Definitions and Explanations

[0107] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0108] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0109] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0110] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0111] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0112] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0113] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. "Optional" or "optionally" means that the events or conditions described below may occur but are not necessary, and the description includes both the occurrence of said events or conditions and the non-occurrence of said events or conditions.

[0114] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0115] The term "empty" means that the substitution does not exist at that point; for example, when T2 is selected from empty, for

[0116] 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. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds. For example, Can be selected wait.

[0117] A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1-6 Alkyl carbonyl group - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0118] Unless otherwise stated, when the group valence bond is marked with a dashed line At times, for example, in In the diagram, the dashed line represents the connection point between the group and other parts of the molecule. Exceptionally, in this invention, In, group valence bond Represents a double bond or single key This indicates that the R6 group can exist. Or the R6 group may not be present.

[0119] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When D3 represents a single bond, it means that the structure is actually

[0120] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0121] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is at this time The phenyl and cyclopentyl groups can be connected in the same direction as the reading order from left to right to form the structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0122] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a "4-6 elemental ring" refers to a "ring" with 4-6 atoms arranged around it.

[0123] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 2-6 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-5 Examples of alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), propyl such as n-propyl (“n-Pr”) or isopropyl (“i-Pr”), butyl such as n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”) or tert-butyl (“t-Bu”), pentyl, hexyl, etc.

[0124] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0125] Unless otherwise specified, the term "C" 1-6"Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0126] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0127] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.

[0128] Unless otherwise specified, "C 2-3 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-3 Alkenyl groups include C3 and C2 alkenyl groups; the C 2-3 Alkenes can be monovalent, divalent, or polyvalent. C 2-3 Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups.

[0129] Unless otherwise specified, "C 4-6"Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4-6 Cycloalkyl groups include C 4-5 C 5-6 C4, C5, and C6 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0130] Unless otherwise specified, the term "4-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "4-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 4-6 membered heterocyclic alkyl includes 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 4-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0131] Unless otherwise specified, the term "5-6 membered heterocyclic group" on its own or in combination with other terms refers to a saturated or unsaturated cyclic group consisting of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Examples of the “5-6 membered heterocyclic group” include, but are not limited to, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydro-2H-pyran-2-one, piperidin-2-one, tetrahydro-2H-pyranyl, and piperidinyl.

[0132] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0133] Unless otherwise specified, the term "cycloalkenyl" in this invention refers to a cyclic alkenyl group. "C" 5-6 "Cycloalkenyl" includes C5 and C6 cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl.

[0134] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0135] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0136] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0137] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0138] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0139] Stereochemical definitions and conventions can be found in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the symbol for rotating the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0140] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0141] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via low-energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0142] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of a disease, for the purpose of curing, alleviating, reducing, altering, treating, improving, modifying, or influencing the disease or its symptoms. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease, for the purpose of preventing the individual from contracting the disease. When a chemical reaction is involved, the terms "treatment," "contact," and "reaction" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0143] As used herein, the term "effective amount" refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compounds of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., route of administration, pharmacokinetics of the compound, severity and course of disease, individual medical history, individual health status, individual response to the drug, etc.).

[0144] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0145] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Detailed Implementation

[0146] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, experimental methods in the following embodiments are generally performed under conventional conditions for such reactions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise stated, liquid ratios are volume ratios.

[0147] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0148] The following abbreviations are used in this invention: DAST represents diethylaminosulfur trifluoride; DCM represents dichloromethane; DCE represents 1,2-dichloroethane; DMF represents N,N-dimethylformamide; Oxone represents potassium persulfate; Selectfluor represents 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate); Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium.

[0149] Example 1: Synthesis of Compound 1

[0150]

[0151] Step 1: Preparation of compounds 1-2

[0152] DMF (55 mL) was added to a mixture of compound 1-1 (2.5 g, 11.4 mmol), palladium acetate (128 mg, 0.57 mmol), iodine (2.9 g, 11.4 mmol), and iodophenyldiacetic acid (3.68 g, 11.4 mmol). The reaction mixture was purged with argon three times and stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove most of the DMF, and the crude product was poured into dilute hydrochloric acid (100 mL, 0.1 M). The mixture was extracted three times with 400 mL of ethyl acetate. The combined organic phases were washed with 1 M sodium thiosulfate, then washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain compound 1-2. The crude product was used directly in the next step.

[0153] Step 2: Preparation of compounds 1-3

[0154] Compounds 1-2 (0.81 g, 2.3 mmol) were dissolved in DMF (5 mL), and potassium carbonate (970 mg, 7.0 mmol) and methyl iodide (0.44 mL, 7.0 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with 60 mL of ethyl acetate. The combined organic phases were washed five times with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compounds 1-3. The crude product was used directly in the next step. LCMS m / z = 358.9 / 360.9 [M+1] + .

[0155] Step 3: Preparation of compounds 1-4

[0156] Compounds 1-3 (1.26 g, 3.5 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos, 243 mg, 0.42 mmol) were dispersed in toluene:acetone (17 mL, v / v = 2:1). Pd₂(dba)₃ (192 mg, 0.21 mmol) and potassium thioacetate (500 mg, 4.4 mmol) were added. The reaction mixture was purged with argon gas, sealed, and heated to 70 °C with stirring for 2 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered. The filter cake was washed twice with dichloromethane. The filtrates were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-4. 1 H NMR (400MHz, CDCl3)δ=7.44-7.41(m,1H),7.25-7.21(m,1H),3.95(s,3H),2.42(s,3H); LCMS m / z=306.9 / 308.9[M+1] + .

[0157] Step 4: Preparation of compounds 1-5

[0158] Compounds 1-4 (1.21 g, 3.9 mmol) were dissolved in 12 mL of methanol, and after purging with argon, cesium carbonate (1.66 g, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Iodomethane (1.22 mL, 20 mmol) was added to the reaction mixture, and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure and dispersed in 30 mL of water. It was extracted three times with 90 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-5. 1 H NMR (400MHz, CDCl3)δ=7.38-7.35(m,1H),7.16-7.11(m,1H),3.99(s,3H),2.45(s,3H); LCMSm / z=247.0 / 249.0[M+1-MeOH] + .

[0159] Step 5: Preparation of compounds 1-6

[0160] To a mixture of compounds 1-5 (5.9 g, 21.1 mmol), trifluoroacetamide (11.9 g, 106 mmol), magnesium oxide (11.9 g, 296 mmol), and iodophenyldiacetic acid (35.4 g, 110 mmol), dichloromethane (150 mL) and rhodium octanoate dimer (140 mg, 0.2 mmol) were added. The reaction mixture was purged with argon and stirred at 40 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered. The filter cake was washed twice with dichloromethane. The filtrates were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-6. 1 H NMR (400MHz, CDCl3) δ = 8.07-8.04 (m, 1H), 7.49-7.45 (m, 1H), 4.07 (s, 3H), 3.05 (s, 3H).

[0161] Step 6: Preparation of compounds 1-7

[0162] To a carbon tetrachloride / acetonitrile (60 mL, 1:1) solution of compounds 1-6 (5.0 g, 12.8 mmol), a solution of sodium periodate (8.22 g, 38.4 mmol) in water (15 mL) and ruthenium trichloride (80 mg, 0.38 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove carbon tetrachloride and acetonitrile. The remaining aqueous phase was extracted three times with 210 mL of ethyl acetate after adding water (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-7. 1 H NMR (400MHz, CDCl3)δ=8.17-8.14(m,1H),7.47-7.43(m,1H),4.01(s,3H),3.61(s,3H); LCMS m / z=406.0 / 408.0[M+1] + .

[0163] Step 7: Preparation of compounds 1-8

[0164] Compounds 1-7 (1.0 g, 2.46 mmol), 3-chloro-5-fluorophenol (1.08 g, 7.39 mmol), and potassium carbonate (510 mg, 3.69 mmol) were added separately to 10 mL of DMF. The reaction mixture was heated to 130 °C in a microwave oven for 10 minutes. After cooling to room temperature, 30 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed three times with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-8. 1H NMR (400MHz, CDCl3) δ = 8.30 (d, J = 8.4Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.07-7.04 (m, 1H), 6.90- 6.88(m,1H),6.74(dt,J=8.8,2.4Hz,1H),4.69(d,J=17.6Hz,1H),4.41(d,J=17.6Hz,1H); LCMS m / z=500.0 / 501.9[M+1] + .

[0165] Step 8: Preparation of compounds 1-9

[0166] Compounds 1-8 (350 mg, 4.26 mmol) were added to 20 mL of acetonitrile, followed by the addition of Na₂CO₃ (222 mg, 2.1 mmol). The mixture was stirred at room temperature for 10 minutes under argon protection, and then Selectfluor (743 mg, 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, 50 mL of water was added, and the mixture was extracted four times with 120 mL of ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-9. 1 H NMR (400MHz, CDCl3) δ = 8.08 (d, J = 8.4Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.05-7.02 (m, 1H), 6.86-6.84 (m, 1H), 6.72 (dt, J = 8.8, 2.4Hz, 1H),5.30(s,1H); LCMS m / z=439.8 / 401.8[M+1] + .

[0167] Step 9: Preparation of compounds 1-10

[0168] Ethyl acetate (180 mg, 2.04 mmol) was dissolved in tetrahydrofuran (4 mL). After purging the solution three times with argon, the temperature was lowered to -70 °C. LDA (1.02 mL, 2.04 mmol, 2 M tetrahydrofuran solution) was slowly added. The reaction mixture was stirred for 30 minutes, and then a tetrahydrofuran solution of compounds 1-9 (300 mg, 0.68 mmol) (3 mL) was slowly added. The reaction mixture was stirred at -70 °C for 1 hour. The reaction mixture was quenched with 10 mL of saturated ammonium chloride solution and then brought to room temperature. It was extracted four times with 40 mL of dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 1-10. LCMS m / z = 528.0 / 530.0 [M+1] + .

[0169] Step 10: Preparation of compounds 1-11

[0170] Compound 1-10 (100 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL). After purging the solution three times with argon, the solution was cooled to -70 °C. Butyllithium (0.38 mL, 0.95 mmol, 2.5 M n-hexane solution) was slowly added. After the addition was complete, the reaction mixture was stirred at -70 °C for 30 minutes. The reaction mixture was quenched with dilute hydrochloric acid (0.5 mL, 0.5 M), then brought to room temperature. 10 mL of water was added, and the mixture was extracted four times with 40 mL of dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated and subjected to column chromatography to obtain compound 1-11. 1 LCMS m / z=404.0 / 406.0[M+1] + .

[0171] Step 11: Preparation of compounds 1-12

[0172] Compound 1-11 (50 mg, 0.12 mmol) was dissolved in ethanol (2 mL). After cooling the reaction solution to -70 °C, sodium borohydride (7 mg, 0.19 mmol) was added. After the addition was complete, the reaction solution was stirred at -70 °C for 15 minutes. The reaction solution was quenched with dilute hydrochloric acid (0.5 mL, 0.5 M), then brought to room temperature. After adding 3 mL of water, the mixture was extracted four times with 12 mL of dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated and subjected to HPLC to obtain compound 1-12.

[0173] 1 H NMR (400MHz, CDCl3) δ = 7.73 (d, J = 8.4Hz, 1H), 7.10 (dd, J = 8.4, 1.6Hz, 1H), 7.00 (dt, J = 8.0, 2.0Hz, 1H), 6.93-6.92 (m, 1H), 6 .76(dt,J=8.4,2.0Hz,1H),5.94(t,J=6.8Hz,1H),3.11(brs,1H),3.01-2.89(m,1H),2.53-2.48(m,1H),2.33(brs,1H); LCMS m / z=406.0 / 408.0[M+1] + .

[0174] Step 12: Preparation of Compound 1

[0175] Compound 1-12 (80 mg, 0.20 mmol) was dissolved in DCE (2 mL). After the reaction solution was cooled to 0 °C, DAST (38 mg, 0.24 mmol) was added. After the addition was complete, the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was quenched with water (3 mL) and then brought to room temperature. It was extracted four times with 12 mL of dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated and subjected to HPLC to obtain compound 1.

[0176] 1 H NMR (400MHz, CDCl3) δ = 7.79 (dd, J = 8.4, 2.0Hz, 1H), 7.11 (dd, J = 8.4, 1.2Hz, 1H), 7.03 (dt, J = 8.0, 2.0Hz, 1H), 6.9 6-6.95(m,1H),6.79(dt,J=8.8,2.4Hz,1H),6.03(dd,J=52.8,5.2Hz,1H),3.75(brs,1H),2.96-2.64(m,2H); LCMS m / z=408.0 / 410.0[M+1] + .

[0177] Example 2: Synthesis of Compound 2

[0178]

[0179] Step 1: Preparation of compound 2-2

[0180] In an ice bath, a turbid solution of Oxone (16.52 g, 26.9 mmol) and water (55 mL) was added dropwise to a methanol (110 mL) solution of compound 1-5 (15.0 g, 53.7 mmol). After the addition was complete, the reaction mixture was allowed to rise naturally to room temperature, and then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove most of the methanol and dispersed in ethyl acetate (200 mL) and water (200 mL). The aqueous phase was extracted three times with 300 mL of ethyl acetate. The combined organic phases were washed with 1 M sodium thiosulfate, then washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the crude product after concentration was purified by rapid silica gel column chromatography to obtain compound 2-2. LCMS m / z = 295.0 / 297.0 [M+1] + .

[0181] Step 2: Preparation of compounds 2-3

[0182] Compound 2-2 (7.0 g, 23.7 mmol) was dissolved in DMF (120 mL) at room temperature, and potassium carbonate (4.92 g, 35.6 mmol) and 3-cyano-5-fluorophenol (4.88 g, 35.6 mmol) were added. The reaction mixture was purged with argon and stirred at 90 °C for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the DMF. The crude product was dispersed in ethyl acetate (100 mL) and water (100 mL). The aqueous phase was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the concentrated filtrate was purified by rapid silica gel column chromatography to obtain compound 2-3. 1 H NMR (400MHz, CDCl3) δ = 8.11 (d, J = 8.8Hz, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.18 (ddd, J = 7.6, 2.4, 1.2Hz, 1H), 7.03-7.02(m,1H),6.96(dt,J=9.2,2.4Hz,1H),4.01(s,3H),2.88(s,3H),LCMSm / z=412.0 / 414.0[M+1] + .

[0183] Step 3: Preparation of compounds 2-4

[0184] To a mixture of compounds 2-3 (3.0 g, 7.28 mmol), trifluoroacetamide (2.88 g, 25.5 mmol), magnesium oxide (2.35 g, 58.2 mmol), and iodophenyldiacetic acid (8.2 g, 25.5 mmol), dichloromethane (30 mL) and rhodium octanoate dimer (113 mg, 0.15 mmol) were added. The reaction mixture was purged with argon and stirred at 40 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered. The filter cake was washed twice with dichloromethane. The filtrates were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by column chromatography to obtain compounds 2-4. 1 H NMR (400MHz, CDCl3) δ = 8.12 (d, J = 8.8Hz, 1H), 7.29 (ddd, J = 7.6, 2.4, 1.2Hz, 1H) ,7.19-7.15(m,2H),7.07(dt,J=8.8,2.4Hz,1H),4.02(s,3H),3.63(s,3H),LCMS m / z=523.0 / 525.0[M+1] + .

[0185] Step 4: Preparation of compounds 2-5

[0186] Compound 2-4 (2.03 g, 3.9 mmol) was dissolved in THF (20 mL), and cesium carbonate (1.52 g, 4.7 mmol) was added. The mixture was then sealed, and the reaction solution was stirred at 90 °C for 1 hour. After the reaction solution cooled to room temperature, 30 mL of water was added, and the mixture was extracted three times with 90 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 2-5. 1 H NMR (400MHz, CDCl3) δ = 8.37 (d, J = 8.8Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.29 (ddd, J = 7.6, 2.4, 1.2Hz, 1H) ,7.13-7.12(m,1H),7.05(dt,J=8.8,2.4Hz,1H),4.70(d,J=17.6Hz,1H),4.43(d,J=17.6Hz,1H),LCMS m / z=491.0 / 493.0[M+1] + .

[0187] Step 5: Preparation of compounds 2-6

[0188] Compound 2-5 (1.00 g, 2.04 mmol) was dissolved in 20 mL of acetonitrile, and Na₂CO₃ (647 mg, 6.1 mmol) and Selectfluor (2.16 g, 6.1 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, 50 mL of water was added, and the mixture was extracted four times with 120 mL of ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated to give crude compound 2-6. LCMS m / z = 449.0 / 451.0 [M + H₂O + 1] + .

[0189] Step 6: Preparation of compounds 2-7

[0190] Compound 2-6 (1.0 g, 2.32 mmol, crude product) was dissolved in DMF (20 mL), and indium (532 mg, 4.64 mmol) and allyl iodine (1.17 g, 6.96 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. 1 M dilute hydrochloric acid (15 mL) was added to the reaction mixture, followed by three fractional extractions with 30 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to give compound 2-7. LCMS m / z = 473.0 / 475.0 [M+1] + .

[0191] Step 7: Preparation of compounds 2-8

[0192] DMF (8 mL) was added to compounds 2-7 (380 mg, 0.80 mmol), triethylamine (0.33 mL, 2.41 mmol), triisopropylidene acetone phosphine (31 mg, 0.08 mmol), and Pd2(dba)3 (74 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated to 90 °C for 3 hours. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed three times with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compounds 2-8. LCMS m / z = 393.0 [M+1] + .

[0193] Step 8: Preparation of compounds 2-9

[0194] Compound 2-8 (100 mg, 0.25 mmol) was dissolved in acetonitrile (6 mL) and water (1 mL). NaIO4 (136 mg, 0.64 mmol) and RuCl3 (5 mg, 0.02 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, NaIO4 (68 mg, 0.32 mmol) and RuCl3 (3 mg, 0.01 mmol) were added. Stirring continued at room temperature for 16 hours. The reaction solution was quenched with saturated sodium thiosulfate (3 mL). After concentrating to remove most of the acetonitrile, the solution was dispersed in 10 mL of ethyl acetate and 10 mL of water. The aqueous phase was extracted four times with 20 mL of ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give crude compound 2-9. LCMS m / z = 395.0 [M+1] + .

[0195] Step 9: Preparation of compounds 2-10

[0196] Compound 2-9 (78 mg, 0.20 mmol) was dissolved in ethanol (1 mL). After cooling the reaction solution to -70 °C, sodium borohydride (14 mg, 0.38 mmol) was added. The reaction solution was stirred at -70 °C for 15 minutes. The reaction solution was quenched with dilute hydrochloric acid (0.5 mL, 0.5 M), then brought to room temperature. 3 mL of water was added, followed by four fractions extraction with 12 mL of dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the crude product was purified by rapid silica gel column chromatography to obtain compound 2-10. LCMS m / z = 397.0 [M+1] + .

[0197] Step 10: Preparation of Compound 2

[0198] Compound 2-10 (80 mg, 0.20 mmol) was dissolved in DCM (5 mL). After cooling the reaction solution to -70 °C, DAST (39 mg, 0.24 mmol) was added. The reaction solution was stirred at -70 °C for 0.5 hours after the addition was complete. Then, DAST (18 mg, 0.12 mmol) was added to the reaction solution, and the reaction solution was stirred at -70 °C for 0.5 hours after the addition was complete. The reaction solution was quenched at -70 °C with methanol (1 mL) and then brought to room temperature. The concentrated reaction solution was then prepared by two separate SFCs (first: column chromatography). (250*25mm, 10μm); mobile phase [0.1% diethylamine, methanol]; B%: 20%–20%. Second test: column. (250*25mm, 10μm); mobile phase [0.1% diethylamine, methanol]; B%: 30%–30%) yielded compound 2 with a retention time of 3.445 min. The retention time was determined using the following analytical column: Column: Dr. Maish Reprosil Chiral-MIC 100*3.0mm 3μm, mobile phase: A: carbon dioxide B: methanol (0.1% diethylamine), 40% B, flow rate: 1.5mL / min, column temperature: 35℃.

[0199] Compound 2: 1 H NMR (400MHz, CD3OD) δ = 7.89 (d, J = 8.4Hz, 1H), 7.54-7.46 (m, 1H), 7.45-7.44 (m, 1H), 7.38 (dd, J = 9.2, 2.4 Hz,1H),7.29(d,J=8.4Hz,1H),6.05(dd,J=53.2,5.2Hz,1H),2.93-2.80(m,1H),2.65-2.58(m,1H), LCMS m / z=399.0[M+1] + .

[0200] Example 3: Synthesis of compounds 3-P1, 3-P2, 3-P3 and 3-P4

[0201]

[0202] Step 1: Preparation of compound 3-2

[0203] Compound 3-1 (1.00 g, 2.64 mmol), 3-methoxypropylamine (470 mg, 5.28 mmol), p-toluenesulfonic acid (45.5 mg, 0.264 mmol), and magnesium sulfate (636 mg, 5.28 mmol) were placed in toluene (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude compound 3-2 (2.11 g), which was used directly in the next step. LC-MS m / z = 450.01 [M+1] + .

[0204] Step 2: Preparation of compound 3-3

[0205] The crude compound 3-2 (1.00 g) was dissolved in acetonitrile (10 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (1.57 g, 4.44 mmol) and anhydrous sodium carbonate (468 mg, 4.44 mmol) were added. The mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was adjusted to pH 5 with 1 M HCl solution (100 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), washed successively with water (50 mL x 3) and saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give compound 3-3 (700 mg, overall yield of 70.8%). LCMS m / z = 397.30 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.05 (t, J = 7.0Hz, 1H), 8.94 (d, J = 2.7Hz, 1H), 8.63 (d, J = 8.6H z,1H),8.50–8.39(m,1H),8.29(s,1H),7.67(d,J=8.6Hz,1H),5.87(d,J=48.7Hz,1H).

[0206] Step 3: Preparation of compounds 3-4

[0207] Sodium borohydride (134 mg, 2.54 mmol) was added to a 10 mL ethanol solution of compound 3-3 (700 mg, 1.77 mmol) at -78 °C, and the reaction was maintained at this temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was poured into a saturated aqueous solution of ammonium chloride (50 mL) and stirred for 10 minutes. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 3-4 (540 mg, yield 76.8%). 1H NMR (400MHz, DMSO-d6) δ = 9.01 (d, J = 1.6 Hz, 1H), 8.95 ( d, J = 3.2 Hz, 1H), 8.48 ( dd, J = 2.7, 1.7 Hz, 1H), 8.32 ( d,J=2.0Hz,1H),8.00(s,2H),7.46(d,J=8.5Hz,1H),6.21(dd,J=49.0,13.5Hz,1H),5.87(d,J=3.3Hz,1H).

[0208] Step 4: Preparation of Compound 3

[0209] At 0 °C, a solution of 2-methyltetrahydrofuran (5 mL) containing 550 mg (1.38 mmol) of compound 3-4 was added dropwise to a solution of 2-methyltetrahydrofuran (5 mL) containing 445 mg (2.76 mmol). The mixture was stirred for 1 hour while maintaining this temperature. TLC showed that the reaction was complete. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 3 (200 mg, yield 36.2%). LCMS m / z = 401.01 [M+1] + .

[0210] Step 5: Preparation of compounds 3-P1, 3-P2, 3-P3 and 3-P4

[0211] Compound 3 (450 mg, 1.12 mmol) was purified by preparative HPLC (FA system) to obtain a mixture of compounds 3-P1 and 3-P2 (300 mg, second eluent) and a mixture of compounds 3-P3 and 3-P4 (30 mg, first eluent).

[0212] A mixture of compounds 3-P1 and 3-P2 (300 mg) was subjected to SFC (column chromatography) (250*25mm, 10μm); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol / L ammonia)]; B%: 0%–30% yielded compound 3-P1 (retention time 2.495 min) and compound 3-P2 (retention time 3.108 min). Retention times were determined using the following analytical method: column: 250*25mm, 10μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol / L ammonia)], 30% B, flow rate: 70mL / min, column temperature: 35℃. SFC separated compound 3-P1 (80.0mg, recovery 17.8%) and crude compound 3-P2 (60.0mg). Crude compound 3-P2 was purified by preparative HPLC (FA system) to obtain compound 3-P2 (49.1mg, recovery 10.9%). Compound 3-P1, 1 H NMR (400MHz, DMSO-d6) δ=9.01(d,J=1.5Hz,1H),8.95(d,J=2.7Hz,1H),8.48(dd,J=2.7,1.7Hz,1H),8.31(dd,J=8 .6, 2.0Hz, 1H), 8.01 (s, 1H), 7.46 (d, J = 8.6Hz, 1H), 6.21 (dd, J = 49.0, 13.5Hz, 1H), 5.80 (dd, J = 46.9, 5.9Hz, 1H). Compound 3-P2, 1 H NMR (400MHz, DMSO-d6) δ=9.01(d,J=1.5Hz,1H),8.95(d,J=2.7Hz,1H),8.48(dd,J=2.7,1.7Hz,1H),8.31(dd,J=8 .6, 2.0Hz, 1H), 8.01 (s, 1H), 7.46 (d, J = 8.6Hz, 1H), 6.21 (dd, J = 49.0, 13.5Hz, 1H), 5.80 (dd, J = 46.9, 5.9Hz, 1H).

[0213] A mixture of compounds 3-P3 and 3-P4 (30 mg) was subjected to SFC (specimen collection) via column chromatography. (250*25mm, 10μm); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol / L ammonia)]; B%: 0%–30% yielded compound 3-P3 (retention time 3.325 min) and compound 3-P4 (retention time 3.544 min). Retention times were determined using the following analytical method: column: 250*25mm, 10μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol / L ammonia)], 30% B, flow rate: 70mL / min, column temperature: 35℃. SFC separated compounds 3-P3 (4.44mg, recovery 0.99%) and 3-P4 (4.26mg, recovery 0.95%). Compound 3-P3, 1H NMR (400MHz, DMSO-d6) δ = 9.00 (d, J = 1.6 Hz, 1H), 8.90 ( d, J = 2.7 Hz, 1H), 8.39 ( dd, J = 2.6, 1.7 Hz, 1H), 8.32 ( dd, J = 8.6 ,1.9Hz,1H),7.93(s,1H),7.51(d,J=8.6Hz,1H),6.09(dd,J=54.6,4.6Hz,1H),5.39(ddd,J=46.7,16.7,4.4Hz,1H). Compound 3-P4, 1 H NMR (400MHz, DMSO-d6) δ = 9.00 (d, J = 1.6 Hz, 1H), 8.90 ( d, J = 2.7 Hz, 1H), 8.39 ( dd, J = 2.6, 1.7 Hz, 1H), 8.32 ( dd, J = 8.6 ,1.9Hz,1H),7.93(s,1H),7.51(d,J=8.6Hz,1H),6.09(dd,J=54.6,4.6Hz,1H),5.39(ddd,J=46.7,16.7,4.4Hz,1H).

[0214] Example 4: Synthesis of compound 4, compound 4-P1, compound 4-P2, compound 4-P3 and compound 4-P4

[0215]

[0216] Step 1: Preparation of compound 4-2

[0217] Compound 4-1 (2.50 g, 6.32 mmol), 3-methoxypropylamine (3.70 g, 41.1 mmol), p-toluenesulfonic acid (109 mg, 0.632 mmol), and magnesium sulfate (1.50 g, 12.6 mmol) were placed in toluene (50 mL). The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude compound 4-2 (7.70 g), which was used directly in the next step. LC-MS m / z = 467.0 [M+1] + .

[0218] Step 2: Preparation of compound 4-3

[0219] The crude compound 4-2 (7.70 g) was dissolved in acetonitrile (100 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (7.50 g, 21.4 mmol) and sodium carbonate (2.27 g, 21.4 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was poured into 1N hydrochloric acid solution (100 mL) and stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate (100 mL x 3), the combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4-3 (1.50 g, two-step yield 57.4%). 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (d, J = 8.6Hz, 1H), 8.24 (s, 1H), 7.90 (d, J = 7.4Hz, 1H ),7.85(s,1H),7.84–7.78(m,1H),7.47(d,J=8.6Hz,1H),5.54(d,J=49.9Hz,1H).

[0220] Step 3: Preparation of compound 4-4

[0221] Compound 4-3 (1.00 g, 2.42 mmol) was dissolved in ethanol (20 mL). Sodium borohydride (184 mg, 4.84 mmol) was added at -78 °C. The reaction was continued at this temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was poured into a saturated ammonium chloride solution (50 mL) and stirred for 10 minutes. Extraction was performed with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4-4 (670 mg, yield 66.7%). 1 H NMR (400MHz, DMSO-d6) δ = 8.12 (d, J = 8.4Hz, 1H), 7.73 (d, J = 8.3Hz, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.50–7.44 (m, 2H), 6.08 (d, J = 9.1Hz, 1H), 5.51–5.27 (m, 2H).

[0222] Step 4: Preparation of Compound 4

[0223] At 0 °C, a solution of compound 4-4 (900 mg, 2.16 mmol) dissolved in 2-methyltetrahydrofuran (20 mL) was added dropwise, followed by the addition of a solution of diethylaminotrifluoride (720 mg, 4.32 mmol) dissolved in 2-methyltetrahydrofuran (10 mL). The mixture was stirred for 1 hour while maintaining this temperature. TLC showed that the reaction was complete. The reaction mixture was poured into a saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 4 (350 mg, yield 38.8%).

[0224] Step 5: Preparation of compounds 4-P1, 4-P2, 4-P3 and 4-P4

[0225] Compound 4 (350 mg, 0.839 mmol) was prepared by SFC (Daicel column) (250*25mm, 10μm); Mobile phase [A: carbon dioxide, B: MeOH (containing 0.1% diethylamine)]; B%: 30%–30% to obtain compounds 4-P1 (retention time 2.217 min), a mixture of compounds 4-P2 and 4-P3, and compound 4-P4 (retention time 2.604 min). Retention times were determined using the following analytical method: Column: DAICEL 100*3.0mm, 3μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5mL / min, column temperature: 35℃.

[0226] A mixture of compounds 4-P2 and 4-P3 was prepared by SFC (column-based) synthesis. (250*25mm, 10μm); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)]; B%: 30%–30%) yielded compound 4-P2 (retention time 2.443 min) and compound 4-P3 (retention time 2.537 min). Retention times were determined using the following analytical method: column: DAICEL 100*3.0mm, 3μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5mL / min, column temperature: 35℃.

[0227] Compound 4-P1 (7.32 mg, recovery 2.09%), 1¹H NMR (400MHz, MeOD) δ=8.02(d,J=8.5Hz,1H),7.52–7.48(m,1H),7.47(d,J=8.6Hz,1H),7.44(s,1H),7.37(dt,J=9.5,2.3Hz,1H),6.36(ddd,J=54.5,10.2,5.1Hz,1H),5.47(ddd,J=50.7,17.9,5.1Hz,1H). Compound 4-P2 (4.88mg, recovery 1.39%) 1 ¹H NMR (400MHz, MeOD) δ=8.02(d,J=8.5Hz,1H),7.52–7.48(m,1H),7.47(d,J=8.6Hz,1H),7.44(s,1H),7.37(dt,J=9.5,2.3Hz,1H),6.36(ddd,J=54.5,10.2,5.1Hz,1H),5.47(ddd,J=50.7,17.9,5.1Hz,1H). Compound 4-P3 (117mg, recovery 33.4%) 1 ¹H NMR (400MHz, MeOD) δ=8.06(dd, J=8.5, 2.0Hz, 1H), 7.57–7.51(m, 2H), 7.45(dt, J=9.3, 2.3Hz, 1H), 7.37(d, J=8.5Hz, 1H), 6.04(dd, J=49.4, 13.3Hz, 1H), 5.63(dd, J=47.5, 5.8Hz, 1H). Compound 4-P4 (119mg, recovery 34.0%) 1 H NMR(400MHz,MeOD)δ=8.06(dd,J=8.5,2.0Hz,1H),7.57–7.51(m,2H),7.45(dt,J=9.3,2.3H z, 1H), 7.37 (d, J = 8.5Hz, 1H), 6.04 (dd, J = 49.4, 13.3Hz, 1H), 5.63 (dd, J = 47.5, 5.8Hz, 1H).

[0228] Experimental Example 1: Luciferase Experiment

[0229] Infecting 786-O purchased from ATCC using a commercially available lentivirus 786-O-HRE-Luc cells were obtained by cell culture. Suitable 786-O-HRE-Luc single-cell clones were screened, expanded, and used for subsequent luciferase assays. For the luciferase assay, 100x DMSO stock solution containing the drug was prepared into 10x compound serial dilutions using experimental medium (RPMI-1640 containing 2% FBS; FBS: 10099141C, Gibco; RPMI-1640: 12440053, Gibco). 20 μL of each 10x compound dilution was added to a 96-well plate (3599, Corning). Approximately 100,000 786-O-HRE-Luc cells were then seeded into the 96-well plate with 180 μL of medium. The final concentration of DMSO (D2650, Sigma) in each well was 0.1%. After incubation for approximately 24 hours, the assay was performed according to the manufacturer's recommended method. Luciferase activity was determined using the Reporter Assay System (E1960, Promega) reagent. EC50 was calculated using the dose-response-inhibition (four-parameter) equation via GraphPadPrism software. 50 Values. The experimental results are shown in Table 1.

[0230] Table 1. EC5 values ​​of selected compounds in luciferase assays 50 value

[0231] Compound numbering <![CDATA[Luciferase EC 50 (nM)]]> Compound 2 46 Compound 3-P1 67.7 Compound 3-P2 3991 Compound 3-P3 12.2 Compound 3-P4 6411 Compound 4-P1 19.2 Compound 4-P2 48.5 Compound 4-P3 6.1 Compound 4-P4 511 US9796697B2 Example 19 59.7

[0232] As shown in Table 1, the experimental results indicate that the compounds of this invention have excellent in vitro activity and can inhibit the level of luciferase expressed in a HIF response element (HRE)-dependent manner.

[0233] Experiment Example 2: VEGF ELISA Experiment

[0234] 100x DMSO stock solution containing the drug was prepared into 10x compound serial dilutions using experimental culture medium (RPMI-1640 containing 2% FBS; FBS: 10099141C, Gibco; RPMI-1640: 12440053, Gibco). 20 μL of each 10x compound dilution was added to a 96-well clear plate (3599, Corning). Approximately 40,000 786-O cells were then placed in 180 μL of culture medium. The culture medium was inoculated into the 96-well plates described above. The final concentration of DMSO (D2650, Sigma) in each well was 0.1%. After incubation in an incubator for approximately 48 hours, 100 μL of the supernatant was aspirated from each well and transferred to a new 96-well plate (3799, Corning). The VEGF concentration was determined using an ELISA kit (DY293B, R&D Systems) based on the OD value at 450 nM measured by a microplate reader. The EC50 was calculated using the dose-response-inhibition (four-parameter) equation via GraphPadPrism software. 50 Values. The experimental results are shown in Table 2.

[0235] Table 2. EC5 values ​​of selected compounds in VEGF ELISA assay 50 value

[0236] Compound numbering <![CDATA[VEGF ELISA EC 50 (nM)]]> Compound 1 115 Compound 3-P1 180.4 Compound 3-P2 2765 Compound 3-P3 30.9 Compound 3-P4 4922 Compound 4-P1 40.5 Compound 4-P2 54.4 Compound 4-P3 15.2

[0237] Compound 4-P4 736.6 US9796697B2 Example 19 165.9

[0238] As shown in Table 2, the experimental results indicate that the compounds of this invention have significant inhibitory activity against VEGF expression.

[0239] Experimental Example 3: Pharmacokinetic Test

[0240] 1. Experimental Objective

[0241] Using SD rats as test animals, compound 3-P3 and comparative compound PT2385 were administered by gavage. The drug concentration in plasma at different time points was determined by LC-MS / MS to study the pharmacokinetic characteristics of the compound of the present invention and the comparative compound in rats.

[0242] 2 Experimental Scheme

[0243] 2.1 Experimental drugs and animals

[0244] Experimental reagents: Compound 3-P3 and comparative example PT2385;

[0245] Animals: Male SD rats, 200-220g, purchased from Shanghai Jiesijie Laboratory Animal Co., Ltd.

[0246] 2.2 Drug Preparation

[0247] Weigh an appropriate amount of compound 3-P3, add an appropriate amount of 10% ethanol + 30% polyethylene glycol 400 + 60% (0.5% sodium carboxymethyl cellulose + 0.5% Tween 80), vortex and sonicate to prepare a 1 mg / mL suspension. Weigh an appropriate amount of compound 3-P3, add an appropriate amount of 10% ethanol + 30% polyethylene glycol 400 + 60% (0.5% sodium carboxymethyl cellulose + 0.5% Tween 80), vortex and sonicate to prepare a 0.5 mg / mL suspension.

[0248] 2.3 Administration

[0249] SD rats in each test compound gavage group (n=3 per group) were fasted overnight and then administered the compound by gavage (PO, dose 10 mg / kg or 5 mg / kg, volume 10 mL / kg). They were fed 4 hours after administration.

[0250] 3 Operations

[0251] Approximately 0.2 mL of blood was collected via the jugular vein before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Heparin sodium was used for anticoagulation. After collection, blood samples were placed on ice and centrifuged to separate the plasma (centrifugation conditions: 1500 g, 10 min). Collected plasma was stored at -40 to -20°C before analysis.

[0252] The content of the target compound in rat plasma after oral administration was determined by LC-MS / MS.

[0253] 4. Pharmacokinetic Parameter Results

[0254] The pharmacokinetic parameters of compound 3-P3 of the present invention and comparative example PT2385 are shown in Table 3.

[0255] Table 3 Pharmacokinetic Results

[0256]

[0257] Conclusion: Compared with the comparative example PT2385, compound 3-P3 showed significant improvements in both blood drug concentration and area under the curve.

[0258] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of the following formula, or a pharmaceutically acceptable salt thereof, is: 。 2. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of HIF2α inhibitors.

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