Tricyclic compounds as HIF2α inhibitors and methods for their preparation and use

Abstract

Disclosed are tricyclic compounds of formula (I) and methods for their preparation and use as HIF2α inhibitors. JPEG2024508773000084.jpg4489

Description

[Technical field]

[0001] The present invention relates to compounds of formula (I), their optical isomers and pharma- ceutically acceptable salts, and to the use of the compounds as HIF2α inhibitors. [Background technology]

[0002] This invention claims priority to the following: CN202110203800.3, filing date: February 23, 2021; CN202210095335.0, application date: January 26, 2022; CN202210135655.4, application date: February 14, 2022.

[0003] Renal cancer accounts for about 2%-3% of adult malignant tumors and 80%-90% of adult renal malignant tumors. According to statistics, the number of newly diagnosed patients with kidney cancer in the world in 2018 was 403,000, and 175,000 people died from kidney cancer. The incidence rate of kidney cancer in China is about 4.0 / 100,000, while the incidence rate in urban areas is about 6.0 / 100,000. Based on this, it is calculated that about 52-78,000 new kidney cancer patients are generated in China every year, and the total number of kidney cancer patients is estimated to be more than 460,000. Gliomas account for 40-50% of brain tumors and are the most common intracranial malignant tumors. Malignant gliomas originate from glia, are histologically heterogeneous and invasive, and have a poor prognosis. Renal cell carcinoma has low sensitivity to radiation therapy and chemotherapy, so targeted therapy has become the main treatment for advanced renal cell carcinoma in recent years, which has significantly extended the survival time of renal cell carcinoma patients, especially those with metastatic advanced renal cell carcinoma. However, almost all patients who received targeted therapy developed drug resistance and tumor recurrence, and also had obvious side effects. Therefore, for clinical selection in drug sequence and combination, it is necessary to develop drugs that target different tumorigenic genes for different signal transduction pathways and different drug resistance mechanisms. Accurate dosing should be gradually achieved according to different patients, different disease subtypes and disease progression stages, so as to maximize disease control, reduce side effects, and improve the quality of life of patients.

[0004] The VHL / HIF2α pathway governs the development of most renal carcinogenesis. VHL is an E3 ligase target protein binding subunit responsible for protein degradation. The VHL gene is a representative tumor suppressor gene, and its dysfunction can cause central nervous system hemangiomas, renal cancer / renal cysts, retinal hemangiomas, pheochromocytomas, pancreatic tumors, etc. Abnormalities in the VHL / HIF2α signaling pathway account for more than 90% of renal cell carcinomas, especially clear cell carcinomas. Mutations, chromosomal deletions, and gene-level methylation modifications of the VHL gene can all cause the inactivation or reduced activity of the VHL gene, and HIF2α cannot be degraded in a timely manner, accumulates, enters the nucleus, and forms a complex with HIF1β, which results in the transcription of a series of downstream genes such as angiogenesis factors (VEGF), platelet-derived growth factor (PDGF), cyclin D, glucose transporter 1 (GLUT1), oxygen transport and metabolism, cell proliferation and migration, and ultimately leads to tumor development and metastasis. Therefore, the development of drugs targeting the VHL / HIF2α pathway may provide new and effective treatments for patients with kidney cancer. Among them, Peloton's HIF2α inhibitor PT2977 has already entered phase III clinical trials for the treatment of kidney cancer. Due to its mechanism of action, HIF2α inhibitors are also expected to be of great use in the treatment of the rare disease VHL syndrome.

[0005] Gliomas are tumors originating from brain glial cells, accounting for 40-50% of brain tumors and are the most common primary intracranial tumors. The annual incidence rate of gliomas in China is 50-8 / 100,000, and the 5-year mortality rate is the third highest after pancreatic cancer and lung cancer among systemic tumors, among which glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. Currently, the main treatment is surgery, followed by postoperative radiotherapy and chemotherapy, but the overall treatment effect is not ideal. The median survival time of newly diagnosed patients after standard treatment is only 15 months, with a high recurrence rate and a median survival time after recurrence of only 5-7 months. It has been clinically found that patients with high expression of HIF2α in glioblastoma have a poorer prognosis. In vitro cytological experiments have found that the expression of HIF2α is closely related to the tumorigenicity of glioma cells. Treatment of glioblastoma with PT2977 is currently in Phase II clinical trials and has proven to have a certain efficacy in patients with this type of tumor, potentially providing a therapeutic armamentarium and a new treatment strategy for a select group of patients.

[0006] HIF2α inhibitors can also be used to treat other tumors. By inhibiting HIF-2a protein, it can reduce the transcription and expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), and inhibit the formation of tumor angiogenesis. Since it has an antiangiogenic mechanism of action, it can be extended to multiple indications of existing angiogenesis inhibitors, except for lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, and kidney cancer, including multiple myeloma, by using it alone or in combination with immune checkpoint inhibitors. In addition, research has shown that HIF2α inhibitors act on immune cell populations in the tumor microenvironment to enhance the killing effect of T cells against tumors or reduce the effect of cells with immune inhibitory functions, thereby playing a role in inhibiting tumor growth. It has been suggested 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. Also worth noting is the use of HIF2α inhibitors in the treatment of hemangiomas.

[0007] Finally, HIF2α also plays an important role in the pathogenesis of non-tumor diseases, such as pulmonary hypertension, gastroesophageal reflux disease, and inflammatory bowel disease, and the successful development of HIF2a inhibitors could provide new therapeutic options for these patients. Summary of the Invention

[0008] The present invention provides a series of novel tricyclic compounds, which show excellent inhibitory effects in luciferase experiments and VEGF ELISA experiments, and can be used for various HIF2α-related diseases, such as renal cancer and malignant glioma.

[0009] The present invention provides a compound represented by formula (I), an optical isomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] However, ring A is C 4-6selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Ring B is C 5-6 cycloalkyl, a 5- to 6-membered heterocyclic group, and a 5- to 6-membered cycloalkenyl; 5-6 The cycloalkyl, 5- to 6-membered heterocyclic group, or 5- to 6-membered cycloalkenyl is optionally substituted by 1, 2, 3, or 4 R; L 1 represents a single bond, -O-, -S- and -N(R L )- is selected from T 1 is -C(R T )- and -N-; T 2 , =NR 9 and blank, T 3 =NR 10 and O; D 1 are independently -C(R D1 ) 2 - and -N(R D1 )- is selected from R 3 , R 4 are each independently selected from H, F, Cl, Br, and I; R 5 are H, OH, F and NH 2 is selected from R 8 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl and C 1-6 alkoxy, 1-6 Alkyl or C 1-6 Alkoxy optionally has one, two or three R 8a is replaced by R 9 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R 10are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R, R T , R D1 , R L , R 8a are each independently H, halogen, OH, or NH 2 , C.N., [ka] , C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl is optionally substituted by 1, 2 or 3 R'; R' is independently H, halogen, OH, NH 2 , CN and C 1-6 alkyl, m is independently 0, 1, 2, 3 or 4; n is independently 0, 1, 2 or 3; The 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl is selected from the group consisting of 1, 2, or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

[0010] The present invention also provides a compound represented by formula (II), an optical isomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] However, ring A is C 4-6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; L 1 represents a single bond, -O-, -S- and -N(R L )- is selected from T 1 is -C(R T )- and -N-; T 2 , =NR 9 and blank, T 3 =NR 10 and O; D 1 are independently -C(R D1 ) 2 - and -N(R D1 )- is selected from [ka] If D 2 and D. 3 are each independently a single bond, -O-, -N(R)-, or -C(R) 2- , -C(=R) - , —C(═O)— and —C(═NR)—; R 6 , R 7 are each independently selected from H, F, Cl, Br, and I; [ka] If D 2 and D. 3 are each independently -C(R)- and N; R 6 , R 7 are each independently selected from H, F, Cl, Br, and I; [ka] If D 2 are independently -C(R)- and N; D 3 are independently a single bond, -O-, -N(R)-, or -C(R) 2 -, -C(=R)-, -C(=O)- and -C(=NR)-, R7 is independently selected from H, F, Cl, Br, and I; R 3 , R 4 are each independently selected from H, F, Cl, Br, and I; R 5 are H, OH, F and NH 2 is selected from R 8 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl and C 1-6 alkoxy, 1-6 Alkyl or C 1-6 Alkoxy optionally has one, two or three R 8a is replaced by R 9 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R 10 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R, R T , R D1 , R L , R 8a are each independently H, halogen, OH, or NH 2 , C.N., [ka] , C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl is optionally substituted by 1, 2 or 3 R'; R' is independently H, halogen, OH, NH 2 , CN and C 1-6 alkyl, m is independently 0, 1, 2, 3 or 4; n is independently 0, 1, 2 or 3; The 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is selected from the group consisting of 1, 2, or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

[0011] The present invention also provides a compound represented by formula (II-A) or formula (II-B), an optical isomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] However, ring A is C 4-6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; L 1 represents a single bond, -O-, -S- and -N(R L )- is selected from T 1 is -C(R T )- and -N-; D 1 are independently -C(R D1 ) 2 - and -N(R D1 )- is selected from [ka] If D 2 -O-, -N(R)-, -C(R) 2 -, -C(=R)-, -C(=O)- and -C(=NR)-, R 6 , R 7 are each independently selected from H, F, Cl, Br, and I; [ka] If D 2 is selected from -C(R)- and N; R 7 is selected from H, F, Cl, Br and I; R 3 , R 4 are each independently selected from H, F, Cl, Br, and I; R 5 are H, OH, F and NH 2 is selected from R 8 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl and C 1-6 alkoxy, 1-6 Alkyl or C 1-6 Alkoxy optionally has one, two or three R 8a is replaced by R 9 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R, R T , R D1 , R L , R 8a are each independently H, halogen, OH, or NH 2 , C.N., [ka] , C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl is optionally substituted by 1, 2 or 3 R'; R' is independently H, halogen, OH, NH 2 , CN and C 1-6 alkyl, m is independently 0, 1, 2, 3 or 4; n is independently 0, 1, 2 or 3; The 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is selected from the group consisting of 1, 2, or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

[0012] In some embodiments of the present invention, the compound of formula (I), its optical isomer, or its pharma- ceutically acceptable salt has the structure represented by formula (III-A). [ka] However, ring A is C 4-6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; L 1 represents a single bond, -O-, -S- and -N(R L )- is selected from T 1 is -C(R T )- and -N-; R 7 , R 10 are each independently selected from H, F, Cl, Br, and I; R 3 , R 4 are each independently selected from H, F, Cl, Br, and I; R 5 are H, OH, F and NH 2 is selected from R 8 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl and C 1-6 alkoxy, 1-6 Alkyl or C 1-6 Alkoxy optionally has one, two or three R 8a is replaced by R T , RL , R 8a are each independently H, halogen, OH, or NH 2 , C.N., [ka] , C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 alkenyl, 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 The alkenyl is optionally substituted by 1, 2 or 3 R'; R' is independently H, halogen, OH, NH 2 , CN and C 1-6 alkyl, m is independently 0, 1, 2, 3 or 4; The 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is selected from the group consisting of 1, 2, or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N. In some embodiments of the present invention, the R 8 is selected from H, F, Cl, Br, I and CN, and the other variables are as defined herein. In some embodiments of the present invention, the R 9 are H, CN, OH, Me, Et, [ka] wherein Me, Et, [ka] is optionally replaced by 1, 2 or 3 R, and the other variables are as defined herein.

[0013] In some embodiments of the present invention, the R 9are H, CN, OH, Me, Et, [ka] and the other variables are as defined herein.

[0014] In some embodiments of the present invention, the R 10 are H, CN, OH, Me, Et, [ka] wherein Me, Et, [ka] is optionally replaced by 1, 2 or 3 R, and the other variables are as defined herein.

[0015] In some embodiments of the present invention, the R 10 are H, CN, OH, Me, Et, [ka] and the other variables are as defined herein.

[0016] In some aspects of the invention, Ring A is selected from phenyl, pyridyl, pyridazinyl, cyclobutyl, cyclopentyl, and cyclohexyl, with other variables as defined herein.

[0017] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the other variables are as defined herein.

[0018] In some embodiments of the present invention, the R, R T , R D1 , R L , R 8a are independently H, F, Cl, Br, I, CN, OH, [ka] and the other variables are as defined herein.

[0019] In some aspects of the invention, Ring B is selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexyl ketone, tetrahydro-2H-pyran-2-one, piperidin-2-one, tetrahydro-2H-pyranyl, and piperidinyl, wherein said cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexyl ketone, tetrahydro-2H-pyran-2-one, piperidin-2-one, tetrahydro-2H-pyranyl, or piperidinyl is optionally substituted by 1, 2, 3, or 4 R, and other variables are as defined herein.

[0020] In some embodiments of the present invention, Ring B is [ka] and the other variables are as defined herein.

[0021] In some embodiments of the present invention, Ring B is [ka] and the other variables are as defined herein.

[0022] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the other variables are as defined herein.

[0023] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the other variables are as defined herein.

[0024] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0025] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0026] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0027] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0028] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0029] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0030] The present invention also provides a compound selected from the following formulas, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka]

[0031] The present invention also provides a compound selected from the following formulas, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof: [ka]

[0032] The present invention also provides use of the above compound or a pharma- ceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for preventing or treating a disease mediated by HIF2α. In some embodiments of the invention, the HIF2α mediated disease is selected from renal cancer, 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, lung squamous cell carcinoma, colon cancer, hemangioma, pulmonary hypertension and inflammatory bowel disease (IBD).

[0033] <Definitions and Explanations> Unless otherwise defined, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless specifically defined, should be understood to have its ordinary definition, not to be indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0034] As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of base in a solution or in 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 the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of acid in a solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0036] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0037] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0038] The compounds of the present invention can exist in a specific form. Unless otherwise defined, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly converted between each other. Tautomers can reach chemical equilibrium of tautomers if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0039] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms constituting the compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14The compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic effect, and extended biological half-life. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is within the scope of the present invention. "Optional" and "optionally" mean that the following items or circumstances are possible but not necessarily present, and the description includes the cases where the items or circumstances described therein are not present when the items or circumstances described therein occur.

[0040] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound after substitution is stable. The term "optionally substituted" refers to either substituted or unsubstituted, and unless otherwise defined, the type and number of substituents are any that are chemically stable and can be realized.

[0041] The term "blank" refers to the absence of a substitution, e.g. 2 If selected from the blank, [ka] It is.

[0042] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in a stable compound. For example, [ka] You can choose from, etc.

[0043] A hyphen ("-") that is not between two letters or symbols indicates a point of attachment for a substituent. For example, C 1-6 Alkylcarbonyl- refers to a C bonded to the rest of the molecule through a carbonyl. 1-6 However, when the binding site of the substituent is clear to one skilled in the art, for example in the case of a halogen substituent, the "-" may be omitted.

[0044] Unless otherwise defined, the valence bonds of groups are indicated with a dashed line, [ka] ", e.g. " [ka] ", the dotted line indicates the point of attachment of the group to the remainder of the molecule. [ka] So, the valence bond of the group [ka] represents [ka] Presence of or R 6 represents the absence of a group.

[0045] When one of the variables is selected from a single bond, the two groups connected thereto are directly linked, e.g. [ka] D in 3If represents a single bond, this structure is actually [ka] become.

[0046] If a named substituent does not specify through which atom it is linked to a substituted substituent, then such substituent may be bonded through any atom thereof; for example, pyridyl as a substituent may be bonded to the substituent through any carbon atom of the pyridine ring.

[0047] When the linking group does not specify the linking direction, the linking direction is arbitrary, for example, [ka] The linking group L in [ka] At this time [ka] is a phenyl and cyclopentyl bond in the same order as reading from left to right. [ka] and can be constructed by linking the phenyl and cyclopentyl in the reverse order of reading from left to right. [ka] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0048] Unless otherwise defined, the number of atoms in a ring is generally defined as the number of ring members, for example, a "4- to 6-membered ring" refers to a "ring" having 4 to 6 atoms arranged around it. Unless otherwise defined, the term "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl has C 1-5 , C 1-4 , C 2-6 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-5 Illustrative examples of alkyl include, inclusively but 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"), s-butyl ("s-Bu") or t-butyl ("t-Bu"), pentyl, and hexyl.

[0049] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl has C 1-2 and C. 2-3 Alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0050] Unless otherwise defined, the term "C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms linked to the remainder of the molecule via an oxygen atom. 1-6 Alkoxy is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C3 Alkoxy and the like are included. C 1-6 Examples of alkyl include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy groups), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0051] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , C 3 and C 2 Alkoxy and the like are included. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0052] Unless otherwise defined, "C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. 2-6 Alkenyl has C 2-4 , C 2-3 , C 4 , C 3 and C 2 Alkenyl and the like are included, which may be monovalent, divalent and polyvalent. 2-6 Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexamadienyl, and the like.

[0053] Unless otherwise defined, "C 2-3"Alkenyl" refers to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. 2-3 Alkenyl has C 3 and C 2 alkenyl, etc., wherein the C2-3 alkenyl may be monovalent, divalent or polyvalent. 2-3 Examples of cycloalkyl include, but are not limited to, vinyl, propenyl, and the like.

[0054] Unless otherwise defined, "C 4-6 "Cycloalkyl" refers to a saturated hydrocarbon group composed of 4 to 6 carbon atoms, which may be monocyclic or bicyclic ring systems, and the C 4-6 Cycloalkyl has C 4-5 , C 5-6 , C 4 , C 5 and C 6 Cycloalkyl and the like are included, which may be monovalent, divalent or polyvalent. C 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0055] Unless otherwise defined, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group composed of 4 to 6 ring atoms, of which 1, 2, 3, and 4 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 are optionally oxidized (i.e., NO and S(O)). P, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, for "4-6 membered heterocycloalkyl", a heteroatom can occupy the position of the connection between the heterocycloalkyl and the rest of the molecule. Said 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Illustrative examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl.

[0056] Unless otherwise defined, the term "5- to 6-membered heterocyclic group" by itself or in combination with other terms refers to a saturated or unsaturated cyclic group composed of 4 to 6 ring atoms, of which 1, 2, 3, and 4 ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). P , p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings and bridged rings. Illustrative examples of the "5-6 membered heterocyclic group" include, but are not limited to, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanonyl, tetrahydro-2H-pyran-2-onyl, piperidin-2-onyl, tetrahydro-2H-pyranyl, piperidinyl and the like.

[0057] Unless otherwise defined, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, of which 1, 2, 3, and 4 ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). P , p is 1 or 2). The 5-6 membered heteroaryl is linked to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5- or 6-membered heteroaryl. Illustrative examples of 5-6 membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), and the like. -triazolyl, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), 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 or 4-pyrimidinyl, etc.).

[0058] Unless otherwise defined, as used herein, the term "cycloalkenyl" refers to a cyclic alkenyl. 5-6 "Cycloalkenyl" has C 5 , C 6 Examples of cycloalkenyl include, but are not limited to, cyclopentenyl and cyclohexenyl.

[0059] Unless otherwise defined, C n-n+m Or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 Including any one of the ranges of n to n+m, for example, C 1-12 is 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 9-12 Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0060] Those skilled in the art should understand that some compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomers. Thus, the compounds of the present invention may exist in the form of individual stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any ratio, such as racemates, and may also exist in the form of their tautomers and geometric isomers, if desired.

[0061] The term "stereoisomers" as used herein refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, etc.

[0062] As used herein, the term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term "diastereomer" refers to stereoisomers in which the molecules have two or more chiral centers and are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, biological activity, etc. Diastereomeric mixtures can be separated by high resolution analytical methods such as electrophoresis and chromatography, e.g., HPLC.

[0063] Stereochemistry definitions and rules follow S.P. 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 optically active forms, i.e., they have the ability to rotate the plane of plane 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 about its chiral center. The prefixes d and 1, or (+) and (-), are used to indicate the representation of the rotated plane polarized light of the compound, with (-) or 1 indicating that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that is not optically active.

[0064] Racemic mixtures can be used as is or resolved into individual isomers. Resolution can provide stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL, Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Single isomers can be prepared from chiral precursors. Alternatively, the mixture can be chemically separated by the formation of diastereomeric salts using chiral acids (e.g., single enantiomers such as 10-camphorsulfonic acid, camphanic acid, α-bromocamboric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.) to obtain single isomers, which can be fractionally crystallized, followed by liberation of one or more of the resolved bases, and optionally repeating the process to obtain one or more isomers free of the other isomer, i.e., the desired stereoisomer having, for example, an optical purity of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as known to those skilled in the art, diastereomers can be obtained by covalently binding the racemic compound to a chiral compound (auxiliary).

[0065] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Bond tautomers include interconversions via recombination of some of the bonding electrons.

[0066] The term "treatment" as used herein refers to the administration of one or more drugs, particularly the compounds of formula (I) and / or pharma- ceutically acceptable salts thereof, to an individual suffering from or having symptoms of a disease, in order to cure, alleviate, mitigate, alter, treat, ameliorate, improve or affect the disease or symptoms of the disease. The term "prevention" as used herein refers to the administration of one or more drugs, particularly the compounds of formula (I) and / or pharma- ceutically acceptable salts thereof, to an individual predisposed to the disease, in order to prevent the individual from contracting the disease. When chemical reactions are involved, the terms "treating," "contacting," and "reacting" refer to the addition and mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., there may be intermediates in the mixture that result in the formation of one or more of the ultimately indicated and / or desired products that are produced.

[0067] The term "effective amount" as used herein refers to an amount that is usually sufficient to produce a beneficial effect in an individual. The effective amount of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials, etc.) in combination with conventional influencing factors (e.g., administration method, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, degree of response of the individual to the drug, etc.).

[0068] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0069] Technical and scientific terms not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually according to the conventional conditions for this type of reaction or according to the conditions recommended by the manufacturer. Unless otherwise defined, the ratios and parts are by weight. Unless otherwise defined, the ratios of liquids are by volume.

[0071] Experimental materials and reagents used in the following examples are commercially available unless otherwise specified. The present invention uses the following abbreviations: DAST stands for diethylaminosulfur trifluoride, DCM stands for dichloromethane, DCE stands for 1,2-dichloroethane, DMF stands for N,N-dimethylformamide, Oxone stands for potassium peroxymonosulfate, Selectfluor stands for 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium(0).

[0072] Example 1: Synthesis of Compound 1

[0073] [ka]

[0074] Step 1: Preparation of Compound 1-2 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 iodobenzene diacetic acid (3.68 g, 11.4 mmol). The reaction solution was replaced with argon gas three times, and the reaction solution was stirred at 100 ° C for 24 hours. The reaction solution was cooled to room temperature and 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), extracted with 400 mL of ethyl acetate three times, the organic phase was combined, washed with 1 M sodium thiosulfate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain compound 1-2, and the crude product was used directly in the next step.

[0075] Step 2: Preparation of Compounds 1-3 Compound 1-2 (0.81 g, 2.3 mmol) was dissolved in DMF (5 mL), and potassium carbonate (970 mg, 7.0 mmol) and iodomethane (0.44 mL, 7.0 mmol) were added. The reaction solution was stirred at room temperature for 18 hours. Water (30 mL) was added to the reaction solution, followed by extraction with 60 mL of ethyl acetate in two portions. The combined organic phase was washed five times with water, then washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-3. The crude product was used directly in the next step. LCMS m / z = 358.9 / 360.9 [M+1] + .

[0076] Step 3: Preparation of Compounds 1-4 Compound 1-3 (1.26 g, 3.5 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 243 mg, 0.42 mmol) were dispersed in toluene:acetone (17 mL, v / v=2:1), and Pd 2 (dba) 3(192 mg, 0.21 mmol) and potassium thioacetate (500 mg, 4.4 mmol) were added, and the reaction solution was replaced with argon gas, sealed, heated to 70°C, and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane, filtered, and the cake was washed twice with dichloromethane. The filtrate was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by column chromatography to obtain compound 1-4. 1 H NMR (400 MHz, CDCl 3 ) 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] + .

[0077] Step 4: Preparation of Compounds 1-5 Compound 1-4 (1.21 g, 3.9 mmol) was dissolved in 12 mL of methanol, and argon gas was substituted. Cesium carbonate (1.66 g, 5.1 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. Iodomethane (1.22 mL, 20 mmol) was added to the reaction solution, and stirring was continued for 16 hours. The reaction solution was concentrated under reduced pressure, dispersed in 30 mL of water, and extracted three times with 90 mL of ethyl acetate. The organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by column chromatography to obtain compound 1-5. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.38-7.35 (m, 1H), 7.16-7.11 (m, 1H), 3.99 (s, 3H), 2.45 (s, 3H);LCMS m / z = 247.0 / 249.0 [M+1-MeOH] + .

[0078] Step 5: Preparation of Compounds 1-6 To a mixture of compound 1-5 (5.9 g, 21.1 mmol), trifluoroacetamide (11.9 g, 106 mmol), magnesium oxide (11.9 g, 296 mmol) and iodobenzene diacetate (35.4 g, 110 mmol), dichloromethane (150 mL) and rhodium (II) octanoate dimer (140 mg, 0.2 mmol) were added, and the reaction solution was replaced with argon gas, and then stirred at 40 ° C for 16 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane, filtered, and the cake was washed twice with dichloromethane. The filtrate was combined and dried over anhydrous sodium sulfate. After filtering and concentrating the filtrate, compound 1-6 was obtained by purification by column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ = 8.07-8.04 (m, 1H), 7.49-7.45 (m, 1H), 4.07 (s, 3H), 3.05 (s, 3H).

[0079] Step 6: Preparation of Compounds 1-7 A solution of sodium periodate (8.22 g, 38.4 mmol) in water (15 mL) and ruthenium (III) chloride (80 mg, 0.38 mmol) were added to a solution of compound 1-6 (5.0 g, 12.8 mmol) in carbon tetrachloride / acetonitrile (60 mL, 1:1), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove carbon tetrachloride and acetonitrile. Water (50 mL) was added to the remaining aqueous phase, which was then extracted three times with 210 mL of ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by column chromatography to obtain compound 1-7. 1 H NMR (400 MHz, CDCl 3 ) 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] + .

[0080] Step 7: Preparation of Compounds 1-8 Compound 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 to DMF (10 mL). The reaction solution was heated to 130° C. by microwave and reacted for 10 minutes. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate three times. The organic phase was combined and washed three times with water, then washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 1-8. 1 H NMR (400 MHz, CDCl 3 ) δ = 8.30 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.07-7.04 (m, 1H), 6.90-6.88 (m, 1H), 6.74 (dt, J = 8.8, 2.4 Hz, 1H), 4.69 (d, J = 17.6 Hz, 1H), 4.41 (d, J = 17.6 Hz, 1H);LCMS m / z = 500.0 / 501.9 [M+1] + .

[0081] Step 8: Preparation of Compounds 1-9 Compound 1-8 (350 mg, 4.26 mmol) was added to 20 mL of acetonitrile and Na 2 CO 3 (222 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for 10 minutes under argon gas protection, and Selectfluor (743 mg, 2.1 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then 50 mL of water was added, and the mixture was extracted with 120 mL of ethyl acetate in four portions. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and then purified by column chromatography to obtain compound 1-9. 1 H NMR (400 MHz, CDCl 3) δ = 8.08 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.05-7.02 (m, 1H), 6.86-6.84 (m, 1H), 6.72 (dt, J = 8.8, 2.4 Hz, 1H), 5.30 (s, 1H);LCMS m / z = 439.8 / 401.8 [M+1] + .

[0082] Step 9: Preparation of Compounds 1-10 Ethyl acetate (180 mg, 2.04 mmol) was dissolved in tetrahydrofuran (4 mL), the solution was replaced with argon gas three times, then cooled to -70 ° C., LDA (1.02 mL, 2.04 mmol, 2 M tetrahydrofuran solution) was slowly added, the reaction solution was stirred for 30 minutes, and then a solution of compound 1-9 (300 mg, 0.68 mmol) in tetrahydrofuran (3 mL) was slowly added. The reaction solution was stirred at -70 ° C. for 1 hour. The reaction solution was quenched with 10 mL of saturated ammonium chloride solution, then warmed to room temperature, extracted with 40 mL of dichloromethane in four portions, the organic phase was combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain compound 1-10. LCMS m / z = 528.0 / 530.0 [M+1] + .

[0083] Step 10: Preparation of Compounds 1-11 Compound 1-10 (100 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), the solution was replaced with argon gas three times, then cooled to -70 ° C., n-butyl lithium (0.38 mL, 0.95 mmol, 2.5 M n-hexane solution) was slowly added, and after the addition was completed, the reaction solution was stirred at -70 ° C. for 30 minutes. The reaction solution was quenched with dilute hydrochloric acid (0.5 mL, 0.5 M), warmed to room temperature, added 10 mL of water, and extracted with 40 mL of dichloromethane in four portions, the organic phase was combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain compound 1-11. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.99-7.93 (m, 1H), 7.11-7.05 (m, 2H), 6.98-6.97 (m, 1H), 6.83-6.80 (m, 1H), 3.26-3.20 (m, 1H), 3.07-3.01 (m, 1H);LCMS m / z = 404.0 / 406.0 [M+1] + .

[0084] Step 11: Preparation of Compounds 1-12 Compound 1-11 (50 mg, 0.12 mmol) was dissolved in ethanol (2 mL), and the reaction solution was cooled to -70°C, followed by the addition of sodium borohydride (7 mg, 0.19 mmol). After the addition was completed, 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 warmed to room temperature, 3 mL of water was added, and the mixture was extracted with 12 mL of dichloromethane in four portions. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and purified by HPLC to obtain compound 1-12.

[0085] 1 H NMR (400 MHz, CDCl 3) δ = 7.73 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 1.6 Hz, 1H), 7.00 (dt, J = 8.0, 2.0 Hz, 1H), 6.93-6.92 (m, 1H), 6.76 (dt, J = 8.4, LCMS m / z = 406.0 / 408.0 [M+1] + . Step 12: Preparation of Compound 1 Compound 1-12 (80 mg, 0.20 mmol) was dissolved in DCE (2 mL), and the reaction solution was cooled to 0°C, after which DAST (38 mg, 0.24 mmol) was added, and after the addition was completed, the reaction solution was stirred at 0°C for 1 hour. The reaction solution was quenched with water (3 mL), then warmed to room temperature, extracted with 12 mL of dichloromethane in four portions, and the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and purified by HPLC to obtain compound 1.

[0086] 1 H NMR (400 MHz, CDCl 3 ) δ = 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.03 (dt, J = 8.0, 2.0 Hz, 1H), 6.96-6.95 (m, 1H), 6.79 (dt, J = LCMS m / z = 408.0 / 410.0 [M+1] + .

[0087] Example 2: Synthesis of Compound 2 [ka]

[0088] Step 1: Preparation of compound 2-2 A suspension of Oxone (16.52 g, 26.9 mmol) in water (55 mL) was added dropwise to a solution of compound 1-5 (15.0 g, 53.7 mmol) in methanol (110 mL) in an ice bath. After the addition was complete, the reaction was allowed to warm to room temperature naturally and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove most of the methanol, dispersed in ethyl acetate (200 mL) and water (200 mL), the aqueous phase was extracted with three portions of 300 mL ethyl acetate, the organic phases were combined, washed with 1 M sodium thiosulfate, then with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by flash silica gel column chromatography to give compound 2-2. LCMS m / z = 295.0 / 297.0 [M+1] + .

[0089] Step 2: Preparation of compound 2-3 At room temperature, compound 2-2 (7.0 g, 23.7 mmol) was dissolved in DMF (120 mL), and potassium carbonate (4.92 g, 35.6 mmol) and 3-cyano-5-fluorophenol (4.88 g, 35.6 mmol) were added. The reaction solution was replaced with argon gas, and then stirred at 90 ° C. for 8 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove most of the DMF, and 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, and the organic phases were combined, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, filtered, and the crude product after concentrating the filtrate was purified by flash silica gel column chromatography to obtain compound 2-3. 1 H NMR (400 MHz, CDCl 3) δ = 8.11 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.18 (ddd, J = 7.6, 2.4, 1.2 Hz, 1H), 7.03-7.02 (m, 1H), 6.96 (dt, J = 9.2, 2.4 Hz, 1H), 4.01 (s, 3H), 2.88 (s, 3H), LCMS m / z = 412.0 / 414.0 [M+1] + .

[0090] Step 3: Preparation of Compound 2-4 To a mixture of compound 2-3 (3.0 g, 7.28 mmol), trifluoroacetamide (2.88 g, 25.5 mmol), magnesium oxide (2.35 g, 58.2 mmol) and iodobenzene diacetate (8.2 g, 25.5 mmol), dichloromethane (30 mL) and rhodium(II) octanoate dimer (113 mg, 0.15 mmol) were added, and the reaction solution was replaced with argon gas, and then stirred at 40°C for 16 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane, filtered, and the cake was washed twice with dichloromethane. The filtrate was combined and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, compound 2-4 was obtained by purification by column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ = 8.12 (d, J = 8.8 Hz, 1H), 7.29 (ddd, J = 7.6, 2.4, 1.2 Hz, 1H), 7.19-7.15 (m, 2H), 7.07 (dt, J = 8.8, 2.4 Hz, 1H), 4.02 (s, 3H), 3.63 (s, 3H), LCMS m / z = 523.0 / 525.0 [M+1] + .

[0091] Step 4: Preparation of Compound 2-5 Compound 2-4 (2.03 g, 3.9 mmol) was dissolved in THF (20 mL), cesium carbonate (1.52 g, 4.7 mmol) was added, and the mixture was sealed. The reaction solution was stirred at 90° C. for 1 hour. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with 90 mL of ethyl acetate in three portions. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by column chromatography to obtain compound 2-5. 1 H NMR (400 MHz, CDCl 3 ) δ = 8.37 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.29 (ddd, J = 7.6, 2.4, 1.2 Hz, 1H), 7.13-7.12 (m, 1H), 7.05 (dt, J = 8.8, 2.4 Hz, 1H), 4.70 (d, J = 17.6 Hz, 1H), 4.43 (d, J = 17.6 Hz, 1H), LCMS m / z = 491.0 / 493.0 [M+1] + .

[0092] Step 5: Preparation of Compounds 2-6 Compound 2-5 (1.00 g, 2.04 mmol) was dissolved in 20 mL of acetonitrile and added with Na 2 CO 3 (647 mg, 6.1 mmol) and Selectfluor (2.16 g, 6.1 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then 50 mL of water was added. The mixture was extracted with 120 mL of ethyl acetate in four portions. The combined organic phase was washed with saturated saline and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain the crude product compound 2-6. LCMS m / z = 449.0 / 451.0 [M+H 2 O+1] + .

[0093] Step 6: Preparation of Compounds 2-7 Compound 2-6 (1.0 g, 2.32 mmol, crude product) was dissolved in DMF (20 mL), indium (532 mg, 4.64 mmol) and allyl iodide (1.17 g, 6.96 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. 1M dilute hydrochloric acid (15 mL) was added to the reaction solution, followed by extraction with 30 mL of ethyl acetate in three portions. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by column chromatography to obtain compound 2-7. LCMS m / z = 473.0 / 475.0 [M+1] + .

[0094] Step 7: Preparation of Compounds 2-8 Compound 2-7 (380 mg, 0.80 mmol), triethylamine (0.33 mL, 2.41 mmol), trimesitylphosphine (31 mg, 0.08 mmol) and Pd 2 (dba) 3 (74 mg, 0.08 mmol) was added with DMF (8 mL). The reaction solution was replaced with nitrogen gas, then heated to 90° C. and reacted for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, and extracted with 100 mL of ethyl acetate three times. The organic phases were combined, washed with water three times, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 2-8. LCMS m / z = 393.0 [M+1] + .

[0095] Step 8: Preparation of Compound 2-9 Compound 2-8 (100 mg, 0.25 mmol) was dissolved in acetonitrile (6 mL) and water (1 mL), and NaIO 4 (136 mg, 0.64 mmol) and RuCl 3 (5 mg, 0.02 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 4 (68 mg, 0.32 mmol) and RuCl 3(3 mg, 0.01 mmol) was added. Stirring was continued at room temperature for 16 hours. The reaction solution was quenched with saturated sodium thiosulfate (3 mL), concentrated to remove most of the acetonitrile, then dispersed in 10 mL of ethyl acetate and 10 mL of water, the aqueous phase was extracted with 4 portions of 20 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the crude product compound 2-9. LCMS m / z = 395.0 [M+1] + .

[0096] Step 9: Preparation of Compounds 2-10 Compound 2-9 (78 mg, 0.20 mmol) was dissolved in ethanol (1 mL), and the reaction solution was cooled to -70°C, followed by the addition of sodium borohydride (14 mg, 0.38 mmol). 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), warmed to room temperature, and added with 3 mL of water. The mixture was extracted with 12 mL of dichloromethane in four portions, and the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by flash silica gel column chromatography to give compound 2-10. LCMS m / z = 397.0 [M+1] + .

[0097] Step 10: Preparation of Compound 2 Compound 2-10 (80 mg, 0.20 mmol) was dissolved in DCM (5 mL), and the reaction solution was cooled to -70°C, after which DAST (39 mg, 0.24 mmol) was added, and after addition was complete, the reaction solution was stirred at -70°C for 0.5 hours. DAST (18 mg, 0.12 mmol) was added to the reaction solution, and after addition was complete, the reaction solution was stirred at -70°C for 0.5 hours. The reaction solution was quenched with methanol (1 mL) at -70°C, warmed to room temperature, concentrated, and then purified by SFC (first run: column DAI CEL CHIRALPAK (registered trademark) AS (250 x 25 mm, 10 μm); mobile phase [0.1% diethylamine, methanol]; B%: 20% to 20%; second run: column DAI CEL CHIRALPAK (registered trademark) IG (250 x 25 mm, 10 μm); mobile phase [0.1% diethylamine, methanol]; B%: 30% to 30) to obtain compound 2, retention time: 3.445 min. Retention times were measured on the following analytical column: Column: Dr.maish Reprosil Chiral-MIC (DAICELCHIRALPAK® IC) 100×3.0 mm 3 μm, Mobile phase: A: Carbon dioxide B: Methanol (0.1% diethylamine), 40% B, Flow rate: 1.5 mL / min, Column temperature: 35° C.

[0098] Compound 2: 1 H NMR (400 MHz, CD 3 OD) δ = 7.89 (d, J = 8.4 Hz, 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 = 8.4 Hz, 1H), 6.05 (dd, J = 53.2, 5.2 Hz, 1H), 2.93-2.80 (m, 1H), 2.65-2.58 (m, 1H),LCMS m / z = 399.0 [M+1] + .

[0099] Example 3: Synthesis of Compound 3-P1, Compound 3-P2, Compound 3-P3, and Compound 3-P4 [ka]

[0100] Step 1: Preparation of compound 3-2 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 added to toluene (10 mL) and the reaction solution was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 3-2 crude product (2.11 g), which was used directly in the next step. LCMS m / z = 450.01 [M+1] + .

[0101] Step 2: Preparation of compound 3-3 Compound 3-2 crude product (1.00 g) was dissolved in acetonitrile (10 mL), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.57 g, 4.44 mmol), anhydrous sodium carbonate (468 mg, 4.44 mmol) were added, and stirring was continued at room temperature for 2 hours. TLC showed that the reaction was completed. The reaction mixture was adjusted to pH=5 with 1M HCl solution (100 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then ethyl acetate (100 mL) was added to dissolve, washed with water (50 mL×3) and saturated saline (50 mL×3) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain compound 3-3 (700 mg, two-step total yield: 70.8%). LCMS m / z =397.30 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) δ = 9.05 (t, J = 7.0 Hz, 1H), 8.94 (d, J = 2.7 Hz, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.50 - 8.39 (m, 1H), 8.29 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 5.87 (d, J = 48.7 Hz, 1H).

[0102] Step 3: Preparation of Compound 3-4 Sodium borohydride (134 mg, 2.54 mmol) was added to a solution of compound 3-3 (700 mg, 1.77 mmol) in ethanol (10 mL) at -78°C, and the reaction was carried out for 1 hour while maintaining the temperature. TLC showed that the reaction was completed. The reaction solution was poured into a saturated aqueous ammonium chloride solution (50 mL) and stirred for 10 minutes. Extraction was carried out with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated saline (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 3-4 (540 mg, yield: 76.8%). 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 2.0 Hz, 1H), 8.00 (s, 2H), 7.46 (d, J = 8.5 Hz, 1H), 6.21 (dd, J = 49.0, 13.5 Hz, 1H), 5.87 (d, J = 3.3 Hz, 1H).

[0103] Step 4: Preparation of compound 3 At 0°C, compound 3-4 (550mg, 1.38mmol) was dissolved in a solution of 2-methyltetrahydrofuran (5mL), and diethylaminosulfur trifluoride (445mg, 2.76mmol) was added dropwise to dissolve in a solution of 2-methyltetrahydrofuran (5mL). The temperature was maintained and stirring was continued for 1 hour. TLC showed that the reaction was completed. The reaction mixture was poured into saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50mL x 2), the combined organic phase was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain compound 3 (200mg, yield: 36.2%). LCMS m / z = 401.01 [M+1] + .

[0104] Step 5: Preparation of Compounds 3-P1, 3-P2, 3-P3, and 3-P4 Compound 3 (450 mg, 1.12 mmol) was purified by preparative HPLC (FA system) to obtain a mixture of compound 3-P1 and compound 3-P2 (300 mg, second effluent) and a mixture of compound 3-P3 and compound 3-P4 (30 mg, first effluent).

[0105] A mixture of compound 3-P1 and compound 3-P2 (300 mg) was subjected to SFC (column DAICELCHIRALPAK (registered trademark) ID (250 × 25 mm, 10 μm)); mobile phase [A: carbon dioxide, B: methanol (0.1% of 7.0 mol / L ammonia water)]; B%: 0% to 30% to obtain compound 3-P1 (retention time: 2.495 minutes) and compound 3-P2 (retention time: 3.108 minutes). Retention time was measured by the following analytical method: column: DAICELCHIRALPAK (registered trademark) IB, 250 × 25 mm, 10 μm, mobile phase [A: carbon dioxide, B: methanol (0.1% of 7.0 mol / L ammonia water)], 30% B, flow rate: 70 mL / min, column temperature: 35 ° C. The mixture was separated by SFC to obtain compound 3-P1 (80.0 mg, recovery rate: 17.8%) and crude product of compound 3-P2 (60.0 mg). The crude product of compound 3-P2 was purified by preparative HPLC (FA system) to obtain compound 3-P2 (49.1 mg, recovery rate: 10.9%). Compound 3-P1, 1H NMR (400 MHz, DMSO-d 6 ) δ = 9.01 (d, J = 1.5 Hz, 1H), 8.95 (d, J = 2.7 Hz, 1H), 8.48 (dd, J = 2.7, 1.7 Hz, 1H), 8.31 (dd, J = 8.6, 2.0 Hz, 1H), 8.01 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.21 (dd, J = 49.0, 13.5 Hz, 1H), 5.80 (dd, J = 46.9, 5.9 Hz, 1H). Compound 3-P2, 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.01 (d, J = 1.5 Hz, 1H), 8.95 (d, J = 2.7 Hz, 1H), 8.48 (dd, J = 2.7, 1.7 Hz, 1H), 8.31 (dd, J = 8.6, 2.0 Hz, 1H), 8.01 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.21 (dd, J = 49.0, 13.5 Hz, 1H), 5.80 (dd, J = 46.9, 5.9 Hz, 1H).

[0106] A mixture of compound 3-P3 and compound 3-P4 (30 mg) was subjected to SFC (column DAICEL CHIRALPAK (registered trademark) IB (250 × 25 mm, 10 μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0 mol / L ammonia water)]; B%: 0% to 30% to obtain compound 3-P3 (retention time 3.325 minutes) and compound 3-P4 (retention time 3.544 minutes). The retention time was measured by the following analytical method: column: DAICEL CHIRALPAK (registered trademark) IB, 250 × 25 mm, 10 μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0 mol / L ammonia water)], 30% B, flow rate: 70 mL / min, column temperature: 35 ° C. Separation by SFC gave compound 3-P3 (4.44 mg, recovery rate: 0.99%) and compound 3-P4 (4.26 mg, recovery rate: 0.95%). Compound 3-P3, 1 H NMR (400 MHz, 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, 1.9 Hz, 1H), 7.93 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.09 (dd, J = 54.6, 4.6 Hz, 1H), 5.39 (ddd, J = 46.7, 16.7, 4.4 Hz, 1H). compound 3-P4, 1 H NMR (400 MHz, DMSO-d 6 ) 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, 1.9 Hz, 1H), 7.93 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.09 (dd, J = 54.6, 4.6 Hz, 1H), 5.39 (ddd, J = 46.7, 16.7, 4.4 Hz, 1H).

[0107] Example 4: Synthesis of Compound 4, Compound 4-P1, Compound 4-P2, Compound 4-P3, and Compound 4-P4 [ka]

[0108] Step 1: Preparation of compound 4-2 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 added to toluene (50 mL). The reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 4-2 crude product (7.70 g), which was used directly in the next step. LCMS m / z = 467.0 [M+1] + .

[0109] Step 2: Preparation of compound 4-3 Compound 4-2 crude product (7.70 g) was dissolved in acetonitrile (100 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.50 g, 21.4 mmol) and sodium carbonate (2.27 g, 21.4 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction solution 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), and the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain compound 4-3 (1.50 g, two-step yield: 57.4%). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.55 (d, J = 8.6 Hz, 1H), 8.24 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.85 (s, 1H), 7.84 - 7.78 (m, 1H), 7.47 (d, J = 8.6 Hz, 1H), 5.54 (d, J = 49.9 Hz, 1H).

[0110] Step 3: Preparation of compound 4-4 Compound 4-3 (1.00 g, 2.42 mmol) was dissolved in ethanol (20 mL). Sodium borohydride (184 mg, 4.84 mmol) was added under the condition of -78 ° C. The reaction was continued for 1 hour while maintaining the temperature. TLC showed that the reaction was completed. The reaction solution was poured into saturated ammonium chloride solution (50 mL) and stirred for 10 minutes. Extraction was performed with ethyl acetate (50 mL × 3), and the combined organic phase was washed with saturated saline (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain compound 4-4 (670 mg, yield: 66.7%). 1 H NMR (400 MHz, DMSO-d 6) δ = 8.12 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.50 - 7.44 (m, 2H), 6.08 (d, J = 9.1 Hz, 1H), 5.51 - 5.27 (m, 2H).

[0111] Step 4: Preparation of compound 4 At 0°C, compound 4-4 (900mg, 2.16mmol) was dissolved in a solution of 2-methyltetrahydrofuran (20mL), and diethylaminosulfur trifluoride (720mg, 4.32mmol) was added dropwise to dissolve in a solution of 2-methyltetrahydrofuran (10mL). The temperature was maintained and stirring was continued for 1 hour. TLC showed that the reaction was completed. The reaction mixture was poured into saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (50mL x 3), the organic phase was combined and washed with saturated saline (50mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain compound 4 (350mg, yield: 38.8%).

[0112] Step 5: Preparation of Compounds 4-P1, 4-P2, 4-P3, and 4-P4 Compound 4 (350 mg, 0.839 mmol) was fractionated using SFC (column DAICEL CHIRALPAK (registered trademark) IB (250 × 25 mm, 10 μm)); mobile phase [A: carbon dioxide, B: MeOH (containing 0.1% diethylamine)]; B%: 30% to 30% to obtain compound 4-P1 (retention time: 2.217 min), a mixture of compound 4-P2 and compound 4-P3, and compound 4-P4 (retention time: 2.604 min). Retention times were measured using the following analytical method: column: DAICEL CHIRALPAK (registered trademark) IB 100 × 3.0 mm, 3 μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5 mL / min, column temperature: 35 ° C.

[0113] The mixture of compound 4-P2 and compound 4-P3 was prepared by preparative SFC (column DAICEL CHIRALCEL (registered trademark) OJ (250 × 25 mm, 10 μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)]; B%: 30% to 30%) to obtain compound 4-P2 (retention time: 2.443 min) and compound 4-P3 (retention time: 2.537 min). The retention time was measured by the following analytical method: column: DAICEL CHIRALPAK (registered trademark) IB 100 × 3.0 mm, 3 μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5 mL / min, column temperature: 35 ° C. Compound 4-P1 (7.32mg, recovery rate: 2.09%), 1 H NMR (400 MHz, MeOD) δ = 8.02 (d, J = 8.5 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.37 (dt, J = 9.5, 2.3 Hz, 1H), 6.36 (ddd, J = 54.5, 10.2, 5.1 Hz, 1H), 5.47 (ddd, J = 50.7, 17.9, 5.1 Hz, 1H). Compound 4-P2 (4.88mg, recovery rate: 1.39%), 1 H NMR (400 MHz, MeOD) δ = 8.02 (d, J = 8.5 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.37 (dt, J = 9.5, 2.3 Hz, 1H), 6.36 (ddd, J = 54.5, 10.2, 5.1 Hz, 1H), 5.47 (ddd, J = 50.7, 17.9, 5.1 Hz, 1H). Compound 4-P3 (117 mg, recovery rate: 33.4%), 11H NMR (400 MHz, MeOD) δ = 8.06 (dd, J = 8.5, 2.0 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.45 (dt, J = 9.3, 2.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.04 (dd, J = 49.4, 13.3 Hz, 1H), 5.63 (dd, J = 47.5, 5.8 Hz, 1H). Compound 4-P4 (119 mg, recovery rate: 34.0%) 1 1H NMR (400 MHz, MeOD) δ = 8.06 (dd, J = 8.5, 2.0 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.45 (dt, J = 9.3, 2.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.04 (dd, J = 49.4, 13.3 Hz, 1H), 5.63 (dd, J = 47.5, 5.8 Hz, 1H).

[0114] Experimental Example 1: Luciferase Experiment 786-O-HRE-Luc cells were obtained in 786-O (ATCC® CRL-1932™) cells purchased from ATCC by infecting with commercially available lentivirus. Appropriate 786-O-HRE-Luc single cell clones were screened, expanded, and used for subsequent luciferase experiments. In luciferase experiments, 100× DMSO stock solutions in which drugs were dissolved were prepared into 10× compound gradient dilutions in experimental medium (RPMI-1640 with 2% FBS; FBS: 10099141C, Gibco; RPMI-1640: 12440053, Gibco), and 20 μL of 10× compound dilutions were added to a clear flat-bottom 96-well plate (3599, Corning). Then, about 100,000 786-O-HRE-Luc cells in 180 μL of medium were inoculated into the above 96-well plate. The final concentration of DMSO (D2650, Sigma) in each well was 0.1%. After culturing in an incubator for about 24 h, luciferase activity was measured with Dual-Luciferase® Reporter Assay System (E1960, Promega) reagent according to the manufacturer's recommended method. EC was calculated using GraphPadPrism software using the following equation: dose-response-inhibition (4 parameters). 50 The values ​​were calculated, and the experimental results are shown in Table 1.

[0115] [Table 1] As can be seen from the experimental results in Table 1, the compounds of the present invention have excellent in vitro activity and can inhibit the expression level of HIF response element (HRE)-dependent luciferase.

[0116] Experimental example 2: VEGF ELISA experiment 100x DMSO stock solution in which drug was dissolved was prepared into 10x compound gradient dilutions in experimental medium (RPMI-1640 with 2% FBS; FBS: 10099141C, Gibco; RPMI-1640: 12440053, Gibco), and 20μL of 10x compound dilutions were added to a clear flat-bottom 96-well plate (3599, Corning). Then, about 40000 786-O cells (ATCC® CRL-1932TM) in 180μL of medium were inoculated into the above 96-well plate. The final concentration of DMSO (D2650, Sigma) per well was 0.1%. After about 48 hours of culture in an incubator, 100μL of upper medium was aspirated per well and added to a 96-well plate (3799, Corning). VEGF concentrations were determined according to the OD value at 450 nM of each well with a microplate reader using an ELISA kit (DY293B, R&D Systems). EC was calculated with GraphPadPrism software using the following equation: dose-response-inhibition (4 parameters). 50 The values ​​were calculated, and the experimental results are shown in Table 2.

[0117] [Table 2] As can be seen from the experimental results in Table 2, the compounds of the present invention have significant activity in inhibiting VEGF expression.

[0118] Experimental Example 3: Pharmacokinetic study 1. Purpose of the experiment:

[0119] SD rats were used as test animals, and compound 3-P3 and comparative example PT2385 were administered intragastrically. The drug concentrations in plasma at different times were measured by LC-MS / MS to study the pharmacokinetic characteristics of the compounds of the present invention and the comparative example compounds in the rat body.

[0120] 2. Experimental Scheme 2.1 Experimental medicines and animals Experimental drugs: Compound 3-P3 and comparative example PT2385; Animals: SD rats, male, 200-220 g, purchased from Shanghai Jiesijie Laboratory Animal Co., Ltd.

[0121] 2.2 Drug manufacturing Weigh out an appropriate amount of compound 3-P3, add an appropriate amount of 10% ethanol + 30% polyethylene glycol 400 + 60% (0.5% sodium carboxymethylcellulose + 0.5% Tween 80), vortex and ultrasonic to prepare a 1mg / mL suspension. Weigh out an appropriate amount of compound 3-P3, add an appropriate amount of 10% ethanol + 30% polyethylene glycol 400 + 60% (0.5% sodium carboxymethylcellulose + 0.5% Tween 80), vortex and ultrasonic to prepare a 0.5mg / mL suspension.

[0122] 2.3 Administration SD rats in each group (3 rats / group) were fasted overnight and then intragastricly administered with each test compound (PO, dose: 10 mg / kg or 5 mg / kg, dose volume: 10 mL / kg), and allowed to eat 4 hours after administration.

[0123] 3.Operation 0.2 mL of blood was collected from the jugular vein before and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing and anticoagulated with sodium heparin. After collection, blood samples were placed on ice and centrifuged to separate plasma (centrifugation conditions: 1500 g, 10 min). Collected plasma was stored at -40 to -20°C before analysis. The content of the test compound in rat plasma after intragastric administration was measured by LC-MS / MS.

[0124] 4. Pharmacokinetic parameters The pharmacokinetic parameters of the compound 3-P3 of the present invention and the comparative example PT2385 are shown in Table 3. [Table 3]

[0125] Conclusion: Compound 3-P3 showed significant improvements in both blood drug concentration and area under the curve compared with comparative example PT2385.

[0126] All documents mentioned in this application are incorporated by reference as if each document was incorporated by reference individually. Furthermore, it will be understood that after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and that equivalents thereof are also included within the scope defined by the appended claims. <Additional Notes> Aspects of the invention include the following. <Section 1> A compound represented by formula (I), an optical isomer thereof, or a pharma- ceutically acceptable salt thereof. [ka] (However, ring A is C 4-6 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; Ring B is C 5-6 cycloalkyl, a 5- to 6-membered heterocyclic group, and a 5- to 6-membered cycloalkenyl; 5-6 The cycloalkyl, 5- to 6-membered heterocyclic group, or 5- to 6-membered cycloalkenyl is optionally substituted by 1, 2, 3, or 4 R; L 1 represents a single bond, -O-, -S- and -N(R L )- is selected from T 1 is -C(R T )- and -N-; T 2 , =NR 9 and blank, T 3 =NR 10 and O; D 1 are independently -C(R D1) 2 - and -N(R D1 )- is selected from R 3 、R 4 are each independently selected from H, F, Cl, Br, and I; R 5 are H, OH, F and NH 2 is selected from R 8 are independently H, F, Cl, Br, I, CN, and C 1-6 Alkyl and C 1-6 alkoxy, 1-6 Alkyl or C 1-6 Alkoxy optionally has one, two or three R 8a is replaced by R 9 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R 10 are H, CN, OH, and C. 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R, R T 、R D1 、R L 、R 8a are each independently H, halogen, OH, or NH 2 , C.N.,

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Claims

1. A compound represented by the following formula, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】

2. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】

3. 3. A pharmaceutical composition comprising a compound according to claim 1 or claim 2 or a pharma- ceutically acceptable salt thereof for preventing or treating a disease mediated by HIF2α.

4. The pharmaceutical composition of claim 3, wherein the disease mediated by HIF2α is selected from renal cancer, glioma, Von Hippel-Lindau syndrome, lung cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, gastric cancer, liver cancer, thyroid cancer, multiple myeloma, pancreatic ductal carcinoma, lung squamous cell carcinoma, colon cancer, hemangioma, pulmonary hypertension and inflammatory bowel disease.

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