Tetracyclic compounds, methods for their preparation and use

Abstract

Disclosed are compounds as set forth in formula (I), their optical isomers, and pharmaceutically acceptable salts, and the use of said compounds as KRAS inhibitors. [Formula 1] JPEG2022543767000284.jpg5565

Description

[Technical Field]

[0001] This disclosure claims priority to Chinese Patent Application No. CN201910712388.0, filed August 2, 2019, Chinese Patent Application No. CN201910899724.7, filed September 23, 2019, Chinese Patent Application No. CN201911157922.2, filed November 22, 2019, and Chinese Patent Application No. CN202010054185.X, filed January 17, 2020.

[0002] The present disclosure relates to compounds of formula (I), their optical isomers, and pharmaceutically acceptable salts, and the use of said compounds as KRAS inhibitors. [Background technology]

[0003] Cancer has been the leading cause of death in China for 31 years. Among cancer types, lung cancer is one of the most common tumors, of which over 80% are non-small cell lung cancer. Furthermore, lung cancer has a high incidence rate and various mutations. To enrich companies' R&D pipelines, focusing on unmet medical needs and developing breakthrough new drugs to treat cancer is highly necessary for companies' long-term growth and is of great economic and social importance.

[0004] Mutations in the RAS gene are found in approximately 30% of cancer patients, and oncogene research has recognized RAS genes as major cancer genes for the past 20 years, including lung, colon, and pancreatic cancers.

[0005] In the United States, RAS mutations are also common in the three cancer types with the highest mortality rates (pancreatic, colon, and lung cancer), occurring in 95%, 52%, and 31% of patients with these cancers, respectively. KRAS mutations are common in pancreatic, colon, and lung cancer, NRAS mutations are common in melanoma and acute myeloid leukemia, and HRAS mutations are common in bladder and head and neck cancers.

[0006] The mutation rate of the KRAS gene in Asian populations is 10-15%. The KRAS gene is mutated in many cancers and is one of the major oncogenes. The most likely target molecular subtype of non-small cell lung cancer (NSCLC) is KRAS mutant tumors, and the mutation rate in NSCLC is approximately 15%-25%. In NSCLC cases, KRAS mutations occur primarily in codons 12 and 13. The most common codon mutation, KRAS-G12C, is observed in approximately 39% of KRAS mutant NSCLC cases.

[0007] In lung adenocarcinoma, the probability of a positive KRAS gene is 1 / 5 to 1 / 4, second only to a positive EGFR mutation. The lack of targeted inhibitors makes both the treatment and prognosis of patients with KRAS-positive non-small cell lung cancer extremely difficult. The NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer (2013) clearly state that KRAS gene testing should be performed before treatment of lung cancer patients with EGFR-TKIs, and the use of targeted EGFR-TKIs as a clinical treatment modality should be determined based on the test results. If the KRAS gene is mutated, molecular targeted therapy using EGFR-TKIs is not recommended for the patient.

[0008] According to the Thomson Reuters Competitive Intelligence drug database (Cortellis for CI), there are 162 drugs directly linked to the RAS gene / protein (data available as of August 18, 2016), of which 18 are KRAS small molecule drugs, including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase modulators, and 2 KRAS gene modulators. One such drug is currently under clinical investigation. Additionally, the first KRAS inhibitor, antroquinol, developed by a Taiwanese company, is in Phase II clinical trials with the US FDA. Selumetinib, an inhibitor targeting MEK in the KRAS downstream pathway, developed by AstraZeneca, is also in Phase II clinical trials. The most important tumor driver gene is KRAS mutation. This mutation accounts for a certain proportion of patients with pancreatic, lung, and colorectal cancer. Currently, no specifically targeted drugs acting on this target are available. Therefore, this project has important medical research value and clinical application value, and will be of greater medical value to the people in China.In the development of small molecule drugs for KRAS-G12C, its molecular mechanism has been substantially elucidated, and the molecular structure and effect of the drug have been verified under existing test conditions, demonstrating its high activity and potential for drug discovery. Summary of the Invention

[0009] The present disclosure provides compounds, optical isomers, and pharmaceutically acceptable salts of formula (I):

[0010] [ka] During the ceremony, R1, R2, and R 11 are each independently H, halogen, OH, NH2, CN, or C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 alkylamino, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6alkylamino is optionally substituted with 1, 2, or 3 R; T1 is selected from N and C(R3); T2 is selected from N and C(R4); R3 and R4 are each independently H, halogen, OH, NH2, CN, or C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; R5 independently represents H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 the aryl or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R; R6 independently represents H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl-OC(=O)-, C 3-6cycloalkyl, and 3- to 6-membered heterocycloalkyl; C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl-OC(=O)-, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; Ring A is C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Ring B is C 6-10 selected from aryl, 5- to 10-membered heteroaryl, benzo 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; R7 is H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 alkylamino, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 alkylamino is optionally substituted with 1, 2, or 3 R; R8 and R9 are each independently H, halogen, CN, or C 1-6 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkylamino, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R;

[0011] [ka] teeth,

[0012] [ka] represents

[0013] [ka] but

[0014] [ka] When R7 and R9 do not exist, L1 is a single bond, CH2,

[0015] [ka] , O, S, S(=O), C(=O), S(=O)2, and N(R 10 ) and L2 is selected from CH2, O, S, and C(=O); L3 is a single bond, C(R 12 R 12 ), and C(=O), L4 is selected from S(=O), S(=O)2, and C(=O); m is selected from 1, 2, 3, and 4; n is selected from 1, 2, 3, and 4; R 10 is H, C 1-6 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; C 1-6 Alkyl, C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; R 12 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, and CF3;

[0016] R independently represents H, halogen, OH, NH2, CN,

[0017] [ka] , C 1-6Alkyl, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamino, and 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamino or 5-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R'; R' is selected from F, Cl, Br, I, OH, NH2, and CH3; 3- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C 1-6 Heterocycloalkyl includes 1, 2, or 3 heteroatoms or groups of heteroatoms independently selected from O, NH, S, C(=O)O, S(=O), S(=O)2, and N.

[0018] In some embodiments of the present disclosure, R is independently H, halogen, OH, NH, CN,

[0019] [ka] , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamino, and 5- to 6-membered heterocycloalkyl; 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The alkylamino or 5-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R', and other variables are as defined in this disclosure.

[0020] In some embodiments of the present disclosure, R is independently H, F, Cl, Br, I, OH, NH, CN, Me,

[0021] [ka] Selected from Me,

[0022] [ka] is optionally substituted with 1, 2, or 3 R', and other variables are as defined in this disclosure.

[0023] In some embodiments of the present disclosure, R is independently H, F, Cl, Br, I, OH, NH, CN, Me,

[0024] [ka] and other variations are as defined in this disclosure.

[0025] In some embodiments of the present disclosure, R, R, and R 11 are each independently H, halogen, OH, NH2, CN, or C 1-3 Alkyl, C 1-3 Alkoxy, and C 1-3 alkylamino; 1-3 Alkyl, C 1-3 Alkoxy, or C 1-3 The alkylamino is optionally substituted with 1, 2, or 3 R, and other variables are as defined in this disclosure.

[0026] In some embodiments of the present disclosure, R, R, and R 11 are each independently H, F, Cl, Br, I, OH, NH2, CN, Me, CF3,

[0027] [ka] and other variations are as defined in this disclosure.

[0028] In some embodiments of the present disclosure, R3 and R4 are each independently H, F, Cl, Br, I, OH, NH2, CN, Me, CF3,

[0029] [ka] and other variations are as defined in this disclosure.

[0030] In some embodiments of the present disclosure, R5 is H, F, Cl, Br, I, OH, NH2, CN, Me, CF3,

[0031] [ka] and other variations are as defined in this disclosure.

[0032] In some embodiments of the present disclosure, R6 is H, F, Cl, Br, I, OH, NH2, CN, Me, CF3,

[0033] [ka] and other variations are as defined in this disclosure.

[0034] In some embodiments of the present disclosure, ring A is C 3-6 Selected from cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, naphthyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indazolyl, and indolyl, other variables being as defined herein.

[0035] In some embodiments of the present disclosure, the moiety

[0036] [ka] teeth,

[0037] [ka] and other variations are as defined in this disclosure.

[0038] In some embodiments of the present disclosure, Ring B is selected from phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, indazolyl, indolyl, 1H-benzo[d][1,2,3]triazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[3,4-b]pyridyl, isoquinolin-1(2H)-onyl, and 1H-benzo[d]imidazolyl, and other variables are as defined herein.

[0039] In some embodiments of the present disclosure, the moiety

[0040] [ka] teeth,

[0041] [ka] and other variations are as defined in this disclosure.

[0042] In some embodiments of the present disclosure, the moiety

[0043] [ka] teeth,

[0044] [ka] and other variations are as defined in this disclosure.

[0045] In some embodiments of the present disclosure, the moiety

[0046] [ka] teeth,

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka] and other variations are as defined in this disclosure.

[0054] In some embodiments of the present disclosure, R7 is H, F, Cl, Br, I, CN, Me, CF3,

[0055] [ka] and other variations are as defined in this disclosure.

[0056] In some embodiments of the present disclosure, R and R are each independently H, F, Cl, Br, I, CN, Me, CF,

[0057] [ka] and other variations are as defined in this disclosure.

[0058] In some embodiments of the present disclosure, the moiety

[0059] [ka] teeth,

[0060] [ka] and other variations are as defined in this disclosure.

[0061] In some embodiments of the present disclosure, the compound, its optical isomers, and pharmaceutically acceptable salts thereof are

[0062] [ka] is selected from During the ceremony, R1, R2, L1, L2, T, T2, R5, R6, ring A, ring B, R7, R8, and R9 are as defined above.

[0063] In some embodiments of the present disclosure, the compound, its optical isomers, and pharmaceutically acceptable salts thereof are

[0064] [ka] is selected from During the ceremony, R1, R2, L1, T, T2, R5, R6, ring A, ring B, R7, R8, and R9 are as defined above.

[0065] In some embodiments of the present disclosure, the compound, its optical isomers, and pharmaceutically acceptable salts thereof are

[0066] [ka] is selected from During the ceremony, R1, R2, L1, T, T2, R5, R6, ring A, ring B, R7, R8, and R9 are as defined above.

[0067] The present disclosure also provides

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075]

change

[0076]

change

[0077]

change

[0078]

change

[0079]

change

[0080]

change

[0081]

change

[0082]

change

[0083]

change

[0084]

change

[0085]

change

[0086]

change

[0087]

change

[0088]

change

[0089]

change

[0090]

change

[0091]

change

[0092]

change

[0093]

change

[0094]

change

[0095]

change

[0096]

change

[0097]

change

[0098]

change

[0099]

change

[0100]

change

[0101]

change

[0102]

change

[0103]

change

[0104]

change

[0105]

change

[0106]

change

[0107] [ka] The present invention provides a compound of the above formula selected from:

[0108] The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0109] The present disclosure also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a KRAS-G12C-associated disease.

[0110] In some embodiments of the present disclosure, the KRAS-G12C-associated disease is selected from non-small cell lung cancer, colon cancer, and pancreatic cancer.

[0111] Definitions and Descriptions Unless otherwise specified, the following terms and phrases used in this disclosure are intended to have the following meanings: A particular term or phrase should not be considered indefinite or unclear but should be interpreted according to its common meaning unless otherwise specified. Reference to a trade name is intended to refer to the corresponding commercial product or its active ingredient.

[0112] The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the bounds of sound medical common sense, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0113] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which is prepared from a compound having a specific substituent of the present disclosure and a relatively non-toxic acid or base. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure 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 a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from organic acids such as 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, and methanesulfonic acid. Also included are salts of organic acids such as amino acids (e.g., arginine) and glucuronic acid. Certain specific compounds of the present disclosure contain both basic and acidic functional groups, allowing the compounds to be converted into base or acid addition salts.

[0114] The pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound that contains an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of the compound with an appropriate stoichiometric amount of base or acid in water or an organic solvent, or a mixture thereof.

[0115] The compounds of the present disclosure may have specific geometric or stereoisomeric forms. All such compounds are contemplated in this disclosure, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and mixtures thereof, such as racemic mixtures and enantiomerically or diastereomerically enriched mixtures, all of which are encompassed within the scope of this disclosure. Substituents such as alkyl may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are encompassed within the scope of this disclosure.

[0116] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0117] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" result from the inability to freely rotate about single or double bonds of ring carbon atoms.

[0118] Unless otherwise specified, the term "diastereomer" refers to stereoisomers whose molecules have two or more centers of chirality and which are not mirror images of one another.

[0119] Unless otherwise specified, the absolute configuration of a stereocenter is indicated by a solid wedge bond.

[0120] [ka] and dashed wedge bonds

[0121] [ka] It is shown as follows.

[0122] The compounds of the present disclosure may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. When tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers, also known as prototropic tautomers, include interconversions via proton migration, such as keto-enol isomerism and imine-enamine isomerism. Valence tautomers include interconversions via recombination of some bond electrons. The interconversion between the tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one is a specific example of keto-enol tautomerism.

[0123] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), or C-14( 14 The compound may be labeled with a radioactive isotope such as CI (C). In another example, hydrogen can be replaced by deuterium to form a deuterated drug, where the bond formed by deuterium and carbon is stronger than the bond formed by typical hydrogen and carbon. Deuterated drugs have fewer toxic side effects, improved stability, enhanced efficacy, and a longer biological half-life than non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples where the event or circumstance occurs and examples where it does not occur.

[0124] The term "substituted" means that one or more hydrogen atoms on a specific atom are replaced with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specific atom is normal and the substituted compound is stable. When a substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Substitution with oxygen does not occur in aromatic groups. The term "optionally substituted" means that an atom may or may not be substituted with a substituent. Unless otherwise specified, the type and number of substituents may be arbitrary, as long as it is chemically achievable.

[0125] When any variable (e.g., R) occurs more than one time in a constitution or structure of a compound, that variable is defined independently at each occurrence. Thus, for example, if a group is substituted with 0 to 2 R, it may be optionally substituted with up to 2 R, and the definition of R at each occurrence is independent. Furthermore, combinations of substituents and / or variants thereof are permissible only if they result in stable compounds.

[0126] One of the variations, when selected from a single bond, means that the two groups are directly linked together. For example,

[0127] [ka] When L3 in represents a single bond, the structure is effectively

[0128] [ka] This means that

[0129] When a listed substituent is not specified by which atom it is attached to the group it replaces, the substituent can be attached through any atom of the group, e.g., pyridyl as a substituent can be attached to the group it replaces through any carbon atom on the pyridine ring.

[0130] If the direction of the bond for a listed linking group is not specified, then the direction of the bond is arbitrary. For example,

[0131] [ka] The bonding group L in

[0132] [ka] When

[0133] [ka] teeth,

[0134] [ka] or by joining the benzene ring and cyclohexane in the same direction as the left-to-right reading order to form

[0135] [ka] The benzene ring and cyclohexane can be linked in the opposite direction from the left-to-right reading order to form: Combinations of linking groups, substituents, and / or variants thereof are permissible only if they result in stable compounds.

[0136] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members in the ring. For example, a "5- to 7-membered ring" refers to a "ring" having 5 to 7 atoms in the ring.

[0137] Unless otherwise specified, "C 1-6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6, C 2-4 C includes alkyl, C, C, etc., and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-6 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, and the like.

[0138] Unless otherwise specified, "C 1-5 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 5 carbon atoms. 1-5 Alkyl is C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 , C5, etc., and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-5 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), and the like.

[0139] Unless otherwise specified, "C 1-4 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms. 1-4 Alkyl is C 1-2 , C 1-3 , C 2-3 and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-4Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), and the like.

[0140] Unless otherwise specified, "C 1-3 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 Alkyl is C 1-2 or C 2-3 C includes, but is not limited to, alkyl, such as alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl). 2-8 "Alkenyl" is used to refer to a straight or branched chain hydrocarbon group containing 2 to 8 carbon atoms and at least one carbon-carbon double bond, which may be located anywhere in the group. 2-8 Alkenyl is C 2-6 , C 2-4 , C 2-3 C2, C3, C2, etc. alkenyl and may be monovalent, divalent, or polyvalent. Examples of C2-8 alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, 1,3-pentadienyl, 1,3-hexadienyl, and the like.

[0141] Unless otherwise specified, "C 2-4 "Alkenyl" is used to refer to a straight or branched chain hydrocarbon group containing 2 to 4 carbon atoms and at least one carbon-carbon double bond, which may be located anywhere in the group. 2-4 Alkenyl is C 2-3 C includes alkenyl such as C, C, C, C, and may be monovalent, divalent, or polyvalent. 2-4Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like. 2-3 "Alkenyl" is used to refer to a straight or branched chain hydrocarbon group containing 2 to 3 carbon atoms and at least one carbon-carbon double bond, which may be located anywhere in the group. 2-3 Alkenyl includes C3 and C2 alkenyl and can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0142] Unless otherwise specified, "C 2-4 "Alkynyl" is used to refer to a straight or branched chain hydrocarbon group containing 2 to 4 carbon atoms and at least one carbon-carbon triple bond, which may be located anywhere in the group. 2-4 Alkynyl is C 2-3 alkynyl, such as C, C, C, C, etc. It may be monovalent, divalent, or polyvalent. 2-4 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0143] Unless otherwise specified, "C 2-3 "Alkynyl" is used to represent a straight or branched chain hydrocarbon group containing 2 to 3 carbon atoms and at least one carbon-carbon triple bond, which may be located anywhere in the group. It may be monovalent, divalent, or polyvalent. 2-3 Alkynyl includes C3 and C2 alkynyl. 2-3 Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

[0144] The term "heteroalkyl," by itself or in combination with other terms, refers to a stable straight or branched chain alkyl radical, or combination thereof, consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, heteroalkyl is selected from C 1-6 In other embodiments, heteroalkyl is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl, including the position at which the alkyl is attached to the remainder of the molecule. However, the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are commonly used expressions and refer to alkyl groups that are attached to the remainder of the molecule via an oxygen atom, an amino atom, or a sulfur atom, respectively. Examples of heteroalkyl include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CHN(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, and -CH-CH-S(=O)-CH. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

[0145] Unless otherwise specified, "C 1-6 The term "alkoxy" refers to alkyl groups, each containing 1 to 6 carbon atoms, attached 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 , C6, C5, C4, C3, etc. alkoxy. 1-6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, and the like.

[0146] Unless otherwise specified, "C 1-3 The term "alkoxy" refers to alkyl groups, each containing 1 to 3 carbon atoms, attached to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 C, C3, C2, etc. 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0147] Unless otherwise specified, "C 1-6 The term "alkylamino" refers to alkyl groups, each containing 1 to 6 carbon atoms, attached to the remainder of the molecule via an amino group. 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C2-6, C 2-4 , including alkylamino of C6, C5, C4, C3, C2, etc. 1-6 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0148] Unless otherwise specified, "C 1-3 The term "alkylamino" refers to alkyl groups each containing 1 to 3 carbon atoms and attached to the remainder of the molecule via an amino group. 1-3 Alkylamino is C 1-2 C, C3, C2, etc. alkylamino. 1-3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0149] Unless otherwise specified, "C 1-6 The term "alkylthio" refers to alkyl groups, each containing 1 to 6 carbon atoms, attached to the remainder of the molecule through a sulfur atom. 1-6 Alkylthio is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , including alkylthio of C6, C5, C4, C3, C2, etc. 1-6 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0150] Unless otherwise specified, "C 1-3 The term "alkylthio" refers to alkyl groups, each containing 1 to 3 carbon atoms, attached to the remainder of the molecule through a sulfur atom. 1-3 Alkylthio is C 1-3 , C 1-2 , C3, etc. 1-3 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0151] Unless otherwise specified, "C 3-6"Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems. 3-6 Cycloalkyl is C 3-5 Cycloalkyl, C 4-5 Cycloalkyl, C 5-6 C may be monovalent, divalent, or polyvalent, including cycloalkyl. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0152] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl," by itself or in combination with other terms, refers to a saturated cyclic group of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from the group consisting of O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidizable (i.e., NO and S(O)). p, where p is 1 or 2). This includes monocyclic or bicyclic systems, and bicyclic systems include spirocyclic, fused, and bridged rings. Additionally, for "3- to 6-membered heterocycloalkyl," a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, 6-membered, etc. heterocycloalkyl. Examples of 3- to 6-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

[0153] Unless otherwise specified, the "C" in this disclosure 6-10 Aromatic ring" and "C 6-10 "C" and "aryl" are used interchangeably. 6-10 Aromatic ring" or "C 6-10 The term "aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms and having a conjugated π-electron system. The group may be a monocyclic, fused bicyclic, or fused tricyclic system, and the rings are aromatic. It may be monovalent, divalent, or polyvalent, and may be C 6-10 Aryl is C 6-9 , C9, C 10 , C6, and other aryl groups. 6-10 Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).

[0154] Unless otherwise specified, in this disclosure, the terms "5- to 10-membered aromatic ring" and "5- to 10-membered aryl" are used interchangeably. The term "5- to 10-membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms and having a conjugated π-electron system, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from the group consisting of O, S, and N, while the others are carbon atoms. This may be a monocyclic, fused bicyclic, or fused tricyclic system, and the ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5- to 10-membered heteroaryl can be bonded to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl includes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, 6-membered, etc. heteroaryl groups.Examples of 5- to 10-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.). ), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl, 6-quinolyl, etc.).

[0155] Unless otherwise specified, in this disclosure, the terms "5- to 6-membered aromatic ring" and "5- to 6-membered aryl" are used interchangeably. The term "5- to 6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms and having a conjugated π-electron system, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from the group consisting of O, S, and N, while the others 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, where p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryl. Examples of 5- to 6-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.). and the like), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furanyl (including 2-furanyl, 3-furanyl, and the like), thienyl (including 2-thienyl, 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like).

[0156] Unless otherwise specified, "benzo 5-6 membered heterocycloalkyl" refers to a double fused ring structure formed by the combination of a phenyl, a heterocycle, and a 5-6 membered heterocycloalkyl, where a substituent can be attached to another structure through either the benzene ring or the 5-6 membered heterocycloalkyl ring. Examples of benzo 5-6 membered heterocycloalkyl include:

[0157] [ka] These include, but are not limited to:

[0158] Unless otherwise specified, "5-6-membered heteroaryl-fused 5-6-membered heterocycloalkyl" refers to a double fused ring structure formed by the combination of a 5-6-membered heteroaryl, a heterocycle, and a 5-6-membered heterocycloalkyl, in which a substituent can be attached to another structure through the 5-6-membered heteroaryl or the 5-6-membered heterocycloalkyl ring. Examples of benzo 5-6-membered heterocycloalkyl include:

[0159] [ka] These include, but are not limited to:

[0160] Unless otherwise specified, C n-n+m or C n-Cn+m includes any one of the specific cases of n to n+m carbon atoms. For example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 It may also include any range between n and 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 to n+m members indicate that the number of atoms in the ring is n to n+m. 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. n to n+m members further represent any range within n to n+m. 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.

[0161] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments described below, embodiments formed in combination with other chemical synthetic methods, and equivalents known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0162] The solvents used in this disclosure are commercially available. The following abbreviations are used in this disclosure: CDCL3 represents deuterated chloroform; CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; TBS represents tert-butyldimethylsilyl.

[0163] Compounds are named according to conventional naming conventions in the art or using ChemDraw® software, and supplier catalogs of commercially available compounds are given. [Example]

[0164] The present application is further illustrated by the following examples, which, however, should not be construed as unduly limiting the scope of the present application. Although the present application has been described in detail herein, it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments without departing from the spirit and scope of the present application.

[0165] Example 1: Preparation of Compound 1

[0166] Step 1: Preparation of Compound 1-2

[0167] [ka]

[0168] Diisopropylethylamine (1.34 g, 10.33 mmol, 1.80 mL) was dissolved in anhydrous tetrahydrofuran (50 mL). The resulting solution was cooled to -78 °C, and n-butyllithium (2.5 M, 47.78 mL) was added dropwise to it. After the addition was complete, the system was warmed to -30 °C and stirred for 10 minutes. The system was cooled to -78 °C, and a solution of compound 1-1 (10 g, 51.94 mmol) in tetrahydrofuran (50 mL) was added to it. The system was stirred at -78 °C for 4 hours. A solution of 1,2-dibromotetrachloroethane (33.82 g, 103.87 mmol) in tetrahydrofuran (50 mL) was added to the system. The system was stirred at -78 °C for 2 hours, then warmed to room temperature (20 °C), and stirred for 16 hours. The system was quenched with water (500 mL) and allowed to stand for separation. The aqueous phase was washed with methyl tert-butyl ether (3 × 30 mL) and acidified with a 2N aqueous solution of hydrochloric acid to pH = 2 (a precipitate appeared). The system was extracted with ethyl acetate (3 × 200 mL), and the organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethanol / ethyl acetate (v / v) = 0-10%) to give 1-2 in the form of a pale yellow gum.

[0169] Step 2: Preparation of Compounds 1-3

[0170] [ka]

[0171] Compound 1-2 (12 g, 44.21 mmol) was dissolved in anhydrous dichloromethane (150 mL), and to the resulting solution, oxalyl chloride (8.42 g, 66.31 mmol, 5.80 mL) and one drop of N,N-dimethylformamide were added dropwise successively at 0 °C. After the addition was complete, the system was stirred at 0 °C for 15 min, then warmed to room temperature (20 °C) and stirred for 2 h. The system was concentrated under reduced pressure to give crude 1-3, which was used in the next step without further purification.

[0172] Step 3: Preparation of Compounds 1-4

[0173] [ka]

[0174] Compound 1-3 (12.8 g, 44.15 mmol) was dissolved in anhydrous dioxane (100 mL), and a solution of ammonia in methanol (7 M, 31.54 mL) was added dropwise to the resulting solution at 0 °C. After the addition was complete, the system was stirred at room temperature (20 °C) for 2 h. The system was concentrated under reduced pressure, diluted with water (200 mL), and extracted with ethyl acetate (3 × 50 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 30%) to give 1-4 in the form of a pale yellow solid.

[0175] MS(ESI)m / z(M+H) + =269.9.

[0176] 1 H NMR(400MHz,DMSO-d6)8.14(s,1H),7.96(s,1H),7.83-7.80(m,1H).

[0177] Step 4: Preparation of Compounds 1-6

[0178] [ka]

[0179] Compound 1-4 (6 g, 22.18 mmol) was dissolved in anhydrous 1,2-dichloromethane (60 mL), and oxalyl chloride (3.94 g, 31.06 mmol) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was warmed to 80 °C and stirred for 1 h. The reaction system was concentrated to half its volume and cooled to 0 °C, and a solution of compound 1-5 (3.50 g, 23.29 mmol) in 1,2-dichloroethane (30 mL) was added dropwise to the reaction system. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The system was concentrated under reduced pressure. The crude product was dried under vacuum to give 1-6 in the form of a white solid, which was used in the next step without further purification.

[0180] Step 5: Preparation of Compounds 1-7

[0181] [ka]

[0182] Compound 1-6 (9 g, 20.15 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL). To the resulting solution, sodium bis(trimethylsilyl)amide (1 M, 40.30 mL) was added under a nitrogen atmosphere at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 1 h. The system was poured into water (500 mL) and extracted with ethyl acetate (3 × 150 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 30%) to give 1-7 as a pale white solid.

[0183] 1 H NMR(400MHz,DMSO-d6)8.58(d,J=5.2Hz,1H),7.34(d,J=4.8Hz,1H),6.40(d,J=6Hz,1H),2.86-2.80(m,1H),2.07(s,3H),1.05-0.98(m,6H)

[0184] Step 6: Preparation of Compounds 1-8

[0185] [ka]

[0186] Compound 1-7 (6 g, 14.06 mmol) was dissolved in acetonitrile (150 mL), and diisopropylethylamine (7.27 g, 56.25 mmol) and phosphorus oxychloride (8.62 g, 56.25 mmol) were added sequentially to the resulting solution. After the addition was complete, the system was warmed to 80 °C and stirred for 4 h. The system was quenched by pouring into ice water (250 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a brown crude product. The crude product was used in the next step without further purification.

[0187] Step 7: Preparation of Compounds 1-10

[0188] [ka]

[0189] Compound 1-9 (3 g, 13.87 mmol) was dissolved in dichloromethane (40 mL), and imidazole (1.42 g, 20.81 mmol) and tert-butyldimethylchlorosilane (2.30 g, 15.26 mmol) were added sequentially to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 16 h. The system was quenched with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give 1-10 as a colorless oil.

[0190] Step 8: Preparation of Compounds 1-11

[0191] [ka]

[0192] Compound 1-8 (5 g, 11.23 mmol) was dissolved in anhydrous 1,2-dichloromethane (50 mL). To the resulting solution, diisopropylethylamine (1.89 g, 14.60 mmol, 2.54 mL) and a solution of compound 1-10 (3.71 g, 11.23 mmol) in 1,2-dichloroethane (5 mL) were added sequentially at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 50 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (88% petroleum / ethyl acetate (v / v) = 0-75%) to give 1-11 as a pale yellow gum.

[0193] Step 9: Preparation of Compounds 1-12

[0194] [ka]

[0195] Compound 1-11 (6.5 g, 8.79 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and tetrabutylammonium fluoride (1 M, 10.55 mL) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 1 h. The system was concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 30-90%) to give 1-12 as a pale yellow solid.

[0196] 1H NMR(400MHz,DMSO-d6)8.84(s,1H),8.57-8.55(m,1H),7.25-7.33(m,1H),6.14-6.10(m,1H),4.24-4.21(m,2H) ),3.99-3.94(m,2H),2.76-2.71(m,5H),2.26-2.23(m,1H),2.04-2.01(m,3H),1.42(s,9H),1.11-1.04(m,6H)

[0197] Step 10: Preparation of Compounds 1-13

[0198] [ka]

[0199] Compound 1-12 (400 mg, 640.07 μmol) was dissolved in toluene (10 mL), and tris(dibenzylideneacetone)dipalladium (36.80 mg, 64.01 μmol), 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (74.07 mg, 128.01 μmol), and potassium phosphate (271.73 mg, 1.28 mmol) were added sequentially to the resulting solution. After the addition was completed, the system was heated to 100 °C and stirred under an argon atmosphere for 16 hours. The system was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (88% petroleum / ethyl acetate (v / v) = 75-100%) and preparative high-performance liquid chromatography (separation conditions: chromatographic column: YMC Triart C18 150 x 25 mm x 5 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 52%-82%) to give compound 1-13 (HPLC reaction time: 9.5 min), which was concentrated and lyophilized to give 1-13 in the form of a white solid.

[0200] MS(ESI)m / z(M+H) + =544.3.

[0201] Step 11: Preparation of Compounds 1-14

[0202] [ka]

[0203] Compound 1-14A (2 g, 11.77 mmol) was dissolved in methanol (3 mL), and potassium bifluoride (4.5 M in water, 8 mL) was added to the resulting solution, resulting in the appearance of a white precipitate. After the addition was complete, the cloudy system was stirred at room temperature (20 °C) for 2 hours. The system was filtered, and the filter cake was washed successively with water (2 × 5 mL) and acetonitrile (5 mL). The resulting crude product was dried under vacuum to give 1-14 in the form of a white solid.

[0204] Step 12: Preparation of Compounds 1-15

[0205] [ka]

[0206] Compound 1-13 (30 mg, 55.15 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL). To the resulting solution, compound 1-14 (51.18 mg, 220.58 μmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (5.26 mg, 11.03 μmol), tris(dibenzylideneacetone)dipalladium (3.17 mg, 5.51 μmol), and potassium carbonate (30.49 mg, 220.58 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to give 1-15 as a pale yellow solid.

[0207] MS(ESI)m / z(M+H) + =634.3.

[0208] Step 13: Preparation of Compounds 1-16

[0209] [ka]

[0210] Compound 1-15 (20 mg, 31.56 μmol) was dissolved in anhydrous dichloromethane (1 mL), and boron tribromide (0.5 M in dichloromethane, 378.74 μL) was added to the resulting solution at 0° C. After the addition was complete, the system was warmed to room temperature (20° C.) and stirred for 4 hours. Methanol (2 mL) was added to the system, and the resulting mixture was stirred for 10 minutes. The system was concentrated and lyophilized to give 1-16 as a pale yellow solid (hydrobromide salt).

[0211] MS(ESI)m / z(M+H) + =520.3.

[0212] Step 14: Preparation of Compound 1

[0213] [ka]

[0214] Compound 1-16 (8 mg, 13.32 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (1 mL) and saturated aqueous NaHCO3 (1 mL). To the resulting solution, acrylic anhydride (0.2 M, 99.92 μL) was added at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. Methanol (1 mL) and lithium hydroxide (0.2 M, 0.1 mL) were added to the system, which was stirred at room temperature (20 °C) for an additional 2 h. The system was concentrated, diluted with methanol (2 mL), and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC: chromatographic column: YMC Triart C18 150 × 25 mm × 5 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 29% to 59%) to obtain compound 1 (HPLC reaction time: 9.5 min).

[0215] MS(ESI)m / z(M+H) + =574.4.

[0216] 1 H NMR(400MHz,DMSO-d6)8.51(d,J=5.2Hz,1H),7.34(d,J=4.8Hz,1H),7.24-7.20(m,1H),6 .88-6.80(m,1H),6.68-6.60(m,2H),6.35-6.30(m,1H),6.06-6.01(m,1H),5.87-5.83(m ,1H),5.08-5.02(m,1H),4.73-4.61(m,3H),4.49-4.35(m,1H),4.25-4.15(m,2H),3.68- 3.46(m,2H),2.88-2.78(m,1H),2.11-2.07(m,3H),1.23-1.21(m,3H),1.21-1.07(m,3H).

[0217] 19 F NMR(376MHz,DMSO-d6)-115.93,-139.68.

[0218] Step 15: Decomposition of Compound 1 Isomers

[0219] [ka]

[0220] Diastereomeric compound 1 (16 mg, 27.89 μmol) was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); mobile phase: [Neu-ethanol]; ethanol %: 30% to 30%). After concentration, compound 1A (peak 1) and compound 1B (peak 2) were obtained.

[0221] Compound 1A

[0222] 1H NMR(400MHz,DMSO-d6)8.51(d,J=5.2Hz,1H),7.34(d,J=4.8Hz,1H),7.24-7.20(m,1H),6 .88-6.80(m,1H),6.68-6.60(m,2H),6.35-6.30(m,1H),6.06-6.01(m,1H),5.87-5.83(m ,1H),5.08-5.02(m,1H),4.73-4.61(m,3H),4.49-4.35(m,1H),4.25-4.15(m,2H),3.68- 3.46(m,2H),2.88-2.78(m,1H),2.11-2.07(m,3H),1.23-1.21(m,3H),1.21-1.07(m,3H)

[0223] 19 F NMR(376MHz,DMSO-d6)-115.93,-139.68.

[0224] HPLC reaction time: 6.443 min

[0225] Separation conditions: Chromatography column: Waters Xbridge C18 3.5 μm, 150 × 4.6 mm; column temperature: 40 °C; mobile phase: water (0.05% aqueous ammonia)-acetonitrile; acetonitrile: 0% to 95% for 10 min, 95% for 5 min; flow rate: 1.0 mL / min.

[0226] SFC reaction time: 3.436 min

[0227] Separation conditions: Chromatographic column: Chiralcel OJ-3 100 x 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: [Neu-isopropanol (0.05% DEA)], Isopropanol %: 5% to 40% 4 min, 40% 2.5 min, 5% 1.5 min; Flow rate: 2.8 mL / min. MS (ESI) m / z (M+H) + =574.4.

[0228] Compound 1B

[0229] 1H NMR(400MHz,DMS0-d6)8.51(d,J=5.2Hz,1H),7.34(d,J=4.8Hz,1H),7.24-7.20(m,1H),6 .88-6.80(m,1H),6.68-6.60(m,2H),6.35-6.30(m,1H),6.06-6.01(m,1H),5.87-5.83(m ,1H),5.08-5.02(m,1H),4.73-4.61(m,3H),4.49-4.35(m,1H),4.25-4.15(m,2H),3.68- 3.46(m,2H),2.88-2.78(m,1H),2.11-2.07(m,3H),1.23-1.21(m,3H),1.21-1.07(m,3H)

[0230] HPLC reaction time: 6.498 min

[0231] Separation conditions: Chromatography column: Waters Xbridge C18 3.5 μm, 150 × 4.6 mm; column temperature: 40 °C; mobile phase: water (0.05% aqueous ammonia)-acetonitrile; acetonitrile: 0% to 95% for 10 min, 95% for 5 min; flow rate: 1.0 mL / min.

[0232] SFC reaction time: 3.780 min

[0233] Separation conditions: Chromatographic column: Chiralcel OJ-3 100 x 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: [Neu-isopropanol (0.05% DEA)], Isopropanol %: 5% to 40% 4 min, 40% 2.5 min, 5% 1.5 min; Flow rate: 2.8 mL / min. MS (ESI) m / z (M+H) + =574.4.

[0234] Example 2: Preparation of Compound 2

[0235] Step 1: Preparation of Compound 2-2

[0236] [ka]

[0237] Compound 2-1 (2.4 g, 11.1 mmol) was dissolved in dichloromethane (30 mL), and imidazole (1.13 g, 16.65 mmol) and tert-butyldimethylchlorosilane (2.17 g, 14.43 mmol) were added sequentially to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 16 h. The system was quenched with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 2-2 as a colorless oil.

[0238] 1 H NMR(400MHz,CDC13)4.02-3.85(m,2H),3.65-3.55(m,1H),3.49-3.42(m,1H),3.03-2.97(m,1H), 2.82-2.75(m,1H),2.75-2.68(m,2H),2.55-2.45(m,1H),1.46(s,9H),0.90(s,9H),0.06(s,6H).

[0239] Step 2: Preparation of Compound 2-3

[0240] [ka]

[0241] Compound 1-8 (2 g, 4.49 mmol) was dissolved in anhydrous acetonitrile (20 mL), and diisopropylethylamine (4.65 g, 35.92 mmol, 6.26 mL) and a solution of compound 2-2 (1.48 g, 4.49 mmol) in acetonitrile (10 mL) were added sequentially to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (88% petroleum / ethyl acetate (v / v) = 0-75%) to give compound 2-3 as a pale yellow gum.

[0242] Step 3: Preparation of Compound 2-4

[0243] [ka]

[0244] Compound 2-3 (3.00 g, 4.06 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and tetrabutylammonium fluoride (1.17 g, 4.46 mmol) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 1 h. The system was concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 30-90%) to give compound 2-4 in the form of a pale yellow solid.

[0245] 1 H NMR(400MHz,DMSO-d6)8.84(s,1H),8.57-8.55(m,1H),7.25-7.33(m,1H),6.14-6.10(m,1H),4.24-4.21(m,2H) ),3.99-3.94(m,2H),2.76-2.71(m,4H),2.26-2.23(m,1H),2.04-2.01(m,3H),1.42(s,9H),1.11-1.04(m,6H)

[0246] Step 4: Preparation of Compound 2-5

[0247] [ka]

[0248] Compound 2-4 (400 mg, 640.07 μmol) was dissolved in toluene (10 mL), and tris(dibenzylideneacetone)dipalladium (36.80 mg, 64.01 μmol), 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (74.07 mg, 128.01 μmol), and potassium phosphate (271.73 mg, 1.28 mmol) were added sequentially to the resulting solution. After the addition was complete, the system was heated to 100 °C and stirred under an argon atmosphere for 16 hours. The system was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 75-100%) and preparative high-performance liquid chromatography (separation conditions: chromatographic column: YMC Triart C18 150 × 25 mm × 5 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 52%-82%) to give compound 1-13 (HPLC reaction time: 9.5 min), which was concentrated and lyophilized to give compound 2-5 in the form of a white solid.

[0249] MS(ESI)m / z(M+H) + =544.3.

[0250] Step 5: Preparation of Compounds 2-6

[0251] [ka]

[0252] Compound 2-5 (15 mg, 27.57 μmol) was dissolved in dioxane (0.5 mL) and water (0.1 mL). To the resulting solution, compound 1-14 (19.19 mg, 82.72 μmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (2.63 mg, 5.51 μmol), tris(dibenzylideneacetone)dipalladium (1.59 mg, 2.76 μmol), and potassium carbonate (11.43 mg, 82.73 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to give compound 2-6 as a pale yellow solid.

[0253] Step 6: Preparation of Compounds 2-7

[0254] [ka]

[0255] Compound 2-6 (15 mg, 23.67 μmol) was dissolved in anhydrous dichloromethane (1 mL), and boron tribromide (0.5 M in dichloromethane, 236.71 μL) was added to the resulting solution at 0° C. After the addition was complete, the system was warmed to room temperature (20° C.) and stirred for 4 hours. Methanol (2 mL) was added to the system, and the resulting mixture was stirred for 10 minutes. The system was concentrated and lyophilized to give compound 2-7 as a pale yellow solid (hydrobromide salt).

[0256] Step 7: Preparation of Compound 2

[0257] [ka]

[0258] Compound 2-7 (14 mg, 26.95 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (1 mL) and saturated aqueous sodium bicarbonate (1 mL). To the resulting solution, acrylic anhydride (0.2 M, 161.68 μL) was added at room temperature (20° C.). After the addition was complete, the system was stirred at room temperature (20° C.) for 1 hour. Methanol (1 mL) and lithium hydroxide (0.2 M, 0.1 mL) were added to the system, which was then stirred at room temperature (20° C.) for an additional 2 hours. The system was concentrated, diluted with methanol (2 mL), and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: YMC Triart C18 150 × 25 mm × 5 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 29% to 59% 9.5 min) to obtain compound 2.

[0259] 1 H NMR(400MHz,DMSO-d6)8.51(d,J=5.2Hz,1H),7.34(d,J=4.8Hz,1H),7.24-7.20(m,1H),6 .88-6.80(m,1H),6.68-6.60(m,2H),6.35-6.30(m,1H),6.06-6.01(m,1H),5.87-5.83(m ,1H),5.08-5.02(m,1H),4.73-4.61(m,3H),4.49-4.35(m,1H),4.25-4.15(m,2H),3.68- 3.46(m,2H),2.88-2.78(m,1H),2.11-2.07(m,3H),1.23-1.21(m,3H),1.21-1.07(m,3H)

[0260] MS(ESI)m / z(M+H) + =574.4.

[0261] Step 8: Preparation of Compounds 2A and 2B

[0262] [ka]

[0263] The diastereomeric compound 2 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 μm); mobile phase: [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 35%). After concentration, compound 2A (peak 1) and compound 2B (peak 2) were obtained.

[0264] Compound 2A:

[0265] 1 H NMR(400MHz,DMS0-d6)8.51(d,J=5.2Hz,1H),7.34(d,J=5.2Hz,1H),7.24-7.20 (m,1H),6.88-6.80(m,1H),6.68-6.60(m,2H),6.35-6.30(m,1H),6.06-6.01(m ,1H),5.87-5.83(m,1H),5.08-5.02(m,1H),4.73-4.31(m,4H),4.25-4.15(m,2 H),3.68-3.46(m,2H),2.88-2.78(m,1H),2.11-2.07(m,3H),1.23-1.05(m,6H)

[0266] 19 F NMR (376 MHz, methanol-d4) δ = -115.6 (s, 1F), -139.6 (s, 1F)

[0267] MS(ESI)m / z(M+H) + =574.4.

[0268] HPLC reaction time: 6.91 min

[0269] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0270] SFC reaction time: 1.657 min.

[0271] Separation conditions: Chromatographic column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0272] Compound 2B:

[0273] 1 H NMR(400MHz,DMSO-d6)8.40(d,J=5.2Hz,1H),7.22(d,J=5.2Hz,1H),7.14-7.07 (m,1H),6.80-6.75(m,1H),6.58-6.45(m,2H),6.25-6.15(m,1H),6.01-5.91(m ,1H),5.75-5.70(m,1H),4.98-4.92(m,1H),4.63-4.21(m,4H),4.15-4.05(m,2 H),3.60-3.37(m,2H),2.78-2.68(m,1H),2.01-1.95(m,3H),1.13-0.95(m,6H)

[0274] 19 F NMR (376 MHz, methanol-d4) δ = -115.7 (s, 1F), -139.6 (s, 1F)

[0275] MS(ESI)m / z(M+H) + =574.4.

[0276] HPLC reaction time: 6.91 min

[0277] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0278] SFC reaction time: 1.844 min.

[0279] Separation conditions: Chromatographic column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0280] Example 3: Preparation of Compound 3

[0281] Step 1: Preparation of Compound 3-2

[0282] [ka]

[0283] Diisopropylethylamine (861.66 mg, 6.67 mmol, 1.16 mL) was dissolved in anhydrous tetrahydrofuran (40 mL). The resulting solution was cooled to -78 °C, and n-butyllithium (2.5 M, 26.67 mL) was added dropwise to it. After the addition was complete, the system was warmed to -30 °C and stirred for 10 minutes. The system was cooled to -78 °C, and a solution of compound 3-1 (7 g, 33.33 mmol) in tetrahydrofuran (40 mL) was added to it. The system was stirred at -78 °C for 4 hours. A solution of 1,2-dibromotetrachloroethane (21.71 g, 66.67 mmol) in tetrahydrofuran (40 mL) was added to the system. The system was stirred at -78 °C for 2 hours, then warmed to room temperature (20 °C), and stirred for 16 hours. The system was quenched with water (200 mL) and allowed to stand for separation. The aqueous phase was washed with methyl tert-butyl ether (3 × 30 mL) and acidified with a 2N aqueous solution of hydrochloric acid to pH = 2 (a precipitate formed). The system was extracted with ethyl acetate (3 × 50 mL), and the organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was slurried with petroleum ether (20 mL) to give compound 3-2.

[0284] Step 2: Preparation of Compound 3-3

[0285] [ka]

[0286] Compound 3-2 (9 g, 31.15 mmol) was dissolved in anhydrous dichloromethane (80 mL), and to the resulting solution, oxalyl chloride (5.93 g, 46.73 mmol, 4.09 mL) and one drop of N,N-dimethylformamide were added dropwise successively at 0 °C. After the addition was complete, the system was stirred at 0 °C for 15 min, then warmed to room temperature (20 °C) and stirred for 2 h. The system was concentrated under reduced pressure to give compound 3-3, which was used in the next step without further purification.

[0287] Step 3: Preparation of Compound 3-4

[0288] [ka]

[0289] Compound 3-3 (9 g, 29.28 mmol) was dissolved in anhydrous dioxane (80 mL), and a solution of ammonia in methanol (7 M, 20 mL) was added dropwise to the resulting solution at 0 °C. After the addition was complete, the system was stirred at room temperature (20 °C) for 2 h. The system was concentrated, diluted with water (200 mL), and filtered. The filter cake was washed with water (2 × 10 mL) and dried under vacuum to give compound 3-4.

[0290] 1 H NMR(400MHz,DMSO-d6)δ=8.20(s,1H),8.14(s,1H)

[0291] Step 4: Preparation of Compounds 3-5

[0292] [ka]

[0293] Compound 3-4 (7.5 g, 26.05 mmol) was dissolved in anhydrous 1,2-dichloromethane (80 mL), and oxalyl chloride (4.63 g, 36.47 mmol) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was warmed to 80 °C and stirred for 1 h. The reaction system was concentrated to half its volume and cooled to 0 °C, and a solution of compound 1-5 (4.11 g, 27.35 mmol) in 1,2-dichloroethane (20 mL) was added dropwise to the reaction system. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The system was concentrated under reduced pressure. The crude product was dried under vacuum to give compound 3-5, which was used in the next step without further purification.

[0294] MS(ESI)m / z(M+H) + =465.0.

[0295] Step 5: Preparation of Compounds 3-6

[0296] [ka]

[0297] Compound 3-5 (12 g, 20.68 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and potassium bis(trimethylsilyl)amide (1 M, 45.51 mL) was added to the resulting solution under a nitrogen atmosphere at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 1 h. The system was poured into water (300 mL) and extracted with ethyl acetate (3 × 150 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 70%) to give compound 3-6.

[0298] 1 H NMR(400MHz,DMSO-d6)δ=12.42(br,1H),8.53(d,J=4.8,1H),7.27(d,J=4.8,1H),3.11-3.04(m,1H),2.13(s,3H),1.09-1.03(m,6H)

[0299] MS(ESI)m / z(M+H) + =383.0.

[0300] Step 6: Preparation of Compounds 3-7

[0301] [ka]

[0302] Compound 3-6 (1.5 g, 3.91 mmol) was dissolved in methanol (35 mL), and sodium methoxide (465.23 mg, 8.61 mmol) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was warmed to 60 °C and stirred for 16 h. The system was concentrated under reduced pressure to give crude 3-7, which was used in the next step without further purification.

[0303] MS(ESI)m / z(M+H) + =379.0.

[0304] Step 7: Preparation of Compounds 3-9

[0305] [ka]

[0306] Compound 3-7 (2.33 g, 10.77 mmol) was dissolved in tetrahydrofuran (80 mL), and sodium hydride (718.02 mg, 17.95 mmol, 60% purity) was added to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 20 minutes, and compound 3-8 (3.4 g, 8.98 mmol) was added. After the addition was complete, the system was warmed to 60 °C and stirred for 2 hours. The system was quenched with a saturated aqueous solution of ammonium chloride (2 mL) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 3-9.

[0307] MS(ESI)m / z(M+H) + =559.2.

[0308] Step 8: Preparation of Compounds 3-10

[0309] [ka]

[0310] Compound 3-9 (0.9 g, 1.61 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.68 g, 3.22 mmol) were dissolved in acetonitrile (10 mL). To the resulting solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.23 g, 8.06 mmol, 1.21 mL) was added dropwise at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 0-100%) to give compounds 3-10.

[0311] 1 H NMR(400MHz,DMSO-d6)δ=8.44(d,J=4.8Hz,1H),7.28-7.13(m,1H),4.72-4.53(m,3H),4.04(br s,2H),3.88(s,4H),3.18(br s,3H),2.92-2.81(m,1H),2.02(d,J=4.9Hz,3H),1.45(s,9H),1.16-0.99(m,6H)

[0312] MS(ESI)m / z(M+H) + =541.3.

[0313] Step 9: Preparation of Compounds 3-11

[0314] [ka]

[0315] Compound 3-10 (350 mg, 647.45 μmol) was dissolved in anhydrous dichloromethane (2 mL), and boron tribromide (1.62 g, 6.47 mmol) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 16 hours. Methanol (10 mL) was added to the system, and the resulting mixture was stirred for 10 minutes. The system was concentrated and lyophilized to give compound 3-11.

[0316] Step 10: Preparation of Compound 3-12

[0317] [ka]

[0318] Compound 3-11 (270 mg, 506.52 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and saturated sodium bicarbonate (2 mL). To the resulting solution, CbzCl (0.5 M, 1.52 mL) was added at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 4 hours. Methanol (2 mL) and an aqueous solution of lithium hydroxide (2 N, 0.2 mL) were added to the system. After the addition was complete, the system was stirred at room temperature for 1 hour. The system was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound 3-12.

[0319] 1 H NMR(400MHz,DMSO-d6)δ=8.38(d,J=4.6Hz,1H),7.44-7.27(m,5H),7.20-7.12(m,1H),5.21-5.09(m,2H),4.70- 4.46(m,3H),4.09-3.85(m,3H),3.57-3.54(m,3H),2.91-2.81(m,1H),2.02(d,J=6.4Hz,3H),1.11-1.01(m,6H).

[0320] Step 11: Preparation of Compound 3-13

[0321] [ka]

[0322] Compound 3-12 (250 mg, 445.97 μmol) was dissolved in acetonitrile (5 mL), and diisopropylethylamine (230.55 mg, 1.78 mmol) and phosphorus oxychloride (2.05 g, 13.38 mmol) were added sequentially to the resulting solution. After the addition was complete, the system was warmed to 80 °C and stirred for 2 h. The system was cooled to room temperature and concentrated. The residue was quenched by pouring it into ice water (10 mL). The resulting mixture was adjusted to neutral pH with saturated sodium bicarbonate and extracted with ethyl acetate (3 × 10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 3-13.

[0323] MS(ESI)m / z(M+H) + =579.3.

[0324] Step 12: Preparation of Compounds 3-14

[0325] [ka]

[0326] Compound 3-13 (60 mg, 103.62 μmol) was dissolved in dioxane (0.8 mL) and water (0.2 mL). To the resulting solution, compound 1-14 (72.13 mg, 310.87 μmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (9.88 mg, 20.72 μmol), tris(dibenzylideneacetone)dipalladium (9.49 mg, 10.36 μmol), and potassium carbonate (42.97 mg, 310.87 μmol) were added sequentially. After the addition was complete, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 3-14.

[0327] MS(ESI)m / z(M+H) + =669.2.

[0328] Step 13: Preparation of Compounds 3-15

[0329] [ka]

[0330] Compound 3-14 (18 mg, 26.92 μmol) was dissolved in anhydrous dichloromethane (1 mL), and boron tribromide (1 M in dichloromethane, 269.18 μL) was added to the resulting solution at 0° C. After the addition was complete, the system was warmed to room temperature (20° C.) and stirred for 4 hours. Methanol (2 mL) was added to the system, and the resulting mixture was stirred for 10 minutes. The system was concentrated and lyophilized to give compound 3-15 (HBr salt).

[0331] MS(ESI)m / z(M+H) + =521.1.

[0332] Step 14: Preparation of Compound 3

[0333] [ka]

[0334] Compound 1-16 (13.85 mg, 21.28 μmol, HBr salt) was dissolved in tetrahydrofuran (1 mL) and saturated aqueous sodium bicarbonate (1 mL). To the resulting solution, acrylic anhydride (0.2 M, 161.68 μL) was added at room temperature (20° C.). After the addition was complete, the system was stirred at room temperature (20° C.) for 1 hour. Methanol (1 mL) and lithium hydroxide (0.2 M, 0.1 mL) were added to the system, which was then stirred at room temperature (20° C.) for an additional 2 hours. The system was concentrated, diluted with methanol (2 mL), and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 10% to 80%, 9.5 min) to give compound 3 in the form of a white solid.

[0335] 1 H NMR (400MHz, methanol-d4) δ=8.44(d,J=5.0Hz,1H),7.32-7.21(m,2H),6.95-6.79(m,1H),6.73-6.61(m,2H),6.32(dd,J=1.7,16.7Hz,1H),5.85( dd,J=1.7,10.7Hz,1H),4.86-4.66(m,3H),4.60-4.14(m,3H),3.79-3. 37(m,3H),2.99(qd,J=6.5,13.1Hz,1H),2.19(s,3H),1.26-1.13(m,6H)

[0336] 19 F NMR (376 MHz, methanol-d4) δ = -116.81 (s, 1F), -137.44 - -140.32 (m, 1F)

[0337] MS(ESI)m / z(M+H) + =575.5.

[0338] Example 4: Preparation of Compound 4

[0339] Step 1: Preparation of Compound 4-1

[0340] [ka]

[0341] Compound 2-4 (750 mg, 1.20 mmol) was dissolved in acetonitrile (20 mL), and to the resulting solution were added (2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (150 mg, 175.56 μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (75.00 mg, 154.74 μmol), and cesium carbonate (825 mg, 2.53 mmol) in succession. After the addition was complete, the system was heated to 80 °C and stirred under an argon atmosphere for 16 hours. The system was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=70% to methanol / dichloromethane (v / v)=30%) to obtain compound 4-1.

[0342] 1 H NMR (400MHz, methanol-d4) δ8.57(d,J=4.9Hz,1H),7.38(d,J=5.1Hz,1H),6.12(d,J=6.0Hz,1H),4.97(br d,J=10.8Hz,1H),4.78-4.55(m,2H),4.22-3.96(m,3H),3.48-3.35(m,3H),2.88-2.64(m,1 H),2.08(d,J=4.4Hz,3H),1.51(s,9H),1.18(dd,J=4.1,6.7Hz,3H),1.10(d,J=6.8Hz,3H).

[0343] MS(ESI)m / z(M+H) + =544.2.

[0344] Step 2: Preparation of Compound 4-3

[0345] [ka]

[0346] Compound 4-1 (60 mg, 110.29 μmol) was dissolved in dioxane (2.5 mL) and water (0.5 mL). To the resulting solution, compound 4-2 (60.00 mg, 319.26 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (12 mg, 25.17 μmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (12 mg, 14.18 μmol), and potassium carbonate (60 mg, 434.12 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an argon atmosphere for 16 hours. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to obtain compound 4-3.

[0347] 1 H NMR (400MHz, methanol-d4) δ8.59-8.46(m,1H),7.44-7.20(m,2H),6.83(d,J=8.6Hz,1H),6.10-5.90(m,1H),5.03(br d,J=12.8Hz,1H),4.75-4.58(m,2H),4.25-4.02(m,3H),3.78-3.61(m,3H),3.54-3.33(m,3H) ),2.91-2.72(m,1H),2.11-2.02(m,3H),1.52(s,9H),1.25-1.18(m,3H),1.13-1.00(m,3H).

[0348] MS(ESI)m / z(M+H) + =652.4.

[0349] Step 3: Preparation of Compound 4-4

[0350] [ka]

[0351] Compound 4-3 (65 mg, 99.74 μmol) was dissolved in anhydrous dichloromethane (1.5 mL), and boron tribromide (1 M, 598.46 μL) was added to the resulting solution at 0° C. After the addition was complete, the system was warmed to room temperature (20° C.) and stirred for 2 hours. Methanol (2 mL) was added to the system, and the resulting mixture was stirred for 10 minutes. The system was concentrated and lyophilized to give compound 4-4 (hydrobromide salt).

[0352] MS(ESI)m / z(M+H) + =538.3.

[0353] Step 4: Preparation of Compound 4

[0354] [ka]

[0355] Compound 4-4 (80 mg, 129.36 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (5 mL) and saturated aqueous sodium bicarbonate (3 mL). To the resulting solution, acrylic anhydride (20 mg, 158.59 μmol) was added at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 2 hours. Methanol (3 mL) and lithium hydroxide (20 mg, 476.60 μmol) were added to the system, which was then stirred at room temperature (20 °C) for another 2 hours. The system was adjusted to a neutral pH with 1 N HCl and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 10% to 80% 9.5 min; flow rate: 30 mL / min) to obtain compound 4.

[0356] 1 H NMR (400 MHz, methanol-d4) δ 8.51 (d, J = 5.0 Hz, 1H), 7.33 (d, J = 5.3 Hz, 1H), 7.16-7.09 (m, 1H), 6.94-6.82 (br s, 1H), 6.62 (br s, 1H), 6.31 (d, J = 15.3 Hz, 1H), 6.09-6.03 (br s,1H),5.84(d,J=12.3Hz,1H),5.08-4.99(m,1H),4.76-4.68(m,2H),4.61(s,1H),4.51-4.31(m,1 H),4.27-4.18(m,1H),3.80-3.40(m,3H),2.90-2.80(m,1H),2.14-1.99(m,3H),1.27-1.00(m,6H).

[0357] MS(ESI)m / z(M+H) + =592.3.

[0358] Step 5: Preparation of Compounds 4A and 4B

[0359] [ka]

[0360] Diastereomeric compound 4 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 30% to 30%; flow rate: 70 mL / min). After concentration, compound 4A (peak 1) and compound 4B (peak 2) were obtained.

[0361] Compound 4A

[0362] 1H NMR (400MHz, methanol-d4) δ8.48(d,J=4.9Hz,1H),7.30(d,J=4.9Hz,1H),7.13-7.16(m,1H),6.94-6.77(m,1H),6.59(br s,1H),6.28(dd,J=1.8,16.8Hz,1H),6.03(br s,1H),5.81(dd,J=1.8,10.6Hz,1H),4.99(br s,1H),4.74-4.66(m,2H),4.58(s,1H),4.45-4.28(m,1H),4.23-4.15(m,1H),3.74-3.37(m,3H),2.88-2.78(m,1H),2.05(br d,J=8.8Hz,3H),1.18-1.01(m,6H).

[0363] MS(ESI)m / z(M+H) + =592.2.

[0364] HPLC reaction time: 3.26 min

[0365] Separation conditions: Chromatography column: Ultimate C18 3.0 × 50 mm, 3 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 1.2 mL / min.

[0366] SFC reaction time: 1.577 min.

[0367] Separation conditions: Chromatographic column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0368] Compound 4B

[0369] 1H NMR (400MHz, methanol-d4) δ8.50(d,J=4.9Hz,1H),7.45-7.26(m,1H),7.21-7.04(m,1H),6.91-6.81(m,1H),6.60(br s,1H),6.30(dd,J=1.9,16.6Hz,1H),6.05(br s,1H),5.91-5.74(m,1H),5.07-4.99(m,1H),4.80-4.66(m,2H),4.60(s,1H),4.51-4.31(m,1H),4.23(br s,1H),3.70-3.62(m,1H),3.58-3.44(m,1H),3.42-3.35(m,1H),2.87-2.77(m,1H),2.19-2.01(m,3H),1.25-1.00(m,6H).

[0370] MS(ESI)m / z(M+H) + =592.3.

[0371] HPLC reaction time: 3.26 min

[0372] Separation conditions: Chromatography column: Ultimate C18 3.0 × 50 mm, 3 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 1.2 mL / min.

[0373] SFC reaction time: 1.761 min

[0374] Separation conditions: Chromatographic column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0375] Example 5: Preparation of Compound 5

[0376] Step 1: Preparation of Compound 5

[0377] [ka]

[0378] Compound 2-7 (100 mg, 157.84 μmol) and 2-fluoroacrylic acid (50 mg, 555.23 μmol) were dissolved in dimethylformamide (4 mL). To the resulting solution, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (240 mg, 631.20 μmol) and N,N-diisopropylethylamine (222.60 mg, 1.72 mmol, 0.3 mL) were added at room temperature (20 °C). After the addition was completed, the system was stirred at room temperature (20 °C) for 1 h. Water (30 mL) was added to the system, which was then extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was dissolved in methanol (5 mL), and potassium carbonate (2 M, 1 mL) was added to the resulting solution. After the addition was complete, the system was stirred at room temperature (20 °C) for 30 minutes. Water (30 mL) was added to the system, which was then neutralized with 1N HCl and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 38% to 68% 9.5 min; flow rate: 30 mL / min) to obtain compound 5.

[0379] 1H NMR (400MHz, methanol-d4) δ8.50(d,J=5.1Hz,1H),7.33(br d,J=3.5Hz,1H),7.20(br d,J=7.5Hz,1H),6.70-6.56(m,2H),6.04(br s,1H),5.42-5.26(m,2H),5.06(br d,J=13.5Hz,1H),4.80-4.61(m,2H),4.58-4.35(m,1H),4.31-4.13(m,2H),3.87-3.60(m,1H),3.60-3.42(m,2H),2.83(br s,1H),2.09(br d,J=11.9Hz,3H),1.28-1.00(m,6H).

[0380] MS(ESI)m / z(M+H) + =592.4.

[0381] Step 2: Preparation of Compounds 5A and 5B

[0382] [ka]

[0383] Diastereomeric compound 4 was purified by SFC (separation conditions: chromatographic column: Phenomenex Lux Cellulose-4 250 × 30 mm × 5 μm; mobile phase: [Neu-ethanol (0.1% aqueous ammonia)]; ethanol %: 40% to 40%, flow rate: 60 mL / min). After concentration, compound 5A (peak 1) and compound 5B (peak 2) were obtained.

[0384] Compound 5A

[0385] 1H NMR (400MHz, methanol-d4) δ8.48(d,J=4.9Hz,1H),7.31(d,J=4.9Hz,1H),7.21-7 .15(m,1H),6.71-6.52(m,2H),6.11-5.92(m,1H),5.44-5.22(m,2H),5.05(br d,J=12.1Hz,1H),4.75-4.62(m,2H),4.58-4.11(m,3H),3.71-3.37(m,3H),3.03-2.70(m,1H),2.07(br d,J=13.7Hz,3H),1.24-0.96(m,6H).

[0386] MS(ESI)m / z(M+H) + =592.2.

[0387] HPLC reaction time: 3.26 min

[0388] Separation conditions: Chromatography column: Ultimate C18 3.0 × 50 mm, 3 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 1.2 mL / min.

[0389] SFC reaction time: 1.449 min

[0390] Separation conditions: Chromatographic column: Cellulose-4 100 x 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: [Neu-ethanol (0.05% DEA)]; Ethanol%: 40%; Flow rate: 28 mL / min.

[0391] Compound 5B

[0392] 1H NMR (400MHz, methanol-d4) δ8.50(d,J=5.1Hz,1H),7.32(d,J=4.9Hz,1H),7.26-7 .13(m,1H),6.75-6.55(m,2H),6.12-5.95(m,1H),5.51-5.21(m,2H),5.06(br d,J=11.5Hz,1H),4.78-4.65(m,2H),4.55-4.13(m,3H),3.78-3.39(m,3H),2.92-2.73(m,1H),2.09(br d,J=12.8Hz,3H),1.24-1.01(m,6H).

[0393] MS(ESI)m / z(M+H) + =592.2.

[0394] HPLC purity 96.11%; reaction time 3.25 min

[0395] Separation conditions: Chromatography: Ultimate C18 3.0 × 50 mm, 3 μm; Column temperature: 40 °C; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% for 6 min, 80% for 2 min; Flow rate: 1.2 mL / min.

[0396] SFC 99.10% ee. Reaction time 1.912 min.

[0397] Separation conditions: Chromatographic column: Cellulose-4 100 x 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: [Neu-ethanol (0.05% DEA)]; Ethanol%: 40%; Flow rate: 28 mL / min.

[0398] Example 6: Preparation of Compound 6

[0399] Step 1: Preparation of Compound 6-2

[0400] [ka]

[0401] Compound 4-1 (80 mg, 147.05 μmol) was dissolved in dioxane (4 mL) and water (0.8 mL). To the resulting solution, compound 6-1 (74.79 mg, 424.99 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (15.98 mg, 33.53 μmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (16.06 mg, 18.97 μmol), and potassium carbonate (80.08 mg, 579.39 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to obtain compound 6-2.

[0402] 1 H NMR (400MHz, methanol-d4) δ8.42(d,J=5.0Hz,1H),7.49-7.41(m,2H),7.32-7.26(m,2H),5.94(d,J=5.5Hz,1H),5.06(br d,J=9.8Hz,1H),4.79-4.64(m,2H),4.29-4.01(m,3H),3.53-3.32(m,3H) ),2.98-2.75(m,1H),2.20-2.10(m,6H),1.52(m,9H),1.29-1.13(m,6H). MS(ESI)m / z(M+H) + =640.1.

[0403] Step 2: Preparation of Compound 6-3

[0404] [ka]

[0405] Compound 6-2 (70 mg, 109.42 μmol) was dissolved in anhydrous dichloromethane (2.5 mL), and trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 3 h. The system was concentrated to give compound 6-3 (trifluoroacetic acid salt), which was used in the next step without further purification.

[0406] MS(ESI)m / z(M+H) + =5403.

[0407] Step 3: Preparation of Compound 6

[0408] [ka]

[0409] Compound 6-3 (71 mg, 108.62 μmol, trifluoroacetate salt) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (2 mL), and acrylic anhydride (13.70 mg, 108.62 μmol) was added to the resulting solution at room temperature (20 °C). After the addition was completed, the system was stirred at room temperature (20 °C) for 30 minutes. The system was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 21% to 51% in 9.5 min; flow rate: 60 mL / min) to obtain compound 6.

[0410] 1H NMR (400MHz, methanol-d4) δ8.43(d,J=5.1Hz,1H),7.54-7.41(m,2H),7.37-7.26(m,2H),6.95-6.79(m,1H),6.31(br d,J=16.5Hz,1H),5.95(d,J=5.7Hz,1H),5.84(br d,J=10.8Hz,1H),5.05(br s,1H),4.77(br s,1H),4.60(br s,2H),4.51-4.15(m,2H),3.85-3.42(m,3H),3.00-2.77(m,1H),2.20-2.05(m,6H),1.23-1.16(m,3H),1.12-0.97(m,3H).

[0411] MS(ESI)m / z(M+H) + =594.4.

[0412] Step 4: Preparation of Compounds 6A and 6B

[0413] [ka]

[0414] Diastereomeric compound 6 was purified by SFC (separation conditions: chromatographic column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm, 5 μm); mobile phase: [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 50%-50%; flow rate: 80 mL / min). After concentration, compound 6A (peak 1) and compound 6B (peak 2) were obtained.

[0415] Compound 6A

[0416] 1H NMR (400MHz, methanol-d4) δ8.42(d,J=4.9Hz,1H),7.53-7.39(m,2H),7.35-7.22(m,2H),6.85(dd,J=10.1,16.8Hz,1H),6.31(br d,J=15.2Hz,1H),5.95(br d,J=5.3Hz,1H),5.84(br d,J=11.2Hz,1H),5.03(br d,J=10.4Hz,1H),4.77(br s,1H),4.65-4.56(m,1H),4.50-4.16(m,3H),3.81-3.45(m,3H),3.00-2.82(m,1H),2.35-1.95(m,6H),1.19(br t,J=7.4Hz,3H),1.14-0.97(m,3H).

[0417] MS(ESI)m / z(M+H) + =594.3.

[0418] HPLC reaction time: 6.73 min

[0419] Separation conditions: Chromatography column: Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0420] SFC reaction time: 5.039 min

[0421] Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol%: 40% ~ 40%; flow rate: 2.8 mL / min.

[0422] Compound 6B

[0423] 1H NMR (400MHz, methanol-d4) δ8.42(br d,J=2.2Hz,1H),7.47(br dd,J=8.9,16.2Hz,2H),7.36-7.23(m,2H),6.95-6.80(m,1H),6.31(br d,J=16.3Hz,1H),5.94(br d,J=5.3Hz,1H),5.84(br d,J=10.1Hz,1H),5.06(br d,J=12.6Hz,1H),4.77(br s,1H),4.61(br s,1H),4.55-4.16(m,3H),3.76-3.37(m,3H),2.97-2.75(m,1H),2.25-2.04(m,6H),1.20(t,J=7.3Hz,3H),1.12-0.97(m,3H).

[0424] MS(ESI)m / z(M+H) + =594.3.

[0425] HPLC reaction time: 6.75 min

[0426] Separation conditions: Chromatography column: Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0427] SFC reaction time: 7.271 min

[0428] Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol%: 40% ~ 40%; flow rate: 2.8 mL / min.

[0429] Example 7: Preparation of Compound 7

[0430] Step 1: Preparation of Compound 7-1

[0431] [ka]

[0432] Compound 3-4 (1.60 g, 5.55 mmol) was dissolved in dioxane (1.20 mL), and a solution of sodium thiomethoxide in N,N-dimethylformamide (20%, 2.30 g) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 2 h. The system was quenched with water (8 mL) and extracted with ethyl acetate (6 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 7-1, which was used in the next step without further purification.

[0433] MS(ESI)m / z(M+H) + =255.0.

[0434] Step 2: Preparation of Compound 7-2

[0435] [ka]

[0436] Compound 7-1 (1.00 g, 0.39 mmol) was dissolved in 1,2-dichloroethane (10 mL), and oxalyl chloride (1.00 g, 0.78 mmol) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was warmed to 80 °C and stirred for 1 h. The system was concentrated. The residue was dissolved in tetrahydrofuran (10 mL), and compound 1-5 (0.75 g, 5 mmol) was added dropwise to the resulting solution at 0 °C. After the addition was complete, the system was stirred for 1 h at room temperature (20 °C). The system was filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 30%) to obtain compound 7-2.

[0437] MS(ESI)m / z(M+H) + =431.0.

[0438] Step 3: Preparation of Compound 7-3

[0439] [ka]

[0440] Compound 7-2 (500 mg, 1.16 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under a nitrogen atmosphere, and a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2 N, 1.2 mL) was added dropwise to the resulting solution at 0 °C. After the addition was complete, the system was cooled to 0 °C and stirred for 1 h. The system was quenched with water (10 mL), adjusted to pH 5.0 with dilute hydrochloric acid (3 N), and extracted with ethyl acetate (5 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to give compound 7-3.

[0441] MS(ESI)m / z(M+H) + =395.0.

[0442] Step 4: Preparation of Compound 7-4

[0443] [ka]

[0444] Compound 7-3 (260 mg, 0.66 mmol) and m-chloroperoxybenzoic acid (300 mg, 1.74 mmol) were dissolved in dichloromethane (4 mL). The mixture was stirred at room temperature (20 °C) for 15 minutes, then warmed to 50 °C and stirred for 15 minutes. The mixture was cooled to room temperature and concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (dichloromethane / methanol (v / v) = 0-10%) to give compound 7-4.

[0445] MS(ESI)m / z(M+H)+ =427.0.

[0446] Step 5: Preparation of Compound 7-5

[0447] [ka]

[0448] Compound 2-1 (137 mg, 0.64 mmol) and sodium hydride (51.2 mg, 60%, 1.28 mmol) were dissolved in tetrahydrofuran (3.0 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature (20 °C) for 5 min. Compound 7-4 (210 mg, 0.49 mmol) was added to the mixture, which was then stirred at room temperature (20 °C) for 1 h. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 7-5.

[0449] MS(ESI)m / z(M+H) + =563.0.

[0450] Step 6: Preparation of Compound 7-6

[0451] [ka]

[0452] Compound 7-5 (75 mg, 0.133 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (124 mg, 0.267 mmol) were dissolved in acetonitrile (2 mL). 1,8-diazabicycloundec-7-ene (81.0 mg, 0.534 mmol) was added dropwise to the resulting solution at room temperature (20 °C). The mixture was stirred at room temperature (20 °C) for 18 h. The mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 7-6.

[0453] MS(ESI)m / z(M+H) + =545.0.

[0454] Step 7: Preparation of Compound 7-8

[0455] [ka]

[0456] Compound 7-7 (2.87 g, 15 mmol) was dissolved in anhydrous N,N-dimethylacetamide (10 mL), and sodium hydride (60%, 660 mg, 16.5 mol) was added to the resulting solution in multiple batches at 0 °C. After the addition was complete, the system was warmed to room temperature and stirred for 10 minutes. Chloromethyl methyl ether (2.4 g, 30 mmol) was added dropwise to the system. After the addition was complete, the system was stirred at room temperature for 10 minutes. The system was quenched by pouring into ice water (50 mL) and extracted with methyl tert-butyl ether (3 × 50 mL). The organic phases were pooled, washed once with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to give compound 7-8.

[0457] 1HNMR (400MHz, CDCl3-d1) 7.24-7.18 (m, 1H), 6.95-6.93 (m, 1H), 6.83-6.79 (m, 1H), 5.26 (s, 2H), 3.52 (s, 3H).

[0458] Step 8: Preparation of Compounds 7-9

[0459] [ka]

[0460] Compound 7-8 (650 mg, 2.77 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and n-butyllithium (2.5 N, 1.22 mL, 3.05 mmol) was added dropwise to the resulting solution at −78°C. The system was stirred at −78°C for 30 minutes, followed by the dropwise addition of isopropyl pinacol boronate (567 mg, 3.05 mmol). The system was stirred at −78°C for 30 minutes. The system was warmed to room temperature, quenched with water, and extracted with ethyl acetate (10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give compound 7-9.

[0461] Step 9: Preparation of Compounds 7-10

[0462] [ka]

[0463] Compound 7-6 (35 mg, 0.064 mmol), compound 7-9 (36.3 mg, 0.128 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.7 mg, 0.0064 mmol), and potassium carbonate (26.0 mg, 0.192 mmol) were dissolved in a tetrahydrofuran / water mixture (2 mL, v / v 10:1) under a nitrogen atmosphere. The mixture was heated to 80 °C and stirred for 2 h. The mixture was cooled to room temperature, quenched with water (1 mL), and extracted with ethyl acetate (1 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 7-10.

[0464] MS(ESI)m / z(M+H) + =665.0.

[0465] Step 10: Preparation of Compounds 7-11

[0466] [ka]

[0467] Compound 7-10 (20 mg, 0.03 mmol) was dissolved in a 6N mixture of methanol and hydrochloric acid (2 mL, v / v = 1:1). The mixture was heated to 55 °C and stirred for 15 min. The mixture was cooled to room temperature and concentrated to give crude compound 7-11, which was used in the next step without further purification.

[0468] MS(ESI)m / z(M+H) + =521.0.

[0469] Step 9: Preparation of Compound 7

[0470] [ka]

[0471] Compounds 7-11 were dissolved in dichloromethane (1 mL), and triethylamine (9.0 mg) and acryloyl chloride (4.0 mg) were added sequentially to the resulting solution at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched with water (1 mL) and extracted with dichloromethane (1 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 21% to 51% 9.5 min; flow rate: 60 mL / min) to obtain compound 7.

[0472] MS(ESI)m / z(M+H) + =575.0.

[0473] Step 10: Preparation of Compounds 7A and 7B

[0474] [ka]

[0475] Diastereomeric compound 7 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); mobile phase: [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 40% to 40%). After concentration, compound 7A (peak 1) and compound 7B (peak B) were obtained.

[0476] Compound 7A:

[0477] 1H NMR (400MHz, methanol-d4)δ=8.44(d,J=5.0Hz,1H),7.34-7.20(m,2H),6.88-6.82(m,1H),6.72-6.60(m,2H),6.32(dd,J=1.9,16.7Hz,1H), 5.85(dd,J=1.9,10.7Hz,1H),4.86-4.64(m,3H),4.62-4.11(m,3H),3.74-3.37(m,3H),3.02-2.95(m,1H),2.19(s,3H),1.29-1.14(m,6H)

[0478] 19 F NMR (376 MHz, methanol-d4) δ = -116.80 (s, 1F), -137.87 - 139.98 (m, 1F)

[0479] MS(ESI)m / z(M+H) + =575.3.

[0480] HPLC reaction time: 6.30 min

[0481] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.06875% trifluoroacetic acid) - acetonitrile (0.0625% trifluoroacetic acid); acetonitrile: 10% to 80% for 10 min, 80% for 5 min; flow rate: 1.5 mL / min.

[0482] SFC reaction time: 5.488 min

[0483] Separation conditions: Chromatographic column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)], isopropanol %: 5% to 40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL / min.

[0484] Compound 7B:

[0485] 1H NMR (400MHz, methanol-d4)δ=8.44(d,J=5.0Hz,1H),7.31-7.21(m,2H),6.96-6.80(m,1H),6.73-6.60(m,2H),6.32(dd,J=1.8,16.8Hz,1H), 5.85(dd,J=1.8,10.5Hz,1H),4.86-4.64(m,3H),4.56-4.14(m,3H),3.87-3.42(m,3H),3.04-2.93(m,1H),2.19(s,3H),1.24-1.15(m,6H)

[0486] 19 F NMR (376 MHz, methanol-d4) δ = -116.81 (s, 1F), -139.04 - 139.11 (m, 1F)

[0487] MS(ESI)m / z(M+H) + =575.3.

[0488] HPLC reaction time: 6.32 min

[0489] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.06875% trifluoroacetic acid)-acetonitrile (0.0625% trifluoroacetic acid); acetonitrile: 10% to 80% for 10 min, 80% for 5 min; flow rate: 1.5 mL / min.

[0490] SFC reaction time: 5.970 min

[0491] Separation conditions: Chromatographic column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)], isopropanol %: 5% to 40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL / min.

[0492] Example 8: Preparation of Compound 8

[0493] Step 1: Preparation of Compound 8-2

[0494] [ka]

[0495] Compound 8-1 (410 mg, 1.774 mmol) and sodium hydride (142 mg, 60%, 3.55 mmol) were dissolved in tetrahydrofuran (3.0 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature (20 °C) for 5 min. Compound 7-4 (750 mg, 1.774 mmol) was added to the mixture, which was then stirred at room temperature (20 °C) for 1 h. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 8-2.

[0496] MS(ESI)m / z(M+H) + =577.2.

[0497] Step 2: Preparation of Compound 8-3

[0498] [ka]

[0499] Compound 8-2 (300 mg, 0.52 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (485 mg, 1.04 mmol) were dissolved in N,N-dimethylformamide (4 mL). 1,8-diazabicycloundec-7-ene (316 mg, 2.08 mmol) was added dropwise to the resulting solution at room temperature (20 °C). The mixture was stirred at room temperature (20 °C) for 8 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (4 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 8-3.

[0500] MS(ESI)m / z(M+H) + =559.2.

[0501] Step 3: Preparation of Compound 8-4

[0502] [ka]

[0503] Compound 8-3 (100 mg, 0.179 mmol), compound 7-9 (100 mg, 0.358 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.0179 mmol), and potassium carbonate (50.0 mg, 0.358 mmol) were dissolved in a tetrahydrofuran / water mixture (2 mL, v / v 10:1) under a nitrogen atmosphere. The mixture was heated to 80 °C and stirred for 2 h. The mixture was cooled to room temperature, quenched with water (1 mL), and extracted with ethyl acetate (1 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give compound 8-4.

[0504] MS(ESI)m / z(M+H) + =679.2.

[0505] Step 4: Preparation of Compound 8-5

[0506] [ka]

[0507] Compound 8-4 (18 mg, 0.0265 mmol) was dissolved in a 6N mixture of methanol and hydrochloric acid (2 mL, v / v = 1:1). The mixture was heated to 55 °C and stirred for 15 min. The mixture was cooled to room temperature and concentrated to give compound 8-5.

[0508] MS(ESI)m / z(M+H) + =535.2.

[0509] Step 5: Preparation of Compound 8

[0510] [ka]

[0511] Compound 8-5 was dissolved in dichloromethane (1 mL), and triethylamine (8.1 mg) and acryloyl chloride (2.1 mg) were added sequentially to the resulting solution at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched with water (1 mL) and extracted with dichloromethane (1 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Welch Xtimate C18 21.2 × 250 mm, 10 μm; column temperature: 25 °C; mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; mobile phase acetonitrile ratio 25%-45%, 12 min; flow rate: 30 mL / min) to obtain compound 8.

[0512] MS(ESI)m / z(M+H) + =589.3.

[0513] Step 6: Preparation of Compounds 8A and 8B

[0514] [ka]

[0515] The diastereomeric compound 8 was purified by SFC (separation conditions: chromatographic column: ChiralPak AD, 300 × 50 mm ID, 10 μm; column temperature: 38 °C; mobile phase [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 35%; flow rate: 80 mL / min). After concentration, compound 8A (peak 1) and compound 8B (peak 2) were obtained.

[0516] Compound 8A:

[0517] 1 H NMR(400MHz,DMSO-d6):10.10(s,1H),8.38-8.32(m,1H),7.25-7.05(m,2H),6.95 -6.75(m,1H),6.67-6.55(m,2H),6.19-6.10(m,1H),5.75-5.65(m,1H),5.00-4.8 3(m,1H),4.73-4.57(m,2H),4.45-4.13(m,2H),4.13-4.00(m,1H),3.93-3.80(m, 1H), 2.90-2.78(m, 1H), 2.05-1.85(m, 4H), 1.20-1.12(s, 3H), 1.08-0.93(m, 6H).

[0518] SFC reaction time: 5.339 min.

[0519] Separation conditions: Chromatographic column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% for 5 min, 40% for 2.5 min; flow rate: 2.5 mL / min.

[0520] Compound 8B:

[0521] 1 H NMR(400MHz,DMSO-d6)10.10(s,1H),8.40-8.28(d,J=8.0Hz,1H),7.25-7.05(m ,2H),6.95-6.75(m,1H),6.70-6.55(m,2H),6.20-6.10(m,1H),5.75-5.68(m,1 H),5.30-5.20(m,1H),5.05-4.80(m,1H),4.45-4.00(m,4H),3.95-3.83(m,1H) ,,2.85-2.75(m,1H),2.03-1.93(m,4H),1.28-1.21(s,3H),1.10-0.90(m,6H).

[0522] SFC reaction time: 5.681 min

[0523] Separation conditions: Chromatographic column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% for 5 min, 40% for 2.5 min; flow rate: 2.5 mL / min.

[0524] MS(ESI)m / z(M+H) + =589.3.

[0525] Example 9: Preparation of Compound 9

[0526] Step 1: Preparation of Compound 9-2

[0527] [ka]

[0528] Compound 4-1 (120 mg, 220.58 μmol) was dissolved in dioxane (5 mL) and water (1 mL). To the resulting solution, compound 9-1 (118.83 mg, 637.48 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (23.98 mg, 50.29 μmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (24.09 mg, 28.46 μmol), and potassium carbonate (120.11 mg, 869.09 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an argon atmosphere for 16 hours. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to obtain compound 9-2.

[0529] MS(ESI)m / z(M+H) + =650.3.

[0530] Step 2: Preparation of Compound 9-3

[0531] [ka]

[0532] Compound 9-2 (100 mg, 153.81 μmol) was dissolved in anhydrous dichloromethane (1 mL), and boron tribromide (260.00 mg, 1.04 mmol, 0.1 mL) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 2 h. Methanol (2 mL) was added to the system, and the resulting mixture was stirred for 30 min. The system was concentrated and lyophilized to give compound 9-3 (hydrobromide salt).

[0533] MS(ESI)m / z(M+H) + =536.2.

[0534] Step 3: Preparation of Compound 9

[0535] [ka]

[0536] Compound 9-3 (100 mg, 162.10 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (3 mL) and saturated aqueous sodium bicarbonate (1.7 mL). To the resulting solution, acrylic anhydride (20.44 mg, 162.10 μmol) was added at room temperature (20 °C). After the addition was completed, the system was stirred at room temperature (20 °C) for 30 minutes. Isopropanol (5 mL) and an aqueous solution of potassium carbonate (2 M, 2 mL) were added to the system, which was then stirred at room temperature (20 °C) for another 3 hours. The system was adjusted to a neutral pH with 1N HCl and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 36% to 66% in 9.5 min; flow rate: 30 mL / min) to obtain compound 9.

[0537] 1 H NMR (400 MHz, acetonitrile-d3) δ 8.47 (d, J = 4.9 Hz, 1H), 7.24-7.17 (m, 2H), 7.00-6.93 (m, 1H), 6.88-6.82 (m, 1H), 6.74 (br s, 1H), 6.25 (dd, J = 2.0, 16.8 Hz, 1H), 5.93-5.86 (m, 1H), 5.75 (dd, J = 2.2, 10.6 Hz, 1H), 4.79 (br s, 1H) s,1H),4.67-4.33(m,3H),4.27-3.99(m,2H),3.66-3.11(m,3H),2.92-2.77(m,1H),2.04-1.99(m,3H),1.13-1.03(m,6H).

[0538] MS(ESI)m / z(M+H) + =590.1.

[0539] Example 10: Preparation of Compound 10

[0540] Step 1: Preparation of Compound 10-2

[0541] [ka]

[0542] Compound 10-1 (2.06 g, 9.50 mmol) was dissolved in tetrahydrofuran (70 mL), and sodium hydride (763.54 mg, 15.84 mmol, 60% purity) was added to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 20 minutes, and compound 3-7 (3 g, 7.92 mmol) was added. After the addition was complete, the system was warmed to 20 °C and stirred for 20 minutes. The system was quenched with a saturated aqueous solution of ammonium chloride (2 mL) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 10-2.

[0543] MS(ESI)m / z(M+H) + =559.2.

[0544] Step 2: Preparation of Compound 10-3

[0545] [ka]

[0546] Compound 10-2 (1.6 g, 2.86 mmol) and PyBOP (2.98 g, 5.73 mmol) were dissolved in acetonitrile (22 mL), and 1,8-diazabicycloundec-7-ene (2.18 g, 14.32 mmol, 2.16 mL) was added dropwise to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (88% petroleum / ethyl acetate (v / v) = 0–100%) to give compound 10-3.

[0547] MS(ESI)m / z(M+H) + =541.3.

[0548] Step 3: Preparation of Compound 10-4

[0549] [ka]

[0550] Compound 10-3 (754 mg, 1.39 mmol) was dissolved in anhydrous dichloromethane (4 mL), and boron tribromide (3.49 g, 13.95 mmol, 1.34 mL) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 16 h. Methanol (10 mL) was added to the system, and the resulting mixture was stirred for 10 min. The system was concentrated and lyophilized to give compound 10-4.

[0551] Step 4: Preparation of Compound 10-5

[0552] [ka]

[0553] Compound 10-4 (594 mg, 1.11 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and saturated sodium bicarbonate (5.5 mL). To the resulting solution, benzyl chloroformate (380.20 mg, 2.23 mmol, 316.83 μL) was added dropwise at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 4 h. Methanol (2 mL) and an aqueous solution of lithium hydroxide (2N, 0.2 mL) were added to the system. After the addition was complete, the system was stirred at room temperature for 1 h. The system was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound 10-5.

[0554] MS(ESI)m / z(M+H) + =561.2.

[0555] Step 5: Preparation of Compound 10-6

[0556] [ka]

[0557] Compound 10-5 (750 mg, 1.34 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (8.21 g, 53.52 mmol, 4.97 mL) was added to the resulting solution. After the addition was complete, the system was warmed to 80 °C and stirred for 2 h. The system was cooled to room temperature and concentrated. The residue was quenched by pouring it into ice water (10 mL). The resulting mixture was adjusted to neutral pH with saturated sodium bicarbonate and extracted with ethyl acetate (3 × 10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 10-6.

[0558] MS(ESI)m / z(M+H) + =579.2.

[0559] Step 6: Preparation of Compound 10-7

[0560] [ka]

[0561] Compound 10-6 (350 mg, 604.47 μmol) was dissolved in dioxane (8 mL) and water (1 mL). To the resulting solution, compound 1-14 (280.50 mg, 1.21 mmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (57.63 mg, 120.89 μmol), tris(dibenzylideneacetone)dipalladium (34.76 mg, 60.45 μmol), and potassium carbonate (250.63 mg, 1.81 mmol) were added sequentially. After the addition was complete, the system was heated to 100 °C and stirred under an argon atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give compound 10-7.

[0562] MS(ESI)m / z(M+H) + =669.3.

[0563] Step 7: Preparation of Compound 10-8

[0564] [ka]

[0565] Compound 10-7 (90 mg, 134.59 μmol) was dissolved in anhydrous dichloromethane (0.5 mL), and boron tribromide (1 M in dichloromethane, 807.55 μL) was added to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 6 h. Methanol (5 mL) was added to the system, and the resulting mixture was stirred for 10 min. The system was concentrated and lyophilized to give compound 10-8 (hydrobromide salt).

[0566] MS(ESI)m / z(M+H)+ =521.2.

[0567] Step 8: Preparation of Compound 10

[0568] [ka]

[0569] Compound 10-8 (81 mg, 107.74 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (5 mL) and saturated aqueous NaHCO3 (5 mL). To the resulting solution, acrylic anhydride (0.2 M, 646.45 μL) was added at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. Methanol (1 mL) and lithium hydroxide (0.2 M, 0.1 mL) were added to the system, which was stirred at room temperature (20 °C) for an additional 2 h. The system was concentrated, diluted with methanol (5 mL), and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 24% to 54% in 9.5 min) to obtain compound 10.

[0570] Step 9: Preparation of Compounds 10A and 10B

[0571] [ka]

[0572] Diastereomeric compound 10 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-isopropanol (0.1% aqueous ammonia)]; isopropanol %: 35%-35%; flow rate: 80 mL / min). After concentration, compound 10A (peak 1) and compound 10B (peak 2) were obtained.

[0573] Compound 10A:

[0574] 1 H NMR (400MHz, methanol-d4)δ=8.32(d,J=5.0Hz,1H),7.20-7.07(m,2H),6.80-6.67(m,1H),6.61-6.49(m,2H),6.20(d,J=16.8Hz,1H), 5.73(dd,J=1.4,10.7Hz,1H),4.72-4.49(m,3H),4.48-4.02(m,3H),3.74-3.27(m,3H),2.87(m,1H),2.07(s,3H),1.14-1.00(m,6H)

[0575] 19 F NMR (376 MHz, methanol-d4) δ = -116.83 (s, 1F), -139.10 (s, 1F)

[0576] MS(ESI)m / z(M+H) + =575.3.

[0577] HPLC reaction time: 6.31 min

[0578] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0579] SFC reaction time: 1.853 min

[0580] Separation conditions: Chromatographic column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0581] Compound 10B:

[0582] 1 H NMR (400MHz, methanol-d4)δ=8.31(d,J=5.0Hz,1H),7.19-7.10(m,2H),6.83-6.67(m,1H),6.61-6.48(m,2H),6.20(dd,J=1.5,16. 8Hz,1H),5.73(dd,J=1.5,10.6Hz,1H),4.75-4.50(m,3H),4.50-3.98(m,3H),3.60-3.23(m,3H),2.86(m,1H),1.15-1.01(m,6H)

[0583] 19 F NMR (376 MHz, methanol-d4) δ = -116.81 (s, 1F), -138.96 (s, 1F)

[0584] MS(ESI)m / z(M+H) + =575.3.

[0585] HPLC reaction time: 6.31 min

[0586] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[0587] SFC reaction time: 2.071 min

[0588] Separation conditions: Chromatographic column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-isopropanol (0.05% DEA)]; isopropanol %: 5% to 40% 2 min, 40% 1.2 min, 5% 0.8 min; flow rate: 4 mL / min.

[0589] Example 11: Preparation of Compound 11

[0590] Step 1: Preparation of Compound 11-1

[0591] [ka]

[0592] Compound 4-1 (270 mg, 496.31 μmol) was dissolved in dioxane (10 mL). To the resulting solution, bis(pinacolato)diboron (270.00 mg, 1.06 mmol), tricyclohexylphosphine tetrafluoroborate (54.00 mg, 146.64 μmol), tris(dibenzylideneacetone)dipalladium (54.00 mg, 58.97 μmol), and potassium acetate (270 mg, 2.75 mmol) were added sequentially. After the addition was complete, the system was heated to 100 °C and stirred under an Ar atmosphere for 3 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to give 11-1.

[0593] 1 H NMR(400MHz,MeOD)δ8.52(d,J=5.1Hz,1H),7.35(d,J=4.9Hz,1H),6.09(br s,1H),4.99(br d,J=14.3Hz,1H),4.73-4.46(m,2H),4.29-3.88(m,3H),3.43-3.31(m,3H) ,2.87-2.58(m,1H),2.05(d,J=3.5Hz,3H),1.50(s,9H),1.33-0.76(m,6H).

[0594] MS(ESI)m / z(M+H) + =554.3.

[0595] Step 2: Preparation of Compound 11-3

[0596] [ka]

[0597] Compound 11-1 (100.00 mg, 126.49 μmol) was dissolved in dioxane (3 mL) and water (0.3 mL). To the resulting solution, compound 11-2 (70.08 mg, 270.70 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (5 mg, 10.49 μmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (5 mg, 5.91 μmol), and potassium carbonate (70 mg, 506.49 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an argon atmosphere for 2 hours. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to give compound 11-3. MS (ESI) m / z (M+H) + =687.0.

[0598] Step 3: Preparation of Compound 11-4

[0599] [ka]

[0600] Compound 11-3 (100 mg, 145.44 μmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (154.00 mg, 1.35 mmol, 100 μL) was added to the resulting solution. The mixture was reacted at room temperature (20 °C) for 3 hours. The mixture was concentrated to give compound 11-4 (trifluoroacetate salt).

[0601] MS(ESI)m / z(M+H) + =587.2.

[0602] Step 4: Preparation of Compound 11

[0603] [ka]

[0604] Compound 11-4 (100 mg, 142.56 μmol, trifluoroacetate salt) was dissolved in tetrahydrofuran (3 mL) and saturated aqueous sodium bicarbonate (2 mL), and acrylic anhydride (17.98 mg, 142.56 μmol) was added to the resulting solution at room temperature (20 °C). After the addition was completed, the system was stirred at room temperature (20 °C) for 30 minutes. Water (10 mL) was added to the system, which was then extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 42% to 72%, 9.5 min) to obtain compound 11.

[0605] 1 H NMR(400Hz,acetonitrile-d3)δ8.56-8.42(m,1H),7.40(br d,J=7.3Hz,1H),7.21(br d,J=4.0Hz,1H),6.75(br s,1H),6.32-6.18(m,1H),5.99(br t,J=5.2Hz,1H),5.75(br dd,J=2.1,10.7Hz,1H),4.89-4.36(m,5H),4.17-4.05(m,1H),3.63-3.38(m,2H),2.92-2.74(m,1H),2.73-2.72(m,1H),2.02(br dd,J=4.7,18.4Hz,3H),1.42-0.78(m,6H).

[0606] MS(ESI)m / z(M+H) + =641.1.

[0607] Step 5: Preparation of Compounds 11A, 11B, 11C, and 11D

[0608] [ka]

[0609] The diastereomeric compound 11 was purified by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-ethanol (0.1% aqueous ammonia)]; ethanol %: 45% to 45%). After concentration, compound 11A, compound 11B, compound 11C, and compound 11D were obtained.

[0610] Compound 11A:

[0611] 1 H NMR(400MHz,MeOD)δ8.50(br d,J=5.1Hz,1H),7.39(br d,J=7.5Hz,1H),7.32(br d,J=3.3Hz,1H),6.84(br s,1H),6.31(br d,J=18.7Hz,1H),5.97(br dd,J=5.4,8.5Hz,1H),5.84(br d,J=12.3Hz,1H),5.00-4.94(m,1H),4.74(br d,J=10.6Hz,2H),4.59-4.23(m,3H),3.63-3.40(m,3H),2.90-2.79(m,1H),2.18-1.98(m,3H),1.19(br dd,J=2.5,6.7Hz,3H),1.14-1.01(m,3H).

[0612] MS(ESI)m / z(M+H) + =641.1.

[0613] HPLC reaction time: 4.142 min

[0614] Separation conditions: Chromatography column: Xbridge Shield RP-18, 5 μm, 2.1 × 50 mm; column temperature: 50 °C; mobile phase: water (0.02% aqueous ammonia)-acetonitrile; acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0615] SFC reaction time: 2.975 min + 7.090 min

[0616] Separation conditions: Chromatographic column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-ethanol (0.05% DEA)]; ethanol%: 40% ~ 40%; flow rate: 2.5 mL / min.

[0617] Compound 11B:

[0618] 1 H NMR(400MHz,MeOD)δ8.58-8.40(m,1H),7.39(br d,J=7.3Hz,1H),7.32(br d,J=4.6Hz,1H),6.85(br dd,J=9.0,16.3Hz,1H),6.31(br d,J=15.9Hz,1H),5.96(br dd,J=5.5,8.6Hz,1H),5.84(br d,J=11.9Hz,1H),5.00(br d,J=14.8Hz,1H),4.84-4.66(m,2H),4.66-4.55(m,1H),4.50-4.33(m,1H),4.23(br s,1H),3.71-3.45(m,3H),2.91-2.74(m,1H),2.23-1.97(m,3H),1.20(br dd,J=3.1,6.4Hz,3H),1.19-1.00(m,3H).

[0619] MS(ESI)m / z(M+H) + =641.1.

[0620] HPLC reaction time: 4.133 min

[0621] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5 μm, 2.1 × 50 mm; column temperature: 50 °C; mobile phase: water (0.02% aqueous ammonia)-acetonitrile; acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0622] SFC reaction time: 2.999 min + 4.228 min + 7.114 min + 9.409 min

[0623] Separation conditions: Chromatographic column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-ethanol (0.05% DEA)]; ethanol%: 40% ~ 40%; flow rate: 2.5 mL / min.

[0624] Compound 11C:

[0625] 1 H NMR(400MHz,MeOD)δ8.50(d,J=5.1Hz,1H),7.39(br d,J=7.5Hz,1H),7.32(br d,J=4.2Hz,1H),6.85(br dd,J=8.6,16.5Hz,1H),6.31(br d,J=16.8Hz,1H),5.97(br dd,J=5.4,8.3Hz,1H),5.84(br dd,J=1.8,10.6Hz,1H),5.00(br d,J=13.2Hz,1H),4.80-4.68(m,2H),4.60-4.23(m,3H),3.63-3.39(m,3H),2.91-2.77(m,1H),2.17-2.00(m,3H),1.25-0.96(m,6H).

[0626] MS(ESI)m / z(M+H) + =641.1.

[0627] HPLC reaction time: 4.136 min

[0628] Separation conditions: Chromatography column: Xbridge Shield RP-18, 5 μm, 2.1 × 50 mm; column temperature: 50 °C; mobile phase: water (0.02% aqueous ammonia)-acetonitrile; acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0629] SFC reaction time: 2.999 min + 4.234 min + 7.118 min + 9.426 min

[0630] Separation conditions: Chromatographic column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-ethanol (0.05% DEA)]; ethanol%: 40% ~ 40%; flow rate: 2.5 mL / min.

[0631] Compound 11D:

[0632] 1 H NMR(400MHz,MeOD)δ8.49(br d,J=4.9Hz,1H),7.39(br d,J=7.5Hz,1H),7.32(br d,J=4.9Hz,1H),6.91-6.79(m,1H),6.31(br d,J=16.8Hz,1H),5.96(br dd,J=5.4,8.7Hz,1H),5.84(br d,J=10.6Hz,1H),5.02-4.68(m,3H),4.60-4.23(m,3H),3.65-3.48(m,3H),2.87-2.74(m,1H),2.15-2.01(m,3H),1.26-0.99(m,6H).

[0633] MS(ESI)m / z(M+H) + =641.1.

[0634] HPLC reaction time: 4.140 min

[0635] Separation conditions: Chromatography column: Xbridge Shield RP-18, 5 μm, 2.1 × 50 mm; column temperature: 50 °C; mobile phase: water (0.02% aqueous ammonia)-acetonitrile; acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0636] SFC reaction time: 4.210 min + 9.403 min

[0637] Separation conditions: Chromatographic column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-ethanol (0.05% DEA)]; ethanol%: 40% ~ 40%; flow rate: 2.5 mL / min.

[0638] Example 12: Preparation of Compound 12

[0639] Step 1: Preparation of Compound 12-2

[0640] [ka]

[0641] Under a nitrogen atmosphere, compound 4-1 (100 mg, 183.82 μmol) and compound 12-1 (80 mg, 292.46 μmol) were dissolved in dioxane (2 mL) and water (0.4 mL), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (20 mg, 23.63 μmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (20 mg, 41.95 μmol), and potassium carbonate (100 mg, 723.54 μmol) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to give compound 12-2.

[0642] MS(ESI)m / z(M+H) + =619.3.

[0643] Step 2: Preparation of Compound 12-3

[0644] [ka]

[0645] Compound 12-2 (0.12 g, 193.96 μmol) was dissolved in dichloromethane (5 mL) at 25 °C, and trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL) was added. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give compound 12-3.

[0646] MS(ESI)m / z(M+H) + =519.3.

[0647] Step 3: Preparation of Compound 12

[0648] [ka]

[0649] Compound 12-3 (0.1 g, 192.84 μmol) was dissolved in tetrahydrofuran (4 mL), and saturated sodium bicarbonate solution (6.05 g, 71.99 mmol, 2.8 mL) and acrylic anhydride (21.89 mg, 173.56 μmol) were added sequentially. The reaction mixture was stirred at 25 °C for 2 h. Methanol (3 mL) and lithium hydroxide (32.37 mg, 771.37 μmol) were added, and the reaction mixture was stirred for an additional 2 h. The reaction mixture was adjusted to pH 7.0 with 1 M hydrochloric acid solution and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 29% to 59%, 9.5 min) to give compound 12.

[0650] MS(ESI)m / z(M+H) + =573.3.

[0651] Step 4: Preparation of Compounds 12A and 12B

[0652] [ka]

[0653] The diastereomeric compound 12 was purified by SFC (separation conditions: chromatographic column: Phenomenex-cellulose-2 (250 mm × 50 mm, 10 μm); mobile phase: [Neu-methanol (0.1% aqueous ammonia)]; methanol: 50% to 50%). After concentration, compound 12A (peak 1) and compound 12B (peak 2) were obtained.

[0654] Compound 12A

[0655] 1 H NMR (400MHz, methanol-d4) δ8.49(d,J=5.1Hz,1H),7.31(d,J=4.9Hz,1H),7.14-7.03(m,1H),6.9 2-6.80(m,J=10.9,16.4Hz,1H),6.53(t,J=8.5Hz,1H),6.42-6.26(m,2H),5.97(dd,J=5.4,9.8 Hz,1H),5.83(dd,J=1.8,10.6Hz,1H),5.02(s,1H),4.74-4.32(m,5H),4.22(s,1H),3.81-3.38 (m,2H),2.97-2.77(m,1H),2.14-2.01(m,3H),1.19(dd,J=3.5,6.6Hz,3H),1.14-1.03(m,3H).

[0656] MS(ESI)m / z(M+H) + =573.3.

[0657] HPLC reaction time: 7.15 min

[0658] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.06875% trifluoroacetic acid) - acetonitrile (0.0625% trifluoroacetic acid); acetonitrile: 10% to 80% for 10 min, 80% for 5 min; flow rate: 1.5 mL / min.

[0659] SFC reaction time: 8.176 min

[0660] Separation conditions: Chromatographic column: cellulose 2 100 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-methanol (0.05% DEA)]; methanol%: 40%-40%; flow rate: 2.8 mL / min.

[0661] Compound 12B

[0662] 1 H NMR (400MHz, methanol-d4)8.49(d,J=5.0Hz,1H),7.32(d,J=4.8Hz,1H),7.13-7.03(m,1H),6.94-6.80(m,1H) ,6.57-6.49(m,1H),6.41-6.26(m,2H),5.96(dd,J=5.5,9.3Hz,1H),5.83(dd,J=1.6,10.7Hz,1H),5.05(br d,J=8.0Hz,1H),4.80-4.16(m,5H),3.76-3.35(m,3H),2.90-2.72(m,1H),2.14-2.04(m,3H),1.19(dd,J=4.4,6.9Hz,3H),1.14-1.02(m,3H).

[0663] MS(ESI)m / z(M+H) + =573.3.

[0664] HPLC reaction time: 7.12 min

[0665] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.06875% trifluoroacetic acid)-acetonitrile (0.0625% trifluoroacetic acid); acetonitrile: 10% to 80% for 10 min, 80% for 5 min; flow rate: 1.5 mL / min.

[0666] SFC reaction time: 10.832 min

[0667] Separation conditions: Chromatographic column: cellulose 2 100 × 4.6 mm ID, 3 μm; column temperature: 35 °C; mobile phase: [Neu-methanol (0.05% DEA)]; methanol%: 40%-40%; flow rate: 2.8 mL / min.

[0668] Example 13: Preparation of Compound 13

[0669] Step 1: Preparation of Compound 13-1

[0670] [ka]

[0671] Compound 3-7 (2 g, 5.28 mmol), triethylamine (801.42 mg, 7.92 mmol), and palladium on carbon (666 mg, 10% on carbon) were dissolved in methanol (100 mL). The mixture was stirred under a hydrogen atmosphere (50 psi) at 30° C. for 20 hours. The mixture was filtered, and the filtrate was concentrated to give compound 13-1.

[0672] MS(ESI)m / z(M+H) + =344.9.

[0673] Step 2: Preparation of Compound 13-2

[0674] [ka]

[0675] Compound 13-1 (1.8 g, 5.23 mmol) and N,N-diisopropylethylamine (2.03 g, 15.68 mmol, 2.73 mL) were dissolved in acetonitrile (30 mL), and phosphorus oxychloride (1.60 g, 10.45 mmol) was added to the resulting solution at room temperature (20 °C). After the addition was completed, the system was warmed to 70 °C and stirred for 1 h. The system was concentrated to give compound 13-2.

[0676] Step 3: Preparation of Compound 13-4

[0677] [ka]

[0678] Compound 13-2 (2.6 g, 4.30 mmol), 13-3 (1.03 g, 5.16 mmol), and N,N-diisopropylethylamine (2.22 g, 17.20 mmol) were dissolved in tetrahydrofuran (20 mL). The mixture was stirred under a nitrogen atmosphere at room temperature (20 °C) for 1 h. The mixture was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-70%) to give compound 13-4.

[0679] MS(ESI)m / z(M+H) + =527.1.

[0680] Step 4: Preparation of Compound 13-5

[0681] [ka]

[0682] Compound 13-4 (1.8 g, 3.42 mmol) was dissolved in dichloromethane (5 mL) and boron tribromide (8.56 g, 34.18 mmol, 3.29 mL) was added. The reaction was stirred at 20 °C for 16 h. The reaction was quenched with methanol (20 mL), stirred for 10 min, and concentrated under reduced pressure to give compound 13-5.

[0683] Step 5: Preparation of Compound 13-6

[0684] [ka]

[0685] Compound 13-5 (1.2 g, 2.43 mmol) was dissolved in tetrahydrofuran (10 mL), and an aqueous solution of sodium bicarbonate (1.02 g, 12.16 mmol in 5 mL HO, 5 mL) and benzyl chloroformate (622.39 mg, 3.65 mmol, 518.65 μL) were added to the resulting solution. After the addition was completed, the system was reacted at room temperature (20 °C) for 16 h. Ethyl acetate (50 mL) was added to the system, followed by liquid separation and extraction. The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was then purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 13-6.

[0686] MS(ESI)m / z(M+H) + =547.1.

[0687] Step 6: Preparation of Compound 13-7

[0688] [ka]

[0689] Compound 13-6 (80 mg, 146.36 μmol) was dissolved in acetonitrile (5 mL), and phosphorus oxychloride (448.83 mg, 2.93 mmol) was added to the resulting solution at room temperature (20 °C). After the addition was completed, the system was warmed to 80 °C and stirred for 4 h. The system was concentrated to give the crude product, which was then purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound 13-7.

[0690] MS(ESI)m / z(M+H) + =565.1.

[0691] Step 7: Preparation of Compound 13-8

[0692] [ka]

[0693] Compound 13-7 (70 mg, 123.89 μmol) was dissolved in dioxane (1 mL) and water (0.1 mL). To the resulting solution, compound 1-14 (43.12 mg, 185.83 μmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (11.81 mg, 24.78 μmol), tris(dibenzylideneacetone)dipalladium (11.34 mg, 12.39 μmol), and sodium carbonate (26.26 mg, 247.77 μmol) were added sequentially. After the addition was completed, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give compound 13-8.

[0694] MS(ESI)m / z(M+H) + =655.2.

[0695] Step 8: Preparation of Compound 13-9

[0696] [ka]

[0697] Compound 13-8 (16 mg, 24.44 μmol) was dissolved in anhydrous dichloromethane (1 mL), and boron tribromide (1 M in dichloromethane, 807.55 μL) was added to the resulting solution at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 2 h. Methanol (5 mL) was added to the system, and the resulting mixture was stirred for 10 min. The system was concentrated and lyophilized to give compound 13-9 (hydrobromide salt).

[0698] MS(ESI)m / z(M+H) + =507.2.

[0699] Step 9: Preparation of Compound 13

[0700] [ka]

[0701] Compound 13-9 (14 mg, 23.83 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (2 mL). To the resulting solution, acrylic anhydride (0.2 M, 178.74 μL) was added at room temperature (20° C.). After the addition was complete, the system was stirred at room temperature (20° C.) for 1 hour. The system was quenched with methanol (1 mL) and extracted with ethyl acetate (5 mL). The system was separated into layers. The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 18% to 48%, 9 min) to obtain compound 13.

[0702] 1 H NMR (400 MHz, methanol-d4) δ = 9.01 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.34-7.24 (m, 2H), 6.96-6.78 (m, 1H), 6.74-6.61 (m, 2H), 6.33 (br d,J=16.3Hz,1H),5.89-5.82(m,1H),5.16-5.04(m,1H),4.62-4.41(m,2H),4.29-4.07(m,1H),3.97-3.5 1(m,2H),3.41-3.34(m,1H),3.05-2.88(m,1H),2.18-2.15(m,3H),1.56-1.45(m,3H),1.24-1.13(m,6H)

[0703] 19 F NMR (376 MHz, methanol-d4) = -116.75 (s, 1F)

[0704] MS(ESI)m / z(M+H) + =583.0.

[0705] Example 14: Preparation of Compound 14

[0706] Step 1: Preparation of compound 14-3

[0707] [ka]

[0708] Compound 14-1 (8.5 g, 41.87 mmol) was dissolved in toluene (20 mL), and compound 14-2 (5.56 g, 41.75 mmol, 6.07 mL) was added to the resulting solution with stirring. After the addition was complete, the system was warmed to 100 °C and stirred under a nitrogen atmosphere for 18 hours. The system was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (30 mL). The system was cooled to 0 °C, and ammonium chloride (18.38 g, 137.84 mmol, 7.53 mL) was added in batches. After the addition was complete, the system was stirred at 0 °C for 30 minutes. The system was slowly warmed to room temperature (25 °C) and then reacted at room temperature (25 °C) for 16 hours. The system was poured into ice water, and dichloromethane (100 mL) was added to the resulting mixture. The system was alkalized with 2 M aqueous sodium hydroxide solution, and then the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 100%) to give compound 14-3.

[0709] 1 H NMR (400 MHz, chloroform-d) δ 9.63 (s, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.83 (dd, J = 5.0, 8.9 Hz, 1H), 7.65 (d, J = 5.5 Hz, 1H), 7.53 (t, J = 8.6 Hz, 1H).

[0710] Step 2: Preparation of compound 14-4

[0711] [ka]

[0712] Compound 14-3 (2 g, 8.85 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperoxybenzoic acid (2.80 g, 13.78 mmol, 85% purity) was added to the resulting solution. After the addition was completed, the system was reacted at room temperature (25 °C) for 2 hours. Dichloromethane (100 mL) was added to the system. After washing with a saturated aqueous solution of sodium bicarbonate (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 14-4, which was used in the next step without further purification.

[0713] 1 H NMR (400 MHz, chloroform-d) 5 9.15 (s, 1H), 8.17 (dd, J = 1.3, 7.1 Hz, 1H), 7.77 (dd, J = 5.0, 8.9 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.44-7.37 (m, 1H).

[0714] MS(ESI)m / z(M+H) + =243.8.

[0715] Step 3: Preparation of compound 14-5

[0716] [ka]

[0717] Compound 14-4 (500 mg, 2.07 mmol) and methyl chloroformate (253.77 mg, 2.69 mmol, 208.01 μL) were dissolved in methanol (10 mL) at 0 °C. To the resulting solution, triethylamine (420.15 mg, 4.15 mmol, 577.92 μL) was added at 0 °C. After the addition was completed, the system was warmed to room temperature (25 °C) and stirred for 16 h. The system was concentrated, and the residue was dissolved in dichloromethane (10 mL). The resulting solution was washed successively with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give compound 14-5.

[0718] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 5.7 Hz, 1H), 7.69 (dd, J = 5.3, 9.0 Hz, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.22 (d, J = 5.7 Hz, 1H), 4.12 (s, 3H).

[0719] MS(ESI)m / z(M+H) + =257.7.

[0720] Step 4: Preparation of compound 14-6

[0721] [ka]

[0722] Compound 11-1 (130 mg, 234.92 μmol) and compound 14-5 (120.31 mg, 469.83 μmol) were dissolved in dioxane (2 mL) and water (0.4 mL). To the resulting solution was added 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (13.00 mg, 27.27 μmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (19.50 mg, 23.04 μmol), and potassium carbonate (97.40 mg, 704.75 μmol). After the addition was complete, the system was heated to 100 °C and stirred under an Ar atmosphere for 16 h. The system was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 7%) to give compound 14-6.

[0723] MS(ESI)m / z(M+H) + =685.3.

[0724] Step 5: Preparation of Compound 14-7

[0725] [ka]

[0726] Compound 14-6 (50 mg, 73.02 μmol), lithium chloride (12.38 mg, 292.09 μmol, 5.98 μL), and p-toluenesulfonic acid (55.56 mg, 292.09 μmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was heated to 120 °C and reacted under microwave conditions for 2 h. The mixture was concentrated to give compound 14-7, which was used in the next step without further purification.

[0727] MS(ESI)m / z(M+H) + =571.1.

[0728] Step 6: Preparation of Compounds 14A and 14B

[0729] [ka]

[0730] Compound 14-7 (50 mg, 87.63 μmol) was dissolved in tetrahydrofuran (2 mL) and a saturated aqueous solution of sodium bicarbonate (2.16 g, 25.71 mmol, 1 mL), and acrylic anhydride (11.05 mg, 87.63 μmol) was added to the resulting solution at room temperature (25 °C). After the addition was completed, the system was stirred at room temperature (25 °C) for 30 minutes. Methanol (2 mL) and an aqueous solution of potassium carbonate (2 mL) were added to the system, which was then stirred at room temperature (25 °C) for another hour. The system was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 29% to 59% 9.5 min) to give compounds 14A and 14B.

[0731] Compound 14A:

[0732] 1H NMR (400MHz, methanol-d4) δ8.53-8.38(m,1H),7.89-7.75(m,1H),7.56(br t,J=9.2Hz,1H),7.36-7.21(m,1H),7.19-7.07(m,1H),7.03-6.88(m,1H),6.73-6.61(m,1H),6.44-6.29(m,1H),5.93-5.83(m,1H),5.81(br d,J=4.4Hz,1H),4.78(br s,1H),4.77-4.72(m,1H),4.63(br s,1H),4.58(br s,1H),4.42(br d,J=10.8Hz,1H),3.88(br s,1H),3.61(br s,1H),3.49(br s,1H),3.01-2.88(m,1H),2.77(td,J=6.9,13.6Hz,1H),2.26-1.98(m,3H),1.88-1.60(m,3H),1.38-0.96(m,6H).

[0733] MS(ESI)m / z(M+H) + =625.2.

[0734] LCMS reaction times: 2.341 & 2.427 & 2.558 min

[0735] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 5% to 95% 0.7 min, 95% 0.4 min; flow rate: 1.5 mL / min.

[0736] Compound 14B:

[0737] 1H NMR (400MHz, methanol-d4) δ8.54-8.39(m,1H),7.85-7.74(m,1H),7.64-7.48(m, 1H),7.33-7.22(m,1H),7.18-7.08(m,1H),7.01-6.88(m,1H),6.73-6.61(m,1 H),6.41-6.30(m,1H),5.97-5.75(m,2H),5.06-4.95(m,1H),4.88-4.41(m,5H ),3.70-3.34(m,3H),2.99-2.75(m,1H),2.14-2.04(m,3H),1.22-1.00(m,6H).

[0738] MS(ESI)m / z(M+H) + =625.3.

[0739] LCMS reaction time: 3.026 min

[0740] Separation conditions: Chromatography column: WELCH Ultimate LP-C18 150 × 4.6 mm 5 μm; column temperature: 40 °C; mobile phase: water (0.0375% trifluoroacetic acid solution) - acetonitrile (0.01875% trifluoroacetic acid solution); acetonitrile: 5% to 95% 0.7 min, 95% 0.4 min; flow rate: 1.5 mL / min.

[0741] Example 15: Preparation of Compound 15

[0742] Step 1: Preparation of Compound 15-2

[0743] [ka]

[0744] Compound 15-1 (50 g, 240.26 mmol) was dissolved in acetonitrile (100 mL), and tert-butylamine (98.40 g, 1.35 mol, 141.38 mL) was added to the resulting solution. After the addition was complete, the system was warmed to 40 °C and stirred for 16 h. The system was concentrated, and the residue was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were pooled, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15-2, which was used in the next step without further purification.

[0745] Step 2: Preparation of compound 15-3

[0746] [ka]

[0747] Compound 15-2 (57.5 g, 220.10 mmol) was dissolved in concentrated hydrochloric acid (12 M, 24.64 mL). After the addition was complete, the system was warmed to 80 °C and stirred for 6 h. The system was concentrated, and the residue was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were pooled, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was dissolved in a mixture of tetrahydrofuran (50 mL) and water (50 mL). The resulting solution was adjusted to pH 10 with 1N sodium hydroxide. After liquid separation and extraction, the aqueous phase was adjusted to pH 3 with 6 M hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic phases were pooled, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15-3.

[0748] 1 H NMR (400MHz, DMSO-d6) δ7.02 (br s, 2H), 7.90 (ddd, J=11.58, 6.28, 1.76Hz, 1H).

[0749] MS(ESI)m / z(M+H) +=192.1.

[0750] Step 3: Preparation of compound 15-4

[0751] [ka]

[0752] Cuprous chloride (13.52 g, 136.57 mmol, 3.27 mL) and tert-butyl nitrite (12.80 g, 124.13 mmol, 14.76 mL) were dissolved in acetonitrile (150 mL), and compound 15-3 (16 g, 83.72 mmol) was added to the resulting solution at 60 °C. The system was stirred at 60 °C for 20 min under a nitrogen atmosphere. The system was cooled to room temperature (25 °C), and hydrochloric acid (4.32 mol, 273 mL, 15% purity) was added. The system was stirred at room temperature (25 °C) for 1 h. The system was quenched with sodium thiosulfate (10%, 5 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were pooled, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), followed by slurrying with petroleum ether (30 mL) at room temperature (25 °C) for 1 h to give compound 15-4.

[0753] 1 H NMR (400 MHz, methanol-d₄) δ 7.60-7.81 (m, 1H).

[0754] Step 4: Preparation of Compound 15-5

[0755] [ka]

[0756] Diisopropylethylamine (1.23 g, 9.50 mmol, 1.65 mL) was dissolved in anhydrous tetrahydrofuran (60 mL), and n-butyllithium (2.5 M, 57.00 mL) was added dropwise to the resulting solution at −78° C. After the addition was complete, the system was stirred at −30° C. for 10 minutes. The system was cooled to −78° C., and a solution of compound 15-4 (10 g, 47.50 mmol) in tetrahydrofuran (60 mL) was added to the system. After the addition was complete, the system was stirred at −78° C. for 4 hours. A solution of 1,2-dibromotetrachloroethane (30.93 g, 94.99 mmol, 11.41 mL) in tetrahydrofuran (60 mL) was added to the system. After the addition was complete, the system was stirred at -78 °C for 2 h, then warmed to room temperature (25 °C) and stirred for 16 h. The system was quenched with water (5 mL) and washed with ethyl acetate (50 mL × 3). The aqueous phase was adjusted to pH ∼2 with 2N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (separation conditions: chromatographic column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile: 30% to 50% acetonitrile, 8 min) to obtain compound 15-5.

[0757] Step 5: Preparation of Compound 15-6

[0758] [ka]

[0759] Compound 15-5 (3 g, 10.37 mmol) was dissolved in anhydrous dichloromethane (10 mL), and oxalyl chloride (1.97 g, 15.55 mmol, 1.36 mL) was added dropwise to the resulting solution at 0 °C, followed by one drop of N,N-dimethylformamide after the addition was complete. The system was stirred at 0 °C for 15 minutes, then warmed to 25 °C, and stirred for 1 hour. The system was concentrated to give the crude product, which was then dissolved in dioxane (5 mL). To the resulting solution, aqueous ammonia (885.05 mg, 51.97 mmol, 867.69 μL) was added dropwise at 0 °C. After the addition was complete, the system was stirred at room temperature (25 °C) for 1 hour. The system was concentrated, and the residue was subjected to liquid separation and extraction with water (20 mL) and ethyl acetate (50 mL × 3). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15-6.

[0760] MS(ESI)m / z(M+H) + =289.7.

[0761] Step 6: Preparation of Compound 15-7

[0762] [ka]

[0763] Compound 15-6 (2.8 g, 9.71 mmol) was dissolved in anhydrous 1,2-dichloromethane (20 mL), and oxalyl chloride (1.72 g, 13.59 mmol, 1.19 mL) was added dropwise to the resulting solution at room temperature (20 °C). After the addition was complete, the system was warmed to 80 °C and stirred for 1 h. The reaction system was concentrated to half its volume and cooled to 0 °C, and a solution of compound 1-5 (1.46 g, 9.71 mmol) in 1,2-dichloroethane (20 mL) was added dropwise to the reaction system. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The system was concentrated under reduced pressure. The crude product was dried under vacuum to give 15-7 in the form of a white solid, which was used in the next step without further purification.

[0764] MS(ESI)m / z(M+H) +=465.9.

[0765] Step 7: Preparation of Compound 15-8

[0766] [ka]

[0767] Compound 15-7 (2.2 g, 4.73 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium bis(trimethylsilyl)amide (1 M, 10.42 mL) was added to the resulting solution under a nitrogen atmosphere at 0 °C. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 0.5 h. The system was poured into water (50 mL) and extracted with ethyl acetate (3 × 150 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was slurried in a mixture of methyl tert-butyl ether and petroleum ether (methyl tert-butyl ether: petroleum ether = 1:5) to give compound 15-8.

[0768] MS(ESI)m / z(M+H) + =445.9.

[0769] Step 8: Preparation of Compound 15-9

[0770] [ka]

[0771] Compound 15-8 (1.4 g, 3.15 mmol) was dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (2.03 g, 15.74 mmol, 2.74 mL) and phosphorus oxychloride (2.41 g, 15.74 mmol, 1.46 mL) were added sequentially to the resulting solution. After the addition was complete, the system was warmed to 80 °C and stirred for 0.5 h. The system was quenched by pouring into ice water (50 mL). The resulting mixture was adjusted to pH 7 with 1 M aqueous sodium hydroxide solution and extracted with ethyl acetate (3 × 10 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15-9, which was used in the next step without further purification.

[0772] (ESI) m / z (M+H) + =459.9.

[0773] Step 9: Preparation of Compound 15-10

[0774] [ka]

[0775] Compound 15-9 (1.45 g, 3.13 mmol) was dissolved in anhydrous acetonitrile (10 mL), and diisopropylethylamine (2.02 g, 15.66 mmol, 2.73 mL) and compound 3-8 (812.61 mg, 3.76 mmol) were added sequentially to the resulting solution. After the addition was complete, the system was warmed to room temperature (20 °C) and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 50 mL). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 60-80%) to give compound 15-10.

[0776] (ESI) m / z (M+H) + =644.0.

[0777] Step 10: Preparation of Compound 15-11

[0778] [ka]

[0779] Compound 15-10 (400 mg, 622.16 μmol) was dissolved in acetonitrile (10 mL), and (2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (100 mg, 117.04 μmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (60 mg, 123.79 μmol), and cesium carbonate (405.42 mg, 1.24 mmol) were added sequentially to the resulting solution. After the addition was complete, the system was heated to 80 °C and stirred under an Ar atmosphere for 16 hours. The system was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / dichloromethane (v / v) = 40 to 40%) to obtain compound 15-11.

[0780] (ESI) m / z (M+H) + =562.2.

[0781] Step 11: Preparation of Compound 15-12

[0782] [ka]

[0783] Compound 15-11 (100 mg, 177.93 μmol) and 1-14A (90.72 mg, 533.80 μmol) were dissolved in dioxane (2.5 mL) and water (0.5 mL). To the resulting solution, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (19.43 mg, 22.95 μmol), potassium carbonate (72.55 mg, 524.90 μmol), and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (19.34 mg, 40.57 μmol) were added sequentially. After the addition was complete, the system was heated to 100 °C and stirred under Ar for 12 h. The system was concentrated to give the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 to 5%) to give compound 15-12.

[0784] (ESI) m / z (M+H) + =652.3.

[0785] Step 12: Preparation of Compound 15-13

[0786] [ka]

[0787] Compound 15-12 (40 mg, 61.38 μmol) was dissolved in anhydrous dichloromethane (0.5 mL), and boron tribromide (76.89 mg, 306.90 μmol, 29.57 μL) was added to the resulting solution at 0 °C. After the addition was completed, the system was warmed to room temperature (20 °C) and stirred for 1 h. Methanol (1 mL) was added to the system, which was then stirred for 10 min. The system was concentrated and lyophilized to give compound 15-13, which was used in the next step without further purification.

[0788] (ESI) m / z (M+H) + =538.1.

[0789] Step 13: Preparation of Compounds 15A, 15B, 15C, and 15D

[0790] [ka]

[0791] Compound 15-13 (37 mg, 59.83 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (1 mL) and saturated aqueous sodium bicarbonate (6.15 g, 73.18 mmol, 2.85 mL). To the resulting solution, acrylic anhydride (9.05 mg, 71.79 μmol) was added at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 10 minutes. Methanol (1 mL) and lithium hydroxide (7 mg, 476.60 μmol) were added to the system, which was then stirred at room temperature (20 °C) for an additional 2 hours. The system was adjusted to pH 7 with 1N hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were pooled, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile content: 24%–54%), followed by two SFC purifications (chromatographic column: DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 μm); mobile phase: [CO₂-isopropanol (0.1% ammonia solution)]; isopropanol content: 35%–35%) (chromatographic column: DAICEL CHIRALCEL OJ (250 mm × 30 mm × 10 μm); mobile phase: [CO₂-ethanol (0.1% ammonia solution)]; ethanol content: 25%–25%) to give compounds 15A, 15B, 15C, and 15D.

[0792] Compound 15A:

[0793] 1H NMR(400MHz,メタノール-d4)δ8.39(br d,J=4.9Hz,1H),7.34-7.13(m,2H),6.84(br dd,J=10.9,16.3Hz,1H),6.67(td,J=8.3,16.9Hz,2H),6.31(br d,J=16.1Hz,1H),5.84(br d,J=10.0Hz,1H),4.79-4.54(m,3H),4.46(br d,J=11.0Hz,1H),4.22(br s,2H),3.81-3.67(m,1H),3.66-3.43(m,2H),3.01-2.88(m,1H),2.14(s,3H),1.46-0.97(m,6H).

[0794] MS(ESI)m / z(M+H) + =592.3.

[0795] SFC response time: 4.229 minutes

[0796] Separation conditions: Chiralcel: Chiralcel OD-3 100×4.6mm ID, 3μm; Chiralcel temperature: 35°C; Mobile phase: CO2-Chiralcel (0.05% DEA), エタノール%: 5%~40% 4 minutes, 40% 2.5 minutes, 5% 1.5 minutes; flow rate: 2.8mL / min.

[0797] Compound 15B:

[0798] 1 H NMR(400MHz,メタノール-d4)δ8.37(br d,J=4.9Hz,1H),7.33-7.14(m,2H),6.83(br dd,J=11.1,16.0Hz,1H),6.72-6.54(m,2H),6.30(br d,J=17.4Hz,1H),5.83(br d,J=9.3Hz,1H),4.71-4.54(m,4H),4.31-4.15(m,2H),3.67(br d,J=12.7Hz,1H),3.48(br d,J=1.7Hz,2H),2.89(br d,J=7.1Hz,1H),2.14(s,3H),1.37-1.04(m,6H).

[0799] MS(ESI)m / z(M+H) + =592.3.

[0800] SFC reaction time: 4.375 min

[0801] Separation conditions: Chromatographic column: Chiralcel OD-3 100 × 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: CO2-ethanol (0.05% DEA), Ethanol %: 5%-40% 4 min, 40% 2.5 min, 5% 1.5 min; Flow rate: 2.8 mL / min.

[0802] Compound 15C:

[0803] 1 H NMR (400MHz, methanol-d4) δ8.40(d,J=4.9Hz,1H),7.29-7.19(m,2H),6.85(br dd,J=10.8,16.4Hz,1H),6.73-6.61(m,2H),6.32(br d,J=16.9Hz,1H),5.85(br d,J=10.8Hz,1H),4.62(br s,3H),4.45(br d,J=13.0Hz,1H),4.22(br s, 2H), 3.82-3.68 (m, 1H), 3.65-3.49 (m, 2H), 3.04-2.92 (m, 1H), 2.15 (s, 3H), 1.23-1.04 (m, 6H).

[0804] MS(ESI)m / z(M+H) + =592.3.

[0805] SFC reaction time: 4.688 min

[0806] Separation conditions: Chromatographic column: Chiralcel OD-3 100 × 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: CO2-ethanol (0.05% DEA), Ethanol %: 5%-40% 4 min, 40% 2.5 min, 5% 1.5 min; Flow rate: 2.8 mL / min.

[0807] Compound 15D:

[0808] 1 H NMR (400MHz, methanol-d4) δ8.39(d,J=4.8Hz,1H),7.30-7.20(m,2H),6.85(br dd,J=10.3,16.6Hz,1H),6.71-6.61(m,2H),6.31(br d,J=16.8Hz,1H),5.84(br d,J=10.5Hz,1H),4.71-4.59(m,3H),4.58-4.43(m,1H),4.23(br s,2H),3.75-3.64(m,1H),3.64-3.37(m,2H),2.96-2.86(m,1H),2.15(s,3H),1.21(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H).

[0809] MS(ESI)m / z(M+H) + =592.3.

[0810] SFC reaction time: 4.891 min

[0811] Separation conditions: Chromatographic column: Chiralcel OD-3 100 × 4.6 mm ID, 3 μm; Column temperature: 35 °C; Mobile phase: CO2-ethanol (0.05% DEA), Ethanol %: 5%-40% 4 min, 40% 2.5 min, 5% 1.5 min; Flow rate: 2.8 mL / min.

[0812] Experimental Example 1: Inhibition of RAS-mediated signaling

[0813] The ability of compounds of the present disclosure to inhibit RAS-mediated signaling was evaluated and demonstrated as follows: NCI-H358 cells (ATCC Accession No. CRL-5807) expressing mutant RAS (G12C) were cultured in RPMI medium containing 10% fetal bovine serum and penicillin / streptomycin double antibody. Cells were seeded at 40,000 cells / well on a 96-well plate (Corning Cat. No. 3699) and allowed to settle overnight to adhere to the bottom of the plate. Cells were treated with or without compounds of the present disclosure (dimethyl sulfoxide, DMSO) to ensure a final DMSO concentration of 0.5%. After 2 hours of treatment, the medium was removed and 4% paraformaldehyde (Beyotime Cat. No. E672002-0100) was added. The resulting mixture was allowed to settle for 20 minutes. After fixation, the cells were washed with PBS and incubated with pre-chilled methanol for 10 minutes to permeabilize the cell membrane. Non-specific antibody binding was blocked by incubation with 1× blocking buffer (Thermo Cat. No. 37520) for 1 hour.

[0814] ERK phosphorylation was detected by enzyme-linked immunosorbent assay (ELISA). Phospho-ERK antibody (Cell Signal Technology Cat. No. 4370) was diluted 1:400 in 1x blocking buffer containing 0.05% Tween 20 and added to a 96-well plate and incubated overnight at 4°C. The plate was washed five times with PBS containing 0.05% Tween 20. HRP-conjugated secondary antibody (Thermo Cat. No. 31460) was diluted 1:10,000 in 1x blocking buffer containing 0.05% Tween 20 and added to the 96-well plate and incubated for 2 hours at room temperature. The plate was washed five times with PBS containing 0.05% Tween 20 and incubated with TMB (Thermo Cat. No. 4816) for 15 minutes at room temperature. The reaction was terminated with 1 mol / L H2SO4, and the OD value was read at a wavelength of 450 nm using EnVision (PerkinElmer).

[0815] The total number of cells per well was determined using Janus Green staining. After ERK phosphorylation detection, the 96-well plate was washed with PBS to remove the stain and then incubated with 0.1% Janus Green (Abcam Cat. No. ab111622) for 10 minutes. After washing with double-distilled water, the plate was incubated with 0.1 mol / L HCl for 10 minutes with shaking. OD values ​​were read at 595 nm using EnVision (PerkinElmer).

[0816] The Janus Green signal values ​​were used to normalize the pERK (Thr202 / Tyr204) signal values, and the percentage of inhibition relative to the DMSO control was calculated after drug treatment. The percentage values ​​were subjected to a four-parameter dose-response curve fit to obtain IC50 values. The results are shown in Table 1.

[0817] [Table 1-1]

[0818] [Table 1-2]

[0819] The compounds of the present disclosure exhibited excellent inhibitory potency against RAS-mediated signaling.

[0820] Experimental Example 2: Cell proliferation assay

[0821] The ability of compounds of the present disclosure to inhibit the proliferation of KRAS-G12C-expressing tumor cell lines was evaluated and demonstrated as follows.

[0822] The ability of compounds of the present disclosure to inhibit the proliferation of KRAS-G12C-expressing cells was evaluated by measuring cell viability and calculating GI50 values.

[0823] The tumor cell line NCI-H358 (ATCC accession number CRL-5807), which expresses KRAS-G12C, was cultured in RPMI medium supplemented with 10% fetal bovine serum and penicillin / streptomycin double antibody. The tumor cell line MIA PaCa2 (ATCC CRL-1420), which expresses KRAS-G12C, was cultured in DMEM medium supplemented with 10% fetal bovine serum, 2.5% horse serum, and penicillin / streptomycin double antibody.

[0824] NCI-H358 and MIA-Paca2 cells were plated at densities of 1000 and 800 cells, respectively, in black, clear-bottom 84-well plates (PerkinElmer Cat. No. 6007460) and allowed to attach overnight (8-12 hours). After the cells had attached to the wells, a compound of the present disclosure diluted to a concentration 5x that of a working solution (containing 0.1% dimethyl sulfoxide, or DMSO, at a final concentration) was added to the experimental group. The same dilution (containing 0.1% DMSO at a final concentration) was added to the control group. After 72 hours, cell proliferation was measured by measuring ATP content using Cell Titer Glo Reagent (Promega Cat. No. G7572) according to the manual. The process is briefly described as follows: The cell plate was removed and equilibrated at normal temperature for 30 minutes. An equal volume of Cell Titer Glo Reagent was added to the culture. The culture plate was placed on a shaker and lysed for 2 minutes. The culture plate was left standing at normal temperature for 10 minutes, and the optical signal value was read using a microplate reader EnVision (PerkinElmer).

[0825] The percentage inhibition was calculated from the data of the experimental group compared with the DMEM group, and the GI was calculated using the data processing software GraphPad by analyzing the inhibition rates obtained at nine administration concentrations resulting from 1:3 compound dilutions. The results are shown in Table 2.

[0826] [Table 2]

[0827] The compounds of the present disclosure have excellent inhibitory activity against the proliferation of NCI-H358 and MIA-Paca2 cells.

Claims

【Request Item 1】 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 A compound of the above formula selected from:

2. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament, wherein the medicament can be used to prevent and / or treat a KRAS-G12C-associated disease.

4. The use according to claim 3, wherein the KRAS-G12C-associated disease is selected from non-small cell lung cancer, colon cancer, and pancreatic cancer.

Images