Compound as MYT1 inhibitor

Abstract

Compounds as MYT1 inhibitors are disclosed in the present invention. In particular, the present invention relates to compounds represented by general formula (1), methods for preparing the same, and the use of the compounds of general formula (1), and their isomers, their crystals, their pharmaceutically acceptable salts, their hydrates or their solvates as MYT1 inhibitors. The compounds of the present invention, and their isomers, their crystals, their pharmaceutically acceptable salts, their hydrates or their solvates can be used for preparing medicaments for treating or preventing diseases related to the MYT1 protein. TIFF2025523030000232.tif40168

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application No. 202210822834.5 filed on July 12, 2022 and Chinese Patent Application No. 202310048632.4 filed on January 31, 2023, which are incorporated herein by reference in their entirety.

[0002] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a group of compounds having an inhibitory effect on MYT1 protein, a method for preparing the same, and the use of the compound in the preparation of a medicament for treating or preventing related diseases mediated by MYT1.

Background Art

[0003] The cell cycle has two checkpoints, G1 and G2, by which cells efficiently repair DNA damage, thereby maintaining genomic stability. Both Wee1 and MYT1 of the Wee kinase family are involved in the regulation of this cell cycle. MYT1 is mainly present in the cell nucleus and specifically phosphorylates threonine at position 14 of its substrate, cyclin-dependent kinase 1 (CDK1). This MYT1-mediated phosphorylation inhibits the activity of the CDK1 / cyclin B complex and prevents the cell from transitioning into mitosis. Since many tumor cells have p53 mutations that result in defective repair of the G1 checkpoint, these tumor cells rely heavily on the G2 checkpoint for DNA damage repair. Therefore, inhibiting the activity of MYT1 to inhibit the G2 checkpoint, selectively damaging tumor cells that rely heavily on the G2 checkpoint, and simultaneously reducing damage to normal cells is a promising targeted strategy.

Summary of the Invention

Problems to be Solved by the Invention

[0004] From the above, it is urgent to research and discover compounds with excellent activity targeting MYT1.

Means for Solving the Problem

[0005] (Summary) The present invention provides a compound of general formula (1), or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

Chem.

Chemical formula

Chemical formula

[0006] In another preferred embodiment, in general formula (1), R a1 , R a2 , R a3 , and R 1is, independently of each other, -H, halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl, -N(R 3 )2, -OR 3 , -C(O)N(R 4 )2, -SO2N(R 4 )2, -SO2R 3a , or -Q-R 3b , where the (C1-C6)alkyl, the (C1-C6)haloalkyl, the (C2-C6)alkenyl, the (C2-C6)alkynyl, the (C3-C8)cycloalkyl, the (C6-C10)aryl, the (5-10-membered)heteroaryl, or the (3-9-membered)heterocycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, aryl, and (5-6-membered)heteroaryl; or R a3 and R 1 , together with the carbon atoms to which they are respectively attached, form (C3-C8-membered)cycloalkyl, (4-8-membered)heterocycloalkyl, phenyl, or (5-6-membered)heteroaryl, where the (C3-C8-membered)cycloalkyl, the (4-8-membered)heterocycloalkyl, the phenyl, or the (5-6-membered)heteroaryl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl.

[0007] In another preferred embodiment, in general formula (1), Ra1 、R a2 、R a3 、およびR 1 are each independently -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2,

Chem.

Chem.

Chem.

[0008] In another preferred embodiment, in general formula (1), R a3 and R 1 together with the carbon atom to which each is attached form the following structural unit:

Chem.

[0009] In another preferred embodiment, in general formula (1), when none of R a1 , R a2 , R a3 , and R 1 is -CN, R 2 is

Chem.

[0010] In another preferred embodiment, in general formula (1), R a1 , R a2 , R a3 , and R 1 are not -CN, R 2 is

Chemical formula

[0011] In another preferred embodiment, in general formula (1), R a1 , R a2 , R a3 , and R 1 are at least one -CN, or R a3 and R 1 together with the carbon atoms to which they are respectively attached form (C4 - C9) cycloalkenyl, (4 - 9 membered) heterocycloalkyl, or (5 - 10 membered) heteroaryl, the (C4 - C9) cycloalkenyl, the (4 - 9 membered) heterocycloalkyl, or the (5 - 10 membered) heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, halogen, -OH, -OR 5 , -N(R 5 )2, -CN, (C1 - C6) alkyl, (C1 - C6) haloalkyl, (C2 - C6) alkenyl, (C2 - C6) alkynyl, and (C3 - C8) cycloalkyl, R 2 is

Chemical formula

[0012] In another preferred embodiment, in general formula (1), when at least one of R a1 , R a2 , R a3 , and R 1 is -CN, or R a3and R 1 When R is bonded to the carbon atoms to which they are respectively bonded to form a (C4-C9) cycloalkenyl, (4-9 membered) heterocycloalkyl, or (5-10 membered) heteroaryl, the (C4-C9) cycloalkenyl, the (4-9 membered) heterocycloalkyl, or the (5-10 membered) heteroaryl is each independently -H, halogen, -OH, -OR 5 , -N(R 5 )2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C8) cycloalkyl, and may be optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of; R 2 is [Chemical formula] as shown below.

[0013] In another preferred embodiment, in general formula (1), each R 3 is independently -H, (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, (5-6 membered) heteroaryl, or -SO2R 3a wherein the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the (3-6 membered) heterocycloalkyl, the phenyl, or the (5-6 membered) heteroaryl is each independently -H, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, -F, -Cl, -Br, or -I, and may be optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of; or two Rs on the same nitrogen atom 3may, together with the nitrogen atom to which they are attached, form a (3- to 6-membered) heterocycloalkyl, wherein the (3- to 6-membered) heterocycloalkyl is independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C3-C6) cycloalkyl.

[0014] In another preferred embodiment, in general formula (1), each R 3 is independently -H,

Chemical formula

Chemical formula

[0015] In another preferred embodiment, in general formula (1), each R 3a is independently (C1-C5) alkyl, (C1-C5) haloalkyl, (C3-C6) cycloalkyl, (3- to 6-membered) heterocycloalkyl, phenyl, or (5- to 6-membered) heteroaryl, wherein the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C3-C6) cycloalkyl, the (3- to 6-membered) heterocycloalkyl, the phenyl, or the (5- to 6-membered) heteroaryl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, -F, -Cl, -Br, or -I.

[0016] In another preferred embodiment, in general formula (1), each R 3a is independently

Chemical formula

[0017] In another preferred embodiment, in general formula (1), each R 3b is independently (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, (5-6 membered) heteroaryl, -N(R 3 )2, -OR 3 , -C(O)N(R 4 )2, -SO2N(R 4 )2, or -SO2R 3a , where the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the phenyl, the (5-6 membered) heteroaryl, or the (3-6 membered) heterocycloalkyl is each independently optionally substituted with one, two, three, or four groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, and (5-6 membered) heteroaryl.

[0018] In another preferred embodiment, in general formula (1), each R 3b is independently -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, [Chemistry] , -CF3, -CH2CF3, [Chemistry] , -OCH2CH3, -OCH(CH3)2, [Chemistry] is as follows.

[0019] In another preferred embodiment, in general formula (1), Q is (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, (3-6 membered) heterocycloalkylene, phenylene, or (5-6 membered) heteroarylene, where the (C1-C3) alkylene, the (C2-C4) alkenylene, the (C2-C4) alkynylene, the (C3-C6) cycloalkylene, the phenylene, the (5-6 membered) heteroarylene, or the (3-6 membered) heterocycloalkylene is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, and (5-6 membered) heteroaryl.

[0020] In another preferred embodiment, in general formula (1), each Q is independently [Chemistry] is as follows.

[0021] In another preferred embodiment, in general formula (1), each R 4is, independently, -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C1-C5)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, or (5-6 membered)heteroaryl, where the (C1-C5)alkyl, the (C1-C5)haloalkyl, the (C1-C5)alkoxy, the (C3-C6)cycloalkyl, the (3-6 membered)heterocycloalkyl, the phenyl, or the (5-6 membered)heteroaryl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I; or two Rs on the same nitrogen atom 4 together with the nitrogen atom to which they are attached may form a (3-6 membered)heterocycloalkyl, where the (3-6 membered)heterocycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl.

[0022] In another preferred embodiment, in general formula (1), each R 4 is, independently, -H, -OCH3, -OCH2CH3, -OCH(CH3)2,

Chemical formula

Chemical formula

[0023] In another preferred embodiment, in general formula (1), each R 5is, independently, -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, or -SO2R 3a wherein said (C1-C5)alkyl, said (C1-C5)haloalkyl, said (C2-C4)alkenyl, said (C2-C4)alkynyl, said (C3-C6)cycloalkyl, said phenyl, said (5-6 membered)heteroaryl, or said (3-6 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I; or two Rs on the same nitrogen atom 5 together with the nitrogen atom to which they are attached may form a (3-6 membered)heterocycloalkyl, where said (3-6 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -CN, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl.

[0024] In another preferred embodiment, in general formula (1), each R 5 is, independently, -H,

Chemical formula

Chemical formula

[0025] In another specific embodiment of the present invention, the compound of general formula (1) has the following structure: [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] has one of the following.

[0026] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and, as an active ingredient, a compound of general formula (1) of the present invention or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0027] The present invention further provides the use of a compound of general formula (1) of the present invention, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with MYT1 protein, wherein the disease is preferably cancer, and the cancer is a hematological cancer or a solid cancer.

[0028] The present invention further provides a method for treating, regulating or preventing a disease associated with MYT1 protein, the method comprising administering a therapeutically effective amount of a compound of general formula (1) of the present invention, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, or the above pharmaceutical composition, to a subject.

[0029] Through the synthesis and careful study of various novel compounds having an inhibitory effect on MYT1, the inventors have discovered that the compounds of general formula (1) have surprisingly strong inhibitory activity against MYT1.

[0030] It should be understood that both the above general description and the following detailed description of the present invention are exemplary and explanatory, and are intended to provide further description of the claimed invention.

[0031] (Synthesis of Compounds) A method for preparing the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not limit the present invention in any way.

[0032] The compounds of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Further, the solvents, temperatures and other reaction conditions described herein may vary. The starting materials for the synthesis of the compounds may be obtained by synthesis or may be commercially available. The compounds described herein and other related compounds having different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 thEd., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., Vols. A and B (Plenum 2000, 2001), as well as Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd It can be synthesized using well-known techniques and starting materials, including the methods found in Ed., (Wiley 1999). General methods for preparing the compounds can be modified by using appropriate reagents and conditions for introducing various groups into the molecular formulas described herein.

[0033] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and time required for the reaction, are not limited to the following description. Also, the compounds of the present invention can be readily prepared by arbitrarily combining various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art relevant to the present invention. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1) prepared using the following general reaction scheme 1.

[0034] General Reaction Scheme 1

Chemical formula

[0035] Embodiments of the compound of general formula (1) can be prepared according to General Reaction Scheme 1, where R 1 , R 2 , X 1 , and X 3is as defined above, where X represents iodine or bromine, N represents nitrogen, O represents oxygen, and Br represents bromine. As shown in General Reaction Scheme 1, Compound 1-1 is subjected to a coupling reaction with Compound 1-2 in the presence of Pd2(dba)3 to produce Compound 1-3, and Compound 1-3 is subjected to a coupling reaction with Compound 1-4 in the presence of Pd(dppf)Cl2 to produce Compound 1-5. The cyano group in Compound 1-5 is hydrolyzed under acidic conditions to produce an amide compound 1-6. Optionally, Compound 1-6 is subjected to deprotection to produce Compound 1-7. Optionally, Compound 1-7 is enantiomerically resolved to produce atropisomers 1-7-A and 1-7-B.

[0036] Further forms of the compound As used herein, "pharmaceutically acceptable" refers to a substance that does not cause the loss of biological activity or properties in a compound, such as a carrier or diluent, and is relatively non-toxic. For example, when administering a certain substance to an individual, the substance does not cause undesirable biological effects or harmful interactions with any of its components.

[0037] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism receiving the administration and does not eliminate the biological activity and properties of the compound. In certain specific embodiments, the pharmaceutically acceptable salt is obtained by subjecting a compound of a general formula to a reaction with an acid or a base, where the acid or base includes, but is not limited to, those described in Stahl and Wermuth, Handbook of Pharmaceutical Salts: properties, Selection, and Use, 1 st Ed., (Wiley, 2002).

[0038] It should be understood that pharmaceutically acceptable salts include solvated or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed upon crystallization in pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water and alcoholates are formed when the solvent is ethanol. Solvates of the compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of the compounds of general formula (1) are conveniently prepared by recrystallization in a mixed solvent of water / organic solvent, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds described herein may exist in either non-solvated or solvated form. In general, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

[0039] In other specific examples, the compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous form, milled form, and nanoparticle form. Furthermore, the compounds of general formula (1) include a crystalline form and may be polymorphs. Polymorphs contain different lattice arrangements of the same elements of the compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical properties, electrical properties, stability, and solubility. Depending on various factors such as the recrystallization solvent, crystallization rate, and storage temperature, a single dominant crystal system may result.

[0040] In another aspect, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and thus may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers, atropisomers and cis-trans isomers. Each chiral center or axial asymmetry independently generates two optical isomers or atropisomers, and all possible optical isomers, atropisomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0041] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compound may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). As another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Generally, compared with non-deuterated pharmaceuticals, deuterated pharmaceuticals have advantages such as a reduction in side effects, an improvement in the stability of the pharmaceutical, an enhancement of efficacy, and an extension of the in vivo half-life. All isotope variations of the compounds of the present invention are included within the scope of the present invention, whether radioactive or not.

[0042] Explanation of Terms Unless otherwise specified, the terms used in this specification, including those described in the specification and claims of the present application, are defined as follows. It should be noted that in this specification and the appended claims, the singular forms "a" and "an" include plural meanings unless otherwise specified. Unless otherwise specified, conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this specification, "or" or "and" means "and / or" unless otherwise specified.

[0043] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group having a straight-chain and branched group containing 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl are preferred. As used herein, "alkyl" includes unsubstituted alkyl and substituted alkyl, particularly alkyl substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu, or t selected from Bu.

[0044] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0045] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon double bond and containing a straight-chain or branched group containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl are preferred.

[0046] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl as defined above.

[0047] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond and containing a straight-chain and branched group containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms such as ethynyl, 1-propynyl, or 1-butynyl are preferred.

[0048] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl as defined above.

[0049] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and a partially unsaturated cycloalkyl may be called "cycloalkenyl" if the carbon ring contains at least one double bond, or "cycloalkynyl" if the carbon ring contains at least one triple bond. Cycloalkyl may include a monocyclic group or a polycyclic group (e.g., having 2, 3, or 4 fused rings), and a spiro ring. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring carbon atoms of cycloalkyl may optionally be oxidized to form an oxo group or a thio group. Cycloalkyl further includes cycloalkylene. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphenyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0050] Unless otherwise specified, "cycloalkylene" refers to the divalent cycloalkyl defined above.

[0051] Unless otherwise specified, "alkoxy" refers to an alkyl group that is bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy is OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO, and t- selected from BuO.

[0052] Unless otherwise specified, "aryl" refers to an aromatic hydrocarbon group that is monocyclic or polycyclic. For example, a monocyclic aryl ring can be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0053] Unless otherwise specified, "aryloxy" refers to an aryl group that is bonded to the remainder of the molecule through an ether oxygen atom. Examples of the aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0054] Unless otherwise specified, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, and phenanthrylene.

[0055] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), preferably an aromatic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, more preferably an aromatic group containing 1 to 2 heteroatoms selected from any of oxygen, sulfur, or nitrogen. Heteroaryl can be monocyclic or polycyclic. For example, a monocyclic heteroaryl ring can be condensed with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl include pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

Chemical formula

[0056] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0057] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylenes as part of the ring structure and has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl is preferably a saturated or partially unsaturated ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, or nitrogen, more preferably a saturated or partially unsaturated ring containing 1 to 2 heteroatoms selected from oxygen, sulfur, or nitrogen. A partially unsaturated heterocycloalkyl may be called "heterocycloalkenyl" when the heterocycloalkyl contains at least one double bond, and may be called "heterocycloalkynyl" when the heterocycloalkyl contains at least one triple bond. Heterocycloalkyl may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused rings or bridged rings). In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of heterocycloalkyl may optionally be oxidized to form oxo groups, thio groups, or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atoms may be quaternized. Heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl is a moiety having one or more aromatic rings fused to the heterocycloalkyl ring (also called a partially unsaturated heterocyclic ring), e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyl containing a fused aromatic ring may be bonded through any ring atom including the ring atoms of the fused aromatic ring.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl, etc., but are not limited thereto.

Chem.

[0058] Unless otherwise specified, "heterocycloalkylene" means the divalent heterocycloalkyl defined above.

[0059] Unless otherwise specified, "oxo" means =O. For example, a group formed by substituting carbon with one oxo is "carbonyl"

Chem.

Chem.

Chemical formula

[0060] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a group name indicates that the group is partially or fully halogenated, i.e., substituted with F, Cl, Br, or I, preferably F or Cl, in any combination.

[0061] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a specified atom or group are substituted with one or more substituents other than hydrogen, within the normal valency of the specified atom. For example, one or more hydrogens of alkyl, alkylene, alkenyl, alkynyl, hydroxy, amino, etc. may be substituted with one or more substituents, where the substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxy, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. The definition of "substituted" does not include similar indeterminate structures obtained by further defining substituents with infinitely bonded substituents (e.g., a substituted aryl having a substituted alkyl, where the substituted aryl is itself substituted with a substituted aryl, and the substituted aryl is further substituted with a substituted heteroalkyl, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to a substituted aryl substituted with ((substituted aryl) substituted substituted aryl). Similarly, the above definition does not include unacceptable substitution patterns (e.g., methyl substituted with five fluorines or heteroaryl having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, "substituted" may represent other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise specified, when a group is described as being optionally substituted, the substituents of that group are themselves unsubstituted.

[0062] "Any" or "optionally" means that the event or situation described thereafter may occur, but does not necessarily occur, and the description includes examples where the event or situation occurs and examples where it does not occur.

[0063] Unless otherwise specified, the word "comprise", or variations thereof such as "comprises" or "comprising", is understood to mean that the specified element or integer, or group of elements or integers, is included, but that other elements or integers, or groups of elements or integers, are not excluded.

[0064] The substituent "-O-CH2-O-" means that two oxygen atoms in the substituent are bonded to two adjacent carbon atoms in a heterocycloalkyl, aryl or heteroaryl, for example, as follows.

Chemical Structure

[0065] When the number of the linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0066] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked. For example, when L in X-L-Y represents a chemical bond, it actually means the structure of X-Y.

[0067] The term "membered ring" includes any cyclic structure. The term "member" refers to the number of backbone atoms forming the ring. For example, cyclohexyl, pyridinyl, pyranyl and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0068] The term "moiety" refers to a particular part or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or bonded to a molecule.

[0069] The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond within a molecule is hindered or very slow due to steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric, i.e., the atropisomer does not require a stereocenter. When the rotational barrier around the single bond is sufficiently high and the interconversion between conformational configurations is sufficiently slow, separation of the individual isomers may be possible, preferably by chiral resolution methods (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005).

[0070] Unless otherwise specified, the absolute configuration of the stereocenter is represented by a wedge-shaped solid bond

Chem.

Chem.

Chem.

Chem.

Chem.

[0071] Unless otherwise specified, a single bond or a double bond is

Chem.

[0072] Specific pharmaceutical and medical terms As used herein, the term "acceptable" means that a formulation ingredient or active ingredient does not exert an excessive and harmful effect on the health of the general subject being treated.

[0073] As used herein, the terms "treatment", "course of treatment", and "therapy" include alleviating, inhibiting, or improving the symptoms or condition of a disease, inhibiting the occurrence of complications, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), alleviating a disease or symptom, regressing a disease or symptom, and alleviating the complications caused by a disease or symptom, or preventing or treating the signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, and in particular, can improve the severity of a disease, delay its onset, slow its progression, or shorten its duration. Administration can be by fixed or single administration, or by continuous or intermittent administration, and can be due to or related to the administration.

[0074] "Active ingredient" refers to a compound of general formula (1) and pharmaceutically acceptable inorganic or organic salts of the compound of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry), and thus may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers, and atropisomers. The possible asymmetric centers may exist depending on the nature of various substituents on the molecule. Each such asymmetric center independently generates two optical isomers, and all possible optical isomers, atropisomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. This means that the present invention includes all such isomeric forms of these compounds.

[0075] As used herein, the terms "compound", "composition", "agent" or "medicine or pharmaceutical product" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), can induce a desired pharmacological and / or physiological response by local and / or systemic action.

[0076] As used herein, the term "administered, administering, or administration" means the direct administration of a compound or composition, or the administration of a prodrug, derivative, analog, etc. of an active compound.

[0077] The numerical ranges and parameters that define the broad scope of the present invention are approximations, but the relevant values shown in the specific embodiments are presented as accurately as possible herein. However, any numerical values inherently contain standard deviations that necessarily result from certain testing methods. Here, "about" generally means that the actual value is within ±10%, 5%, 1%, or 0.5% of a specific value or range. Alternatively, the term "about" indicates that the actual numerical value is within the range of an acceptable standard error of the mean, as would be understood by those skilled in the art. Unless otherwise excluded or specifically stated in the experimental examples, all ranges, amounts, values, and percentages (e.g., for describing the amount of a substance, the length of time, temperature, operating conditions, ratio of amounts, etc.) used herein are understood to be modified by the term "about". Therefore, unless otherwise specifically stated, the numerical parameters described in this specification and the appended claims are all approximate values that can vary as desired. At a minimum, these numerical parameters should be construed as being obtained using the indicated significant figures or the conventional rounding rules.

[0078] Unless otherwise defined herein, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Further, singular nouns used herein include their plurals unless the context is inconsistent, and plural nouns used include their singulars.

[0079] Therapeutic uses The compound or pharmaceutical composition of general formula (1) of the present invention is generally useful for inhibiting the MYT1 protein and for treating one or more diseases related to the activity of the MYT1 protein. Thus, in certain embodiments, the present invention provides a method for treating MYT1 protein-mediated diseases, the method comprising administering to a patient in need thereof a compound of general formula (1) of the present invention or a pharmaceutically acceptable composition thereof.

[0080] In some embodiments, a method for treating cancer is provided, the method comprising administering to an individual in need thereof an effective amount of the aforementioned pharmaceutical composition containing a compound of general structural formula (1). In some embodiments, the cancers include, but are not limited to, hematological malignancies (leukemia, lymphoma, and myelomas including multiple myeloma, myelodysplastic syndrome, and myeloproliferative familial syndrome), solid cancers (prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, and cancers such as soft tissue cancer, osteosarcoma, and stromal tumors), preferably breast cancer, endometrial cancer, ovarian cancer, uterine carcinosarcoma, ovarian carcinosarcoma, pancreatic ductal adenocarcinoma, lung cancer, intestinal cancer, colorectal cancer, and esophageal cancer.

[0081] Route of administration The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into various preparations containing a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject being treated.

[0082] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and low toxicity. "Compatibility" as used herein means that the components of the composition can be intermixed with the compounds of the present invention without significantly reducing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose or cellulose acetate), gelatin, talc, solid lubricants (such as stearic acid or magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, or olive oil), polyols (such as propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), coloring agents, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0083] When administering the compounds of the present invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously) or topically.

[0084] Solid dosage forms for oral administration include capsules, tablets, pills, powders (pulvises) and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following components: (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxy methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders such as paraffin; (f) absorption promoters such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may further contain buffering agents.

[0085] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. These may contain opacifying agents and the active compound or compounds in such compositions may be released in a delayed manner in specific parts of the digestive tract. Examples of embedding components that can be used include polymeric substances and wax-like substances. Optionally, the active compound can form microcapsules together with one or more of the above excipients.

[0086] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, among others. In addition to the active compound, the liquid dosage forms may contain water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, which are inert diluents commonly used in the art.

[0087] In addition to such inert diluents, the composition may further contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes.

[0088] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar, or mixtures of these substances.

[0089] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non - aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non - aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0090] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants, among others. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required as necessary.

[0091] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When the pharmaceutical compositions of the present invention are used, a safe and effective amount of the compounds of the present invention is administered to the mammal (such as a human) to be treated, where the dosage is a pharmaceutically effective dosage. In the case of a 60 kg human, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, in specific dosages, factors such as the route of administration and the health status of the patient are also considered, but these are well known to those skilled in the art.

[0092] The features described in the present invention, or the above features in the embodiments, can be arbitrarily combined. All features disclosed in this specification can be used in any composition form, and various features disclosed in this specification can be replaced with any alternative features that provide the same, equivalent or similar purposes. Therefore, unless otherwise specified, the features disclosed in this specification are merely general examples of equivalent or similar features.

[0093] (Detailed Description) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions are described in detail as follows, which will make the content of the present invention very clear. It should be understood that the following detailed description and examples only describe specific examples for reference. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0094] In all examples, 1 The 1H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and the chemical shifts are represented in δ (ppm). Silica gel for separation was silica gel of 200 - 300 mesh if not otherwise specified, and the ratio of the eluent was a volume ratio.

[0095] The following abbreviations are used in the present invention. (Boc)2O is di-tert-butyl dicarbonate; CDCl3 is deuterated chloroform; Cs2CO3 is cesium carbonate; CuI is cuprous iodide; EtOAc is ethyl acetate; Hexane is n-hexane; HPLC is high performance liquid chromatography; MeCN is acetonitrile; DCM is dichloromethane; DDQ is 2,3-dichloro-5,6-dicyano-p-benzoquinone; DIPEA is diisopropylethylamine; Dioxane is 1,4-dioxane; DME is glycol dimethyl ether; DMEDA is N,N-dimethylethylenediamine; DMF is N,N-dimethylformamide; DMAP is 4-(dimethylamino)pyridine; DMSO is dimethyl sulfoxide; EtOH is ethanol; EtOAc is ethyl acetate; EA is ethyl acetate; h is hour; IPA is isopropanol; ISCO® is Biotage Isolera Prime flash preparative liquid chromatograph; min is minute; K2CO3 is potassium carbonate; KOAc is potassium acetate; KOH is potassium hydroxide; K3PO4 is potassium phosphate; LiBH4 is lithium borohydride; min is minute; m-CPBA is m-chloroperbenzoic acid; MeOH is methanol; MeONa is sodium methoxide; MS is mass spectrometry; NaBH(OAc)3 is sodium triacetoxyborohydride; NaH is sodium hydride; NMR is nuclear magnetic resonance; NBS is N-bromosuccinimide; NIS is N-iodosuccinimide; Pd / C is palladium on carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd(OAc)2 is palladium acetate; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE is petroleum ether; Petroleum ether is petroleum ether; PMBNH2 is 4-methoxybenzylamine; PPh3 is triphenylphosphine; TEA is triethylamine; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; THF is tetrahydrofuran; TsOH is p-toluenesulfonic acid; TsCl is p-toluenesulfonyl chloride; TfOH is trifluoromethanesulfonic acid; TLC is thin layer chromatography; SFC is supercritical fluid chromatography;XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos represents 2-dicyclohexylphosphonium-2′,4′,6′-triisopropylbiphenyl; XantPhos Pd G3 represents [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate.

[0096] Example 1: Synthesis of Compound 1

Chemical Structure

[0097] Step 1: Synthesis of Compound int_1-3

Chemical Structure

[0098] Int_1-1 (3.00 g, 9.47 mmol), int_1-2 (16.6 g, 66.3 mmol, 18.5 mL, 50% purity), Pd(dppf)Cl2 (693 mg, 947 μmol), and K2CO3 (5.23 g, 37.9 mmol) were dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (12 mL). The mixed solution was purged with nitrogen three times, heated to 80 °C, and stirred for 2 hours. The completion of the reaction was indicated by TLC monitoring. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / DCM = 19 / 1) to obtain a white solid (1.2 g, yield 67.7%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 6.94 (t, J = 9.0 Hz, 1H), 2.24 - 2.13 (m, 6H).

[0099] Step 2: Synthesis of Compound int_1-4 [Chemical formula]

[0100] Int_1-3 (1.00 g, 5.34 mmol) was dissolved in methanol (10 mL), and MeONa (1.06 g, 5.88 mmol, 30% purity) was added at 0 °C. The reaction solution was reacted at 80 °C for 2 hours. Additional MeONa (3.85 g, 21.37 mmol, 30% purity) was added, and the reaction solution was reacted at 80 °C for 8 hours. Additional MeONa (4.81 g, 26.7 mmol, 30% purity) was added, and the reaction solution was reacted at 80 °C for 10 hours. TLC monitoring indicated the completion of the reaction. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (880 mg), which was used as such in the next step. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 11.0 Hz, 1H), 3.86 (s, 3H), 2.13 (dd, J = 1.3, 14.5 Hz, 6H).

[0101] Step 3: Synthesis of compound int_1-5: [Chemical formula]

[0102] Int_1-4 (880 mg, 4.42 mmol) was dissolved in ethanol (3 mL) and water (2 mL), and NH4Cl (2.36 g, 44.2 mmol) and acetic acid (133 mg, 2.21 mmol, 126 μL) were added. The mixed solution was heated to 50 °C, and iron powder (1.23 g, 22.1 mmol) was slowly added. After the addition, the mixed solution was heated to 80 °C and stirred for 0.5 h. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 10 / 1 - 5 / 1) to give a solid (730 mg, yield 97.7%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 6.15 (d, J = 11.7 Hz, 1H), 3.83 (br s, 2H), 3.78 (s, 3H), 2.06 (d, J = 1.5 Hz, 3H), 2.04 (s, 3H). ESI-MS m / z: 170 [M+H] + 。

[0103] Step 4: Synthesis of compound int_1-7:

Chemical Structure

[0104] Int_1-5 (700 mg, 4.14 mmol) and int_1-6 (1.10 g, 4.14 mmol) were dissolved in DME (10 mL), and Cs2CO3 (3.24 g, 9.93 mmol), Xantphos (239 mg, 414 μmol), and Pd2(dba)3 (379 mg, 414 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 90 °C, and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 10 / 1) to obtain a solid (1.2 g, yield 82.1%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 7.45 (s, 1H), 6.55 (d, J = 11.4 Hz, 1H), 6.20 (br s, 1H), 3.82 (s, 3H), 2.24 - 2.11 (m, 6H), 2.05 (d, J = 2.8 Hz, 6H). ESI-MS m / z: 353 [M+H] + .

[0105] Step: Synthesis of compound int_1-9: [Chemical formula]

[0106] Int_1-8 (118 mg, 1.78 mmol, 112 μL) and Cs2CO3 (609 mg, 1.87 mmol) were dissolved in DMF (4 mL). The reaction solution was heated to 40 °C and reacted for 0.5 h. Int_1-7 (300 mg, 849 μmol), CuI (80.9 mg, 425 μmol), and DMEDA (37.4 mg, 425 μmol) were added to the reaction solution. The reaction solution was purged with nitrogen three times, heated to 90 °C, and reacted for 16 h. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 0 - 4 / 1) to obtain a solid (270 mg, yield 94.0%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 7.51 (s, 1H), 6.78 (d, J = 11.1 Hz, 1H), 4.53 (s, 2H), 3.87 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 1.82 (d, J = 2.0 Hz, 3H), 1.80 (s, 3H). ESI-MS m / z: 339 [M+H] + 。

[0107] Step 6: Synthesis of compound int_1-10:

Chemical Structure

[0108] At 0 °C, sulfuric acid (4 mL) was slowly added to int_1-9 (220 mg, 650 μmol). The reaction solution was reacted at 0 °C for 3 hours. Completion of the reaction was indicated by LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 0 to 3 / 1) to obtain a solid (160 mg, yield 69.1%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 7.38 (s, 1H), 6.77 (d, J = 11.2 Hz, 1H), 5.89 (br s, 2H), 5.43 (br s, 2H), 3.87 (s, 3H), 2.38 (d, J = 19.8 Hz, 6H), 1.88 - 1.78 (m, 6H). MS (ESI): 357 [M+H] + 。

[0109] Step 7: Synthesis of Compound 1:

Chemical formula

[0110] Int_1-10 (80.0 mg, 224 μmol) was dissolved in dichloromethane (2 mL) under a nitrogen atmosphere, and BBr3 (562 mg, 2.24 mmol, 216 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 1 hour under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution, and NaH2PO4 (1.5 g) was added. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain Compound 1 (70 mg, yield 91.3%). 11H NMR (400 MHz, DMSO-d6) δ 10.03 (br s, 1H), 7.83 (s, 1H), 6.84 (s, 2H), 6.79 (d, J = 11.3 Hz, 1H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.63 (s, 3H), 1.61 (s, 3H). MS (ESI): 343 [M+H] + .

[0111] Example 2: Synthesis of Compound 2 and Compound 3 [Chemical Structure]

[0112] Compound 1 (120 mg, 0.35 mmol) was subjected to preparative SFC chiral resolution (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 50% - 50%, gradient), to obtain Compound 3 (20 mg, yield 33.3%) and Compound 2 (20 mg, yield 33.3%). Compound 2: 1 1H NMR (400 MHz, DMSO-d6) δ 10.03 (br s, 1H), 7.83 (s, 1H), 6.84 (s, 2H), 6.79 (d, J = 11.3 Hz, 1H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H). MS (ESI): 343 [M+H] + .

[0113] Analytical SFC retention time: 2.129 min (instrument: Waters UPCC with PDA Detector, column: Cellulose-2, 100×4.6 mm, inner diameter 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), Isocratic: 40% of B, flow rate: 2.8 mL / min, column temperature: 35 °C, ABPR: 1500 psi). Compound 3: 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (br s, 1H), 7.84 (s, 1H), 6.85 (s, 2H), 6.79 (d, J = 11.3 Hz, 1H), 6.66 (br s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.65 (s, 3H), 1.62 (s, 3H). MS (ESI): 343 [M+H] + .

[0114] Analysis SFC retention time: 2.708 min (Instrument: Waters UPCC with PDA Detector, Column: Cellulose-2, 100×4.6 mm, Inner diameter 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Isocratic: 40% of B, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi).

[0115] Example 3: Synthesis of Compound 5:

Chem.

[0116] Step 1: Synthesis of Compound int_5-2:

Chem.

[0117] int_5-1 (23.0 g, 163 mmol) was dissolved in acetonitrile (400 mL), and NBS (72.5 g, 407 mmol) was slowly added. The reaction solution was stirred at room temperature for 5 hours. Completion of the reaction was indicated by TLC monitoring. Water (500 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 10% THF / petroleum ether gradient) to obtain an orange solid (7 g, yield 14.4%). ESI-MS m / z: 299 [M+H] + 。

[0118] Step 2: Synthesis of compound int_5-3:

Chemical formula

[0119] int_5-2 (7.00 g, 23.4 mmol), int_1-2 (4.41 g, 35.1 mmol, 4.91 mL), Pd(dppf)Cl2 (1.71 g, 2.34 mmol), and Cs2CO3 (22.9 g, 70.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (8 mL). The mixed solution was purged with nitrogen three times, heated to 100 °C, and stirred for 12 hours. Completion of the reaction was indicated by TLC monitoring. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 50% THF / petroleum ether gradient) to obtain a white solid (2.2 g, yield 55.5%). ESI-MS m / z: 170 [M+H] + 。

[0120] Step 3: Synthesis of compound int_5-4: [Chemical formula]

[0121] int_5-3 (2.00 g, 11.8 mmol) and int_1-6 (3.44 g, 13.0 mmol) were dissolved in DME (25 mL), and Cs2CO3 (9.24 g, 28.4 mmol), Xantphos (684 mg, 1.18 mmol), and Pd2(dba)3 (1.08 g, 1.18 mmol) were added. The reaction solution was purged with nitrogen three times, heated to 90 °C, and reacted for 16 hours. LC-MS monitoring indicated the completion of the reaction. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 50% THF / petroleum ether gradient) to obtain a solid (3.8 g, yield 91.3%). 1 H NMR: (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.32 (s, 1H), 7.00 (d, J = 12.0 Hz, 1H), 3.78 (s, 3H), 2.08 (s, 3H), 2.06 (s, 6H), 2.02 (s, 3H). ESI-MS m / z: 353 [M+H] + .

[0122] Step 4: Synthesis of compound int_5-5: [Chemical formula]

[0123] int_1-8 (823 mg, 12.5 mmol, 784 μL) and Cs2CO3 (3.69 g, 11.3 mmol) were dissolved in DMF (20 mL). The reaction solution was heated to 40 °C and reacted for 0.5 h. int_5-4 (2.00 g, 5.66 mmol), CuI (324 mg, 1.70 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (242 mg, 1.70 mmol) were added to the reaction solution. The reaction solution was purged with nitrogen three times, heated to 100 °C, and reacted for 16 h. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 50% THF / petroleum ether gradient) to obtain a solid (400 mg, yield 20.9%). ESI-MS m / z: 339 [M+H] + 。

[0124] Step 5: Synthesis of compound int_5-6:

Chemical formula

[0125] At 0 °C, sulfuric acid (6 mL) was slowly added to int_5-5 (0.500 g, 1.48 mmol). The reaction solution was reacted at 25 °C for 2 h. Completion of the reaction was indicated by LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 80% EA / petroleum ether gradient) to obtain a solid (300 mg, yield 57%). MS (ESI): 357 [M+H]+ 。

[0126] Step 6: Synthesis of Compound 5:

Chem.

[0127] int_1-10 (0.300 g, 842 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (2.11 g, 8.42 mmol, 811 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 2 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was adjusted to pH 7 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 10% MeOH / DCM gradient) to obtain Compound 5 (150 mg, yield 52.1%). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.10 (d, J = 11.5 Hz, 1H), 6.86 - 6.77 (m, 2H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H). MS (ESI): 343 [M+H] + 。

[0128] Example 4: Synthesis of Compound 6 and Compound 7:

Chem.

[0129] Compound 5 (150 mg, 438 μmol) was subjected to preparative SFC chiral resolution (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: A: CO2, B: EtOH (0.1% NH3H2O), B%: 25% - 25%, fractionation) to obtain Compound 6 (30 mg, yield 40%) and Compound 7 (30 mg, yield 40%). Compound 7: 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (br s, 1H), 7.83 (s, 1H), 7.10 (d, J = 11.5 Hz, 1H), 6.82 (br s, 2H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H). MS (ESI): 343 [M+H] + .

[0130] Analytical SFC retention time: 3.545 minutes (instrument: Waters UPCC with PDA Detector, column: Chiralpak AD-3, 150×4.6 mm, inner diameter, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: from 5% to 40% of B in 4 minutes, from 40% to 5% of B in 0.2 minutes, then hold 5% of B for 1.8 minutes, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi). Compound 6: 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J = 1.3 Hz, 1H), 7.83 (s, 1H), 7.10 (d, J = 11.5 Hz, 1H), 6.85 - 6.77 (m, 2H), 6.65 (br s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H). MS (ESI): 343 [M+H] + .

[0131] Analysis of SFC retention time: 3.727 minutes (instrument: Waters UPCC with PDA Detector, column: Chiralpak AD-3, 150×4.6 mm, inner diameter, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: from 5% to 40% of B in 4 minutes, from 40% to 5% of B in 0.2 minutes, then hold 5% of B for 1.8 minutes, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi).

[0132] Example 5: Synthesis of Compound 9:

Chemical formula

[0133] Step 1: Synthesis of Compound int_9-2:

Chemical formula

[0134] int_9-1 (7.30 g, 41.0 mmol) was dissolved in THF (25 mL), and NBS (7.30 g, 41.0 mmol) was slowly added to the reaction solution. The reaction solution was heated to 60 °C and stirred for 9.5 hours. Completion of the reaction was indicated by TLC monitoring. When water (30 mL) was added to the reaction solution, a solid precipitated. The reaction solution was filtered. The filter cake was washed with water (10 mL), collected, and dried in vacuo to obtain the crude product (6.05 g, yield 69.3%). This crude product was used as such in the next step. 1 H NMR: (400 MHz, DMSO-d6) δ 12.91 (br s, 1H), 8.19 (s, 1H), 2.38 (s, 3H).

[0135] Step 2: Synthesis of Compound int_9-3:

Chemical formula

[0136] POBr3 (81.4 g, 284 mmol, 28.9 mL) was heated to 60 °C, and then int_9-2 (6.05 g, 28.4 mmol) was slowly added to POBr3. The reaction solution was heated to 100 °C and reacted for 1 hour. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution (800 mL) was added to the reaction solution to adjust the pH value to 8. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 10 / 1) to obtain a solid (6.1 g, yield 77.9%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 2.72 (s, 3H).

[0137] Step 3: Synthesis of compound int_9-5:

Chemical formula

[0138] int_9-3 (3.80 g, 13.8 mmol) and int_9-4 (2.50 g, 16.5 mmol) were dissolved in toluene (40 mL), and Cs2CO3 (4.71 g, 14.5 mmol), Xantphos (797 mg, 1.38 mmol), and Pd2(dba)3 (1.26 g, 1.38 mmol) were added. The reaction solution was purged with nitrogen three times, heated to 80 °C, and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 30 / 1) to obtain a solid (1.2 g, yield 25.1%). 11H NMR: (400 MHz, CHLOROFORM-d) δ 7.81 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H).

[0139] Step 4: Synthesis of compound int_9-7: [Chemical formula]

[0140] int_9-6 (859 mg, 8.66 mmol, 767 μL) was dissolved in DME (12 mL). The reaction solution was cooled to -30 °C, and NaH (693 mg, 17.3 mmol, purity 60%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 hour. Next, int_9-5 (500 mg, 1.44 mmol) and Pd(dppf)Cl2·CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 90 °C and reacted for 1 hour under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (423 mg, yield 80.7%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 8.16 (br s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.72 (br s, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 2.63 (s, 3H), 1.90 (s, 3H), 1.83 (s, 3H). ESI-MS m / z: 365 [M+H] + .

[0141] Step 5: Synthesis of compound int_9-8:

Chem.

[0142] int_9-7 (335 mg, 919 μmol) and NaOH (4 M, 6.89 mL) were dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL). The reaction solution was heated to 50 °C and reacted for 24 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature, and tetrahydrofuran (10 mL) was added to the reaction solution. The resulting mixture was concentrated under reduced pressure to obtain a solid, which was dissolved in DMSO (10 mL) and filtered. The filter cake was washed with water (10 mL), recovered, and dried under vacuum to obtain a crude product (128 mg, yield 40%), which was used as it was in the next step. ESI-MS m / z: 351 [M+H] + 。

[0143] Step 6: Synthesis of compound int_9-9:

Chem.

[0144] int_9-8 (385 mg, 1.10 mmol), PMBNH2 (756 mg, 5.51 mmol, 716 μL), and TEA (893 mg, 8.82 mmol, 1.23 mL) were dissolved in a mixed solvent of acetonitrile (15 mL) and DMSO (15 mL), and HATU (1.47 g, 3.86 mmol) was slowly added to the reaction solution at 0 °C. Subsequently, the reaction solution was heated to 20 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 2 / 1) to obtain a solid (150 mg, yield 29%). 1 1H NMR: (400 MHz, CHLOROFORM-d) δ 7.71 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.96 (br d, J = 8.6 Hz, 2H), 6.10 (br s, 2H), 5.77 (s, 1H), 4.66 (d, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.62 (s, 3H), 1.92 (s, 3H), 1.85 (s, 3H). ESI-MS m / z: 470 [M+H] + .

[0145] Step 7: Synthesis of compound int_9-10:

Chemical Structure

[0146] int_9-9 (150 mg, 319 μmol) and TFA (3 mL) were dissolved in acetonitrile (1 mL). Next, the reaction solution was heated to 50 °C and reacted for 4 hours. Completion of the reaction was indicated by LC-MS monitoring. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, PE / EtOAc = 2 / 3) to obtain a solid (53 mg, yield 47.7%). ESI-MS m / z: 350 [M+H] + 。

[0147] Step 8: Synthesis of Compound 9:

Chemical Structure

[0148] int_9-10 (53.1 mg, 152 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 2) to obtain Compound 9 (40 mg, yield 78.5%). 1 1H NMR: (400 MHz, DMSO-d6) δ 9.62 (br s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.91 (br s, 2H), 2.54 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H). MS (ESI): 336 [M+H] + 。

[0149] Example 6: Synthesis of Compound 10 and Compound 11:

Chemical Structure

[0150] Compound 9 (40 mg, 119 μmol) was subjected to preparative SFC chiral resolution (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 30% - 30%, isocratic elution) to obtain Compound 10 (9 mg, yield 45%) and Compound 11 (10 mg, yield 50%). Compound 10: 1 H NMR: (400 MHz, DMSO-d6) δ 9.62 (br s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.91 (br s, 2H), 2.54 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H). MS (ESI): 336 [M+H] + 。

[0151] Analytical SFC retention time: 3.941 min (instrument: Waters UPCC with PDA Detector, column: Chiralcel OJ-3, 150 × 4.6 mm i.d., 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: B from 5% to 40% in 4 min, hold 40% for 2 min, then hold B at 5% for 2 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi). Compound 11: 11H NMR: (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.91 (br s, 2H), 2.58 - 2.52 (m, 3H), 1.74 (s, 3H), 1.65 (s, 3H). MS (ESI): 336 [M+H] + .

[0152] SFC retention time: 4.240 min (Instrument: Waters UPCC with PDA Detector, Column: Chiralcel OJ-3, 150×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: ethanol (0.05% DEA), Gradient: B from 5% to 40% in 4 min, hold 40% for 2 min, then hold B at 5% for 2 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi).

[0153] Example 7: Synthesis of Compound 12

Chem.

[0154] Step 1: Synthesis of Compound int_12-2:

Chem.

[0155] int_12-1 (40.0 g, 174 mmol) was dissolved in DCM (1500 mL), and m-CPBA (106 g, 522 mmol, purity 85.0%) was slowly added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and stirred for 16 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was filtered to remove excess m-CPBA, and the filtrate was collected. The filtrate was added to saturated Na2S2O3 solution and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% EA / petroleum ether gradient) to obtain a solid (17 g, yield 39.7%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.18 (d, J = 0.6 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 3.94 (s, 3H), 2.22 (s, 3H).

[0156] Step 2: Synthesis of compound int_12-3:

Chemical Structure

[0157] int_12-2 (16.0 g, 65.0 mmol) was dissolved in DMF (200 mL), and TFAA (150 g, 715 mmol, 99.4 mL) was slowly added to the reaction solution at 20 °C. The reaction solution was stirred at room temperature for 16 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was poured into ice water and neutralized by adding saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 10% EA / petroleum ether gradient) to obtain a solid (12 g, yield: 75%).

[0158] Step 3: Synthesis of compound int_12-4:

[0159]

Chem.

[0160] int_12-3 (4.00 g, 16.3 mmol) was slowly added to POBr3 (46.6 g, 163 mmol, 16.5 mL). The reaction solution was heated to 90 °C and reacted for 4 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature and poured into ice water. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 10% EA / petroleum ether gradient) to obtain a solid (3 g, yield 59.7%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.87 (s, 1H), 3.99 (s, 3H), 3.52 (s, 1H), 2.56 (s, 3H).

[0161] Step 4: Synthesis of compound int_12-5:

[0162]

Chem.

[0163] int_12-4 (2.00 g, 6.47 mmol) and int_9-4 (979 mg, 6.47 mmol) were dissolved in DME (30.0 mL) and Cs2CO3 (4.22 g, 13.0 mmol), Xantphos (375 mg, 647 μmol), and Pd2(dba)3 (593 mg, 647 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 95 °C, and reacted for 16 h. LC-MS monitoring showed the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-10% EA / petroleum ether gradient) to give a solid (1 g, 40.7% yield). ESI-MS m / z: 379 [M+H] + .

[0164] Step 5: Synthesis of compound int_12-6:

[0165] [ka]

[0166] int_12-5 (1.00 g, 2.64 mmol) was dissolved in aqueous ammonia (20.0 mL). The reaction solution was heated to 55 °C and reacted for 16 h. LC-MS monitoring showed the completion of the reaction. After the reaction solution was cooled to room temperature, the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-20% EA / petroleum ether gradient) to obtain a solid (0.6 g, yield: 62.5%). 11H NMR (400 MHz, CHLOROFORM-d) δ = 7.68 (s, 1H), 7.32 - 7.23 (m, 2H), 7.09 (d, J = 8.4Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.37 (s, 1H), 3.86 (s, 3H), 2.60 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H). ESI-MS m / z: 364 [M+H] + .

[0167] Step 6: Synthesis of compound int_12-7:

[0168] [Chemical formula]

[0169] int_12-6 (0.600 g, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL), and TEA (1.08 g, 10.7 mmol, 1.49 mL) and TFAA (900 mg, 4.28 mmol, 595 μL) were slowly added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and stirred for 16 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was poured into ice water. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 20% EA / petroleum ether gradient) to obtain a solid (550 mg, yield 96.4%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.71 (s, 1H), 7.13 - 7.03 (m, 1H), 6.84 - 6.73 (m, 1H), 6.54 - 6.41 (m, 1H), 3.87 (s, 3H), 2.40 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H). ESI-MS m / z: 346 [M+H] +。

[0170] Step 7: Synthesis of compound int_12-8:

[0171]

Chem.

[0172] int_9-6 (1.22 g, 8.66 mmol, 1.24 mL) was dissolved in DME (15 mL). The reaction solution was cooled to -30 °C, and NaH (693 mg, 17.3 mmol, purity 60.0%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 h. Next, Int_12-7 (500 mg, 1.44 mmol) and Pd(dppf)Cl2·CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 90 °C and reacted for 1 h under a nitrogen atmosphere. The completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 100% EA / petroleum ether gradient) to obtain a solid (500 mg, yield 95.2%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.93 - 7.84 (m, 1H), 7.28 (s, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 2.61 (s, 3H), 1.95 - 1.89 (m, 3H), 1.85 (s, 3H). ESI-MS m / z: 365 [M+H] + 。

[0173] Step 8: Synthesis of compound int_12-9:

[0174]

Chem.

[0175] int_12-8 (400 mg, 1.10 mmol) and NaOH (4.00 M, 8.23 mL) were dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL). The reaction solution was heated to 50 °C and reacted for 72 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid, which was dissolved in water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3) and neutralized to pH 5 - 6 with 1 M aqueous hydrochloric acid. Next, the aqueous phase was extracted with ethyl acetate (30 mL × 3), and at this point, the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product (208 mg, yield 54%). This crude product was used as it was in the next step. ESI-MS m / z: 351 [M+H] + 。

[0176] Step 9: Synthesis of compound int_12-10:

[0177]

Chem.

[0178] int_12-9 (223 mg, 639 μmol), PMBNH2 (263 mg, 1.92 mmol, 249 μL), and TEA (323 mg, 3.20 mmol, 445 μL) were dissolved in a mixed solvent of acetonitrile (5 mL) and DMSO (5 mL), and HATU (851 mg, 2.24 mmol) was slowly added to the reaction solution at 0 °C. Subsequently, the reaction solution was heated to 20 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. Water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 10% EA / petroleum ether gradient) to obtain a solid (160 mg, yield 53.3%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 - 7.36 (m, 3H), 7.26 - 7.20 (m, 1H), 6.96 (br d, J = 8.6 Hz, 3H), 6.44 - 6.10 (m, 1H), 5.95 - 5.81 (m, 1H), 4.71 - 4.66 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.59 (s, 3H), 1.92 (s, 4H), 1.85 (s, 4H). ESI-MS m / z: 470 [M+H] + 。

[0179] Step 10: Synthesis of compound int_12-11:

[0180]

Chemical Structure

[0181] int_12-10 (100 mg, 213 μmol) was dissolved in TFA (11.5 g, 101 mmol, 7.50 mL). The reaction solution was heated to 80 °C and reacted for 16 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, PE / EtOAc = 1 / 2) to obtain a solid (40 mg, yield 53.8%). ESI-MS m / z: 350 [M+H] + 。

[0182] Step 11: Synthesis of Compound 12:

[0183]

Chemical Structure

[0184] int_12-11 (35.0 mg, 100 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (376 mg, 1.50 mmol, 145 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted for 1 hour at 0 °C under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, PE / ethyl acetate = 1 / 4) to obtain Compound 12 (5.7 mg, yield 17%). 11H NMR (400 MHz, CHLOROFORM-d) δ = 9.57 (s, 1H), 7.93 (s, 1H), 7.17 (br s, 2H), 7.13 - 7.04 (m, 3H), 6.94 (d, J = 8.3 Hz, 1H), 6.84 (br s, 2H), 2.61 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H). MS (ESI): 336 [M+H] + .

[0185] Example 8: Synthesis of Compound 15 [Chemical Structure]

[0186] Step 1: Synthesis of Compound int_15-2: [Chemical Structure]

[0187] int_15-1 (15.0 g, 82.8 mmol) was dissolved in DCM (150 mL), and BBr3 (31.1 g, 124 mmol, 12.0 mL) was slowly added to the reaction solution at 0 °C under a nitrogen atmosphere. The reaction solution was heated to room temperature and stirred for 16 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to 0 °C, and methanol (100 mL) was added to the reaction solution. The reaction solution was further stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 80% EA / petroleum ether gradient) to obtain a solid (12 g, yield 86.7%).

[0188] Step 2: Synthesis of Compound int_15-3:

[0189] [Chemical Structure]

[0190] int_15-2 (16.0 g, 65.0 mmol) and K2CO3 (18.2 g, 132 mmol) were dissolved in acetonitrile (100 mL), and bromomethyl methyl ether (9.87 g, 78.9 mmol, 6.45 mL) was slowly added to the reaction solution at 20 °C. The reaction solution was heated to 50 °C and stirred for 2 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% EA / petroleum ether gradient) to obtain a solid (10 g, yield 72.9%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.12 - 7.05 (m, 2H), 7.97 (s, 1H), 5.22 (s, 2H), 3.50 (s, 3H), 2.19 - 2.55 (d, 6H), 5.10 (s, 2H), 4.81 (s, 2H), 1.76 (s, 3H), 1.67 (s, 3H).

[0191] Step 3: Synthesis of compound int_15-4:

[0192]

Chemical Structure

[0193] int_15-3 (10.0 g, 47.4 mmol) and Pd / C (5 g, purity 10%) were dissolved in methanol (100 mL). The reaction solution was stirred at room temperature for 16 hours under a hydrogen atmosphere (50 psi). Completion of the reaction was indicated by TLC monitoring. The reaction solution was filtered to remove palladium carbon, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% EA / petroleum ether gradient) to obtain a solid (8 g, yield 93.2%). ESI-MS m / z: 182 [M+H] + .

[0194] Step 4: Synthesis of compound int_15-6:

[0195]

Chemical formula

[0196] int_15-5 (50.0 g, 256 mmol) was dissolved in methanol (500 mL), and Br2 (81.9 g, 512 mmol, 26.4 mL) was slowly added to the reaction solution at 0 °C. The reaction solution was heated to 55 °C and stirred for 48 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was diluted with aqueous ammonia to adjust the pH value to 8. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 50% EA / petroleum ether gradient) to obtain a solid (56 g, yield 79.8%). ESI-MS m / z: 274 [M+H] + 。

[0197] Step 5: Synthesis of compound int_15-7:

[0198]

Chemical formula

[0199] Under a nitrogen atmosphere, int_15-6 (30.0 g, 109 mmol) was dissolved in ethanol (350 mL), and NaBH4 (24.9 g, 657 mmol) was slowly added to the reaction solution at 0 °C, and then CaCl2 (10.9 g, 98.5 mmol) was slowly added. The reaction solution was heated to room temperature and stirred for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. 2N aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH value to 2 - 3. The reaction solution was stirred at room temperature for an additional 2 hours and then concentrated under reduced pressure to obtain a solid. The solid was neutralized with saturated aqueous sodium hydrogen carbonate solution and adjusted to pH 7. The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 80% EA / petroleum ether gradient) to obtain a solid (15 g, yield 62.9%). ESI-MS m / z: 217 [M+H] + 。

[0200] Step 6: Synthesis of compound int_15-8:

[0201]

Chemical Structure

[0202] int_15-7 (15.0 g, 68.8 mmol) was dissolved in DMF (200 mL) under a nitrogen atmosphere. First, NaH (16.5 g, 413 mmol, purity 60%) was slowly added to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h, and TosCl (13.1 g, 68.8 mmol) was added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 16 h. Completion of the reaction was indicated by LC-MS monitoring. Water (700 mL) was added to the reaction solution to quench the reaction. The aqueous phase was extracted with ethyl acetate (600 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% EA / petroleum ether gradient) to obtain a solid (2.5 g, yield 18.2%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.70 (s, 1H), 5.02 (m, 2H), 4.92 (m, 2H).

[0203] Step 7: Synthesis of compound int_15-9:

[0204]

Chemical Structure

[0205] int_15-8 (5.00 g, 25.0 mmol) was dissolved in DCM (100 mL), and m-CPBA (15.39 g, 25.0 mmol, purity 80%) was slowly added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and stirred for 16 h. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 100% EA / petroleum ether gradient) to obtain a solid (5 g, yield 92.6%). ESI-MS m / z: 216 [M+H] + .

[0206] Step 8: Synthesis of compound int_15-10:

[0207]

Chem.

[0208] int_15-9 (1.00 g, 4.63 mmol) was slowly added to POBr3 (7.00 g, 24.4 mmol, 2.48 mL). The reaction solution was heated to 70 °C and reacted for 2 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was first purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% EA / petroleum ether gradient), and then by preparative SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-EtOH]; B%: 30% - 30%, min) to obtain a solid (0.3 g, yield 23.2%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.73 (s, 1H), 5.15 - 5.02 (m, 2H), 4.92 - 4.91 (m, 2H).

[0209] Step 9: Synthesis of compound int_15-11:

[0210]

Chem.

[0211] int_15-10 (0.300 g, 1.08 mmol) and int_15-4 (292 mg, 1.61 mmol) were dissolved in DME (10.0 mL) and Cs2CO3 (701 mg, 2.15 mmol), Xantphos (62.2 mg, 108 μmol), and Pd2(dba)3 (98.5 mg, 108 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 90 °C, and reacted for 3 h. LC-MS monitoring showed the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-20% EA / petroleum ether gradient) to give a solid (0.3 g, 73.6% yield). ESI-MS m / z: 379 [M+H] + .

[0212] Step 10: Synthesis of compound int_15-12:

[0213] [ka]

[0214] int_1-8 (83.6 mg, 1.27 mmol, 79.6 μL) was dissolved in DME (5 mL). The reaction solution was cooled to -30 °C, and NaH (236 mg, 5.91 mmol, purity 60%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 h. Next, int_15-11 (0.160 g, 422 μmol) and Pd(dppf)Cl2·CH2Cl2 (34.45 mg, 42.19 μmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 80 °C and reacted for 1 h under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (10 mL) was added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 50% EA / petroleum ether gradient) to obtain a solid (110 mg, yield 71.6%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.64 (s, 1H), 7.25 - 7.18 (m, 2H), 5.31 - 5.19 (m, 4H), 5.01 (s, 2H), 4.62 (s, 2H), 3.54 (s, 3H), 1.92 (d, J=19.2 Hz, 6H). ESI-MS m / z: 365 [M+H] + 。

[0215] Step 11: Synthesis of compound int_15-13:

[0216]

Chemical Structure

[0217] int_15-12 (80.0 mg, 220 μmol) and LiOH·H₂O (64.48 mg, 1.54 mmol) were dissolved in a mixed solution of ethanol (6 mL) and water (2 mL), and H₂O₂ (360 mg, 2.85 mmol, 305 μL, purity 27%) was added dropwise to the reaction solution at 20 °C. The reaction solution was heated to 60 °C and reacted for 0.5 h. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 100% EA / petroleum ether gradient) to obtain a solid (65 mg, yield 77.4%). MS (ESI): 383 [M+H] + 。

[0218] Step 12: Synthesis of Compound 15:

[0219]

Chemical Structure

[0220] int_15-13 (60.0 mg, 157 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and HCl / dioxane solution (4 M, 3.00 mL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 20 °C for 0.5 h under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO₂, DCM / MeOH = 10 / 1) to obtain Compound 15 (35 mg, yield 65.9%). 11H NMR (400 MHz, DMSO-d6) δ = 9.53 (s, 1H), 7.97 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.74 (s, 2H), 5.10 (s, 2H), 4.81 (s, 2H), 1.76 (s, 3H), 1.67 (s, 3H). MS (ESI): 339 [M+H] + .

[0221] Example 9: Synthesis of Compound 16 and Compound 17: [Chemical Structure]

[0222] Compound 15 (35 mg, 103 μmol) was subjected to preparative SFC chiral resolution (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: MeOH (0.1% NH3H2O); B%: 30% - 30%, fractionation) to obtain Compound 16 (7 mg, yield 40%) and Compound 17 (8 mg, yield 45.7%). Compound 17: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 7.94 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.93 - 6.84 (m, 3H), 6.71 (s, 2H), 5.07 (s, 2H), 4.78 (s, 2H), 1.73 (s, 3H), 1.64 (s, 3H). MS (ESI): 339 [M+H] + .

[0223] Analysis of SFC retention time: 3.457 minutes (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak IG-3, 100×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: B increased from 5% to 40% in 4 minutes, held at 40% for 0.5 minutes, then B held at 5% for 1.5 minutes, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi). Compound 16: 1 H NMR (400 MHz, DMSO-d6) δ = 9.52 (s, 1H), 7.96 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.95 - 6.86 (m, 3H), 6.73 (s, 2H), 5.09 (s, 2H), 4.80 (s, 2H), 1.75 (s, 3H), 1.66 (s, 3H). MS (ESI): 339 [M+H] + .

[0224] Analysis of SFC retention time: 3.663 minutes (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak IG-3, 100×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: B increased from 5% to 40% in 4 minutes, held at 40% for 0.5 minutes, then B held at 5% for 1.5 minutes, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi).

[0225] Example 10: Synthesis of Compound 96

Chemical Structure

[0226] Step 1: Synthesis of Compound int96-3:

Chemical Structure

[0227] Int_96-1 (40.0 g, 201 mmol), int_96-2 (21.4 g, 301 mmol, 25.1 mL), and TsOH·H2O (3.82 g, 20.1 mmol) were dissolved in toluene (400 mL). The reaction solution was heated to 100 °C and reacted for 16 hours under a nitrogen atmosphere. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to 0 °C and concentrated under reduced pressure to obtain a crude product (50 g, yield 98.7%), which was used as is in the next step.

[0228] Step 2: Synthesis of compound int_96-5:

Chemical formula

[0229] Int_96-3 (50.0 g, 198 mmol) and int_96-4 (20.5 g, 297 mmol) were dissolved in toluene (500 mL). The reaction solution was heated to 100 °C and stirred for 10 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:MeOH = 96:4) to obtain a solid (18.7 g, yield 37.9%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 1.49 (s, 9H) 2.76 (br t, J = 5.56 Hz, 2H) 3.67 (br t, J = 5.50 Hz, 2H) 4.32 (br s, 2H) 6.45 (d, J = 9.29 Hz, 1H) 7.21 (d, J = 9.17 Hz, 1H). ESI-MS m / z: 251 [M+H] + .

[0230] Step 3: Synthesis of compound int_96-6:

Chemical formula

[0231] int_96-5 (10.0 g, 40.0 mmol) was dissolved in dichloromethane (100 mL), and Py.Br3 (14.1 g, 44.0 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 1 hour. Completion of the reaction was indicated by TLC monitoring. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:ethyl acetate = 7:3) to obtain a solid (2.7 g, yield 20%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 1.49 (s, 9 H) 2.78 (br s, 2 H) 3.68 (br s, 2 H) 4.34 (br s, 2 H) 7.61 (s, 1 H). ESI-MS m / z: 329 [M+H] + 。

[0232] Step 4: Synthesis of compound int_96-7:

Chemical formula

[0233] int_96-6 (2.70 g, 8.20 mmol) was dissolved in HCl / dioxane solution (30.0 mL). The reaction solution was stirred at 0 °C for 1 hour. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was filtered, and the filter cake was collected and dried in vacuo to obtain a crude product (1.6 g, yield 85.5%). This was used directly in the next step. ESI-MS m / z: 229 [M+H] + 。

[0234] Step 5: Synthesis of compound int_96-8:

Chemical formula

[0235] int_96-7 (2.00 g, 7.53 mmol, hydrochloride) was dissolved in formic acid (20 mL), and HCHO (905 mg, 9.04 mmol, 830 μL, purity 30.0%) was added to the reaction solution. The reaction solution was heated to 100 °C and stirred for 3 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product (1.3 g, yield 73.5%), which was used directly in the next step. ESI-MS m / z: 243 [M+H] + 。

[0236] Step 6: Synthesis of compound int_96-9:

Chem.

[0237] int_96-8 (1.00 g, 4.11 mmol) was slowly added to POBr3 (11.8 g, 41.1 mmol, 4.18 mL). The reaction solution was heated to 90 °C and reacted for 3 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (80 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, DCM / MeOH = 10 / 1) to obtain a solid (230 mg, yield 18.4%). ESI-MS m / z: 305 [M+H] + 。

[0238] Step 7: Synthesis of compound int_96-10:

Chem.

[0239] int_96-9 (220 mg, 719 μmol) and int_9-4 (109 mg, 719 μmol) were dissolved in toluene (3.0 mL), and Cs2CO3 (469 mg, 1.44 mmol), Xantphos (41.6 mg, 71.9 μmol), and Pd2(dba)3 (65.8 mg, 71.9 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 100 °C, and reacted for 3 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:MeOH = 95:5) to obtain a solid (227 mg, yield 84%). ESI-MS m / z: 376 [M+H] + 。

[0240] Step 8: Synthesis of compound int_96-11:

Chemical Structure

[0241] int_1-8 (87.8 mg, 1.33 mmol, 83.6 μL) was dissolved in DME (3 mL). The reaction solution was cooled to -30 °C, and NaH (266 mg, 6.64 mmol, purity 60.0%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 hour. Next, int_96-10 (250 mg, 664 μmol) and Pd(dppf)Cl2·CH2Cl2 (54.3 mg, 66.4 μmol) were added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 2 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:MeOH = 1:0 to 20:1) to obtain a solid (201 mg, yield 84.1%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 1.84 (s, 3 H) 1.90 (s, 3 H) 2.54 (s, 3 H) 2.83 (br s, 2 H) 2.95 - 3.03 (m, 2 H) 3.75 (br s, 2 H) 3.88 (s, 3 H) 6.95 (d, J = 8.36 Hz, 1 H) 7.20 (d, J = 8.58 Hz, 1 H) 7.40 (s, 1 H). ESI-MS m / z: 362 [M+H] + .

[0242] Step 9: Synthesis of compound int_96-12: [Chemical formula]

[0243] At 0 °C, sulfuric acid (3 mL) was slowly added to int_96-11 (220 mg, 609 μmol). The reaction solution was reacted at 25 °C for 2 hours. Completion of the reaction was indicated by LC-MS monitoring. Ice water (10 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:MeOH = 10:1) to obtain a solid (179 mg, yield 77.8%). MS (ESI): 380 [M+H] + .

[0244] Step 10: Synthesis of compound 96: [Chemical formula]

[0245] Int_96-12 (200 mg, 527 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (660 mg, 2.64 mmol, 254 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 1 hour under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain compound 96 (103 mg, yield 53.5%). 1 H NMR (400 MHz, DMSO-d6) δ 1.66 (s, 3 H) 1.75 (s, 3 H) 2.39 (s, 3 H) 2.64 - 2.70 (m, 2 H) 2.72 (br d, J = 3.96 Hz, 2 H) 3.60 (br s, 2 H) 6.66 (br s, 2 H) 6.82 (br s, 2 H) 6.90 (d, J = 8.36 Hz, 1 H) 7.05 (d, J = 8.36 Hz, 1 H) 7.72 (s, 1 H) 9.51 (s, 1 H). MS (ESI): 366 [M+H] + 。

[0246] Example 11: Synthesis of Compound 97 and Compound 98:

Chemical formula

[0247] Compound 96 (103 mg, 281 μmol) was subjected to preparative SFC chiral resolution (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: MeOH (0.1% NH3H2O); B%: 50% - 50%, gradient) to obtain compound 97 (23 mg, yield 44.6%) and compound 98 (29 mg, yield 56.3%). Compound 97: 11H NMR (400 MHz, DMSO-d6) δ 1.66 (s, 3 H) 1.75 (s, 3 H) 2.39 (s, 3 H) 2.64 - 2.70 (m, 2 H) 2.72 (br d, J = 3.96 Hz, 2 H) 3.60 (br s, 2 H) 6.66 (br s, 2 H) 6.82 (br s, 2 H) 6.90 (d, J = 8.36 Hz, 1 H) 7.05 (d, J = 8.36 Hz, 1 H) 7.72 (s, 1 H) 9.51 (s, 1 H). MS (ESI): 366 [M+H] + .

[0248] Analysis SFC retention time: 3.501 minutes (Instrument: Agilent 1260 with DAD Detector, Column: Cellulose-4, 100×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 40% of B, Flow rate: 2.8 mL / min, Column temperature: 40 °C, ABPR: 100 bar). Compound 98: 1 1H NMR (400 MHz, DMSO-d6) δ 1.66 (s, 3 H) 1.75 (s, 3 H) 2.35 (s, 3 H) 2.62 (br d, J = 5.28 Hz, 2 H) 2.70 (br d, J = 5.50 Hz, 2 H) 3.54 (s, 2 H) 6.65 (br s, 2 H) 6.80 (br s, 2 H) 6.91 (d, J = 8.14 Hz, 1 H) 7.04 (d, J = 8.36 Hz, 1 H) 7.70 (s, 1 H) 9.42 - 9.82 (m, 1 H). MS (ESI): 366 [M+H] + .

[0249] Analysis of SFC retention time: 4.702 minutes (Instrument: Agilent 1260 with DAD Detector, Column: Cellulose-4, 100×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% DEA), Gradient: 40% of B, Flow rate: 2.8 mL / min, Column temperature: 40 °C, ABPR: 100 bar).

[0250] Example 12: Synthesis of Compound 115:

Chemical formula

[0251] Step 1: Synthesis of Compound int_115-2:

Chemical formula

[0252] int_115-1 (20.0 g, 99.5 mmol) was dissolved in acetonitrile (200 mL), and NIS (33.6 g, 149 mmol) and TFA (17.0 g, 149 mmol, 11.1 mL) were added to the reaction solution at room temperature. The reaction solution was heated to 70 °C and reacted for 16 hours under a nitrogen atmosphere. The completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to 0 °C and concentrated under reduced pressure to obtain a solid. The solid was dissolved in dichloromethane (100 mL), washed with water (50 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (26.3 g, yield 80.9%), which was used directly in the next step. 1 HNMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 2.34 (s, 3H).

[0253] Step 2: Synthesis of Compound int_115-4:

Chemical formula

[0254] int_115-2 (25.0 g, 76.5 mmol), int_115-3 (17.3 g, 76.5 mmol), Pd(dppf)Cl2 (5.59 g, 7.65 mmol), and Cs2CO3 (2 M, 76.46 mL) were dissolved in 1,4-dioxane (250 mL). The reaction solution was purged with nitrogen three times, heated to 100 °C, and stirred for 3 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), 330 g SepaFlash (registered trademark) Silica Flash Column, eluent: 0 - 10% ethyl acetate / petroleum ether gradient) to obtain a solid (12 g, yield 52.5%).

[0255] Step 3: Synthesis of compound int_115-5:

Chemical Structure

[0256] int_115-4 (12.0 g, 40.1 mmol) and acetic acid (241 mg, 4.01 mmol, 229 μL) were dissolved in ethyl acetate (100 mL), and Pd / C (10.0 g, 401 mmol, purity 10%) was added to the reaction solution. The reaction solution was stirred at room temperature for 1 hour, purged with hydrogen three times, and reacted at room temperature under a hydrogen atmosphere (50 PSI) for 3 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (12 g, yield 99.3%), which was used directly in the next step. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.09 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 4.23 - 4.09 (m, 3H), 3.88 - 3.79 (m, 4H), 3.06 (t, J = 7.8 Hz, 2H), 2.68 - 2.55 (m, 3H), 2.35 (s, 3H), 1.36 - 1.21 (m, 5H).

[0257] Step 4: Synthesis of compound int_115-6:

Chemical formula

[0258] int_115-5 (12.0 g, 39.8 mmol) was dissolved in methanol (80.0 mL), and NaOH (1 M, 79.7 mL) was added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. 1N aqueous HCl solution was added dropwise to the reaction solution at 0 °C to adjust the pH to 3 - 4. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (10 g, yield 91.9%), which was used as is in the next step.

[0259] Step 5: Synthesis of compound int_115-7:

Chemical formula

[0260] int_115-6 (10.0 g, 36.6 mmol) was dissolved in toluene (150 mL), and SOCl2 (8.71 g, 73.23 mmol, 5.31 mL) was added to the reaction solution. The reaction solution was heated to 110 °C and stirred for 3 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product (10.7 g, yield 100%), which was used as is in the next step.

[0261] Step 6: Synthesis of compound int_115-8:

Chemical formula

[0262] int_115-7 (10.7 g, 36.6 mmol) was dissolved in dichloromethane (150 mL), and AlCl3 (4.88 g, 36.6 mmol) was added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 1 hour. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and poured into ice water (100 mL). The aqueous phase was extracted with dichloromethane (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (8 g, yield 85.6%), which was used directly in the next step.

[0263] Step 7: Synthesis of compound int_115-9:

Chemical formula

[0264] int_115-8 (8.00 g, 31.4 mmol) was dissolved in TFA (100 mL), and triethylsilane (36.46 g, 313.59 mmol, 50.09 mL) was added to the reaction solution at 0 °C. The reaction solution was heated to 75 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was diluted with water (100 mL) and adjusted to pH 8 - 9 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 0 - 3 / 1) to obtain the product (6 g, yield 79.4%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 6.72 (s, 1H), 3.89 - 3.79 (m, 4H), 3.05 - 3.00 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 2.15 - 2.05 (m, 2H).

[0265] Step 8: Synthesis of compound int_115-11: [Chemical]

[0266] Under a nitrogen atmosphere, int_115-9 (1.00 g, 4.15 mmol) and int_115-10 (1.13 g, 6.22 mmol, 1.04 mL) were dissolved in 1,4-dioxane (20 mL), and sodium tert-butoxide (797 mg, 8.29 mmol) and XantPhos Pd G3 (393 mg, 415 μmol) were added to the reaction solution at room temperature. The reaction solution was purged with nitrogen three times, heated to 110 °C, and reacted for 3 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (2.5 g), which was used as is in the next step.

[0267] Step 9: Synthesis of compound int_115-12: [Chemical]

[0268] Under a nitrogen atmosphere, int_115-11 (2.5 g, 7.32 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and water (10 mL), and an aqueous HCl solution (13 M, 21.52 mL) was added at room temperature. The reaction solution was reacted at room temperature for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain a solid. The solid was diluted with water (20 mL) and adjusted to pH 8-9 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 0 - 3 / 1) to obtain the product (1 g, yield 77.5%).

[0269] Step 10: Synthesis of compound int_115-13: [Chemical]

[0270] int_115-12 (800 mg, 4.51 mmol) and int_1-6 (358.76 mg, 1.35 mmol) were dissolved in DME (4.0 mL) and Cs2CO3 (2.94 g, 9.03 mmol), Xantphos (261.16 mg, 451.36 μmol), and Pd2(dba)3 (413 mg, 451 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 110 °C, and reacted for 3 h. LC-MS monitoring showed the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 0 to 3 / 1) to obtain the product (600 mg, yield 36.8%). ESI-MS m / z: 361 [M+H] + .

[0271] Step 11: Synthesis of compound int_115-14: [ka]

[0272] int_1-8 (252 mg, 3.82 mmol, 240 μL) and int_115-13 (0.6 g, 1.66 mmol) were dissolved in DMF (20 mL), and CuI (158 mg, 830 μmol), Cs2CO3 (1.62 g, 4.98 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (47.3 mg, 332 μmol) were added to the reaction solution under nitrogen atmosphere. The reaction solution was heated to 120 °C and reacted for 16 h under nitrogen atmosphere. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®, 20 g SepaFlash® Silica Flash Column, eluent: 0-50% ethyl acetate / petroleum ether gradient) to give the product (150 mg, 26.1% yield). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (s, 1H), 6.94 (s, 1H), 4.67 (s, 2H), 3.88 (s, 3H), 3.04 - 2.98 (m, 2H), 2.58 - 2.50 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.10 - 2.02 (m, 2H), 1.86 (s, 3H). ESI-MS m / z: 347 [M+H] + .

[0273] Step 12: Synthesis of compound int_115-15:

Chemical formula

[0274] At 0 °C, sulfuric acid (8.28 g, 84.4 mmol, 4.50 mL) was slowly added to int_115-14 (0.15 g, 433 μmol). The reaction solution was reacted at 25 °C for 1 hour. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 - 9 with aqueous ammonia and extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain a solid (80 mg, yield 50.7%). MS (ESI): 365 [M+H] + .

[0275] Step 13: Synthesis of compound 115:

Chemical formula

[0276] Int_115-15 (0.06 g, 164 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (412.45 mg, 1.65 mmol, 158.64 μL) was added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), 4 g SepaFlash (registered trademark) Silica Flash Column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient) to obtain compound 115 (37 mg, yield 64.4%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (br t, J = 8.1 Hz, 3H), 2.26 (d, J = 5.3 Hz, 8H), 1.93 (br d, J = 6.6 Hz, 2H), 1.67 (s, 3H). MS (ESI): 351 [M+H] + 。

[0277] Example 13: Synthesis of Compound 116 and Compound 117:

Chemical formula

[0278] Compound 115 (37 mg, 100 μmol) was subjected to preparative SFC chiral resolution (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 30% - 30%, for a certain time) to obtain compound 116 (9 mg, yield 48.6%) and compound 117 (8 mg, yield 43.2%). Compound 116: 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (br t, J = 8.1 Hz, 2H), 2.26 (d, J = 5.3 Hz, 6H), 1.93 (br d, J = 6.6 Hz, 2H), 1.67 (s, 3H). MS (ESI): 351 [M+H] + .

[0279] Analysis SFC retention time: 3.738 min (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak AS-3, 150×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: ethanol (0.05% DEA), Gradient: B from 5% to 40% in 4 min, B from 40% to 5% in 0.2 min, then hold 5% for 1.8 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi). Compound 117: 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (br t, J = 8.1 Hz, 2H), 2.26 (d, J = 5.3 Hz, 6H), 1.93 (br d, J = 6.6 Hz, 2H), 1.67 (s, 3H). MS (ESI): 351 [M+H] + .

[0280] Analysis of SFC retention time: 4.344 minutes (Instrument: Waters UPCC with PDA Detector, Column: Chiralpak AS-3, 150×4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: ethanol (0.05% DEA), Gradient: B from 5% to 40% in 4 minutes, then B from 40% to 5% in 0.2 minutes, and then hold at 5% for 1.8 minutes, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi).

[0281] Example 14: Synthesis of Compound 137

Chem.

[0282] Step 1: Synthesis of Compound int137-1:

Chem.

[0283] int_9-3 (3.3 g, 12 mmol) and int_1-5 (2.45 g, 14.5 mmol) were dissolved in toluene (40 mL), and Cs2CO3 (4.71 g, 14.5 mmol), Xantphos (694 mg, 1.2 mmol), and Pd2(dba)3 (1.09 g, 1.2 mmol) were added. The reaction solution was purged with nitrogen three times and heated to 80 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 30 / 1) to obtain a solid (1.1 g, yield 25.1%). ESI-MS m / z: 364 [M+H] + .

[0284] Step 2: Synthesis of Compound int137-2:

Chem.

[0285] int_9-6 (859 mg, 8.66 mmol, 767 μL) was dissolved in DME (12 mL). The reaction solution was cooled to -30 °C, and NaH (693 mg, 17.3 mmol, purity 60%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 h. Next, int_137-1 (524 mg, 1.44 mmol) and Pd(dppf)Cl2·CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 90 °C and reacted for 1 h under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 3 / 1) to obtain a solid (410 mg, yield 74.4%). ESI-MS m / z: 383 [M+H] + 。

[0286] Step 3: Synthesis of compound int137-3:

Chemical formula

[0287] int_137-2 (350 mg, 915 μmol) and NaOH (4 M, 7 mL) were dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL). The reaction solution was heated to 50 °C and reacted for 24 h. Completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature, and tetrahydrofuran (10 mL) was added to the reaction solution. The resulting mixture was concentrated under reduced pressure to obtain a solid, which was dissolved in DMSO (10 mL) and filtered. The filter cake was washed with water (10 mL), collected, and dried under vacuum to obtain a crude product (115 mg, yield 34.1%), which was used as such in the next step. ESI-MS m / z: 369 [M+H] + 。

[0288] Step 4: Synthesis of compound int137-4:

Chem.

[0289] int_137-3 (368 mg, 1 mmol), PMBNH2 (756 mg, 5.51 mmol, 716 μL), and TEA (893 mg, 8.82 mmol, 1.23 mL) were dissolved in a mixed solvent of acetonitrile (15 mL) and DMSO (15 mL), and HATU (1.47 g, 3.86 mmol) was slowly added to the reaction solution at 0 °C. Then, the reaction solution was heated to 20 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (178 mg, yield 36.5%). ESI-MS m / z: 488 [M+H] + 。

[0290] Step 5: Synthesis of compound int137-5:

Chem.

[0291] int_137-4 (170 mg, 348 μmol) and TFA (3 mL) were dissolved in acetonitrile (1 mL). The reaction solution was heated to 50 °C and reacted for 4 hours. Completion of the reaction was indicated by LC-MS monitoring. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, PE / EtOAc = 2 / 3) to obtain a solid (60 mg, yield 46.8%). ESI-MS m / z: 368 [M+H] + 。

[0292] Step 5: Synthesis of Compound 137:

Chemical formula

[0293] int_137-5 (60 mg, 163 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 2) to obtain Compound 137 (39 mg, yield 67.5%). MS (ESI): 354 [M+H] + 。

[0294] Example 15: Synthesis of Compound 143

Chemical formula

[0295] Step 1: Synthesis of Compound 143-1:

Chem.

[0296] int_12-4 (2.00 g, 6.47 mmol) and int_1-5 (1.09 g, 6.47 mmol) were dissolved in DME (30.0 mL), and Cs2CO3 (4.22 g, 13.0 mmol), Xantphos (375 mg, 647 μmol), and Pd2(dba)3 (593 mg, 647 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 95 °C, and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0-10% EA / petroleum ether gradient) to obtain a solid (1.5 g, yield 58.3%). ESI-MS m / z: 397 [M+H] + 。

[0297] Step 2: Synthesis of Compound int_143-2:

[0298]

Chem.

[0299] int_143-1 (993 mg, 2.5 mmol) was dissolved in aqueous ammonia (20.0 mL). The reaction solution was heated to 55 °C and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 20% EA / petroleum ether gradient) to obtain a solid (0.7 g, yield 73.2%). ESI-MS m / z: 382 [M+H] + 。

[0300] Step 3: Synthesis of compound int_143-3:

[0301]

Chemical Structure

[0302] int_143-2 (0.700 g, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL), and TEA (1.08 g, 10.7 mmol, 1.49 mL) and TFAA (900 mg, 4.28 mmol, 595 μL) were slowly added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and stirred for 16 hours. Completion of the reaction was indicated by TLC monitoring. The reaction solution was poured into ice water. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 20% EA / petroleum ether gradient) to obtain a solid (500 mg, yield 75%). ESI-MS m / z: 364 [M+H] + 。

[0303] Step 4: Synthesis of compound int_143-4:

[0304] [Chemistry]

[0305] int_9-6 (1.22 g, 8.66 mmol, 1.24 mL) was dissolved in DME (15 mL). The reaction solution was cooled to -30 °C, and NaH (693 mg, 17.3 mmol, purity 60.0%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 hour. Then, int_143-3 (546 mg, 1.5 mmol) and Pd(dppf)Cl2·CH2Cl2 (122 mg, 150 μmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 90 °C and reacted for 1 hour under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 100% EA / petroleum ether gradient) to obtain a solid (510 mg, yield 88.9%). ESI-MS m / z: 383 [M+H] + 。

[0306] Step 5: Synthesis of compound int_143-5:

[0307] [Chemistry]

[0308] int_143-4 (382 mg, 1 mmol) and NaOH (4.00 M, 8.23 mL) were dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL). The reaction solution was heated to 50 °C and reacted for 72 hours. The completion of the reaction was indicated by TLC monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid, which was dissolved in water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3) and neutralized to pH 5 - 6 with 1 M aqueous hydrochloric acid. Next, the aqueous phase was extracted with ethyl acetate (30 mL × 3), and at this point, the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (205 mg, yield 55.6%). This crude product was used directly in the next step. ESI-MS m / z: 369 [M+H] + 。

[0309] Step 6: Synthesis of compound int_143-6:

[0310]

Chemical Structure

[0311] int_143-5 (235 mg, 640 μmol), PMBNH2 (263 mg, 1.92 mmol, 249 μL), and TEA (323 mg, 3.20 mmol, 445 μL) were dissolved in a mixed solvent of acetonitrile (5 mL) and DMSO (5 mL), and HATU (851 mg, 2.24 mmol) was slowly added to the reaction solution at 0 °C. Then, the reaction solution was heated to 20 °C and reacted for 16 hours. The completion of the reaction was indicated by LC-MS monitoring. Water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 10% EA / petroleum ether gradient) to obtain a solid (175 mg, yield 56%). ESI-MS m / z: 488 [M+H] + 。

[0312] Step 7: Synthesis of compound int_143-7:

[0313]

Chemical formula

[0314] int_143-6 (100 mg, 205 μmol) was dissolved in TFA (11.5 g, 101 mmol, 7.50 mL). The reaction solution was heated to 80 °C and reacted for 16 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate chromatography (SiO2, PE / ethyl acetate = 1 / 2) to obtain a solid (53 mg, yield 70.3%). ESI-MS m / z: 368 [M+H] + 。

[0315] Step 8: Synthesis of compound 143:

[0316]

Chemical formula

[0317] int_143-7 (53 mg, 144 μmol) was dissolved in dichloromethane (3 mL) under a nitrogen atmosphere, and BBr3 (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / ethyl acetate = 1 / 2) to obtain compound 143 (35 mg, yield 68.7%). MS (ESI): 354 [M+H] + 。

[0318] Example 16: Synthesis of Compound 149

Chem.

[0319] Step 1: Synthesis of Compound int_149-2:

[0320]

Chem.

[0321] int_149-1 (34.0 g, 281 mmol) was dissolved in a mixed solvent of toluene (300 mL) and water (30.0 mL), and I2 (71.2 g, 281 mmol) and NaHCO3 (35.4 g, 421 mmol) were added at room temperature. The reaction solution was reacted at room temperature for 18 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was washed with saturated Na2S2O3 solution (350 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 5% EA / petroleum ether gradient) to obtain the product (60 g, yield 86.5%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.39 - 7.37 (m, 1H), 7.29 - 7.28 (m, 1H), 6.88 - 6.85 (m, 1H), 2.24 - 2.22 (m, 3H), 2.21 - 2.20 (m, 3H).

[0322] Step 2: Synthesis of Compound int_149-3:

[0323]

Chem.

[0324] int_149-2 (60.0 g, 243 mmol), CuI (4.62 g, 24.3 mmol), Pd(PPh3)2Cl2 (3.41 g, 4.86 mmol), and ethynyl(trimethyl)silane (28.6 g, 291 mmol, 40.4 mL) were dissolved in triethylamine (500 mL). The reaction solution was purged with nitrogen three times and stirred at room temperature for 18 h. TLC monitoring showed the reaction was complete. The reaction solution was diluted with water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative column chromatography (ISCO®, Silica Flash Column, eluent: 0-20% ethyl acetate / petroleum ether gradient) to obtain a solid (35 g, 66.3% yield). MS (ESI): 218 [M+H] + .

[0325] Step 3: Synthesis of compound int_149-4:

[0326] [ka]

[0327] int_149-3 (1.65 g, 7.59 mmol) and CuI (2.89 g, 15.2 mmol) were dissolved in DMF (40 mL). The reaction solution was purged with nitrogen three times, heated to 100 °C, and reacted for 2.5 h. LC-MS monitoring showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (ISCO®; Silica Flash Column, eluent: 0-30% ethyl acetate / petroleum ether gradient) to give the product (0.4 g, 36.3% yield). 11H NMR (400 MHz, CHLOROFORM-d) δ 8.06 - 7.93 (m, 1H), 7.35 - 7.31 (m, 1H), 7.23 - 7.18 (m, 1H), 6.88 (s, 1H), 6.56 - 6.48 (m, 1H), 2.54 - 2.43 (m, 6H). MS (ESI): 146 [M+H] + .

[0328] Step 4: Synthesis of compound int_149-5:

[0329] [Chemical Structure]

[0330] int_149-4 (11.0 g, 75.8 mmol) was dissolved in acetic acid (100 mL), and NaBH3CN (9.52 g, 152 mmol) was added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 2 hours. The completion of the reaction was indicated by LC-MS monitoring. The reaction solution was diluted with water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 30% ethyl acetate / petroleum ether gradient) to obtain the product (7.3 g, yield 65.5%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 6.76 - 6.69 (m, 1H), 6.65 - 6.55 (m, 1H), 3.51 - 3.39 (m, 2H), 3.39 - 3.28 (m, 1H), 2.96 - 2.88 (m, 2H), 2.18 - 1.98 (m, 6H). MS (ESI): 148 [M+H] + .

[0331] Step 5: Synthesis of compound int_149-6:

[0332]

Chem.

[0333] int_149-5 (1.00 g, 6.79 mmol) was dissolved in H2SO4 (20.0 mL) at 0 °C, and HNO3 (611 mg, 6.79 mmol, 437 μL, purity 70.0%) was added dropwise to the reaction solution at 0 °C. The reaction solution was heated to 20 °C and stirred for 1 hour. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was poured into ice water (150 mL), and the pH of the aqueous phase was adjusted to 8 - 9 with 6N NaOH. The aqueous phase was extracted with dichloromethane (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 20% ethyl acetate / petroleum ether gradient) to obtain the product (1.1 g, yield 84.3%). MS (ESI): 193 [M+H] + 。

[0334] Step 6: Synthesis of compound int_149-7:

[0335]

Chem.

[0336] int_149-6 (1.10 g, 5.72 mmol) was dissolved in dichloromethane (20 mL), and DMAP (140 mg, 1.14 mmol), TEA (1.74 g, 17.2 mmol, 2.39 mL), and Boc2O (2.50 g, 11.5 mmol, 2.63 mL) were added to the reaction solution at 0 °C. The reaction solution was heated to room temperature and reacted for 8 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 20% ethyl acetate / petroleum ether gradient) to obtain the product (1 g, yield 59.8%). MS (ESI): 293 [M+H] + 。

[0337] Step 7: Synthesis of compound int_149-8:

[0338]

Chemical formula

[0339] int_149-7 (0.90 g, 3.08 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and Fe (2.58 g, 46.2 mmol) and NH4Cl (1.65 g, 30.8 mmol) were added to the reaction solution. The reaction solution was heated to 80 °C and reacted for 8 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), Silica Flash Column, eluent: 0 - 20% ethyl acetate / petroleum ether gradient) to obtain the product (0.7 g, yield 86.8%). 11H NMR (400 MHz, DMSO-d6) δ 6.69 (s, 1H), 3.34 - 3.33 (m, 6H), 2.06 - 2.02 (m, 3H), 1.93 (s, 3H), 1.45 (s, 9H). MS (ESI): 263 [M+H] + .

[0340] Step 8: Synthesis of compound int_149-9:

[0341] [Chemical formula]

[0342] int_149-8 (0.65 g, 2.48 mmol) and int_1-6 (722 mg, 2.73 mmol) were dissolved in 1,4-dioxane (20 mL), and Cs2CO3 (1.61 g, 4.96 mmol), Xantphos (215 mg, 372 μmol), and Pd2(dba)3 (340 mg, 372 μmol) were added. The reaction solution was purged with nitrogen three times, heated to 110 °C, and reacted for 5 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (SiO2, PE / THF = 1 / 0~9 / 1) to obtain the product (730 mg, yield 66%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ 7.48 - 7.43 (m, 1H), 7.00 - 6.95 (m, 1H), 6.24 - 6.06 (m, 1H), 4.16 - 4.08 (m, 2H), 3.01 - 2.94 (m, 2H), 2.24 - 2.16 (m, 6H), 2.16 - 2.10 (m, 6H), 1.57 - 1.52 (m, 9H). ESI-MS m / z: 446 [M+H] + .

[0343] Step 9: Synthesis of compound int_149-10:

[0344]

Chemical formula

[0345] int_1-8 (370 mg, 5.60 mmol, 353 μL) and int_149-9 (0.50 g, 1.12 mmol) were dissolved in DMF (7 mL), and CuI (427 mg, 2.24 mmol), Cs2CO3 (1.09 g, 3.36 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (31.9 mg, 224 μmol) were added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 140 °C and reacted for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark), 20 g SepaFlash (registered trademark) Silica Flash Column, eluent: 0 - 30% ethyl acetate / petroleum ether gradient) to obtain the product (50 mg, yield 10.4%). ESI-MS m / z: 432 [M+H] + 。

[0346] Step 10: Synthesis of compound 149:

[0347]

Chemical formula

[0348] At 0 °C, sulfuric acid (1 mL) was slowly added to int_149-10 (45.0 mg, 104 μmol). The reaction solution was reacted at 20 °C for 1 hour. Completion of the reaction was indicated by LC-MS monitoring. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 8 - 9 with triethylamine and extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain a solid (30 mg, yield 82.6%). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.75 (m, 1H), 6.96 - 6.92 (m, 1H), 6.70 - 6.57 (m, 4H), 5.33 (br s, 1H), 3.55 - 3.47 (m, 2H), 3.07 - 2.92 (m, 2H), 2.29 - 2.22 (m, 6H), 1.75 - 1.67 (m, 3H), 1.62 - 1.55 (m, 3H). MS (ESI): 350 [M+H] + 。

[0349] Example 17: Synthesis of Compound 150 and Compound 151:

Chemical Structure

[0350] Compound 149 (50 mg, 143 μmol) was subjected to preparative SFC chiral resolution (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 60% - 60%, fractionation) to obtain Compound 150 (8 mg, yield 32%) and Compound 151 (8 mg, yield 32%). Compound 150: 11H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.75 (m, 1H), 6.96 - 6.92 (m, 1H), 6.70 - 6.57 (m, 4H), 5.33 (br s, 1H), 3.55 - 3.47 (m, 2H), 3.07 - 2.92 (m, 2H), 2.29 - 2.22 (m, 6H), 1.75 - 1.67 (m, 3H), 1.62 - 1.55 (m, 3H). MS (ESI): 350 [M+H] + .

[0351] Analytical SFC retention time: 3.482 min (Instrument: Waters UPCC with PDA Detector, Column: Cellulose-2, 100×4.6 mm, inner diameter 3 μm, Mobile phase: A: CO2, B: ethanol (0.05% DEA), Gradient: 40% of B, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi). Compound 151: 1 1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.01 - 6.91 (m, 1H), 6.69 - 6.55 (m, 4H), 5.37 - 5.28 (m, 1H), 3.55 - 3.49 (m, 2H), 3.08 - 2.92 (m, 2H), 2.30 - 2.23 (m, 6H), 1.71 (s, 3H), 1.61 - 1.56 (m, 3H). MS (ESI): 350 [M+H] + .

[0352] Analytical SFC retention time: 4.748 min (Instrument: Waters UPCC with PDA Detector, Column: Cellulose-2, 100×4.6 mm, inner diameter 3 μm, Mobile phase: A: CO2, B: ethanol (0.05% DEA), Gradient: 40% of B, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi).

[0353] Example 18: Synthesis of Compound 153: [Chemical]

[0354] Step 1: Synthesis of Compound 153:

[0355] [Chemical]

[0356] Int_149 (0.16 g, 461 μmol) was dissolved in tetrahydrofuran (5 mL), and DDQ (105 mg, 461 μmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 3 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography (ISCO (registered trademark); Silica Flash Column, eluent: 0 - 65% EA / petroleum ether gradient) to obtain the product (120 mg, yield 74.9%). 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (br s, 1H), 7.85 - 7.81 (m, 1H), 7.44 (t, J = 2.8 Hz, 1H), 7.41 - 7.39 (m, 1H), 6.77 - 6.68 (m, 2H), 6.63 (br s, 2H), 6.48 - 6.46 (m, 1H), 2.27 (s, 3H), 2.23 - 2.20 (m, 3H), 2.05 - 2.03 (m, 3H), 1.89 - 1.86 (m, 3H). MS (ESI): 348 [M+H] + .

[0357] Example 19: Synthesis of Compound 176: [Chemical]

[0358] Step 1: Synthesis of Compound int_176-2:

[0359]

Chem.

[0360] int_176-1 (1.2 g, 7.89 mmol) and int_1-6 (2.51 g, 9.47 mmol) were dissolved in DME (50 mL), and Cs2CO3 (3.7 g, 11.364 mmol), Xantphos (456 mg, 0.789 mmol), and Pd2(dba)3 (722 mg, 0.789 mmol) were added. The reaction solution was purged with nitrogen three times, heated to 90 °C, and reacted for 16 hours. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain a solid (1.4 g, yield 52.8%). ESI-MS m / z: 336 [M+H] + 。

[0361] Step 2: Synthesis of compound int_176-3:

[0362]

Chem.

[0363] int_1-8 (283 mg, 4.28 mmol) was dissolved in DME (30 mL). The reaction solution was cooled to -30 °C, and NaH (214 mg, 5.355 mmol, purity 60.0%) was slowly added to the reaction solution under a nitrogen atmosphere. The reaction solution was heated to 0 °C and reacted for 0.5 h. Subsequently, int_176-2 (1.2 g, 3.57 mmol) and Pd(dppf)Cl2 (261 mg, 0.357 mmol) were added to the reaction solution at 0 °C. The reaction solution was heated to 90 °C and reacted for 12 h under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain a solid (670 mg, yield 58.7%). ESI-MS m / z: 322 [M+H] + 。

[0364] Step 3: Synthesis of compound int_176-4:

[0365]

Chemical Structure

[0366] int_176-3 (670 mg, 2.09 mmol), potassium carbonate (577 mg, 4.17 mmol), and 30% aqueous hydrogen peroxide solution (711 mg, 6.27 mmol) were dissolved in a mixed solvent of DMSO (10 mL) and water (2 mL). The reaction solution was reacted at 25 °C for 2 h. Completion of the reaction was indicated by LC-MS monitoring. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with dichloromethane (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain a solid (120 mg, yield 16.9%). MS (ESI): 340 [M+H] + 。

[0367] Step 4: Synthesis of Compound 176:

[0368] [Chemical Formula]

[0369] Int_176-4 (50 mg, 0.147 mmol) was dissolved in dichloromethane (15 mL) under a nitrogen atmosphere, and BBr3 (626 mg, 2.5 mmol) was added to the reaction solution at 0 °C. The reaction solution was reacted at 0 °C for 2 hours under a nitrogen atmosphere. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was adjusted to pH 7 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (40 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative column chromatography to obtain Compound 176 (12 mg, yield 25.5%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 6.95 (s, 2H), 6.67 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.92 (s, 3H), 1.69 (s, 3H). MS (ESI): 326 [M+H] + .

[0370] By changing the starting materials and using the above synthesis method, target compounds 4, 8, 18 - 95, 99 - 114, 118 - 136, 140 - 142, 144 - 148, 152, 154 - 175, and 177 - 225 in Table 1 were obtained.

[0371]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0372] Biological Example 1: In Vitro Assay of the Compounds of the Invention for Inhibiting MYT1 Kinase Activity The recombinant MYT1 protein and the compound were pre-incubated at room temperature for 15 minutes, and then 10 μM ATP was added to initiate the reaction. The mixture was incubated at room temperature for an additional 60 minutes, and Promega's ADP-GLO reagent was added. The resulting mixture was incubated in the dark for 40 minutes, then the detection solution was added, and the mixture was incubated for an additional 45 - 60 minutes. Chemiluminescence was measured using ENVISION. The inhibition rate and IC 50 were calculated compared to the DMSO group. The results are shown in Table 2 below.

[0373]

Table 2-1

Table 2-2

Table 2-3

[0374] +++ indicates that the IC 50 is 200 nM or less. ++ indicates that the IC 50 is between 200 nM and 500 nM. + indicates that the IC 50 is greater than 500 nM.

[0375] Biological Example 2: In Vitro Antiproliferative Activity of the Compounds of the Invention Against MIA PaCa-2 Cells MIA PaCa-2 cells were seeded in a 384-well plate at 3000 cells / well. After overnight adherent culture, DMSO or the compound serially diluted at a ratio of 1:5 from 10 μM was added. The viability after 72 hours of administration was evaluated by measuring the intracellular ATP content. The inhibition rate of viable cells by the compound was calculated compared to the DMSO group, and the IC 50 value was calculated. The results are shown in Table 3 below.

[0376] [Table 3]

[0377] The reference compound RP-6306 is Compound 182 in International Publication No. WO2021195781A1.

[0378] [Chemical Formula]

[0379] As can be seen from the data in Table 3, when the compounds of the present invention are used alone, they do not show strong antiproliferative activity against MIA PaCa-2 cells.

[0380] Biological Example 3: In Vitro Antiproliferative Activity of the Compounds of the Invention in Combination with Gemcitabine Against MIA PaCa-2 Cells MIA PaCa-2 cells were seeded in a 384-well plate at 3000 cells / well, and 20 nM of gemcitabine was added. After overnight adherent culture, DMSO or the compound serially diluted at a ratio of 1:5 from 1000 nM was added. The viability after 72 hours of administration was evaluated by measuring the intracellular ATP content. The inhibition rate of viable cells by the compound was calculated compared to the DMSO group, and the IC 50 value was calculated. The results are shown in Table 4 below.

[0381]

Table 4

[0382] As can be seen from the data in Table 4, the compounds of the present invention have strong anti-proliferative activity against MIA PaCa-2 cells in vitro when used in combination with gemcitabine. Compound 2 of the present invention has stronger anti-proliferative activity than RP-6306 when used in combination with gemcitabine.

[0383] Biological Example 4: In Vivo Pharmacokinetic Experiment of the Compounds of the Present Invention CD-1 female mice aged 7 - 10 weeks were intravenously and orally administered 2 mg / kg and 10 mg / kg, respectively. The mice were fasted for at least 12 hours before administration, fed after 4 hours of administration, and allowed to drink water freely during the experiment. On the day of the experiment, the animals in the intravenous administration group were injected once via the tail vein with the corresponding compound at a dose of 10 mL / kg, and the animals in the oral administration group were administered once by intragastric injection with the corresponding compound at a dose of 10 mL / kg. The body weight of the animals was measured before administration, and the dosage was calculated according to the body weight. The sample collection times were 0.083 hours (injection group), 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Approximately 200 μL of whole blood was collected from the submandibular venous plexus at each time point and used for plasma preparation for concentration measurement by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). After collecting the PK samples at the last time point, all the animals were euthanized by CO2 anesthesia. The plasma concentration was processed using the non-compartmental model of the pharmacokinetic software Phoenix WinNonlin (trademark) version 8.3 (Certara), and the pharmacokinetic parameters were calculated using the logarithmic linear trapezoidal method. The in vivo pharmacokinetic results are shown in Table 5 below.

[0384]

Table 5

[0385] As can be seen from the data in Table 5, in the pharmacokinetic experiment of mice, for Compound 2 of the present invention, the half-life T 1 / 2 is longer compared to RP-6306, indicating that Compound 2 has better metabolic stability in vivo. Furthermore, Compound 2 has a greater increase in Vdss compared to RP-6306, indicating that Compound 2 is not much distributed in plasma but more distributed in other tissues, which has great advantages for the treatment of solid tumors. Thus, Compound 2 has unexpectedly improved pharmacokinetic properties compared to RP-6306.

[0386] Biological Example 5: In Vitro Permeability Experiment of the Compounds of the Present Invention The permeability in vitro, or the ability to function as a P-glycoprotein (P-gp) transport substrate, was tested using MDCK cells (MDCK wild type) or MDCK cells stably transfected with MDR1 (MDCK-MDR1), respectively. The permeability experiment was performed twice at a single concentration (5 μM) in a Transwell system. The cells were incubated for 90 minutes. For the corresponding compounds, the apical-to-basolateral (A to B, A-B) transport and basolateral-to-apical (B to A, B-A) transport were measured, and the permeability rate (apparent permeability) (Papp×10 -6 cm / sec) and efflux ratio (P app (B-A) / P app (A-B)) of the test compound were calculated. Digoxin, metoprolol, and atenolol were used as controls. The results of the in vitro permeability experiment are shown in Table 6 below.

[0387]

Table 6

[0388] As can be seen from the data in Table 6, for Compound 2 of the present invention, compared to RP-6306, the transport rate from apical to basolateral (A to B, A-B) in MDCK cells and MDCK-MDR1 cells is faster, and the efflux ratio (P app (B-A) / P appSince (A - B) is low, it was shown that Compound 2 has better permeability than RP - 6306.

[0389] Biological Example 6: In vitro Solubility and Stability Experiments of the Compounds of the Present Invention

[0390] Preparation of Standard Curve: Weighed 10.01 mg of the sample and placed it in a volumetric flask, and made the volume to 10 mL with acetonitrile / water (v / v, 9 / 1) to prepare a standard solution of 1.001 mg / mL. Next, the standard solution was serially diluted to 0.5005 mg / mL, 0.1001 mg / mL, 0.05005 mg / mL, 0.01001 mg / mL, and 0.001001 mg / mL to prepare a standard curve, and a linear equation was fitted with the peak area of the sample as the vertical axis and the concentration as the horizontal axis.

[0391] Solubility and Stability Tests: Added 15 mg of the sample to 3 mL of vehicle (FaSSIF, FeSSIF, SGF, or water) to prepare the corresponding suspension with a target concentration of 5 mg / mL. The prepared suspension was stirred at 37 °C for 0.5 h on a shaker (800 rpm), and then the suspension was filtered. The filtrate was diluted by the corresponding multiple with a diluent so that the peak height did not exceed the standard curve, and the solubility and purity were detected using HPLC.

[0392] The results of the in vitro solubility and stability experiments of the compounds of the present invention are shown in Table 7 below.

[0393]

Table 7

[0394] N.D. indicates that it was not detected.

[0395] As can be seen from the data in Table 7, Compound 2 of the present invention has higher solubility in various vehicles (FaSSIF, FeSSIF, SGF, water, methanol, tetrahydrofuran) compared to RP-6306, and Compound 2 is more stable than RP-6306 in FaSSIF, FeSSIF, and water.

[0396] Biological Example 7: In Vivo Pharmacodynamic Test - Mouse HT29 Subcutaneous Xenograft Tumor Model HT29 is a colon cancer cell. 5×10 6 cells were subcutaneously implanted into each nude mouse. When the tumor grew to 100 - 200 mm 3 , the compound was orally administered once a day alone or intraperitoneally injected once a week in combination with gemcitabine, and the tumor volume was measured twice a week and at the end of the administration. The tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the treatment group - tumor volume on day 1 of the treatment group) / (tumor volume on day 28 of the vehicle control group - tumor volume on day 1 of the treatment group) was used to calculate the tumor growth inhibition rate of this compound.

[0397] The test results indicate that the compound of the present invention has better activity in the mouse HT29 subcutaneous xenograft tumor model.

[0398] Biological Example 8: In Vivo Pharmacodynamic Test - Mouse HCC1569 Subcutaneous Xenograft Tumor Model HCC1569 is a breast cancer cell. 10×10 6 cells were subcutaneously implanted into each nude mouse. When the tumor grew to 100 - 200 mm 3 , the compound was orally administered once a day alone or intraperitoneally injected once a week in combination with gemcitabine, and the tumor volume was measured twice a week and at the end of the administration. The tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the treatment group - tumor volume on day 1 of the treatment group) / (tumor volume on day 28 of the vehicle control group - tumor volume on day 1 of the treatment group) was used to calculate the tumor growth inhibition rate of this compound.

[0399] The test results indicate that the compound of the present invention has better activity in the mouse HCC1569 subcutaneous xenograft tumor model.

[0400] Biological Example 9: In Vivo Pharmacodynamics Test - Mouse OVCAR-3 Subcutaneous Xenograft Tumor Model OVCAR-3 is an ovarian cancer cell. 10×10 6 OVCAR-3 cells were subcutaneously transplanted into each nude mouse. When the tumor grew to 100 - 200 mm 3 , the compound was orally administered once a day alone, or intraperitoneally injected once a week in combination with gemcitabine, and the tumor volume was measured twice a week and at the end of the administration. The tumor growth inhibition rate (TGI) = 1 - (tumor volume on the 28th day of the treatment group - tumor volume on the 1st day of the treatment group) / (tumor volume on the 28th day of the vehicle control group - tumor volume on the 1st day of the treatment group) was used to calculate the tumor growth inhibition rate of the compound.

[0401] The test results indicate that the compound of the present invention has better activity in the mouse OVCAR-3 subcutaneous xenograft tumor model.

[0402] Biological Example 10: In Vitro Manual Patch-Clamp Experiment for Detecting the Inhibitory Activity of Compounds against hERG Ion Channels The HEK-293 cell line stably expressing the hERG potassium channel was used. The HEK293 cell line stably expressing the hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37 °C and 5% carbon dioxide.

[0403] Cell passage: The old medium was removed, and the cells were washed once with PBS, then 1 mL of TrypLE (trademark) Express solution was added and incubated at 37 °C for about 0.5 minutes. When the cells detached from the bottom of the dish, about 5 mL of pre-warmed complete medium was added. The cell suspension was gently collected with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to recover the cells. The cells were seeded into a 6 cm cell culture dish at a seeding cell amount of 2.5×10 5Cells were seeded at a cell count per dish (final volume: 5 mL) and subjected to expansion culture or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%.

[0404] The liquid used during the electrophysiological examination was recorded.

[0405] Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2-2H2O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4-2H2O, adjusted to pH = 7.4 with NaOH.

[0406] Intracellular fluid: 20 mM KCl, 115 mM K-aspartate, 1 mM MgCl2-6H2O, 5 mM EGTA, 10 mM HEPES, and 2 mM Na2-ATP, adjusted to pH = 7.2 with KOH.

[0407] Detection by patch clamp: Before the test, cells were isolated with TrypLE (trademark) Express, and 4×10 3 individual cells were seeded onto a cover glass. The test detection was performed 18 hours after culturing in a 24-well plate (final volume: 500 μL). The voltage stimulation scheme of the whole-cell patch clamp for recording the whole-cell hERG potassium current was as follows: When the whole-cell seal was formed, the cell membrane voltage was clamped at -80 mV. The clamp voltage was depolarized from -80 mV to -50 mV and maintained for 0.5 seconds (used for detecting leakage current), then stepped up to 30 mV and maintained for 2.5 seconds, and then rapidly returned to -50 mV and maintained for 4 seconds to excite the tail current of the hERG channel. To observe the effect of the drug on the hERG tail current, data were collected repeatedly every 10 seconds. The leakage current was detected with a -50 mV stimulation for 0.5 seconds. The test data were collected with an EPC-10 amplifier (HEKA) and saved in PatchMaster (HEKA) software.

[0408] The capillary glass tube was drawn into the recording electrode using a micropipette puller. Under an inverted microscope, the microelectrode manipulator was operated to bring the recording electrode into contact with the cell. Suction was applied under negative pressure to form a GΩ seal. After forming the GΩ seal, rapid capacitance correction was performed. The cell membrane was ruptured under continuous negative voltage to form the whole-cell recording mode. Thereafter, slow capacitance correction was performed, and the membrane capacitance and series resistance were recorded without leak compensation.

[0409] Administration was started when the hERG current in the whole-cell recording became stable. After maintaining each drug concentration for 5 minutes (or until the current became stable), the next concentration was measured. Multiple concentrations were measured for each test compound. The cover glass seeded with cells was placed in the recording chamber of the inverted microscope. The test substance and the extracellular fluid without the test substance were sequentially flowed into the recording chamber from low concentration to high concentration using the gravity perfusion method to act on the cells, and liquid exchange was performed using a vacuum pump during recording. For each cell, the current detected in the extracellular fluid without the compound was used as each control group. Multiple cells were repeatedly and independently tested. All electrophysiological experiments were performed at room temperature.

[0410] Data analysis: The current acting at each drug concentration and the current of the blank control were normalized

Number

Number

Number

[0411] The dose-dependent effect was non-linearly fitted using the above formula. Here, C is the concentration of the test substance, IC 50represents the half-maximal inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC 50 calculations were performed using IGOR software.

[0412] Conclusion: The compound of the present invention has no significant inhibitory activity against hERG.

[0413] Biological Example 11: Test on Inhibition against Cytochrome P450 Isozyme

[0414] Experimental procedure: First, the test compound (10.0 mM) was diluted to prepare a working solution with a concentration of 1.00 mM (100-fold of the final concentration). At the same time, working solutions of positive inhibitors for P450 isoenzymes (CYP2C9 (using diclofenac as a probe substrate), CYP2D6 (using dextromethorphan as a probe substrate), CYP3A (using midazolam or testosterone as a probe substrate)) and their specific probe substrates were prepared. Human liver microsomes stored in a refrigerator below -80°C were thawed on ice. After all were thawed, the human liver microsomes were diluted with potassium phosphate buffer (PB) to prepare a working solution with a specific concentration (0.127 mg / mL). 20.0 μL of the probe substrate (add 20.0 μL of PB to the blank well) and 158 μL of the working solution of human liver microsomes were added to the reaction plate, placed on ice for use, and then 2.00 μL of the test compound (N = 1) and specific inhibitor (N = 2) were added to the corresponding wells. In the group without inhibitors (test compound or positive inhibitor), the corresponding organic solvent was added. The organic layers of the test compound control samples and the organic phases of the positive control samples were set as 1:1 DMSO:MeOH and 1:9 DMSO:MeOH, respectively. After pre-incubating in a water bath at 37°C for 10 minutes, 20.0 μL of the coenzyme factor (NADPH) solution was added to the reaction plate. For the CYP3A metabolic reaction using midazolam as the probe substrate, the reaction time was 3 minutes; for the CYP2D6 reaction using dextromethorphan as the probe substrate, the reaction time was 20 minutes; and the other reactions were all carried out for 10 minutes. 400 μL of a pre-cooled acetonitrile solution (containing 200 ng / mL of tolbutamide and labetalol as internal standards) was added to terminate the reaction. The reaction plate was placed on a shaker and shaken for 10 minutes. The reaction plate was centrifuged at 4°C and 4000 rpm for 20 minutes, and 200 μL of the supernatant was collected, diluted by adding 100 μL of water to the sample. Finally, the plate was sealed and vibrated to shake evenly and subjected to LC / MS / MS detection.

[0415] Data analysis: Using XL Fit, the relationship between the ratio of the control group and the test compound concentration was plotted, and non-linear regression analysis of the data was performed. IC 50The value was determined using a three-parameter or four-parameter logical equation: Three-parameter logical equation: [Number] and four-parameter logical equation: [Number]

[0416] Conclusion: The compounds of the present invention do not show significant inhibitory effects on all subtypes of CYP enzymes.

[0417] Biological Example 12: Metabolic Stability of Hepatocytes Several 96-well sample precipitation plates were prepared, and were used as T0, T15, T30, T60, T90, T0-MC, T90-MC, and blank substrate respectively. The recovery medium and the culture medium were taken out in advance and placed in a 37 °C water bath for preheating. The cryopreserved hepatocytes were taken out from the liquid nitrogen tank and immediately immersed in a 37 °C water bath (for about 90 seconds). After thawing and loosening the cryopreserved hepatocytes, they were poured into a centrifuge tube containing 40 mL of recovery medium, and the tube was gently inverted to resuspend the cells in the recovery medium. The cells were centrifuged at 100×g for 5 minutes at room temperature, and the supernatant was removed. The hepatocytes were resuspended in an appropriate amount of culture medium, and the cell viability was calculated using the trypan blue staining method. 198 μL of hepatocyte suspension (0.51×10 6 cells / mL) was added to the preheated culture plate. In the medium control group, 198 μL of culture medium without hepatocytes was added to the T0-MC culture plate and the T90-MC culture plate. All culture plates were pre-incubated in a 37 °C incubator for 10 minutes.

[0418] Next, 2 μL of the working solutions of the test substance and the control compound were added and mixed well. The incubation plate was immediately placed on the shaker in the incubator, and the timer was started to initiate the reaction. Two replicate samples were prepared for each time point of each compound. The incubation conditions were 37 °C, saturated humidity, and 5% CO2.

[0419] In the test system, the final concentration of the test substance was 1 μM, the final concentration of the control sample was 3 μM, the final concentration of hepatocytes was 0.5×10 6 cells / mL, the final concentration of the total organic solvent was 0.96%, and among them, the final concentration of DMSO was 0.1%. At the end of incubation at the corresponding time points, the incubation plate was taken out, and 25 μL of the cell mixture of this compound and the control compound was added to a sample plate containing 125 μL of acetonitrile stop solution (containing 200 ng / mL of tolbutamide and labetalol as internal standards). To the blank sample plate, 25 μL of culture medium without hepatocytes was directly added. After sealing, all sample plates were shaken at 600 rpm for 10 minutes and then centrifuged at 3220×g for 20 minutes. The supernatants of the test substance and the control samples were diluted with ultrapure water at a ratio of 1:3. All samples were mixed well and analyzed by LC / MS / MS.

[0420] Data analysis: The residual rate of the compound after incubation was calculated using the following formula:

Equation

[0421] t 1 / 2 and Clint were calculated using the following first-order kinetic equation:

Equation

[0422] Conclusion: The compound of the present invention has good metabolic stability in hepatocytes.

[0423] The specific embodiments of the present invention have been described above. However, these embodiments are merely illustrative, and those skilled in the art will understand that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. 【Chemical 1】 (In general formula (1), R Ａ is -C(O)NH(R ４ ), -C(O)(R ３ａ ), or -SO ２ R ３ａ and is; R Ｂ is -H or -N(R ３ ) ２ and; X １ is either CR ａ１ or N; X ２ is either CR ａ２ or N; X ３ is either CR ａ３ or N; R ａ１ 、R ａ２ 、R ａ３ 、and R １ are each independently, -H, halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, -N(R ３ ), -OR ２ 、-C(O)N(R ３ ), -SO ４ N(R ２ ), -SO ２ R ４ ), or -Q-R ２ wherein said (C1-C6)alkyl, said (C1-C6)haloalkyl, said (C2-C6)alkenyl, said (C2-C6)alkynyl, said (C3-C8)cycloalkyl, said (C6-C10)aryl, said (5-10 membered)heteroaryl, or said (3-9 membered)heterocycloalkyl are each independently, -H, halogen, -OH, -OR ２ R ３ａ 、or -Q-R ３ｂ and wherein said (C1-C6)alkyl, said (C1-C6)haloalkyl, said (C2-C6)alkenyl, said (C2-C6)alkynyl, said (C3-C8)cycloalkyl, said (C6-C10)aryl, said (5-10 membered)heteroaryl, or said (3-9 membered)heterocycloalkyl are each independently, -H, halogen, -OH, -OR ５ 、-N(R ５ ), -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl and may be optionally substituted with 1, 2, 3, or 4 groups of; or, R ２ and R ａ３ together with the carbon atom to which they are each attached form (C4-C9)cycloalkyl, (C4-C9)cycloalkenyl, (4-9 membered)heterocycloalkyl, phenyl, or (5-10 membered)heteroaryl, wherein said (C4-C9)cycloalkyl, said (C4-C9)cycloalkenyl, said (4-9 membered)heterocycloalkyl, said phenyl, or said (5-10 membered)heteroaryl are each independently, -H, halogen, -OH, -OR １ 、-N(R ５ , -N(R ５ ), ２ , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl, which may be optionally substituted with one, two, three, or four groups of them; R ａ１ 、R ａ２ 、R ａ３ 、and R １ none of which is -CN, R ２ is 【Chemical 2】 and where X ４ X ５ X ６ X ７ and X ８ are each independently -H, -OH, -OR ３ , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl, and X ４ X ５ X ６ X ７ and X ８ are not simultaneously -H; or each pair of X ４ / X ５ X ５ / X ６ X ６ / X ７ and X ７ / X ８ may independently form, together with the carbon atom to which each is attached, (C4-C10)cycloalkyl, (4-10 membered)heterocycloalkyl, phenyl, or (5-10 membered)heteroaryl, where the (C4-C10)cycloalkyl, the (4-10 membered)heterocycloalkyl, the phenyl, or the (5-10 membered)heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, halogen, -OH, -OR ５ , -N(R ５ ) ２ , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl; or R ２ is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, where the (6-10 membered)heterocycloalkyl or the (6-10 membered)heteroaryl are each independently -H, -OH, -OR ３ 、 halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, and (3-6 membered)heterocycloalkyl, which may be optionally substituted with one, two, three, or four groups selected from the group consisting of; R ａ１ 、R ａ２ 、R ａ３ 、and R １ in which at least one of them is -CN, or when R ａ３ and R １ together with the carbon atom to which they are respectively attached form a (C4-C9) cycloalkenyl, (4-9 membered) heterocycloalkyl, or (5-10 membered) heteroaryl, the said (4-9 membered) heterocycloalkyl or the said (5-10 membered) heteroaryl may each independently be optionally substituted with one, two, three, or four groups selected from -H, halogen, -OH, -OR ５ 、-N(R ５ ) ２ 、-CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C8) cycloalkyl, and R ２ is 【Chemical Formula 3】 and wherein X ４ X ５ X ６ X ７ and X ８ are each independently -H, -OH, -OR ３ , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl, and at least two of X ４ X ５ X ６ X ７ and X ８ are not -H at the same time; or each pair of X ４ / X ５ X ５ / X ６ X ６ / X ７ and X ７ / X ８ may independently form, together with the carbon atom to which each is attached, (C4-C10)cycloalkyl, (4-10 membered)heterocycloalkyl, phenyl, or (5-10 membered)heteroaryl, where the (C4-C10)cycloalkyl, the (4-10 membered)heterocycloalkyl, the phenyl, or the (5-10 membered)heteroaryl may each independently be optionally substituted with one, two, three, or four groups of -H, halogen, -OH, -OR ３ , -N(R ３ ) ２ , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl; or R ２ is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, where the (6-10 membered)heterocycloalkyl or the (6-10 membered)heteroaryl may each independently be -H, -OH, -OR ３ 、 halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, and (3-6 membered)heterocycloalkyl, which may be optionally substituted with one, two, three, or four groups selected from the group consisting of; Each R ３ is independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, or -SO ２ R ３ａ wherein said (C1-C6)alkyl, said (C1-C6)haloalkyl, said (C2-C6)alkenyl, said (C2-C6)alkynyl, said (C3-C8)cycloalkyl, said (C6-C10)aryl, said (5-10 membered)heteroaryl, or said (3-9 membered)heterocycloalkyl are each optionally independently substituted with 1, 2, 3, or 4 groups of -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; or two R ３ may be taken together with the nitrogen atom to which they are attached to form a (3- to 9-membered)heterocycloalkyl, wherein each of said (3- to 9-membered)heterocycloalkyl is independently -H, halogen, -OH, -OR ５ , -N(R ５ ) ２ , —CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl; ３ａ is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, or (5-10 membered)heteroaryl, wherein said (C1-C6)alkyl, said (C1-C6)haloalkyl, said (C3-C8)cycloalkyl, said (3-9 membered)heterocycloalkyl, said (C6-C10)aryl, or said (5-10 membered)heteroaryl are each optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; Each R ３ｂ is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, -N(R ３ ) ２ , -OR ３ , -C(O)N(R ４ ) ２ , -SO ２ N(R ４ ) ２ , or -SO ２ R ３ａ wherein said (C1-C6)alkyl, said (C1-C6)haloalkyl, said (C2-C6)alkenyl, said (C2-C6)alkynyl, said (C3-C8)cycloalkyl, said (C6-C10)aryl, said (5-10 membered)heteroaryl, or said (3-9 membered)heterocycloalkyl is each independently optionally substituted with 1, 2, 3 or 4 groups selected from -H, halogen, -OH, -OR ５ , -N(R ５ ) ２ , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl: Q is a (C1-C6) alkylene, a (C2-C6) alkenylene, a (C2-C6) alkynylene, a (C3-C8) cycloalkylene, a (3-9 membered) heterocycloalkylene, a (C6-C10) arylene, or a (5-10 membered) heteroarylene, wherein the (C1-C6) alkylene, the (C2-C6) alkenylene, the (C2-C6) alkynylene, the (C3-C8) cycloalkylene, the (C6-C10) arylene, the (5-10 membered) heteroarylene, or the (3-9 membered) heterocycloalkylene is each independently -H, a halogen, -OH, -OR ５ , -N(R ５ ) ２ , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl; Each R ４ is, independently, -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl, where the (C1-C6)alkyl, the (C1-C6)haloalkyl, the (C1-C6)alkoxy, the (C3-C8)cycloalkyl, the (3-9-membered)heterocycloalkyl, the (C6-C10)aryl, or the (5-10-membered)heteroaryl is each independently optionally substituted with 1, 2, 3, or 4 groups of -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; or two Rs ４ on the same nitrogen atom may together with the nitrogen atom to which they are attached form a (3-9-membered)heterocycloalkyl, where the (3-9-membered)heterocycloalkyl is independently optionally substituted with 1, 2, 3, or 4 groups of -H, halogen, -OH, -OR ５ , -N(R ５ ), -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl; ２ ​ Each R ５ is, independently, -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl, or -SO ２ R ３ａ wherein the (C1-C6)alkyl, the (C1-C6)haloalkyl, the (C2-C6)alkenyl, the (C2-C6)alkynyl, the (C3-C8)cycloalkyl, the (C6-C10)aryl, the (5-10-membered)heteroaryl, or the (3-9-membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; or two R ５ on the same nitrogen atom may together with the nitrogen atom to which they are attached form a (3-9-membered)heterocycloalkyl, wherein the (3-9-membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, halogen, -OH, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C8)cycloalkyl.)

2. In the general formula (1), R ａ１ , R ａ２ , R ａ３ , and R １ are each independently -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R ３ ) ２ , -OR ３ , -C(O)N(R ４ ) ２ , -SO ２ N (R ４ ) ２ , -SO ２ R ３ａ , or -Q-R ３ｂ wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C8) cycloalkyl, the (C6-C10) aryl, the (5-10 membered) heteroaryl, or the (3-9 membered) heterocycloalkyl is each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, aryl, and (5-6 membered)heteroaryl; or R ａ３ and R １ forms, together with the carbon atoms to which they are respectively attached, (C3-C8 member) cycloalkyl, (4-8 member) heterocycloalkyl, phenyl, or (5-6 member) heteroaryl, where the (C3-C8 member) cycloalkyl, the (4-8 member) heterocycloalkyl, the phenyl, or the (5-6 member) heteroaryl are each independently -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -N(CH ３ ), ２ , -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C3-C6) cycloalkyl, optionally substituted with 1, 2, 3, or 4 groups of the compounds according to claim 1, or isomers thereof, crystals thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof.

3. In the general formula (1), R ａ１ and R ａ２ and R ａ３ and R １ are each independently -H, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, -C(O)N(CH ３ ) ２ , -C(O)NH(CH ３ ), -C(O)NH ２ , -SO ２ N(CH ３ ) ２ , -SO ２ NH(CH ３ ), -SO ２ NH ２ , -SO ２ CH ３ , -SO ２ CH ２ CH ３ , -SO ２ CH(CH ３ ) ２ , 【Chemical Formula 4】 , -CF ３ , -CH ２ CF ３ , 【Chemical Formula 5】 , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , [Chemical Formula 6] The compound according to claim 2, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

4. In general formula (1), R ａ３ and R １ together with the carbon atoms to which they are attached respectively, have the following structural units: [Chemical Formula 7] The compound according to claim 2, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which forms

5. In general formula (1), R ａ１ R ａ２ R ａ３ and R １ none of which is -CN, R ２ is [Chemical 8] and where X ４ X ５ X ６ X ７ and X ８ are each independently -H, -OH, -OR ３ , halogen, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl, and X ４ X ５ X ６ X ７ and X ８ are not simultaneously -H; or, each pair of X ４ / X ５ X ５ / X ６ X ６ / X ７ and X ７ / X ８ may each independently form, together with the carbon atom to which they are attached, (C4-C6)cycloalkyl, (4-6 membered)heterocycloalkyl, phenyl, or (5-6 membered)heteroaryl, where the (C4-C6)cycloalkyl, the (4-6 membered)heterocycloalkyl, the phenyl, or the (5-6 membered)heteroaryl are each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -N(CH ３ ) ２ , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl and may be optionally substituted with 1, 2, 3, or 4 groups of; or, R ２ is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, where the (6-10 membered)heterocycloalkyl or the (6-10 membered)heteroaryl are each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ 、 -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, and (3-6 membered) heterocycloalkyl, optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of, the compound according to any one of claims 1 to 4, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

6. In general formula (1), R ａ１ , R ａ２ , R ａ３ , and R １ are not -CN, R ２ is 【Chemical Formula 9】 The compound according to claim 5, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

7. In general formula (1), R ａ１ , R ａ２ , R ａ３ , and R １ , when at least one of them is -CN, or when R ａ３ and R １ together with the carbon atoms to which they are respectively attached form a (C4-C9) cycloalkenyl, a (4-9 membered) heterocycloalkyl, or a (5-10 membered) heteroaryl, the (C4-C9) cycloalkenyl, the (4-9 membered) heterocycloalkyl, or the (5-10 membered) heteroaryl may each independently be optionally substituted with one, two, three, or four groups selected from -H, halogen, -OH, -OR ５ , -N(R ５ ) ２ , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C8) cycloalkyl, and R ２ is 【Chemical 10】 and wherein X ４ X ５ X ６ X ７ and X ８ are each independently -H, -OH, -OR ３ , halogen, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl, and X ４ X ５ X ６ X ７ and X ８ at least four of which are not -H simultaneously; or X ４ / X ５ X ５ / X ６ X ６ / X ７ and X ７ / X ８ each pair of which may independently form, together with the carbon atom to which they are attached, (C4-C6)cycloalkyl(cycloalkylo), (4-6 membered)heterocycloalkyl(heteroaryleno), phenyl, or (5-6 membered)heteroaryl(heteroaryleno), wherein the (C4-C6)cycloalkyl, the (4-6 membered)heterocycloalkyl, the phenyl, or the (5-6 membered)heteroaryl is each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -N(CH ３ ) ２ , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl, optionally substituted with 1, 2, 3, or 4 groups of; or R ２ is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, wherein the (6-10 membered)heterocycloalkyl or the (6-10 membered)heteroaryl is each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ 、 -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, and (3-6 membered) heterocycloalkyl, optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of the compounds according to any one of claims 1 to 4, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

8. In general formula (1), R ａ１ , R ａ２ , R ａ３ , and R １ , when at least one of them is -CN, or R ａ３ and R １ together with the carbon atoms to which they are respectively attached form a (C4-C9) cycloalkenyl, a (4-9 membered) heterocycloalkyl, or a (5-10 membered) heteroaryl, the (C4-C9) cycloalkenyl, the (4-9 membered) heterocycloalkyl, or the (5-10 membered) heteroaryl may each independently be optionally substituted with one, two, three, or four groups selected from -H, halogen, -OH, -OR ５ , -N(R ５ ) ２ , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C8) cycloalkyl, and R ２ is 【Chemical 11】 The compound according to claim 7, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

9. In general formula (1), each R ３ is independently -H, (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, (5-6 membered) heteroaryl, or -SO ２ R ３ａ wherein the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the (3-6 membered) heterocycloalkyl, the phenyl, or the (5-6 membered) heteroaryl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, -F, -Cl, -Br, or -I; or two Rs ３ on the same nitrogen atom may together with the nitrogen atom to which they are attached form a (3-6 membered) heterocycloalkyl, where the (3-6 membered) heterocycloalkyl is independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C3-C6) cycloalkyl, A compound according to any one of claims 1 to 8, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.

10. In the general formula (1), each R ３ is independently -H, 【Chemical Formula 12】 , -CF ３ , -CH ２ CF ３ , 【Chemical 13】 , -SO ２ CH ３ , -SO ２ CH ２ CH ３ , or -SO ２ CH(CH ３ ) ２ The compound according to claim 9, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein it is

11. In general formula (1), each R ３ａ is independently (C1-C5) alkyl, (C1-C5) haloalkyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, or (5-6 membered) heteroaryl, where the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C3-C6) cycloalkyl, the (3-6 membered) heterocycloalkyl, the phenyl, or the (5-6 membered) heteroaryl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, -F, -Cl, -Br, or -I. The compound according to any one of claims 1 to 10, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

12. In general formula (1), each R ３ａ is independently 【Chemical 14】 , -CF ３ , -CH ２ CF ３ , 【Chemical Formula 15】 The compound according to claim 11, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

13. In general formula (1), each R ３ｂ is independently (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, (5-6 membered) heteroaryl, -N(R ３ ), -OR ２ , -C(O)N(R ３ ), -SO ４ N(R ２ ), or -SO ２ R ４ ), where the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the phenyl, the (5-6 membered) heteroaryl, or the (3-6 membered) heterocycloalkyl is each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ２ ２ ３ａ ３ ２ ３ ３ ２ ２ ３ ３ ), -NH ３ ), -N(CH ２ ), -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, and (5-6 membered) heteroaryl, and may be optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of, a compound according to any one of claims 1 to 12, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

14. In general formula (1), each R ３ｂ is independently, -H, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -C(O)N(CH ３ ) ２ , -C(O)NH(CH ３ ), -C(O)NH ２ , -SO ２ N(CH ３ ) ２ , -SO ２ NH(CH ３ ), -SO ２ NH ２ , -SO ２ CH ３ , -SO ２ CH ２ CH ３ , -SO ２ CH(CH ３ ) ２ , 【Chemical Formula 16】 , -CF ３ , -CH ２ CF ３ , 【Chemical 17】 , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , 【Chemical 18】 The compound according to claim 13, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

15. In general formula (1), Q is (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, (3-6 membered) heterocycloalkylene, phenylene, or (5-6 membered) heteroarylene, where the (C1-C3) alkylene, the (C2-C4) alkenylene, the (C2-C4) alkynylene, the (C3-C6) cycloalkylene, the phenylene, the (5-6 membered) heteroarylene, or the (3-6 membered) heterocycloalkylene are each independently -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ), ２ , -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, and (5-6 membered) heteroaryl, optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of, a compound according to any one of claims 1 to 14, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

16. In general formula (1), each Q is independently 【Chemical Formula 19】 The compound according to claim 15, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

17. In general formula (1), each R ４ is independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C1-C5)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, or (5-6 membered)heteroaryl, where the (C1-C5)alkyl, the (C1-C5)haloalkyl, the (C1-C5)alkoxy, the (C3-C6)cycloalkyl, the (3-6 membered)heterocycloalkyl, the phenyl, or the (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I; or two Rs ４ on the same nitrogen atom may together with the nitrogen atom to which they are attached form a (3-6 membered)heterocycloalkyl, where the (3-6 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl. The compound according to any one of claims 1 to 16, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.

18. In general formula (1), each R ４ is independently -H, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ), ２ , 【Chemical 20】 , -CF ３ , -CH ２ CF ３ , 【Chemical 21】 The compound according to claim 17, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is

19. In general formula (1), each R ５ is independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, or -SO ２ R ３ａ wherein the (C1-C5)alkyl, the (C1-C5)haloalkyl, the (C2-C4)alkenyl, the (C2-C4)alkynyl, the (C3-C6)cycloalkyl, the phenyl, the (5-6 membered)heteroaryl, or the (3-6 membered)heterocycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I; or two Rs ５ on the same nitrogen atom may together with the nitrogen atom to which they are attached form a (3-6 membered)heterocycloalkyl, wherein the (3-6 membered)heterocycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 groups selected from -H, -F, -Cl, -Br, -I, -OH, -CN, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, and (C3-C6)cycloalkyl, the compound according to any one of claims 1 to 18, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.

20. In general formula (1), each R ５ is independently -H, 【Chemical 22】 , CF ３ , -CH ２ CF ３ , 【Chemical 23】 , -SO ２ CH ３ , -SO ２ CH ２ CH ３ 、or -SO ２ CH(CH ３ ) ２ The compound according to claim 19, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein it is

21. The compound according to any one of claims 1 to 20, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein the compound has one of the following structures: 【Chemical 24-1】 ​ 【Chemical 24-3】 【Chemical 24-4】 【Chemical Formula 24-5】 【Chemical Formula 24-6】 【Chemical 24-7】 [Chemical 24-8] 【Chemical Formula 24-9】 【Chemical Formula 24-10】

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as an active ingredient, the compound according to any one of claims 1 to 21, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

23. Use of a compound according to any one of claims 1 to 21, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for treating a related disease mediated by MYT1.

24. Use according to claim 23, wherein the disease is cancer and the cancer is a hematological cancer or a solid cancer.

Images