Sulfoximine compounds and uses thereof

Abstract

Sulfoximine compounds and uses thereof Specifically disclosed are compounds represented by the formula: or a pharma- ceutically acceptable salt thereof: [Formula 1] TIFF2024526156000141.tif7344

Description

[Technical field]

[0001] This application claims priority to the following applications: CN202110694497.1 filed on June 22, 2021 CN202210002094.0 filed on January 14, 2022 CN202210665753.9 filed on June 13, 2022

[0002] The present disclosure relates to a class of sulfoximine compounds and uses thereof, specifically, to a compound represented by formula (II) or a pharma- ceutically acceptable salt thereof: [Background technology]

[0003] The Janus kinase (JAK) family is a group of intracellular non-receptor tyrosine kinases that are primarily responsible for regulating cytokine receptor-mediated signaling pathways. These signaling pathways can be activated by various cytokines, growth factors, and receptors and are involved in important physiological processes, such as proliferation, differentiation, apoptosis, angiogenesis, and immune regulation of various types of cells. The Janus kinase family has four isoforms in mammals: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2).

[0004] Like other kinases in the same family, TYK2 also has four conserved structural domains consisting of seven JAK homology domains (JH), including a C-terminal pseudo-kinase domain (JH2) and a kinase domain (JH1), as well as an N-terminal FERM domain (Four.1 protein, Ezrin, Radixin, Moesin) and an SH2 domain (srchomology 2 domain).

[0005] Intracellularly, TYK2 can dimerize with JAK2 to mediate the signal transduction of IL-23 and IL-12, and can also dimerize with JAK1 to mediate type I interferon responses. These cytokines are involved in the pathogenesis of various inflammatory autoimmune diseases, such as psoriasis, inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). By inhibiting TYK2, the signal transduction pathways of some inflammatory cytokines can be blocked, achieving the purpose of treating related diseases.

[0006] Current TYK2 inhibitors mainly include orthosteric inhibitors that inhibit the kinase domain (JH1) and allosteric inhibitors that inhibit the pseudokinase domain (JH2). Orthosteric inhibitors are represented by Pfizer's PF-06826647, which is used to treat diseases such as plaque and ulcerative colitis and is currently in phase 2 clinical trials. Allosteric inhibitors are represented by BMS-986165. Clinical trials of BMS-986165 for the treatment of nodular psoriasis have progressed to phase 3, showing remarkable clinical efficacy and excellent safety. At the same time, BMS-986165 is also under clinical study for various autoimmune diseases, including Crohn's disease, psoriatic arthritis, and systemic lupus erythematosus. In addition to BMS-986165, Nimbus also has several TYK2 allosteric inhibitors in preclinical screening, and TYK2 allosteric inhibitor FTP-637 from Fronthera, which was recently acquired by Haisco, is preparing to enter Phase 1 clinical trials. Summary of the Invention

[0007] The present disclosure relates to a compound of formula (II): [ka] [In the formula, Ring A is a 6-membered heteroaryl; X1 and X2 are each independently selected from N and CH; R1 and R2 are independently selected from the group consisting of C 1-3alkyl, wherein C 1-3 Alkyl is one, two, three or four R a may be optionally substituted with; Alternatively, R and R together with the S atom to which they are attached form a 4-6 membered heterocycloalkyl, where the 4-6 membered heterocycloalkyl is selected from 1, 2, 3 or 4 R a may be optionally substituted with; R3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, or C 1-3 Alkyl, and C 1-3 alkoxy; R4 is hydrogen, -C(=O)R 41 , -C(=O)NR 42 R 43 , 5-10 membered heteroaryl, and phenyl, wherein the 5-10 membered heteroaryl and phenyl are selected from 1, 2 or 3 R b may be optionally substituted with; R 41 is C 1-3 Alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, phenyl, and 4- to 6-membered heterocycloalkyl, where C 1-3 Alkyl, C 3-8 Cycloalkyl, 5- to 6-membered heteroaryl, phenyl, and 4- to 6-membered heterocycloalkyl can each be selected from 1, 2, 3, or 4 R c may be optionally substituted with; R 42 is hydrogen and C 1-3 alkyl; R 43 is C 1-3 Alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 3-8 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl can each be selected from 1, 2, 3, or 4 R c may be optionally substituted with; R5 is hydrogen and C 1-3alkyl; R6 is C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -NH-C 1-3 Alkyl, and -NH-C 3-6 cycloalkyl, where C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -NH-C 1-3 Alkyl, and -NH-C 3-6 Cycloalkyl can have one, two, three or four R d may be optionally substituted with; R a , R b , R c , and R d are independently H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH2, C 1-3 Alkyl, and C 1-3 alkoxy; n is selected from 0, 1, 2 and 3. or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present disclosure relates to a compound of formula (II): [ka] [In the formula, Ring A is a 6-membered heteroaryl; X1 and X2 are independently selected from N and CH; R1 and R2 are independently selected from the group consisting of C 1-3 alkyl, wherein C 1-3 Alkyl is one, two, three or four R a may be optionally substituted with; Alternatively, R and R together with the S atom to which they are attached form a 4-6 membered heterocycloalkyl, where the 4-6 membered heterocycloalkyl is selected from 1, 2, 3 or 4 R a may be optionally substituted with; R3 is independently hydrogen, deuterium, fluorine, chlorine, bromine, or C 1-3 Alkyl, and C 1-3 alkoxy; R4 is hydrogen, -C(=O)R 41 and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from 1, 2 or 3 R b may be optionally substituted with; R 41 is C 1-3 Alkyl and C 3-6 cycloalkyl, where C 1-3 Alkyl and C 3-6 Cycloalkyl can have one, two, three or four R c may be optionally substituted with; R5 is hydrogen and C 1-3 alkyl; R6 is C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -NH-C 1-3 Alkyl, and -NH-C 3-6 cycloalkyl, where C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -NH-C 1-3 Alkyl, and -NH-C 3-6 Cycloalkyl can have one, two, three or four R d may be optionally substituted with; R a , R b , R c , and R d are independently H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH2, C 1-3 Alkyl, and C 1-3 alkoxy; n is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0009] In some embodiments of the present disclosure, Ring A is [ka] and other variables are as defined herein.

[0010] In some embodiments of the present disclosure, Ring A is [ka] and other variables are as defined herein.

[0011] In some embodiments of the present disclosure, R and R are independently selected from methyl, ethyl, and propyl, where methyl, ethyl, and propyl are selected from 1, 2, 3, or 4 R a and other variables are as defined herein.

[0012] In some embodiments of the present disclosure, R1 and R2 are independently selected from methyl and ethyl, and other variables are as defined herein.

[0013] In some embodiments of the present disclosure, R1 and R2 are independently selected from methyl, and other variables are as defined herein.

[0014] In some embodiments of the present disclosure, R and R together with the S atom to which they are attached form a 4-6 membered heterocycloalkyl, where the 4-6 membered heterocycloalkyl is selected from 1, 2, 3, or 4 R a and other variables are as defined herein.

[0015] In some embodiments of the present disclosure, R1 and R2 together with their attached S atoms are [ka] where: [ka] can have 1, 2, 3 or 4 R a and other variables are as defined herein.

[0016] In some embodiments of the present disclosure, R1 and R2 together with their attached S atoms are [ka] where the other variables are as defined herein.

[0017] In some embodiments of the present disclosure, the R a is selected from hydrogen, and other variables are as defined herein.

[0018] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0019] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0020] In some embodiments of the present disclosure, each X1 is selected from N, and the other variables are as defined herein.

[0021] In some embodiments of the present disclosure, each X1 is selected from CH, and other variables are as defined herein.

[0022] In some embodiments of the present disclosure, each R3 is independently selected from hydrogen and fluorine, and other variables are as defined herein.

[0023] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0024] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0025] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0026] In some embodiments of the present disclosure, [ka] The structure of [ka] and other variables are as defined herein.

[0027] In some embodiments of the present disclosure, R4 is hydrogen, -C(O)R 41 , -C(O)NR 42 R 43 , [ka] where: [ka] is 1, 2 or 3 R b and other variables are as defined herein.

[0028] In some embodiments of the present disclosure, R4 is hydrogen, -C(O)R 41 , [ka] where: [ka] is 1, 2 or 3 R b and other variables are as defined herein.

[0029] In some embodiments of the present disclosure, the R b is selected from hydrogen, deuterium, fluorine, CN, NH2, methyl, ethyl, methoxy, and ethoxy, and other variables are as defined herein.

[0030] In some embodiments of the present disclosure, the R b is selected from hydrogen, fluorine, CN, and methyl, and other variables are as defined herein.

[0031] In some embodiments of the present disclosure, the R b is selected from hydrogen, and other variables are as defined herein.

[0032] In some embodiments of the present disclosure, the R b is selected from fluorine, and the other variables are as defined herein.

[0033] In some embodiments of the present disclosure, the R b is selected from CN, and other variables are as defined herein.

[0034] In some embodiments of the present disclosure, the R b is selected from methyl, and other variables are as defined herein.

[0035] In some embodiments of the present disclosure, the R b is selected from methoxy, and other variables are as defined herein.

[0036] In some embodiments of the present disclosure, the R 41 is methyl, ethyl, propyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, where methyl, ethyl, propyl, C 3-8 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl can each be selected from 1, 2, 3, or 4 R c and other variables are as defined herein.

[0037] In some embodiments of the present disclosure, the R 41 is methyl, ethyl, propyl, and C 3-4 cycloalkyl, where methyl, ethyl, propyl, and C 3-4 Cycloalkyl can have one, two, three or four R cand other variables are as defined herein.

[0038] In some embodiments of the present disclosure, the C 3-4 Cycloalkyl is selected from cyclopropyl and cyclobutyl, where cyclopropyl and cyclobutyl are selected from 1, 2, 3 or 4 R c and other variables are as defined herein.

[0039] In some embodiments of the present disclosure, the R 41 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, [ka] wherein methyl, ethyl, propyl, cyclopropyl, cyclobutyl, [ka] can have 1, 2, 3 or 4 R c and other variables are as defined herein.

[0040] In some embodiments of the present disclosure, the R 41 is selected from cyclopropyl and cyclobutyl, and other variables are as defined herein.

[0041] In some embodiments of the present disclosure, the R c is hydrogen, and other variables are as defined herein.

[0042] In some embodiments of the present disclosure, the R 41 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, [ka] and other variables are as defined herein.

[0043] In some embodiments of the present disclosure, the R 42 is selected from hydrogen, and other variables are as defined herein.

[0044] In some embodiments of the present disclosure, the R 43 is selected from methyl, ethyl, propyl, cyclopropyl, and cyclobutyl, where methyl, ethyl, propyl, cyclopropyl, and cyclobutyl are selected from 1, 2, 3, or 4 R c and other variables are as defined herein.

[0045] In some embodiments of the present disclosure, the R 43 is selected from cyclopropyl, and other variables are as defined herein.

[0046] In some embodiments of the present disclosure, R4 is [ka] and other variables are as defined herein.

[0047] In some embodiments of the present disclosure, R4 is [ka] and other variables are as defined herein.

[0048] In some embodiments of the present disclosure, R5 is selected from hydrogen, methyl, and ethyl, and other variables are as defined herein.

[0049] In some embodiments of the present disclosure, R5 is selected from hydrogen, and other variables are as defined herein.

[0050] In some embodiments of the present disclosure, R5 is selected from methyl, and other variables are as defined herein.

[0051] In some embodiments of the present disclosure, R6 is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH3, -NHCH2CH3, -NH-cyclopropyl, and -NH-cyclobutyl, where methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH3, -NHCH2CH3, -NH-cyclopropyl, and -NH-cyclobutyl are selected from 1, 2, 3, or 4 R d and other variables are as defined herein.

[0052] In some embodiments of the present disclosure, R6 is selected from methyl, ethyl, -NHCH3, and cyclopropyl, where methyl, ethyl, -NHCH3, and cyclopropyl are selected from 1, 2, 3, or 4 R d and other variables are as defined herein.

[0053] In some embodiments of the present disclosure, R6 is selected from methyl, ethyl, and -NHCH3, where methyl, ethyl, and -NHCH3 are selected from 1, 2, 3, or 4 R d and other variables are as defined herein.

[0054] In some embodiments of the present disclosure, the R d is selected from hydrogen, and other variables are as defined herein.

[0055] In some embodiments of the present disclosure, the R d is selected from deuterium, and other variables are as defined herein.

[0056] In some embodiments of the present disclosure, the R dis selected from methoxy, and other variables are as defined herein.

[0057] In some embodiments of the present disclosure, R6 is selected from -CH2CD3, -CH2CH3, -NHCD3, -CH2OCH3, -CH3, and cyclopropyl, and other variables are as defined herein.

[0058] In some embodiments of the present disclosure, R6 is selected from -CH2CD3, -CH2CH3, -NHCD3, and -CH2OCH3, and other variables are as defined herein.

[0059] In some embodiments of the present disclosure, the compound has formula (II-1) or (II-2): [ka] wherein R1, R2, R3, R4, R5, R6, X1, X2, and n are as defined herein.

[0060] In some embodiments of the present disclosure, the compound has formula (II-1-1) or (II-1-2): [ka] wherein R1, R2, R3, R4, R5, R6, X1, and n are as defined herein.

[0061] In some embodiments of the present disclosure, the compound has formula (II-1-1-1) or (II-1-1-2): [ka] wherein R1, R2, R3, R4, R5, X1, and n are as defined herein.

[0062] The present disclosure also includes embodiments resulting from any combination of the above variables.

[0063] In some embodiments of the present disclosure, the compound is [ka] [ka] [ka] is selected from.

[0064] The disclosure also provides the use of the compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with Tyk2 JH2.

[0065] The present disclosure also provides a method for treating a disease associated with Tyk2 JH2 in a subject in need of such treatment, comprising providing to said subject an effective dose of a compound defined in any of the above technical solutions or a pharma- ceutically acceptable salt thereof.

[0066] Technical effects The compounds of the present disclosure have potent inhibitory activity against the Tyk2 pseudokinase domain (Tyk2 JH2).

[0067] Definitions and Terminology Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: A particular term or phrase should not be considered unclear or indefinite in the absence of a specific definition, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0068] The term "pharmacologically acceptable" is used herein in reference to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable risk-benefit ratio.

[0069] The term "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein prepared by reacting a compound having certain substituents disclosed herein with a relatively non-toxic acid or base. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When a compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Some specific compounds disclosed herein contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0070] The pharma- ceutically acceptable salts disclosed herein can be prepared from a parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0071] The compounds disclosed herein may exist in specific geometric or stereoisomers. The present disclosure contemplates and encompasses within the scope disclosed herein all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as mixtures enriched in enantiomers or diastereoisomers. Additional asymmetric carbon atoms may also be present in substituents such as alkyl. All such isomers and their mixtures are encompassed within the scope disclosed herein.

[0072] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0073] Unless otherwise noted, the terms "cis-trans isomers" or "geometric isomers" result from the inability to freely rotate about a double bond or a single bond between ring-forming carbon atoms.

[0074] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers in which there are two or more centers of chirality in a molecule and which are not mirror images of each other.

[0075] Unless otherwise specified, "(+)" means dextrorotatory isomer, "(-)" means levorotatory isomer, and "(±)" means racemic.

[0076] Unless otherwise stated, [ka] and [ka] indicates the absolute configuration of the stereocenter, [ka] and [ka] indicates the relative configuration of the stereocenters, [ka] teeth, [ka] or [ka] or [ka] teeth, [ka] and [ka] Shows.

[0077] Unless otherwise stated, the term "tautomer" or "tautomeric form" means that different functional groups in an isomer are in dynamic equilibrium and can be rapidly converted into one another at room temperature. Where tautomers are possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0078] Unless otherwise specified, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" mean that one isomer or enantiomer is less than 100% concentrated, and that isomer or enantiomer is present at 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0079] Unless otherwise specified, the term "isomer excess" or "enantiomeric excess" refers to the difference in relative proportions of two isomers or two enantiomers. For example, if one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0080] Optically active (R)- and (S)-isomers, or D- and L-isomers, can be prepared using chiral synthesis or chiral reagents or other conventional techniques. When one enantiomer of some of the compounds disclosed herein is obtained, the pure desired enantiomer can be obtained by asymmetric synthesis or derivatization of a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and cleavage of the auxiliary. Alternatively, when the molecule contains a basic (such as amino) or acidic (such as carboxyl) functional group, the compound can be reacted with an appropriate optically active acid or base to form a diastereomeric salt, which can then be diastereoisomerically resolved by methods conventional in the art to obtain the pure enantiomers. Furthermore, enantiomers and diastereoisomers are generally separated by chromatography using chiral stationary phases, optionally with chemical derivatization (e.g., formation of carbamates from amines).

[0081] The compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3 H), Iodine-125( 125 I), or C-14( 14 In another example, hydrogen may be replaced with deuterium to form a deuterated drug. The deuterium-carbon bond is stronger than a normal hydrogen-carbon bond. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, improved drug stability, enhanced efficacy, and increased biological half-life of the drug. All variations in the isotopic composition of the compounds disclosed herein, whether radioactive or not, are included within the scope of the present disclosure.

[0082] Unless otherwise noted, "D" or " 2 The term "H" refers to deuterium, also known as heavy hydrogen, another stable form of hydrogen isotope.

[0083] The term "optional" or "optionally" means that the subsequently described event or condition may occur but need not occur, and that the description includes cases where the event or condition occurs and cases where the event or condition does not occur.

[0084] The term "substituted" means that one or more hydrogen atoms on a particular atom are replaced with a substituent, such as deuterium and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic rings.

[0085] The term "optionally substituted" means that an atom may or may not be substituted. Unless otherwise specified, the type and number of substituents are optional, as long as it is chemically achievable.

[0086] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, each definition of that variable is independent. Thus, for example, if a group is substituted with 0-2 R, then that group may optionally be substituted with up to 2 R, where each definition of R is independent. Further, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0087] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0088] If one of the variables is a single bond, it means that the two groups that are connected by the single bond are directly bonded. For example, if L in ALZ represents a single bond, it means that the structure of ALZ is actually AZ.

[0089] If a substituent is empty, it means that the substituent does not exist. For example, if X of AX is empty, the structure of AX is actually A. If a described substituent does not indicate through which atom it is bonded to the substituted group, such a substituent may be bonded through any of the atoms. For example, a pyridyl group as a substituent may be bonded to the substituted group through any of the carbon atoms on the pyridine ring.

[0090] Unless otherwise specified, the terms "six-membered heteroaromatic ring" and "six-membered heteroaryl" may be used interchangeably. The term "six-membered heteroaryl" refers to a monocyclic group having a conjugated pi-electron system and composed of six ring atoms, where one, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, the nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 6-membered heteroaryl may be attached to the remainder of the molecule via a heteroatom or a carbon atom. Examples of 6-membered heteroaryl include, but are not limited to, pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0091] Unless otherwise specified, "C 1-3 The term "alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups and the like are included. They may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), and the like.

[0092] Unless otherwise specified, "C 1-3 The term "alkoxy" means an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy groups include C 1-2 , C 2-3 C, C3, and C2 alkoxy groups, and the like. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0093] Unless otherwise specified, the term "4- to 6-membered heterocycloalkyl", alone or in combination with other terms, means a saturated ring group consisting of 4 to 6 ring atoms, respectively, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, the nitrogen atoms may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). 4-6 membered heterocycloalkyl includes monocyclic and bicyclic ring systems, where bicyclic systems include spiro, fused, and bridged rings. Additionally, for "4-6 membered heterocycloalkyl," a heteroatom may be present at the position of attachment of the heterocycloalkyl group to the remainder of the molecule. 4-6 membered heterocycloalkyl groups include 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups, and the like. Examples of 4-6 membered heterocycloalkyls include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl and the like), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc. Examples of aryl groups include, but are not limited to, aryl, piperazinyl (including 1-piperazinyl and 2-piperazinyl and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, and the like.

[0094] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" may be used interchangeably. The term "5-10 membered heteroaryl" refers to a ring group having a conjugated pi electron system and composed of 5-10 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. It may be a monocyclic, fused bicyclic, or fused tricyclic ring system, where each ring is aromatic, the nitrogen atoms may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 5-10 membered heteroaryl may be attached to the remainder of the molecule via a heteroatom or a carbon atom. 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups, and the like. Examples of 5-10 membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, and the like). (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, and the like), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and the like). furyl (including 2-furyl and 3-furyl, and the like), thienyl (including 2-thienyl and 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like), benzothiazolyl (including 5-benzothiazolyl, and the like), purine benzimidazolyl (including 2-benzimidazolyl and the like), benzoxazolyl, indolyl (including 5-indolyl and the like), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl, and the like), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, and the like) or quinolyl (including 3-quinolyl, 6-quinolyl, and the like), substituted or unsubstituted pyridonyl. [ka] These include, but are not limited to:

[0095] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" may be used interchangeably. The term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated pi-electron system and composed of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, the nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). The 5- to 6-membered heteroaryl group may be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl group includes 5- and 6-membered heteroaryl groups. Examples of 5- to 6-membered heteroaryl groups include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, and the like), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, and the like). Examples of alkyl groups include, but are not limited to, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and the like), furyl (including 2-furyl and 3-furyl, and the like), thienyl (including 2-thienyl and 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like).

[0096] Unless otherwise specified, "C 3-8 "Cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, including monocyclic and bicyclic ring systems, where bicyclic ring systems include spirocyclic, fused, and bridged rings. 3-8 Cycloalkyl groups include C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 , or C 5-6 cycloalkyl groups and the like, which may be monovalent, divalent, or polyvalent. 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0097] Unless otherwise specified, "C 3-6 "Cycloalkyl" means a monocyclic or bicyclic saturated cyclic hydrocarbon group of 3 to 6 carbon atoms. 3-6 Cycloalkyl includes C 3-5 , C 4-5 , and C 5-6 cycloalkyl, etc., and may be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0098] Unless otherwise specified, "C 3-4 "Cycloalkyl" means a monocyclic saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms. 3-5 Cycloalkyl includes C3 and C4 cycloalkyl, and may be monovalent, divalent, or polyvalent. 3-4Examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl. The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonic acid groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy such as acetoxy, trifluoroacetoxy, and the like.

[0099] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group", or "thio protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen. Representative amino protecting groups include, but are not limited to, formyl; acyl such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxy. Representative hydroxy protecting groups include, but are not limited to, alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0100] The compounds disclosed herein may be prepared by a variety of synthetic methods known to those skilled in the art, including the embodiments listed below, embodiments formed by combining the embodiments listed below with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0101] The structure of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. When the present disclosure relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD). In single crystal X-ray diffraction (SXRD), the diffraction intensity data of the grown single crystal is collected using a Bruker D8 venture diffractometer in φ / ω scan mode with CuKα radiation as the source, and after collecting the relevant data, the crystal structure is further analyzed by direct methods (Shelxs97) to confirm the absolute configuration.

[0102] Compounds are named according to naming conventions common in the art or by ChemDraw® software; commercially available compounds are named using the supplier's catalog name.

[0103] Detailed Description of the Invention The present disclosure will be described in detail below with examples. However, these examples are not intended to have any adverse limitations on the present disclosure. The present disclosure is described in detail herein, and embodiments are also disclosed herein. It is clear to those skilled in the art that various changes and modifications may be made to the embodiments disclosed herein without departing from the technical idea and scope disclosed herein. EXAMPLES

[0104] Example 1 [ka] Synthetic Route [ka]

[0105] Step 1: Synthesis of Compound 1-2 To a solution of compound 1-1 (13 g, 67.71 mmol) in dichloromethane (200 mL), N,N-diisopropylethylamine (43.75 g, 338.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (30.89 g, 81.25 mmol) were added, and the mixture was stirred at 20 °C for 0.5 h. N,O-dimethylhydroxylamine hydrochloride (7.93 g, 81.25 mmol) was added. After stirring at 20 °C for 15.5 h, the reaction solution was concentrated, and the obtained crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 1-2. MS m / z: 235[M+H] +

[0106] Step 2: Synthesis of compounds 1-3 To a solution of compound 1-2 (13 g, 55.30 mmol) in tetrahydrofuran (130 mL) was added methylmagnesium bromide (3M, in diethyl ether, 36.87 mL) under nitrogen at 0° C., and the mixture was stirred at 0° C. for 2 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution (60 mL), diluted with water (100 mL), and subsequently extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with brine (100 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1 to 15 / 1) to give compound 1-3. 1 H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.44 (s, 1H), 2.66 (s, 3H)

[0107] Step 3: Synthesis of compounds 1-4 To a solution of 1-3 (8 g, 42.10 mmol) and dimethyl carbonate (42.80 g, 475.15 mmol) in tetrahydrofuran (40 mL), 60% sodium hydride (5.05 g, 126.30 mmol) was added slowly in portions at 0°C, and the mixture was stirred at 20°C for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), quenched with aqueous hydrochloric acid (50 mL 2M), and washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 1-4. MS m / z: 244[M+H] +

[0108] Step 4: Synthesis of Compounds 1-5 To a solution of 1-4 (8.2 g, 32.65 mmol) and potassium carbonate (4.96 g, 35.91 mmol) in N,N-dimethylformamide (80 mL) was added deuterated iodomethane (4.97 g, 34.28 mmol) at 0 °C, and the mixture was stirred at 20 °C for 6 h. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to obtain compound 1-5. MS m / z: 261[M+H] +

[0109] Step 5: Synthesis of Compounds 1-6 To a solution of 1-5 (5.8 g, 18.02 mmol, 81%) in acetic acid (30 mL), 35% concentrated hydrochloric acid (61.20 g, 587.48 mmol) was added, and the mixture was stirred at 130° C. for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=30 / 1 to 1 / 1) to give compound 1-6. MS m / z: 189[M+H] +

[0110] Step 6: Synthesis of Compounds 1-7 To a solution of 1-6 (2.5 g, 12.33 mmol) in acetonitrile (80 mL), phosphorus oxychloride (7.56 g, 49.30 mmol) was added, and the mixture was stirred at 85° C. for 1 h. The reaction solution was concentrated and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0-50 / 1) to give compound 1-7. MS m / z: 207[M+H] +

[0111] Step 7: Synthesis of Compounds 1-8 A solution of compound 1-7 (50 mg, 241.46 μmol), cyclopropylcarboxamide (20.55 mg, 241.46 μmol), potassium carbonate (66.75 mg, 482.92 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.94 mg, 48.29 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (22.11 mg, 24.15 μmol) in dioxane (2 mL) was purged with nitrogen three times. The mixture was stirred at 80 °C for 2 h. The reaction solution was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give compound 1-8. MS m / z: 256[M+H] +

[0112] Step 8: Synthesis of Compounds 1-10 Compound 1-9 (2 g, 10.34 mmol) was dissolved in dioxane (40 mL). Dimethylsulfoximine (1.01 g, 10.86 mmol), cesium carbonate (6.74 g, 20.68 mmol), tris(dibenzylideneacetone)dipalladium (946.85 mg, 1.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.20 g, 2.07 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 110 °C and stirred under nitrogen for 4 h. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 4). The fraction was concentrated under reduced pressure and stirred with petroleum ether / ethyl acetate = 5 / 1 (12 mL) at 20 °C for 1 h. The mixture was filtered and the filter cake was collected and dried to give compound 1-10. MS m / z: 206[M+H] +

[0113] Step 9: Synthesis of Compounds 1-12 Compound 1-10 (400 mg, 1.94 mmol) was dissolved in dioxane (8 mL) and water (2 mL). Compound 1-11 (532.95 mg, 2.14 mmol), potassium phosphate (825.68 mg, 3.89 mmol), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (142.31 mg, 194.49 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100 °C and stirred under nitrogen for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1). The fraction was concentrated under reduced pressure and stirred with petroleum ether / ethyl acetate = 1 / 1 (4 mL) at 20 °C for 1 h. The mixture was filtered, and the filter cake was collected and dried to obtain compound 1-12. MS m / z: 293[M+H] +

[0114] Step 10: Synthesis of Compound 1 A solution of compound 1-8 (70 mg, 273.74 μmol), compound 1-12 (88.03 mg, 301.12 μmol), cesium carbonate (178.38 mg, 547.48 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (34.09 mg, 54.75 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (25.07 mg, 27.37 μmol) in dioxane (4 mL) was purged with nitrogen three times, and the mixture was stirred at 110 °C for 4 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 1 / 3), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 34% to 64%, 8 min) to obtain compound 1. MS m / z: 512[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.92 (s, 1H), 8.88 (s, 1H), 8.59 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.03 (s, 1H), 7.53 (dd, J = 1.4, 7.8 Hz, 1H), 7.48 (dd, J = 1.3, 7.8 Hz, 1H), 7.32 - 7.25 (m, 1H), 3.52 (s, 3H), 3.47 (s, 6H), 3.11 (s, 2H), 2.06 - 1.96 (m, 1H), 0.79 (d, J = 6.1Hz, 4H)

[0115] Example 2 [ka] Synthetic Route [ka]

[0116] Step 1: Synthesis of compound 2-2 Compound 2-1 (1 g, 6.41 mmol) was dissolved in phosphorus oxychloride (5 mL) at 20° C., and triethylamine (648.25 mg, 6.41 mmol, 891.68 μL) was added. The mixture was stirred at 110° C. for 120 min. The reaction solution was directly concentrated under reduced pressure, then diluted with 1,2-dichloroethane (40 mL), and concentrated under reduced pressure again to give crude product 2-2, which was used directly in the next reaction.

[0117] Step 2: Synthesis of compound 2-3 Compound 2-2 (1.35 g, 6.38 mmol) was dissolved in tetrahydrofuran (15 mL) at 20°C, and deuterated methylamine hydrochloride (225.19 mg, 3.19 mmol) and N,N-diisopropylethylamine (2.48 g, 19.15 mmol, 3.34 mL) were added. The mixture was stirred at 20°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain the crude product. The crude product was separated by preparative HPLC (Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 3%-33%, 11 min) to give compound 2-3. MS m / z: 209[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (br s, 1H), 8.48 (s, 1H)

[0118] Step 3: Synthesis of Compounds 2-4 Compound 2-3 (55.06 mg, 263.38 μmol) and compound 1-12 (70 mg, 239.43 μmol) were dissolved in tetrahydrofuran (3 mL) under nitrogen at 0° C., and lithium methyldisilazide (1 M, 718.30 μL) was added dropwise. The mixture was stirred at 20° C. for 1 h. The reaction solution was quenched by adding aqueous ammonium chloride solution (10 mL) at 0° C., diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by thin layer chromatography (silica gel, petroleum ether / ethyl acetate=1 / 5) to give compound 2-4. MS m / z: 465[M+H] +

[0119] Step 4: Synthesis of compound 2 Compound 2-4 (75 mg, 161.31 μmol) was dissolved in dioxane (2 mL). Cyclopropylformamide (41.18 mg, 483.93 μmol), cesium carbonate (157.67 mg, 483.93 μmol), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (14.62 mg, 16.13 μmol) were added. The atmosphere was replaced with nitrogen three times, and then the mixture was heated to 110°C and stirred under nitrogen for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 1 / 3.5) to obtain compound 2. MS m / z: 514[M+H] + 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 9.02 (br s, 1H), 8.74 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.59 (dd, J = 1.5, 7.8 Hz, 1H), 7.47 (dd, J = 1.2, 7.8 Hz, 1H), 7.29 (s, 1H), 3.60 (s, 3H), 3.44 (s, 6H), 1.75 - 1.70 (m, 1H), 1.15 - 1.10 (m, 2H), 0.96 - 0.90 (m, 2H)

[0120] Example 3 [ka] Synthetic Route [ka]

[0121] Step 1: Synthesis of compound 3-2 Compound 3-1 (2 g, 10.42 mmol) was dissolved in dichloromethane (10 mL) at 0° C., and oxalyl chloride (1.98 g, 15.63 mmol, 1.37 mL) and N,N-dimethylformamide (19.00 mg, 259.94 μmol, 20 μL) were added. The mixture was stirred at 20° C. for 1 h. TLC showed that the starting material was completely consumed. The reaction solution was directly concentrated under reduced pressure to give crude 3-2, which was used directly in the next reaction.

[0122] Step 2: Synthesis of compound 3-3 Compound 3-2 (804.43 mg, 11.40 mmol) was dissolved in dichloromethane (20 mL) at 0° C., and N,N-diisopropylethylamine (27.53 g, 213.04 mmol, 37.11 mL) and deuterated methylamine hydrochloride (2 g, 9.50 mmol) were added. The mixture was stirred at 15° C. for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was slurried in petroleum ether / ethyl acetate=3 / 1 (10 mL) at 15° C. for 1 hour, filtered, and dried to give compound 3-3. MS m / z: 208[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (br s, 1H), 8.48 (s, 1H), 7.90 (s, 1H)

[0123] Step 3: Synthesis of Compound 3-4 Compound 3-3 (55.00 mg, 264.35 μmol) and compound 1-12 (70.26 mg, 240.32 μmol) were dissolved in tetrahydrofuran (3 mL). Under nitrogen, lithium hexamethyldisilazide (1 M, 720.95 μL) was added dropwise to the mixture at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL) in an ice-water bath, diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was stirred with ethyl acetate (2 mL) at 20° C. for 0.5 h, filtered, and dried to give compound 3-4. MS m / z: 464[M+H] +

[0124] Step 4: Synthesis of compound 3 Compound 3-4 (80 mg, 172.43 μmol) was dissolved in dioxane (2 mL). Cyclopropylcarboxamide (44.02 mg, 517.29 μmol), cesium carbonate (168.54 mg, 517.29 μmol), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (15.63 mg, 17.24 μmol) were added. The atmosphere was replaced with nitrogen three times, and then the mixture was heated to 110°C and stirred under nitrogen for 4 hours. The reaction solution was diluted with dichloromethane (50 mL) and extracted with water (5 mL×3). The organic phase was washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (silica gel, ethyl acetate / ethanol=10 / 1) to give compound 3. MS m / z: 513[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.66 (s, 1H), 8.66 - 8.56 (m, 2H), 8.52 (s, 1H), 8.14 (d, J = 1.1 Hz, 1H), 8.06 (s, 1H), 7.45 (br d, J = 7.5 Hz, 2H), 7.31 - 7.19 (m, 1H), 3.53 (s, 3H), 3.46 (s, 6H), 1.05 (t, J = 7.0 Hz, 1H), 0.77 (br d, J = 5.0 Hz, 4H)

[0125] Example 4 [ka] Synthetic Route [ka]

[0126] Step 1: Synthesis of compound 4-1 Ethyl magnesium bromide (3M in diethyl ether, 4.25 mL) was added dropwise to a solution of compound 1-2 (1 g, 4.25 mmol) in tetrahydrofuran (20 mL) under nitrogen at 0° C., and the mixture was stirred at 20° C. for 3 h. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with brine (30 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=30 / 1 to 15 / 1) to give compound 4-1. MS m / z: 204[M+H] +

[0127] Step 2: Synthesis of compound 4-2 A solution of compound 4-1 (390 mg, 1.74 mmol), cyclopropylcarboxamide (133.07 mg, 1.56 mmol), potassium carbonate (480.24 mg, 3.47 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (201.05 mg, 347.47 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (159.09 mg, 173.73 μmol) in dioxane (10 mL) was purged with nitrogen three times, and the mixture was stirred at 80 °C for 2 h. The reaction solution was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give compound 4-2. MS m / z: 253[M+H] +

[0128] Step 3: Synthesis of compound 4 A solution of 4-2 (70 mg, 277.01 μmol), 1-12 (80.99 mg, 277.01 μmol), cesium carbonate (180.51 mg, 554.02 μmol), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (34.50 mg, 55.40 μmol), and tris(dibenzylideneacetone)dipalladium chloroform (25.37 mg, 27.70 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 1 / 3) and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 34% to 64%, 9 min) to obtain compound 4. MS m / z: 509[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.91 (s, 1H), 8.88 (s, 1H), 8.59 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 8.02 (s, 1H), 7.52 (dd, J = 1.5, 7.8 Hz, 1H), 7.47 (dd, J = 1.3, 7.9 Hz, 1H), 7.33 - 7.24 (m, 1H), 3.52 (s, 3H), 3.46 (s, 6H), 3.13 (d, J = 7.2 Hz, 2H), 2.01 (quin, J = 6.1 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H), 0.78 (d, J = 6.2 Hz, 4H)

[0129] Example 5 [ka] Synthetic Route [ka]

[0130] Step 1: Synthesis of compound 5-2 To a solution of compound 5-1 (400 mg, 3.84 mmol) in methanol (20 mL), iodobenzene diacetate (3.09 g, 9.60 mmol) and ammonium carbamate (599.56 mg, 7.68 mmol) were added, and the reaction solution was stirred at 25° C. for 2 h. The reaction solution was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=4 / 1 to 1 / 2) to obtain compound 5-2. MS m / z: 136[M+H] +

[0131] Step 2: Synthesis of compound 5-3 A solution of compound 5-2 (220.15 mg, 1.63 mmol), 1-9 (300 mg, 1.55 mmol), cesium carbonate (1.01 g, 3.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (179.48 mg, 310.19 μmol), and tris(dibenzylideneacetone)dipalladium (142.02 mg, 155.10 μmol) in dioxane (10 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 5-3. MS m / z: 248[M+H] +

[0132] Step 3: Synthesis of compound 5-4 A solution of compound 5-3 (240 mg, 968.91 μmol), 1-11 (253.44 mg, 1.02 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (70.90 mg, 96.89 μmol), and potassium phosphate (411.34 mg, 1.94 mmol) in dioxane (8 mL) and water (2 mL) was purged with nitrogen three times. The mixture was stirred at 100 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 1 / 3) to give compound 5-4. MS m / z: 335[M+H] +

[0133] Step 4: Synthesis of compound 5 A solution of 5-4 (104.61 mg, 312.85 μmol), 1-8 (80 mg, 312.85 μmol), cesium carbonate (203.86 mg, 625.70 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (38.96 mg, 62.57 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (28.65 mg, 31.28 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 to 1 / 3) and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 37% to 67%, 9 min) to obtain compound 5. MS m / z: 554[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.91 (s, 1H), 8.88 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 8.03 (s, 1H), 7.53 (dd, J = 1.3, 7.8 Hz, 1H), 7.48 (s, 1H), 7.32 - 7.25 (m, 1H), 4.12 (ddd, J = 3.0, 5.7, 12.6 Hz, 2H), 4.05 - 3.93 (m, 2H), 3.84 (td, J = 2.7, 14.4 Hz, 2H), 3.71 - 3.58 (m, 2H), 3.53 (s, 3H), 3.11 (s, 2H), 2.08 - 1.96 (m, 1H), 0.78 (d, J = 5.9 Hz, 4H)

[0134] Example 6 [ka] Synthetic Route [ka]

[0135] Step 1: Synthesis of compound 6-2 Compound 6-1 (500 mg, 6.74 mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of iodobenzene diacetate (5.43 g, 16.86 mmol) and ammonium carbamate (1.05 g, 13.49 mmol). The mixture was stirred at 25 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1 to 1 / 2) to obtain compound 6-2. MS m / z: 106[M+H] +

[0136] Step 2: Synthesis of compound 6-3 Compound 1-9 (600.00 mg, 3.10 mmol) and 6-2 (600 mg, 5.71 mmol) were dissolved in anhydrous dioxane (10 mL), followed by the addition of cesium carbonate (2.02 g, 6.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (358.97 mg, 620.38 μmol), and tris(dibenzylideneacetone)dipalladium (284.05 mg, 310.19 μmol). The mixture was stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 6-3. MS m / z: 218[M+H] +

[0137] Step 3: Synthesis of compound 6-4 Compound 1-11 (50.35 mg, 202.14 μmol) and 6-3 (40 mg, 183.76 μmol) were dissolved in dioxane (2 mL), and a solution of potassium phosphate (78.01 mg, 367.52 μmol) in water (0.5 mL) was added. Then, 1,1-bis(diphenylphosphino)ferrocene palladium chloride (13.45 mg, 18.38 μmol) was added. The system was purged with nitrogen gas and stirred at 100°C for 4 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 to 1 / 3) to obtain compound 6-4. MS m / z: 305[M+H] +

[0138] Step 4: Synthesis of compound 6 Compound 6-4 (80 mg, 262.84 μmol) and compound 1-8 (67.21 mg, 262.84 μmol) were dissolved in anhydrous dioxane (2 mL), and cesium carbonate (171.28 mg, 525.68 μmol) was added. Then tris(dibenzylideneacetone)dipalladium (36.10 mg, 39.43 μmol) and (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (32.73 mg, 52.57 μmol) were added, and the mixture was stirred at 90° C. for 6 hours. The reaction solution was concentrated to obtain a crude product, which was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 6. MS m / z: 524[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.11 (s, 1 H), 8.57 - 8.70 (m, 2 H), 8.23 ​​(d, J = 1.38 Hz, 1 H), 7.91 - 8.08 (m, 2 H), 7.49 (dd, J = 7.82, 1.56 Hz, 1 H), 7.46 (dd, J = 7.88, 1.63 Hz, 1 H), 7.21 (s, 1 H), 4.41 (br d, J = 6.63 Hz, 2 H), 4.20 - 4.33 (m, 2 H), 3.42 (s, 3 H), 2.95 (s, 2 H), 2.34 - 2.46 (m, 2 H), 1.01 (br dd, J = 4.25, 3.00 Hz, 1 H), 0.78 - 0.84 (m, 4 H)

[0139] Example 7 [ka] Synthetic Route [ka]

[0140] Step 1: Synthesis of compound 7-2 Compound 7-1 (500 mg, 4.80 mmol) was dissolved in anhydrous methanol (10 mL), and iodobenzene diacetate (3.87 g, 12.00 mmol) and ammonium carbamate (749.45 mg, 9.60 mmol) were added. The mixture was stirred at 25°C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1 to 1 / 2) to obtain compound 7-2. MS m / z: 120[M+H] +

[0141] Step 2: Synthesis of compound 7-3 Compound 1-9 (973.76 mg, 5.03 mmol) and 7-2 (600 mg, 5.03 mmol) were dissolved in anhydrous dioxane (15 mL), followed by the addition of cesium carbonate (3.28 g, 10.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (582.58 mg, 1.01 mmol), and tris(dibenzylideneacetone)dipalladium (460.99 mg, 503.42 μmol). The mixture was stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 7-3. MS m / z: 232[M+H] +

[0142] Step 3: Synthesis of compound 7-4 Compound 1-11 (236.53 mg, 949.50 μmol) and 7-3 (200 mg, 863.18 μmol) were dissolved in dioxane (3 mL), and a solution of potassium phosphate (366.45 mg, 1.73 mmol) in water (0.5 mL) was added to the system. Then, 1,1-bis(diphenylphosphino)ferrocene palladium chloride (63.16 mg, 86.32 μmol) was added. The atmosphere was replaced with nitrogen, and the system was stirred at 100 °C for 4 hours. The reaction system was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 to 1 / 3) to obtain compound 7-4. MS m / z: 319[M+H] +

[0143] Step 4: Synthesis of compound 7 Compound 7-4 (100 mg, 314.08 μmol) and compound 1-8 (80.31 mg, 314.08 μmol) were dissolved in anhydrous dioxane (2 mL), followed by the addition of cesium carbonate (204.66 mg, 628.15 μmol). The atmosphere was replaced with nitrogen. Tris(dibenzylideneacetone)dipalladium (43.14 mg, 47.11 μmol) and (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (39.11 mg, 62.82 μmol) were then added. The atmosphere was replaced with nitrogen again, and the system was stirred at 90° C. for 6 hours. The reaction solution was concentrated, and the crude product was purified by preparative chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 39%-69%, 10 min) to obtain compound 7. MS m / z: 538[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.11 (s, 1 H), 8.63 - 8.69 (m, 2 H), 8.23 ​​(d, J = 1.50 Hz, 2 H), 8.01 (s, 1 H), 7.47 (ddd, J = 13.60, 7.91, 1.50 Hz, 2 H), 7.20 - 7.23 (m, 1 H), 3.61 (dt, J = 13.41, 6.86 Hz, 2 H), 3.52 (s, 3 H), 3.34 (dt, J = 13.45, 6.79 Hz, 2 H), 2.95 (s, 2 H), 2.27 - 2.38 (m, 2 H), 2.16 - 2.26 (m, 2 H), 1.42 - 1.51 (m, 1 H), 1.02 (br dd, J = 4.38, 3.00 Hz, 2 H), 0.81 (dd, J = 7.75, 3.13 Hz, 2 H)

[0144] Example 8 [ka] Synthetic Route [ka]

[0145] Step 1: Synthesis of compound 8-2 To a solution of compound 8-1 (5 g, 48.46 mmol) in water (50 mL) and tetrahydrofuran (50 mL), sodium carbonate (10.27 g, 96.91 mmol) and di-tert-butyl dicarbonate (11.10 g, 50.88 mmol) were added. The mixture was stirred at 25° C. for 15 h. The mixture was extracted with ethyl acetate (60 mL×3). The combined organic phase was washed with saturated brine (50 mL×1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 8-2. 1 H NMR (400 MHz, CDCl3) δ 3.66 - 3.57 (m, 4H), 2.50 (brs, 4H), 1.39 (s, 9H)

[0146] Step 2: Synthesis of compound 8-3 To a solution of compound 8-2 (2 g, 9.84 mmol) in methanol (40 mL), iodobenzene diacetate (6.65 g, 20.66 mmol) and ammonium carbamate (1.23 g, 15.74 mmol) were added. The mixture was stirred at 25 °C for 2 h. The reaction solution was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, then ethyl acetate / methanol = 40 / 0 to 40 / 1) to give compound 8-3. MS m / z: 235[M+H] + 1 H NMR (400 MHz, CDCl3) δ 4.03 - 3.92 (m, 2H), 3.92 - 3.78 (m, 2H), 3.06 (br s, 4H), 1.49 (s, 9H)

[0147] Step 3: Synthesis of compound 8-4 Compound 8-3 (1.62 g, 6.91 mmol) was dissolved in dioxane (22 mL), and 1-9 (1.41 g, 6.91 mmol), potassium carbonate (1.91 g, 13.83 mmol), tris(dibenzylideneacetone)dipalladium (316.55 mg, 345.69 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400.04 mg, 691.38 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was heated to 90 °C and stirred for 4 hours. The reaction solution was directly filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain compound 8-4. MS m / z: 347[M+H] +

[0148] Step 4: Synthesis of compound 8-5 Compound 8-4 (500 mg, 1.44 mmol) was dissolved in methanol (2 mL), and hydrochloric acid in methanol (4 M, 4 mL) was added. The mixture was stirred at 25° C. for 4 hours. The reaction solution was concentrated to give compound 8-5. MS m / z: 247[M+H] +

[0149] Step 5: Synthesis of compound 8-6 To a solution of compound 8-5 (500 mg, 2.03 mmol) in dichloroethane (5 mL) was added 37% aqueous formaldehyde (608.51 mg, 7.50 mmol) and sodium triacetoxyborohydride (859.05 mg, 4.05 mmol) under nitrogen at 0°C. The mixture was stirred at 25°C for 2 h. Thin layer chromatography showed that the starting material was completely consumed. The mixture was treated with saturated sodium bicarbonate (50 mL) and the mixture was stirred for 10 min, followed by extraction with dichloromethane (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give compound 8-6. MS m / z: 261[M+H] +

[0150] Step 6: Synthesis of compound 8-7 To a solution of compound 8-6 (290 mg, 1.16 mmol) in dioxane (8 mL), compound 1-11 (318.72 mg, 1.22 mmol) was added under nitrogen at 0°C. The mixture was mixed evenly, followed by the addition of a solution of potassium phosphate (494.21 mg, 2.33 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85.18 mg, 116.41 μmol) in water (2 mL). The mixture was stirred at 100°C for 2 h. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 8 / 1 to 0 / 1) to give compound 8-7. MS m / z: 348[M+H] +

[0151] Step 7: Synthesis of compound 8 To a solution of compound 8-7 (100 mg, 287.82 μmol) in dioxane (5 mL), compound 1-8 (82.24 mg, 316.60 μmol), cesium carbonate (187.55 mg, 575.64 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (35.84 mg, 57.56 μmol), and tris(dibenzylideneacetone)dipalladium (26.36 mg, 28.78 μmol) were added successively under nitrogen at 0° C. The mixture was stirred at 110° C. for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=4 / 1-0 / 1), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia, 0.05% v / v)-acetonitrile]; acetonitrile%: 28%-58%) to obtain compound 8. MS m / z: 567[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.27 (br s, 1H), 9.46 - 9.11 (m, 1H), 8.60 (d, J = 1.2 Hz, 2H), 8.22 (d, J = 1.5 Hz, 1H), 8.03 (s, 1H), 7.54 (br d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.26 - 7.21 (m, 1H), 3.73 - 3.67 (m, 2H), 3.49 - 3.42 (m, 2H), 3.10 - 2.71 (m, 8H), 2.24 - 2.01 (m, 3H), 1.58 (br s, 1H), 0.84 (br d, J = 4.4 Hz, 4H)

[0152] Example 9 [ka] Synthetic Route [ka]

[0153] Step 1: Synthesis of compound 9-2 A solution of compound 9-1 (500 mg, 2.58 mmol), dimethylsulfoximine (264.86 mg, 14.85 mmol), cesium carbonate (1.68 g, 5.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (299.14 mg, 516.99 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (236.71 mg, 258.49 μmol) in dioxane (10 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 4 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to obtain compound 9-2. MS m / z: 206[M+H] +

[0154] Step 2: Synthesis of compound 9-3 A solution of compound 9-2 (100 mg, 496.23 μmol), 1-11 (133.24 mg, 534.85 μmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (35.58 mg, 48.62 μmol), and potassium phosphate (206.42 mg, 972.46 μmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen three times. The mixture was stirred at 100 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 1 / 4) to give compound 9-3. MS m / z: 293[M+H] +

[0155] Step 3: Synthesis of compound 9 A solution of 9-3 (95 mg, 324.95 μmol), 1-8 (91.40 mg, 357.44 μmol), cesium carbonate (211.75 mg, 649.89 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (40.47 mg, 64.99 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (29.76 mg, 32.49 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 4 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 3-1 / 3) and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 30%-60%, 9min.) to obtain compound 9. MS m / z: 512[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.07 - 10.97 (m, 1H), 10.93 - 10.85 (m, 1H), 8.97 - 8.82 (m, 1H), 8.50 (s, 2H), 8.02 (s, 1H), 7.57 - 7.47 (m, 2H), 7.33 - 7.18 (m, 1H), 3.71 - 3.61 (m, 3H), 3.39 (s, 6H), 3.10 (s, 2H), 2.01 (quin, J = 6.1 Hz, 1H), 0.78 (d, J = 6.1 Hz, 4H)

[0156] Example 10 [ka] Synthetic Route [ka]

[0157] Step 1: Synthesis of compound 10-2 A solution of compound 10-1 (0.2 g, 965.85 μmol), 1-7 (90.90 mg, 965.85 μmol), potassium carbonate (266.97 mg, 1.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111.77 mg, 193.17 μmol), and tris(dibenzylideneacetone)dipalladium (88.44 mg, 96.58 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 16 h. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution. The layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1 to 10 / 1) to obtain compound 10-2. MS m / z: 265[M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.27 (br d, J = 4.8 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.90 (s, 1H), 7.67 - 7.52 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.89 (dd, J = 5.4, 6.8 Hz, 1H), 2.91 (s, 2H)

[0158] Step 2: Synthesis of compound 10 A solution of compound 10-2 (0.08 g, 302.20 μmol), 1-12 (88.35 mg, 302.20 μmol), cesium carbonate (196.93 mg, 604.40 μmol), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (37.63 mg, 60.44 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (27.67 mg, 30.22 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 6 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution. A separation operation was performed. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1-1 / 3), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 38%-68%, 8 min) to obtain compound 10. MS m / z: 521[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 8.75 - 8.64 (m, 2H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (dd, J = 1.2, 4.9 Hz, 1H), 7.59 (s, 1H), 7.55 - 7.48 (m, 3H), 7.45 (br s, 1H), 7.25 - 7.21 (m, 1H), 7.17 (s, 1H), 6.79 (ddd, J = 0.8, 5.6, 6.7 Hz, 1H), 3.55 (s, 3H), 3.36 (s, 6H), 2.94 (s, 2H)

[0159] Example 11 [ka] Synthetic Route [ka]

[0160] Step 1: Synthesis of compound 11-2 A solution of compound 11-1 (0.2 g, 965.85 μmol), 1-7 (108.28 mg, 965.85 μmol), potassium carbonate (266.97 mg, 1.93 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111.77 mg, 193.17 μmol), and tris(dibenzylideneacetone)dipalladium (88.44 mg, 96.58 μmol) in dioxane (40 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 16 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution. The layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1 to 10 / 1) to obtain compound 11-2. MS m / z: 283[M+H] +

[0161] Step 2: Synthesis of compound 11 A solution of compound 11-2 (0.14 g, 495.20 μmol), 1-12 (144.77 mg, 495.20 μmol), cesium carbonate (322.69 mg, 990.40 μmol), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (61.67 mg, 99.04 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (45.35 mg, 49.52 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 6 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution. The layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 1-1 / 3), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 8min.) to obtain compound 11. MS m / z: 539[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.00 - 10.93 (m, 1H), 8.72 - 8.65 (m, 2H), 8.20 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 2.9 Hz, 1H), 7.53 (dd, J = 1.6, 7.8 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.34 - 7.32 (m, 1H), 7.29 - 7.25 (m, 1H), 7.19 (s, 3H), 3.55 (s, 3H), 3.36 (s, 6H), 2.94 (s, 2H)

[0162] Example 12 [ka] Synthetic Route [ka]

[0163] Step 1: Synthesis of compound 12-2 A solution of compound 12-1 (0.25 g, 1.21 mmol), 1-7 (144.14 mg, 1.21 mmol), potassium carbonate (334.47 mg, 2.42 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (140.03 mg, 242.00 μmol), and tris(dibenzylideneacetone)dipalladium (110.80 mg, 121.00 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 16 h. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution. The layers were separated. The aqueous phase was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (2 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=15 / 1 to 8 / 1) to obtain compound 12-2. MS m / z: 290[M+H] +

[0164] Step 2: Synthesis of compound 12 A solution of compound 12-2 (0.03 g, 103.54 μmol), 1-12 (27.24 mg, 93.19 μmol), cesium carbonate (67.47 mg, 207.09 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (12.89 mg, 20.71 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (9.48 mg, 10.35 μmol) in dioxane (5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 6 h. 5 mL of water and 5 mL of ethyl acetate were added to the reaction solution. The layers were separated. The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (2 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin layer chromatography (silica gel, petroleum ether / ethyl acetate=2:1), followed by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 38%~68%, 8 min) to obtain compound 12. MS m / z: 546[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.42 (s, 1H), 8.89 (s, 1H), 8.61 (d, J = 1.4 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.95 (s, 1H), 7.92 - 7.85 (m, 1H), 7.83 - 7.77 (m, 1H), 7.70 (dd, J = 1.4, 7.9 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.45 - 7.36 (m, 1H), 3.56 (s, 3H), 3.47 (s, 6H), 2.17 - 2.05 (m, 1H), 2.08 (s, 1H)

[0165] Example 13 [ka] Synthetic Route [ka]

[0166] Step 1: Synthesis of compound 13-2 To a solution of 1-7 (0.1 g, 482.92 μmol) in dioxane (2 mL), 13-1 (47.43 mg, 434.63 μmol), potassium carbonate (133.49 mg, 965.85 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (55.89 mg, 96.59 μmol), and tris(dibenzylideneacetone)dipalladium (44.22 mg, 48.29 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 110 °C for 4 h. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=50 / 1 to 1 / 1), followed by preparative thin layer chromatography (silica gel, petroleum ether / ethyl acetate=2 / 1) to obtain compound 13-2. MS m / z: 280[M+H] +

[0167] Step 2: Synthesis of compound 13 To a solution of 13-2 (30 mg, 107.24 μmol) in dioxane (2 mL), 1-12 (31.35 mg, 107.24 μmol), cesium carbonate (69.88 mg, 214.49 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (13.36 mg, 21.45 μmol), and tris(dibenzylideneacetone)dipalladium (9.82 mg, 10.72 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 110 °C for 6 h. The reaction solution was directly filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (silica gel, petroleum ether / ethyl acetate=0 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 30%~60%, 8 min) to obtain compound 13. MS m / z: 536[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.24 (s, 1H), 8.87 (s, 1H), 8.63 - 8.54 (m, 2H), 8.14 (d, J = 1.5 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.63 (dd, J = 1.4, 8.0 Hz, 1H), 7.54 (dd, J = 1.5, 7.8 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 3.55 (s, 3H), 3.46 (s, 6H), 3.08 (s, 3H), 2.30 (s, 2H)

[0168] Example 14 [ka] Synthetic Route [ka]

[0169] Step 1: Synthesis of compound 14-2 Compound 14-1 (515.03 mg, 2.49 mmol) was dissolved in dioxane (10 mL), and 1-7 (246.56 mg, 2.49 mmol), potassium carbonate (687.49 mg, 4.97 mmol), tris(dibenzylideneacetone)dipalladium (227.76 mg, 248.72 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (287.83 mg, 497.44 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was heated to 90 °C and stirred for 16 h. The reaction solution was directly filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 3 / 1) to obtain compound 14-2. MS m / z: 270[M+H] +

[0170] Step 2: Synthesis of compound 14 Compound 14-2 (100 mg, 370.73 μmol) was dissolved in dioxane (4 mL), and 11-4 (90.32 mg, 308.94 μmol), cesium carbonate (201.32 mg, 617.88 μmol), tris(dibenzylideneacetone)dipalladium (28.29 mg, 30.89 μmol), and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (38.47 mg, 61.79 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was heated to 110 °C and stirred for 16 h. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 9 min) to obtain compound 14. MS m / z: 526[M+H] + 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 8.64 (d, J = 1.4 Hz, 1H), 8.49 (s, 1H), 8.22 - 8.18 (m, 2H), 8.14 (s, 1H), 7.68 (dd, J = 1.6, 7.8 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.33 - 7.28 (m, 1H), 3.51 (s, 3H), 2.91 (s, 2H), 2.34 - 2.18 (m, 6H), 2.02 - 1.76 (m, 7H)

[0171] Example 15 [ka] Synthetic Route [ka]

[0172] Step 1: Synthesis of compound 15-2 Compound 15-1 (5 g, 24.39 mmol) was dissolved in concentrated sulfuric acid (20 mL). Concentrated nitric acid (2.21 g, 34.99 mmol, 1.58 mL) was added dropwise at -10 °C, and the mixture was stirred at -10 °C for 0.5 h. Thin layer chromatography showed that the starting material was completely consumed. The reaction solution was quenched by pouring it onto crushed ice and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 15-2. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (dd, J = 3.1, 7.1 Hz, 1H), 7.54 (dd, J = 3.1, 7.3 Hz, 1H), 4.01 (s, 3H)

[0173] Step 2: Synthesis of compound 15-3 Compound 15-2 (3 g, 12.00 mmol) was dissolved in water (30 mL) and ethanol (10 mL), and iron powder (3.35 g, 59.99 mmol) and ammonium chloride (6.42 g, 119.99 mmol) were added. The mixture was stirred at 100 °C for 2 h, and TLC showed that the starting material was completely consumed. The reaction solution was filtered through diatomaceous earth to remove the iron powder. The filtrate was diluted with ethyl acetate (150 mL) and washed with water (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 40 / 1) to obtain compound 15-3. 1 H NMR (400 MHz, DMSO-d6) δ 6.63 (dd, J = 2.9, 8.1 Hz, 1H), 6.41 (dd, J = 2.9, 9.8 Hz, 1H), 3.80 (s, 3H)

[0174] Step 3: Synthesis of compound 15-4 Compound 15-3 (1 g, 4.54 mmol) was dissolved in dioxane (30 mL). Bis(pinacolato)diboron (1.73 g, 6.82 mmol), potassium acetate (1.34 g, 13.63 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane (185.57 mg, 227.23 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100 °C for 3 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 40 / 1 to 8 / 1) to obtain compound 15-4. MS m / z: 268[M+H] +

[0175] Step 4: Synthesis of compound 15-5 A solution of compound 15-4 (100.00 mg, 374.40 μmol), 1-10 (70 mg, 340.36 μmol), potassium phosphate (144.49 mg, 680.72 μmol), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (24.90 mg, 34.04 μmol) in dioxane (2 mL) and water (0.5 mL) was purged with nitrogen three times. The mixture was stirred at 100 °C for 2 h. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (5 mL × 3). The organic phases were combined, washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 1 / 2) to give compound 15-5. MS m / z: 311[M+H] +

[0176] Step 5: Synthesis of compound 15 Compound 15-5 (90 mg, 290.00 μmol) was dissolved in dioxane (4 mL), and compound 1-8 (83 mg, 324.58 μmol), cesium carbonate (211.51 mg, 649.16 μmol), tris(dibenzylideneacetone)dipalladium (29.72 mg, 32.46 μmol), and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (40.42 mg, 64.92 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 110° C. for 3 hours. The reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 37%-67%, 9 min) to obtain compound 15. MS m / z: 530[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.98 (s, 1H), 8.91 (s, 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.15 (d, J = 1.1 Hz, 1H), 8.11 (s, 1H), 7.34 (ddd, J = 3.0, 9.5, 18.1 Hz, 2H), 3.53 (s, 3H), 3.47 (s, 6H), 3.11 (s, 2H), 2.07 - 1.98 (m, 1H), 0.87 - 0.75 (m, 4H)

[0177] Example 16 [ka] Synthetic Route [ka]

[0178] Step 1: Synthesis of compound 16-2 Compound 16-1 (5 g, 28.74 mmol) was dissolved in concentrated sulfuric acid (15 mL), and the solution was cooled to 0° C. and stirred for 10 min. Nitric acid (4.2 g, 66.65 mmol) was then added dropwise to the reaction solution. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 25° C. for 16 h. The reaction solution was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated saline (100 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound 16-2, which was used directly in the next reaction. MS m / z: 219[M+H] + , 221[M+2+H] +

[0179] Step 2: Synthesis of compound 16-3 Compound 16-2 (4.6 g, 16.80 mmol, 80% purity) was dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (4.64 g, 33.61 mmol) was added. The mixture was stirred at 25°C for 10 min. Methyl iodide (4.77 g, 33.61 mmol) was added dropwise to the above solution. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 25°C for 16 h. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated saline (50 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 16-3. MS m / z: 233[M+H] + , 235[M+2+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.23 ​​(m, 1H), 8.21 - 8.18 (m, 1H), 3.97 (s, 3H)

[0180] Step 3: Synthesis of compound 16-4 Compound 16-3 (1.48 g, 6.35 mmol) was dissolved in ethanol (4 mL) and water (2 mL). Acetic acid (4 mL) and iron powder (1.77 g, 31.76 mmol) were added. The mixture was stirred at 25° C. for 1.5 h. The reaction solution was filtered. The filtrate was washed successively with saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was stirred with petroleum ether and ethyl acetate (petroleum ether / ethyl acetate=5 / 1) and filtered. The filter cake was collected to give compound 16-4. MS m / z: 203[M+H] + , 205[M+2+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 1H), 6.22 (s, 2H), 3.69 (s, 3H)

[0181] Step 4: Synthesis of compound 16-5 A solution of compound 16-4 (0.5 g, 2.46 mmol), bis(pinacolato)diboron (1.25 g, 4.93 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride and tris(dibenzylideneacetone)dipalladium (180.19 mg, 246.26 μmol), and potassium acetate in dioxane (25 mL) was purged with nitrogen three times. The mixture was stirred at 80 °C for 16 h. To the reaction solution, compound 1-10 (1.52 g, 7.39 mmol), potassium phosphate (1.05 g, 4.93 mmol), and water (6 mL) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100 °C for 16 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1, then ethyl acetate / ethanol = 10 / 1), followed by preparative thin layer chromatography (silica gel, ethyl acetate / ethanol = 10 / 1) to obtain compound 16-5. MS m / z: 294[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 1.4 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 5.3 Hz, 1H), 6.90 (d, J = 5.3 Hz, 1H), 5.97 (s, 2H), 3.55 (s, 3H), 3.47 (s, 6H)

[0182] Step 5: Synthesis of compound 16 A solution of 16-5 (25.70 mg, 87.60 μmol), 1-8 (0.028 g, 109.50 μmol), cesium carbonate (71.35 mg, 218.99 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (12.89 mg, 20.71 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (10.03 mg, 10.95 μmol) in dioxane (2 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 6 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1), and then separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 31% to 61%, 8 min) to obtain compound 16. MS m / z: 513[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.93 (s, 1H), 9.69 (s, 1H), 8.97 (s, 1H), 8.78 (d, J = 1.5 Hz, 1H), 8.28 - 8.11 (m, 2H), 7.41 (d, J = 5.3 Hz, 1H), 3.71 (s, 3H), 3.50 (s, 6H), 3.15 (s, 2H), 2.08 (s, 1H), 0.92 - 0.80 (m, 4H)

[0183] Example 17 [ka] Synthetic Route [ka]

[0184] Step 1: Synthesis of compound 17-3 At -65°C, isopropylmagnesium chloride (2 M, 8.81 mL) was added dropwise to a solution of compound 17-1 (2 g, 8.81 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at -65°C for 1 h. A solution of compound 17-2 (1.6 g, 12.02 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at 20°C for 2 h. Thin layer chromatography showed that the starting material was completely consumed. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to give compound 17-3. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.46 (s, 1H), 4.53 (s, 2H), 3.46 (s, 3H)

[0185] Step 2: Synthesis of compound 17-4 Compound 17-3 (200 mg, 908.87 μmol) was dissolved in dioxane (5 mL), and compound cyclopropylcarboxamide (81.22 mg, 954.32 μmol), potassium carbonate (376.85 mg, 2.73 mmol), tris(dibenzylideneacetone)dipalladium (83.23 mg, 90.89 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (105.18 mg, 181.77 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 80 °C for 6 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=5 / 1 to 3 / 1) to obtain compound 17-4. MS m / z: 269[M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.44 (br s, 1H), 8.37 (s, 1H), 4.59 (s, 2H), 3.48 (s, 3H), 1.59 (dt, J = 3.9, 8.1 Hz, 1H), 1.18 - 1.13 (m, 2H), 1.00 - 0.95 (m, 2H)

[0186] Step 3: Synthesis of compound 17 Compound 17-4 (90 mg, 334.95 μmol) was dissolved in dioxane (4 mL), and compound 1-12 (88.13 mg, 301.46 μmol,), potassium carbonate (92.58 mg, 669.90 μmol), palladium acetate (7.52 mg, 33.50 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.76 mg, 66.99 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 80 °C for 4 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 29%-59%, 10 min) to obtain compound 17. MS m / z: 525[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.84 (s, 1H), 8.76 (s, 1H), 8.59 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 8.04 (s, 1H), 7.54 (dd, J = 1.4, 7.8 Hz, 1H), 7.49 (dd, J = 1.3, 7.9 Hz, 1H), 7.33 - 7.26 (m, 1H), 4.80 (s, 2H), 3.53 (s, 3H), 3.47 (s, 6H), 3.39 (s, 3H), 2.02 (quin, J = 6.1 Hz, 1H), 0.79 (d, J = 6.1Hz, 4H)

[0187] Example 18 [ka] Synthetic Route [ka]

[0188] Step 1: Synthesis of compound 18-1 To a solution of compound 1-2 (1 g, 4.25 mmol) in THF (10 mL), methylmagnesium bromide (3M in diethyl ether, 2.13 mL) was added, and the mixture was stirred at 0° C. for 1 h. The reaction solution was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=50 / 1 to 3 / 1) to give compound 18-1. MS m / z: 190[M+H] +

[0189] Step 2: Synthesis of compound 18-2 To a solution of compound 18-1 (200 mg, 1.05 mmol) in dioxane (3 mL), cyclopropylcarboxamide (98.53 mg, 1.16 mmol), potassium carbonate (290.92 mg, 2.10 mmol), tris(dibenzylideneacetone)dipalladium (48.19 mg, 52.62 μmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (60.90 mg, 105.25 μmol) were added under nitrogen. The mixture was stirred at 90 °C for 3 h. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give compound 18-2. 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (br s, 1H), 8.79 (s, 1H), 8.24 (s, 1H), 2.61 (s, 3H), 2.09 - 1.99 (m, 1H), 0.89 - 0.84 (m, 4H)

[0190] Step 3: Synthesis of compound 18 To a solution of compound 18-2 (117.56 mg, 492.55 μmol) in dioxane (2 mL), compound 1-12 (120 mg, 410.46 μmol), cesium carbonate (267.47 mg, 820.922 μmmol), tris(dibenzylideneacetone)dipalladium (48.19 mg, 52.62 μmol), and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (25.56 mg, 41.05 μmol) were added slowly in portions under nitrogen. The mixture was stirred at 110 °C for 4 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1-3 / 1), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia, 0.05% v / v)-acetonitrile]; acetonitrile%: 22%-52%, 9 min) to obtain compound 18. MS m / z: 495[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 11.44 (s, 1H), 9.34 (s, 1H), 9.09 (s, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.01 (br dd, J = 7.6, 19.6 Hz, 2H), 7.85 - 7.72 (m, 1H), 4.01 (s, 3H), 3.97 (s, 6H), 3.15 (s, 3H), 2.57 - 2.48 (m, 1H), 1.29 (br d, J = 5.9 Hz, 4H)

[0191] Example 19 [ka] Synthetic Route [ka]

[0192] Step 1: Synthesis of compound 19-1 To a solution of compound 1-2 (1 g, 4.25 mmol) in THF (10 mL), cyclopropylmagnesium bromide (0.5 M tetrahydrofuran solution, 25.52 mL) was added, and the mixture was stirred at 0° C. for 1 h. The reaction solution was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=50 / 1 to 1 / 1) to obtain compound 19-1. MS m / z: 216[M+H] +

[0193] Step 2: Synthesis of compound 19-2 To a solution of compound 19-1 (200 mg, 925.65 μmol) in dioxane (3 mL), cyclopropylcarboxamide (86.65 mg, 1.02 mmol), potassium carbonate (255.86 mg, 1.85 mmol), tris(dibenzylideneacetone)dipalladium (42.38 mg, 46.28 μmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (53.56 mg, 92.57 μmol) were added under nitrogen. The mixture was stirred at 90 °C for 3 h. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give compound 19-2. 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 2.66 - 2.61 (m, 1H), 2.09 - 1.99 (m, 1H), 1.16 - 1.11 (m, 2H), 1.11 - 1.07 (m, 2H), 0.88 (d, J = 2.3 Hz, 2H), 0.86 (s, 2H)

[0194] Step 3: Synthesis of compound 19 To a solution of compound 19-2 (95.07 mg, 359.15 μmol) in dioxane (2 mL), compound 1-12 (100 mg, 342.05 μmol), cesium carbonate (222.89 mg, 684.10 μmmol), tris(dibenzylideneacetone)dipalladium (15.66 mg, 17.10 μmol), and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (21.30 mg, 34.20 μmol) were added slowly in portions under nitrogen. The mixture was stirred at 110 °C for 4 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1-3 / 1), and then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia, 0.05% v / v)-acetonitrile]; acetonitrile%: 27%-57%, 9 min) to obtain compound 19. 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 8.03 (s, 1H), 7.50 (ddd, J = 1.3, 7.8, 18.3 Hz, 2H), 7.31 - 7.25 (m, 1H), 3.50 (s, 3H), 3.46 (s, 6H), 3.07 - 2.94 (m, 1H), 2.09 - 1.96 (m, 1H), 1.13 - 1.01 (m, 4H), 0.79 (d, J = 6.1Hz, 4H)

[0195] Example 20 [ka] Synthetic Route [ka]

[0196] Step 1: Synthesis of compound 20-2 To a solution of compound 20-1 (0.8 g, 5.83 mmol) in dioxane (12 mL), cyclobutylamine (999.20 mg, 17.50 mmol) was added and the mixture was stirred for 3 h at 25° C. The reaction solution was concentrated under reduced pressure, and the crude was purified by slurrying in dichloromethane to give compound 20-2. 1 H NMR (400 MHz, DMSO-d6) δ 5.73 (br s, 2H), 3.75 (t, J = 7.5 Hz, 4H), 2.08 (t, J = 7.5 Hz, 2H)

[0197] Step 2: Synthesis of compound 20-3 A solution of compound 20-2 (100 mg, 482.92 μmol), compound 1-7 (53.18 mg, 531.22 μmol), potassium carbonate (200.24 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium (22.11 mg, 24.15 μmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (27.94 mg, 48.29 μmol) in dioxane (2 mL) was purged with nitrogen three times, and the mixture was stirred at 90 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to obtain compound 20-3. MS m / z: 271[M+H] +

[0198] Step 3: Synthesis of compound 20 A solution of 1-12 (100 mg, 342.05 μmol), 20-3 (111.12 mg, 410.46 μmol), cesium carbonate (222.89 mg, 684.10 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (21.30 mg, 34.20 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (15.66 mg, 17.10 μmol) in dioxane (2 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1-0 / 1 and dichloromethane / methanol=5 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia, 0.05% v / v)-acetonitrile]; acetonitrile%: 23%-53%, 9 min) to obtain compound 20. MS m / z: 527[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (br s, 1H), 9.17 (br s, 1H), 8.80 (br s, 1H), 8.60 (br s, 1H), 8.14 (br s, 1H), 7.89 (br s, 1H), 7.49 (br t, J = 8.0 Hz, 2H), 7.28 (br t, J = 7.4 Hz, 1H), 3.96 (br s, 4H), 3.53 (br s, 3H), 3.46 (br s, 6H), 3.07 (br s, 2H), 2.18 - 2.08 (m, 2H)

[0199] Example 21 [ka] Synthetic Route [ka]

[0200] Step 1: Synthesis of compound 21-2 Compound 21-1 (10 g, 65.30 mmol) was dissolved in N,N-dimethylformamide (100 mL). N-bromosuccinimide (13.95 g, 78.36 mmol) was added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 25°C for 20 hours. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated saline (100 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0) to obtain compound 21-2. 1 H NMR (400 MHz,DMSO-d6) δ 10.77 (br s, 1H), 7.94 - 7.63 (m, 2H), 2.29 - 2.25 (m, 3H)

[0201] Step 2: Synthesis of compound 21-3 To a solution of compound 21-2 (1 g, 4.31 mmol) and potassium carbonate (1.19 g, 8.62 mmol) in N,N-dimethylformamide (3.5 mL) was added methyl iodide (734.06 mg, 5.17 mmol, 321.96 μL) at 25 °C. The mixture was stirred at 60 °C for 4 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 21-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (br d, J = 2.1 Hz, 1H), 7.76 (br s, 1H), 3.87 (s, 3H), 2.34 (s, 3H)

[0202] Step 3: Synthesis of compound 21-4 To a solution of compound 21-3 (2 g, 8.13 mmol, 1 eq) in ethanol (32 mL) and water (8 mL) was added iron (2.27 g, 40.64 mmol) and ammonium chloride (4.35 g, 81.28 mmol). The mixture was stirred at 80° C. for 16 h. The reaction solution was filtered and the filtrate was extracted with ethyl acetate (5 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 21-4. 1 H NMR (400 MHz, DMSO-d6) δ 6.52 (d,J = 1.5 Hz, 1H), 6.49 (s, 1H), 5.10 (br s, 2H), 3.65 (s, 3H), 2.11 (s, 3H)

[0203] Step 4: Synthesis of compound 21-5 To a solution of compound 21-4 (1.7 g, 7.87 mmol) in dioxane (25 mL), bis(pinacolato)diboron (3.00 g, 11.80 mmol), potassium acetate (2.32 g, 23.60 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (287.84 mg, 393.38 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 100 °C for 15 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to obtain compound 21-5. 1 H NMR (400 MHz, DMSO-d6) δ 6.60 (s, 1H), 6.56 (s, 1H), 4.70 (br s, 2H), 3.60 (s, 3H), 2.11 (s, 3H), 1.27 (s, 12H)

[0204] Step 5: Synthesis of compound 21-6 To a solution of compound 21-5 (1.34 g, 5.11 mmol) and 1-10 (1 g, 4.86 mmol) in dioxane (16 mL) and water (4 mL), potassium phosphate (2.06 g, 9.72 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71.16 mg, 97.25 μmol) were added. The mixture was stirred at 100 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound 21-6. MS m / z: 307[M+H] +

[0205] Step 6: Synthesis of compound 21 A solution of compound 21-6 (200 mg, 652.78 μmol), 1-8 (200.31 mg, 783.33 μmol), cesium carbonate (425.38 mg, 1.31 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (40.65 mg, 65.28 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (28.89 mg, 32.64 μmol) in dioxane (10 mL) was purged with nitrogen three times. The mixture was stirred at 100 °C for 3 h. The reaction solution was diluted with water (20 mL), and ethyl acetate (20 mL × 3) was added. The obtained organic phase was washed with brine (10 mL × 2) and dried over anhydrous sodium sulfate. The dried organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1), followed by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (ammonia, 0.05% v / v)-acetonitrile]; acetonitrile%: 34% to 64%, 8 min) to obtain compound 21. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.88 (s, 1H), 8.86 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 3.49 (s, 3H), 3.47 (s, 6H), 3.09 (s, 2H), 2.31 (s, 3H), 2.02 (quin,J= 5.9 Hz, 1H), 0.79 (br d, J = 5.5 Hz, 4H)

[0206] Example 22 [ka] Synthetic Route [ka]

[0207] Step 1: Synthesis of compound 22-2 Compound 22-1 (1 g, 5.91 mmol, 806.45 μL) was dissolved in water (5 mL) and glacial acetic acid (15 mL). Potassium bromide (703.59 mg, 5.91 mmol, 255.85 μL) and bromine (944.86 mg, 5.91 mmol, 304.79 μL) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 25 °C for 1 h. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 15 / 1) to obtain compound 22-2. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (br s, 1H), 7.63 (t, J = 2.6 Hz, 1H), 7.48 (dd, J = 1.4, 3.0 Hz, 1H), 3.78 (s, 3H)

[0208] Step 2: Synthesis of compound 22-3 To a solution of compound 22-2 (1.2 g, 4.84 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.34 g, 9.68 mmol) and potassium iodide (824.06 mg, 5.81 mmol, 361.43 μL) at 20 °C. The mixture was stirred at 60 °C for 4 h. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), diluted with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 22-3. 1 H NMR (400 MHz,CDCl3) δ 7.35 (d, J = 3.1 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H)

[0209] Step 3: Synthesis of compound 22-4 To a solution of compound 22-3 (0.75 g, 2.86 mmol) in ethanol (5 mL) and water (5 mL), iron powder (799.13 mg, 14.31 mmol) and ammonium chloride (1.53 g, 28.62 mmol) were added. The mixture was stirred at 80° C. for 6 h. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 22-4. 1 H NMR (400 MHz, CDCl3) δ 6.47 (d, J = 2.8 Hz, 1H), 6.25 (d, J = 2.9 Hz, 1H), 3.93 (br s, 2H), 3.79 (s, 3H), 3.72 (s, 3H)

[0210] Step 4: Synthesis of compound 22-5 To a solution of compound 22-4 (700 mg, 3.02 mmol) in dioxane (7 mL), bis(pinacolato)diboron (1.15 g, 4.52 mmol), potassium acetate (592.05 mg, 6.03 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44.14 mg, 60.33 μmol) were added. The atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 90 °C for 20 h. Bis(pinacolato)diboron (382.97 mg, 1.51 mmol), potassium acetate (296.02 mg, 3.02 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44.14 mg, 60.33 μmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 90° C. for 24 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated saline (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to obtain compound 22-5. MS m / z: 280[M+H] +

[0211] Step 5: Synthesis of compound 22-6 To a solution of compound 22-5 (354 mg, 1.27 mmol) and 1-10 (230 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL), potassium phosphate (474.76 mg, 2.24 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.37 mg, 22.37 μmol) were added. The mixture was stirred at 100 °C for 4 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give compound 22-6. MS m / z: 323[M+H]+

[0212] Step 6: Synthesis of compound 22 To a solution of compound 22-6 (126 mg, 390.84 μmol) in isopropanol (2 mL), concentrated hydrochloric acid (97.71 μmol, 9.44 μL) was added, and the mixture was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to remove isopropanol and concentrated hydrochloric acid to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (HCl, 0.05% v / v)-acetonitrile]; acetonitrile%: 19%~39%, 8 min) to obtain compound 22 hydrochloride. MS m / z: 542[M+H] + 1 H NMR (400 MHz, CDCl3) δ 12.20 (br s, 1H), 11.61 (s, 1H), 9.03 (br s, 1H), 9.00 (br s, 1H), 8.42 (br s, 1H), 7.85 (s, 1H), 7.38 (br s, 1H), 7.03 (s, 1H), 3.93 (s, 3H), 3.57 (br s, 6H), 3.51 (br s, 3H), 3.09 (br s, 2H), 2.04 - 1.93 (m, 1H), 1.11 (br d, J = 3.5 Hz, 2H), 1.05 - 0.96 (m, 2H)

[0213] Example 23 [ka] Synthetic Route [ka]

[0214] Step 1: Synthesis of compound 23-1 Cyclopropylamine (1 g, 17.51 ​​mmol, 1.21 mL) and potassium cyanate (1.70 g, 21.02 mmol, 827.61 μL) were dissolved in water (6 mL) and the mixture was refluxed at 100° C. for 30 min. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in isopropanol (10 mL). The solution was heated to 85° C., stirred for 30 min, and filtered. The filter cake was washed with isopropanol (10 mL) and the filtrate was concentrated under reduced pressure to give compound 23-1. 1 H NMR (400 MHz, DMSO-d6) δ 6.22 (br s, 1H), 5.51 (br s, 2H), 2.40 - 2.32 (m, 1H), 0.58 - 0.49 (m, 2H), 0.34 - 0.27 (m, 2H)

[0215] Step 2: Synthesis of compound 23-2 Compound 1-7 (200 mg, 965.85 μmol) was dissolved in dioxane (4 mL). 23-1 (125.71 mg, 1.26 mmol), cesium carbonate (629.38 mg, 1.93 mmol), palladium acetate (21.68 mg, 96.58 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111.77 mg, 193.17 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 80 °C for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to obtain compound 23-2. MS m / z: 271[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.65 (s, 1H), 7.77 (s, 1H), 7.55 (br s, 1H), 2.96 (s, 2H), 2.59 (dt, J = 3.4, 6.8 Hz, 1H), 0.71 - 0.63 (m, 2H), 0.48 - 0.41 (m, 2H)

[0216] Step 3: Synthesis of compound 23 Compound 23-2 (60 mg, 221.62 μmol) and 1-12 (61.55 mg, 210.54 μmol) were dissolved in isopropanol (2 mL). Hydrochloric acid (55.41 μmol, 5.35 μL, 37% purity) was added, and the mixture was stirred at 80°C for 16 hours. The mixture was diluted with 30 mL of a mixed solution of ethyl acetate and ethanol (ethyl acetate / ethanol = 4 / 1) and washed with saturated sodium bicarbonate (10 mL × 3). The combined organic layer was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 34%~64%, 8 min) to obtain compound 23. MS m / z: 527[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.15 (br s, 1H), 8.80 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.94 (br s, 1H), 7.53 (dd, J = 1.5, 7.8 Hz, 1H), 7.48 (dd, J = 1.5, 7.9 Hz, 1H), 7.36 (s, 1H), 7.33 - 7.26 (m, 1H), 3.52 (s, 3H), 3.47 (s, 6H), 3.06 (s, 2H), 2.60 - 2.54 (m, 1H), 0.68 - 0.61 (m, 2H), 0.44 - 0.37 (m, 2H)

[0217] Example 24 [ka] Synthetic Route [ka]

[0218] Step 1: Synthesis of compound 24-1 1-7 (1 g, 4.83 mmol) and 1-12 (1.27 g, 4.35 mmol) were dissolved in isopropanol (15 mL). 0.3 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 70° C. for 16 h. The reaction solution was filtered, and the filter cake was collected and washed with isopropyl alcohol to obtain the crude product. The crude product was stirred with a mixture of ethyl acetate and ethanol (ethyl acetate / ethanol=8 mL / 2 mL) and filtered. The filter cake was collected to obtain compound 24-1. MS m / z: 463[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.98 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.45 - 7.34 (m, 1H), 6.97 (s, 1H), 3.60 (s, 3H), 3.53 (s, 6H), 3.22 (s, 2H)

[0219] Step 2: Synthesis of compound 24 A solution of 24-1 (50 mg, 108.00 μmol), 2-picolinamide (26.38 mg, 216.00 μmol), cesium carbonate (70.38 mg, 216.00 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (12.50 mg, 21.60 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (9.89 mg, 10.80 μmol) in dioxane (1.5 mL) was purged with nitrogen three times. The mixture was stirred at 110° C. for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0~0 / 1), followed by separation by preparative high performance liquid chromatography (column: Waters Xbridge 75*30mm*3μm; mobile phase: [water (HCl, 0.05% v / v)-acetonitrile]; acetonitrile%: 12%~42%, 8 min) to obtain compound 24 hydrochloride. MS m / z: 549[M+H] + 1 H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 8.75 - 8.64 (m, 2H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (dd, J = 1.2, 4.9 Hz, 1H), 7.59 (s, 1H), 7.55 - 7.48 (m, 3H), 7.45 (br s, 1H), 7.25 - 7.21 (m, 1H), 7.17 (s, 1H), 6.79 (ddd, J = 0.8, 5.6, 6.7 Hz, 1H), 3.55 (s, 3H), 3.36 (s, 6H), 2.94 (s, 2H)

[0220] Example 25 [ka] Synthetic Route [ka]

[0221] Step 1: Synthesis of compound 25 A solution of 24-1 (100 mg, 216.00 μmol), nicotinamide (52.76 mg, 432.00 μmol), cesium carbonate (140.75 mg, 432.00 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (25.00 mg, 43.20 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (19.78 mg, 21.60 μmol) in dioxane (1.5 mL) was purged with nitrogen three times. The mixture was stirred at 110° C. for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0~0 / 1), followed by separation by preparative high performance liquid chromatography (column: Waters Xbridge 75*30mm*3μm; mobile phase: [water (HCl, 0.05% v / v)-acetonitrile]; acetonitrile%: 4%~34%, 8 min) to obtain compound 25 hydrochloride. MS m / z: 549[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 12.10 - 11.77 (m, 1H), 11.30 (br d, J = 3.9 Hz, 1H), 9.29 - 9.17 (m, 1H), 9.04 (d, J = 2.9 Hz, 1H), 8.87 (br d, J = 3.3 Hz, 1H), 8.63 (d, J = 1.3 Hz, 1H), 8.56 - 8.41 (m, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.87 - 7.63 (m, 3H), 7.55 (br d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 3.57 (s, 3H), 3.47 (s, 6H), 3.17 (s, 2H)

[0222] Example 26 [ka] Synthetic Route [ka]

[0223] Step 1: Synthesis of compound 26 A solution of 24-1 (100 mg, 216.00 μmol), 4-pyridinecarboxamide (52.76 mg, 432.00 μmol), cesium carbonate (140.75 mg, 432.00 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (25.00 mg, 43.20 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (19.78 mg, 21.60 μmol) in dioxane (1.5 mL) was purged with nitrogen three times. The mixture was stirred at 110° C. for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0~0 / 1), followed by separation by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (HCl, 0.05% V / V)-acetonitrile]; B%: 4%~34%, 8 min) to obtain compound 26 hydrochloride. MS m / z: 549[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (br s, 1H), 11.07 (s, 1H), 8.97 (s, 1H), 8.81 - 8.70 (m, 2H), 8.63 (d, J = 1.5 Hz, 1H), 8.22 - 8.11 (m, 2H), 7.91 - 7.80 (m, 2H), 7.64 - 7.49 (m, 2H), 7.43 - 7.28 (m, 1H), 3.57 (s, 3H), 3.47 (s, 6H), 3.16 (s, 2H)

[0224] Example 27 [ka] Synthetic Route [ka]

[0225] Step 1: Synthesis of compound 27-1 To a solution of diethyl sulfide (2.32 g, 25.72 mmol, 2.77 mL) in anhydrous methanol (4 mL), iodobenzene diacetate (20.71 g, 64.31 mmol) and ammonium carbamate (4.02 g, 51.45 mmol) were added, and the mixture was stirred at 20° C. for 16 h. The reaction solution was concentrated under reduced pressure to give compound 27-1. 1 H NMR (400 MHz, CDCl3) δ 3.06 (q, J = 7.4 Hz, 4H), 1.46 - 1.37 (m, 6H)

[0226] Step 2: Synthesis of compound 27-2 To a solution of compound 27-1 (626.59 mg, 5.17 mmol) and 1-9 (1 g, 5.17 mmol) in dioxane (20 mL), cesium carbonate (3.37 g, 10.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (236.71 mg, 258.49 μmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (299.14 mg, 516.99 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 110 °C for 2 h. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1 to 4 / 1) to obtain crude compound 27-2. MS m / z: 234[M+H] +

[0227] Step 3: Synthesis of compound 27-3 To a solution of compound 27-2 (389 mg) and 1-11 (348.52 mg, 1.40 mmol) in dioxane (5 mL) and water (1 mL), potassium phosphate (539.94 mg, 2.54 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18.61 mg, 25.44 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 100 °C for 18 h. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give crude compound 27-3. MS m / z: 321[M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.27 (s, 1H), 7.12 - 7.05 (m, 1H), 7.01 (dt, J = 2.3, 7.7 Hz, 1H), 6.79 (br d, J = 7.6 Hz, 1H), 4.13 (dq, J = 2.1, 7.1 Hz, 2H), 3.61 - 3.47 (m, 7H), 1.54 - 1.41 (m, 6H)

[0228] Step 4: Synthesis of compound 27 To a solution of compound 27-3 (50 mg) in isopropanol (2 mL), 1-8 (40 mg, 156.42 μmol) and concentrated hydrochloric acid (3.34 mg, 33.91 μmol, 3.28 μL, 37% purity) were added, and the mixture was stirred at 80 °C for 16 h. Ammonia was added dropwise to the reaction solution to adjust the pH to 8-9. The reaction solution was concentrated under reduced pressure to remove isopropanol and concentrated hydrochloric acid to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 41%-71%, 8 min) to obtain compound 27. MS m / z: 540 [M+H] + 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.90 (s, 1H), 8.87 (s, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.52 (dd, J = 1.4, 7.8 Hz, 1H), 7.47 (dd, J = 1.3, 7.9 Hz, 1H), 7.32 - 7.24 (m, 1H), 3.59 (q, J = 7.4 Hz, 4H), 3.51 (s, 3H), 3.10 (s, 2H), 2.05 - 1.97 (m, 1H), 1.30 (t, J = 7.3 Hz, 6H), 0.78 (d, J = 6.0 Hz, 4H)

[0229] Example 28

Chem.

Chem.

[0230] Step 1: Synthesis of compound 28-2 Compound 28-1 (0.5 g, 3.96 mmol) was dissolved in N,N-dimethylformamide (5 mL), and the solution was cooled to 0° C. and stirred for 10 min. Sodium hydride (190.29 mg, 4.76 mmol, 60% purity) was then added to the reaction solution, and the mixture was stirred at 0° C. for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (727.10 mg, 4.36 mmol) was added to the reaction solution, and the mixture was stirred at 0° C. for 2 h. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain compound 28-2. MS m / z: 257[M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.01 - 7.89 (m, 1H), 5.46 (s, 2H), 3.86 (s, 3H), 3.69 - 3.53 (m, 2H), 0.97 - 0.91 (m, 2H), 0.00 (s, 9H)

[0231] Step 2: Synthesis of compound 28-3 Compound 28-2 (0.7 g, 2.73 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL). A solution of sodium hydroxide (0.25 g, 6.25 mmol) in water (3 mL) was added, and the mixture was stirred at 25° C. for 2 hours. The reaction solution was adjusted to pH 3 with 2M aqueous hydrochloric acid and filtered. The filter cake was washed with water (15 mL) to give compound 28-3. MS m / z: 243[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 12.88 - 11.99 (m, 1H), 8.46 (s, 1H), 7.92 (s, 1H), 5.48 (s, 2H), 3.68 - 3.56 (m, 2H), 0.88 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H)

[0232] Step 3: Synthesis of compound 28-4 Compound 28-3 (0.25 g, 1.03 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). N,N-diisopropylethylamine (399.97 mg, 3.09 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (431.46 mg, 1.13 mmol), and 1-hydroxybenzotriazole (139.39 mg, 1.03 mmol) were added, and the mixture was stirred at 25°C for 1 h. Ammonium chloride (275.90 mg, 5.16 mmol) was then added, and the mixture was stirred at 25°C for 16 h. Saturated saline (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1 to 0 / 1, dichloromethane / methanol=10 / 1) to obtain compound 28-4. MS m / z: 242[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.89 (s, 1H), 7.61 (br s, 1H), 7.07 (br s, 1H), 5.41 (s, 2H), 3.57 - 3.49 (m, 2H), 0.94 - 0.74 (m, 2H), -0.05 (s, 9H)

[0233] Step 4: Synthesis of compound 28-5 A solution of compound 28-4 (100 mg, 216.00 μmol), 24-1 (62.56 mg, 259.20 μmol), cesium carbonate (140.75 mg, 432.00 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (25.00 mg, 43.20 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (19.78 mg, 21.60 μmol) in dioxane (1.5 mL) was purged with nitrogen three times. The mixture was stirred at 110 °C for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by thin layer chromatography (silica gel, ethyl acetate) to give compound 28-5. MS m / z: 668[M+H] +

[0234] Step 5: Synthesis of compound 28 Compound 28-5 (0.04 g, 59.89 μmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure. Dichloromethane (5 mL) and saturated aqueous sodium bicarbonate solution (2 mL) were added. A separation operation was performed. The organic phase was washed with saturated aqueous sodium bicarbonate solution (2 mL) and saturated saline solution (2 mL), respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 26%~56%, 8 min) to obtain compound 28. MS m / z: 538[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 13.42 - 13.13 (m, 1H), 11.05 (s, 1H), 10.59 (s, 1H), 8.91 (s, 1H), 8.69 - 8.47 (m, 2H), 8.28 - 8.07 (m, 3H), 7.56 (d, J = 7.9 Hz, 2H), 7.45 - 7.26 (m, 1H), 3.55 (s, 3H), 3.47 (s, 6H), 3.13 (s, 2H)

[0235] Example 29 [ka] Synthetic Route [ka]

[0236] Step 1: Synthesis of compound 29-1 Compound 1 (5 g, 9.77 mmol) was dissolved in water (25 mL) and ethanol (25 mL). Sodium hydroxide (781.79 mg, 19.55 mmol) was added. The mixture was stirred at 100° C. for 3 h. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with brine (15 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 1-0 / 1, ethyl acetate / ethanol=10 / 1-4 / 1) to obtain compound 29-2. MS m / z: 444[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.66 - 8.56 (m, 2H), 8.14 (d, J = 1.5 Hz, 1H), 7.47 (ddd, J = 1.4, 7.9, 11.1 Hz, 2H), 7.31 - 7.22 (m, 1H), 6.55 (br s, 2H), 6.12 (s, 1H), 3.54 (s, 3H), 3.47 (s, 6H), 2.94 (s, 2H)

[0237] Step 2: Synthesis of compound 29-3 To a solution of compound 29-2 (500 mg, 3.28 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (157.28 mg, 3.93 mmol) under nitrogen at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (600.97 mg, 3.60 mmol) was added, and the mixture was stirred at 0 °C for 2 h. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 8 / 1) to give compound 29-3. 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.57 (s, 1H), 7.48 - 7.36 (m, 1H), 6.53 (d, J = 3.1 Hz, 1H), 5.58 (s, 2H), 3.55 - 3.50 (m, 2H), 0.98 - 0.93 (m, 2H), 0.00 (s, 9H)

[0238] Step 3: Synthesis of compound 29-4 Compound 29-3 (191.31 mg, 676.38 μmol) was dissolved in toluene (5 mL). 29-1 (200 mg, 450.92 μmol), cesium carbonate (293.84 mg, 901.84 μmol), tris(dibenzylideneacetone)dipalladium (41.29 mg, 45.09 μmol), and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (42.99 mg, 90.18 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was heated to 110° C. and stirred for 5 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 5), followed by preparative high performance liquid chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 47% to 77%, 10 min) to obtain compound 29-4. MS m / z: 690[M+H] +

[0239] Step 4: Synthesis of compound 29 Compound 29-4 (250 mg, 362.36 μmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (15.40 g, 135.06 mmol) was added, and the mixture was stirred at 25° C. for 3 hours. The reaction solution was concentrated. Ethanol (20 mL) and potassium carbonate (500.00 mg, 3.62 mmol) were added, and the mixture was stirred at 60° C. for 3 hours. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0-8 / 1, ethyl acetate / methanol = 100 / 1-30 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 32%-62%, 10 min) to obtain compound 29. MS m / z: 560[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (br s, 1H), 11.05 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.85 (br s, 1H), 7.65 (br d, J = 7.9 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.49 (br d, J = 7.8 Hz, 1H), 7.39 - 7.26 (m, 1H), 6.42 (br s, 1H), 3.57 (s, 3H), 3.51 - 3.45 (m, 6H), 3.05 (s, 2H)

[0240] Example 30 [ka] Synthetic Route [ka]

[0241] Step 1: Synthesis of compound 30 Compound 30-1 (40.45 mg, 360.74 μmol) was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (153.85 mg, 1.19 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (150.88 mg, 396.81 μmol) were added, and the mixture was stirred at 25° C. for 1 h. Compound 29-1 (0.08 g, 180.37 μmol) was then added to the reaction solution, and the mixture was stirred at 25° C. for 16 h. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution. A separation operation was performed. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 33%~63%, 10 min) to obtain compound 30. MS m / z: 538[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.35 (s, 1H), 8.89 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.04 (s, 1H), 7.61 - 7.48 (m, 2H), 7.41 - 7.22 (m, 1H), 3.54 (s, 3H), 3.48 (s, 6H), 3.32 - 3.30 (m, 3H), 2.09 (s, 6H)

[0242] Example 31 [ka] Synthetic Route [ka]

[0243] Step 1: Synthesis of compound 31 Compound 31-1 (50 mg, 390.24 μmol) was dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (151.30 mg, 1.17 mmol, 203.91 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (163.22 mg, 429.27 μmol) were added, and the mixture was stirred at 15° C. for 20 minutes. Compound 29-1 (86.54 mg, 195.12 μmol) was added to the mixture, and the mixture was stirred at 60° C. for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine (5 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 31% to 61%, 8 min) to obtain compound 31. MS m / z: 554[M+H] + 11H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.82 (s, 1H), 8.88 (s, 1H), 8.59 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.53 (dd, J = 1.5, 7.8 Hz, 1H), 7.47 (dd, J = 1.5, 7.9 Hz, 1H), 7.33 - 7.26 (m, 1H), 3.80 (d, J = 8.7 Hz, 2H), 3.63 (d, J = 8.4 Hz, 2H), 3.52 (s, 3H), 3.47 (s, 6H), 3.10 (s, 2H), 2.07 (d, J = 1.8 Hz, 2H), 1.94 (br d, J = 2.1 Hz, 1H)

[0244] Example 32

Chem.

Chem.

[0245] Step 1: Synthesis of compound 32 To a solution of compound 32-1 (94.81 mg, 676.38 μmol) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (262.25 mg, 2.03 mmol, 353.44 μL) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (282.90 mg, 744.02 μmol) were added, and the mixture was stirred at 20 °C for 1 h. Then 29-1 (100 mg, 225.46 μmol) was added. The mixture was stirred at 60 °C under nitrogen for 3 h. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed successively with water (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by preparative high performance liquid chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 10 min) to obtain compound 32. MS m / z: 566[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.41 (s, 1H), 8.84 (s, 1H), 8.59 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 1.3 Hz, 1H), 8.04 (s, 1H), 7.53 (dd, J = 1.4, 7.8 Hz, 1H), 7.49 (dd, J = 1.4, 7.9 Hz, 1H), 7.34 - 7.26 (m, 1H), 3.51 (s, 3H), 3.45 (s, 6H), 3.18 (t, J = 8.3 Hz, 1H), 3.08 (s, 2H), 2.11 - 2.05 (m, 4H), 1.98 (br t, J = 6.8 Hz, 2H), 1.85 - 1.78 (m, 2H), 1.77 - 1.69 (m, 2H)

[0246] Example 33 [ka] Synthetic Route [ka]

[0247] Step 1: Synthesis of compound 33 Compound 33-1 (50.00 mg, 356.69 μmol) was dissolved in acetonitrile (1.5 mL). Methylimidazole (102.50 mg, 1.25 mmol, 99.51 μL) and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (120.09 mg, 428.02 μmol) were added, and the mixture was stirred at 15° C. for 20 minutes. Compound 29-1 (79.10 mg, 178.34 μmol) was added to the mixture, and the mixture was stirred at 15° C. for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 45%-75%, 8 min) to obtain compound 33. MS m / z: 566[M+H] + 11H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.46 (s, 1H), 8.86 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.06 (s, 1H), 7.54 (dd, J = 1.5, 7.8 Hz, 1H), 7.51 (dd, J = 1.4, 7.9 Hz, 1H), 7.37 - 7.27 (m, 1H), 3.53 (s, 3H), 3.47 (s, 6H), 3.10 (s, 2H), 2.97 - 2.89 (m, 1H), 1.62 - 1.54 (m, 1H), 1.53 - 1.34 (m, 3H), 1.33 - 1.11 (m, 6H)

[0248] Example 34

Chem.

Chem.

[0249] Step 1: Synthesis of compound 34 Compound 29-1 (50 mg, 112.73 μmol) was dissolved in dioxane (2 mL). 34-1 (21.20 mg, 112.73 μmol), cesium carbonate (110.19 mg, 338.19 μmol), tris(dibenzylideneacetone)dipalladium (10.32 mg, 11.27 μmol), and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (10.75 mg, 22.55 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 80° C. for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 36% to 66%, 8 min) to obtain compound 34. MS m / z: 551[M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.61 (d, J = 1.3 Hz, 1H), 8.48 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.61 (dd. (s, 6H), 3.05 (s, 2H)

[0250] Example 35 [ka] Synthetic Route [ka]

[0251] Step 1: Synthesis of compound 35 Compound 29-1 (50 mg, 112.73 μmol) was dissolved in dioxane (2 mL). 35-1 (25.43 mg, 135.28 μmol), cesium carbonate (110.19 mg, 338.19 μmol), tris(dibenzylideneacetone)dipalladium (10.32 mg, 11.27 μmol), and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (10.75 mg, 22.55 μmol) were added. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 100° C. for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine (5 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1), followed by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μμm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 27% to 57%, 8 min) to obtain compound 35. MS m / z: 551[M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.44 (s, 1H), 8.90 (s, 1H), 8.61 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.57 (dd, J = 1.2, 7.7 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.36 - 7.28 (m, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.53 (s, 1H), 6.34 (dd, J = 2.3, 7.5 Hz, 1H), 3.54 (s, 3H), 3.47 (s, 6H), 3.31 (br s, 3H), 3.08 (s, 2H)

[0252] Biological evaluation Assay Example 1: Evaluation of in vitro enzyme activity Experimental procedure for Tyk2 JH2 enzyme activity assay 0.5 nM TYK2 protein (His-TVMV-TYK2 JH2(575-869)), 0.2 nM terbium-labeled His antibody, associated K d The fluorescein-labeled kinase tracer and the assay compound were added to a buffer containing 20 mM Hepes pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 2 mM DTT, and 50 μg / mL BSA. The assay system was incubated at room temperature for 90 minutes. The resulting HTRF (homogeneous time-resolved fluorescence) signal, i.e., the ratio of the fluorescence intensity of the fluorescein acceptor (520 nm) and the terbium donor (495 nm) at the emission wavelength, was then measured using an Envision plate reader, and IC50 values ​​were calculated based on this. The results of the in vitro enzyme activity assay of the compounds of the present disclosure are shown in Table 1.

[0253] Table 1: In vitro enzyme activity assay results for compounds of the present disclosure (IC 50 ) [Table 1]

[0254] Assay conclusion: The compounds of the present disclosure have potent inhibitory activity against Tyk2 JH2.

[0255] Assay Example 2: Assessment of in vitro cellular activity Assay for IFNα-stimulated phosphorylated STAT1 Human peripheral blood mononuclear cells (hPBMC) at 1x10 5 The cells were seeded at a cell density of 10000 cells / well and placed in a 37°C incubator for 90 minutes. Different concentrations of compounds were then added to the cells, where the concentration of each compound started at 2 μM and was serially diluted 5-fold to a total of 8 concentrations. The compounds and cells were incubated at 37°C for 30 minutes. IFN-α (1000U / ml) was used to stimulate hPBMCs, and then flow cytometry was used to detect the level of phosphorylated STAT1 in CD4+ T cells to evaluate the inhibitory activity of the compounds against the IFN-α pathway. The results of the in vitro cell activity assay of the compounds of the present disclosure are shown in Table 2.

[0256] Table 2: In vitro cellular activity assay results for compounds of the present disclosure (IC 50 ) [Table 2]

[0257] Assay conclusion: Compounds of the present disclosure have potent cellular activity towards Tyk2-associated IFNα-stimulated phosphorylation STAT1.

[0258] Assay Example 3: Evaluation of Compound Pharmacokinetics in Mice Purpose of the assay: To assay the pharmacokinetics of the compound in Balb / c mice Materials: Male Balb / c mice, fasted Assay Procedure: The pharmacokinetic profile of Compound 1 in rodents following intravenous injection and oral administration was assayed using standard protocols.

[0259] Upon arrival at the facility, Balb / c mice were acclimated / quarantined for at least 3 days. After completion of acclimation / quarantine, a veterinarian or designated staff examined the health status of the Balb / c mice and assessed whether the animals were suitable for assay testing. All Balb / c mice were fasted overnight before dosing and resumed feeding 4 hours after dosing. In the assay, candidate compounds were formulated into homogenous solutions and given to Balb / c mice as a single intravenous injection and oral dose. The intravenous vehicle was a clear solution of 80% polyethylene glycol 400 / 20% water, and the oral vehicle was a homogenous suspension of ethanol / vitamin E polyethylene glycol succinate / polyethylene glycol 300 (5 / 5 / 90). Animals were weighed before dosing and dose volumes were calculated based on body weight. Whole blood samples were collected within 24 hours by jugular vein puncture. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, the blood samples were centrifuged at 3200g for 10 minutes at 4°C. The supernatant plasma was aspirated and quickly placed on dry ice, then stored at -60°C or below for LC-MS / MS analysis. The WinNonlin software package (Version 6.3 or higher) was used to analyze the blood drug concentration-time data using a non-compartmental model. Pharmacokinetic parameters were calculated, including (if data permitted) but not limited to) peak concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T1 / 2), area under the blood concentration-time curve (AUC), mean residence time (MRT), and bioavailability. The assay results for Compound 1 of the present disclosure are shown in Table 3.

[0260] Table 3: Pharmacokinetic assay results [Table 3] Note: Vd: volume of distribution; Cl: clearance rate; T 1 / 2 : Half-life; AUC: Exposure (area under the curve); C max :Maximum concentration;T max : Time to peak concentration; F%: Bioavailability; IV: Intravenous injection; PO: Oral administration

[0261] Assay conclusions: The compounds of the present disclosure exhibit excellent pharmacokinetic properties, low clearance rates, and high oral bioavailability.

Claims

1. A compound of formula (II): 【Chemical 1】 Wherein Ring A is a 6-membered heteroaryl; X １ and X ２ are each independently selected from N and CH; R １ and R ２ are each independently selected from C １－３ alkyl, where C １－３ alkyl may be optionally substituted with one, two, three or four R ａ groups; Alternatively, R １ and R ２ together with the S atoms to which they are attached form a 4- to 6-membered heterocycloalkyl, where the 4- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 R ａ ; R ３ is, independently of one another, selected from hydrogen, deuterium, fluorine, chlorine, bromine, C １－３ alkyl, and C １－３ alkoxy; R ４ is selected from hydrogen, -C(=O)R ４１ , -C(=O)NR ４２ R ４３ , 5- to 10-membered heteroaryl, and phenyl, where the 5- to 10-membered heteroaryl and phenyl may be optionally substituted with 1, 2 or 3 R ｂ ; R ４１ is selected from C １－３ alkyl, C ３－８ cycloalkyl, 5- to 6-membered heteroaryl, phenyl, and 4- to 6-membered heterocycloalkyl, where C １－３ alkyl, C ３－８ cycloalkyl, 5- to 6-membered heteroaryl, phenyl, and 4- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 R ｃ ; R ４２ is selected from hydrogen and C １－３ alkyl; R ４３ is selected from C １－３ alkyl, C ３－８ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, where C １－３ alkyl, C ３－８ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 R ｃ ; R ５ is selected from hydrogen and C １－３ alkyl; R ６ is selected from C １－３ alkyl, C １－３ alkoxy, C ３－６ cycloalkyl, -NH-C １－３ alkyl, and -NH-C ３－６ cycloalkyl, where C １－３ alkyl, C １－３ alkoxy, C ３－６ cycloalkyl, -NH-C １－３ alkyl, and -NH-C ３－６ cycloalkyl may be optionally substituted with 1, 2, 3 or 4 R ｄ ; R ａ 、 R ｂ 、 R ｃ 、 and R ｄ are, independently, selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH ２ 、 C １－３ alkyl, and C １－３ alkoxy; n is selected from 0, 1, 2 and 3 Or a pharmaceutically acceptable salt thereof.

2. Ring A is selected from [Chemical Formula 2] ; or alternatively, ring A is selected from [Chemical Formula 3] ; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ and R ２ are each independently selected from methyl, ethyl, and propyl, where methyl, ethyl, and propyl may each be optionally substituted with 1, 2, 3, or 4 R ａ groups; Alternatively, R １ and R ２ are each independently selected from methyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ and R ２ together with the S atoms to which they are attached form a 4- to 6-membered heterocycloalkyl, where the 4- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ａ groups, and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. The 4- to 6-membered heterocycloalkyl is selected from 【Chemical 4】 ; where 【Chemical Formula 5】 is 1, 2, 3 or 4 Rs ａ may be appropriately replaced; alternatively, the 4- to 6-membered heterocycloalkyl is selected from 【Chemical Formula 6】 ; The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. R ａ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from hydrogen.

7. The following definitions: i) 【Chemical 7】 The structure of is selected from 【Chemical 8】 ; ii) X １ is selected from N and CH; iii) R ３ is each independently selected from hydrogen and fluorine; iv) 【Chemical Formula 9】 The structure of is selected from 【Chemical 10】 ; v) R ｂ is selected from hydrogen, fluorine, CN, and methyl; vi) R ４ is 【Chemical 11】 Selected from; vii) R ５ is selected from hydrogen, methyl, and ethyl The compound according to claim 1 or a pharmaceutically acceptable salt thereof having any one of.

8. R ４ is hydrogen, -C(O)R ４１ -C(O)NR ４２ R ４３ , 【Chemical Formula 12】 Selected from, where 【Chemical 13】 is 1, 2 or 3 Rs ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be appropriately substituted with

9. The following definitions: i) R ４１ is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, 【Chemical Formula 14】 Selected from, where methyl, ethyl, propyl, cyclopropyl, cyclobutyl, 【Chemical Formula 15】 may be appropriately replaced by 1, 2, 3, or 4 Rs; ｃ ​ ii) R ４２ is selected from hydrogen; iii) R ４３ is selected from methyl, ethyl, propyl, cyclopropyl, and cyclobutyl, where methyl, ethyl, propyl, cyclopropyl, and cyclobutyl may be optionally substituted with one, two, three, or four R ｃ groups The compound according to claim 8 or a pharmaceutically acceptable salt thereof having any one of.

10. R ｃ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R is selected from H.

11. R ６ is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH ３ , -NHCH ２ CH ３ , -NH-cyclopropyl, and -NH-cyclobutyl, where methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH ３ , -NHCH ２ CH ３ , -NH-cyclopropyl, and -NH-cyclobutyl may be optionally substituted with 1, 2, 3, or 4 R ｄ ; Alternatively, R ６ is selected from methyl, ethyl, -NHCH ３ , and cyclopropyl, where methyl, ethyl, -NHCH ３ , and cyclopropyl may be optionally substituted with 1, 2, 3 or 4 R ｄ ; Alternatively, R ６ is selected from -CH ２ CD ３ , -CH ２ CH ３ , -NHCD ３ , -CH ２ OCH ３ , -CH ３ , and cyclopropyl The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ｄ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, deuterium, and methoxy.

13. Formula (II-1) or (II-2): 【Chemical 16】 represented by, wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ , X １ , X ２ , and n are as defined in claim 1; alternatively, formula (II-1-1) or (II-1-2): 【Chemical 17】 represented by, wherein R １ , R ２ , R ３ , R ４ , R ５ , X １ , and n are as defined in claim 1; R ６ is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH ３ , -NHCH ２ CH ３ , -NH-cyclopropyl, and -NH-cyclobutyl, where methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH ３ , -NHCH ２ CH ３ , -NH-cyclopropyl, and -NH-cyclobutyl may be optionally substituted with 1, 2, 3 or 4 R ｄ s, where R ｄ is selected from hydrogen, deuterium, and methoxy; Or, R ６ is selected from methyl, ethyl, -NHCH ３ , and cyclopropyl, where methyl, ethyl, -NHCH ３ , and cyclopropyl may be optionally substituted with 1, 2, 3 or 4 R ｄ , where R ｄ is selected from hydrogen, deuterium, and methoxy; alternatively, formula (II-1-1-1) or (II-1-1-2): 【Chemical 18】 represented by, wherein R １ and R ２ and R ３ and R ４ and R ５ and X １ and n are as defined in claim 1, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. One of the following compounds, or a pharmaceutically acceptable salt thereof. 【Chemical 19】 【Chemical 20】 【Chemical 21】

15. A pharmaceutical composition for treating a disease related to Tyk2 JH2, comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

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