Sulfilimine compounds and their use

Abstract

The present application relates to sulfϊnamide compounds and uses thereof. Specifically disclosed are compounds of the following formula or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to:

[0002] CN202110694497.1, filing date: June 22, 2021;

[0003] CN202210002094.0, filing date: January 4, 2022;

[0004] CN202210665753.9, filing date: June 13, 2022. TECHNICAL FIELD

[0005] The present application relates to a class of sulfϊnϊmides and their applications, in particular to a compound represented by formula (II) or a pharmaceutically acceptable salt thereof. BACKGROUND

[0006] The Janus kinase (JAKs) family is a class of intracellular non-receptor tyrosine kinases, which is mainly responsible for regulating the signal transduction pathway mediated by cytokine receptors. These signal 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 in mammals includes four different subtypes: JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2).

[0007] Like other kinases of the same family, TYK2 is structurally composed of 7 homologous domains (JAK homology domain, JH) consisting of 4 conserved domains, including the C-terminal pseudo-kinase domain (JH2) and the kinase domain (JH1), as well as the N-terminal FERM (Four.1 protein, Ezrin, Radixin, Moesin) region and the SH2 domain (srchomology 2 domain).

[0008] TYK2 forms a dimer with JAK2 in cells to mediate the signal transduction of IL-23 and IL-12, and can also form a dimer with JAK1 to mediate the response of type I interferons, which are related to the pathogenesis of various inflammatory and 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, and the purpose of treating related diseases can be achieved.

[0009] 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 II clinical trials. While allosteric inhibitors are represented by BMS-986165, which has been used in clinical trials for treating plaque psoriasis and has advanced to phase III, and has outstanding clinical effects and good safety, and is also used in clinical research for various autoimmune diseases including Crohn's disease, psoriatic arthritis and systemic lupus erythematosus. In addition to BMS-986165, Nimbus also has multiple TYK2 allosteric inhibitors in preclinical screening, and recently reported that Hisik's acquisition of Fronthera's TYK2 allosteric inhibitor FTP-637 is preparing to enter phase I clinical trials. SUMMARY

[0010] The present application provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] wherein,

[0013] Ring A is a 6-membered heteroaryl;

[0014] X1and X2are each independently selected from N and CH;

[0015] R1and R2are independently selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, 3, or 4 R a substituents;

[0016] or R1, R2and the S atom to which they are attached together form a 4-6 membered heterocycloalkyl, said 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 R a substituents;

[0017] R3is each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl, and C 1-3 alkoxy;

[0018] R4is selected from hydrogen, -C(=O)R 41 , -C(=O)NR 42 R 43 , 5-10 membered heteroaryl, and phenyl, said 5-10 membered heteroaryl and phenyl is optionally substituted with 1, 2, or 3 R b substituents;

[0019] R 41 is selected from C 1-3 alkyl, C 3-8cycloalkyl, 5-6 membered heteroaryl, phenyl and 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl, phenyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3 and 4 R c substituents;

[0020] R 42 is selected from hydrogen and C 1-3 alkyl;

[0021] R 43 is selected from C 1-3 alkyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3 and 4 R c substituents;

[0022] R5is selected from hydrogen and C 1-3 alkyl;

[0023] R6is 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, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl are optionally substituted with 1, 2, 3 or 4 R d substituents;

[0024] R a , R b , R c and R d are independently selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH2, C 1-3 alkyl and C 1-3 alkoxy;

[0025] n is selected from 0, 1, 2 and 3.

[0026] The present application provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof,

[0027]

[0028] wherein,

[0029] Ring A is 6 membered heteroaryl;

[0030] X1and X2are independently selected from N and CH;

[0031] R1and R2are independently selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, 3 or 4 R a substituents;

[0032] or R1, R2and the S atom to which they are attached together form a 4-6 membered heterocyclyl group, said 4-6 membered heterocyclyl group is optionally substituted with 1, 2, 3 or 4 R a substituents;

[0033] R3is each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl and C 1-3 alkoxy;

[0034] R4is selected from hydrogen, -C(=O)R 41 and 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R b substituents;

[0035] R 41 is selected from C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl and C 3-6 cycloalkyl is optionally substituted with 1, 2, 3 and 4 R c substituents;

[0036] R5is selected from hydrogen and C 1-3 alkyl;

[0037] R6is 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, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl is optionally substituted with 1, 2, 3 or 4 R d substituents;

[0038] R a , R b , R c and R d are independently selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH2, C 1-3 alkyl and C 1-3 alkoxy;

[0039] n is 0, 1, 2, or 3.

[0040] In some embodiments of the application, ring A is selected from The other variables are as defined in the application.

[0041] In some embodiments of the application, ring A is selected from The other variables are as defined in the application.

[0042] In some embodiments of the application, R1and R2are independently selected from the group consisting of methyl, ethyl, and propyl, said methyl, ethyl, and propyl being optionally substituted with 1, 2, 3, or 4 R a The other variables are as defined in the application.

[0043] In some embodiments of the application, R1and R2are independently selected from the group consisting of methyl and ethyl, the other variables being as defined in the application.

[0044] In some embodiments of the application, R1and R2are independently selected from the group consisting of methyl, the other variables being as defined in the application.

[0045] In some embodiments of the application, R1, R2, and the S atom to which they are attached together form a 4-6 membered heterocyclyl group, said 4-6 membered heterocyclyl group being optionally substituted with 1, 2, 3, or 4 R a The other variables are as defined in the application.

[0046] In some embodiments of the application, R1, R2, and the S atom to which they are attached together form The is optionally substituted with 1, 2, 3, or 4 R a The other variables are as defined in the application.

[0047] In some embodiments of the application, R1, R2, and the S atom to which they are attached together form The other variables are as defined in the application.

[0048] In some embodiments of the application, R a is selected from the group consisting of hydrogen, the other variables being as defined in the application.

[0049] In some embodiments of the application, the structural unit is selected from the group consisting of The other variables are as defined in the application.

[0050] In some embodiments of the application, the structural unit is selected from the group consisting of The other variables are as defined in the application.

[0051] In some embodiments of the application each X1is selected from N, and the other variables are as defined in the application.

[0052] In some embodiments of the application each X1is selected from CH, and the other variables are as defined in the application.

[0053] In some embodiments of the application each R3is independently selected from hydrogen and fluorine, and the other variables are as defined in the application.

[0054] In some embodiments of the application each structural unit is selected from and the other variables are as defined in the application.

[0055] In some embodiments of the application each is selected from and the other variables are as defined in the application.

[0056] In some embodiments of the application each is selected from and the other variables are as defined in the application.

[0057] In some embodiments of the application each is selected from and the other variables are as defined in the application.

[0058] In some embodiments of the application each R4is selected from hydrogen, -C(O)R 41 , 42 R 43 , said is optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the application.

[0059] In some embodiments of the application each R4is selected from hydrogen, -C(O)R 41 , said is optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the application.

[0060] In some embodiments of the application each R b is selected from hydrogen, deuterium, fluorine, CN, NH2, methyl, ethyl, methoxy, and ethoxy, and the other variables are as defined in the application.

[0061] In some embodiments of the application each Rb selected from hydrogen, fluorine, CN and methyl, and the other variables are as defined in the present application.

[0062] In some embodiments of the present application, the above R b is selected from hydrogen, and the other variables are as defined in the present application.

[0063] In some embodiments of the present application, the above R b is selected from fluorine, and the other variables are as defined in the present application.

[0064] In some embodiments of the present application, the above R b is selected from CN, and the other variables are as defined in the present application.

[0065] In some embodiments of the present application, the above R b is selected from methyl, and the other variables are as defined in the present application.

[0066] In some embodiments of the present application, the above R b is selected from methoxy, and the other variables are as defined in the present application.

[0067] In some embodiments of the present application, the above R 41 is selected from methyl, ethyl, propyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, which methyl, ethyl, propyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 and 4 R c groups, and the other variables are as defined in the present application.

[0068] In some embodiments of the present application, the above R 41 is selected from methyl, ethyl, propyl and C 3-4 cycloalkyl, which methyl, ethyl, propyl and C 3-4 cycloalkyl is optionally substituted with 1, 2, 3 and 4 R c groups, and the other variables are as defined in the present application.

[0069] In some embodiments of the present application, the above C 3-4 cycloalkyl is selected from cyclopropyl and cyclobutyl, which cyclopropyl and cyclobutyl is optionally substituted with 1, 2, 3 and 4 R c groups, and the other variables are as defined in the present application.

[0070] In some embodiments of the present application, the above R 41 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, which methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted with 1, 2, 3, and 4 R c substituted, and other variables are as defined herein.

[0071] In some embodiments of the application, the above R 41 is selected from cyclopropyl and cyclobutyl, and other variables are as defined herein.

[0072] In some embodiments of the application, the above R c is hydrogen, and other variables are as defined herein.

[0073] In some embodiments of the application, the above R 41 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and other variables are as defined herein.

[0074] In some embodiments of the application, the above R 42 is selected from hydrogen, and other variables are as defined herein.

[0075] In some embodiments of the application, the above R 43 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted with 1, 2, 3, and 4 R c substituted, and other variables are as defined herein.

[0076] In some embodiments of the application, the above R 43 is selected from cyclopropyl, and other variables are as defined herein.

[0077] In some embodiments of the application, the above R4is selected from

[0078] and other variables are as defined herein.

[0079] In some embodiments of the application, the above R4is selected from and other variables are as defined herein.

[0080] In some embodiments of the application, the above R5is selected from hydrogen, methyl, and ethyl, and other variables are as defined herein.

[0081] In some embodiments of the application, the above R5is hydrogen, and other variables are as defined herein.

[0082] In some embodiments of the application, the above R5is methyl, and other variables are as defined herein.

[0083] In some embodiments of the application, the above R6is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH3, -NHCH2CH3, -NH-cyclopropyl, and -NH-cyclobutyl, optionally substituted with 1, 2, 3, or 4 R d substituents, and the other variables are as defined in the application.

[0084] In some embodiments of the application, the above R6is selected from methyl, ethyl, -NHCH3, and cyclopropyl, optionally substituted with 1, 2, 3, or 4 R d substituents, and the other variables are as defined in the application.

[0085] In some embodiments of the application, the above R6is selected from methyl, ethyl, and -NHCH3, optionally substituted with 1, 2, 3, or 4 R d substituents, and the other variables are as defined in the application.

[0086] In some embodiments of the application, the above R d is selected from hydrogen, and the other variables are as defined in the application.

[0087] In some embodiments of the application, the above R d is selected from deuterium, and the other variables are as defined in the application.

[0088] In some embodiments of the application, the above R d is selected from methoxy, and the other variables are as defined in the application.

[0089] In some embodiments of the application, the above R6is selected from -CH2CD3, -CH2CH3, -NHCD3, -CH2OCH3, -CH3, and cyclopropyl, and the other variables are as defined in the application.

[0090] In some embodiments of the application, the above R6is selected from -CH2CD3, -CH2CH3, -NHCD3, and -CH2OCH3, and the other variables are as defined in the application.

[0091] In some embodiments of the application, the compound is of formula (II-1) or (II-2):

[0092]

[0093] wherein R1, R2, R3, R4, R5, R6, X1, X2, and n are as defined in the application.

[0094] In some embodiments of the present application, the compound is represented by formula (II-1-1) or (II-1-2):

[0095]

[0096] wherein R1, R2, R3, R4, R5, R6, X1 and n are as defined in the present application.

[0097] In some embodiments of the present application, the compound is represented by formula (II-1-1-1) or (II-1-1-2):

[0098]

[0099] wherein R1, R2, R3, R4, R5, X1 and n are as defined in the present application.

[0100] The present application also provides some embodiments of the above-mentioned compounds or pharmaceutically acceptable salts thereof.

[0101] In some embodiments of the present application, the compound is selected from,

[0102]

[0103]

[0104]

[0105] The present application also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating a Tyk2 JH2 related disease.

[0106] The present application also provides a method for treating a Tyk2 JH2 related disease in a subject in need thereof, comprising providing an effective amount of the compound defined in any of the above-mentioned embodiments or a pharmaceutically acceptable salt thereof to the subject.

[0107] Technical effects

[0108] The compound of the present application has strong Tyk2 pseudokinase domain (Tyk2 JH2) inhibitory activity.

[0109] Definitions and explanations

[0110] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being indefinite or unclear unless specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0111] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0112] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is within the scope of sound medical judgment, of a compound of the present application having particular substituents discovered in the present application, with a relatively nontoxic acid or base. Alkali addition salts are obtained by contacting a compound of the present application having a relatively acidic functional group with a sufficient amount of the base in a pure solution or in a suitable inert solvent. Acid addition salts are obtained by contacting a compound of the present application having a relatively basic functional group with a sufficient amount of the acid in a pure solution or in a suitable inert solvent. Certain specific compounds of the present application contain both basic and acidic functionalities that allow the compounds to be converted into either alkali or acid addition salts.

[0113] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts are prepared either by contacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid, in waters or in an organic solvent, or in a mixture of the two.

[0114] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures thereof, such as those that are substantially free of any of the impurities. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0115] The term "enantiomeric" or "optical isomer" means a stereoisomer that is a mirror image of the other and is not superimposable.

[0116] The term "cis- or trans-isomer" or "geometric isomer" means a stereoisomer that results from the restricted rotation about a single bond or ring atom single bond.

[0117] The term "diastereomeric" means a stereoisomer that has two or more chiral centers and is not a mirror image of the other.

[0118] Unless otherwise stated, "(+)" means dextrorotary, "(-)" means levorotary, and "(±)" means racemic.

[0119] Unless otherwise indicated, the wedge-shaped solid line bond and the wedge-shaped dashed line bond indicate the absolute configuration of a stereocenter, the straight solid line bond and the straight dashed line bond indicate the relative configuration of a stereocenter, and the wavy line indicates the wedge-shaped solid line bond or the wedge-shaped dashed line bond or the wavy line indicates the straight solid line bond and the straight dashed line bond

[0120] Unless otherwise indicated, the term "tautomer" or "tautomer forms" refers to different functional group isomers that are in dynamic equilibrium at room temperature and rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur by migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0121] Unless otherwise indicated, the term "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" means that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0122] Unless otherwise indicated, the term "enantiomeric excess" or "isomeric excess" means the difference between the relative percentages of two isomers or two enantiomers. For example, where one isomer or enantiomer is present in 90% and the other isomer or enantiomer is present in 10%, the enantiomeric or isomeric excess (ee value) is 80%.

[0123] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to yield the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the diastereomeric salt separated by conventional means, and the desired enantiomer recovered by treating with base or acid, as appropriate.

[0124] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, increased efficacy, increased biological half-life, etc. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0125] The term "D" or "D" means another stable isotopic variation of hydrogen, "deuterium", also known as heavy hydrogen. 2 H" means another stable isotopic variation of hydrogen, "deuterium", also known as heavy hydrogen.

[0126] The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the described event or circumstance occurs and instances where it does not.

[0127] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent, which can include variations of hydrogen, provided that the valency of the designated atom is not exceeded and that the substitution results in a stable compound. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0128] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents, if present, are any and all chemically possible.

[0129] When any variable (e.g., R) occurs more than one time in a compound, each definition can be independent. Thus, for example, if a group is substituted with 0-2 R, said group can optionally be substituted up to two times, and each R can be independently selected at each occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0130] When the number of linking groups is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0131] When one of the variables is selected from a single bond, it indicates that the two groups to which it is attached are directly connected, such as when L represents a single bond in A-L-Z, the structure actually is A-Z.

[0132] When a substituent is absent, it indicates that the substituent is absent, such as when X is absent in A-X, the structure actually is A. When a recited substituent does not specify through which of the available atoms it is bonded to the rest of the molecule, it can be bonded through any of its available atoms, for example, a pyridyl group as a substituent can be bonded to the rest of the molecule through any of the carbon atoms of the pyridyl ring.

[0133] Unless otherwise specified, "6-membered heteroaromatic ring" and "6-membered heteroaryl" are used interchangeably, and the term "6-membered heteroaryl" means a monocyclic ring group consisting of 6 ring atoms having a conjugated pi-electron system, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, and the remainder of which are carbon atoms. The nitrogen atom(s) are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 6-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or carbon atom. Examples of the 6-membered heteroaryl include, but are not limited to, pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0134] Unless otherwise specified, the term "C 1-3 "alkyl" is used to represent a straight or branched chain, saturated carbon hydride group consisting of one to three carbon atoms. The C 1-3 alkyl group includes C 1-2 alkyl, C 2-3 alkyl, etc.; it can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0135] Unless otherwise specified, the term "C 1-3"Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0136] Unless otherwise specified, the term "4-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "4-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 4-6 membered heterocyclic alkyl includes 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 4-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0137] Unless otherwise specified, the terms "5-10-membered heteroaryl" and "5-10-membered heteroaryl" are used interchangeably in this invention. The term "5-10-membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 5-10 membered heteroaryl group can be attached to the rest of the molecule by a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups, and the like. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 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 (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 (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and the like), furanyl (including 2-furanyl and 3-furanyl, and the like), thiophenyl (including 2-thiophenyl and 3-thiophenyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like), benzothiazolyl (including 5-benzothiazolyl, and the like), purinyl, benzimidazolyl (including 2-benzimidazolyl, and the like), benzoxazolyl, indolyl (including 5-indolyl, and the like), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, and the like), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, and the like), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, and the like), substituted or unsubstituted pyridonyl (such as ).

[0138] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably, and the term "5-6 membered heteroaryl" means a monocyclic ring group consisting of 5 to 6 ring atoms having a conjugated pi electron system, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, and the rest of which are carbon atoms. Of the nitrogen atoms, one is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule by a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryls. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0139] Unless otherwise specified, "C 3-8 "Cycloalkyl" denotes a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro, fused, and bridged rings. The C 3-8 Cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl, etc.; which can be monovalent, divalent, or multivalent. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0140] Unless otherwise specified, "C 3-6 "Cycloalkyl" denotes a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, the C 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; which can be monovalent, divalent, or multivalent. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0141] Unless otherwise specified, "C 3-4 "Cycloalkyl" denotes a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic ring system, the C 3-4Cycloalkyl groups include C3and C4cycloalkyl groups and the like; they can be monovalent, divalent, or multivalent. C 3-4 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl. The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include triflate; chloro, bromo, iodo; sulfonate groups, such as mesylate, tosylate, brosylate, p-tosylate, and the like; acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0142] The term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "thiol-protecting group." The term "amino-protecting group" refers to a protecting group suitable for blocking the amino nitrogen against side reactions. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for blocking the hydroxyl group against side reactions. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0143] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments with other chemical synthetic methods, and equivalents thereof as known to those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0144] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art, and if the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), a single crystal is grown and diffracted intensity data is collected using a Bruker D8 venture diffractometer with Cu Kα radiation, scanning mode: After the relevant data is collected, the crystal structure is further resolved using the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0145] Compounds are named according to the nomenclature conventions of the art or using software nomenclature, commercially available compounds use the vendor catalog name. DETAILED DESCRIPTION

[0146] The present application is described in detail below with reference to Examples, but is not meant to be limited by any of the details of these Examples. The present application has been described in detail by specific embodiments, and it also discloses specific modes for its implementation, to those skilled in the art, it will be obvious that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0147] Example 1

[0148]

[0149] Synthetic route:

[0150]

[0151] Step 1: synthesis of compound 1-2

[0152] To a solution of compound 1-1 (13 g, 67.71 mmol) in dichloromethane (200 mL) was added 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), stirred at 20 °C for 0.5 h, and then N, O-dimethylhydroxylamine hydrochloride (7.93 g, 81.25 mmol) was added. Stirred 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 ~ 3 / 1) to give compound 1-2.

[0153] MS m / z: 235 [M+H] + .

[0154] Step 2: synthesis of compound 1-3

[0155] To a solution of compound 1-2 (13 g, 55.30 mmol) in tetrahydrofuran (130 mL) was added methyl magnesium bromide (3 M, ethyl ether solution, 36.87 mL) at 0 °C under nitrogen protection, and 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 then extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 15 / 1) to give compound 1-3.

[0156] 1 H NMR (400 MHz, CDC13) δ 8.59 (s, 1H), 7.44 (s, 1H), 2.66 (s, 3H).

[0157] Step 3: Synthesis of compound 1-4

[0158] To a solution of 1-3 (8 g, 42.10 mmol) in dimethyl carbonate (42.80 g, 475.15 mmol) in tetrahydrofuran (40 mL) was added sodium hydride (5.05 g, 126.30 mmol) portionwise at 0 °C, and stirred at 20 °C for 16 h. The reaction was diluted with ethyl acetate (100 mL), quenched with hydrochloric acid aqueous solution (50 mL 2M), washed with saturated brine (50 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 3 / 1) to give compound 1-4.

[0159] MS m / z: 244 [M+H] + .

[0160] Step 4: Synthesis of compound 1-5

[0161] 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 methyl iodide (4.97 g, 34.28 mmol) at 0 °C, and stirred at 20 °C for 6 h. The reaction was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 4 / 1) to give compound 1-5.

[0162] MS m / z: 261 [M+H] + .

[0163] Step 5: Synthesis of compound 1-6

[0164] To a solution of 1-5 (5.8 g, 18.02 mmol, 81%) in acetic acid (30 mL) was added 35% concentrated hydrochloric acid (61.20 g, 587.48 mmol), and stirred at 130 °C for 16 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 ~ 1 / 1) to give compound 1-6.

[0165] MS m / z: 189 [M+H] + .

[0166] Step 6: Synthesis of compound 1-7

[0167] To a solution of 1-6 (2.5 g, 12.33 mmol) in acetonitrile (80 mL) was added phosphorus oxychloride (7.56 g, 49.30 mmol) and stirred at 85 °C for 1 h. The reaction was concentrated and diluted with ethyl acetate (100 mL), the organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered and 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.

[0168] MS m / z: 207 [M+H] + .

[0169] Step 7: Synthesis of compound 1-8

[0170] 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 for three times and stirred at 80 °C for 2 h. The reaction was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 10 / 1) to give compound 1-8.

[0171] MS m / z: 256 [M+H] + .

[0172] Step 8: Synthesis of compound 1-10

[0173] Compound 1-9 (2 g, 10.34 mmol) was dissolved in dioxane (40 mL), dimethyl sulfoximine (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, and after nitrogen replacement for three times, the temperature was raised to 110 °C, and stirred for 4 hours under nitrogen protection. 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 = 10 / 1 ~ 1 / 4). After concentration under reduced pressure, it was stirred with petroleum ether / ethyl acetate = 5 / 1 (12 mL) at 20 °C for 1 hour, the filter cake was collected and dried to obtain compound 1-10.

[0174] MS m / z: 206 [M+H] + .

[0175] Step 9: synthesis of compound 1-12

[0176] 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), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (142.31 mg, 194.49 μmol) were added, and after nitrogen replacement for three times, the temperature was raised to 100 °C, and stirred for 2 hours under nitrogen protection. 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 ~ 0 / 1). After concentration under reduced pressure, it was stirred with petroleum ether / ethyl acetate = 1 / 1 (4 mL) at 20 °C for 1 hour, the filter cake was collected and dried to obtain compound 1-12.

[0177] MS m / z: 293 [M+H] +

[0178] Step 10: synthesis of compound 1

[0179] 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-naphthylidene (34.09 mg, 54.75 µmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (25.07 mg, 27.37 µmol) in dioxane (4 mL) was replaced with nitrogen for three times and stirred at 110 °C for 4 h. The reaction mixture was concentrated to get the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 ~ 1 / 3) and then by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 34% - 64%, 8 min) to afford compound 1.

[0180] MS m / z: 512 [M+H] + ;

[0181] 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 = 6.1 Hz, 4H).

[0182] Example 2

[0183]

[0184] Synthesis route:

[0185]

[0186] Step 1: Synthesis of compound 2-2

[0187] Compound 2-1 (1 g, 6.41 mmol) was dissolved in phosphorus oxychloride (5 mL) at 20 °C, triethylamine (648.25 mg, 6.41 mmol, 891.68 μL) was added, and 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 again under reduced pressure to obtain the crude product 2-2, which was directly used in the next reaction.

[0188] Step 2: Synthesis of compound 2-3

[0189] Compound 2-2 (1.35 g, 6.38 mmol) was dissolved in tetrahydrofuran (15 mL) at 20 °C, deuterated methylamine hydrochloride (225.19 mg, 3.19 mmol) and N,N-diisopropylethylamine (2.48 g, 19.15 mmol, 3.34 mL) were added, and the mixture was stirred at 20 °C for 16 h. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 2), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 5 / 1) to obtain the crude product, which was separated by preparative HPLC (Waters Xbridge CI 8 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 3% - 33%, 11 min) to obtain compound 2-3.

[0190] MS m / z: 209 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 8.90 (br s, 1H), 8.48 (s, 1H).

[0191] Step 3: Synthesis of compound 2-4

[0192] Compound 2-3 (55.06 mg, 263.38 μmol) and compound 1-12 (70 mg, 239.43 μmol) were dissolved in tetrahydrofuran (3 mL) at 0 °C under nitrogen protection, lithium hexamethyldisilazide (1M, 718.30 μL) was added dropwise, and the mixture was stirred at 20 °C for 1 h. The reaction solution was quenched by adding an aqueous solution of ammonium chloride (10 mL) at 0 °C, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 2), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 5) to obtain compound 2-4.

[0193] MS m / z: 465 [M+H] +

[0194] Step 4: Synthesis of compound 2

[0195] Compound 2-4 (75 mg, 161.31 μmol) was dissolved in dioxane (2 mL), cyclopropylcarboxamide (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) (14.62 mg, 16.13 μmol) were added, and after nitrogen was replaced for three times, the temperature was raised to 110 °C, and stirred for 3 hours under nitrogen protection. 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 ~ 1 / 3.5) to obtain compound 2.

[0196] MS m / z: 514 [M+H] + ;

[0197] 1 H NMR (400 MHz, CDC13) 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).

[0198] Example 3

[0199]

[0200] Synthesis route:

[0201]

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

[0203] Compound 3-1 (2 g, 10.42 mmol) was dissolved in dichloromethane (10 mL) at 0 °C, oxalyl chloride (1.98 g, 15.63 mmol, 1.37 mL) and N,N-dimethylformamide (19.00 mg, 259.94 umol, 20 uL) were added, the mixture was stirred at 20 °C for 1 h. TLC showed that the starting material was consumed. The reaction was directly concentrated under reduced pressure to give the crude product 3-2, which was directly used in the next reaction.

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

[0205] Compound 3-2 (804.43 mg, 11.40 mmol) was dissolved in dichloromethane (20 mL) at 0 °C, 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 h. The reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was slurry with petroleum ether / ethyl acetate = 3 / 1 (10 mL) at 15 °C for 1 h, filtered and dried to give compound 3-3.

[0206] MS m / z: 208 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d 8.59 (br s, 1H), 8.48 (s, 1H), 7.90 (s, 1H).

[0207] Step 3: synthesis of compound 3-4

[0208] Compound 3-3 (55.00 mg, 264.35 umol), compound 1-12 (70.26 mg, 240.32 umol) were dissolved in tetrahydrofuran (3 mL), lithium hexamethyldisilazide (1 M, 720.95 uL) was added dropwise to the mixture under nitrogen protection at 0 °C, the mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) under ice water bath condition, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 2), finally the organic phase was dried over anhydrous sodium sulfate, filtered and 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.

[0209] MS m / z: 464 [M+H] + .

[0210] Step 3: Synthesis of compound 3

[0211] Compound 3-4 (80 mg, 172.43 μmol) was dissolved in dioxane (2 mL), and cyclopropylcarboxamide (44.02 mg, 517.29 μmol), cesium carbonate (168.54 mg, 517.29 μmol) and methane sulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15.63 mg, 17.24 μmol) were added. After nitrogen replacement for three times, the reaction was heated to 110 °C and stirred for 4 h under nitrogen protection. The reaction was diluted with dichloromethane (50 mL), extracted with water (5 mL x 3), washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography (silica gel, ethyl acetate / ethanol = 10 / 1) to give compound 3.

[0212] MS m / z: 513 [M+H] + ;

[0213] 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).

[0214] Example 4

[0215]

[0216] Synthesis route:

[0217]

[0218] Step 1: Synthesis of compound 4-1

[0219] To a solution of compound 1-2 (1 g, 4.25 mmol) in tetrahydrofuran (20 mL) was added ethyl magnesium bromide (3 M in ether, 4.25 mL) dropwise at 0 °C under nitrogen protection, and stirred at 20 °C for 3 h. The reaction was quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1-15 / 1) to give compound 4-1.

[0220] MS m / z: 204 [M+H] +

[0221] Step 2: Synthesis of compound 4-2

[0222] 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 replaced with nitrogen for three times, and stirred at 80 °C for 2 h. The reaction was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1-5 / 1) to give compound 4-2.

[0223] MS m / z: 253 [M+H] + .

[0224] Step 3: Synthesis of compound 4

[0225] A solution of compound 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 replaced with nitrogen for three times, and stirred at 110 °C for 3 h. The reaction was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1-1 / 3), and then by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 34%-64%, 9 min) to give compound 4.

[0226] MS m / z: 509 [M+H] +

[0227] 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).

[0228] Example 5

[0229]

[0230] Synthesis route:

[0231]

[0232] Step 1: synthesis of compound 5-2

[0233] To a solution of compound 5-1 (400 mg, 3.84 mmol) in methanol (20 mL), diacetoxyiodobenzene (3.09 g, 9.60 mmol) and ammonium carbamate (599.56 mg, 7.68 mmol) were added, and the reaction was stirred at 25 °C for 2 hours. The reaction was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1 ~ 1 / 2) to give compound 5-2.

[0234] MS m / z: 136 [M+H] + .

[0235] Step 2: synthesis of compound 5-3

[0236] A mixture 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 for three times and stirred at 110 oC for 3 h. The reaction mixture was concentrated and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 4 / 1) to give compound 5-3.

[0237] MS m / z: 248 [M+H] + .

[0238] Step 3: Synthesis of compound 5-4

[0239] A mixture 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 for three times and stirred at 100 oC for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 ~ 1 / 3) to give compound 5-4.

[0240] MS m / z: 335 [M+H] + .

[0241] Step 4: Synthesis of compound 5

[0242] A mixture of compound 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-naphthyl (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 for three times and stirred at 110 oC for 3 h. The reaction mixture was concentrated to give the crude product which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 ~ 1 / 3) and then by preparative HPLC (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate) – acetonitrile]; acetonitrile%: 37% – 67%, 9 min.) to give compound 5.

[0243] MS m / z: 554 [M+H] + ;

[0244] 1 H 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).

[0245] Example 6

[0246]

[0247] Synthesis route:

[0248]

[0249] Step 1: synthesis of compound 6-2

[0250] Compound 6-1 (500 mg, 6.74 mmol) was dissolved in anhydrous methanol (10 mL), then diacetyl iodobenzene (5.43 g, 16.86 mmol) and ammonium carbamate (1.05 g, 13.49 mmol) were added, and the mixture was stirred at 25 °C for three hours. 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 ~ 1 / 2) to obtain compound 6-2.

[0251] MS m / z: 106 [M+H] + .

[0252] Step 2: synthesis of compound 6-3

[0253] Compound 1-9 (600.00 mg, 3.10 mmol) and 6-2 (600 mg, 5.71 mmol) were dissolved in anhydrous dioxane (10 mL), then 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) were added, the mixture was stirred at 110 °C for four hours, the reaction mixture was concentrated under reduced pressure, the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 4 / 1) to obtain compound 6-3.

[0254] MS m / z: 218 [M+H] + .

[0255] Step 3: synthesis of compound 6-4

[0256] Compound 1-11 (50.35 mg, 202.14 μmol) and 6-3 (40 mg, 183.76 μmol) were dissolved in dioxane (2 mL), then a solution of potassium phosphate (78.01 mg, 367.52 μmol) dissolved in water (0.5 mL) was added, 1,1-bis(diphenylphosphino)ferrocene palladium chloride (13.45 mg, 18.38 μmol) was added, the system was replaced with nitrogen, and then stirred at 100 °C for four hours. After the reaction solution was concentrated, the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 ~ 1 / 3) to obtain compound 6-4.

[0257] MS m / z: 305 [M+H] + .

[0258] Step 4: synthesis of compound 6

[0259] 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), 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-naphthyl (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 the crude product, which was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 6.

[0260] MS m / z: 524 [M+H] + ;

[0261] 1H NMR (400 MHz, CDC13) δ 11.11 (s, 1H), 8.57-8.70 (m, 2H), 8.23 (d, J = 1.38 Hz, 1H), 7.91-8.08 (m, 2H), 7.49 (dd, J = 7.82, 1.56 Hz, 1H), 7.46 (dd, J = 7.88, 1.63 Hz, 1H), 7.21 (s, 1H), 4.41 (br d, J = 6.63 Hz, 2H), 4.20-4.33 (m, 2H), 3.42 (s, 3H), 2.95 (s, 2H), 2.34-2.46 (m, 2H), 1.01 (br dd, J = 4.25, 3.00 Hz, 1H), 0.78-0.84 (m, 4H).

[0262] Example 7

[0263]

[0264] Synthesis route:

[0265]

[0266] Step 1: Synthesis of compound 7-2

[0267] Compound 7-1 (500 mg, 4.80 mmol) was dissolved in anhydrous methanol (10 mL), diacetoxyiodobenzene (3.87 g, 12.00 mmol) and ammonium carbamate (749.45 mg, 9.60 mmol) were added, and the mixture was stirred at 25 °C for three hours. 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 ~ 1 / 2) to obtain compound 7-2.

[0268] MS m / z: 120 [M+H] + .

[0269] Step 2: Synthesis of compound 7-3

[0270] Compound 1-9 (973.76 mg, 5.03 mmol) and 7-2 (600 mg, 5.03 mmol) were dissolved in anhydrous dioxane (15 mL), and 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) were added, and the mixture was stirred at 110 °C for four hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 4 / 1) to obtain compound 7-3.

[0271] MS m / z: 232 [M+H] + .

[0272] Step 3: Synthesis of compound 7-4

[0273] Compound 1-11 (236.53 mg, 949.50 µmol) and 7-3 (200 mg, 863.18 µmol) were dissolved in dioxane (3 mL), and then potassium phosphate (366.45 mg, 1.73 mmol) dissolved in water (0.5 mL) was added, finally 1,1-bis(diphenylphosphino)ferrocene palladium chloride (63.16 mg, 86.32 µmol) was added, and then the system was replaced by nitrogen, and stirred at 100 ℃ for 4 h. After the reaction system was concentrated, the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 ~ 1 / 3) to obtain compound 7-4.

[0274] MS m / z: 319 [M+H] + .

[0275] Step 4: Synthesis of compound 7

[0276] 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), and then cesium carbonate (204.66 mg, 628.15 µmol) was added after nitrogen replacement, finally tris(dibenzylideneacetone)dipalladium (43.14 mg, 47.11 µmol) and (±)-2,2-bis(diphenylphosphino)-1,1-naphthylhydride (39.11 mg, 62.82 µmol) were added after nitrogen replacement, and the system was stirred at 90 ℃ for 6 h. After the reaction solution was concentrated, the crude product was purified by preparative chromatography (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 39%-69%, 10 min) to obtain compound 7.

[0277] MS m / z: 538 [M+H] + ;

[0278] 1H NMR (400 MHz, CDCI3) 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).

[0279] Example 8

[0280]

[0281] Synthesis route:

[0282]

[0283] Step 1: Synthesis of compound 8-2

[0284] 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, and the mixture was stirred at 25 °C for 15 hours. The mixture was extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 1), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 8-2.

[0285] 1 H NMR (400 MHz, CDCI3) δ 3.66-3.57 (m, 4 H), 2.50 (br s, 4 H), 1.39 (s, 9 H).

[0286] Step 2: Synthesis of compound 8-3

[0287] To a solution of compound 8-2 (2 g, 9.84 mmol) in methanol (40 mL) was added diacetoxyiodobenzene (6.65 g, 20.66 mmol) and ammonium carbamate (1.23 g, 15.74 mmol). The mixture was stirred at 25 °C for 2 h. The reaction solution was concentrated to get the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 1, then ethyl acetate / methanol = 40 / 0 ~ 40 / 1) to give compound 8-3.

[0288] MS m / z: 235 [M+H] + ;

[0289] 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).

[0290] Step 3: synthesis of compound 8-4

[0291] 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 mixture was purged with nitrogen for 3 times, and stirred at 90 °C for 4 h. The reaction solution was directly filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 2 / 1) to give compound 8-4.

[0292] MS m / z: 347 [M+H] + .

[0293] Step 4: synthesis of compound 8-5

[0294] Compound 8-4 (500 mg, 1.44 mmol) was dissolved in methanol (2 mL), and hydrochloric acid methanol solution (4 M, 4 mL) was added. The mixture was stirred at 25 °C for 4 h. The reaction solution was concentrated to give compound 8-5.

[0295] MS m / z: 247 [M+H] +

[0296] Step 5: synthesis of compound 8-6

[0297] To a solution of compound 8-5 (500 mg, 2.03 mmol) in dichloroethane (5 mL) was added 37% aqueous formaldehyde solution (608.51 mg, 7.50 mmol) and sodium triacetoxyborohydride (859.05 mg, 4.05 mmol) at 0 °C under nitrogen protection. The mixture was stirred at 25 °C for 2 h. TLC showed that the starting material was consumed completely. The mixture was treated with saturated sodium bicarbonate (50 mL) and stirred for 10 min, then extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 ~ 0 / 1) to give compound 8-6.

[0298] MS m / z: 261 [M+H] + .

[0299] Step 6: Synthesis of compound 8-7

[0300] To a solution of compound 8-6 (290 mg, 1.16 mmol) in dioxane (8 mL) was added compound 1-11 (318.72 mg, 1.22 mmol) at 0 °C under nitrogen protection. After being mixed well, potassium phosphonate (494.21 mg, 2.33 mmol) in water (2 mL) and [1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride (85.18 mg, 116.41 µmol) were added. The mixture was stirred at 100 °C for 2 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 8 / 1 ~ 0 / 1) to give compound 8-7.

[0301] MS m / z: 348 [M+H] + .

[0302] Step 7: Synthesis of compound 8

[0303] To a solution of compound 8-7 (100 mg, 287.82 µmol) in dioxane (5 mL) was added compound 1-8 (82.24 mg, 316.60 µmol), cesium carbonate (187.55 mg, 575.64 µmol), 2,2-bis(diphenylphosphino)-1,1-naphthylidine (35.84 mg, 57.56 µmol) and tris(dibenzylideneacetone)dipalladium (26.36 mg, 28.78 µmol) successively at 0 °C under nitrogen protection. The mixture was stirred at 110 °C for 3 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1 ~ 0 / 1) and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (ammonia water, 0.05% v / v) - acetonitrile]; acetonitrile%: 28% - 58%) to give compound 8.

[0304] MS m / z: 567 [M+H] + ;

[0305] 1 H NMR (400 MHz, CDCl3) d 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).

[0306] Example 9

[0307]

[0308] Synthetic route:

[0309]

[0310] Step 1: Synthesis of compound 9-2

[0311] A mixture of compound 9-1 (500 mg, 2.58 mmol), dimethyl sulfoxide (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 for three times and stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 2) to give compound 9-2.

[0312] MS m / z: 206 [M+H] + .

[0313] Step 2: Synthesis of compound 9-3

[0314] A mixture 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 for three times and stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 ~ 1 / 4) to give compound 9-3.

[0315] MS m / z: 293 [M+H] + .

[0316] Step 3: Synthesis of compound 9

[0317] A mixture of compound 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-naphthyl (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 for three times and stirred at 110 °C for 4 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 ~ 1 / 3) and then by preparative HPLC (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate) – acetonitrile]; acetonitrile%: 30% – 60%, 9 min.) to give compound 9.

[0318] MS m / z: 512 [M+H] + ;

[0319] 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).

[0320] Example 10

[0321]

[0322] Synthesis route:

[0323]

[0324] Step 1: synthesis of compound 10-2

[0325] 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 replaced with nitrogen for three times and stirred at 110 °C for 16 hours. The reaction was diluted with water (20 mL) and ethyl acetate (20 mL), the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 10 / 1) to give compound 10-2.

[0326] MS m / z: 265 [M+H] + ;

[0327] 1H NMR (400 MHz, CDC13) 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).

[0328] Step 2: synthesis of compound 10

[0329] 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 replaced with nitrogen for three times and stirred at 110 °C for 6 h. The reaction was diluted with 20 mL water and 20 mL ethyl acetate, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 ~ 1 / 3) and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 38% - 68%, 8 min.) to give compound 10.

[0330] MS m / z: 521 [M+H] + ;

[0331] 1 H NMR (400 MHz, CDC13) 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).

[0332] Example 11

[0333]

[0334] Synthesis route:

[0335]

[0336] Step 1: synthesis of compound 11-2

[0337] 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 replaced with nitrogen for three times and stirred at 110 °C for 16 h. The reaction was diluted with 20 mL water and 20 mL ethyl acetate, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1~10 / 1) to give compound 11-2. MS m / z: 283 [M+H] +

[0338] Step 2: synthesis of compound 11

[0339] 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 replaced with nitrogen for three times and stirred at 110 °C for 6 h. The reaction was diluted with 20 mL water and 20 mL ethyl acetate, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1~1 / 3), then by high performance liquid chromatography preparation separation (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 8 min.) to give compound 11.

[0340] MS m / z: 539 [M+H] + ;

[0341] 1 H NMR (400 MHz, CDC13) 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).

[0342] Example 12

[0343]

[0344] Synthesis route:

[0345]

[0346] Step 1: synthesis of compound 12-2

[0347] 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 replaced with nitrogen three times and stirred at 110 °C for 16 hours. The reaction solution was divided into water (10 mL) and ethyl acetate (10 mL), the water phase was extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (2 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 15 / 1 ~ 8 / 1) to give compound 12-2.

[0348] MS m / z: 290 [M+H] + .

[0349] Step 2: synthesis of compound 12

[0350] 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-naphthylidene (12.89 mg, 20.71 µmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (9.48 mg, 10.35 µmol) in dioxane (5 mL) was replaced with nitrogen for three times and stirred at 110 °C for 6 h. The reaction was diluted with 5 mL water and 5 mL ethyl acetate, the aqueous phase was extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (2 mL x 1), dried over anhydrous sodium sulfate, filtered and 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), and then by high performance liquid chromatography (preparative column: Waters Xbridge BEH C18 150*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 38%-68%, 8 min.) to give compound 12.

[0351] MS m / z: 546 [M+H] + ;

[0352] 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).

[0353] Example 13

[0354]

[0355] Synthetic route:

[0356]

[0357] Step 1: Synthesis of compound 13-2

[0358] To a solution of 1-7 (0.1 g, 482.92 μmol) in dioxane (2 mL) was added 13-1 (47.43 mg, 434.63 μmol), potassium carbonate (133.49 mg, 965.85 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55.89 mg, 96.59 μmol) and tris(dibenzylideneacetone)dipalladium (44.22 mg, 48.29 μmol). The flask was purged with nitrogen for 3 times and stirred at 110 °C for 4 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1) and then by preparative thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give compound 13-2.

[0359] MS m / z: 280 [M+H] + .

[0360] Step 2: Synthesis of compound 13

[0361] To a solution of 13-2 (30 mg, 107.24 μmol) in dioxane (2 mL) was added 1-12 (31.35 mg, 107.24 μmol), cesium carbonate (69.88 mg, 214.49 μmol), 2,2-bis(diphenylphosphino)-1,1-naphthylhydride (13.36 mg, 21.45 μmol) and tris(dibenzylideneacetone)dipalladium (9.82 mg, 10.72 μmol). The flask was purged with nitrogen for 3 times and stirred at 110 °C for 6 h. The reaction mixture was directly filtered and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 0 / 1) and then by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 30%-60%, 8 min) to give compound 13.

[0362] MS m / z: 536 [M+H] + ;

[0363] 1H 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).

[0364] Example 14

[0365]

[0366] Synthesis route:

[0367]

[0368] Step 1: synthesis of compound 14-2

[0369] Compound 14-1 (515.03 mg, 2.49 mmol) was dissolved in dioxane (10 mL), 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 mixture was purged with nitrogen for three times, the mixture was warmed to 90 °C and stirred for 16 hours. The reaction was filtered directly and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1 ~ 3 / 1) to give compound 14-2. MS m / z: 270 [M+H] + .

[0370] Step 2: synthesis of compound 14

[0371] Compound 14-2 (100 mg, 370.73 μmol) was dissolved in dioxane (4 mL), added 1-12 (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), the gas was replaced with nitrogen for 3 times, the mixture was warmed to 110 °C and stirred for 16 hours. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 40% - 70%, 9 min) to give compound 14.

[0372] MS m / z: 526 [M+H] + ;

[0373] 1 H 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).

[0374] Example 15

[0375]

[0376] Synthesis route:

[0377]

[0378] Step 1: synthesis of compound 15-2

[0379] Compound 15-1 (5 g, 24.39 mmol) was dissolved in concentrated sulfuric acid (20 mL), added concentrated nitric acid (2.21 g, 34.99 mmol, 1.58 mL) dropwise at -10 °C, the mixture was stirred at -10 °C for 0.5 hours. Thin layer chromatography showed that the raw material was consumed, the reaction liquid was poured into crushed ice for quenching, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and 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) to give compound 15-2.

[0380] 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).

[0381] Step 2: synthesis of compound 15-3

[0382] Compound 15-2 (3 g, 12.00 mmol) was dissolved in water (30 mL) and ethanol (10 mL), 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 hours, thin layer chromatography showed that the raw material was consumed. The reaction was filtered with diatomite to remove iron powder, the filtrate was diluted with ethyl acetate (150 mL), washed with water (10 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 ~ 40 / 1) to give compound 15-3.

[0383] 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).

[0384] Step 3: synthesis of compound 15-4

[0385] 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, replaced with nitrogen three times, stirred at 100 °C for 3 hours. Water (10 mL) was added to the reaction to dilute, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 40 / 1 ~ 8 / 1) to give compound 15-4.

[0386] MS m / z: 268 [M+H] + .

[0387] Step 4: synthesis of compound 15-5

[0388] A mixture 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 palladium chloro(1,1'- bis(diphenylphosphino)ferrocene) (24.90 mg, 34.04 μmol) in dioxane (2 mL) and water (0.5 mL) was purged with nitrogen for three times, stirred at 100 °C for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL), extracted with water (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and 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 ~ 1 / 2) to give compound 15-5.

[0389] MS m / z: 311 [M+H] + .

[0390] Step 5: Synthesis of compound 15

[0391] A mixture of compound 15-5 (90 mg, 290.00 μmol) in dioxane (4 mL) was added 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), purged with nitrogen for three times, stirred at 110 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 37% - 67%, 9 min) to give compound 15.

[0392] MS m / z: 530 [M+H] + ;

[0393] 1 H 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).

[0394] Example 16

[0395]

[0396] Synthesis route:

[0397]

[0398] Step 1: Synthesis of compound 16-2

[0399] Compound 16-1 (5 g, 28.74 mmol) was dissolved in concentrated sulfuric acid (15 mL) and cooled to 0 °C and stirred for 10 min. Then nitric acid (4.2 g, 66.65 mmol) was added dropwise to the reaction solution, replaced with nitrogen three times, and stirred at 25 °C for 16 h. The reaction solution was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 16-2, which was used directly in the next reaction.

[0400] MS m / z: 219 [M+H] + , 221 [M+2+H] + .

[0401] Step 2: Synthesis of compound 16-3

[0402] Compound 16-2 (4.6 g, 16.80 mmol, 80% purity) was dissolved in N,N- dimethylformamide (50 mL), and potassium carbonate (4.64 g, 33.61 mmol) was added, and stirred at 25 °C for 10 min. Iodomethane (4.77 g, 33.61 mmol) was added dropwise to the above solution, replaced with nitrogen three times, and stirred at 25 °C for 16 h. Water (100 mL) was added to the reaction solution to dilute, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and 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 ~ 20 / 1) to give compound 16-3.

[0403] MS m / z: 233 [M+H] + , 235 [M+2+H] + ;

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 8.25-8.23 (m, 1H), 8.21-8.18 (m, 1H), 3.97 (s, 3H).

[0405] Step 3: Synthesis of compound 16-4

[0406] 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, and stirred at 25 °C for 1.5 h. The reaction solution was filtered, the filtrate was washed with saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL) in turn, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was stirred with (petroleum ether / ethyl acetate = 5 / 1), the filter cake was collected by filtration to obtain compound 16-4.

[0407] MS m / z: 203 [M+H] + , 205 [M+2+H] + ;

[0408] 1 H 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).

[0409] Step 4: synthesis of compound 16-5

[0410] 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) were replaced with nitrogen for three times, and stirred at 80 °C for 16 h. To the reaction solution was added compound 1-10 (1.52 g, 7.39 mmol), potassium phosphate (1.05 g, 4.93 mmol) and water (6 mL), replaced with nitrogen for three times, and 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 ~ 0 / 1, then ethyl acetate / ethanol = 10 / 1), and then by preparative thin layer chromatography (silica gel, ethyl acetate / ethanol = 10 / 1) to obtain compound 16-5.

[0411] MS m / z: 294 [M+H] + ;

[0412] 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).

[0413] Step 5: Synthesis of compound 16

[0414] A solution of compound 16-5 (25.70 mg, 87.60 μmol), compound 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 replaced with nitrogen for three times and stirred at 110 °C for 6 h. The reaction mixture was concentrated to get the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 ~ 0 / 1) and then by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 31% - 61%, 8 min) to give compound 16. MS m / z: 513 [M+H] + ;

[0415] 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).

[0416] Example 17

[0417]

[0418] Synthesis route:

[0419]

[0420] Step 1: Synthesis of compound 17-3

[0421] Isopropyl magnesium chloride (2M, 8.81 mL) was added dropwise to a solution of compound 17-1 (2 g, 8.81 mmol) in tetrahydrofuran (10 mL) at -65 °C. After stirring 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. The mixture was stirred at 20 °C for 2 h. TLC showed that the starting material was completely consumed. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 ~ 30 / 1) to give compound 17-3.

[0422] 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.46 (s, 1H), 4.53 (s, 2H), 3.46 (s, 3H).

[0423] Step 2: synthesis of compound 17-4

[0424] Compound 17-3 (200 mg, 908.87 µmol) was dissolved in dioxane (5 mL), 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 mixture was replaced with nitrogen for three times, stirred at 80 °C for 6 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 ~ 3 / 1) to give compound 17-4.

[0425] MS m / z: 269 [M+H] + ;

[0426] 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).

[0427] Step 3: Synthesis of compound 17

[0428] Compound 17-4 (90 mg, 334.95 umol) was dissolved in dioxane (4 mL), compound 1-12 (88.13 mg, 301.46 umol,), potassium carbonate (92.58 mg, 669.90 umol), palladium acetate (7.52 mg, 33.50 umol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.76 mg, 66.99 umol) were added, replaced with nitrogen for three times, stirred at 80 °C for 4 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 29%-59%, 10 min) to give compound 17.

[0429] MS m / z: 525 [M+H] + ;

[0430] 1 H 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 = 6.1 Hz, 4H).

[0431] Example 18

[0432]

[0433] Synthesis route:

[0434]

[0435] Step 1: Synthesis of compound 18-1

[0436] To a solution of compound 1-2 (1 g, 4.25 mmol) in THF (10 mL) was added methyl magnesium bromide (3 M in ether, 2.13 mL), stirred at 0 °C for 1 h, the reaction was concentrated, the obtained crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 ~ 3 / 1) to give compound 18-1.

[0437] MS m / z: 190 [M+H] + .

[0438] Step 2: Synthesis of compound 18-2

[0439] To a solution of compound 18-1 (200 mg, 1.05 mmol) in dioxane (3 mL) was added 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-bis(diphenylphosphino)-9,9-dimethylxanthene (60.90 mg, 105.25 μmol) under nitrogen protection, stirred at 90 °C for 3 h. The reaction was concentrated under reduced pressure to give a crude, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 3 / 1) to give compound 18-2.

[0440] 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).

[0441] Step 3: Synthesis of compound 18

[0442] To a solution of compound 18-2 (117.56 mg, 492.55 umol) in dioxane (2 mL) were added compound 1-12 (120 mg, 410.46 umol), cesium carbonate (267.47 mg, 820.922 umol), tris(dibenzylideneacetone)dipalladium (48.19 mg, 52.62 umol) and (R)-(+)-2,2-bis(diphenylphosphino)-1,1'-binaphthyl (25.56 mg, 41.05 umol) portionwise slowly under nitrogen at 110 °C for 4 h. The reaction was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1~3 / 1) and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia water, 0.05% v / v) - acetonitrile]; acetonitrile%: 22% - 52%, 9 min) to give compound 18.

[0443] MS m / z: 495 [M+H] + ;

[0444] 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).

[0445] Example 19

[0446]

[0447] Synthesis route:

[0448]

[0449] Step 1: Synthesis of compound 19-1

[0450] To a solution of compound 1-2 (1 g, 4.25 mmol) in THF (10 mL) was added cyclopropyl magnesium bromide (0.5 M in tetrahydrofuran, 25.52 mL) and stirred at 0 °C for 1 h. The reaction was concentrated to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1~1 / 1) to give compound 19-1.

[0451] MS m / z: 216 [M+H] + .

[0452] Step 2: Synthesis of compound 19-2

[0453] To a solution of compound 19-1 (200 mg, 925.65 pmol) in dioxane (3 mL) was added cyclopropylcarboxamide (86.65 mg, 1.02 mmol), potassium carbonate (255.86 mg, 1.85 mmol), tris(dibenzylideneacetone)dipalladium (42.38 mg, 46.28 pmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.56 mg, 92.57 pmol) under nitrogen protection, and stirred at 90 °C for 3 h. The reaction was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1) to give compound 19-2.

[0454] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0455] Step 3: Synthesis of compound 19

[0456] To a solution of compound 19-2 (95.07 mg, 359.15 pmol) in dioxane (2 mL) was added compound 1-12 (100 mg, 342.05 pmol), cesium carbonate (222.89 mg, 684.10 pmol), tris(dibenzylideneacetone)dipalladium (15.66 mg, 17.10 pmol) and (R)-(+)-2,2-bis(diphenylphosphino)-1,1'-binaphthyl (21.30 mg, 34.20 pmol) slowly in portions under nitrogen protection, and stirred at 110 °C for 4 h. The reaction was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 3 / 1), and then by high performance liquid chromatography preparation separation (column: Waters Xbridge 150*25mm*5pm; mobile phase: [water (ammonia water, 0.05% v / v) - acetonitrile]; acetonitrile%: 27% - 57%, 9 min) to give compound 19.

[0457] 1H 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 = 6.1 Hz, 4H).

[0458] Example 20

[0459]

[0460] Synthesis route:

[0461]

[0462] Step 1: synthesis of compound 20-2

[0463] To a solution of compound 20-1 (0.8 g, 5.83 mmol) in dioxane (12 mL) was added cyclobutylamine (999.20 mg, 17.50 mmol) and stirred at 25 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by slurry with dichloromethane to give compound 20-2.

[0464] 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).

[0465] Step 2: synthesis of compound 20-3

[0466] A solution of compound 20-2 (100 mg, 482.92 μmol) and 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-bis(diphenylphosphino)-9,9-dimethylxanthene (27.94 mg, 48.29 μmol) in dioxane (2 mL) was replaced with nitrogen for three times and 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 ~ 1 / 1) to give compound 20-3.

[0467] MS m / z: 271 [M+H]+ .

[0468] Step 3: Synthesis of compound 20

[0469] A solution of compound 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- naphthylhydride (21.30 mg, 34.20 μmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (15.66 mg, 17.10 μmol) in dioxane (2 mL) was replaced by nitrogen for three times and stirred at 110 °C for 3 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 0 / 1 and dichloromethane / methanol = 5 / 1) and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia water, 0.05% v / v) - acetonitrile]; acetonitrile%: 23% - 53%, 9 min) to give compound 20.

[0470] MS m / z: 527 [M+H] + ;

[0471] 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).

[0472] Example 21

[0473]

[0474] Synthesis route:

[0475]

[0476] Step 1: Synthesis of compound 21-2

[0477] To a solution of compound 21-1 (10 g, 65.30 mmol) in N,N-dimethylformamide (100 mL) was added N-bromosuccinimide (13.95 g, 78.36 mmol), replaced with nitrogen for 3 times, stirred at 25 °C for 20 hours. The reaction solution was diluted with water (300 mL), extracted with ethyl acetate (300 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0) to give compound 21-2.

[0478] 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).

[0479] Step 2: synthesis of compound 21-3

[0480] To a solution of compound 21-2 (1 g, 4.31 mmol), potassium carbonate (1.19 g, 8.62 mmol) in N,N-dimethylformamide (3.5 mL) was added iodomethane (734.06 mg, 5.17 mmol, 321.96 μL) at 25 °C. The mixture was stirred at 60 °C for 4 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 21-3.

[0481] 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).

[0482] Step 3: synthesis of compound 21-4

[0483] 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), stirred at 80 °C for 16 hours. The reaction solution was filtered, the filtrate was extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 21-4.

[0484] 1H 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).

[0485] Step 4: Synthesis of compound 21-5

[0486] To a solution of compound 21-4 (1.7 g, 7.87 mmol) in dioxane (25 mL) was added bis(pinacolato)diboron (3.00 g, 11.80 mmol), potassium acetate (2.32 g, 23.60 mmol), and [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium (287.84 mg, 393.38 μmol), and the mixture was purged with nitrogen for 3 times. The reaction was stirred at 100 °C for 15 h. The reaction was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 6 / 1) to give compound 21-5.

[0487] 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).

[0488] Step 5: Synthesis of compound 21-6

[0489] 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) was added potassium phosphate (2.06 g, 9.72 mmol) and [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium (71.16 mg, 97.25 μmol), and the mixture was stirred at 100 °C for 3 h. The reaction was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give compound 21-6.

[0490] MS m / z: 307 [M+H] + .

[0491] Step 6: Synthesis of compound 21

[0492] 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 replaced with nitrogen for three times and stirred at 100 °C for 3 h. The reaction solution was diluted with water (20 mL) and added into ethyl acetate (20 mL x 3). The organic phase was washed with brine (10 mL x 2) and dried over anhydrous sodium sulfate. The dried organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 ~ 0 / 1). Further purification was performed by high performance liquid chromatography (preparative column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (ammonia water, 0.05%, v / v) - acetonitrile]; acetonitrile%: 34% - 64%, 8 min) to give compound 21.

[0493] 1 H 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).

[0494] Example 22

[0495]

[0496] Synthetic route:

[0497]

[0498] Step 1: Synthesis of compound 22-2

[0499] 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), bromine (944.86 mg, 5.91 mmol, 304.79 μL) were added, replaced with nitrogen for 3 times, stirred at 25 °C for 1 h. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 15 / 1) to give compound 22-2.

[0500] 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).

[0501] Step 2: synthesis of compound 22-3

[0502] To a solution of 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), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 22-3.

[0503] 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).

[0504] Step 3: synthesis of compound 22-4

[0505] To a solution of compound 22-3 (0.75 g, 2.86 mmol) in ethanol (5 mL) and water (5 mL) was added iron powder (799.13 mg, 14.31 mmol) and ammonium chloride (1.53 g, 28.62 mmol) and stirred at 80 °C for 6 h. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 22-4.

[0506] 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).

[0507] Step 4: Synthesis of compound 22-5

[0508] To a solution of compound 22-4 (700 mg, 3.02 mmol) in dioxane (7 mL) was added bis(pinacolato)diboron (1.15 g, 4.52 mmol), potassium acetate (592.05 mg, 6.03 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (44.14 mg, 60.33 μmol), and stirred at 90 °C for 20 h. To the reaction was added bis(pinacolato)diboron (382.97 mg, 1.51 mmol), potassium acetate (296.02 mg, 3.02 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (44.14 mg, 60.33 μmol), and stirred at 90 °C for 24 h. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 ~ 10 / 1) to give compound 22-5.

[0509] MS m / z: 280 [M+H] + .

[0510] Step 5: Synthesis of compound 22-6

[0511] 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) was added potassium phosphate (474.76 mg, 2.24 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (16.37 mg, 22.37 μmol), stirred at 100 °C for 4 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the crude was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 ~ 0 / 1) to give compound 22-6.

[0512] MS m / z: 323 [M+H] + .

[0513] Step 6: Synthesis of compound 22

[0514] To a solution of compound 22-6 (126 mg, 390.84 μmol) in isopropanol (2 mL) was added concentrated hydrochloric acid (97.71 μmol, 9.44 μL), stirred at 80 °C for 16 h. The reaction was concentrated under reduced pressure to remove isopropanol and concentrated hydrochloric acid to give the crude. The crude was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (HC1, 0.05% v / v) - acetonitrile]; acetonitrile%: 19% - 39%, 8 min) to give the hydrochloride salt of compound 22.

[0515] MS m / z: 542 [M+H] + ;

[0516] 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).

[0517] Example 23

[0518]

[0519] Synthesis route:

[0520]

[0521] Step 1: Synthesis of compound 23-1

[0522] Cyclopropylamine (1 g, 17.51 mmol, 1.21 mL), potassium cyanate (1.70 g, 21.02 mmol, 827.61 μί) were dissolved in water (6 mL), the mixture was refluxed at 100 °C for half an hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in isopropanol (10 mL), heated to 85 °C and stirred for 30 minutes, filtered, the filter cake was washed with isopropanol (10 mL), the filtrate was concentrated under reduced pressure to obtain compound 23-1.

[0523] 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).

[0524] Step 2: Synthesis of compound 23-2

[0525] 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, replaced with nitrogen for three times, stirred at 80 °C for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 2) to obtain compound 23-2.

[0526] MS m / z: 271 [M+H] + ;

[0527] 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).

[0528] Step 3: Synthesis of compound 23

[0529] Compound 23-2 (60 mg, 221.62 μmol), 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, stirred at 80 °C for 16 hours. The mixture was diluted with a mixture of ethyl acetate / ethanol = 4 / 1 30 mL, washed with saturated sodium bicarbonate (10 mL x 3). The combined organic layer was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and 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 (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 34%-64%, 8 min) to give compound 23.

[0530] MS m / z: 527 [M+H] + ;

[0531] 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).

[0532] Example 24

[0533]

[0534] Synthesis route:

[0535]

[0536] Step 1: synthesis of compound 24-1

[0537] A mixture of 1-7 (1 g, 4.83 mmol,), 1-12 (1.27 g, 4.35 mmol), 0.3 mL of concentrated hydrochloric acid in isopropanol (15 mL) was stirred at 70 °C for 16 h. The reaction mixture was filtered to collect the filter cake, which was washed with isopropanol to give the crude product. The crude product was stirred in a mixture of ethyl acetate and ethanol (ethyl acetate / ethanol = 8 mL / 2 mL), and the filter cake was collected by filtration to give compound 24-1.

[0538] MS m / z: 463 [M+H] + ;

[0539] 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).

[0540] Step 2: Synthesis of compound 24

[0541] A mixture of 24-1 (50 mg, 108.00 μmol), 2-pyridinecarboxamide (26.38 mg, 216.00 μmol), cesium carbonate (70.38 mg, 216.00 μmol), 2,2-bis(diphenylphosphino)-1,1- naphthylidene (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 and stirred at 110 °C for 16 h. The reaction mixture 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) and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 75*30mm*3μm; mobile phase: [water (HC1, 0.05% v / v) - acetonitrile]; acetonitrile%: 12% - 42%, 8 min.) to give the hydrochloride salt of compound 24.

[0542] MS m / z: 549 [M+H] + ;

[0543] 1H NMR (400 MHz, CDC13) 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).

[0544] Example 25

[0545]

[0546] Synthesis route:

[0547]

[0548] 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 and stirred at 110 °C for 16 h. The reaction 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), and then by high performance liquid chromatography (preparative) (column: Waters Xbridge 75*30mm*3μm; mobile phase: [water (HC1, 0.05% v / v) - acetonitrile]; acetonitrile%: 4% to 34% in 8 min.) to give compound 25 hydrochloride.

[0549] MS m / z: 549 [M+H] + ;

[0550] 1H 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).

[0551] Example 26

[0552]

[0553] Synthesis route:

[0554]

[0555] Step 1: synthesis of compound 26

[0556] 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 for three times and stirred at 110 °C for 16 hrs. The reaction was concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1), then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (HC1, 0.05% V / V) - acetonitrile]; B%: 4% - 34%, 8 min.) to give compound 26 hydrochloride.

[0557] MS m / z: 549 [M+H] + ;

[0558] 1H 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).

[0559] Example 27

[0560]

[0561] Synthesis route:

[0562]

[0563] Step 1: synthesis of compound 27-1

[0564] To a solution of diethyl sulfide (2.32 g, 25.72 mmol, 2.77 mL) in anhydrous methanol (4 mL) was added diacetoxyiodobenzene (20.71 g, 64.31 mmol) and ammonium carbamate (4.02 g, 51.45 mmol), stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 27-1.

[0565] 1 H NMR (400 MHz, CDCl3) δ 3.06 (q, J = 7.4 Hz, 4H), 1.46 - 1.37 (m, 6H).

[0566] Step 2: synthesis of compound 27-2

[0567] 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) was added cesium carbonate (3.37 g, 10.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (236.71 mg, 258.49 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (299.14 mg, 516.99 μmol), replaced with nitrogen for 3 times, stirred at 110 °C for 2 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 ~ 4 / 1) to obtain compound 27-2 crude product.

[0568] MS m / z: 234 [M+H] + .

[0569] Step 3: Synthesis of compound 27-3

[0570] 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) was added potassium phosphate (539.94 mg, 2.54 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium (18.61 mg, 25.44 μmol), replaced with nitrogen for 3 times, stirred at 100 °C for 18 hours. The reaction was diluted with water (15 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 2) to give compound 27-3.

[0571] MS m / z: 321 [M+H] + ;

[0572] 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).

[0573] Step 4: Synthesis of compound 27

[0574] To a solution of compound 27-3 (50 mg) in isopropanol (2 mL) was added 1-8 (40 mg, 156.42 μmol) and concentrated hydrochloric acid (3.34 mg, 33.91 μmol, 3.28 μL, 37% purity), stirred at 80 °C for 16 hours. To the reaction was added ammonia water dropwise to adjust pH = 8-9, the reaction was concentrated under reduced pressure to remove isopropanol and concentrated hydrochloric acid 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 (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 41% - 71%, 8 min) to give compound 27.

[0575] MS m / z: 540 [M+H] + ;

[0576] 1 H 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).

[0577] Example 28

[0578]

[0579] Synthesis route:

[0580]

[0581] Step 1: synthesis of compound 28-2

[0582] Compound 28-1 (0.5 g, 3.96 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cooled to 0 °C for 10 min. Then sodium hydride (190.29 mg, 4.76 mmol, 60% purity) was added to the reaction solution and 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 stirred at 0 °C for 2 h. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, then diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 10 / 1) to give compound 28-2.

[0583] MS m / z: 257 [M+H] + ;

[0584] 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).

[0585] Step 2: synthesis of compound 28-3

[0586] Compound 28-2 (0.7 g, 2.73 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), an aqueous solution of sodium hydroxide (0.25 g, 6.25 mmol) (3 mL) was added, and stirring was performed at 25 °C for 2 h. The pH of the reaction solution was adjusted to 3 with 2M aqueous hydrochloric acid solution, and filtration was performed, and the filter cake was washed with water (15 mL) to obtain compound 28-3.

[0587] MS m / z: 243 [M+H] + ;

[0588] 1 H 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).

[0589] Step 3: synthesis of compound 28-4

[0590] 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), 1-hydroxybenzotriazole (139.39 mg, 1.03 mmol) were added, and stirring was performed at 25 °C for 1 h. Then ammonium chloride (275.90 mg, 5.16 mmol) was added, and stirring was performed at 25 °C for 16 h. Saturated brine (10 mL) was added to the reaction solution, extraction was performed with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and 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 ~ 0 / 1, dichloromethane / methanol = 10 / 1) to obtain compound 28-4.

[0591] MS m / z: 242 [M+H] + ;

[0592] 1H 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).

[0593] Step 4: synthesis of compound 28-5

[0594] 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- naphthylhydride (25.00 mg, 43.20 μmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (19.78 mg, 21.60 μmol) in dioxane (1.5 mL) was replaced by nitrogen for three times and stirred at 110 °C for 16 hrs. The reaction was concentrated under reduced pressure to get the crude product. The crude product was purified by thin layer chromatography (silica gel, ethyl acetate) to get compound 28-5.

[0595] MS m / z: 668 [M+H] + .

[0596] Step 5: synthesis of compound 28

[0597] Compound 28-5 (0.04 g, 59.89 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added and stirred at 25 °C for 1 hr. The reaction was concentrated under reduced pressure, dichloromethane (5 mL) and saturated aqueous sodium bicarbonate solution (2 mL) were added and the mixture was divided, the organic phase was washed with saturated aqueous sodium bicarbonate solution (2 mL) and saturated brine (2 mL) respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The crude product was separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 26% - 56%, 8 min.) to get compound 28.

[0598] MS m / z: 538 [M+H] + ;

[0599] 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).

[0600] Example 29

[0601]

[0602] Synthesis route:

[0603]

[0604] Step 1: synthesis of compound 29-1

[0605] 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, and stirred at 100 °C for 3 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a 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 give compound 29-2.

[0606] MS m / z: 444 [M+H] + ;

[0607] 1 H 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).

[0608] Step 2: synthesis of compound 29-3

[0609] 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) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (600.97 mg, 3.60 mmol) was added. The mixture was stirred at 0 °C for 2 h. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 ~ 8 / 1) to give compound 29-3.

[0610] 1 H NMR (400 MHz, CDCb) d 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).

[0611] Step 3: Synthesis of compound 29-4

[0612] Compound 29-3 (191.31 mg, 676.38 pmol) was dissolved in toluene (5 mL). 29-1 (200 mg, 450.92 pmol), cesium carbonate (293.84 mg, 901.84 pmol), tris(dibenzylideneacetone)dipalladium (41.29 mg, 45.09 pmol) and 2-dicyclohexylphosphino-2,4,6-triisopropyl biphenyl (42.99 mg, 90.18 pmol) were added. The mixture was purged with nitrogen for 3 times. The mixture was stirred at 110 °C for 5 h. The reaction was filtered directly and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 5), and then by preparative high performance liquid chromatography (column: Waters Xbridge C18 150*50mm*10pm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 47% - 77%, 10 min) to give compound 29-4.

[0613] MS m / z: 690 [M+H] + .

[0614] Step 4: Synthesis of compound 29

[0615] 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 h. 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 h. The mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 1), and finally the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a 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), and then by high performance liquid chromatography preparation and separation (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 32% - 62%, 10 min) to give compound 29.

[0616] MS m / z: 560 [M+H] + ;

[0617] 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).

[0618] Example 30

[0619]

[0620] Synthesis route:

[0621]

[0622] Step 1: synthesis of compound 30

[0623] 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, stirred at 25 °C for 1 h, then compound 29-1 (0.08 g, 180.37 μmol) was added to the reaction solution, stirred at 25 °C for 16 h. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution and separated into water phase and organic phase, the water phase was extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*50mm*10μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 33%-63%, 10 min.) to give compound 30.

[0624] MS m / z: 538 [M+H] + ;

[0625] 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).

[0626] Example 31

[0627]

[0628] Synthetic route:

[0629]

[0630] Step 1: synthesis of compound 31

[0631] 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 min. Compound 29-1 (86.54 mg, 195.12 μmol) was added to the mixture and stirred at 60 °C for 16 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 ~ 0 / 1), then by high performance liquid chromatography preparation separation (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 31% - 61%, 8min) to give compound 31.

[0632] MS m / z: 554 [M+H] + ;

[0633] 1 H 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).

[0634] Example 32

[0635]

[0636] Synthesis route:

[0637]

[0638] Step 1: synthesis of compound 32

[0639] To a solution of compound 32-1 (94.81 mg, 676.38 umol) in N,N- dimethylformamide (4 mL) was added N,N-diisopropylethylamine (262.25 mg, 2.03 mmol, 353.44 uL) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (282.90 mg, 744.02 umol), stirred at 20 °C for 1 h. Then 29-1 (100 mg, 225.46 umol) was added, stirred at 60 °C for 3 h under nitrogen protection. The reaction was diluted with water (15 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with water (20 mL x 3) and saturated brine (20 mL x 3) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was separated by preparative high performance liquid chromatography (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 40% - 70%, 10 min) to give compound 32.

[0640] MS m / z: 566 [M+H] + ;

[0641] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0642] Example 33

[0643]

[0644] Synthetic route:

[0645]

[0646] Step 1: synthesis of compound 33

[0647] Compound 33-1 (50.00 mg, 356.69 umol) was dissolved in acetonitrile (1.5 mL), methylimidazole (102.50 mg, 1.25 mmol, 99.51 uL) and N,N,N,N-tetramethylchloroformamidium hexafluorophosphate (120.09 mg, 428.02 umol) were added, and the mixture was stirred at 15 °C for 20 min. Compound 29-1 (79.10 mg, 178.34 umol) was added to the mixture, and the reaction was stirred at 15 °C for 16 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 45% - 75%, 8 min) to give compound 33.

[0648] MS m / z: 566 [M+H] + ;

[0649] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0650] Example 34

[0651]

[0652] Synthesis route:

[0653]

[0654] Step 1: synthesis of compound 34

[0655] Compound 29-1 (50 mg, 112.73 μmol) was dissolved in dioxane (2 mL), added 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-triisopropyl biphenyl (10.75 mg, 22.55 μmol), replaced nitrogen three times, stirred at 80 °C for 16 hours. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 ~ 0 / 1), then subjected to high performance liquid chromatography preparation separation (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 36% - 66%, 8min) to give compound 34.

[0656] MS m / z: 551 [M+H] + ;

[0657] 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, J = 1.1, 7.9 Hz, 1H), 7.48 (dd, J = 1.3, 7.8 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.06 (s, 1H), 6.24 (t, J = 7.2 Hz, 1H), 3.55 (s, 3H), 3.52 (s, 3H), 3.47 (s, 6H), 3.05 (s, 2H).

[0658] Example 35

[0659]

[0660] Synthesis route:

[0661]

[0662] Step 1: synthesis of compound 35

[0663] 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-triisopropyl biphenyl (10.75 mg, 22.55 μmol) were added, the reaction was purged with nitrogen for three times, stirred at 100 °C for 16 h. The reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and 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 ~ 0 / 1), then by high performance liquid chromatography (preparative) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 27% - 57% in 8 min) to give compound 35.

[0664] MS m / z: 551 [M+H] + ;

[0665] 1 H 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).

[0666] Biological evaluation

[0667] Experimental Example 1: In vitro enzyme activity evaluation

[0668] Tyk2 JH2 enzyme activity test experimental procedure

[0669] In a buffer solution containing 20 mM Hepes pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 2 mM DTT and 50 μg / mL BSA, 0.5 nM of TYK2 protein (His-TVMV-TYK2 JH2 (575-869)), 0.2 nM of terbium-labeled His antibody, in the presence of the relevant K dThe luciferin-labeled kinase tracer and the test compound were incubated at room temperature for 90 minutes. Subsequently, the generated HTRF (homogeneous time-resolved fluorescence) signal, i.e., the ratio of fluorescence intensity at the emission wavelength of the luciferin acceptor (520 nm) to that of the terbium donor (495 nm), was measured on an Envision plate reader, and the IC50 value was calculated based on this. The in vitro enzyme activity assay results of the compounds of this invention are shown in Table 1:

[0670] Table 1: Results of in vitro enzyme activity assay of the compounds of the present invention (IC50) 50 )

[0671]

[0672]

[0673]

[0674] Experimental conclusion: The compound of this invention has strong inhibitory activity against Tyk2 JH2.

[0675] Experimental Example 2: Evaluation of In Vitro Cell Viability

[0676] IFNα-stimulated phosphorylation of STAT1 experiment

[0677] Human peripheral blood mononuclear cells (hPBMCs) were seeded into plates at a cell density of 1×10⁻⁶. 5 Cells were incubated per well at 37°C for 90 minutes. Different concentrations of the compound were then added to the cells, starting at 2 μM and serially diluted 5-fold for a total of 8 concentration gradients. The compounds and cells were incubated at 37°C for 30 minutes. hPBMCs were stimulated with IFN-α (1000 U / ml), and the level of phosphorylated STAT1 in CD4+ T cells was detected by flow cytometry to evaluate the inhibitory activity of the compounds on the IFN-α pathway. The results of the in vitro cell activity assays of the compounds of this invention are shown in Table 2.

[0678] Table 2: Results of in vitro cell activity assays of the compounds of the present invention (IC50) 50 )

[0679] No. IFN alpha-stimulated phosphorylated STAT1 (IC 50 nM)]]> Compound 1 1.1 Compound 2 0.2 Compound 3 2.1 Compound 4 0.6 Compound 8 0.4 Compound 9 0.5

[0680] Experimental conclusion: The compound of this invention has strong cellular activity against Tyk2-related IFNα-stimulated phosphorylated STAT1.

[0681] Experimental Example 3: Pharmacokinetic Evaluation of Compounds in Mice

[0682] Experimental objective: To test the pharmacokinetics of the compound in Balb / c mice.

[0683] Experimental materials: Male Balb / c mice, fasted

[0684] Experimental operation:

[0685] The pharmacokinetic characteristics of compound 1 in rodents after intravenous injection and oral administration were tested according to standard protocols.

[0686] After the Balb / c mice arrived at the facility, they were acclimated / quarantined for at least 3 days. At the end of acclimation / quarantine, a veterinarian or designated personnel will check the health status of the Balb / c mice to assess whether the animals are suitable for the experimental study. All Balb / c mice were fasted overnight before dosing and food was restored 4 hours after dosing. The candidate compound was prepared as a homogeneous solution and administered to the Balb / c mice as a single intravenous injection and oral administration. The injection vehicle was a clear solution of 80% polyethylene glycol 400 / 20% water and the oral vehicle was a homogeneous suspension of ethanol / vitamin E polyethylene glycol succinate / polyethylene glycol 300 = 5 / 5 / 90. The animal body weight was measured before dosing and the dosing volume was calculated based on the body weight. Whole blood samples were collected within 24 hours by neck vein puncture and all blood samples were immediately transferred to labeled commercialized K2-EDTA containing centrifuge tubes. After blood sampling, the supernatant plasma was aspirated by centrifugation at 3200g for 10 minutes at 4°C, quickly placed on dry ice, and then stored at -60°C or lower for LC-MS / MS analysis. The blood concentration-time data were analyzed and pharmacokinetic parameters were calculated using a non-compartmental model using the WinNonlin software package (Version 6.3 and above) and the PK parameters included, but were not limited to, peak concentration (Cmax), time to peak (Tmax), elimination half-life (T1 / 2), area under the plasma concentration-time curve (AUC), mean residence time (MRT), bioavailability, etc. if the data permitted. The experimental results of compound 1 of the present application are shown in Table 3:

[0687] Table 3 Pharmacokinetic test results

[0688]

[0689] Note: Vd: distribution volume; Cl: clearance; T 1 / 2 : half-life; AUC: exposure (area under the curve); C max : maximum concentration; T max : concentration peak time; F%: bioavailability; IV: intravenous injection; PO: oral administration

[0690] Experimental conclusion: The compound of the present application showed excellent pharmacokinetic properties, lower clearance, and higher oral bioavailability.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, ， in, Ring A is selected from pyrazinyl and pyrimidinyl groups; X1 and X2 are independently selected from N and CH, respectively; R1 and R2 are independently selected from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. a replace; Alternatively, R1, R2, and the S atom attached thereto can form a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic group is optionally surrounded by 1, 2, 3, or 4 R atoms. a replace; R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, and C. 1-3 Alkyl and C 1-3 Alkoxy; R4 is selected from hydrogen, -C(=O)R 41 and 5-6 heteroaryl groups, wherein the 5-6 heteroaryl groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R 41 Selected from C 1-3 Alkyl and C 3-6 cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3, or 4 R's. c replace; R5 is selected from hydrogen and C. 1-3 alkyl; R6 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, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 Alkyl and -NH-C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. d replace; R a R b、 R c and R d Independently selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH2, C 1-3 Alkyl and C 1-3 Alkoxy; n can be 0, 1, 2, or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... and .

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... and .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from methyl, ethyl, and propyl, wherein the methyl, ethyl, and propyl groups are optionally surrounded by 1, 2, 3, or 4 R groups. a replace.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from methyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1, R2 and the S atom attached thereto form a 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group optionally surrounded by 1, 2, 3 or 4 R atoms. a replace.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the 4-6 membered heterocyclic group is selected from... , , , and The self , , , and Choose 1, 2, 3 or 4 Rs a replace.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the 4-6 membered heterocyclic group is selected from... , , , and .

9. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, R a Selected from hydrogen.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, structural unit Selected from , , , and .

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is selected from N.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is selected from CH.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from hydrogen and fluorine.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, structural unit for , or .

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, -C(O)R 41 , and The and Choose 1, 2, or 3 Rs b replace.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 41 Selected from methyl, ethyl, propyl and C 3-4 cycloalkyl, wherein methyl, ethyl, propyl and C 3-4 The cycloalkyl group is optionally surrounded by 1, 2, 3, or 4 R's. c replace.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein C 3-4 The cycloalkyl group is cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl group is optionally surrounded by 1, 2, 3, or 4 R groups. c replace.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from... , , , , and .

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from hydrogen, methyl, and ethyl.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH3, -NHCH2CH3, -NH-cyclopropyl, and -NH-cyclobutyl, wherein the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH3, -NHCH2CH3, -NH-cyclopropyl, and -NH-cyclobutyl are optionally represented by 1, 2, 3, or 4 R6 groups. d replace.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from methyl, ethyl, and -NHCH3, wherein the methyl, ethyl, and -NHCH3 are optionally surrounded by 1, 2, 3, or 4 R6 groups. d replace.

22. The compound according to any one of claims 20-21, or a pharmaceutically acceptable salt thereof, R d It is either deuterium or methoxy.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from -CH2CD3, -CH2CH3, -NHCD3 and -CH2OCH3.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (II-1) or (II-2): or , in, R1, R2, R3, R4, R5, R6, X1, X2, and n are as defined in claim 1.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein the compound is shown in formula (II-1-1) or (II-1-2): or , in, R1, R2, R3, R4, R5, R6, X1, and n are as defined in claim 24.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II-1-1-1) or (II-1-1-2): or , in, R1, R2, R3, R4, R5, X1, and n are as defined in claim 1.

27. The following compounds or their pharmaceutically acceptable salts, 。 28. A compound of the following formula or a pharmaceutically acceptable salt thereof, 。 29. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-28 in the preparation of a medicament for treating Tyk2JH2-related diseases.

Images