Compound as well as composition and application thereof

Abstract

The invention relates to a compound as well as a composition and application thereof, the compound can be used for preparing an STAT3 inhibitor, and can also be used for preventing or treating diseases related to inhibition of STAT3, including but not limited to cancers, rheumatoid arthritis, Crohn's disease, atherosclerosis or inflammatory bowel disease and the like. The compound has the following structural formula,

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a compound that can be used as a STAT3 inhibitor, its composition, and its use. Background Technology

[0002] Signal transducers and activators of transcription (STATs) are a class of cytoplasmic transcription factors responsible for transducing signals from extracellular cytokines and growth factors, as well as activating gene transcription. In mammalian cells, the STAT family comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5α, STAT5β, and STAT6, sharing 20% ​​to 50% homology among them. Genes regulated by STAT proteins include those involved in cell cycle control, cell survival, and immune responses.

[0003] Among the STAT family proteins, STAT2 is a key transcription factor in the type I interferon (IFN-α / β) signaling pathway, renowned for its role in mediating antiviral immunity and antiproliferative signaling. Similar to STAT2, STAT6 and STAT4 are specifically activated by IL-4 and IL-12, respectively, and play central roles in the regulation of immune responses. In addition to its role in regulating immune responses, STAT1 has been found to inhibit tumor cell proliferation and promote tumor cell apoptosis. Conversely, STAT3 and STAT5 are downstream oncogenic mediators of the JAK-STAT pathway, promoting cancer cell proliferation and survival. In particular, STAT3 controls cell cycle progression and anti-apoptosis, and is therefore most commonly associated with the progression and poor prognosis of various human cancers. Besides its role in cancer, STAT3 is also associated with autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, atherosclerosis, and inflammatory bowel disease. Therefore, STAT3 is widely considered an attractive target for developing inhibitors of STAT3-related diseases, such as cancer, autoimmune diseases, and inflammatory diseases.

[0004] Currently, there is still a lack of safe and effective STAT3 inhibitors on the market. Summary of the Invention

[0005] The main objective of this invention is to provide a compound and its composition and uses, which can be used to prepare STAT3 inhibitors and to prevent or treat diseases related to the inhibition of STAT3, including but not limited to cancer, rheumatoid arthritis, Crohn's disease, atherosclerosis or inflammatory bowel disease.

[0006] To achieve the above objectives, the present invention provides the following technical solutions.

[0007] The first aspect of the present invention provides compounds of formula (I), their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their hydrates, their solvates, or polycrystalline forms:

[0008]

[0009] in,

[0010] L1 is selected from C1-C3 alkylene, -N(R5)-, C1-C3 alkylene optionally substituted with -N(R5)2, or C1-C3 haloalkylene;

[0011] L2 is selected from C1-C4 alkylene, -N(R5)- or halogen-substituted C1-C3 alkylene;

[0012] R1 is selected from C1-C3 alkylene, -N(R5)-, -N(R5)-C(=O)- or halogen-substituted C1-C3 alkylene;

[0013] R2 is selected from H, C1-C3 alkyl, -N(R5)2, halogen, or halogen-substituted C1-C3 alkyl;

[0014] Alternatively, R1, R2, and the atoms bonded to them together form a 4-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl. The 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl can be formed by one or more R... c Replace, each R c Each is independently selected from halogens, C1-C3 alkyl groups, -OH, or CN;

[0015] Each R5 is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl or -C 1-3 Alkylene-C(=O)-N(R) 51 )2, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 )2 can be optionally replaced by one or more halogens; each R 51Each R5 is independently selected from H or C1-C3 alkyl; or, each R5 is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 2. -SH (=O), -S (=O)-C 1-3 Alkyl, -S(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-S(=O)-C 1-3 Alkyl, -SH(=O)2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 3-8 cycloalkyl, -C 1-3 Alkylene-S(=O)2-C 1-3 Alkyl; C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 2. -SH (=O), -S (=O)-C 1-3 Alkyl, -S(=O)-C 3-8 Cycloalkyl, -S(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-S(=O)-C 1-3 Alkyl, -SH(=O)2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 3-8 Cycloalkyl, -S(=O)2-3~6-membered heterocycloalkyl, -C 1-3 Alkylene-S(=O)2-C 1-3The alkyl group may be optionally substituted with one or more halogens, or optionally substituted with one or more C1-C3 alkyl groups, or optionally substituted with one or more C1-C3 alkoxy groups, or optionally substituted with one or more C1-C3 haloalkyl groups, or optionally substituted with one or more C1-C3 haloalkoxy groups, or optionally substituted with one or more substituents each independently selected from the following: halogen, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 carboxylic acid, C1-C3 ester, -N(R5)2; each R 51 Each is independently selected from H or C1-C3 alkyl groups;

[0016] In some implementations, each R 51 Each is independently selected from H, C1-C3 alkyl, or halo-C1-C3 alkyl;

[0017] R3 is selected from H, C1-C3 alkyl groups, and -N(R) 3a 2. Halogenated or halogen-substituted C1-C3 alkyl groups; each R 3a Each is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 The alkyl group may optionally be substituted with one or more halogens;

[0018] X1 is selected from -CH- or N;

[0019] R4 is selected from H, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl;

[0020] Ring A is selected from Ring E is selected from imidazole ring or pyrazole ring; at least two of X2, X3, and X4 are NR. a2 The other is -CH-, and each R a2 Each is independently selected from either non-existent or H; each R a1 Each is independently selected from halogens, C1-C3 alkyl groups, -N(R5)2, or C1-C3 haloalkyl groups; in some embodiments, each R a1 Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl;

[0021] Ring B is selected from Or by n R b1 Substituted triazole; ring F is triazole; at least two of X5, X6, X7, and X8 are NR. b2 The rest are -CH-, and each R b2 Each is independently selected from either non-existent or H; each R b1 Each is independently selected from halogens, C1-C3 alkyl groups, -N(R5)2, or C1-C3 haloalkyl groups; in some embodiments, each R b1 Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl;

[0022] Each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0023] In some embodiments, the compound has a structure of formula (II-1), (II-2), (II-3), (II-4), (II-5), or (II-6):

[0024]

[0025]

[0026] In some implementations, each n is independently selected from 0, 1, or 2.

[0027] In some embodiments, L1 is selected from -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-, -N(R5)- or C1-C3 alkylene groups substituted with -N(R5)2, and each R5 in L1 is independently selected from H, -C(=O)-CH3, -C(=O)-CF3, -C(=O)-CCl3, -C(=O)-CBr3, -CH2-C(=O)-NH2, -CH2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl or halocyclopropyl; or L1 Each R5 is independently selected from H, -C(=O)-CH3, -CH(=O), -C(=O)-CF3, -C(=O)-CCl3, -C(=O)-CBr3, -CH2-C(=O)-NH2, -CH2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl, halocyclopropyl, methylcyclopropyl, oxacyclobutyl, -S(=O)2-CH3; or each R5 in L1 is independently selected from H, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH(=O), -C(= -C(=O)-CF3, -C(=O)-CH2CF3, -C(=O)-CH2CH2CF3, -C(=O)-CCl3, -C(=O)-CH2CCl3, -C(=O)-CH2CH2Cl3, -C(=O)-CBr3, -C(=O)-CH2CBr3, -C(=O)-CH2CH2Br3, -CH2CH2-C(=O)-NH2, -CH2CH2CH2-C(=O)-NH2, -C(CH3)2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl, halocyclopropyl, methylcyclopropyl, oxacyclobutyl, -S(=O)2-CH3, -C (=O)-N(CH3)2, -C(=O)-NHCH2CH3, -C(=O)-CH=CH2, -C(=O)-CH2CH=CH2, -C(=O)-spiropentyl, -C(=O)-CH2C(=O)OH, -C(=O)-(CH2)2C(=O)OH, -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-cyclopropyl, -C(=O)-halocyclopropyl, -C(=O)-methylcyclopropyl, -C(=O)-halomethylcyclopropyl; these R5s are optionally substituted with one or more halogens, amino, hydroxyl, alkyl, alkoxy, ester, carboxylic acid, sulfonic acid, cycloalkyl, aryl, or heteroaryl groups.

[0028] In some embodiments, R1 is -N(R5)-C(=O)-, where R5 in R1 is selected from H, halogens, C1-C3 alkyl groups or halogenated C1-C3 alkyl groups.

[0029] In some embodiments, R2 is selected from -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, and may be substituted by one or more halogens.

[0030] In some embodiments, R1 together with R2 and the atoms attached to them forms a cyclobutyl group, which may optionally be substituted by one or more of the following substituents: -NH2, -CH3, or halogen.

[0031] In some embodiments, R3 is selected from H, halogens, C1-C3 alkyl groups, and -N(R) 3a 2. Halogenated or halogen-substituted C1-C3 alkyl groups; each R 3a Each is independently selected from H, halogen, C1-C3 alkyl, -CH(=O), -C(=O)-CH3, -C(=O)-O-CH3, -C(=O)-NH2, and -C(=O)-CH3 and -C(=O)-O-CH3 can be substituted by one or more halogens.

[0032] In some embodiments, R4 is selected from H, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl; each R5 in R4 is independently selected from H, C1-C3 alkyl, -CH(=O) or -C(=O)-CH3, and -C(=O)-CH3 may be substituted with one or more halogens.

[0033] In some implementations, each R a1 Each is independently selected from F, Cl, C1-C3 alkyl or C1-C3 haloalkyl; each n in ring A is independently 0, 1 or 2.

[0034] In some implementations, each R b1 Each is independently selected from F, Cl, C1-C3 alkyl or C1-C3 haloalkyl; each n in ring B is independently 0, 1 or 2.

[0035] In some embodiments, L2 is selected from -CH2-, -N(CH3)-, and is optionally substituted with one or more halogens, alkyl, amino, hydroxyl, alkoxy, ester, carboxylic acid, sulfonic acid, cycloalkyl, aryl, or heteroaryl groups.

[0036] In some embodiments, the following compounds are included: their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their hydrates, their solvates, or polycrystalline forms:

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] In some embodiments, the following compounds are included: their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their hydrates, their solvates, or polycrystalline forms:

[0046]

[0047]

[0048]

[0049]

[0050] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate or polycrystalline form, and a pharmaceutically acceptable carrier, excipient or diluent.

[0051] The third aspect of the invention provides the use of the compounds of the first aspect, their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their transisomers, their pharmaceutically acceptable salts, their deuterated derivatives, their hydrates, their solvates or polycrystalline forms, or the pharmaceutical compositions of the second aspect, in the preparation of STAT3 inhibitors.

[0052] The fourth aspect of the invention provides the use of the compounds of the first aspect, their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their stereoisomers, their transisomers, their deuterated derivatives, their hydrates, their solvates or polycrystalline forms, or the pharmaceutical compositions of the second aspect, in the preparation of medicaments for the prevention and / or treatment of diseases associated with the inhibition of STAT3.

[0053] In some implementations, the diseases associated with STAT3 inhibition include cancer, rheumatoid arthritis, Crohn's disease, atherosclerosis, or inflammatory bowel disease.

[0054] A fifth aspect of the present invention provides a method for preventing and / or treating and inhibiting STAT3-related diseases, comprising:

[0055] The steps of administering to a patient in need a therapeutically effective amount of a first-aspect compound, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its transisomer, its pharmaceutically acceptable salt of its deuterated derivative, its hydrate, its solvate or polycrystalline form, or a therapeutically effective amount of a second-aspect pharmaceutical composition.

[0056] definition

[0057] Unless otherwise stated, the term "halogen" as used interchangeably herein refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0058] Unless otherwise stated, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having a straight chain or branched chain. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl, etc. Similarly, C 1-6 C in alkyl 1-6Alkyl groups are defined as groups that identify straight or branched chains having 1, 2, 3, 4, 5, or 6 carbon atoms. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0059] Unless otherwise stated, the term "haloalkyl" as used herein refers to the alkyl group described above that is substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkyl group is interchangeably -C 1-6 Haloalkyl or haloC1-6 alkyl, wherein -C 1-6 Halogenated alkyl or halogenated C 1-6 C in alkyl 1-6 This indicates that the alkyl group has a total of 1 to 6 carbon atoms. In some embodiments, -C 1-6 Haloalkyl is -C 1-3 Haloalkyl. In some embodiments, -C 1-3 The haloalkyl group is substituted with 1, 2, 3, 4, 5, or 6 -F groups (methyl, ethyl, propyl, or isopropyl); preferably, -C 1-3 The alkyl halotype is -CF3.

[0060] The term "alkylene" refers to a bifunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. Examples include methylene (i.e., -CH2-) and ethylene (i.e., -CH2-CH). 2- Or -CH(CH3)-) and propylidene (i.e. -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0061] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically ranging in length from 2 to 20 carbon atoms. For example, "-C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hexenyl, heptenyl, octenyl, etc.

[0062] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically ranging in length from 2 to 20 carbon atoms. For example, "-C 2-6 The "alkynyl" group contains 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, hepynyl, octyynyl, etc.

[0063] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl groups, including but not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OCH3, and -CH2CH2OCH3.

[0064] Unless otherwise stated, the term "haloalkoxy" as used herein refers to the aforementioned alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkoxy group is interchangeably -C 1-6 Halogenated alkoxy or halogenated C 1-6 Alkoxy, where -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 This indicates that the total number of carbon atoms in the alkoxy group is 1 to 6. In some embodiments, -C 1-6 The haloalkoxy group can be substituted with 1, 2, 3, 4, 5 or 6 -F, -Cl or -Br (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy); the preferred -C1-3 haloalkoxy group is -OCF3.

[0065] Unless otherwise stated, the terms "aryl" or "aromatic ring" as used herein refer to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only a carbon ring atom. Preferred aryl groups are 6-10 membered aromatic ring systems, either monocyclic or bicyclic. Phenyl and naphthyl are preferred aryl groups.

[0066] Unless otherwise stated, the term "heterocyclic group" as used herein refers to a saturated or unsaturated group having a cyclic carbon atom and one or more cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 0, 1, 2, or 3 double or triple bonds, including monocyclic heterocyclic groups, bicyclic heterocyclic groups, bridged heterocyclic groups, fused-ring heterocyclic groups, and spirocyclic heterocyclic groups. In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 4-8 membered heterocyclic group is preferred, which is a 4- to 8 membered non-aromatic ring system having a ring carbon atom and one or more ring heteroatoms; the heterocyclic group also includes a ring system in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the connection point is on the heterocyclic ring, or a ring system in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. The heterocyclic group also includes the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. The heterocyclic group also includes the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxadiol, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxacyclobutyl, and thiohexacyclobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thioheptanyl.

[0067] Unless otherwise stated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups or heterocyclic rings can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in their ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused rings, spirocyclic rings, or bridged rings; for example, bicyclic heteroaryl groups are polycyclic heteroaryl groups. Bicyclic heteroaryl rings may contain 8 to 12 member atoms. Monocyclic heteroaryl rings may contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, phenylpyrimidinyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

[0068] The term "carbocyclic" refers to a monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms, whether substituted or unsubstituted. Preferably, the ring is tri- to ten-membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included within this definition. Carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Heterocyclic" refers to a "cycloalkyl" group in which one ring carbon atom is substituted by a heteroatom.

[0069] The term "one or more" refers to one or more. In some embodiments, "one or more" refers to 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" refers to 1, 2, 3, or 4. In some embodiments, "one or more" refers to 1, 2, or 3. In some embodiments, "one or more" refers to 1 or 2. In some embodiments, "one or more" refers to 1. In some embodiments, "one or more" refers to 2. In some embodiments, "one or more" refers to 3. In some embodiments, "one or more" refers to 4. In some embodiments, "one or more" refers to 5. In some embodiments, "one or more" refers to 6.

[0070] In this invention, when a ring is substituted by one or more substituents, this means that each substituent can independently substitute for each ring atom of the ring, including but not limited to ring carbon atoms or cyclic heteroatoms (e.g., nitrogen, sulfur, etc.). Furthermore, when the ring is a polycyclic ring, such as a fused ring, bridged ring, or spirocyclic ring, each substituent can independently substitute for each ring atom of the polycyclic ring.

[0071] The term "oxo" refers to the process by which oxygen and the carbon atoms bonded to it together form oxygen. Group.

[0072] It can be a single key or a double key.

[0073] In the structure of ring A or ring B This refers to the connection between the ring and the adjacent segment in the general formula of the compound. If Drawing the ring along its sides rather than at its endpoints usually indicates that the connection to an adjacent segment can be any of the ring's allowed endpoints.

[0074] In this invention, the term "composition" is intended to cover a product containing a specific amount of a specific ingredient, as well as any product produced directly or indirectly from a combination of specific amounts of the specific ingredients. Therefore, pharmaceutical compositions containing compounds of this invention as active ingredients, and methods for preparing the compounds of this invention, are also part of this invention. Furthermore, some crystalline forms of the compounds may exist in polymorphic forms, and are therefore intended to be included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

[0075] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic alkalis, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure, and especially at least 98% pure (% by weight).

[0076] This invention includes prodrugs of the compounds of this invention within its scope. Typically, such prodrugs are functional derivatives of compounds that readily convert into the desired compound in vivo. Therefore, in the treatment methods of this invention, the term "administration" should include treating various conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted into a specific compound in vivo after administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" (ed. 25 H. Bundgaard, Elsevier, 1985).

[0077] The definition of any substituent or variable at a specific position in a molecule is intended to be independent of the definition of substituents or variables at other positions in the molecule. It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to provide chemically stable compounds that can be readily synthesized using techniques known in the art and the methods set forth herein.

[0078] The compounds of this invention may contain one or more asymmetric centers, and therefore may exist in a variety of stereoisomeric forms, producing diastereomers and optical isomers. This invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0079] This invention includes all stereoisomers of compounds and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and isolated specific stereoisomers. The products of these steps, either during the synthetic steps used to prepare these compounds or during the use of racemic or epimerization methods known to those skilled in the art, can be mixtures of stereoisomers.

[0080] As used in this invention, "stereoisomer" refers to isomers in a molecule that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements. Stereoisomers include configurational isomers and conformational isomers. Configurational isomers further include geometrical isomers and optical isomers, while optical isomers mainly include enantiomers and diastereomers. This invention encompasses all possible stereoisomers of the compound.

[0081] Some of the compounds described herein can exist as trans-isomers, which are conformational stereoisomers that occur when rotation around the single bonds in the molecule is prevented or significantly slowed down due to steric interactions with other parts of the molecule. The compounds described herein include all trans-isomers, including pure, standalone trans-isomers, individually enriched trans-isomers, or mixtures of their respective nonspecificities. Separation of trans-isomers can be allowed if the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is slow enough.

[0082] This invention aims to include all atomic isotopes present in the compounds of this invention. An isotope is an atom having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Hydrogen isotopes can be represented as 1H (hydrogen), 2H (deuterium), and 3H (tritium). They are also commonly represented as D (deuterium) and T (tritium). In this invention, CD3 represents methyl, where all hydrogen atoms are deuterium. Carbon isotopes include 13C and 14C. Using suitable isotopically labeled reagents instead of unlabeled reagents, the isotopically labeled compounds of this invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0083] Unless otherwise stated, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are replaced by deuterium atoms ("D"). It will be appreciated that variations in the abundance of natural isotopes can occur in synthetic compounds depending on the source of the chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the "deuterated derivatives" of the compounds disclosed herein, at least one hydrogen atom is replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives disclosed in this invention have an isotope enrichment factor of at least 3500 for each deuterium atom (containing 52.5% deuterium in each specified deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), or at least 6600 (containing 99% deuterium).

[0084] When the compounds of the present invention have tautomers, the present invention includes any possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0085] The pharmaceutical compositions of the present invention comprise, as an active ingredient, a compound of the present invention (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Although the most suitable route of administration in any given case will depend on the specific host and the nature and severity of the condition (to which the active ingredient is being administered for treatment), the compositions include those suitable for oral, rectal, topical, and non-gastrointestinal (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions can be conveniently present in unit dosage forms and prepared by any method well known in the pharmaceutical field.

[0086] In practice, according to conventional pharmaceutical formulation techniques, the compounds of the present invention, or their prodrugs, or their metabolites, or pharmaceutically acceptable salts, can be combined as active ingredients with a pharmaceutical carrier to form a close mixture. Depending on the desired route of administration, the carrier can take various forms, such as oral or parenteral (including intravenous) administration. Therefore, the pharmaceutical compositions of the present invention can exist as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can exist as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the common dosage forms described above, the compounds of the present invention, or their pharmaceutically acceptable salts, can also be administered via controlled-release methods and / or delivery devices. The composition can be prepared by any pharmaceutical method. Typically, such methods involve the step of combining the active ingredient with a carrier constituting one or more essential components. Typically, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both. The product can then be conveniently shaped into the desired form.

[0087] Therefore, the pharmaceutical compositions of the present invention may include pharmaceutically acceptable carriers and compounds or pharmaceutically acceptable salts. The compounds of the present invention or their pharmaceutically acceptable salts may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0088] The drug carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient drug medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms such as suspensions, syrups, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units that use solid drug carriers due to ease of administration. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0089] The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0090] The pharmaceutical compositions of the present invention suitable for injectable use comprise sterile aqueous solutions or dispersions. Alternatively, the composition may be in the form of a sterile powder for the ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively flowable for injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0091] In addition to the carrier components described above, the pharmaceutical formulations may suitably include one or more other carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compound or its pharmaceutically acceptable salt may also be prepared in powder or liquid concentrate form.

[0092] The compounds or salts thereof of the present invention can effectively treat cancer, rheumatoid arthritis, Crohn's disease, atherosclerosis, or inflammatory bowel disease.

[0093] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, combination of drugs, and the severity of the specific disease being treated.

[0094] Unless the context otherwise indicates, when a value is expressed as “approximately” X or “about X”, the specified value of X shall be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0095] These and other aspects will become apparent from the following written description of the invention. Detailed Implementation

[0096] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed within the technical skill and judgment of those skilled in the art.

[0097] Example

[0098] The following examples are provided to better illustrate the invention. Unless otherwise explicitly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

[0099] Synthesis of intermediate 1:

[0100]

[0101] INT 1-1 (50 g, 303 mmol) was dissolved in 300 mL of ultra-dry tetrahydrofuran, purged with nitrogen, and methyl magnesium bromide (3 M, 303 mL) was slowly added at 0 °C. The mixture was stirred at 0 °C for 10 min, then stirred at room temperature for 5 h. After the reaction was complete, the system was cooled to 0 °C, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then slurried with diethyl ether to give a yellow-brown solid INT 1-2 (35 g, 80%). LCMS: m / z = 145.6 [M+H] + .

[0102] INT 1-2 (10 g, 69 mmol) was dissolved in 100 mL of tetrahydrofuran, followed by the addition of 3,4-dihydro-2H-pyran (11.6 g, 138 mmol), and then p-toluenesulfonic acid (2.37 g, 13.8 mmol). The reaction was carried out at 70 °C for 48 hours. After the reaction was completed, the solvent was evaporated and the mixture was separated by normal-phase chromatography (PE / EA) to give a pale yellow liquid, INT 1-3 (11.5 g, 73%). LCMS: m / z = 229.6 [M+H] + .

[0103] INT 1-3 (10 g, 43.7 mmol), (E)-2-(ethoxycarbonyl)vinylboronic acid pinacol ester (10.9 g, 48 mmol), PdCl2 (dtbpf) (854 mg, 1.31 mmol), and sodium carbonate (9.26 g, 87.4 mmol) were dissolved in 100 mL of an ultradry mixed solvent of 1,4-dioxane and 20 mL of water. Nitrogen gas was purged, and the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was dispersed in ethyl acetate, filtered, and the solvent was evaporated to dryness again. The mixture was then slurried with diethyl ether, yielding only 5 g of solid. The remainder was separated by normal-phase column chromatography (PE / EA) to give a white solid INT 1-4 (10 g, 78%). LCMS: m / z = 293.1 [M+H] + .

[0104] Dissolve INT 1-4 (4.1 g, 14.2 mmol) in 80 mL of methanol, add 10% Pd / C (2 g), and react at 30 °C for 1 hour in a medium-pressure hydrogen generator (approximately 0.4 MPa). After the reaction is complete, filter off the Pd / C, and evaporate the solvent to obtain crude INT 1-5, which can be used directly in the next step.

[0105] INT 1-5 (4 g, 13.6 mmol) was dissolved in a mixed solvent of 32 mL tetrahydrofuran and 8 mL water. Lithium hydroxide (651 mg, 27.2 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was evaporated to dryness, and the product was extracted with water and ethyl acetate to remove impurities. The pH of the aqueous phase was then adjusted to 2-3, and the product was extracted with ethyl acetate to give a colorless, transparent liquid, INT 1-6 (3.02 g, 83%). LCMS: m / z = 267.1 [M+H] + .

[0106] INT 1-6 (3.76 g, 14.1 mmol) was dissolved in 50 mL of tetrahydrofuran, and the borane-tetrahydrofuran complex (1 M, 28 mL) was stirred at room temperature for 30 min at 0 °C. After the reaction was complete, the system was cooled to 0 °C, quenched with methanol, and the solvent was evaporated to dryness. The solution was then separated by normal phase column chromatography (PE / EA) to give a colorless, transparent liquid INT 1-7 (3.5 g, 98%). LCMS: m / z = 253.1 [M+H] + .

[0107] INT 1-7 (5 g, 19.8 mmol) was dissolved in 80 mL of dichloromethane, and 5 g of 100-200 mesh silica gel powder was added. Pyridinium chlorochromate (6.4 g, 30 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 7 hours. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the solution was separated by normal-phase column chromatography (PE / EA) to obtain a pale yellow transparent liquid, INT 1 (3.07 g, 62%). LCMS: m / z = 251.1 [M+H] + .

[0108] Synthesis of intermediate 2:

[0109]

[0110] INT 1-2 (19.7 g, 136.3 mmol) was dissolved in 200 mL of DMF. NaH (6 g, 60% 150 mmol) was added at 0 °C, and after 20 min, SEM-Cl (25 g, 150 mmol) was added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the solution was washed with saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by normal-phase chromatography (PE / EA) to obtain a yellow liquid, INT 2-1 (20.8 g, 56%). LCMS: m / z = 275.1 [M+H] + .

[0111] INT 2-1 (20 g, 73 mmol), (E)-2-(ethoxycarbonyl)vinylboronic acid pinacol ester (18.1 g, 80 mmol), PdCl2 (dtbpf) (1.43 g, 2.19 mmol), and sodium carbonate (15.5 g, 146 mmol) were dissolved in 150 mL of an ultradry mixed solvent of 1,4-dioxane and 30 mL of water. Nitrogen gas was purged, and the mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was dispersed in ethyl acetate. The solution was filtered, the solvent was evaporated to dryness again, and the mixture was separated by normal-phase column chromatography (PE / EA) to obtain a red oily liquid INT 2-2 (16 g, 65%). LCMS: m / z = 339.2 [M+H] + .

[0112] Dissolve INT 2-2 (14 g, 41 mmol) in 1400 mL of methanol, add 10% Pd / C (7 g), and react at 30 °C for 1 hour in a medium-pressure hydrogen generator (approximately 0.4 MPa). After the reaction is complete, filter off the Pd / C and evaporate the solvent to obtain crude INT 2-3, which can be used directly in the next step.

[0113] INT 2-3 (13.8 g, 40.7 mmol) was dissolved in a mixed solvent of 130 mL tetrahydrofuran and 33 mL water. Lithium hydroxide (1.95 g, 81.4 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the solvent was evaporated to dryness, and the product was extracted with water and ethyl acetate to remove impurities. The pH of the aqueous phase was then adjusted to 2-3, and the product was extracted with ethyl acetate to give a yellow liquid INT2-4 (12 g, 94%). LCMS: m / z = 313.1 [M+H] + .

[0114] INT 2-4 (12 g, 38.4 mmol) was dissolved in 120 mL of tetrahydrofuran, and the borane-tetrahydrofuran complex (1 M, 77 mL) was stirred at room temperature for 30 min at 0 °C. After the reaction was complete, the system was cooled to 0 °C, quenched with methanol, and the solvent was evaporated to dryness. The solution was then separated by normal phase column chromatography (PE / EA) to give a pale yellow transparent liquid, INT 2-5 (9 g, 78%). LCMS: m / z = 299.1 [M+H] + .

[0115] INT 2-5 (5 g, 16.8 mmol) was dissolved in 80 mL of dichloromethane, and 5 g of 100-200 mesh silica gel powder was added. Pyridinium chlorochromate (5.4 g, 25 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 7 hours. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the solution was separated by normal-phase column chromatography (PE / EA) to obtain a pale yellow transparent liquid, INT 2 (3.11 g, 62%). LCMS: m / z = 297.1 [M+H] + .

[0116] Synthesis of intermediate 3:

[0117]

[0118] 2,5-Difluoro-4-iodopyridine (30 g, 124.5 mmol) was dissolved in 350 mL of 1,4-dioxane, and nitrogen gas was introduced. Hydrazine hydrate (73.3 g, 50.06 mmol) was slowly added at 25 °C, and the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was extracted with water and ethyl acetate. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain crude INT 3-1, which was used directly in the next step. LCMS: m / z = 254.0 [M+H] + .

[0119] INT 3-1 (20 g, 253 mmol) was dissolved in 234 g formic acid, purged with nitrogen, and stirred at 100 °C for 12 hours. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was separated by normal-phase chromatography (PE / EA) to give a pale yellow solid INT 3-2 (15 g, 72%). LCMS: m / z = 264.0 [M+H] + .

[0120] INT 3-2 (16 g, 60.8 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (17 g, 140 mmol), CuI (579 mg, 3.04 mmol), Pd(PPh3)4, and triethylamine (18.5 g, 182 mmol) were dissolved in 450 mL of 1,2-dichloroethane, purged with nitrogen, and stirred at 60 °C for 12 hours. After the reaction was complete, the mixture was filtered, the solvent was evaporated to dryness, and the solution was separated by normal-phase chromatography (PE / EA) to give a yellow solid INT 3-3 (15.23 g, 91%). LCMS: m / z = 276.1 [M+H] + .

[0121] INT 3-3 (13.2 g, 50 mmol) was dissolved in 200 mL of methanol, and p-toluenesulfonic acid (15.7 g, 91 mmol) was added. The mixture was stirred at 40 °C for 1 hour. After the reaction was complete, the solvent was evaporated to dryness, and the solution was separated by normal-phase chromatography (DCM / MeOH) to give a yellow solid INT 3-4 (8.31 g, 86%). LCMS: m / z = 194.1 [M+H] + .

[0122] INT 3-4 (10 g, 51.7 mmol) was dissolved in 150 mL of methanol, and 10% Pd / C (4 g) was added. The mixture was reacted at 30 °C for 1 hour in a medium-pressure hydrogen generator (approximately 0.4 MPa). After the reaction was complete, the Pd / C was filtered off, the solvent was evaporated to dryness, and the mixture was separated by normal-phase chromatography (DCM / MeOH) to obtain a pale yellow solid INT 3-5 (8.3 g, 81%). LCMS: m / z = 198.1 [M+H] + .

[0123] INT 3-5 (8.3 g, 42.6 mmol) was dissolved in 150 mL of dichloromethane. Tetramethylpiperidine oxide (200 mg, 1.28 mmol) and an aqueous solution of potassium bromide (507 mg, 4.26 mmol) were added at 0 °C. Then, a solution of sodium bicarbonate (4.3 g, 51.12 mmol) in sodium hypochlorite (63.4 g, 51.12 mmol) was added dropwise. The reaction was carried out at 0 °C for 0.5 hours. After the reaction was complete, the solvent was evaporated to dryness, and the solution was separated by normal-phase chromatography (DCM / MeOH) to obtain a yellow oily liquid INT 3 (500 mg, 6%). LCMS: m / z = 194.1 [M+H] + .

[0124] Synthesis of intermediate 4:

[0125]

[0126] INT 4-1 (28.22 g, 100 mmol) and DMF (1 mL) were dissolved in DCM (300 mL). Then, (COCl)₂ (15.2 g, 120 mmol) was added to the suspension at room temperature. After stirring at room temperature for 2 hours, the mixture was cooled to 0°C. INT 4-2 (150 mmol, 11.0 g) and Et₃N (20.2 g, 200 mmol) were dissolved in DCM (100 mL) and added dropwise to the mixture. After stirring at room temperature for 2 hours, the mixture was quenched with water. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The mixture was then extracted once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. The crude product obtained by rotary evaporation was pulped with PE / EA to give a white solid INT 4-3 (36 g, 89%). LCMS: m / z = 337.1 [M+H] + .

[0127] INT 4-3 (33.7 g, 100 mmol) and THF (400 mL) were added to a three-necked flask and purged three times with N2. The flask was cooled to -78 °C. LDA (60 mL, 120 mol, 2.0 M in THF) was slowly added, and the mixture was stirred at -78 °C for 2 hours after the addition was complete. DMF (36.5 g, 500 mmol) was then added, and the mixture was stirred at this temperature for 2 hours. The mixture was quenched with 200 mL of saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product obtained by rotary evaporation was purified by column chromatography to give a white solid INT 4-4 (16.5 g, 45%). LCMS: m / z = 366.1 [M+H] + .

[0128] INT 4-4 (19.5 g, 53 mmol) was dissolved in HCl (5% w / w, 80 mL) and AcOH (80 mL), and the mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were neutralized with saturated sodium bicarbonate solution, and the organic phases were collected separately and dried over sodium sulfate. The crude product obtained by rotary evaporation was slurryed with PE / EA to give a white solid INT 4-5 (7 g, 43%). LCMS: m / z = 310.9 [M+H] + .

[0129] INT 4-5 (3.1 g, 10 mmol) and NH₂NH₂·H₂O (600 mg, 12 mmol) were dissolved in EtOH (50 mL) and stirred under reflux for 5 hours. The reaction solution was cooled to room temperature and filtered to obtain a white solid INT 4-6 (2.0 g, 67%). LCMS: m / z = 306.9 [M+H] + .

[0130] INT 4-6 (17 g, 55.5 mmol) was dissolved in DMF (170 mL) and cooled to 0 °C. NaH (3.3 g, 83.3 mmol) was added in portions, and the mixture was stirred at 0 °C for 30 min after the addition was complete. A DMF (20 mL) solution of CH3I (11.8 g, 83.3 mmol) was added to the above solution, and the mixture was stirred at room temperature for 16 hrs. The solution was quenched with 200 mL of water, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The crude product obtained by rotary evaporation was purified by column chromatography to give a white solid INT 4 (16 g, 89.7%). LCMS: m / z = 320.9 [M+H] + .

[0131] Synthesis of Intermediate 5:

[0132]

[0133] (Methoxymethyl)triphenylphosphine chloride (103 g, 300 mmol) was added to THF (500 mL) to replace N2. The mixture was cooled to 0 °C, and LDA (157.5 mL, 315 mmol, 2 M in THF) was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 30 min. The reaction mixture was then cooled to 0 °C, and INT 5-1 (31.8 g, 150 mmol) was dissolved in THF (200 mL) and added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to 25 °C and the reaction was allowed to proceed for 30 min. H2O (300 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 500 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain an off-white solid INT 5-2 (33 g, 91.6%). LCMS [M+H-56] + =184.1.

[0134] Compound INT 5-2 (33 g, 137 mmol) was added to DCM (330 mL) and H2O (165 mL), and the mixture was cooled to 0 °C. TFA (78 g, 684 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to 25 °C, and the reaction was allowed to proceed for 1 hour. H2O (200 mL) was then added to the reaction mixture, followed by the addition of saturated NaHCO3 aqueous solution to adjust the pH to 8–9. The mixture was extracted with DCM (3 x 300 mL), and the organic phase was dried over sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography to obtain a white solid INT 5-3 (26 g, 83.6%). LCMS [M+H-56] + =170.3.

[0135] INT 4 (12 g, 37 mmol) was added to THF (240 mL) to replace N2, and the mixture was cooled to 0 °C. i-PrMgCl LiCl (42.3 mL, 55 mmol, 1.3 M in THF) was slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed for 30 min. INT 5-3 (9.2 g, 40.7 mmol) was dissolved in THF (25 mL) and added dropwise to the reaction mixture. After the reaction was complete, the reaction mixture was heated to 25 °C and reacted for 30 min. H2O (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 300 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid INT 5-4 (12 g, 76.4%). LCMS [M+H-56] + =364.1.

[0136] Compound INT 5-4 (12 g, 28.5 mmol) was added to DCM (120 mL), and the mixture was cooled to 0 °C. DMP (13.2 g, 31 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to 25 °C, and the reaction was allowed to proceed for 2 hours. H₂O (200 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 200 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid INT 5-5 (11 g, 92.1%). LCMS [M+H] + =362.1.

[0137] INT 5-5 (4 g, 9.5 mmol) was added to DCM (40 mL), and the mixture was cooled to 0 °C. TFA (15 mL) was slowly added dropwise to the reaction mixture. After the reaction was complete, the temperature was raised to 25 °C and the reaction proceeded for 1 hour. The reaction solution was concentrated and evaporated to dryness to obtain a white solid INT 5-6 (4 g, 96.7%). LCMS [M+H] + =318.2.

[0138] Compound INT 5-6 (2.5 g, 5.7 mmol) was added to DCM (25 mL), and the mixture was cooled to 0 °C. TEA (0.581 g, 5.7 mmol) was slowly added dropwise to the reaction mixture, followed by INT 1 (1.58 g, 6.3 mmol) and AcOH (2.5 mL). After reacting for 30 min, STAB (2.4 g, 11.4 mmol) was added. The mixture was then heated to 25 °C and reacted for 2 h s. H₂O (200 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 200 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid INT 5-7 (1.1 g, 34.4%). LCMS [M+H] + =552.4.

[0139] Compound INT 5-7 (500 mg, 0.9 mmol) was added to EtOH (10 mL), followed by the slow addition of Py (426 mg, 5.4 mmol) to the reaction mixture. Then, NH₂OH·HCl (189 mg, 2.7 mmol) was added. After completion, the mixture was heated to 80 °C and reacted overnight. H₂O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid INT 5 (400 mg, 77.8%). LCMS [M+H] + =567.3.

[0140] Example 1

[0141] Synthesis of Compound 1:

[0142]

[0143] INT 5-7 (100 mg, 0.18 mmol), cyclopropylamine (12.4 mg, 0.22 mmol), acetic acid (32 mg, 0.54 mmol), and sodium cyanoborohydride (33 mg, 0.54 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at 80 °C for 36 hours. After the reaction was completed, the solvent was evaporated, and the crude product 1-1 was used directly in the next step.

[0144] Compound 1-1 (approximately 10 mg, LCMS content) was dissolved in 1 mL of dichloromethane, and 0.1 mL of trifluoroacetic acid was added. The mixture was stirred at 42 °C for 2 hours. After the reaction was completed, it was separated preparatively to obtain a white solid – compound 1 (2 mg, 100% Purity). LCMS: m / z = 509.3 [M+H] + .

[0145] Example 2

[0146] Synthesis of compound 2:

[0147]

[0148] INT 5-6 (1.19 g, 2.76 mmol) was dissolved in 20 mL of dichloromethane. INT 3 (800 mg, 4.14 mmol), triethylamine (281 mg, 2.76 mmol), and acetic acid (4 mL) were added at 0 °C. The mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (1.5 g, 7 mmol) was added at 0 °C, and the reaction was carried out at 40 °C for 16 h. After the reaction was complete, the mixture was diluted with dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was separated by reversed-phase chromatography (water / acetonitrile) to obtain a pale yellow oily liquid 2-1 (540 mg, 40%).

[0149] 2-1 (520 mg, 1.05 mmol), hydroxylamine hydrochloride (219 mg, 3.15 mmol), and pyridine (498 mg, 6.3 mmol) were dissolved in 7 mL of ethanol and reacted at 80 °C for 6 hours. After the reaction was completed, the solvent was evaporated and the mixture was separated by normal phase chromatography (DCM / MeOH) to obtain a light yellow oily liquid 2-2 (534 mg, 99%).

[0150] Dissolve 2-2 (300 mg, 0.59 mmol) in 5 mL of acetic acid. Add zinc powder (385 mg, 5.9 mmol) in portions at 0 °C, purging with nitrogen. React for 6 hours, then at 60 °C for 7 hours. After the reaction is complete, evaporate the solvent to dryness and separate by reversed-phase chromatography (H2O / MeCN) to obtain a pale yellow oily liquid 2-3 (74 mg, 25%).

[0151] Compound 2-3 (74 mg, 0.15 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (22.7 mg, 0.23 mmol) was added at 0 °C, followed by trifluoroacetic anhydride (38 mg, 0.18 mmol) after 15 minutes. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was preparatively separated to give a white solid – compound 2 (14 mg, 95.5% Purity). LCMS: m / z = 592.3 [M+H] + .

[0152] Compound 2: 1 H NMR (400MHz, DMSO-d6) δ9.99(d,J=7.7Hz,1H),9.16(s,1H),8.74(d,J=4.7Hz,1H),8.65(s ,1H),8.15(s,1H),7.90(d,J=8.3Hz,1H),7.79(d,J=8.4Hz,1H),7.70(d,J=6.5Hz,1H),5.5 0–5.44(m,1H),3.68(s,3H),3.57–3.49(m,2H),2.90–2.79(m,1H),2.71–2.65(m,4H),2.34 –2.28(m,1H),2.13–2.06(m,1H),2.03–1.89(m,2H),1.87–1.79(m,1H),1.71–1.62(m,2H).

[0153] Example 3

[0154] Synthesis of compound 3:

[0155]

[0156] INT 5 (300 mg, 0.53 mmol) was dissolved in 6 mL of acetic acid. Zinc powder (1.04 g, 15.9 mmol) was added in portions at 0 °C, purging with nitrogen, and the mixture was stirred overnight at room temperature. After the reaction was complete, the product was extracted with H₂O / EA. The product was in the aqueous phase. The aqueous phase was evaporated to dryness and passed through a reversed-phase column (H₂O / MeCN), but the product was finally eluted with pure methanol to give a yellow oily liquid 3-1 (33 mg, 11%). LCMS: m / z = 553.1 [M+H] + .

[0157] Dissolve 3-1 (33 mg, 0.06 mmol) in 1 mL of dichloromethane. Add triethylamine (9 mg, 0.09 mmol) at 0 °C. After 15 min, add acetic anhydride (7.4 mg, 0.072 mmol) and 4-dimethylaminopyridine (0.4 mg, 0.05 mmol). Stir at room temperature for 2 hours. After the reaction is complete, evaporate the solvent directly to obtain crude 3-2, which is then added to the solution.

[0158] Compound 3-2 (crude product) was dissolved in 0.5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was evaporated to obtain a white solid, compound 3 (3.2 mg, 97.16% Purity). LCMS: m / z = 511.1 [M+H] + .

[0159] Compound 3: 1 H NMR (400MHz, DMSO) δ12.75(s,1H),8.63(s,1H),8.40(d,J=8.2Hz,1H),8.16(s,1H),7.84(d,J =8.3Hz,1H),7.70(d,J=8.3Hz,1H),7.65(s,1H),5.36–5.30(m,1H),3.67(s,3H),3.18–3.10(m ,2H),2.69–2.59(m,2H),2.47–2.40(m,4H),2.24–2.17(m,1H),2.06–2.00(m,1H),1.98(s,3H ),1.95–1.87(m,1H),1.81(s,3H),1.73(dd,J=11.5,8.6Hz,1H),1.47(dt,J=14.3,7.2Hz,2H).

[0160] Example 4

[0161] Synthesis of Compound 4

[0162]

[0163] INT 5-4 (2 g, 4.7 mmol), 4-1 (695 mg, 4.7 mmol), and PPh3 (1.47 g, 5.6 mmol) were added to THF (20 mL) to replace N2. The mixture was cooled to 0 °C, and DEAD (980 mg, 5.6 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for 2 hours. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid 4-2 (2.5 g, 95.6%). LCMS [M+H-56]+ =493.2.

[0164] Compound 4-2 (2.5 g, 4.5 mmol) and N₂H₄·H₂O (400 mg, 6.75 mmol) were added to MeOH (25 mL) and heated to 70 °C overnight. H₂O (100 mL) was then added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid 4-3 (1.7 g, 89.1%). LCMS [M+H-56] + =363.2.

[0165] At 0 °C, 4-3 (900 mg, 2.1 mmol), 4-4 (336 mg, 3.2 mmol), HATU (1.6 g, 4.2 mmol), and DIEA (819 mg, 6.3 mmol) were added to DMF (10 mL), replacing N2, and the reaction was carried out at 25 °C for 2 hours. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid 4-5 (340 mg, 31.3%). LCMS [M+H-56] + =449.3.

[0166] Add 4-5 (340 mg, 0.67 mmol) to DCM (4 mL), cool to 0 °C, and slowly add TFA (1.5 mL) dropwise to the reaction mixture. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction solution and evaporate to dryness to obtain a white solid 4-6 (340 mg, 97.3%). LCMS [M+H] + =405.3.

[0167] Compounds 4-6 (200 mg, 0.38 mmol) were added to DCM (2 mL), cooled to 0 °C, and TEA (39 mg, 0.38 mmol) was slowly added dropwise. Then, INT 2 (169 mg, 0.57 mmol) and AcOH (0.2 mL) were added. After reacting for 30 min, STAB (161 mg, 0.76 mmol) was added. The mixture was then heated to 25 °C and reacted for 2 h s. H₂O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid 4-7 (200 mg, 75.7%). LCMS [M+H] + =685.7.

[0168] Compounds 4-7 (200 mg, 0.29 mmol) were added to DCM (2 mL), cooled to 0 °C, and after the addition of TFA (2 mL) was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 30 min. H₂O (100 mL) was added to the reaction mixture, followed by the addition of saturated NaHCO₃ aqueous solution to adjust the pH to 8–9. Extraction was performed using DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. Preparative separation yielded a white solid mixture of 4A and 4B (33.8 mg, 20.8%). LCMS [M+H] + =555.4.

[0169] 4A and 4B: 1 H NMR(400MHz,Chloroform-d)δ10.55(s,1H),8.41(d,J=4.8Hz,1H),7.65(d,J=8.2Hz,1H),7.56(s,1H),7 .45(dd,J=8.3,2.8Hz,1H),6.03(dd,J=51.6,7.8Hz,1H),5.56(dt,J=17.6,8.8Hz,1H),4.82–4.57(m,1H ),3.80(s,3H),3.52–3.25(m,4H),2.79–2.65(m,1H),2.61–2.48(m,4H),2.41(t,J=9.5Hz,1H),2.32–2. 15(m,2H),2.11(s,3H),2.01(d,J=7.3Hz,1H),1.91–1.70(m,2H),1.70–1.57(m,2H),1.19–1.06(m,1H).

[0170] Example 5

[0171] Synthesis of Compound 5

[0172]

[0173] At 0 °C, 4-3 (800 mg, 1.9 mmol), 5-1 (294 mg, 2.8 mmol), HATU (1.44 g, 3.8 mmol), and DIEA (741 mg, 5.7 mmol) were added to DMF (8 mL), replacing N2. The reaction was carried out at 25 °C for 2 hours. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid, 5-2 (500 mg, 51.8%). LCMS [M+H-56] + =449.3.

[0174] Add 5-2 (500 mg, 0.99 mmol) to DCM (5 mL), cool to 0 °C, and slowly add TFA (1.5 mL) dropwise to the reaction mixture. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction solution and evaporate to dryness to obtain a white solid 5-3 (500 mg, 97.3%). LCMS [M+H] + =405.3.

[0175] Compound 5-3 (200 mg, 0.38 mmol) was added to DCM (2 mL), cooled to 0 °C, and TEA (39 mg, 0.38 mmol) was slowly added dropwise. Then, INT 2 (169 mg, 0.57 mmol) and AcOH (0.2 mL) were added. After reacting for 30 min, STAB (161 mg, 0.76 mmol) was added. The mixture was then heated to 25 °C and reacted for 2 h s. H₂O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid 5-4 (150 mg, 56.8%). LCMS [M+H] + =685.7.

[0176] Compound 5-4 (150 mg, 0.21 mmol) was added to DCM (2 mL), cooled to 0 °C, and after the addition of TFA (2 mL) was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 30 min. H₂O (100 mL) was added to the reaction mixture, followed by the addition of saturated NaHCO₃ aqueous solution to adjust the pH to 8–9. Extraction was performed using DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. Preparative separation yielded a white solid mixture of 5A and 5B (36.4 mg, 29.9%). LCMS [M+H] + =555.4.

[0177] 5A and 5B: 1H NMR(400MHz,Chloroform-d)δ11.05(s,1H),8.43(d,J=3.3Hz,1H),7.65(dd,J=8.2,3.2Hz,1H ),7.56(s,1H),7.48(dd,J=8.3,4.6Hz,1H),6.63(dd,J=51.5,8.5Hz,1H),5.49(q,J=8.7Hz,1H ),4.93–4.63(m,1H),3.79(s,3H),3.67–3.29(m,4H),2.74(p,J=8.0Hz,1H),2.70–2.48(m,4H) ,2.37–2.15(m,2H),2.08(s,3H),2.01(d,J=6.6Hz,1H),1.96–1.77(m,2H),1.45–1.27(m,4H).

[0178] Example 6

[0179] Synthesis of compound 6:

[0180]

[0181] 4-3 (274 mg, 0.65 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (99 mg, 0.98 mmol) was added at 0 °C. After 15 min, acetic anhydride (80 mg, 0.78 mmol) and 4-dimethylaminopyridine (4 mg, 0.033 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated and the mixture was separated by normal-phase column chromatography (DCM / MeOH) to give a white solid compound 6-1 (260 mg, 86%). LCMS: m / z = 405.2 (product MS-56) [M+H]+.

[0182] Dissolve 6-1 (260 mg, 0.56 mmol) in 3 mL of dichloromethane, add 0.6 mL of trifluoroacetic acid at 0 °C, and stir for 1 hour at room temperature. After the reaction is complete, evaporate the solvent to obtain crude 6-2, which can be used directly in the next step. LCMS: m / z = 361.1 [M+H]+.

[0183] 6-2 (100 mg, 0.21 mmol) was dissolved in 2 mL of dichloromethane. INT 3 (61 mg, 0.32 mmol), triethylamine (21 mg, 0.21 mmol), and acetic acid (0.5 mL) were added at 0 °C. The mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added at 0 °C, and the reaction was allowed to proceed for 4 hours at room temperature. After the reaction was complete, the solvent was evaporated to obtain a white solid – compound 6 (20 mg, 99.67% Purity). LCMS: m / z = 538.2 [M+H]+.

[0184] Compound 6: 1 H NMR (400MHz, DMSO) δ9.15(s,1H),8.73(d,J=4.7Hz,1H),8.63(s,1H),8.41(d,J=8.2Hz,1H),8.22(s,1H) ,7.83(d,J=8.3Hz,1H),7.69(t,J=7.0Hz,2H),5.33(t,J=8.8Hz,1H),3.67(s,3H),3.33(dd,J=13.1,7.5H z,2H),3.27(d,J=7.8Hz,1H),3.21(d,J=7.7Hz,1H),2.70–2.59(m,3H),2.54(d,J=6.8Hz,1H),2.21(t,J =8.2Hz,1H),2.07–1.88(m,2H),1.81(s,3H),1.73(dd,J=11.4,8.5Hz,1H),1.62(dt,J=13.8,6.8Hz,2H).

[0185] Example 7

[0186]

[0187] Dissolve 4-6 (171 mg, 0.33 mmol) in 3 mL of dichloromethane. Add INT 3 (70 mg, 0.36 mmol), triethylamine (33 mg, 0.33 mmol), and acetic acid (0.6 mL) at 0 °C. Stir at room temperature for 15 min. Add sodium triacetoxyborohydride (105 mg, 0.5 mmol) at 0 °C and react at room temperature for 4 h. After the reaction is complete, evaporate the solvent to prepare compound 7 (22 mg, 99.48% Purity), a mixture of white solid compounds 7A and 7B. LCMS: m / z = 582.2 [M+H]+.

[0188] A mixture of 7A and 7B: 1H NMR (400MHz, DMSO) δ9.16 (s, 1H), 8.74 (d, J = 4.7Hz, 1H), 8.69–8.62 (m, 1H), 8.59–8.16 (m, 1H), 7.85 ( dd,J=8.3,2.8Hz,1H),7.74–7.67(m,2H),5.46–5.27(m,1H),4.94–4.64(m,1H),3.67(d,J=3.9Hz,3H ),3.50(s,2H),3.41(d,J=18.9Hz,2H),2.75–2.62(m,5H),2.26(dd,J=9.6,6.3Hz,1H),2.15–2.08(m ,1H),2.03–1.95(m,1H),1.82–1.74(m,2H),1.70–1.62(m,2H),1.56–1.44(m,1H),1.07–0.95(m,1H).

[0189] Example 8

[0190]

[0191] At 0 °C, 4-3 (300 mg, 0.72 mmol), 7-1 (86 mg, 0.86 mmol), HATU (548 mg, 1.44 mmol), and DIEA (279 mg, 2.16 mmol) were added to DMF (4 mL), and the reaction was carried out at 25 °C for 1 hour. H2O (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 50 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a colorless, transparent oily liquid 7-2 (320 mg, 88% yield). LCMS [M+H] + =501.1.

[0192] Add 7-2 (500 mg, 0.99 mmol) to DCM (5 mL), cool to 0 °C, and slowly add TFA (1 mL) dropwise to the reaction system. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction solution and evaporate to dryness to obtain a pale yellow oily liquid 7-3 (500 mg, 97.3% yield). LCMS [M+H] + =401.2.

[0193] Compound 7-3 (300 mg, 0.58 mmol) was added to DCM (3 mL), and the mixture was cooled to 0 °C. Triethylamine (117 mg, 1.16 mmol) was slowly added dropwise to the reaction mixture, followed by INT 2 (259 mg, 0.87 mmol) and AcOH (0.6 mL). After reacting for 15 min, STAB (184 mg, 0.87 mmol) was added. The mixture was then heated to 25 °C and reacted for 1 hr. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a pale yellow oily liquid 7-4 (345 mg, 87% yield). LCMS [M+H] + =681.5.

[0194] Compound 7-4 (340 mg, 0.5 mmol) was added to DCM (3 mL), cooled to 0 °C, and TFA (3 mL) was added. The mixture was then heated to 25 °C and reacted for 30 min. H₂O (50 mL) was added to the reaction mixture, followed by the addition of saturated NaHCO₃ aqueous solution to adjust the pH to 8–9. The mixture was extracted with DCM (3 x 50 mL), and the organic phase was dried over sodium sulfate. The crude product, compound 7-5, obtained by concentration under reduced pressure was used directly in the next step. LCMS [M+H] + =581.3.

[0195] Compounds 7-5 were added to MeOH (3.5 mL), cooled to 0 °C, and then ammonia (1.5 mL) was added. The mixture was then heated to 25 °C and reacted for 30 min. The crude product obtained by vacuum concentration was preparatively separated to give a white solid mixture of 8A and 8B – compound 8 (37 mg, 13.4% yield). LCMS [M+H] + =551.26.

[0196] Compound 8: 1H NMR (400MHz, CDCl3) δ8.41(d,J=9.7Hz,1H),7.62(dd,J=8.2,2.1Hz,1H),7.56(s,1H),7.45(dd,J=8.2,4.8Hz,1H),6.37(t ,J=9.2Hz,1H),5.52(dd,J=14.5,8.6Hz,1H),3.78(d,J=3.6Hz,4H),3.72–3.69(m,1H),3.56(d,J=9.1Hz,1H),2.84–2.68( m,3H),2.58–2.43(m,3H),2.42–2.32(m,1H),2.27–2.19(m,1H),2.07(s,3H),1.89(dd,J=12.4,7.8Hz,1H),1.77–1.67(m, 2H),1.40–1.32(m,1H),1.31–1.23(m,3H),1.19–1.12(m,1H),1.11–1.07(m,2H),1.03(d,J=6.0Hz,1H),0.62–0.51(m,1H).

[0197] Example 9

[0198]

[0199] Dissolve 4-3 (300 mg, 0.72 mmol) in 3 mL of DCM. Add 8-1 (187 mg, 1.07 mmol), DMAP (4 mg, 0.036 mmol), and triethylamine (182 mg, 1.8 mmol) at 0 °C, and react at 25 °C for 1 hour. Add 50 mL of H2O to the reaction mixture, extract with EA (3 x 50 mL), dry the organic phase with sodium sulfate, concentrate under reduced pressure to obtain crude product, and purify by column chromatography to give white solid 8-2 (320 mg, 89.6% yield). LCMS [M+H-56] + =441.1.

[0200] Add 8-2 (320 mg, 0.64 mmol) to DCM (3 mL), cool to 0 °C, and slowly add TFA (0.6 mL) dropwise to the reaction system. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction solution and evaporate to dryness to obtain a pale yellow oily liquid 8-3 (300 mg, 92% yield). LCMS [M+H] + =511.1.

[0201] Compound 8-3 (500 mg, 0.98 mmol) was added to DCM (5 mL), and the mixture was cooled to 0 °C. Triethylamine (198 mg, 1.96 mmol) was slowly added dropwise to the reaction mixture, followed by INT 2 (435 mg, 1.47 mmol) and AcOH (1 mL). After reacting for 15 min, STAB (312 mg, 1.47 mmol) was added. The mixture was then heated to 25 °C and reacted for 1 hr. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a pale yellow oily liquid 8-4 (646 mg, 95% yield). LCMS [M+H] + =677.4.

[0202] Compound 8-4 (646 mg, 0.95 mmol) was added to DCM (6 mL), cooled to 0 °C, and TFA (5 mL) was added. The mixture was then heated to 25 °C and reacted for 30 min. H₂O (50 mL) was added to the reaction mixture, and a saturated NaHCO₃ aqueous solution was added to adjust the pH to 8–9. The mixture was extracted with DCM (3 x 50 mL), and the organic phase was dried over sodium sulfate. The crude product obtained by concentration under reduced pressure was used directly in the next step. LCMS [M+H] + =577.1.

[0203] Compound 8-5 was added to MeOH (5 mL), cooled to 0 °C, then ammonia (2.5 mL) was added, and the mixture was heated to 25 °C and reacted for 30 min. The crude product obtained by vacuum concentration was then preparatively separated to give compound 9 (109 mg, 21% yield) as a white solid. LCMS [M+H] + =547.1.

[0204] Compound 9: 1 H NMR (400MHz, DMSO) δ12.82(s,1H),8.79(s,1H),7.97(d,J=7.6Hz,1H),7.91( d,J=8.3Hz,1H),7.86(d,J=8.3Hz,1H),7.67(s,1H),5.04(t,J=8.0Hz,1H),4. 00–3.82(m,4H),3.68(s,3H),3.03–2.97(m,2H),2.74(s,3H),2.54–2.45(m,3 H),2.25(d,J=8.5Hz,2H),1.99(s,3H),1.96–1.82(m,2H),1.66–1.55(m,2H).

[0205] Example 10

[0206]

[0207] Dissolve 4-3 (300 mg, 0.72 mmol) in 3 mL of ethyl formate and react at 60 °C for 1.5 hrs. Concentrate under reduced pressure to obtain crude product 9-1, which is used directly in the next step. LCMS [M+H-56] + =391.2.

[0208] Add 9-1 (320 mg, 0.72 mmol) to DCM (3 mL), cool to 0 °C, and slowly add TFA (0.6 mL) dropwise to the reaction system. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction solution and evaporate to dryness to obtain a light yellow oily liquid 9-2, which can be used directly in the next step. LCMS [M+H] + =347.1.

[0209] Compound 9-2 (580 mg, 1.26 mmol) was added to DCM (6 mL), and the mixture was cooled to 0 °C. Triethylamine (255 mg, 2.52 mmol) was slowly added dropwise to the reaction mixture, followed by INT 2 (560 mg, 1.89 mmol) and AcOH (1.2 mL). After reacting for 15 min, STAB (400 mg, 1.89 mmol) was added. The mixture was then heated to 25 °C and reacted for 1 hr. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a pale yellow oily liquid 9-3 (487 mg, 62% yield). LCMS [M+H] + =627.6.

[0210] Compound 9-3 (487 mg, 0.78 mmol) was added to DCM (5 mL), cooled to 0 °C, and TFA (4 mL) was added. The mixture was then heated to 25 °C and reacted for 30 min. H₂O (50 mL) was added to the reaction mixture, and a saturated NaHCO₃ aqueous solution was added to adjust the pH to 8–9. The mixture was extracted with DCM (3 x 50 mL), and the organic phase was dried over sodium sulfate. The crude product, compound 9-4, was concentrated under reduced pressure and used directly in the next step. LCMS [M+H] + =527.2.

[0211] Compound 9-4 was added to MeOH (4 mL), cooled to 0 °C, then ammonia (2 mL) was added, and the mixture was heated to 25 °C and reacted for 30 min. The crude product obtained by vacuum concentration was then preparatively separated to give compound 10 (143 mg, 37% yield) as a white solid. LCMS [M+H] + =497.2.

[0212] Compound 10: 1H NMR (400MHz, DMSO) δ12.81(s,1H),8.76(d,J=8.2Hz,1H),8.66(s,1H),8.07(s,1H),7.86(d,J=8.3Hz,1H) ,7.71(d,J=8.3Hz,1H),7.67(s,1H),5.47(t,J=8.7Hz,1H),3.99(q,J=9.9Hz,2H),3.89(q,J=10.4Hz,2H), 3.67(s,3H),3.06–2.95(m,2H),2.69(dt,J=17.1,8.5Hz,1H),2.51–2.46(m,2H),2.34–2.26(m,1H),2.16 (dd,J=11.8,8.5Hz,1H),2.09–2.02(m,1H),1.99(s,3H),1.92(dd,J=11.7,8.9Hz,1H),1.66–1.56(m,2H).

[0213] Example 11

[0214]

[0215] At 0°C, 4-3 (250 mg, 0.6 mmol) and DABCO (135 mg, 1.2 mmol) were added to DCM (2.5 mL), followed by 10-1 (97 mg, 0.9 mmol). After completion, the temperature was raised to 25°C, and the reaction was allowed to proceed for 2 hours. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 50 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid 10-2 (260 mg, 88.4%). LCMS [M+H-56] + =434.2.

[0216] At 0°C, 10⁻² (250 mg, 0.51 mmol) was added to DCM (3 mL), followed by slow dropwise addition of TFA (1 mL). After completion, the temperature was raised to 25°C, and the reaction was allowed to proceed for 1 hour. The reaction solution was concentrated and evaporated to dryness to obtain a yellow oil 10⁻³ (250 mg, 92.3%). LCMS [M+H] + =390.3.

[0217] At 0 °C, compound 10⁻³ (250 mg, 0.5 mmol) was added to DCM (3 mL), followed by the slow addition of triethylamine (102 mg, 1 mmol), then INT 2 (223 mg, 0.75 mmol) and AcOH (0.3 mL). After reacting for 30 min, STAB (159 mg, 0.75 mmol) was added. The mixture was then heated to 25 °C and reacted for 2 h s. H₂O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid 10⁻⁴ (200 mg, 57.1%). LCMS [M+H] + =670.5.

[0218] Compound 10-4 (200 mg, 0.3 mmol) was added to DCM (2 mL), cooled to 0 °C, and after the addition of TFA (2 mL) was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 30 min. The reaction solution was dried, and H2O (50 mL) was added to the reaction mixture. A saturated NaHCO3 aqueous solution was then added to adjust the pH to 8–9. The mixture was extracted with DCM (3 x 50 mL), and the organic phase was dried over sodium sulfate. The crude product was concentrated under reduced pressure. The crude compound was dissolved in MeOH (2 mL), and ammonia (1 mL) was added. The reaction was allowed to proceed for 30 min at 25 °C. The reaction solution was dried, and the mixture was separated preparatively to obtain a white solid 11 (27.3 mg, 16.9%). LCMS [M+H] + =540.1.

[0219] Compound 11: 1 H NMR(400MHz,Chloroform-d)δ10.74(s,1H),8.59(s,1H),7.65(d,J=8.2Hz,1H),7.56(s,1H),7.47(d ,J=8.3Hz,1H),5.37(dd,J=9.7,7.4Hz,1H),4.60(d,J=7.4Hz,1H),3.80(s,3H),3.72(q,J=7.0Hz,1H) ,3.52(d,J=24.2Hz,4H),2.87(s,6H),2.67(d,J=9.5Hz,3H),2.55(t,J=7.8Hz,2H),2.47(d,J=10.3Hz ,1H),2.29(dd,J=12.2,7.7Hz,1H),2.12(s,3H),1.84(dd,J=12.4,8.0Hz,1H),1.68(q,J=7.7Hz,2H).

[0220] Example 12

[0221]

[0222] At 0°C, triphosgene (891 mg, 3 mmol) was added to DCM (8 mL), followed by MeOH (360 mg, 9 mmol) and Py (pyridine, 711 mg, 9 mmol). The reaction was heated to 10°C and reacted for 1.5 hrs. Then, 4-3 (250 mg, 0.6 mmol) and triethylamine (306 mg, 3 mmol) dissolved in DCM (3 mL) at 0°C were slowly added dropwise. After completion, the reaction was carried out at 25°C for 2 hrs. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 x 50 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid 11-1 (90 mg, 31.6%). LCMS [M+H-56] + =421.1.

[0223] At 0°C, 11-1 (90 mg, 0.19 mmol) was added to DCM (2 mL), followed by slow dropwise addition of TFA (0.6 mL). After completion, the temperature was raised to 25°C, and the reaction was allowed to proceed for 1 hour. The reaction solution was concentrated and evaporated to dryness to obtain a yellow oil 11-2 (85 mg, 91.7%). LCMS [M+H] + =377.2.

[0224] Compound 11-2 (85 mg, 0.17 mmol) was added to DCM (2 mL) at 0 °C. Triethylamine (34.7 mg, 0.34 mmol) was slowly added dropwise to the reaction mixture, followed by INT 2 (77 mg, 0.26 mmol) and AcOH (0.2 mL). After reacting for 30 min, STAB (55.1 mg, 0.26 mmol) was added. The mixture was then heated to 25 °C and reacted for 2 h s. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 100 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give a white solid 11-3 (50 mg, 43.9%). LCMS [M+H] + =657.4.

[0225] Compound 11-3 (50 mg, 0.08 mmol) was added to DCM (1 mL), cooled to 0 °C, and after the addition of TFA (1 mL) was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 30 min. The reaction solution was dried, H2O (30 mL) was added to the reaction mixture, and then saturated NaHCO3 aqueous solution was added to adjust the pH to 8-9. The mixture was extracted with DCM (3 x 30 mL), the organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude compound was dissolved in MeOH (1 mL), ammonia (0.5 mL) was added, and the reaction was allowed to proceed at 25 °C for 30 min. The reaction solution was dried, and the mixture was separated preparatively to obtain a white solid 12 (13.2 mg, 32.8%). LCMS [M+H] + =527.1.

[0226] Compound 12: 1 H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.49(s,1H),7.68(d,J=8.2Hz,1H),7.55( s,1H),7.48(d,J=8.3Hz,1H),5.16(s,1H),5.03(s,1H),3.81(s,3H),3.65(s,3H),3.35 –3.13(m,4H),2.64(s,1H),2.49(dt,J=23.0,7.4Hz,4H),2.37(s,1H),2.18(d,J=14.6 Hz,1H),2.13(s,3H),2.08(s,1H),1.79(dd,J=12.2,8.2Hz,1H),1.58(q,J=7.4Hz,2H).

[0227] Example 13

[0228]

[0229] Add 4-2 (700 mg, 1.27 mmol) to DCM (5.6 mL), cool to 0 °C, and slowly add TFA (1.4 mL) dropwise to the reaction mixture. After completion, heat to 25 °C and react for 1 hour. Concentrate the reaction mixture to dryness, add saturated sodium bicarbonate (50 mL), and then extract with (3 x 50 mL) solution. Dry the organic phase with sodium sulfate and concentrate under reduced pressure to obtain crude product 12-1 (0.7 g, 96%). LCMS [M+H] + =449.2.

[0230] INT 3-5 (2.5 g, 12.7 mmol) was dissolved in 50 mL of acetonitrile, and pyridine (3.0 g, 38.0 mmol) was added. A solution of methanesulfonic anhydride in acetonitrile (3.3 mg, 18.9 mmol) was added dropwise at 0 °C. The reaction was allowed to proceed for 2 hours at room temperature. After the reaction was complete, 100 mL of H₂O was added to the reaction mixture, and the mixture was extracted with EA (3 x 100 mL). Separation was performed using a normal-phase column (DCM / MeOH) to give a white solid 12-2 (1.7 g, 48.5%). LCMS: m / z = 274.1 [M+H] + .

[0231] Dissolve 12-2 (409 mg, 1.5 mmol) and 12-1 (560 g, 1.25 mmol) in 11 mL of acetonitrile, add potassium carbonate (517 mg, 38.0 mmol), and react at 80 °C for 16 hrs. After the reaction is complete, separate by reversed-phase C18 column (ACN / H2O) to give a white solid 12-3 (150 mg, 19.1%). LCMS: m / z = 626.2 [M+H] + .

[0232] Compound 12-3 (150 mg, 0.24 mmol) and N₂H₄·H₂O (32 mg, 0.48 mmol) were added to MeOH (3 mL) and heated to 70 °C. The reaction was allowed to proceed overnight. H₂O (10 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 x 10 mL). The organic phase was dried over sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give an off-white solid 12-4 (50 mg, 42.3%). LCMS [M+H-56] + =496.2.

[0233] 12-4 (50 mg, 0.1 mmol) was dissolved in 1 mL of LMF, and 12-5 (12.6 mg, 0.12 mmol), DIPEA (39 mg, 0.3 mmol), and HATU (57.6 mg, 0.15 mmol) were added. The mixture was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was evaporated to obtain a white solid compound 13 (10 mg, 99.3% Purity). LCMS: m / z = 582.05 [M+H]+.

[0234] Compound 13: 1H NMR(400MHz,Chloroform-d)δ8.76(s,1H),8.43(d,J=13.3Hz,1H),8.03(d,J=3.8Hz,1H),7.67 (dd,J=8.2,2.1Hz,1H),7.60–7.54(m,1H),7.51(d,J=8.3Hz,1H),6.48–6.38(m,1H),5.48(q,J =8.4Hz,1H),4.88-4.62(m,1H),3.80(d,J=3.9Hz,3H),3.47-3.30(m,4H),2.79-2.71(m,3H),2 .65-2.58(m,2H),2.48-2.39(m,1H),2.31–2.12(m,2H),1.83-1.74(m,3H),1.46–1.23(m,3H).

[0235] Synthesis of intermediate 6:

[0236]

[0237] 2-Chloro-5-iodobenzoic acid was dissolved in THF, and oxalyl chloride and 1 drop of DMF were added at 0°C. After stirring at 0°C for 2 h, N-isopropylmethylamine was added, and the mixture was stirred at room temperature for 4 h. The solution was concentrated under reduced pressure and extracted with DCM and water. After concentrating the organic phase, the solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain INT6-1. LCMS: m / z = 338.0 [M+H] + .

[0238] INT6-1 was dissolved in 2-methyltetrahydrofuran, purged with nitrogen, and stirred at -78°C for 30 min. Then, LDA tetrahydrofuran solution was added, and the mixture was stirred at -78°C for 1 h. DMF was added, and the mixture was stirred at -78°C for 2 h. The reaction was quenched with dilute hydrochloric acid, and the mixture was extracted three times with EA. The organic phase was concentrated under reduced pressure to obtain crude INT6-2. LCMS: m / z = 366.0 [M+H] + .

[0239] INT6-2 was dissolved in a mixed solvent of acetic acid and dioxane in equal volume ratio. Methylhydrazine sulfate was added, and the mixture was stirred at 100°C for 2 days. After the reaction was cooled to room temperature, most of the solvent was concentrated under reduced pressure. Water was then added, and a solid precipitated. The solid was filtered and washed with water to obtain crude INT6. LCMS: m / z = 320.8 [M+H] + .

[0240] Synthesis of intermediate 7:

[0241]

[0242] 2,5-Difluoro-4-iodopyridine was dissolved in dioxane, and hydrazine hydrate was added. The mixture was stirred overnight at 80°C, and then cooled to room temperature. After concentration under reduced pressure, the mixture was extracted with water and EA. The organic phase was concentrated to give crude INT7-1. LCMS: m / z = 253.9 [M+H] + .

[0243] INT7-1 was dissolved in formic acid and stirred overnight at 100°C. The reaction was then cooled to room temperature, concentrated under reduced pressure, and water was added. A solid precipitated, which was filtered and washed with water to obtain crude INT7-2. LCMS: m / z = 263.9 [M+H] + .

[0244] INT7-2 was dissolved in DCE, and 2-(2-propynyl-1-oxy)tetrahydro-2H-pyran, cuprous iodide, TEA, and tetraphenylphosphine palladium were added. The mixture was purged with nitrogen and stirred overnight at 80°C. After cooling to room temperature, the solution was filtered through diatomaceous earth, washed with EA, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH) to obtain INT7-3. LCMS: m / z = 276.2 [M+H] + .

[0245] INT7-3 was dissolved in a 1M hydrochloric acid-methanol solution and stirred at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain crude INT7-4. LCMS: m / z = 192.0 [M+H] + .

[0246] INT7-4 was dissolved in methanol, and 10% palladium / carbon was added. The mixture was stirred at 30 psi hydrogen pressure for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT7-5. LCMS: m / z = 196.1 [M+H] + .

[0247] INT7-5 was dissolved in acetonitrile, and pyridine and methanesulfonic anhydride were added at 0°C. The mixture was stirred at 0°C for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (DCM / MeOH) to obtain INT7. LCMS: m / z = 274.0 [M+H] + .

[0248] Synthesis of intermediate 8:

[0249]

[0250] 4,5-Dichloropyridazine-3(2H)-one was dissolved in THF, purged with nitrogen, and a solution of methyl magnesium bromide in tetrahydrofuran was added at 0°C. The reaction was brought to room temperature and stirred for 2 hours, then quenched with saturated ammonium chloride solution and extracted with EA. The organic phase was concentrated under reduced pressure to give crude INT8-1. LCMS: m / z = 145.0 [M+H] + .

[0251] INT8-1 was dissolved in DMF, purged with nitrogen, and sodium hydride was added at 0°C. The mixture was stirred for 15 min, then SEM-Cl was added, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with water, extracted three times with EA, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain INT8-2. LCMS: m / z = 275.1 [M+H] + .

[0252] INT8-2 was dissolved in DMF, and 2-(2-propynyl-1-oxy)tetrahydro-2H-pyran, cuprous iodide, potassium carbonate, and tetraphenylphosphine palladium were added. The mixture was purged with nitrogen and stirred at 80°C for 4 hours. After cooling to room temperature, the solution was filtered through diatomaceous earth, washed with EA, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH) to obtain INT8-3. LCMS: m / z = 379.3 [M+H] + .

[0253] INT8-3 was dissolved in methanol, and 10% palladium / carbon and hydrochloric acid were added. The mixture was stirred for 4 hours under 30 psi hydrogen pressure. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT8-4. LCMS: m / z = 299.2 [M+H] + .

[0254] INT8-4 was dissolved in acetonitrile, and pyridine and methanesulfonic anhydride were added at 0°C. The mixture was stirred at 0°C for 2 hours. After concentration under reduced pressure, the solution was purified by silica gel column chromatography (DCM / MeOH) to obtain INT8. LCMS: m / z = 377.2 [M+H] + .

[0255] Example 14

[0256]

[0257] INT6 (1 g, 1 e.g.), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (794 mg, 1.2 eq.), Cs₂CO₃ (3.05 g, 3 e.g.), XantPhos (361 mg, 0.2 eq.), and Pd₂(dba)₃ (285 mg, 0.1 eq.) were dissolved in dioxane (25 mL), and N₂ was introduced. The mixture was reacted at 100 °C for 3 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 14⁻¹ (1.1 g, 87%). LCMS: m / z = 405.3 [M + H₂]. + .

[0258] 14-1 (0.3 g, 1.0 eq) was dissolved in DCM (5 mL), pyridine (195 mg, 3 e. q.) was added, and propionyl chloride (151 mg, 2 e. q.) was added dropwise at 0 °C. After the reaction was completed at room temperature for 3 h, the reaction was quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 14-2 (383 mg, 86%). LCMS: m / z = 405.3 [M + H - 56] + .

[0259] 14-2 (383 mg, 1.0 eq) was dissolved in MeCN (7 mL), and p-toluenesulfonic acid (272 mg, 2 e.q.) was added. The reaction was carried out at 60 °C for 2 h. After concentration under reduced pressure, the mixture was not purified and proceeded directly to the next step to obtain compound 14-3 (280 mg, 98%). LCMS: m / z = 361.3 [M+H] + .

[0260] 14-3 (280 mg, 1.0 eq), INT7 (315 mg, 1.5 eq), and K3PO4 (825 mg, 5 e.q.) were dissolved in DMA (6 mL) and reacted at 60 °C for 16 h. After concentration under reduced pressure, the product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 14 (9.7 mg, 2%). 1 HNMR (400MHz, DMSO-d6): δ9.16 (s, 1H), 8.74 (d, J = 4.8Hz, 1H), 8.04 (s, 1H), 7 .95(d,J=8.4Hz,1H),7.76(d,J=8.0Hz,1H),7.68(d,J=6.8Hz,1H),4.91–4.87 (m,1H),3.69(s,3H),2.68–2.64(m,3H),2.34–2.24(m,2H),2.03–1.83(m,3H ),1.74–1.62(m,4H),1.24(s,4H),0.87–0.83(m,3H).LCMS:m / z=538.38[M+H] + .

[0261] Example 15

[0262]

[0263] 14-1 (500 mg, 1.0 eq) was dissolved in MeCN (10 mL), and p-toluenesulfonic acid (425 mg, 2 e.q.) was added. The reaction was carried out at 60 °C for 2 h. After concentration under reduced pressure, the solution was directly proceeded to the next step without purification to obtain 15-1 (365 mg, 98%). LCMS: m / z = 305.1 [M+H] + .

[0264] 15-1 (365 mg, 1.0 eq), INT7 (273 mg, 1.5 eq), and K3PO4 (1.06 g, 5 e. q.) were dissolved in DMA (10 mL) and reacted at 60 °C for 16 h. After concentration under reduced pressure, the solution was purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 15-2 (120 mg, 21%). LCMS: m / z = 482.2 [M+H] + .

[0265] 15-2 (120 mg, 1.0 eq) was dissolved in DMF (5 mL), pyridine (59 mg, 3 e. q.) was added, and methyl 3-chloro-3-oxopropionate (68 mg, 1.5 eq) was added at 0 °C. After the reaction was completed at room temperature for 3 h, the reaction was quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain crude 15-3 (190 mg, 100%). LCMS: m / z = 582.3 [M+H] + .

[0266] 15-3 (190 mg, 1.0 eq) was dissolved in a mixed solution of concentrated sulfuric acid (1.8 mL) and H2O (5 mL), and the reaction was carried out at 80 °C for 6 h. After concentration under reduced pressure, the product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 15 (9.7 mg, 2%). 1 HNMR (400MHz, DMSO-d6): δLCMS: m / z=568.31[M+H] + . 1HNMR (400MHz, DMSO-d6): δ9.15(s,1H),8.72(d,J=4.4Hz,1H),8.19(s,1H),7.93(dd,J=8.4,4.4Hz,1H),7.70–7.58(m,1H),4.91–4.68(m,1H ),3.86–3.69(m,2H),3.53(s,3H),3.45–3.35(m,4H),3.18–2.88(m,4H),2.66(dd,J=14.0,6.4Hz,1H),2.04–1.90(m,2H),1.80–1.49(m,5H).

[0267] Example 16

[0268]

[0269] 14-1 (0.3 g, 1.0 eq) was dissolved in THF (1 mL), pyridine (1 mL) was added, and acetyl chloride (2 e. q.) was added dropwise at 0 °C. The reaction was allowed to return to room temperature for 3 h. After the reaction was complete, the reaction was quenched with water, and the product was concentrated under reduced pressure to obtain crude 16-1 (330 mg, 100%). LCMS: m / z = 391.2 [M + H - 56] + .

[0270] 16-1 (330 mg, 1.0 eq) was dissolved in TFA (1.5 mL) and DCM (3 mL), reacted at room temperature for 2 h, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH) to obtain 16-2 (112 mg, 44%). LCMS: m / z = 347.1 [M+H] + .

[0271] 16-2 (110 mg, 1.0 eq), INT8 (2.5 eq), and K3PO4 (5 e. q.) were dissolved in DMA (6 mL) and reacted at 60 °C for 16 h. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (DCM / MeOH) to obtain 16-3 (44 mg, 22%). LCMS: m / z = 627.3 [M+H] + .

[0272] 16-3 (44 mg, 1.0 eq) was dissolved in TFA (1.5 mL) and DCM (1.5 mL), and the reaction was completed at room temperature for 2 h. After concentration under reduced pressure, the product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 16 (10 mg, 28%). LCMS: m / z = 497.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.05(s,1H),7.95(d,J=8.3Hz,1H),7.76(d,J=8.3Hz,1H),7.63(s,1H),4.84(q,J=8.6Hz,1H),3.68(s,3H),2 .95(s,2H),2.41(dd,J=17.5,9.9Hz,4H),2.26(m,4H),1.96(s,3H),1.86( t,J=10.3Hz,1H),1.59(d,J=10.6Hz,3H),1.46–1.37(m,2H),1.23(s,1H).

[0273] Example 17

[0274]

[0275] INT6 (2 g, 1 e.g.) was dissolved in THF (15 mL), N2 was introduced, and i-PrMgCl·LiCl (1 M, 1.5 eq) was added at 0 °C. After stirring for 30 min, a THF solution of 6-formyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (773 mg, 1.1 eq) was added. The reaction was completed at room temperature for 30 min, and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 17-1 (1.4 g, 54%). LCMS: m / z = 364.1 [M+1-56] + .

[0276] 17-1 (1.4 g, 1 e.q.), phthalimide (1.1 eq.), and triphenylphosphine (1.1 eq.) were dissolved in THF (20 mL), N2 was introduced, and DIAD (1.2 eq.) was added at 0 °C. The mixture was stirred at 40 °C for 5 h, and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 17-2 (1.5 g, 81%). LCMS: m / z = 493.2 [M+1-56] + .

[0277] 17-2 (1.5 g, 1 e.q.) and hydrazine hydrate (15 e.q.) were dissolved in methanol (10 mL), and N2 was introduced. The mixture was reacted at 70 °C for 5 h. The solution was purified by silica gel column chromatography (dichloromethane / methanol) to give 17-3 (900 mg, 79%). LCMS: m / z = 363.1 [M+1-56] + .

[0278] 17-3 (140 mg, 1 e.q.), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (1.2 eq.), HATU (1.25 eq.), and TEA (2 e.q.) were dissolved in DCM (3 mL), purged with N2, and reacted at room temperature for 3 h. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give 17-4 (160 mg, 96%). LCMS: m / z = 445.2 [M+1-56] + .

[0279] 17-4 (160 mg, 1 e.q.) was dissolved in TFA (1 mL) and DCM (2 mL), N2 was introduced, and the mixture was reacted at room temperature for 3 h. The solution was then concentrated under reduced pressure to obtain crude 17-5 (128 mg, 100%). LCMS: m / z = 401.1 [M+1] + .

[0280] 17-5 (100 mg, 1.0 eq), INT7 (2.5 eq), and K3PO4 (5 e. q.) were dissolved in DMA (6 mL) and reacted at 60 °C for 16 h. After concentration under reduced pressure, the product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 17 (10 mg, 36%). 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=6.5Hz,1H),8.72(t,J=5.5Hz,1H),8.61(d,J=14.3Hz,1H),8.54(d,J=8.0Hz,1H),7.84(dd,J=8.3,5 .7Hz,1H),7.69(dt,J=11.5,7.9Hz,2H),5.40–5.27(m,1H),3.66(dd,J=6.9,2.3Hz,3H),3.26(dd,J=14.8,7.3Hz,3H),3.16(d,J=7.4H z,1H),2.66(t,J=7.6Hz,2H),2.26–2.17(m,1H),2.10–1.88(m,3H),1.71(dt,J=11.6,7.3Hz,1H),1.61(p,J=7.4Hz,2H),1.30(dt,J=8 .5,4.3Hz,1H),1.22(d,J=6.9Hz,3H),1.03(d,J=6.0Hz,2H),0.97(d,J=5.8Hz,2H),0.85(q,J=6.9,5.6Hz,1H).LCMS:m / z=578.3[M+H] + .

[0281] Example 18

[0282]

[0283] 17-3 (300 mg, 1 e.q.), (R)-spiro[2,2]pentane-1-carboxylic acid (1 e.q.), DIPEA (2 e.q.), EDCI (1.25 eq.), and HOBT (1.25 eq.) were dissolved in DMF (5 mL), purged with N2, and reacted at room temperature for 2 h. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give 18-1 (230 mg, 62.5%). LCMS: m / z = 457.2 [M+1-56] + .

[0284] 18-1 (160 mg, 1 e.q.) was dissolved in TFA (1 mL) and DCM (2 mL), and the mixture was purged with N2 and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol) to obtain 18-2 (200 mg, 100%). LCMS: m / z = 413.2 [M+1] + .

[0285] 18-2 (170 mg, 1.0 eq), INT2 (1.5 eq), and sodium cyanoborohydride (2 e. q.) were dissolved in methanol (3 mL). The reaction was carried out at room temperature for 3 h. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (dichloromethane / methanol) to give 18-3 (80 mg, 28%). LCMS: m / z = 693.5 [M+1] + .

[0286] 18-3 (80 mg, 1 e.q.) was dissolved in TFA (2 mL) and DCM (2 mL), and N2 was introduced. The mixture was reacted at room temperature for 2 h. After concentration under reduced pressure, the solution was separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 18 (20 mg, 30%). LCMS: m / z = 563.5 [M+1] + .

[0287] 1H NMR (400MHz, DMSO) δ12.81(s,1H),8.57(d,J=19.7Hz,1H),8.42(dd,J=8.4,4.6Hz,1H),7.85(dd,J=8.3,6.7H z,1H),7.74–7.64(m,2H),5.46–5.28(m,1H),3.85(s,3H),3.67(d,J=1.9Hz,3H),2.93(s,2H),2.68(q,J=8.4H z,1H),2.29(s,1H),2.12(m,2H),1.99(s,3H),1.90(dt,J=7.3,4.5Hz,1H),1.86–1.79(m,1H),1.59(s,2H),1. 31(t,J=3.9Hz,1H),1.27–1.22(m,3H),1.17(m,1H),0.89–0.79(m,2H),0.79–0.72(m,1H),0.67–0.41(m,1H).

[0288] Example 19

[0289]

[0290] INT6 (220 mg, 1 e.q.), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (175 mg, 1.2 eq.), Cs₂CO₃ (672 mg, 3 e.q.), XantPhos (i.e., 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, 79 mg, 0.2 eq.), and Pd₂(dba)₃ (63 mg, 0.1 eq.) were placed in 1,4-dioxane (10 mL) and reacted overnight at 100 °C under a N₂ atmosphere. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 0%–10%) to obtain 19-1 (223 mg, 80.2%). LCMS: m / z = 405.2 [M+H]. + .

[0291] Dissolve 19-1 (120 mg, 1.0 eq) in DCM (5 mL), add pyridine (71 mg, 3 e.q.), lower the temperature to 0 °C under a N2 atmosphere, and slowly add acetyl chloride (28 mg, 1.2 eq). Stir at room temperature for 3 h. After the reaction is complete, concentrate under reduced pressure to obtain crude 19-2 (115 mg). LCMS: m / z = 391.1 [M-56+H] + .

[0292] 19-2 (115 mg, 1.0 eq) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 0%–10%) to obtain 19-3 (84 mg, 44%). LCMS: m / z = 347.1 [M+H] + .

[0293] 19-3 (84 mg, 1.0 eq), INT7 (166 mg, 2.5 eq), and K3PO4 (258 mg, 5 e.q.) were placed in DMA (5 mL) and reacted overnight at 60 °C under a N2 atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain 19 (5.1 mg, 4%). LCMS: m / z = 524.2 [M+H] + .

[0294] 1 H NMR (400MHz, DMSO) δ9.17(s,1H),8.76(d,J=4.7Hz,1H),8.06(s,1H),7.96(d,J= 8.2Hz,1H),7.77(d,J=8.3Hz,1H),7.72(d,J=6.7Hz,1H),4.93–4.81(m,1H),3.6 9(s,3H),3.11–2.88(m,2H),2.71(dd,J=18.8,11.6Hz,2H),2.29(d,J=33.4Hz,2 H),2.06–1.91(m,2H),1.73(s,3H),1.62(s,2H),1.45(s,1H),1.31–1.19(m,3H).

[0295] Example 20

[0296]

[0297] Compound 20-1 (240 mg, 1 eq) was dissolved in a dry DCM solution (4 mL), and DIPEA (230 mg, 3 e q) was added. The mixture was cooled to 0 °C under a N2 atmosphere, and acryloyl chloride (81 mg, 1.5 eq) was slowly added dropwise. The mixture was stirred at room temperature for 3.5 h. After the reaction was complete, the solution was concentrated under reduced pressure and separated by column chromatography (EA / PE = 0%–50% + Et3N) to obtain the target compound 20-2 (236 mg, 86.7%). LCMS: m / z = 403.2 [M-56+H] + .

[0298] Compound 20-2 (236 mg, 1 eq) was dissolved in a dry DCM solution (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude compound 20-3 (180 mg). LCMS: m / z = 359.1 [M+H] + .

[0299] Compound 20-3 (180 mg, 1 eq) and compound 20-4 (243 mg, 2.5 eq) were dissolved in a dry THF / MeOH mixture (6 mL / 2 mL). AcOH (0.2 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature. After half an hour, 2-methylpyridineborane (81 mg, 1.5 eq) was added, and the reaction was continued at 40 °C for 1 hour. The reaction was cooled to 0 °C, quenched with saturated NH4Cl, concentrated under reduced pressure, and separated by prep-HPLC to obtain a white solid 20 (20.16 mg, 7%, 95.1% purity). LCMS: m / z = 536.2 [M+H] + .

[0300] 1 H NMR (400MHz, DMSO) δ9.13(s,1H),8.71(d,J=4.7Hz,1H),7.99(s,1H),7.94(d,J=8.3Hz,1H),7.70(d,J=8.2 Hz,1H),7.64(d,J=6.7Hz,1H),6.16(d,J=16.8Hz,1H),5.77–5.63(m,1H),5.50(d,J=9.6Hz,1H),4.95–4.81 (m,1H),3.66(d,J=11.2Hz,3H),3.13(dd,J=10.9,6.7Hz,2H),2.79(dd,J=18.4,7.2Hz,2H),2.65–2.58(m,2 H),2.30(t,J=6.8Hz,3H),2.20(s,1H),1.92–1.83(m,1H),1.66–1.57(m,1H),1.53(dd,J=14.6,7.1Hz,2H).

[0301] Example 21

[0302]

[0303] Compound 21-1 (360 mg, 1 eq) was dissolved in a dry DCM solution (6 mL), and pyridine (212 mg, 3 e q) was added. The mixture was cooled to 0 °C under a N2 atmosphere, and succinic acid monomethyl ester chloride (201 mg, 1.5 eq) was slowly added dropwise. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated under reduced pressure and separated by column chromatography (EA / PE = 0%–40% + Et3N) to obtain the target compound 21-2 (480 mg, 104%). LCMS: m / z = 519.3 [M + H] + .

[0304] Compound 21-2 (480 mg, 1 eq) was dissolved in a dry DCM solution (6 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude compound 21-3 (360 mg). LCMS: m / z = 419.2 [M+H] + .

[0305] Compound 21-3 (360 mg, 1 eq) and compound 21-4 (416 mg, 2.5 eq) were dissolved in a dry THF / MeOH (9 mL / 3 mL) mixture. AcOH (0.2 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature. After half an hour, 2-methylpyridineborane (138 mg, 1.5 eq) was added, and the reaction was continued at 40 °C for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated NaCl, dried over anhydrous Na₂SO₄, filtered, and purified by reverse-phase separation (H₂O / MeCN = 5%–40%) to give a light brown solid 21-5 (252 mg, 49.2%). LCMS: m / z = 596.4 [M+H] + .

[0306] Compound 21-5 (252 mg, 1 eq) was placed in a 25 mL single-necked flask, and dilute sulfuric acid solution (H₂SO₄ / H₂O = 1 / 6) was added. The mixture was heated to 80 °C under a N₂ atmosphere. After 5.5 h, the reaction was monitored. Once the reaction was complete, the temperature was lowered to 0 °C, the pH was adjusted to 8 with 4N NaOH solution, and the mixture was extracted with dichloromethane and washed with H₂O. The aqueous phase was then adjusted to pH 4 with 4N HCl and extracted with ethyl acetate. LC-MS showed that the target compound was present in the aqueous phase. The aqueous phase was concentrated under reduced pressure and purified by prep-HPLC to give a white solid 21 (17.5 mg, 7.1%). LC-MS: m / z = 582.3 [M+H] + .

[0307] 1H NMR (400MHz, DMSO) δ9.14(s,1H),8.71(d,J=4.6Hz,1H),8.06(s,1H),7.97(d,J=8.2Hz ,1H),7.76(d,J=8.3Hz,1H),7.65(d,J=6.7Hz,1H),4.93–4.78(m,1H),3.69(s,3H),3. 14(s,2H),2.81(dd,J=19.6,6.9Hz,2H),2.69–2.58(m,2H),2.29(dd,J=16.9,6.2Hz,6 H),2.16(s,1H),2.11–1.95(m,1H),1.85(dd,J=22.7,12.7Hz,2H),1.63–1.46(m,2H).

[0308] Example 22

[0309]

[0310] Compound 22-1 (200 mg, 1 eq) and DMAP (6 mg, 0.1 eq) were dissolved in a dry DCM solution (4 mL). Pyridine (117 mg, 3 e q.) was added, and the mixture was cooled to 0 °C under a N2 atmosphere. Trifluoroacetic anhydride (156 mg, 1.5 eq) was slowly added dropwise, and the mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated under reduced pressure and separated by column chromatography (EA / PE = 0%–40%) to obtain the target compound 22-2 (217 mg, 87.7%). LCMS: m / z = 445.2 [M-56+H] + .

[0311] Compound 22-2 (217 mg, 1 eq) was dissolved in a dry DCM solution (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude compound 22-3 (190 mg). LCMS: m / z = 401.2 [M+H] + .

[0312] Compound 22-3 (190 mg, 1 eq) and compound 22-4 (259 mg, 2 e q.) were dissolved in a dry DMA solution (4 mL), followed by the addition of K3PO4 (504 mg, 5 e q.). The mixture was heated to 60 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, concentrated, and purified by prep-HPLC to obtain a white solid 22 (1.53 mg, 0.6%, 98.92% purity). LCMS: m / z = 578.2 [M+H] + .

[0313] 1H NMR (400MHz, DMSO) δ9.16 (s, 1H), 8.75 (d, J = 4.7Hz, 1H), 8.34 (s, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.69 (d, J = 6. 7Hz,1H),4.87–4.77(m,1H),3.70(s,3H),2.70–2.63(m,2H),2.33(d,J=1.8Hz,1H),2.05–1.94(m,6H),1.65(s,2H),1.46(s,2H).

[0314] Example 23

[0315]

[0316] Compound 23-1 (200 mg, 1 eq) and compound INT 2 (296 mg, 2 eq) were dissolved in a dry THF / MeOH (6 mL / 2 mL) mixture. AcOH (0.2 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature. After half an hour, 2-methylpyridineborane (80 mg, 1.5 eq) was added, and the reaction was continued at 40 °C for 1 hour. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated NaCl, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography (MeOH / DCM = 0%–10%) to obtain the target white solid compound 23-2 (339 mg, 99.7%). LCMS: m / z = 681.4 [M+H] + .

[0317] Compound 23-2 (339 mg, 1 e.q.) was dissolved in DCM (4 mL), and TFA (2 mL) was added dropwise while stirring at room temperature for 1 h. The crude product was concentrated under reduced pressure. This crude product was redissolved in MeOH (4 mL) solution, and NH3·H2O (1 mL) was added dropwise. After the reaction was complete, the temperature was lowered to 0 °C, and the pH was adjusted to 4 by slowly adding 4N HCl. The product was concentrated under reduced pressure and purified by prep-HPLC to obtain the target compound as a white solid 23 (45.84 mg, 16.7%). LCMS: m / z = 551.3 [M+H] + .

[0318] 1H NMR (400MHz, DMSO) δ8.33 (s, 1H), 8.18 (s, 1H), 7.97 (dd, J = 17.0, 8.3Hz, 2H), 7.63 (s ,1H),4.88–4.72(m,1H),3.69(s,3H),3.22(dd,J=16.2,6.9Hz,2H),2.92(dd,J=22.8 ,7.5Hz,2H),2.45–2.38(m,2H),2.38–2.34(m,1H),2.32(t,J=6.6Hz,2H),2.23–2.1 0(m,1H),2.05–1.98(m,1H),1.96(s,3H),1.66(t,J=10.5Hz,1H),1.49–1.36(m,2H).

[0319] Example 24

[0320]

[0321] 2,2,4,4-Tetramethylpiperidine (836 mg, 1.3 eq) was dissolved in a dry THF (10 mL) solution. The solution was cooled to -78 °C under a N2 atmosphere, and n-BuLi (2.37 mL, 2.5 M hexane solution, 1.3 eq) was slowly added dropwise. After 30 minutes, bis[(pinacol)boryl]methane (1.59 g, CAS: 118786-86-9, 1.3 eq) in THF (5 mL) was slowly added dropwise. After 5 minutes, 2-(BOC-amino)-6-oxospiro[3.3]heptane (1 g, 1 e.q.) in THF (4 mL) was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched in ice water, extracted with ethyl acetate (30 mL), and washed with water and saturated brine (20 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA / PE = 0%–30%) to give 24-1 white solid (1.36 g, 87.7%). LCMS: m / z = 294.2 [M-56+H] + .

[0322] Compounds 24-2 (220 mg, 1 e.q.), 24-1 (276 mg, 1.2 eq.), Pd(dppf)₂Cl₂ (51 mg, 0.1 eq.), and Cs₂CO₃ (448 mg, 2 e.q.) were placed in a single-necked flask containing 1,4-dioxane / H₂O (11 mL / 1.1 mL) and heated to 90 °C under a N₂ atmosphere. The reaction was monitored after 5 h. Once complete, the mixture was cooled to room temperature, filtered, washed with EA, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0%–30% + Et₃N) to obtain the target compound 24-3 (248 mg, 86.9%). LCMS: m / z = 460.2 [M + H] + .

[0323] Compound 24-3 (248 mg, 1 e.q.) and Rh / Al₂O₃ (49 mg, 0.2 eq.) were placed in a single-necked flask containing EA (5 mL) and reacted under H₂ atmosphere for 2.5 h. After the reaction was complete, the mixture was filtered, washed with EA, and concentrated under reduced pressure to obtain the target compound 24-4 (214 mg, 85.9%). LCMS: m / z = 418.2 [M+H] + .

[0324] Compound 24-4 (88 mg, 1 e.g.) was dissolved in a dry DMF solution, cooled to 0 °C under a nitrogen atmosphere, and NaH (17 mg, 60% e.g., 2 e.g.) was added. After 30 minutes, MeI was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. Once the reaction was complete, it was quenched with saturated NH4Cl solution, extracted with EA, washed with H2O and saturated NaCl, dried over anhydrous Na2SO4, and purified by prep-TLC (EA / PE = 1 / 3) to obtain the target compound 24-5 (82 mg, 90.2%). LCMS: m / z = 376.1 [M-56+H] + .

[0325] Dissolve 24-5 (82 mg, 1 e.g.) in DCM (5 mL), add TFA (2.5 mL), and stir at room temperature for 1 h. After the reaction is complete, concentrate under reduced pressure to obtain crude 24-6 (127 mg). LCMS: m / z = 332.2 [M+H] + .

[0326] Compound 24-6 (180 mg, 1 eq) and compound 24-7 (195 mg, 2 eq) were dissolved in a dry THF / DMF mixture (3.5 mL / 3.5 mL). AcOK (80 mg, 1.5 eq) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature. After half an hour, NaBH(OAc)3 (230 mg, 2 e.q.) was added. After the reaction was complete, the mixture was filtered and purified by prep-HPLC to obtain the target white solid compound 24 (12.06 mg, 4.5%, 98.53% purity). LCMS: m / z = 495.2 [M+H] + .

[0327] 1 H NMR (400MHz, DMSO) δ9.15(s,1H),8.72(d,J=4.7Hz,1H),8.45(s,1H),7.81–7.71(m,2H),7.59(d,J=8.1Hz,1H),3.66(s,3H),3.32(s,3H),3.02( d,J=7.5Hz,2H),2.78(s,1H),2.39(dt,J=15.8,8.0Hz,1H),2.07(s,4H) ,2.04–1.95(m,2H),1.82(s,1H),1.78–1.71(m,1H),1.71–1.58(m,2H).

[0328] Example 25

[0329]

[0330] 25-1 (144 mg, 1 e.g.) was dissolved in 6 mL of dry DCM, and DIPEA (89 mg, 2 e.g.) was added. The mixture was cooled to 0 °C, and a solution of methanesulfonic anhydride in dichloromethane was slowly added dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure and purified by column chromatography (MeOH / DCM = 0%–10%) to give the target compound 25-2 (153 mg, 89.6%). LCMS: m / z = 441.1 [M-56+H] + .

[0331] 25-2 (153 mg, 1 e.g.) was dissolved in DCM (4 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude 25-3 (122 mg). LCMS: m / z = 397.1 [M+H] + .

[0332] Compound 25-3 (82 mg, 1.0 eq), 25-4 (56 mg, 1 e.q.), and K3PO4 (220 mg, 5 e.q.) were added to DMA (3 mL) solution and reacted overnight at 60 °C under a N2 atmosphere. After concentration under reduced pressure, the mixture was purified by prep-HPLC to obtain the target compound 25 (11.67 mg, 9.8%). LCMS: m / z = 574.2 [M+H] + .

[0333] 1 H NMR (400MHz, DMSO) δ9.14 (s, J = 0.5Hz, 1H), 8.78 (s, 1H), 8.72 (d, J = 4.7Hz, 1H), 7.92 (d, J=7.2Hz,1H),7.87(q,J=8.3Hz,2H),7.67(d,J=6.8Hz,1H),5.01(d,J=7.6Hz,1H),3.67( s,3H),3.15(dd,J=26.5,18.6Hz,5H),2.76(s,3H),2.65(t,J=7.3Hz,2H),2.45(d,J=8.2 Hz,2H),2.20–2.10(m,2H),1.83–1.73(m,1H),1.68(t,J=8.7Hz,1H),1.64–1.52(m,2H).

[0334] Example 26

[0335]

[0336] Step 1: Weigh 26-1 (278 mg, 0.16 mmol), add 3 mL of HCl dioxane solution (4 M), and stir at room temperature for 1 h. Concentrate under reduced pressure to obtain crude product 26-2 (200 mg), a pale yellow solid. LCMS: m / z = 335.0 [M+H] + .

[0337] Step 2: Weigh 26-2 (189 mg, 0.51 mmol) and INT2 (227 mg, 0.765 mmol), dissolve them in methanol (1.5 mL) and THF (4.5 mL), add glacial acetic acid (0.15 mL, 2.55 mmol), stir at room temperature for 30 min, add MePyBH3 (82 mg, 0.765 mmol), concentrate under reduced pressure, and purify by column chromatography, successively with DCM / MeOH = 20 / 1 to 10 / 1 to obtain the product 26-3 (95.6 mg, 30.5%) as a white solid. LCMS: m / z = 615.3 [M+H] + .

[0338] Step 3: Weigh 26-3 (95 mg, 0.15 mmol), dissolve in DCM (1 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 3 h. Concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, dissolve in methanol (1 mL), alkalize with ammonia (1 mL), and stir at room temperature for 5 min. Concentrate under reduced pressure and prepare the product by chromatographic purification to obtain a white solid 26 (12.3 mg, 16.8%). LCMS: m / z = 485.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ12.75 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 7.2Hz, 1H), 7. 86(d,J=8.0Hz,1H),7.78(d,J=7.2Hz,1H),7.65(s,1H),5.53(quint,J=6.8Hz,1H) ,3.68(s,3H),3.21(dd,J=6.8,3.6Hz,2H),2.92(dd,J=10.4,6.8Hz,2H),2.45(t, J=7.6Hz,2H),2.30(t,J=6.8Hz,2H),1.98(s,3H),1.46-1.42(m,3H),1.37(s,3H).

[0339] Example 27

[0340]

[0341] Step 1: Weigh 6-chloro-2-formyl-3-iodo-N-methyl-N-(prop-2-yl)benzamide (6.47 g, 17.7 mmol), dissolve it in 1,4-dioxane (60 mL) and acetic acid (20 mL), add methylhydrazine sulfate (7.654 g, 53.1 mmol), purge with nitrogen, and stir at 100 °C for 48 h. Concentrate under reduced pressure to approximately 20 mL, add 80 mL of water, stir at room temperature for 1 h, filter, wash the residue with water, and dry to obtain the product, a pale yellow solid 27-1 (5.179 g, 75.5%). LCMS: m / z = 321.0 [M+H] + .

[0342] Step 2: Weigh (2-BOC-2-azaspiro[3.3]heptane-6-ylidene)methylboronic acid pinacol ester (912 mg, 2.72 mmol), 27-1 (872 mg, 2.72 mmol), Pd(dppf)Cl2 (398 mg, 0.544 mmol), and anhydrous cesium carbonate (1.772 g, 5.44 mmol). Add 1,4-dioxane (15 mL) and water (1.5 mL), and stir overnight at 70 °C. Cool to room temperature, wash with water, extract three times with ethyl acetate, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 2 / 1 to give the product 27-2 (929.8 mg, 85.1%) as a pale yellow solid. LCMS: m / z = 402.2 [M+H] + .

[0343] Step 3: Weigh 27-2 (929 mg, 2.31 mmol), dissolve in ethyl acetate (10 mL), add Rh / Al₂O₃ (188 mg), purge with hydrogen gas, and stir at room temperature for 3.5 h. Filter, wash the residue with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain crude product 27-3 (882.4 mg, 94.6%), a yellow solid. LCMS: m / z = 404.1 [M+H] + .

[0344] Step 4: Weigh 27-3 (832 mg, 2.06 mmol) and p-toluenesulfonic acid (709 mg, 4.12 mmol), dissolve in acetonitrile (10 mL), and heat and stir at 60 °C for 1 h. Concentrate under reduced pressure to obtain crude product 27-4 (1.29 g), a yellowish-brown solid. LCMS: m / z = 304.1 [M+H] + .

[0345] Step 5: Weigh 34 g (206 mmol) of 4,5-dichloropyridazin-3-one, dissolve it in 600 mL of THF, and add MeMgCl solution (206 mL, 618 mmol, 3 M THF solution) dropwise under an ice-water bath. Stir for 2 h after returning to room temperature. Quench the reaction by slowly adding 300 mL of saturated ammonium chloride at 0 °C, add 300 mL of HCl solution (2 M), extract three times with ethyl acetate, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to give the crude product, a yellow solid 27-5 (27.2 g, 91.3%). LCMS: m / z = 145.0 [M+H] + .

[0346] Step 6: Weigh 27-5 (6.057 g, 41.9 mmol), dissolve in DMF (60 mL), add NaH (1.844 g, 46.1 mmol) under ice-water bath, stir at 0℃ for 10 min, slowly add SEMCl (8.2 mL, 46.1 mmol), and stir for 1 h at room temperature. Quench the reaction with saturated ammonium chloride, extract three times with ethyl acetate, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 20 / 1 to obtain the product 27-6 (6.6922 g, 58.1%) as a yellow liquid. LCMS: m / z = 275.1 [M+H] + .

[0347] Step 7: Weigh 27-6 (6.54 g, 23.8 mmol), Pd(PPh3)4 (1.375 g, 1.19 mmol), and potassium carbonate (6.579 g, 47.6 mmol). Dissolve in 1,4-dioxane (80 mL) and water (16 mL). Add allyl borate pinacol ester (6.7 mL, 35.7 mmol) and heat and stir overnight at 100 °C. Wash with water, extract with ethyl acetate, wash with saturated NaCl on the organic phase, and dry on anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 10 / 1, to obtain the product 27-7 (4.703 g, 70.5%), a yellow oily liquid. LCMS: m / z = 281.2 [M+H] + Step 8: Weigh 27-7 (4.7 g, 16.5 mmol), dissolve in tert-butanol (30 mL) and water (15 mL), weigh potassium permanganate (2.868 g, 18.15 mmol) and NaOH (726 mg, 18.15 mmol), dissolve in water (45 mL), and slowly add to the reaction system under an ice-water bath. Stir at 0 °C for 30 min. Concentrate under reduced pressure, purify by column chromatography, DCM / MeOH = 20 / 1 to obtain the product 27-8 (2.2115 g, 42.6%), a yellow oily liquid. LCMS: m / z = 315.2 [M+H] + .

[0348] Step 9: Weigh 27-8 (2.21 g, 7 mmol), dissolve in ultra-dry DCM (25 mL), add triethylamine (2.9 mL, 21 mmol), DMAP (86 mg, 0.7 mmol), and slowly add TBDPSCl (2.73 mL, 10.5 mmol) under ice-water bath. Return to room temperature and stir overnight. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 4 / 1 to obtain the product, a colorless oily liquid 27-9 (2.9383 g, 75.9%). LCMS: m / z = 553.5 [M+H] + .

[0349] Step 10: Weigh 27-9 (2.938 g, 5.3 mmol) and triphenylphosphine (2.5 g, 9.54 mmol), dissolve in THF (30 mL), add DPPA (2.3 mL, 10.6 mmol) under ice-water bath, stir for 2 min, then add DIAD (1.3 mL, 6.36 mmol) dropwise, and stir for 1 h at room temperature. Wash with water, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 6 / 1 to give the product 27-10 (2.5739 g, 84%) as a white solid. LCMS: m / z = 578.4 [M+H] + .

[0350] Step 11: Weigh 27-10 (2.57 g, 4.45 mmol), dissolve in methanol (30 mL), add 860 mg Pd / C (containing water), add hydrogen gas, and stir at room temperature and 0.4 MPa for 2 h. Filter, concentrate the filtrate under reduced pressure, and purify by column chromatography. DCM / MeOH = 40 / 1 to obtain the product 27-11 (1.1371 g, 46.3%), a pale yellow oily liquid. LCMS: m / z = 552.4 [M+H] + .

[0351] Step 12: Weigh 27-11 (1.1 g, 2 mmol), dissolve in DCM (15 mL), add triethylamine (0.42 mL, 3 mmol), and slowly add acetic anhydride (0.21 mL, 2.2 mmol). Stir at room temperature for 30 min. Quench with water, extract three times with DCM, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain the crude product, a white solid 27-12. LCMS: m / z = 594.4 [M+H] + .

[0352] Step 13: Weigh 27-12 (1.2 g, 2 mmol), dissolve in THF (10 mL), add TBAF (2.4 mL, 2.4 mmol, 1 M THF solution), and stir at room temperature for 1 h. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, DCM / MeOH = 20 / 1 to give the product 27-13 (632 mg, 89%) as a colorless viscous liquid. LCMS: m / z = 356.4 [M+H] + .

[0353] Step 14: Weigh 27-13 (356 mg, 1 mmol), dissolve in DCM (3 mL), add triethylamine (0.42 mL, 3 mmol), dissolve methanesulfonic anhydride (261 mg, 1.5 mmol) in DCM (2 mL), add to the system under ice-water bath, and stir for 1 h at room temperature. Quench with water, extract three times with DCM, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain crude product 27-14, a pale yellow liquid. LCMS: m / z = 434.3 [M+H] + .

[0354] Step 15: Weigh 27-14 (434 mg, 1 mmol) and 27-5 (381 mg, 0.8 mmol), dissolve in DCM (1 mL), add triethylamine (0.42 mL, 3 mmol), and stir at room temperature for 1 h. Concentrate under reduced pressure and purify by column chromatography. DCM / MeOH = 20 / 1 to give the product 27-15 (316.7 mg, 61.7%) as a pale yellow solid. LCMS: m / z = 641.5 [M+H] + .

[0355] Step 16: Weigh 27-15 (316 mg, 0.49 mmol), dissolve it in 4 mL of HCl in a 1,4-dioxane solution (4 M), and stir at room temperature for 1 h. Concentrate under reduced pressure to remove the HCl from the 1,4-dioxane solution, dissolve in methanol (2 mL), alkalize with ammonia (2 mL), and stir at room temperature for 5 min. Concentrate under reduced pressure and prepare the product by chromatographic purification to obtain a white solid 27 (15.2 mg, 6.1%). LCMS: m / z = 511.14 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ8.48 (s, 1H), 7.80-7.71 (m, 2H), 7.62 (d, J = 8.0Hz, 1H), 7.4 8(d,J=8.0Hz,1H),7.11(d,J=8.4Hz,1H),4.32-4.22(m,2H),3.93-3.79(m,6H),3.68(s, 3H),3.04(d,J=7.6Hz,2H),2.71(dd,J=13.2,4.8Hz,1H),2.61(dd,J=13.2,7.6Hz,1H), 2.29(s,1H),2.22(t,J=10.0Hz,2H),2.02(s,3H),1.95-1.89(m,2H),1.88-1.84(m,2H).

[0356] Example 28

[0357]

[0358] Step 1: Weigh (methoxymethyl)triphenylphosphine chloride (32.9 g, 96 mmol), dissolve in ultra-dry THF (200 mL), purge with nitrogen, and slowly add LDA (50.4 mL, 100.8 mmol, 2 M in THF) under an ice-water bath. Return to room temperature and stir for 30 min. Cool to 0 °C, dissolve 10.14 g, 48 mmol of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester in ultra-dry THF (100 mL) and slowly add dropwise to the system. Return to room temperature and stir for 30 min. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 10 / 1 to obtain a pale yellow oily liquid 28-1 (6.1593 g, 53.6%). LCMS: m / z = 240.1 [M+H] + .

[0359] Step 2: Weigh 28-1 (6.159 g, 25.7 mmol), dissolve in DCM (60 mL), slowly add TFA (9.5 mL, 128.5 mmol), and stir at room temperature for 1 h. Adjust the pH to 8 with saturated sodium bicarbonate solution, extract three times with DCM, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain crude product 28-2 (5.7505 g, 99.3%), a pale yellow solid. LCMS: m / z = 226.1 [M+H] + Step 3: Weigh 28-3 (3.91 g, 12.2 mmol), dissolve in ultra-dry THF (40 mL), and slowly add i-PrMgClLiCl solution (14 mL, 18.3 mmol, 1.3 M) dropwise under an ice-water bath, stirring at 0 °C for 30 min. Dissolve 28-2 (3.023 g, 13.42 mmol) in ultra-dry THF (20 mL), slowly add to the reaction system, and stir for 30 min at room temperature. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 1 / 1 to give product 28-4 (3.6112 g, 70.5%) as a white solid. LCMS: m / z = 420.1 [M+H] + .

[0360] Step 4: Weigh 28-4 (3.61 g, 8.5 mmol), triphenylphosphine (2.452 g, 9.54 mmol), and phthalimide (1.376 g, 9.35 mmol), dissolve in THF (40 mL), add DEAD (1.6 mL, 10.2 mmol) dropwise, and stir at room temperature for 1 h. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 2 / 1 to give the product 28-5 (4.8337 g, containing triphenylphosphine). LCMS: m / z = 549.2 [M+H] + .

[0361] Step 5: Weigh 28-5 (4.8 g, 8.5 mmol), dissolve in methanol (50 mL), add hydrazine hydrate (751 mg, 12.75 mmol, 85%), and stir at 70 °C for 5 h. Cool to room temperature, concentrate under reduced pressure, and purify by column chromatography. DCM / MeOH = 40 / 1 to give the product 28-6 (1.2273 g, 34.5% for 2 steps) as a yellow solid. LCMS: m / z = 419.1 [M+H] + .

[0362] Step 6: Weigh 28-6 (293 mg, 0.7 mmol), add ethyl formate (5 mL) to dissolve, and stir at 60 °C for 2 h. Cool to room temperature, concentrate under reduced pressure to obtain crude product 28-7, a pale yellow solid. LCMS: m / z = 447.1 [M+H] + .

[0363] Step 7: Weigh 28-7 (0.7 mmol), dissolve it in DCM (4 mL), slowly add trifluoroacetic acid (2 mL), and stir at room temperature for 2 hours. Concentrate under reduced pressure, add water, and freeze-dry to obtain the crude product, a pale yellow oily liquid 28-8. LCMS: m / z = 347.2 [M+H] + .

[0364] Step 8: Weigh 50.1 g (208 mmol) of 4-iodo-2,5-difluoropyridine, dissolve it in 600 mL of 1,4-dioxane, add 122 g (2.08 mol, 85%) of hydrazine hydrate, and stir overnight at 80 °C. Cool to room temperature, concentrate under reduced pressure, add 500 mL of water, stir for 1 min at room temperature, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and give crude product 28-9 (41.4 g, 78.7%) as a white solid. LCMS: m / z = 254.0 [M+H] + .

[0365] Step 9: Weigh 28-9 (41.15 g, 162.6 mmol), dissolve in formic acid (500 mL), and heat and stir at 80 °C for 24 h. Concentrate under reduced pressure, add 500 mL of water, adjust pH to 8-9 with saturated sodium bicarbonate solution, filter, wash the residue with water, and dry the residue under reduced pressure to obtain the product 28-10 (29.0384 g, 67.9%), a pale yellow solid. LCMS: m / z = 364.2 [M+H] + .

[0366] Step 10: Weigh 28-10 (15 g, 57 mmol), Pd(PPh3)4 (3.293 g, 2.85 mmol), and cuprous iodide (543 g, 2.85 mmol). Dissolve in DCE (200 mL), tetrahydro-2-(2-propynoxy)-2H-pyran (16.1 mL, 114 mmol), and triethylamine (23.8 mL, 171 mmol). Heat and stir overnight at 42 °C. Concentrate under reduced pressure and purify by column chromatography. DCM / MeOH = 50 / 1 to give the product 28-11 (14.9997 g, 95.6%), a yellow oily liquid. LCMS: m / z = 276.0 [M+H] + .

[0367] Step 11: Weigh 28-11 (14.7 g, 53.4 mmol), dissolve in methanol (150 mL), add p-toluenesulfonic acid (17.471 g, 101.46 mmol), and heat at 40 °C for 30 min. Concentrate under reduced pressure, purify by column chromatography, DCM / MeOH = 5 / 1 to obtain the product 28-12 (10 g, 98%) as a yellow solid. LCMS: m / z = 192.1 [M+H] + .

[0368] Step 12: Weigh 28-12 (10g, 53.4mmol), dissolve in methanol (100mL), add 3g Pd / C (containing water), add hydrogen gas, and stir overnight at room temperature and 0.45MPa. Filter, concentrate the filtrate under reduced pressure, and purify by column chromatography. DCM / MeOH = 15 / 1 to give the pale yellow solid-liquid product 28-13 (10g, 98%). LCMS: m / z = 196.1 [M+H] + .

[0369] Step 13: Weigh 28-13 (1.562 g, 8 mmol), dissolve in acetonitrile (15 mL), add pyridine (1.93 mL, 24 mmol), and add methanesulfonic anhydride (2.508 g, 14.4 mmol) under an ice-water bath. Stir at ℃ for 30 min. Quench with water, extract three times with DCM, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, DCM / MeOH = 50 / 1 to give the product 28-14 (1.2981 g, 59.4%), a pale yellow solid. LCMS: m / z = 274.2 [M+H] + .

[0370] Step 14: Weigh 28-8 (323 mg, 0.7 mmol), 28-14 (230 mg, 0.84 mmol), and potassium phosphate (742 mg, 3.5 mmol), dissolve in DMA (5 mL), and stir overnight at 60°C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain the product 28 (28 mg, 7.6%) as a white solid. LCMS: m / z = 524.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ9.16 (s, 1H), 8.74 (d, J = 4.8Hz, 1H), 8.73-8.68 (m, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 8.06 (s, 1H) ,7.85(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,1H),7.69(d,J=6.4Hz,1H),5.44(t,J=8.8Hz,1H),3.67(s,3H),3.40(d,J=8.0Hz ,1H),3.36(d,J=7.6Hz,1H),3.31(d,J=8.4Hz,1H),3.26(d,J=8.0Hz,1H),2.67(t,J=6.4Hz,2H),2.57(t,J=7.2Hz,2H),2. 24-2.16(m,1H),2.07(dd,J=8.4,12.0Hz,1H),1.98-1.91(m,1H),1.80(dd,J=8.4,11.6Hz,1H),1.64(quint,J=7.6Hz,2H).

[0371] Example 29

[0372]

[0373] Step 1: Weigh triphosgene (249 mg, 0.84 mmol), dissolve it in ultra-dry DCM (3 mL), add methanol (0.1 mL, 2.52 mmol), slowly add pyridine (0.2 mL, 2.52 mmol) under an ice-water bath, and stir at 10 °C for 1.5 h.

[0374] Step 2: Weigh 28-6 (293 mg, 0.7 mmol), dissolve in ultra-dry DCM (30 mL), add triethylamine (0.15 mL, 1.05 mmol), and slowly add the reaction mixture from Step 1 to the reaction mixture from Step 2 under an ice-water bath. Stir for 1 hour at room temperature. Quench with water, extract three times with DCM, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, and obtain a white solid 29-1 (220.9 mg, 66.1%) with a PE / EA ratio of 2 / 1. LCMS: m / z = 477.2 [M+H] + .

[0375] Step 3: Weigh 29-1 (220 mg, 0.46 mmol), dissolve in DCM (2 mL), slowly add trifluoroacetic acid (1 mL), and stir at room temperature for 30 min. Concentrate under reduced pressure, add water, and freeze-dry to obtain the crude product, a pale yellow solid 29-2. LCMS: m / z = 377.2 [M+H] + .

[0376] Step 4: Weigh 29-2 (226 mg, 0.46 mmol), 28-14 (251 mg, 0.92 mmol), and potassium phosphate (488 mg, 2.3 mmol). Dissolve in DMA (5 mL) and stir overnight at 60°C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain a white solid 29 (31.7 mg, 12.4%). LCMS: m / z = 554.30 [M+H] + . 1H NMR (400MHz, DMSO-d6, ppm) δ9.16 (s, 1H), 8.74 (d, J = 4.8Hz, 1H), 8.70 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.85 (d ,J=8.4Hz,1H),7.73(d,J=8.0Hz,1H),7.68(d,J=6.4Hz,1H),5.09(t,J=8.8Hz,1H),3.68(s,3H),3.37-3.16( m,5H),2.67(t,J=7.6Hz,2H),2.63-2.57(m,1H),2.54(t,J=7.2Hz,2H),2.23-2.15(m,1H),2.09(dd,J=8.4, 12.0Hz, 1H), 1.88-1.80 (m, 1H), 1.75 (dd, J=8.8, 11.6Hz, 1H), 1.62 (quint, J=7.2Hz, 2H), 1.30-1.18 (m, 2H).

[0377] Example 30

[0378]

[0379] Step 1: Weigh 28-6 (293 mg, 0.7 mmol), 1-fluorocyclopropanecarboxylic acid (73 mg, 0.7 mmol), EDCI (161 mg, 0.84 mmol), and HOBt (114 mg, 0.84 mmol), dissolve in ultra-dry DMF (4 mL), add DIEA (0.24 mL, 1.4 mmol), and stir at room temperature for 3 h. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, PE / EA = 2 / 1 to give the product as a white solid 30-1 (306.6 mg, 86.9%). LCMS: m / z = 505.3 [M+H] + .

[0380] Step 2: Weigh 30-1 (306 mg, 0.6 mmol) and p-toluenesulfonic acid (364 mg, 1.2 mmol), dissolve in acetonitrile (4 mL), and stir at 60 °C for 1 h. Concentrate under reduced pressure to obtain crude product 30-2, a pale yellow solid. LCMS: m / z = 405.3 [M+H] + .

[0381] Step 3: Weigh 30-2 (0.6 mmol), 28-14 (246 mg, 0.9 mmol), and potassium phosphate (637 mg, 3 mmol), dissolve in DMA (5 mL), and stir overnight at 60°C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain a white solid 30 (81.8 mg, 23.4%). LCMS: m / z = 582.38 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ9.16(s,1H),8.95(d,J=8.0Hz,1H),8.74(d,J=4.8Hz,1H),8.69(s,1H),7.87( d,J=8.4Hz,1H),7.84(d,J=8.4Hz,1H),7.68(d,J=6.8Hz,1H),5.43(dd,J=8.4,10.8Hz,1H),3.68(s,3H),2 .93-2.82(m,1H),2.67(t,J=6.4Hz,2H),2.47-2.41(m,1H),2.32-2.23(m,1H),2.10-1.94(m,2H),1.92-1. 84(m,1H),1.71(dd,J=8.4,12.0Hz,1H),1.61(quint,J=7.2Hz,2H),1.37-1.13(m,7H),1.12-1.03(m,1H).

[0382] Example 31

[0383]

[0384] Step 1: Weigh 28-6 (293 mg, 0.7 mmol), (1S)-2,2-difluorocyclopropane-1-carboxylic acid (94 mg, 0.77 mmol), EDCI (161 mg, 0.84 mmol), and HOBt (114 mg, 0.84 mmol). Dissolve in ultra-dry DMF (4 mL), add DIEA (0.24 mL, 1.4 mmol), and stir at room temperature for 1.5 h. Quench with water, extract three times with ethyl acetate, wash with saturated NaCl on the organic phase, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a white solid 31-1. Separate it into two fractions and purify them by column chromatography with different mobile phases to obtain two chiral isomers. Purify with mobile phase PE / EA = 2 / 1 to obtain product white solid 31-1A (179.6 mg). Purify with mobile phase PE / EA = 1 / 1 to obtain product white solid 31-1B (177.6 mg). LCMS: m / z = 523.3 [M+H] +The above synthetic route only uses a mixture of two isomers as an example. 31-2 is a mixture of 31-2A and 31-2B, and 31 is a mixture of 31A and 31B.

[0385] Step 2: Weigh 31-1A (179 mg, 0.34 mmol) and p-toluenesulfonic acid (124 mg, 0.68 mmol), dissolve in acetonitrile (4 mL), and stir at 60 °C for 1 h. Concentrate under reduced pressure to obtain crude product 31-2A, a pale yellow solid. LCMS: m / z = 423.3 [M+H] + .

[0386] Weigh 177 mg (0.34 mmol) of 31-1B and 124 mg (0.68 mmol) of p-toluenesulfonic acid, dissolve them in 4 mL of acetonitrile, and stir at 60 °C for 1 h. Concentrate under reduced pressure to give crude product 31-2B, a pale yellow solid. LCMS: m / z = 423.3 [M+H] + .

[0387] Step 3: Weigh 31-2A (0.34 mmol), 28-14 (121 mg, 0.44 mmol), and potassium phosphate (361 mg, 1.7 mmol). Dissolve in DMA (3 mL) and stir overnight at 60°C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain the product 31A (40.5 mg, 19.9%) as a white solid. LCMS: m / z = 600.39 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ9.15(s,1H),8.88(d,J=8.0Hz,1H),8.73(d,J=4.4Hz,1H),8.61(s,1H),7.85(d,J =8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.67(d,J=6.8Hz,1H),5.42(t,J=8.8Hz,1H),3.67(s,3H),3.19-3.12(m,2 H),3.11-3.00(m,2H),2.70-2.63(m,3H),2.58(dt,J=11.2,2.8Hz,1H),2.39(t,J=7.6Hz,2H),2.25-2.16(m,1 H), 2.05 (dd, J=11.6, 8.0Hz, 1H), 1.94-1.80 (m, 3H), 1.73 (dd, J=12.0, 8.4Hz, 1H), 1.58 (quint, J=7.2Hz, 2H).

[0388] Weigh 0.34 mmol of 31-2B, 121 mg (0.44 mmol) of 28-14, and 1.7 mmol of potassium phosphate. Dissolve in 3 mL of DMA and stir overnight at 60 °C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to give a white solid 31B (19 mg, 9.3%). LCMS: m / z = 600.43 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ9.15(d,J=0.8Hz,1H),8.89(d,J=8.0Hz,1H),8.73(d,J=4.8Hz,1H),8.59(s,1H),7.85(d,J= 8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.67(d,J=6.8Hz,1H),5.38(t,J=8.8Hz,1H),3.67(s,3H),3.14(q,J=7.2Hz,2H),3.08 (d,J=7.2Hz,1H),3.01(d,J=7.2Hz,1H),2.66(t,J=8.0Hz,3H),2.60(dt,J=11.2,2.8Hz,1H),2.38(t,J=7.6Hz,2H),2.23 -2.15(m,1H),2.05(dd,J=11.6,8.0Hz,1H),1.93-1.83(m,3H),1.73(dd,J=11.6,8.0Hz,1H),1.58(quint,J=7.2Hz,2H).

[0389] Example 32

[0390]

[0391] Step 1: Weigh 26-2 (20 mg, 0.06 mmol), 28-14 (16 mg, 0.06 mmol), and triethylamine (25 μL, 0.18 mmol), dissolve in DMF (0.5 mL), and stir overnight at 60 °C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain a white solid 32 (3.7 mg, 12.06%). LCMS: m / z = 512.3 [M+H] + .

[0392] Example 33

[0393]

[0394] Step 1: Weigh 28-6 (200 mg, 0.477 mmol), (1S)-2,2-difluorocyclopropane-1-carboxylic acid (0.525 mg, 0.588 mmol), EDCI (109.4 mg, 0.572 mmol), and HOBt (109.4 mg, 0.572 mmol). Dissolve in ultra-dry DMF (4 mL). Add DIEA (123.3 mg, 0.954 mmol) and stir at room temperature for 1.5 h. Quench with water, extract three times with ethyl acetate, wash the organic phase with saturated NaCl, and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, purify by column chromatography, and obtain a white solid 33-1 (250 mg) with PE / EA = 1 / 1. LCMS: m / z = 513.2 [M+H] + .

[0395] Step 2: Weigh 33-1 (250 mg, 0.48 mmol) and p-toluenesulfonic acid (168 mg, 0.97 mmol), dissolve in acetonitrile (4 mL), and stir at 60 °C for 1 h. Concentrate under reduced pressure, quench with water, extract three times with ethyl acetate, wash with saturated NaCl on the organic phase, and dry on anhydrous sodium sulfate. Purify by chromatography with mobile phase PE / EA = 2 / 1 to obtain crude product 33-2A (120 mg) as a pale yellow solid. Purify by chromatography with mobile phase PE / EA = 1 / 1 to obtain crude product 33-2B (50 mg) as a pale yellow solid. LCMS: m / z = 413.2 [M+H] + The above synthetic route only uses a mixture of two isomers as an example. 33-2 is a mixture of 33-2A and 33-2B, and 33 is a mixture of 33A and 33B.

[0396] Step 3: Weigh 33-2A (120 mg, 0.53 mmol), 28-14 (188 mg, 0.69 mmol), and potassium phosphate (563 mg, 2.65 mmol). Dissolve in DMA (3 mL) and stir overnight at 60°C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to obtain the product 33A (5 mg, 1.6%) as a white solid. LCMS: m / z = 590.2 [M+H] + .

[0397] Weigh 50 mg (0.22 mmol) of 33-2B, 78.5 mg (0.29 mmol) of 28-14, and 234 mg (1.1 mmol) of potassium phosphate. Dissolve in 3 mL of DMA and stir overnight at 60 °C. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, and purify by preparative chromatography to give a white solid 33B (1.1 mg, 0.84%). LCMS: m / z = 590.3 [M+H] + .

[0398] The pharmacological effects and physicochemical properties of the above compounds are as follows. The structures and synthetic methods of the control compounds are shown in the table below.

[0399]

[0400] 1. SUPM2 cell viability assay

[0401] The test compound was dissolved in DMSO at a concentration of 10 mM to prepare a stock solution. 36 μL of the stock solution was added to a 384-well polypropylene plate. A 3-fold serial dilution was performed. The plate was centrifuged at 1000 rpm for 1 minute at room temperature, followed by shaking on a shaker for 2 minutes. 40 nmL of the diluted compound solution was transferred to the cell plate.

[0402] Transfer the SUPM2 cell suspension to conical centrifuge tubes and centrifuge at 120g for 10 minutes to collect the cell pellet. Resuspend the cells in culture medium and count the cells. Dilute the cells to the desired density with culture medium; add 40 μL of the cell suspension to each pre-treated 384-well cell culture plate. After capping the plate, incubate at room temperature for 30 minutes, then incubate the compound-treated plate in a 37°C, 5% CO2 incubator. After 4 days of compound treatment, remove the plate from the incubator and equilibrate at room temperature for 15 minutes. Thaw the CellTiter Glo reagent and allow it to equilibrate to room temperature before starting the experiment. Add 30 μL of reagent to each well; gently shake at 200 rpm on a horizontal shaker during incubation. Then incubate at room temperature for 30 minutes before reading the signal using a BMG microplate reader.

[0403] Inhibitory activity is calculated using the following formula: %Vehicle = 100% - 100% × (LumHC - LumSample) / (LumHC - LumLC)

[0404] Wherein, HC is the luminescence value obtained by treating cells with only 0.1% DMSO, and LC is the luminescence value when only culture medium is present (cell-free).

[0405] The results showed that compounds 1 to 33 of the above embodiments all had significant inhibitory activity against SUPM2 cells, with compound 3 exhibiting the highest inhibitory activity against SUPM2 IC50. 50 The IC50 values ​​of compounds 4 to 7, 19, and 24 against SUPM2 reached levels below 100 nM. 50 It has reached a level below 500nM.

[0406] 2. qPCR detection of SOCS3 gene in human whole blood

[0407] The mRNA level of the SOCS3 gene was upregulated after stimulation with IL-10. The effect of a STAT3 inhibitor (the compound of this invention) on the transcriptional expression level of the SOCS3 gene was detected using human whole blood. The procedure was as follows: First, different concentrations of the compound were mixed with human whole blood and incubated at 37°C for 1 hour; then, the blood was stimulated with human IL-10 for 1 hour, and the transcriptional level of SOCS3 was measured by qPCR. The cDNA and qPCR procedures were performed according to the instruction manual, and the qPCR amplification program was selected as the "three-step method" (see instruction manual, YEASEN, 11123ES60 and 11201ES08 for details). In each human whole blood donor test, the IL-10-only stimulation group was used as a positive control, and the DMSO group as a negative control.

[0408] The results showed that the compounds of this invention significantly inhibited SOCS3 gene transcription, and IC50... 50 All are below 1μM.

[0409] 3. In vitro study on the metabolic stability of liver microsomes

[0410] The compound was incubated in parallel with phosphate-buffered saline (pH 7.4) containing coenzyme factor from different species of liver microsomes for 60 minutes. Sampling was performed at 0.5, 5, 10, 15, 30, and 60 minutes to terminate the incubation. UPLC-MS / MS analysis was used to determine the compound concentration. The elimination rate constant (k) was determined by linearly fitting the natural logarithm of the remaining percentage of parent drug against time. The intrinsic clearance (in vitro CLint) and half-life (t) were calculated. 1 / 2 ), where t 1 / 2 =0.693 / k; clearance rate = kV / N, where V = incubation volume per well, and N = microparticle content per well.

[0411] The results show that the compounds of the present invention have good stability, and some compounds even have significantly better metabolic stability than the control compounds, as shown in Table 1.

[0412] Table 1 Results of liver microsomal stability

[0413]

[0414] 4. Mouse PK test

[0415] Three male ICR mice were used for each compound. Mice were treated with a single dose of 10 mg / kg (orally by gavage). Blood samples were collected from each mouse at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours post-administration. Whole blood samples were placed in tubes containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm and 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma samples was determined using LC-MS / MS. Based on the bioanalytical data, pharmacokinetic parameters were calculated using a non-compartmental model analysis method with WinNonlin Phoenix software. The results are shown in Table 2.

[0416] Table 2 Results of mouse PK test

[0417]

[0418] It should be understood that if this invention references any prior art publications, such reference does not imply an admission that such publication is part of common general knowledge in the field in any country.

[0419] All publicly available texts, patents, patent applications, and published patent applications used in this article are incorporated herein by reference in their entirety.

[0420] Although the invention has been described in considerable detail by way of illustration and examples for purposes of clarity, it will be apparent to those skilled in the art that certain minor changes and modifications will be apparent. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. Compounds of formula (I), their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their hydrates, their solvates, or polycrystalline forms: in, L1 is selected from C1-C3 alkylene, -N(R5)-, C1-C3 alkylene optionally substituted with -N(R5)2, or C1-C3 haloalkylene; L2 is selected from C1-C4 alkylene, -N(R5)- or halogen-substituted C1-C3 alkylene; R1 is selected from C1-C3 alkylene, -N(R5)-, -N(R5)-C(=O)- or halogen-substituted C1-C3 alkylene; R2 is selected from H, C1-C3 alkyl, -N(R5)2, halogen, or halogen-substituted C1-C3 alkyl; Alternatively, R1, R2, and the atoms bonded to them together form a 4-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl. The 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl can be formed by one or more R... c Replace, each R c Each is independently selected from halogens, C1-C3 alkyl groups, -OH, or CN; Each R5 is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl or -C 1-3 Alkylene-C(=O)-N(R) 51 )2, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 )2 can be optionally replaced by one or more halogens; each R 51 Each R5 is independently selected from H, C1-C3 alkyl, or halogenated C1-C3 alkyl; or, each R5 is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 2. -SH (=O), -S (=O)-C 1-3 Alkyl, -S(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-S(=O)-C 1-3 Alkyl, -SH(=O)2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 3-8 cycloalkyl, -C 1-3 Alkylene-S(=O)2-C 1-3 Alkyl; C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 51 2. -SH (=O), -S (=O)-C 1-3 Alkyl, -S(=O)-C 3-8 Cycloalkyl, -S(=O)-3 to 6-membered heterocycloalkyl, -C 1-3 Alkylene-S(=O)-C 1-3 Alkyl, -SH(=O)2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 3-8 Cycloalkyl, -S(=O)2-3~6-membered heterocycloalkyl, -C 1-3 Alkylene-S(=O)2-C 1-3 The alkyl group may be optionally substituted with one or more halogens, or optionally substituted with one or more C1-C3 alkyl groups, or optionally substituted with one or more C1-C3 alkoxy groups, or optionally substituted with one or more C1-C3 haloalkyl groups, or optionally substituted with one or more C1-C3 haloalkoxy groups, or optionally substituted with one or more substituents each independently selected from the following: halogen, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 carboxylic acid, C1-C3 ester, -N(R5)2; each R 51 Each is independently selected from H, C1-C3 alkyl, or halo-C1-C3 alkyl; R3 is selected from H, C1-C3 alkyl groups, and -N(R) 3a 2. Halogenated or halogen-substituted C1-C3 alkyl groups; each R 3a Each is independently selected from H, halogen, C1-C3 alkyl, C3-C8 cycloalkyl, -CH (=O), -C (=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl, -C 1-3 Alkylene-C(=O)-C 1-3 Alkyl, C1-C3 alkyl, C3-C8 cycloalkyl, -CH(=O), -C(=O)-C 1-3 Alkyl, -C(=O)-C 3-8 cycloalkyl, -C 1-3 Alkylene-C(=O)-C 1-3 The alkyl group may optionally be substituted with one or more halogens; X1 is selected from -CH- or N; R4 is selected from H, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl; Ring A is selected from Ring E is selected from imidazole ring or pyrazole ring; at least two of X2, X3, and X4 are NR. a2 The other is -CH-, and each R a2 Each is independently selected from either non-existent or H; each R a1 Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl; Ring B is selected from Or by n R b1 Substituted triazole; ring F is triazole; at least two of X5, X6, X7, and X8 are NR. b2 The rest are -CH-, and each R b2 Each is independently selected from either non-existent or H; each R b1 Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl; Each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound according to claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, its transisomer, its pharmaceutically acceptable salt, its deuterated derivative, its hydrate, its solvate, or polycrystalline form, wherein the compound has a structure of formula (II-1), (II-2), (II-3), (II-4), (II-5), or (II-6):

3. The compound according to claim 1 or 2, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form. Each n is independently selected from 0, 1, or 2.

4. The compound according to claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form. L1 is selected from -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-, -N(R5)- or C1-C3 alkylene groups substituted with -N(R5)2, and each R5 in L1 is independently selected from H, -C(=O)-CH3, -C(=O)-CF3, -C(=O)-CCl3, -C(=O)-CBr3, -CH2-C(=O)-NH2, -CH2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl or halocyclopropyl; or each R5 in L1 is independently selected from H, -C(=O)-CH3, -C(=O)-CF3, -C(=O)-CCl3, -C(=O)-CBr3, -CH2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl or halocyclopropyl; The R5 in L1 is selected from H, -C(=O)-CH3, -CH(=O), -C(=O)-CF3, -C(=O)-CCl3, -C(=O)-CBr3, -CH2-C(=O)-NH2, -CH2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl, halocyclopropyl, methylcyclopropyl, oxacyclobutyl, -S(=O)2-CH3; or each R5 in L1 is independently selected from H, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH(=O), -C(=O)-CF 3. -C(=O)-CH2CF3, -C(=O)-CH2CH2CF3, -C(=O)-CCl3, -C(=O)-CH2CCl3, -C(=O)-CH2CH2Cl3, -C(=O)-CBr3, -C(=O)-CH2CBr3, -C(=O)-CH2CH2Br3, -CH2CH2-C(=O)-NH2, -CH2CH2CH2-C(=O)-NH2, -C(CH3)2-C(=O)-NH-CH3, -CH2-C(=O)-N(CH3)2, cyclopropyl, halocyclopropyl, methylcyclopropyl, oxacyclobutyl, -S(=O)2-CH3, -C(= The following groups are listed: -C(=O)-N(CH3)2, -C(=O)-NHCH2CH3, -C(=O)-CH=CH2, -C(=O)-CH2CH=CH2, -C(=O)-spiropentyl, -C(=O)-CH2C(=O)OH, -C(=O)-(CH2)2C(=O)OH, -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-cyclopropyl, -C(=O)-halocyclopropyl, -C(=O)-methylcyclopropyl, -C(=O)-halomethylcyclopropyl; these R5 groups are optionally substituted with one or more halogens, amino groups, hydroxyl groups, alkyl groups, alkoxy groups, ester groups, carboxylic acid groups, sulfonic acid groups, cycloalkyl groups, aryl groups, and heteroaryl groups; Preferably, R1 is -N(R5)-C(=O)-, and R5 in R1 is selected from H, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl. Preferably, R2 is selected from -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, and can be substituted by one or more halogens.

5. The compound according to claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form. R1 and R2, along with the atoms attached to them, form a cyclobutyl group, which may be optionally substituted by one or more of the following substituents: -NH2, -CH3, or halogen.

6. The compound according to claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form. R3 is selected from H, halogens, C1-C3 alkyl groups, and -N(R) 3a 2. Halogenated or halogen-substituted C1-C3 alkyl groups; each R 3a Each is independently selected from H, halogen, C1-C3 alkyl, -CH(=O), -C(=O)-CH3, -C(=O)-O-CH3, -C(=O)-NH2, and -C(=O)-CH3 and -C(=O)-O-CH3 can be substituted by one or more halogens; Preferably, R4 is selected from H, halogen, C1-C3 alkyl, -N(R5)2 or C1-C3 haloalkyl; each R5 in R4 is independently selected from H, C1-C3 alkyl, -CH(=O) or -C(=O)-CH3, and -C(=O)-CH3 may be substituted by one or more halogens.

7. The compound according to claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form. Each R a1 Each is independently selected from F, Cl, C1-C3 alkyl or C1-C3 haloalkyl; each n in ring A is independently 0, 1 or 2; Preferably, each R b1 Each element is independently selected from F, Cl, C1-C3 alkyl, or C1-C3 haloalkyl; each n in ring B is independently 0, 1, or 2; Preferably, L2 is selected from -CH2-, -N(CH3)-, and is optionally substituted by one or more halogens, alkyl, amino, hydroxyl, alkoxy, ester, carboxylic acid, sulfonic acid, cycloalkyl, aryl, or heteroaryl groups.

8. The compound of claim 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the transisomer, its pharmaceutically acceptable salt of the deuterated derivative, its hydrate, its solvate, or polycrystalline form, comprising the following: Preferably, it includes the following:

9. A pharmaceutical composition, characterized in that: Includes the compounds of claims 1-8, their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their deuterated derivatives, their hydrates, their solvates or polycrystalline forms, as well as pharmaceutically acceptable carriers, excipients or diluents.

10. Use of the compound of any one of claims 1-8, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its transisomer, its pharmaceutically acceptable salt of its deuterated derivative, its hydrate, its solvate or polycrystalline form, or the pharmaceutical composition of claim 9 in the preparation of a STAT3 inhibitor.

11. The use of any one of the compounds of claims 1-8, their stereoisomers, their transisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their transisomers, their pharmaceutically acceptable salts, their deuterated derivatives, their hydrates, their solvates or polycrystalline forms, or the pharmaceutical composition of claim 9 in the preparation of a medicament for the prevention and / or treatment of diseases associated with the inhibition of STAT3; Preferably, the diseases associated with STAT3 inhibition include cancer, rheumatoid arthritis, Crohn's disease, atherosclerosis, or inflammatory bowel disease.

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