Compounds used as SHP2 inhibitors and their use

Abstract

The present invention relates to compounds used as SHP2 inhibitors and their applications. Specifically, the compounds of the present invention have a structure shown in Formula I', wherein the definitions of each group and substituent are as described in the specification. The compounds have a high inhibitory effect on the activity of SHP2 phosphatase and can be used to prevent or treat diseases related to SHP2.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to compounds used as SHP2 inhibitors, and applications thereof in regulating SHP2 activity or treating related diseases. Background Art

[0002] SHP2 (encoded by the PTPN11 gene) is a member of the PTP family and contains a conserved tyrosine phosphatase domain, two N-terminal SH2 domains, and a C-terminal tail. The two SH2 domains determine the subcellular localization and functional regulation of SHP2. SHP2 is widely expressed and participates in multiple cell signaling processes, such as Ras-Erk, PI3K-Akt, JakStat, Met, FGFR, EGFR, as well as the insulin receptor and NF-kB pathways. It is very important for multiple cell functions such as mitogenesis, metabolic control, transcriptional regulation, and cell migration.

[0003] SHP2 has been implicated in the development of a variety of diseases, such as Noonan syndrome, as well as several forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myeloid leukemia) and a variety of solid tumors (e.g., lung cancer, colon cancer, neuroblastoma, glioblastoma, melanoma, and liver cancer).

[0004] There are two major strategies for the development of SHP2 inhibitors: the development of inhibitors targeting the PTP catalytic region of SHP2 and the development of allosteric inhibitors in the non-catalytic region. Due to the problems of selectivity and poor drugability of PTP catalytic region inhibitors, more research is currently tending to the development of allosteric inhibitors. In recent years, researchers have found that inhibiting the activity of SHP2 through allosteric sites can improve activity and selectivity, and drug research has also made some progress. However, there is still a need to develop better SHP2 inhibitors in order to obtain drugs with excellent activity and better pharmacokinetic properties for the treatment of SHP2-mediated related diseases. Summary of the invention

[0005] The object of the present invention is to provide a compound represented by formula I' and its application in regulating SHP2 activity or treating related diseases.

[0006] In a first aspect of the present invention, there is provided a compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0007]

[0008] Wherein: R1 is selected from the following group: bicyclic C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, C6-C10 aryl heterocycloalkyl; any hydrogen atom on R1 is optionally substituted by one or more of the following substituents: deuterium, hydroxyl, halogen, cyano, =O, ester, amide, ketocarbonyl, amino, hydroxy-substituted C1-C4 alkyl, -C(O)OR a 、-NHC(O)R a 、-NHC(O)OR a , -C(O)(C1-C4 alkylene)OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S; R a is a C1-C4 alkyl group; the C6-C10 arylheterocycloalkyl group is -(C6-C10 aryl)-(a saturated or unsaturated 3-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S); R1 is a bicyclic structure and a parallel ring structure;

[0009] R2 is selected from the group consisting of H, deuterium, amino, cyano, halogen, hydroxyl, methyl, CH2OH, CH(CH3)OH, C(CH3)2OH, halomethyl, deuterated methyl, CONH2, CF2OH, NHSO2Me, CH2NHSO2Me;

[0010] R3 is selected from the group consisting of hydrogen, deuterium, hydroxy, amino, cyano, halogen, methyl, deuterated methyl, and halomethyl;

[0011] Ring A is selected from the following groups: monocyclic or bicyclic 3-11-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S, 6-10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, -(3-8-membered heterocycloalkylene containing 1-3 heteroatoms selected from N, O, and S)-(3-8-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S), and 4-8-membered heterobridged cycloalkyl containing 1-3 heteroatoms selected from N, O, and S;

[0012] Any hydrogen atom on the A ring is unsubstituted or mono-, di- or tri-substituted by the following substituents: (CH2) n NHR'1, (CH2) n CONH2, (CH2) n CF2H, (CH2) n CF3, (CH2) nOH, =O, C1-C6 alkyl, halogen, amino, hydroxyl, -N-(C1-C6 alkyl), -(C1-C6 alkylene)-NH2, wherein the hydrogen on the alkyl is unsubstituted or mono- or di-substituted by OR'1;

[0013] R'1 is selected from the group consisting of H, C1-C4 alkyl, and hydroxy-substituted C1-C4 alkyl;

[0014] n is selected from the following group: 0, 1, 2, 3.

[0015] In another preferred embodiment, R1 is selected from the following group: a monocyclic or bicyclic C6-C10 aryl group, a 6-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, and a C6-C10 aryl heterocycloalkyl group; any hydrogen atom on R1 is optionally substituted by one or more of the following substituents: deuterium, hydroxyl, halogen, cyano, =O, ester, amide, ketocarbonyl, amino, hydroxy-substituted C1-C4 alkyl, -C(O)OR a 、-NHC(O)R a 、-NHC(O)OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S; R a is a C1-C4 alkyl group;

[0016] R2 is selected from the group consisting of H, deuterium, amino, cyano, halogen, hydroxyl, methyl, CH2OH, CH(CH3)OH, C(CH3)2OH, halomethyl, deuterated methyl;

[0017] R3 is selected from the group consisting of hydrogen, deuterium, hydroxy, amino, cyano, halogen, methyl, deuterated methyl, and halomethyl;

[0018] Ring A is selected from the following groups: monocyclic or bicyclic 3-11-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S, 6-10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, -(3-8-membered heterocycloalkylene containing 1-3 heteroatoms selected from N, O, and S)-(3-8-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S), and 4-8-membered heterobridged cycloalkyl containing 1-3 heteroatoms selected from N, O, and S;

[0019] Any hydrogen atom on the A ring is unsubstituted or mono-, di- or tri-substituted by the following substituents: (CH2) n NHR'1, (CH2) n CONH2, (CH2) n CF2H, (CH2)n CF3, (CH2) n OH, =O, C1-C6 alkyl, halogen, amino, hydroxyl, -N-(C1-C6 alkyl), -(C1-C6 alkylene)-NH2, wherein the hydrogen on the alkyl is unsubstituted or mono- or di-substituted by OR'1;

[0020] R'1 is selected from the group consisting of H, C1-C4 alkyl, and hydroxy-substituted C1-C4 alkyl;

[0021] n is selected from the following group: 0, 1, 2, 3.

[0022] In another preferred embodiment, R1 is a B ring and a C ring, wherein,

[0023] Ring B and Ring C are each independently selected from the following group: C5-C6 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, C5-C6 cycloalkyl, saturated 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S;

[0024] Any hydrogen atom on R1 is optionally substituted by one or more of the following substituents: deuterium, hydroxyl, halogen, cyano, =O, amino, C1-C4 alkyl substituted with hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylamino, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, -C(O)C(CH3)2OH.

[0025] In another preferred embodiment, R1 is selected from the following group: a monocyclic or bicyclic C6-C10 aryl group, a 6-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S;

[0026] Any hydrogen atom on R1 is optionally substituted by one or more of the following substituents: deuterium, hydroxyl, halogen, cyano, =O, amino, hydroxy-substituted C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0027] In another preferred embodiment, R1 is selected from the following group:

[0028] Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, and Z9 are each independently selected from the group consisting of N, O, S, C, and C(R4) m , NR4;

[0029] R4 is independently selected from the following group: hydrogen, deuterium, hydroxyl, halogen, cyano, =O, amino, hydroxy-substituted C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylamino, C6-C10 aryl, 6-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, -COC(CH3)2OH;

[0030] is a single bond or a double bond;

[0031] m is each independently selected from the following group: 1, 2.

[0032] In another preferred embodiment, R1 is selected from the following group:

[0033] In another preferred embodiment, ring A is

[0034] In another preferred embodiment, ring A is selected from the following groups: a monocyclic or bicyclic 3-11-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a 6-10-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, -(a 3-8-membered heterocycloalkylene group containing 1-3 heteroatoms selected from N, O, and S)-(a 3-8-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S), and a 4-8-membered heterobridged cycloalkyl group containing 1-3 heteroatoms selected from N, O, and S;

[0035] Any hydrogen atom on the A ring is unsubstituted or mono-, di- or tri-substituted by the following substituents: (CH2) n NHR'1, (CH2) n CONH2, (CH2) n CF2H, (CH2) n CF3, (CH2) n OH, =O, C1-C6 alkyl, halogen, amino, hydroxyl, -N-(C1-C6 alkyl), -(C1-C6 alkylene)-NH2, wherein the hydrogen on the alkyl is unsubstituted or mono- or di-substituted by OR'1;

[0036] R'1 is selected from the group consisting of H, C1-C4 alkyl, and hydroxy-substituted C1-C4 alkyl;

[0037] n is selected from the following group: 0, 1, 2, 3.

[0038] In another preferred embodiment, the bicyclic 3-11-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O and S is a spiro ring structure.

[0039] In another preferred embodiment, the compound is selected from the following group:

[0040]

[0041]

[0042] In another preferred embodiment, the compound is selected from the following group:

[0043]

[0044]

[0045]

[0046] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

[0047] In another preferred embodiment, the inorganic acid salt is selected from the following group: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate.

[0048] In another preferred embodiment, the organic acid salt is selected from the following group: formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.

[0049] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0050] The third aspect of the present invention provides a use of the pharmaceutical composition according to the second aspect of the present invention for preparing a drug used as a SHP2 inhibitor.

[0051] The fourth aspect of the present invention provides a use of the pharmaceutical composition according to the second aspect of the present invention for preparing a drug for regulating SHP2 activity or treating SHP2-related diseases.

[0052] In another preferred embodiment, the SHP2-related disease is selected from the following group: Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, acute myeloid leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, gastric cancer, head cancer, anaplastic large cell lymphoma, neuroblastoma, glioblastoma, squamous cell carcinoma of the head and neck, colon cancer, and liver cancer.

[0053] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0054] After long-term and in-depth research, the inventors obtained a class of compounds with high inhibitory effects on the activity of SHP2 phosphatase through structural design. On this basis, the inventors completed the present invention.

[0055] the term

[0056] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0057] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0058] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. "C1-C4 alkyl" has a similar meaning.

[0059] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0060] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0061] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. "C3-C6 cycloalkyl" and "C5-C6 cycloalkyl" have similar meanings.

[0062] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0063] In the present invention, the term "heterocycloalkyl" refers to a 3-11 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0064] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0065] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0066] In the present invention, the term "halo" means substituted with halogen.

[0067] In the present invention, the term "deuterated" means substituted with deuterium.

[0068] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0069] In the present invention, the term "plurality" refers to 1-7.

[0070] In the present invention, the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0071] The term "ester group" has a -C(O)-O-R' or R'-C(O)-O- structure, wherein R' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl, heterocyclic group, as defined above.

[0072] The term "ketocarbonyl" has RC(=O)-, wherein R is alkyl, cycloalkyl, etc. as described above.

[0073] The term "amido" refers to a group having the structure -CONRR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.

[0074] The term "C6-C10 arylheterocycloalkyl" refers to a cyclic structure containing 6 to 10 carbon atoms formed by a cycloalkyl group containing a heteroatom and an aryl group, or a cycloalkyl group containing a heteroatom is connected to an aryl group through an atom on the ring.

[0075] The term "amino" refers to -NH2.

[0076] The term "C1-C6 heteroalkyl" refers to a substituted alkyl having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, Si or a combination thereof. A numerical range may be given, for example, a C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a "C3" heteroalkyl. Its connection to the rest of the molecule may be through a heteroatom or carbon in the heteroalkyl chain. Examples of "heteroalkyl" include, but are not limited to, CH2OCH3, CH2CH2OCH3, CH2NHCH3, CH2CH2NHCH3, Me3Si, Me3SiCH2CH2O-, Me3SiCH2CH2OCH2-(SEM). "Heteroalkylene" refers to an optionally substituted divalent alkyl having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, Si or a combination thereof.

[0077] The term "C1-C6 alkylamino group" refers to a group having an alkyl-NR-structure, wherein R is H, or an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, etc. as described above.

[0078] The term "C3-C8 cycloalkylamino" refers to a group of the formula -NRaRb, wherein Ra is H, an alkyl group as defined herein, or a cycloalkyl group as defined herein, and Rb is a cycloalkyl group as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl. As used herein, C3-C8 cycloalkylamino refers to an amine group containing 3-8 carbon atoms.

[0079] The term "heterobridged cycloalkyl" refers to a heterocycloalkyl group having a bridge carbon atom.

[0080] Compound

[0081] The present invention provides a compound of formula I', or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0082]

[0083] Wherein, the definitions of each group are as shown above.

[0084] In another preferred embodiment, in the compound, any one of R1, R2, R3, and Ring A is independently a corresponding group in the specific compound of the present invention.

[0085] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0086] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0087] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0088] The term "prodrug" includes a substance which may be biologically active or inactive, and which undergoes metabolism or chemical reactions in the human body to be converted into a compound of Formula I', or a salt or solution of a compound of Formula I' after being taken by an appropriate method. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0089] Pharmaceutical compositions and methods of administration

[0090] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0091] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0092] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0093] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0094] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0096] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0097] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0098] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0099] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0100] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0101] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0102] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0103] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0104] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0105] Compared with the prior art, the present invention has the following main advantages:

[0106] (1) The compounds of the present invention have excellent SHP2 activity inhibitory effects;

[0107] (2) The compounds of the present invention have good bioavailability and lower toxicity.

[0108] The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0109] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0110] Synthesis of intermediate A:

[0111] The synthetic route is as follows:

[0112]

[0113] Under ice-water cooling, compound 1 (2 g, 5.3 mmol) was dissolved in a mixed solvent consisting of trifluoroacetic acid and dichloromethane (7 mL / 21 mL), and then the reaction solution was moved to room temperature and stirred for 40 min. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 2.5 g of trifluoroacetate salt of compound A. Ms[M+H]+275.3

[0114] NMR data of compound A: 1H NMR (400 MHz, Chloroform-d) δ 4.27-4.22 (m, 1H), 4.04 (d, J = 10.8 Hz, 1H), 3.92 (d, J = 9.6 Hz, 1H), 3.66-3.57 (m, 2H), 3.54-3.42 (m, 2H), 3.16-3.05 (m, 2H), 2.25-2.08 (m, 2H), 1.87-1.73 (m, 2H), 1.31 (s, 9H), 1.24 (d, J = 6.4 Hz, 3H).

[0115] Synthesis of intermediate B

[0116] The synthetic route is as follows:

[0117]

[0118] 1. Synthesis of Compound 2

[0119] Compound 1 (54.7 g, 0.48 mol) was dissolved in 440 mL of N, N-dimethylformamide, and then 4-methoxybenzyl chloride (83.6 g, 0.53 mol) and potassium carbonate (100.2 g, 0.73 mol) were added in sequence, and the temperature was raised to 80°C for reaction for 3 hours. After the reaction, the reaction solution was cooled to room temperature and dripped into 2 L of water, and then extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 110 g of compound 2.

[0120] NMR data of compound 2: 1H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.92 (s, 1H), 7.19-7.17 (d, J = 8.39 Hz, 2H), 6.87-6.85 (d, J = 8.39 Hz, 2H), 5.17 (s, 2H), 3.75 (s, 3H).

[0121] 2. Synthesis of Compound 3

[0122] Compound 2 (50.6 g, 0.22 mol) was dissolved in 500 mL of anhydrous tetrahydrofuran. Under nitrogen protection, the reaction solution was cooled to -60°C, and 260 mL of 1 M bis(trimethylsilyl)amide lithium tetrahydrofuran solution was added dropwise. After the addition was complete, the reaction solution was stirred at -60°C for 1 hour, and then a solution of hexachloroethane (61.6 g, 0.26 mol) dissolved in 300 mL of anhydrous tetrahydrofuran was added dropwise at -60°C and stirred for 1 hour. After the reaction was completed, 1 L of saturated ammonium chloride solution was added dropwise at -60°C to quench the reaction, and then the reaction solution was warmed to room temperature, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 43.5 g of compound 3.

[0123] NMR data of compound 3: 1H NMR (90 MHz, Chloroform-d3) δ 8.08 (s, 1H), 7.23-7.13 (m, 2H), 6.85-6.75 (m, 2H), 5.22 (s, 2H), 3.72 (s, 3H).

[0124] 3. Synthesis of compound 4

[0125] Compound 3 (43.5 g, 0.16 mmol) and L-serine ethyl ester hydrochloride (83.2 g, 0.49 mmol) were dissolved in a mixed solvent consisting of 600 mL ethanol and 600 mL water, and then sodium bicarbonate (110 g, 1.31 mol) was added, and the reaction solution was heated to 90°C and stirred for 72 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, and diluted with dichloromethane, and separated. Concentrated hydrochloric acid was added dropwise to the aqueous phase until pH <4, and then extracted with ethyl acetate. The ethyl acetate organic phase was combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 49 g of compound 4. Ms[M+Na]+359.1

[0126] NMR data of compound 4: 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.17-7.14 (d, J = 8.91 Hz, 2H), 6.88-6.86 (d, J = 8.39 Hz, 2H), 6.82 (s, 1H), 6.06-6.05 (d, J = 3.68 Hz, 1H), 5.04-5.03 (d, J = 2.55 Hz, 2H), 4.89-4.87 (t, 1H), 3.80-3.76 (q, 1H), 3.72 (s, 3H), 3.60-3.57 (t, 2H).

[0127] 4. Synthesis of Compound 5

[0128] Compound 4 (8.5 g, 25.3 mmol) was dissolved in 340 mL of acetic acid, and reduced iron powder (14.1 g, 253 mmol) was added. The mixture was heated to 50 °C under nitrogen protection for 6 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The residue was adjusted to pH>7 with saturated sodium bicarbonate, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.4 g of crude compound 5. Ms[M+H]+289.1

[0129] NMR data of compound 5: 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.16-7.14 (d, J = 9.03 Hz, 2H), 6.88-6.86 (d, J = 8.53 Hz, 2H), 6.82 (s, 1H), 6.08-6.07 (d, J = 3.51 Hz, 1H), 5.04-5.03 (d, J = 2.23 Hz, 2H), 4.92-4.89 (t, 1H), 3.80-3.77 (q, 1H), 3.72 (s, 3H), 3.60-3.57 (t, 2H).

[0130] 5. Synthesis of Compound 6

[0131] The crude compound 5 (3.47 g, 12 mmol) was dissolved in 25 mL of N, N-dimethylformamide, and imidazole (2.47 g, 36 mmol) was added. Under ice-water cooling, tert-butyldiphenylsilyl chloride (9.9 g, 36 mmol) was slowly added dropwise under nitrogen protection. After the addition was completed, the reaction solution was gradually heated to room temperature and reacted for 1 hour. After the reaction was completed, a saturated sodium chloride solution was added to dilute the reaction system, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 5.4 g of compound 6. Ms[M+H]+527.4

[0132] NMR data of compound 6: 1H NMR (400 MHz, Chloroform-d3) δ 7.96 (s, 1H), 7.60-7.56 (m, 4H), 7.47-7.40 (m, 2H), 7.39-7.35 (m, 4H), 7.13-7.11 (m, 2H), 7.06 (s, 1H), 6.80 (d, J = 8.6 Hz, 2H), 4.09-4.04 (m, 1H), 3.96-3.91 (m, 3H), 3.72 (s, 3H), 2.92 (d, J = 28.3 Hz, 2H), 0.99 (s, 9H).

[0133] 6. Synthesis of Compound 7

[0134] Compound 6 (5.4 g, 10.24 mmol) was dissolved in 70 mL of dioxane, and manganese dioxide (4.47 g, 51.35 mmol) was added, and the mixture was heated to 35°C for 1 hour. After the reaction, the reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain 4.95 g of compound 7. Ms[M+H]+525.2

[0135] NMR data of compound 7: 1H NMR (400 MHz, Chloroform-d3) δ 7.78-7.71 (m, 4H), 7.48 (s, 1H), 7.42-7.36 (m, 2H), 7.36-7.28 (m, 6H), 6.84-6.77 (m, 2H), 5.48 (s, 2H), 5.04 (s, 2H), 3.76 (s, 3H), 1.16 (s, 9H).

[0136] 7. Synthesis of Compound 8

[0137] Compound 7 (5 g, 9.54 mmol) was dissolved in 45 mL of N, N-dimethylformamide, and then triethylamine (5.4 mL, 38 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (6.8 g, 19 mmol) were added in turn under ice-water cooling, and then the reaction solution was moved to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was diluted with saturated brine, and then extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 8 g of compound 8.

[0138] 8. Synthesis of Compound 9

[0139] Compound 8 (3.9 g, 5.87 mmol) was dissolved in 70 mL of acetonitrile, and then N, N-diisopropylethylamine (10 mL, 53 mmol) and trifluoroacetate of compound A (1.46 g, 5.3 mmol) were added. The reaction solution was stirred at 75°C for 20 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3.2 g of compound 9. Ms[M+H]+781.4

[0140] NMR data of compound 9: 1H NMR (400 MHz, DMSO-d6) δ8.17 (s, 1H), 7.75-7.73 (m, J = 8.0 Hz, 4H), 7.44-7.37 (m, 6H), 7.21 (dd, J = 8.8, 2.2 Hz, 2H), 6.85-6.78 (m, 2H), 5.51 (s, 2H), 5.11 (d, J = 10.8 Hz, 1H), 4.97 (s, 2H), 4.16-4.10 (m , 1H), 3.78 (d, J=8.6Hz, 1H), 3.69 (s, 3H), 3.48 (d, J=8.6Hz, 1H), 3.43-3.39 (m, 1H), 3.26-3.22 (m, 2H), 2.83(m, 2H), 1.94-1.79(m, 2H), 1.60(m, 2H), 1.18(s, 9H), 1.10(d, J=6.4Hz, 3H), 1.01(s, 9H).

[0141] 9. Synthesis of Compound 10

[0142] Compound 9 (1.4 g, 1.79 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (2.7 mL, 2.7 mmol) was added under ice-water cooling, and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction was diluted with ethyl acetate, washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 830 mg of compound 10. Ms [M + H] + 543.4

[0143] NMR data of compound 10: 1H NMR (400 MHz, DMSO-d6) δ8.17 (s, 1H), 7.28-7.20 (m, 2H), 6.91-6.83 (m, 2H), 5.58 (s, 2H), 5.42 (s, 1H), 5.14 (d, J=10.8 Hz, 1H), 4.71 (s, 2H), 4.16-4.10 (m, 1H), 3.82 (d, J=8.6Hz, 1H), 3.70(s, 3H), 3.52(d, J=8.6Hz, 1H), 3.46-3.42(m, 3H), 2.85-2.84(m, 2H), 1.97-1.90 (m, 2H), 1.66 (t, J=16.5Hz, 2H), 1.18 (s, 9H), 1.11 (d, J=6.4Hz, 3H).

[0144] 10. Synthesis of Compound 11

[0145] Compound 10 (1.5 g, 2.77 mmol) was dissolved in 40 mL of dichloromethane, triethylamine (0.78 mL, 5.54 mmol) was added, and then tert-butylsulfenyl chloride (584 mg, 4.16 mmol, dissolved in 2 mL of dichloromethane) was added dropwise under ice-water cooling. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and then the reaction solution was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.26 g of compound 11. Ms[M+H]+647.4

[0146] NMR data of compound 11: 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.27-7.17 (m, 2H), 6.90-6.80 (m, 2H), 5.56 (s, 2H), 5.37-5.27 (m, 2H), 5.15 (d, J = 10.5 Hz, 1H), 4.16-4.10 (m, 1H), 3.82 (d, J = 8.6 Hz, 1H), 3 .70(s, 3H), 3.57-3.48(m, 1H), 3.48-3.42(m, 1H), 3.29-3.21(m, 2H), 2.95-2.81(m, 2H) , 1.99-1.92(m, 2H), 1.71-1.62(m, 2H), 1.18(s, 9H), 1.14(s, 9H), 1.11(d, J=6.3Hz, 3H).

[0147] 11. Synthesis of Compound B

[0148] Compound 11 (1.26 g, 1.86 mmol) was dissolved in 12 mL of trifluoroacetic acid under ice-water bath, replaced with nitrogen three times, trifluoromethanesulfonic acid (1.2 mL) was added under ice-water bath cooling, and stirred at room temperature for 2.5 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added under ice-water bath cooling to adjust pH to 8, the reaction solution was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 700 mg of compound B. Ms [M + H] + 527.4

[0149] NMR data of compound B: 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 5.29-5.23 (m, 2H), 5.15 (d, J = 10.7 Hz, 1H), 4.19-4.13 (m, 1H), 3.85-3.80 (m, 1H), 3.55-3.51 (m, 1H), 3.49-3.45 (m, 1H), 3.32-3.23 (m, 2H), 2.95-2.85 (m, 2H), 1.98-1.93 (m, 2H), 1.72-1.64 (m, 2H), 1.18 (s, 9H), 1.14 (s, 9H), 1.11 (d, J = 6.4 Hz, 3H).

[0150] Example 1

[0151] The compound synthesized by the present invention:

[0152]

[0153] The synthetic route of compound C2 is as follows:

[0154]

[0155] 1. Synthesis of C2-2

[0156] Compound B (90 mg, 0.17 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C2-1 (60 mg, 0.34 mmol), copper acetate (31 mg, 0.17 mmol) and pyridine (27 mg, 0.34 mmol) were added in sequence, and stirred at 25°C for 3 hours under oxygen protection. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride, and the organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 60 mg of compound C2-2. Ms[M+H]+657.5

[0157] 2. Synthesis of C2

[0158] Compound C2-2 (60 mg, 0.09 mmol) was dissolved in 2 mL of methanol, and then 5 mL of methanolic hydrochloric acid was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then heated to 55 °C and stirred for 5 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 5 mg of trifluoroacetate salt of compound C2. Ms[M+H]+449.4

[0159] NMR data of compound C2: 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.33 (s, 1H), 7.57-7.48 (m, 2H), 4.84 (s, 2H), 4.27-4.22 (m, 1H), 4.09 (s, 3H), 3.84 (d, J = 8.6 Hz, 1H), 3.71 (d, J = 8.7 Hz, 1H), 3.44-3.39 (m, 2H), 3.13-2.95 (m, 3H), 1.97-1.89 (m, 2H), 1.79-1.75 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H).

[0160] Example 2

[0161] The compound synthesized by the present invention:

[0162]

[0163] The synthetic route of compound C3 is as follows:

[0164]

[0165] 1. Synthesis of compound C3-2

[0166] Compound B (100 mg, 0.19 mmol) was dissolved in 5 mL of acetonitrile, and compound C3-1 (146 mg, 0.57 mmol), copper acetate (35 mg, 0.19 mmol) and boric acid (23 mg, 0.38 mmol) were added in sequence, and stirred at 80°C overnight under oxygen protection. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 35 mg of compound C3-2. Ms[M+H]+655.3

[0167] 2. Synthesis of compound C3

[0168] Compound C3-2 (35 mg, 0.054 mmol) was dissolved in 1.5 mL of methanol, and then 3.5 mL of 4 M hydrogen chloride methanol solution was added. The mixture was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 3 hours. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 3 mg of trifluoroacetate salt of compound C3. Ms[M+H]+447.2

[0169] NMR data of compound C3: 1H NMR (400 MHz, Methanol-d4) δ 9.28 (d, J = 2.4 Hz, 1H), 9.01 (dd, J = 9.3, 2.4 Hz, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.39 (s, 1H), 8.28 (d, J = 9.3 Hz, 1H), 4.96 (s, 2H), 4.35-4.31 (m, 1H) , 4.00 (d, J = 9.1Hz, 1H), 3.90 (d, J = 9.1Hz, 1H), 3.67-3.56 (m, 2H), 3.52-3.49 (m, 1H), 3.14-3.02 ( m, 2H), 2.10-2.04 (m, 2H), 1.98 (d, J=13.3Hz, 1H), 1.81 (d, J=12.8Hz, 1H), 1.35 (d, J=6.5Hz, 3H).

[0170] Example 3

[0171] The compound synthesized by the present invention:

[0172]

[0173] The synthetic route of compound C4 is as follows:

[0174]

[0175] 1. Synthesis of compound C4-2

[0176] Compound B (80 mg, 0.15 mmol) was dissolved in 6 mL N, N-dimethylformamide, and compound C4-1 (54 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and pyridine (24 mg, 0.30 mmol) were added in sequence, and stirred at 25°C for 5 hours under oxygen protection. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 70 mg of compound C4-2. Ms[M+H]+657.5

[0177] 2. Synthesis of compound C4

[0178] Compound C4-2 (70 mg, 0.11 mmol) was dissolved in 4 mL of methanol, and then 6 mL of 4 M hydrogen chloride methanol solution was added. The mixture was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 4 hours. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 8 mg of trifluoroacetate of C4. Ms[M+H]+449.2

[0179] NMR data of compound C4: 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.33 (s, 1H), 8.22 (dd, J = 8.8, 1.8 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.93 (dd, J = 8.8, 0.7 Hz, 1H), 4.95 (s, 2H), 4.37-4.32 (m , 1H), 4.17 (s, 3H), 4.00 (d, J=12Hz, 1H), 3.90 (d, J=12Hz, 1H), 3.65-3.51 (m, 3H) , 3.13-3.01(m, 2H), 2.11-1.97(m, 3H), 1.83-1.79(m, 1H), 1.36(d, J=6.5Hz, 3H).

[0180] Example 4

[0181] The compound synthesized by the present invention:

[0182]

[0183] The synthetic route of compound C5 is as follows:

[0184]

[0185] 1. Synthesis of compound C5-2

[0186] Compound B (100 mg, 0.19 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C5-1 (67 mg, 0.38 mmol), copper acetate (35 mg, 0.19 mmol) and pyridine (30 mg, 0.38 mmol) were added in sequence, and stirred at 25°C for 2 hours under oxygen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 76 mg of compound C5-2. Ms[M+H] + 656.4

[0187] 2. Synthesis of compound C5

[0188] Compound C5-2 (70 mg, 0.11 mmol) was dissolved in 4 mL of methanol, and then 6 mL of 4 M hydrogen chloride methanol solution was added. The mixture was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 5 h. After the reaction, the reaction solution was cooled to room temperature, concentrated by spin drying, and purified to obtain 3 mg of trifluoroacetate salt of C5. Ms[M+H] + 448.3

[0189] NMR data of compound C5: 1H NMR (400MHz, Methanol-d4) δ8.33 (s, 1H), 7.68 (dd, J=7.7, 0.8Hz, 1H), 7.54-7.51 (m, 1H), 7. 38 (t, J=7.8Hz, 1H), 7.27 (d, J=3.2Hz, 1H), 6.63 (dd, J=3.2, 0.9Hz, 1H), 4.86 (s, 2H), 4.35-4. 33 (m, J=6.5, 4.1Hz, 1H), 4.00 (d, J=9.1Hz, 1H), 3.91-3.89 (m, 4H), 3.63-3.48 (m, 3H), 3.13- 2.98 (m, 2H), 2.10-2.04 (m, 2H), 1.99-1.95 (m, 1H), 1.82-1.79 (m, 1H), 1.36 (d, J=6.5Hz, 3H).

[0190] Example 5

[0191] The compound synthesized by the present invention:

[0192]

[0193] The synthetic route of compound C6 is as follows:

[0194]

[0195] 1. Synthesis of compound C6-2

[0196] Compound B (100 mg, 0.19 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C6-1 (120 mg, 0.57 mmol), copper acetate (17 mg, 0.095 mmol) and pyridine (45 mg, 0.57 mmol) were added in sequence, and stirred at 25°C for 1 hour under oxygen protection. After the reaction was completed, the reaction was diluted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 80 mg of compound C6-2. Ms[M+H]+691.3

[0197] 2. Synthesis of compound C6

[0198] Compound C6-2 (80 mg, 0.12 mmol) was dissolved in 3 mL of methanol, and then 5 mL of 4 M hydrogen chloride methanol solution was added. The reaction liquid was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 4 h. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 20 mg of trifluoroacetate of C6. Ms[M+H]+483.2

[0199] NMR data of compound C6: 1H NMR (400MHz, Methanol-d4) δ8.52 (s, 1H), 8.34 (s, 1H), 7.74 (dd, J=9.0, 09Hz, 1H), 7.44 (d, J=8.9Hz, 1H), 4.82 (s, 2H), 4.38-4.32 (m, 4H), 4.00 (d, J=9.1 Hz, 1H), 3.89 (d, J=9.2Hz, 1H), 3.62-3.49 (m, 3H), 3.11-2.98 (m, 2H), 2.05 (d , J=9.5Hz, 2H), 1.98-1.95 (m, 1H), 1.82-1.79 (m, 1H), 1.35 (d, J=6.5Hz, 3H).

[0200] Example 6

[0201] The compound synthesized by the present invention:

[0202]

[0203] The synthetic route of compound C7 is as follows:

[0204]

[0205] 1. Synthesis of compound C7-2

[0206] Compound B (70 mg, 0.13 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C7-1 (49 mg, 0.26 mmol), copper acetate (28 mg, 0.13 mmol) and pyridine (21 mg, 0.26 mmol) were added in sequence, and stirred at 25°C for 3 hours under an oxygen atmosphere. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 30 mg of compound C7-2. Ms[M+H]+657.4

[0207] 2. Synthesis of compound C7

[0208] Compound C7-2 (30 mg, 0.046 mmol) was dissolved in 2 mL of methanol, and then 4 mL of 4 M hydrogen chloride methanol solution was added. The reaction liquid was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 6 h. After the reaction was completed, the reaction liquid was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 3 mg of C7 trifluoroacetate. Ms[M+H]+449.2

[0209] NMR data of compound C7: 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.15 (s, 1H), 7.98 (dd, J = 8.2, 1.0 Hz, 1H), 7.51 (dd, J = 7.3, 1.0 Hz, 1H), 7.32 (dd, J = 8.1, 7.3 Hz, 1H), 4.78 (s, 2H), 4.35-4.29 (m, 1H), 3 .98(d, J=9.1Hz, 1H), 3.87(d, J=9.1Hz, 1H), 362-3.47(m, 3H), 3.42(s, 3H), 3.10-2.97( m, 2H), 2.09-2.00 (m, 2H), 1.96-1.93 (m, 1H), 1.80-1.77 (m, 1H), 1.33 (d, J=6.5Hz, 3H).

[0210] Example 7

[0211] The compound synthesized by the present invention:

[0212]

[0213] The synthetic route of compound C8 is as follows:

[0214]

[0215] 1. Synthesis of compound C8-1

[0216] Compound 9 (700 mg, 0.90 mmol) was dissolved in a mixed solvent of 8 mL acetonitrile and 8 mL acetic acid, and N-bromosuccinimide (480 mg, 2.69 mmol) was added in batches under ice-salt cooling, and the mixture was stirred for 30 min. The reaction was then moved to room temperature and stirred for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 500 mg of compound C8-1. Ms[M+H]+755.4

[0217] 2. Synthesis of compound C8-2

[0218] Compound C8-1 (500 mg, 0.66 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (10 mL / 1 mL), and then methylboric acid (120 mg, 1.99 mmol), 1,1′-bis(di-phenylphosphino)ferrocenepalladium chloride, dichloromethane complex (54 mg, 0.66 mmol) and sodium carbonate (210 mg, 1.98 mmol) were added in sequence. The reaction solution was stirred at 100°C for 10 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 270 mg of compound C8-2. Ms[M+H]+691.5

[0219] 3. Synthesis of compound C8-3

[0220] Compound C8-2 (270 mg, 0.39 mmol) was dissolved in 5 mL of tetrahydrofuran, and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.47 mL, 0.47 mmol) was added under an ice-water bath, and then stirred at room temperature for 2 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure and purified to obtain 180 mg of compound C8-3.

[0221] NMR data of compound C8-3: 1H NMR (400 MHz, DMSO-d6) δ7.25-7.18 (m, 2H), 6.89-6.83 (m, 2H), 5.49 (s, 2H), 5.36 (t, J = 5.9 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.11-4.04 (m, 1H), 3.70 (s, 4H), 3.51 (d, J=8.3Hz, 1H), 3.46-3.40 (m, 1H), 3.28-3.20 (m, 2H), 3.02-2.89 (m, 2 H), 2.44 (s, 3H), 1.91-1.76 (m, 2H), 1.68-1.53 ​​(m, 2H), 1.10 (d, J=6.5Hz, 3H).

[0222] 4. Synthesis of compound C8-4

[0223] Compound C8-3 (200 mg, 0.44 mmol) was dissolved in 6 mL of dichloromethane, triethylamine (0.2 mL, 132 mmol) was added, and then a dichloromethane solution of tert-butylsulfenyl chloride (160 mg, 1.1 mmol, dissolved in 3 mL of dichloromethane) was added dropwise under ice-water cooling. After the addition was complete, the reaction solution was moved to room temperature and stirred for 1 hour. After the reaction was completed, water was added to quench the reaction, and dichloromethane was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 180 mg of compound C8-4. Ms[M+H]+661.4

[0224] 5. Synthesis of compound C8-5

[0225] Compound C8-4 (180 mg, 0.27 mmol) was dissolved in 2 mL of trifluoroacetic acid under ice-water bath, and trifluoromethanesulfonic acid (0.2 mL) was slowly added dropwise under ice-water bath cooling. After the addition was complete, the reaction solution was moved to room temperature and stirred for 6.5 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added dropwise under ice-water bath cooling, adjusted to pH 8, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 90 mg of compound C8-5. Ms[M+H]+541.3

[0226] 6. Synthesis of Compound C8-7

[0227] Compound C8-5 (90 mg, 0.16 mmol) was dissolved in 5Ml N, N-dimethylformamide, and compound C8-6 (60 mg, 0.34 mmol), copper acetate (31 mg, 0.17 mmol) and pyridine (27 mg, 0.34 mmol) were added in sequence, and stirred at 25°C for 2 hours under oxygen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 70 mg of compound C8-7. Ms[M+H]+671.4

[0228] 7. Synthesis of Compound C8

[0229] Compound C8-7 (70 mg, 0.10 mmol) was dissolved in 3 mL of methanol, and then 6 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then the reaction solution was heated to 55 °C and stirred for 7 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 3 mg of trifluoroacetate of C8. Ms[M+H]+463.2

[0230] NMR data of compound C8: 1H NMR (400 MHz, Methanol-d4) δ8.46 (s, 1H), 8.20 (dd, J = 8.8, 1.8 Hz, 1H), 8.03 (d, J = 1.0 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 4.92 (s, 2H), 4.36-4.29 (m, 1H), 4.14 (s, 3H), 3.99 (d , J=9.1Hz, 1H), 3.89 (d, J=9.2Hz, 1H), 3.60-3.46 (m, 3H), 3.10-2.98 (m, 2H), 2.65 (s, 3H), 2.10-2.01(m, 2H), 1.98-1.95(m, 1H), 1.81-1.78(m, 1H), 1.34(d, J=6.5Hz, 3H).

[0231] Example 8

[0232] The compound synthesized by the present invention:

[0233]

[0234] The synthetic route of compound C9 is as follows:

[0235]

[0236] 1. Synthesis of compound C9-2

[0237] Compound B (90 mg, 0.17 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C9-1 (70 mg, 0.34 mmol), copper acetate (31 mg, 0.17 mmol) and pyridine (27 mg, 0.34 mmol) were added in sequence, and stirred at 25°C for 3 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 130 mg of compound C9-2. Ms[M+H]+686.4

[0238] 2. Synthesis of compound C9

[0239] Compound C9-2 (60 mg, 0.19 mmol) was dissolved in 3 mL of methanol, and then 4 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then heated to 55 °C and stirred for 5 h. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 7 mg of trifluoroacetate of C9. Ms[M+H]+436.3.

[0240] NMR data of compound C9: 1H NMR (400 MHz, Methanol-d4) δ8.30 (s, 1H), 7.92 (dd, J = 8.1, 0.9 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 4.33-4.29 (m, 1H), 4.00-3.96 (d, J = 12 Hz, 1H), 3.88 -3.84 (d, J=12Hz, 1H), 3.79 (t, J=7.9Hz, 2H), 3.62-3.45 (m, 5H), 3.09-2.97 (m, 2H ), 2.09-2.03(m, 2H), 1.96-1.93(m, 1H), 1.80-1.76(m, 1H), 1.34(d, J=6.4Hz, 3H).

[0241] Example 9

[0242] The compound synthesized by the present invention:

[0243]

[0244] The synthetic route of compound C10 is as follows:

[0245]

[0246] 1. Synthesis of compound C10-2

[0247] Compound B (90 mg, 0.17 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C10-1 (63 mg, 0.34 mmol), copper acetate (34 mg, 0.17 mmol) and pyridine (27 mg, 0.34 mmol) were added in sequence, and stirred at 25°C for 2 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 52 mg of compound C10-2. Ms[M+H]+656.4

[0248] 2. Synthesis of compound C10

[0249] Compound C10-2 (52 mg, 0.08 mmol) was dissolved in 2 mL of methanol, and then 2 mL of oxychloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then the reaction solution was heated to 55 °C and stirred for 8 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 2.08 mg of trifluoroacetate of C10. Ms[M+H]+448.3

[0250] NMR data of compound C10: 1H NMR (400 MHz, Methanol-d4) δ8.26 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 7.87 (dd, J = 8.8, 2.1 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 6.55 (d, J = 3.1 Hz, 1H), 4.88 (s, 2H), 4.36-4.28 (m, 1H), 3. 98(d, J=9.2Hz, 1H), 3.91-3.83(m, 4H), 3.61-3.52(m, 2H), 3.49-3.48(m, 1H), 3.10-2.95(m, 2 H), 2.07-2.00 (m, 2H), 1.95 (d, J=12.9Hz, 1H), 1.78 (d, J=12.8Hz, 1H), 1.33 (d, J=6.5Hz, 3H).

[0251] Example 10

[0252] The compound synthesized by the present invention:

[0253]

[0254] The synthetic route of compound C11 is as follows:

[0255]

[0256] 1. Synthesis of compound C11-2

[0257] Compound B (100 mg, 0.19 mmol) was dissolved in 5 mL of N, N-dimethylformamide, and compound C11-1 (67 mg, 0.38 mmol), copper acetate (35 mg, 0.19 mmol) and pyridine (30 mg, 0.38 mmol) were added in sequence, and stirred at 25°C for 2 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 35 mg of compound C11-2. Ms[M+H]+657.4

[0258] 1. Synthesis of compound C11

[0259] Compound C11-2 (35 mg, 0.05 mmol) was dissolved in 2 mL of methanol, and then 2 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then the reaction mixture was heated to 55 °C and stirred for 6 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 8.32 mg of trifluoroacetate of C11. Ms[M+H]+449.2

[0260] NMR data of compound C11: 1H NMR (400 MHz, Methanol-d4) δ8.65 (d, J = 1.9 Hz, 1H), 8.31 (dd, J = 9.1, 1.9 Hz, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 4.92 (s, 2H), 4.37-4.31 (m, 1H), 4.15 (s, 3H), 4.00 ( d, J=9.2Hz, 1H), 3.89 (d, J=9.2Hz, 1H), 3.64-3.47 (m, 3H), 3.11-2.99 (m, 2H), 2.92 (s, 3H) , 2.11-2.05 (m, 2H), 1.97 (d, J = 12.9Hz, 1H), 1.81 (d, J = 12.8Hz, 1H), 1.36 (d, J = 6.5Hz, 3H).

[0261] Embodiment 11

[0262] The compound synthesized by the present invention:

[0263]

[0264] The synthetic route of compound C12 is as follows:

[0265]

[0266] 1. Synthesis of compound C12-2

[0267] Compound B (70 mg, 0.13 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C12-1 (46 mg, 0.26 mmol), copper acetate (24 mg, 0.13 mmol) and pyridine (21 mg, 0.26 mmol) were added in sequence, and stirred at 25°C for 2 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 104 mg of compound C12-2. Ms[M+H]+656.4

[0268] 2. Synthesis of compound C12

[0269] Compound C12-2 (104 mg, 0.16 mmol) was dissolved in 5 mL of methanol, and then 5 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then heated to 55 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 1 mg of trifluoroacetate salt of compound C12. Ms[M+H]+448.2

[0270] Example 12

[0271] The compound synthesized by the present invention:

[0272]

[0273] The synthetic route of compound C13 is as follows:

[0274]

[0275] 1. Synthesis of compound C13-2

[0276] Compound C13-1 (2.4 g, 12.12 mmol) was dissolved in 90 mL of anhydrous tetrahydrofuran, and sodium hydride (970 mg, 24.24 mmol) was added in batches under nitrogen protection and ice-water bath cooling. The temperature was maintained and stirred for 30 min, and then iodomethane (1.5 mL, 24.24 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was moved to room temperature and stirred for 16 h. After the reaction was completed, water was slowly added dropwise under ice-water bath cooling to quench the reaction. The reaction solution was extracted with ethyl acetate, washed with saturated brine, separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 1.43 g of compound C13-2. Ms[M+H]+212

[0277] 2. Synthesis of compound C13-3

[0278] Compound C13-2 (1.0 g, 4.7 mmol) was dissolved in 25 mL of 1,4-dioxane, and then diboric acid pinacol ester (1.44 g, 5.66 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride dichloromethane complex (192 mg, 0.24 mmol) and potassium acetate (1.4 g, 14.1 mmol) were added in sequence. Under nitrogen protection, the reaction solution was heated to 95 ° C and stirred for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, saturated salt water reaction solution was added, ethyl acetate was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 600 mg of compound C13-3. Ms[M+H]+260.2

[0279] 3. Synthesis of compound C13-4

[0280] Compound C13-3 (300 mg, 1.15 mmol) was dissolved in 12 mL of tetrahydrofuran, and then 12 mL of 1 M dilute hydrochloric acid aqueous solution was added to the reaction solution and stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure, recrystallized with PE / EA, filtered, and the filter cake was rinsed with petroleum ether. The filter cake was dried to obtain 70 mg of compound C13-4. .Ms[M+H]+178.1

[0281] 4. Synthesis of Compound C13-5

[0282] Compound B (80 mg, 0.15 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C13-4 (60 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and pyridine (24 mg, 0.30 mmol) were added in sequence, and stirred overnight at 25 °C under an oxygen atmosphere. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated brine, separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 70 mg of compound C13-5. Ms[M+H]+658.4

[0283] 5. Synthesis of Compound C13

[0284] Compound C13-5 (70 mg, 0.11 mmol) was dissolved in 3 mL of methanol, and 4 mL of 4 M hydrogen chloride methanol solution was added. The mixture was stirred at 25 °C for 30 min under nitrogen protection, and then heated to 55 °C and stirred for 5 h. After the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 7 mg of trifluoroacetate salt of compound TYK-00745. Ms[M+H]+450.3.

[0285] NMR data of compound C13: 1H NMR (400 MHz, Methanol-d4) δ8.24 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 4.83 (s, 2H), 4.36-4.28 (m, 1H), 3.97 (d, J = 9.1 Hz, 1H), 3.87 (d, J = 9. 2Hz, 1H), 3.60-3.50 (m, 2H), 3.49-3.47 (m, 1H), 3.38-3.33 (m, 2H), 3.10-2.94 (m, 4H), 2.8 2(s, 3H), 2.09-1.99(m, 2H), 1.98-1.92(m, 1H), 1.81-1.74(m, 1H), 1.33(d, J=6.5Hz, 3H).

[0286] Example 13

[0287] The compound synthesized by the present invention:

[0288]

[0289] The synthetic route of compound C14 is as follows:

[0290]

[0291] 1. Synthesis of compound C14-2

[0292] Compound B (70 mg, 0.13 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C14-1 (46 mg, 0.26 mmol), copper acetate (24 mg, 0.13 mmol) and 2,2'-bipyridine (42 mg, 0.26 mmol) were added in sequence, and stirred at 25°C for 2 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 74 mg of compound C14-2. Ms[M+H]+657.4

[0293] 2. Synthesis of compound C14

[0294] Compound C14-2 (74 mg, 0.11 mmol) was dissolved in 5 mL of methanol, and then 5 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25°C for 30 min, and then the reaction solution was heated to 55°C and stirred for 6 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 23 mg of trifluoroacetate salt of compound C14. Ms[M+H]+449.2

[0295] NMR data of compound C14: 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.27-8.26 (m, 2H), 8.06 (dd, J = 9.1, 1.8 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 4.90 (s, 2H), 4.36-4.28 (m, 1H), 4.25 (s, 3H), 3.98 (d, J = 9.2 Hz, 1 H), 3.87 (d, J=9.1Hz, 1H), 3.65-3.51 (m, 2H), 3.49 (d, J=4.1Hz, 1H), 3.10-2.98 (m, 2H), 2 .11-2.00 (m, 2H), 1.95 (d, J = 13.4Hz, 1H), 1.78 (d, J = 12.8Hz, 1H), 1.34 (d, J = 6.4Hz, 3H).

[0296] Embodiment 14

[0297] The compound synthesized by the present invention:

[0298]

[0299] The synthetic route of compound C15 is as follows:

[0300]

[0301] 1. Synthesis of compound C15-2

[0302] Compound C15-1 (2.0 g, 10.15 mmol) was dissolved in 50 mL of 1,4-dioxane, and then diboric acid pinacol ester (3.10 g, 12.18 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride dichloromethane complex (414 mg, 0.51 mmol) and anhydrous potassium acetate (3 g, 30.45 mmol) were added in sequence. Under nitrogen protection, the reaction solution was heated to 95 ° C and stirred for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, saturated brine was added to dilute the reaction, ethyl acetate was extracted, the liquid was separated, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3.0 g of compound C15-2. Ms[M+H]+245.1

[0303] 2. Synthesis of compound C15-3

[0304] Compound C15-2 (1 g, 4.10 mmol) was dissolved in 50 mL of methanol, and then an aqueous solution (50 mL) of potassium bifluoride (1.6 g, 20.5 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure, the residue was diluted and dissolved with acetonitrile, and then impurities were extracted with petroleum ether, the liquids were separated, and the acetonitrile phase was concentrated under reduced pressure and purified to obtain 400 mg of compound C15-3. Ms[M+H]+163.0

[0305] 3. Synthesis of compound C15-4

[0306] Compound C15-3 (400 mg, 2.47 mmol) was dissolved in 15 mL of tetrahydrofuran, and 4-N, N-dimethylaminopyridine (30 mg, 0.25 mmol) and di-tert-butyl dicarbonate (1.1 g, 4.94 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, saturated brine was added to dilute the reaction, extracted with ethyl acetate, separated, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 80 mg of a mixture of compounds C15-4A and C15-4B. Ms[M+H]+263.1

[0307] 4. Synthesis of compound C15-5

[0308] Compound B (80 mg, 0.15 mmol) was dissolved in 5 mL N, N-dimethylformamide, and a mixture of compounds C15-4A and C15-4B (80 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and 2,2'-bipyridine (50 mg, 0.30 mmol) were added in sequence, and stirred at 25°C for 20 hours under an oxygen atmosphere. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 90 mg of a mixture of compounds C15-5A and C15-5B. Ms[M+H]+743.4

[0309] 5. Synthesis of compound C15

[0310] The mixture of compounds C15-5A and C15-5B (90 mg, 0.12 mmol) was dissolved in 3 mL of methanol, and then 4 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then heated to 55 °C and stirred for 5 h. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified to obtain the trifluoroacetate salt of compound C15. Ms[M+H]+435.2.

[0311] NMR data of compound C15: 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.29 (s, 1H), 8.19 (dd, J = 8.8, 1.8 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 4.91 (s, 2H), 4.36-4.27 (m, 1H), 3.98 ( d, J=9.2Hz, 1H), 3.88 (d, J=9.2Hz, 1H), 3.65-3.47 (m, 3H), 3.10-2.97 (m, 2H), 2 .10-2.00(m, 2H), 1.99-1.91(m, 1H), 1.82-1.75(m, 1H), 1.34(d, J=6.5Hz, 3H).

[0312] Embodiment 15

[0313] The compound synthesized by the present invention:

[0314]

[0315] The synthetic route of compound C16 is as follows:

[0316]

[0317] 1. Synthesis of compound C16-1

[0318] Compound intermediate 10 (600 mg, 1.1 mmol) was dissolved in 30 mL of dichloromethane, and Dess-Martin oxidant (1.2 g, 2.76 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, saturated sodium bicarbonate and saturated sodium thiosulfate aqueous solutions were added to quench the reaction, extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 500 mg of compound C16-1. Ms[M+H]+541.3

[0319] NMR data of compound C16-1: 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.28 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.61 (s, 2H), 5.14 (d, J = 10.7 Hz, 1H), 4.19-4.12 (m, 1H), 3.82 (d, = 8.7 Hz, 1H) , 3.7 (s, 3H), 3.63-3.60 (m, 1H), 3.55-3.5 (m, 2H), 3.44 (dd, J=10.8, 5.8Hz, 1H), 3.13- 3.00 (m, 2H), 1.97-1.91 (m, 2H), 1.70-1.61 (m, 2H), 1.16 (s, 9H), 1.10 (d, J=6.3Hz, 3H).

[0320] 2. Synthesis of compound C16-2

[0321] Compound C16-1 (300 mg, 0.56 mmol) was dissolved in 30 mL of dichloromethane, and diethylaminosulfur trifluoride (267 mg, 1.67 mmol) was slowly added dropwise under nitrogen protection and ice bath cooling. After the addition was completed, the reaction solution was transferred to room temperature and stirred for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction, and dichloromethane was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 189 mg of compound C16-3. Ms[M+H]+563.3

[0322] 3. Synthesis of compound C16-3

[0323] Compound C16-2 (180 mg, 0.32 mmol) was dissolved in 2 mL of trifluoroacetic acid, trifluoromethanesulfonic acid (0.2 mL) was added to the reaction solution under ice bath cooling, stirred for 5 minutes under nitrogen protection, and then transferred to room temperature and stirred for another 2 hours. After the reaction was completed, the reaction solution was poured into ice water, and then saturated sodium bicarbonate aqueous solution was added to quench the reaction, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 141 mg of compound C16-3. Ms [M + H] + 443.2

[0324] 4. Synthesis of compound C16-5

[0325] Compound C16-3 (107 mg, 0.24 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C16-4 (85 mg, 0.48 mmol), copper acetate (44 mg, 0.24 mmol) and pyridine (33 mg, 0.48 mmol) were added in sequence, and stirred at 25°C for 16 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 159 mg of compound C16-5. Ms[M+H]+573.3

[0326] 5. Synthesis of Compound C16

[0327] Compound C16-5 (150 mg, 0.27 mmol) was dissolved in 5 mL of methanol, and then 5 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25°C for 30 min, and then heated to 55°C and stirred for 6 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain 159 mg of trifluoroacetate salt of compound C16. Ms[M+H]+469.3

[0328] NMR data of compound C16: 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.43 (s, 1H), 8.19 (dd, J = 8.8, 1.7 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 53.7 Hz, 1H), 4.35-4.29 (m, 1H), 4.13 (s, 3H) , 3.99 (d, J=9.2Hz, 1H), 3.89 (d, J=9.2Hz, 1H), 3.61-3.41 (m, 3H), 3.20-3.04 (m, 2H), 2. 16-2.02 (m, 2H), 1.97 (d, J = 13.4Hz, 1H), 1.80 (d, J = 12.9Hz, 1H), 1.34 (d, J = 6.5Hz, 3H).

[0329] Example 16

[0330] The compound synthesized by the present invention:

[0331]

[0332] The synthetic route of compound C17 is as follows:

[0333]

[0334] 1. Synthesis of compound C17-2

[0335] Compound C17-1 (1.0 g, 4.7 mmol) was dissolved in 25 mL of 1,4-dioxane, and then diboric acid pinacol ester (1.8 g, 7.07 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride dichloromethane complex (200 mg, 0.24 mmol) and potassium acetate (1.4 g, 14.1 mmol) were added in sequence. Under nitrogen protection, the reaction solution was heated to 95 ° C and stirred for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, saturated brine was added to dilute the reaction solution, ethyl acetate was extracted, the liquid was separated, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.6 g of compound C17-2. Ms[M+H]+260.1

[0336] 2. Synthesis of compound C17-3

[0337] Compound C17-2 (300 mg, 1.23 mmol) was dissolved in 20 mL of methanol, and then an aqueous solution (20 mL) of potassium bifluoride (480 mg, 6.15 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly evaporated under reduced pressure, the residue was diluted and dissolved with acetonitrile, impurities were extracted with petroleum ether, the liquids were separated, and the acetonitrile phase was concentrated under reduced pressure and purified to obtain 90 mg of compound C17-3. Ms[M+H]+178.0

[0338] NMR data of compound C17-3: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 2H), 8.09-8.00 (m, 1H), 7.98-7.93 (m, 1H), 7.83-7.77 (m, 1H), 4.32 (s, 3H).

[0339] 3. Synthesis of compound C17-4

[0340] Compound B (80 mg, 0.15 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C17-3 (60 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and 2,2'-bipyridine (24 mg, 0.30 mmol) were added in sequence, and stirred overnight at 25°C under an oxygen atmosphere. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 90 mg of compound C17-4. Ms[M+H]+658.3

[0341] NMR data of compound C17-4: 1H NMR (400 MHz, DMSO-d6) δ 8.69-8.65 (m, 1H), 8.63 (s, 1H), 8.44-8.38 (m, 1H), 8.24-8.20 (m, 1H), 5.40 (s, 2H), 5.16 (d, J = 10.7 Hz, 1H), 4.38 (s, 3H), 4.21-4.13 (m, 1H), 3.87-3.8 2(m, 1H), 3.57-3.52(m, 1H), 3.51-3.44(m, 1H), 3.43-3.38(m, 2H), 3.04-2.90(m, 2H), 2.04-1.95 (m, 2H), 1.76-1.64 (m, 2H), 1.18 (s, 9H), 1.15 (s, 9H), 1.12 (d, J=6.4Hz, 3H).

[0342] 4. Synthesis of Compound C17

[0343] Compound C17-4 (90 mg, 0.14 mmol) was dissolved in 3 mL of methanol, and then 4 mL of methanol hydrochloric acid (4 M) was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then the reaction solution was heated to 55 °C and stirred for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified to obtain the trifluoroacetate salt of C17. Ms[M+H]+450.2

[0344] NMR data of compound C17: 1H NMR (400 MHz, Methanol-d4) δ 8.76 (s, 1H), 8.55 (dd, J = 9.1, 1.9 Hz, 1H), 8.33 (s, 1H), 8.13 (d, J = 9.1 Hz, 1H), 4.94 (s, 2H), 4.42 (s, 3H), 4.36-4.29 (m, 1H), 3.98 (d, J = 9.2H z, 1H), 3.88 (d, J=9.1Hz, 1H), 3.62-3.51 (m, 2H), 3.51-3.47 (m, 1H), 3.10-2.98 (m, 2 H), 2.10-2.01(m, 2H), 2.00-1.93(m, 1H), 1.83-1.75(m, 1H), 1.34(d, J=6.5Hz, 3H).

[0345] Embodiment 17

[0346] The compound synthesized by the present invention:

[0347]

[0348] The synthetic route of compound C18 is as follows:

[0349]

[0350] 1. Synthesis of compound C18-2

[0351] Compound B (80 mg, 0.15 mmol) was dissolved in 5 mL of N, N-dimethylformamide, and compound C18-1 (60 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and 2,2'-bipyridine (47 mg, 0.30 mmol) were added in sequence, and stirred overnight at 25°C under an oxygen atmosphere. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 100 mg of compound C18-2. Ms[M+H]+671.4

[0352] 2. Synthesis of compound C18

[0353] Compound C18-2 (100 mg, 0.15 mmol) was dissolved in 3 mL of methanol, and then 4 mL of 4 M hydrogen chloride methanol solution was added. Under nitrogen protection, the mixture was stirred at 25 °C for 30 min, and then heated to 55 °C and stirred for 5 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified to obtain the trifluoroacetate salt of C18. Ms[M+H]+463.2.

[0354] NMR data of compound C18: 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.30 (s, 1H), 8.21-8.16 (m, 1H), 8.07 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H), 4.55 (q, J = 7.3 Hz, 2H), 4.36-4.28 (m, 1H), 3.98 (d, J = 9.1Hz, 1H), 3.88 (d, J=9.1Hz, 1H), 3.62-3.47 (m, 3H), 3.11-2.98 (m, 2H), 2.12-2.01 (m, 2H), 2.00-1.92(m, 1H), 1.83-1.75(m, 1H), 1.53(t, J=7.2Hz, 3H), 1.34(d, J=6.5Hz, 3H).

[0355] Embodiment 18

[0356] The compound synthesized by the present invention:

[0357]

[0358] The synthetic route of compound C19 is as follows:

[0359]

[0360] 1. Synthesis of compound C19-2

[0361] Compound C19-1 (1.0 g, 5.08 mmol) was dissolved in 10 mL of N, N-dimethylformamide, cesium carbonate (5.0 g, 15.24 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Trifluoroiodoethane (2.13 g, 10.2 mmol) was added, and then heated to 50°C and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 552 mg of compound C19-2. Ms[M+H]+278.9

[0362] NMR data of compound C19-2: 1H NMR (90 MHz, CDCl3) δ 8.04 (s, 1H), 7.67-7.57 (m, 2H), 7.38-7.2 (m, 1H), 4.90 (q, 3H).

[0363] 2. Synthesis of compound C19-3

[0364] Compound C19-2 (500 mg, 1.8 mmol) was dissolved in 30 mL 1,4-dioxane, and diboric acid pinacol ester (914 mg, 3.6 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (73 mg, 0.09 mmol) and potassium acetate (529 mg, 5.4 mmol) were added in sequence. The reaction solution was stirred at 95°C for 20 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 930 mg of compound C19-3. Ms[M+H]+327.1

[0365] 3. Synthesis of compound C19-4

[0366] Compound C19-3 (400 mg, 1.22 mmol) was dissolved in 40 mL of methanol, and an aqueous solution (40 mL) of potassium bifluoride (478 mg, 6.13 mmol) was added to the reaction solution, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure, the residue was diluted and dissolved with acetonitrile, and then impurities were extracted with petroleum ether, and the liquids were separated. After the acetonitrile phase was concentrated under reduced pressure, 80 mg of compound C19-4 was obtained. Ms[M+H]+245.0

[0367] 4. Synthesis of compound C19

[0368] Synthesis of reference compound C18, data are shown in Table 1.

[0369] Embodiment 19

[0370] The compound synthesized by the present invention:

[0371]

[0372] The synthetic routes of compounds C20 and C21 are as follows:

[0373]

[0374] 1. Synthesis of compound C20-2

[0375] Compound C20-1 (5 g, 23.87 mmol) was dissolved in 25 mL of tetrahydrofuran, then moved to a dry ice bath, cooled to -62°C, slowly added LDA (26.3 mL, 26.26 mmol), stirred at -62°C for 1 hour, then slowly added DMF (2.617 g, 35.81 mmol), the reaction solution was naturally warmed to room temperature, and stirred for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was placed in an ice water bath, and saturated ammonium chloride aqueous solution was slowly added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 2.559 g of compound C20-2. Ms[M+H]+236.9

[0376] 2. Synthesis of compound C20-3

[0377] Compound C20-2 (2.459 g, 10.36 mmol) was dissolved in 25 mL of tetrahydrofuran, and potassium carbonate (1.714 g, 12.43 mmol) and methoxyamine (951 mg, 11.39 mmol) were added in sequence. The reaction solution was stirred at 45°C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 2.250 g of compound C20-3. Ms[M+H]+265.9

[0378] 3. Synthesis of compound C20-4

[0379] Compound C20-3 (1.45 g, 5.44 mmol) was dissolved in 15 mL of dimethyl sulfoxide, and then hydrazine hydrate (544 mg, 10.88 mmol) was added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.22 g of compound C20-4. Ms [M + H] + 230.9

[0380] 4. Synthesis of compounds C20-5 and C21-5

[0381] Compound C20-4 (1.220 g, 5.27 mmol) was dissolved in 15 mL of tetrahydrofuran, then moved to an ice-water bath, sodium hydride (253 mg, 6.32 mmol) was slowly added, stirred at 0°C for 60 minutes, and iodomethane (1.123 g, 7.91 mmol) was slowly added dropwise, the reaction solution was moved to room temperature, and stirred overnight under nitrogen protection. After the reaction was completed, the reaction solution was placed in an ice-water bath, water was slowly added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain compounds C20-5 and C21-5.

[0382] 5. Synthesis of compounds C20-7 and C21-7

[0383] The synthesis of compounds C20-7 and C21-7 was based on the synthesis method of compound C19-4.

[0384] 6. Synthesis of compounds C20 and C21

[0385] Synthesis of reference compound C18, data are shown in Table 1.

[0386] Embodiment 20

[0387] The compound synthesized by the present invention:

[0388]

[0389] The synthetic routes of compounds C22 and C23 are as follows:

[0390]

[0391] 1. Synthesis of compound C22-2

[0392] Compound C22-1 (3.0 g, 13.5 mmol) was dissolved in 60 mL of tetrahydrofuran, and potassium carbonate (2.2 g, 16.3 mmol) and methoxyamine hydrochloride (1.3 g, 14.9 mmol) were added in sequence. The reaction solution was stirred at 45°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure and purified to obtain 3.0 g of compound C22-2. Ms[M+H]+250.0

[0393] 2. Synthesis of compound C22-3

[0394] Compound C22-2 (3.0 g, 12.1 mmol) was dissolved in 15 mL of dimethyl sulfoxide, and then 7 mL of hydrazine hydrate was added. The reaction solution was stirred at 90 °C for 36 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 2.2 g of compound C22-3. Ms[M+H]+215.0

[0395] 3. Synthesis of compounds C22-4 and C23-4

[0396] Compound C22-3 (2.2 g, 10.1 mmol) was dissolved in 40 mL of tetrahydrofuran, and sodium hydride (489 mg, 12.2 mmol) was added in batches under ice-water cooling. After the addition, the reaction solution was slowly heated to room temperature and stirred for 1 h, then cooled to 0 ° C, and methyl iodide (2.2 g, 15.3 mmol) was slowly added dropwise. After the addition, the reaction solution was moved to room temperature and stirred. After the reaction was completed, the reaction solution was placed in an ice-water bath, and water was slowly added to quench the reaction. The reaction was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain 710 mg of compound C22-4 and 1.44 g of compound C23-4. Ms [M + H] + 229.0

[0397] 4. Synthesis of compounds C22-5 and C23-5

[0398] Compound C22-4 (900 mg, 3.95 mmol) was dissolved in 10 mL 1,4-dioxane, and then diboric acid pinacol ester (1.2 g, 4.74 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride, dichloromethane complex (144 mg, 0.2 mmol) and potassium acetate (1.16 g, 11.85 mmol) were added in sequence. Under nitrogen protection, the reaction solution was stirred at 95 ° C for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to quench the reaction solution, ethyl acetate was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 996 mg of compound C22-5. Ms [M + H] + 277.1

[0399] Compound C23-4 (1.84 g, 8.07 mmol) was dissolved in 20 mL of 1,4-dioxane, and then diboric acid pinacol ester (2.46 g, 9.68 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (295 mg, 0.4 mmol) and potassium acetate (2.37 g, 24.21 mmol) were added in sequence. The reaction solution was stirred at 95°C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.98 g of compound C23-5. Ms[M+H]+277.1

[0400] 5. Synthesis of compounds C22-6 and C23-6

[0401] Compound C22-5 (996 mg, 3.6 mmol) was dissolved in 100 mL of methanol, and then an aqueous solution (100 mL) of potassium bifluoride (254 mg, 3.44 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly spin-dried, dissolved in acetonitrile, extracted with petroleum ether, and then the acetonitrile phase was retained. The acetonitrile phase was filtered to remove the residue, and the filtrate was concentrated under reduced pressure to obtain 392 mg of compound C22-6. Ms [M + H] + 195.0

[0402] Compound C23-5 (500 mg, 1.8 mmol) was dissolved in 50 mL of methanol, and then an aqueous solution (50 mL) of potassium bifluoride (700 mg, 9 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly dried, dissolved in acetonitrile, extracted with petroleum ether, and then the acetonitrile phase was retained, the residue was filtered, and concentrated under reduced pressure to obtain 102 mg of compound C23-6. Ms [M + H] + 195.0

[0403] 6. Synthesis of compounds C22 and C23

[0404] Synthesis of reference compound C18, data are shown in Table 1.

[0405] Embodiment 21

[0406] The compound synthesized by the present invention:

[0407]

[0408] The synthetic route of compound C24 is as follows:

[0409]

[0410] 1. Synthesis of compound C24-2

[0411] Compound B (80 mg, 0.15 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C24-1 (192 mg, 0.75 mmol), copper acetate (27 mg, 0.15 mmol) and 2,2'-bipyridine (47 mg, 0.30 mmol) were added in sequence. The mixture was stirred at 90°C for 7 hours under an oxygen atmosphere. After the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified to obtain compound C24-2. Ms[M+H]+656.3

[0412] 2. Synthesis of compound C24

[0413] The synthesis of compound C24 was based on the synthesis of compound C18, and the data are shown in Table 1.

[0414] Embodiment 22

[0415] The compound synthesized by the present invention:

[0416]

[0417] The synthetic routes of compounds C25 and C26 are as follows:

[0418]

[0419] 1. Synthesis of compounds C25-2 and C26-2

[0420] Compound C25-1 (5.0 g, 20.3 mmol) was dissolved in 200 mL of acetonitrile, and potassium carbonate (10.75 g, 40.6 mmol) and diethyl bromodifluoromethyl phosphate (8.15 g, 24.3 mmol) were added in sequence. The reaction solution was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3.29 g of a mixture of compound C25-2 and compound C26-2. Ms[M+H]+246.9

[0421] 2. Synthesis of compounds C25-3 and C26-3

[0422] The mixture of compounds C25-2 and C26-2 (1.2 g, 4.8 mmol) was dissolved in 60 mL of 1,4-dioxane, and then diboric acid pinacol ester (2.48 g, 9.7 mmol), 1,1'-bis(di-phenylphosphino)ferrocenepalladium chloride (175 mg, 0.24 mmol) and potassium acetate (1.4 g, 14.4 mmol) were added in sequence. The reaction solution was stirred at 95° C. for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 120 mg of compound C25-3 and 1.165 g of compound C26-3.

[0423] Compound C25-3: Ms[M+H]+295.1

[0424] Compound C26-3: Ms[M+H]+295.1

[0425] NMR data of compound C26-3: 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.0 Hz, 1H), 8.17 (t, J = 60 Hz, 1H), 8.05 (d, J = 1.3 Hz, 1H), 7.78 (dd, J = 8.6, 1.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 1.32 (s, 12H).

[0426] 3. Synthesis of compounds C25 and C26

[0427] The syntheses of compounds C25 and C26 were prepared with reference to the syntheses of compounds C22 and C23. The data are shown in Table 1.

[0428] Embodiment 23

[0429] The compound synthesized by the present invention:

[0430]

[0431] The synthetic routes of compound C27 and compound C28 are as follows:

[0432]

[0433] The syntheses of compounds C27 and C28 were based on the synthesis of compound C22. The data are shown in Table 1.

[0434] Embodiment 24

[0435] The compound synthesized by the present invention:

[0436]

[0437] The synthetic route of compound C29 is as follows:

[0438]

[0439] 1. Synthesis of compound C29-2:

[0440] Compound C29-1 (2.0 g, 10.15 mmol) was dissolved in 20 mL N, N-dimethylformamide, and sodium hydride (609 mg, 15.23 mmol) with a 60% content was added under ice bath. After stirring at room temperature for 0.5 hours under nitrogen protection, iodomethane (1.86 g, 13.2 mmol) was added dropwise under ice water bath cooling. After the addition was completed, the reaction solution was moved to room temperature and stirred for 2 hours. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.29 g of compound C29-2. Ms[M+H]+210.9

[0441] 2. Synthesis of compound C29-3:

[0442] Compound C29-2 (700 mg, 3.33 mmol) was dissolved in 7 mL of tetrahydrofuran. Under nitrogen protection, the reaction solution was cooled to -78°C, and then a tetrahydrofuran solution of n-butyl lithium (2.5 M, 2 mL, 5 mmol) was added dropwise. After stirring at the same temperature for 0.5 h, isopropoxy borate (930 mg, 5 mmol) was added dropwise, and then stirred at -78°C for another 1 h. After the reaction was completed, water was added dropwise at -78°C to quench the reaction, and the reaction solution was warmed to room temperature, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 170 mg of compound C29-3. Ms[M+H]+259.1

[0443] 3. Synthesis of compound C29-4:

[0444] Compound B (80 mg, 0.155 mmol) was dissolved in 5 mL N, N-dimethylformamide, and compound C29-3 (120 mg, 0.46 mmol), copper acetate (42 mg, 0.23 mmol) and pyridine (72 mg, 0.465 mmol) were added in sequence. The reaction solution was heated to 95°C and stirred for 16 hours under an oxygen atmosphere. After the reaction was completed, it was diluted with ethyl acetate, washed with saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain compound C29-4. Ms[M+H]+657.3

[0445] 4. Synthesis of compound C29:

[0446] Synthesis of reference compound C22, data are shown in Table 1.

[0447] Embodiment 25

[0448] The compound synthesized by the present invention:

[0449]

[0450] The synthetic route of compound C30 is as follows:

[0451]

[0452] The synthesis of C30 was based on the synthesis of compound C22, and the data are shown in Table 1.

[0453] Embodiment 26

[0454] The compound synthesized by the present invention:

[0455]

[0456] The synthetic route of compound C31 is as follows:

[0457]

[0458] The synthesis of C31 was based on the synthesis of compound C22, and the data are shown in Table 1.

[0459] Embodiment 27

[0460] The compound synthesized by the present invention:

[0461]

[0462] The synthetic route of compound C32 is as follows:

[0463]

[0464] The synthesis of C32 was based on the synthesis of compound C22, and the data are shown in Table 1.

[0465] Embodiment 28

[0466] The compound synthesized by the present invention:

[0467]

[0468] The synthetic route of compound C33 is as follows:

[0469]

[0470] The synthesis of C33 was based on the synthesis of compound C22, and the data are shown in Table 1.

[0471] Embodiment 29

[0472] The compound synthesized by the present invention:

[0473]

[0474] The synthetic route of compound C34 is as follows:

[0475]

[0476] The synthesis of C34 was based on the synthesis of compound C22, and the data are shown in Table 1.

[0477] Embodiment 30

[0478] The compound synthesized by the present invention:

[0479]

[0480] The synthetic routes of compounds C35 and C36 are as follows:

[0481]

[0482] The syntheses of C35 and C36 were based on the synthesis of compound C22. The data are shown in Table 1.

[0483] Table 1

[0484]

[0485]

[0486]

[0487]

[0488] The following are some biological activity tests on some of the synthesized compounds.

[0489] Example 1: In vitro evaluation

[0490] 1. Experimental reagents and materials

[0491] a) Purified full-length SHP2 protein (Kamed Bio-Tianjin)

[0492] b) SHP2 activating peptide (BPS Bioscience);

[0493] c)DiFMUP;

[0494] d) Reaction buffer (120 mM HEPES pH 7.2, 200 mM NaCl, 1 mM EDTA, 0.002% Brij35), after autoclaving, add 0.04% BSA, store at 4°C, dilute to 1× before use, and add 2 mM DTT.

[0495] 2. Experimental steps

[0496] a) Add 10uL of the test compound No. 2 solution to a 384-well plate and dilute it 3-fold to a total of 8 concentrations;

[0497] b) 5uL of No. 4 Niv activation peptide (2uM) and 5uL of 4× full-length SHP2 protein (0.88nM) were added to the sample wells to be tested, no inhibitor was added to the control wells, and no SHP2 activation peptide and inhibitor were added to the blank wells;

[0498] c) Seal the 384-well plate, mix well and incubate at room temperature for 1 hour;

[0499] d) Add 5uL 5×DiFMUP (125uM), seal the 384-well plate, mix well, incubate at room temperature for 1 hr, and detect with EnVision;

[0500] 3. Data analysis and results

[0501] The inhibition rate calculation formula is as follows:

[0502] %Inhibition=[1-(RFU sample -RFU blank ) / (RFU total -RFU blank )]X100

[0503] Nonlinear regression analysis was performed using Graphpad 8.0, using Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)) equation was used to fit the curve of enzyme activity changing with compound concentration to obtain the IC of each compound. 50 IC of compounds inhibiting SHP2 enzyme activity 50 As shown in Table 2:

[0504] (In the following table, the following designations are used: <50 nM = A; 50-500 nM = B; >500 nM = C.)

[0505] Table 2

[0506]

[0507]

[0508] Example 2: Evaluation of the cell activity of compound MV4-11

[0509] The biological activity test experimental process is as follows:

[0510] Take MV4-11 cells in the logarithmic growth phase, make a cell suspension, inoculate 160uL / well in a 96-well plate, the inoculation density is 5000 cells / well, and culture overnight in a 37°C cell culture incubator. Prepare 5× test compound solution, 4-fold gradient dilution, a total of 8 concentrations, double wells. Add the test compound solution to the 96-well plate at 40uL / well, add the corresponding volume of solvent to the blank well and the control well, shake and mix, incubate in a 37°C cell culture incubator for 72hr, and detect cell viability by CTG method.

[0511] The raw data were converted into inhibition rate using the equation (Sample-blank) / (control-blank)*100%, and the IC50 value was obtained by four-parameter curve fitting ("log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism). The results are shown in Table 3. (In the table below, the following names are used: <100nM=A; 100-500nM=B; >500nM=C.)

[0512] Table 3

[0513]

[0514]

[0515] As can be seen from the above table, through in vitro biological activity screening, RMC-4630 was used as the reference substance (structural formula is ), the compound we synthesized has a good inhibitory ability on SHP2. It is expected to be further developed into a drug for regulating SHP2 activity or treating SHP2-related diseases. The structural formula reported in Example 5 of patent WO2021148010A1 is Compared with this compound, we found that our compound has better inhibitory ability against SHP2.

[0516] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula I', or a pharmaceutically acceptable salt thereof, in: R2 is CH2OH; R3 is hydrogen; Ring A is R1 is selected from the following group: R4 is each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

2. A compound, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

3. A pharmaceutical composition, characterized in that It comprises a pharmaceutically acceptable carrier and a safe and effective amount of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Use of the pharmaceutical composition according to claim 3, characterized in that: For use in the preparation of drugs used as SHP2 inhibitors.

5. Use of the pharmaceutical composition according to claim 3, characterized in that: Used for preparing drugs for regulating SHP2 activity or treating SHP2-related diseases.

6. The use according to claim 5, characterized in that The SHP2-related disease is selected from the following group: Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, acute myeloid leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, lung cancer, gastric cancer, head cancer, anaplastic large cell lymphoma, neuroblastoma, glioblastoma, squamous cell carcinoma of the head and neck, colon cancer, and liver cancer.

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